hc9780851865621-00001

1 Three-membered Rings

BY D. J. MAITLAND

1 Introduction

This chapter reports on developments in the chemistry of three-membered, saturated heterocyclic ring compounds. As is usual in such Reports a certain degree of selectivity has been necessary. However, in general the author has tried to steer as neutral a course as possible, not being swayed by his own special interests, as can so easily happen. A break has been made with a pattern set in earlier Reports, in that a separate section on ‘Physical Methods’ has not been compiled. It is this author’s opinion that as such techniques are now almost routine tools in most chemical laboratories they no longer merit special attention, an opinion substantiated by the fact that almost every paper published today includes in the discussion a report on the application of various physical methods to the problem in question.

2 Oxirans

In the M.T.P. review series three-membered ring compounds have been reviewed.l The synthesis, reactivity, and synthetic applications of a$- epoxy-ketones have been summarized.2 Reviews have been published on the synthesis and characteristics of epoxides3 and arene oxides: selectivity in the reactions of epoxides,6 and the electrocyclic ring-opening reactions of bicyclic aziridines with oxirans.6

Formation-Direct Insertion. Oxygen atom insertion. The most common reaction in this category is the oxidation of alkenes to epoxides by organic peroxy-acids. However, some other reactions which involve either molecular

D. R. Marshall, in ‘Heterocyclic Compounds’, ed. K. Schofield, M.T.P. International Review of Science, Organic Chemistry, Series One, Vol. 4, Butterworths, London, 1973, p. 1. T. Iizuka, Yuki Gosei Kagaku Kyokui Shi, 1973, 31, 271 (Chem. A h . , 1974, 80, 59 803u). Y. Tanaka, A. Okada, and I. Tomizuka, Epoxy Resins: Chem. Technol., 1973,9-134, 7 3 7 - 4 0 (Chem. Abs., 1974,80, 82 507J).

D. N. Kirk, Chem. and Ind., 1973, 109. K. Matsumoto, Kaguku No Ryoiki, 1973, 27, 148 (Chem. A h . , 1973,79,42 253w).

1

‘ D. M. Jerina, H. Yagi, and J. W. Daly, Heterocycles, 1973, 1, 267.

2 Saturated Heterocyclic Chemistry oxygen or ozone have been reported. Hexaflu~ropropylene~ has been epoxidized (79 %) by reaction with oxygen at 200 "C over a silica catalyst, activated either by pre-treatment with hexafluoropropylene or by pre-treatment with 1 M hydrochloric acid8 followed by washing and treatment with hexafluoropropylene. Tetrafluoroethylene and chlorotrifluoroethylene were also successfully epoxidized at 25 "C by a variation of the same te~hnique.~

The conversion of styrene into 1 -phenyl-1 ,2-epoxyethane, without serious competition from polymerization, has been achieved by the oxidationlo of styrene at 120 "C and 83 or 160 mmHg partial pressure of oxygen or by heating styrene, t-butyl hydroperoxide, or di-t-butyl peroxidell in chlorobenzene at 120 "C.

While investigating the thermal cycloreversion of the bicyclo [3,1 ,O]hex-2- ene system, Padwa and Brodsky12 found that when exo,exo-3,4,6-triphenyl- bicyclo[3,1 ,O]hex-2-ene (1) was heated for 48 h at reflux temperature in xylene, the major product was the oxiran (2). Similar treatment of the exo,endo-isomer (3) gave a 2:2:1 mixture of (l), (2), and the oxiran (4).

Ph Ph

A, 02-xylene

Ph'

*Ip Ph A, 02-mesitylene ' H35-/$;+u)+~2) Ph Ph

(3) (4)

Heating (1) or (3) at 160°C under nitrogen afforded a 16:l equilibrium mixture of (1) and (3). Thus the oxirans must be formed by therrnal epoxidation of the olefins by molecular oxygen, and the reactions can be rationab ized in terms of a biradical intermediate formed by cleavage of the cyclopropane ring.

A continuous process for the preparation of epichlorohydrin has been

G. M. Atkins, jun., U.S.P. 3 775 439/1973. * R. J. Cavanaugh, U.S.P. 3 775 438/1973. * R. J. Cavanaugh and G. M. Atkins, jun., U.S.P. 3 775 440/1973.

l o M. E. Pudel, L. G. Privalova, Z . K. Maizus, and I. V. Kalechits, Neftekhimiya, 1973,

l1 P. Koelewijn, B.P. 1 304 403/1973. la A. Padwa and L. Brodsky, Tetrahedron Letters, 1973, 1045.

13, 669 (Chem. Abs., 1974,80,95 624v).

Three-membered Rings 3 reported. l-Chloroprop-2-ene in dimethyl phthalate containing 10-12 % acetaldehyde is oxidized13 by air in a flow system at 150-160 "C.

The reaction of ozone with encumbered allenes at -78 "C in dichloromethane has recently been studied.14 1,1,3-Tri-t-butylallene on treatment with two equivalents of ozone afforded the corresponding diepoxide (5 ) , which rearranged to 2,2,4-tri-t-butyl-1-oxacyclobutan-3-one (6) on standing. One equivalent of ozone gave the diepoxide ( 5 ) as the principal product and the

allene oxide (7) in low yield. Neither 1 ,l-di-t-butylallene (8) nor 1,3-di-t- butylallene (9) gave an oxiran when treated with ozone. The allene (8) afforded di-t-butyl ketone and 2,2-di-t-butylcyclopropanone whereas (9) gave exclusively pivaldehyde. The degree of substitution of the allene is obviously a critical factor.

But But But -c-

But H - -H (8) (9)

The epoxidation of allenes by organic peroxy-acids has also been studied by Crandall et a1.l5 The products are rationalized in terms of an initial epoxidation of the allene (lo), followed by competitive partitioning of the monoepoxide (1 1) between valence isomerism to the related cyclopropanone (12) and further oxidation of (11) to a dioxaspiropentane derivative (13) (Scheme 1). The cyclopropanones may react further with the peroxy-acid to yield /3-lactones (14) or undergo oxidative decarbonylation to the corresponding olefins (15), which are usually transformed into their epoxides (16) under the reaction conditions. The dioxaspiropentanes may also add carboxylic acids, yielding a-acyloxy-a'-hydroxy-ketones (1 7). An excess of peracetic acid in buffered methanol gave (18) and (19) as the major products from tetramethylallene. A small quantity of the lactone (20) was also detected, the a-acetoxy-ketone (1 8) arising by acetoxylation of the epoxyallene. Under the same conditions 1 ,l-dimethylallene gave analogous products. Under acid conditions, tetramethylallene upon epoxidation gave the a- methoxy-ketone (21) as the only product (Scheme 2).

la Sh. K. Kazimov, A. S. Rzaeva, G. Z. Ponomareva, Khim. Prom., 1973,49,824 (Chem.

l4 J. K . Crandall and W. W. Conover, J.C.S. Chem. Comm., 1973, 340. l5 J. K. Crandall, W. H. Machleder, and S. A. Sojka, J. Org. Chem., 1973, 38, 1149.

Abs., 1974, 80, 70 613c).

4 Saturated Heterocyclic Chemistry

R\A / - C - C ,R R \o/ ‘**R

II \ IC\ /R R

R /c-c\R

I R

R’ ‘.R \c=c/ + HOAc + COz

0

I I I 1

Me-C-C-Me Me “ Me Me, / O \ p ,c-c

Me ‘Me Me Me I H-C

Me I

Me

Three-membered Rings 5

0- 0

> = f? -) \iu - -n(o*c (11;R = Me) \

Cyclonona-l,2-diene with excess peracetic acid in buffered methanol affords the epoxide (22), the lactone (23), cyclo-octene, and the a-acyloxy- a'-hydr oxy-ket one (24).

oo 4-Oxoisophorone (25) when epoxidized16 with hydrogen peroxide (30 %)

affords oxabicycloheptanedione (26), which with 20 % sulphuric acid yields 2-hydroxy-3,5,5-trimethylcyclohex-2-en-1,4-dione.

(25) (26)

@-Unsaturated f-alkoxy-ketones (27) can be converted into the corresponding epoxides (28) in good yield by treatment at 40 "C (with one equivalent of alkaline hydrogen per0xide.l' Excess alkaline hydrogen peroxide effects destructive oxidation, affording formic acid, acetone, and a B-alkoxy- carboxylic acid.

16 D. L. Roberts and B. P. Bonita, U.S.P. 3 775 437/1973. 17 I. G. Tishchenko and V. V. Berezovskii, Vesti Akad. Navuk belarusk. S.S.R., Ser.

khim., Navuk, 1973, 113 (Chem. Abs., 1973,79,4939s).

6 Saturated Heterocyclic Chemistry Olefins can be epoxidized in high yield and with high selectivity by hydrogen

peroxide in the presence of fluoro(ha1ogeno)acetone catalysts.l* Thus oct-1 -ene was epoxidized (100 %) in the presence of hexafluoroacetone. Similarly effective were Cl,CCOCCl,F and ClF,CCOCFCl,. Propylene, ally1 alcohol, trans-stilbene, and 1,5-cyclo-octadiene were similarly epoxidized in high yield.

Fluoro-oxirans have been preparedlg by the epoxidation of RCF=CF, at -20 OC with hydrogen peroxide in methanolic potassium hydroxide.

Substituted cyclohexenes20 with an olefinic side-chain undergo selective epoxidation with peracetic acid to afford the corresponding epoxycyclohexane. Thus 2,6,6-trimethyl-l-(but-3-en-l -ol)cyclohex-1 -ene (29) gave the epoxycyclohexane (30).

Cyclohex-3-ene-l-carboxylates (31), obtained by treatment of the appropriate cyclohexenecarboxylic acid with R1CO2CH,CH2Cl in xylene containing aqueous potassium hydroxide, afford21 the corresponding oxirans (32) on treatment with 50 % peracetic acid in chloroform.

C02CH2CH20COR1 ~ ~ O z C H 2 C H 2 0 C O R 1 MeC03H-CHC'3+ 0 oR2 Treatment of endo-tricyclo [5,2,1 ,02~6]deca-3 ,8-dienes with t-butyl hydro-

peroxide or peracetic acid affords a mixture of epoxides22 which can be separated by steam-distilling the product mixture to isolate the diepoxy- endo-tricyclo [5,2,1 ,02*6]decane. The residual monoepoxide mixture is then distilled in the presence of 0.1 % bis-(l-naphthy1)amine to give 3,4-epoxy- endo-tricyclo [5,2,1 ,02*6]dec-8-ene (33) and the 8,9-epoxy-isomer.

l8 L. Kim, Ger. Offen 2 239 681/1973 (Chem. Abs., 1973,78, 159 400n). A. Y. Zapevalov, I. P. Kolenko, and V. S. Plashkin, Zhur. org. Khim., 1973, 9, 2013 (Chem. Abs., 1974, 80,47 722d).

2o E. Kovats, G. Ohloff, E. Demole, and M. Stoll, Swiss P. 536 834/1973 (Chem. Abs., 1973,79,91 972p).

a1 B. F. Pishnamazzade and A. K. Mamishov, Zhur. org. Khim., 1973,9,715 (Chem. A h . , 1973,79, 31 748k).

29 H. Fuerst, H. G. Hauthal, and D. Schied, East Ger. P. 98 925/1973, (Chern. Abs., 1974,80,70 67th).


(3 3)

Epoxidat ion of 1 -(p-methoxybenzyl)-2-methyl-l,2,3,4,5,6,7,8-octahydro- isoquinoline (34) with performic acid23 affords the isomeric epoxides (35) and (36) and the two diols (37) and (38) (Scheme 3). Hydrolysis of the epox-

CH2C6H,0Me-p

(34)

I I

CHnCsH40Me-p CH2CsHtOMe-p

(36) (35)

&Le HC) ' cj?-JMe HO ; C H ~ C ~ H ~ O M ~ - ~ CHpCeH40 Me-p

(38) (3 7) Scheme 3

ides (35) and (36) with 10% sulphuric acid affords quantitative conversion into the diols (37) and (38), respectively, in a ratio of 1 : 15. Therefore formation of the cis-epoxide (36) predominates. Chemical evidence shows that performic acid exclusively attacks from the side cis to the 1-substituent. Interpretation of this result is difficult, but it has been shown that the amino- group in the isoquinoline ring does not particularly participate in the formation of the epoxides, and a particular role of the ArCH, group in the transition state would be suggested. The transition state (39) for the formation of

23 M. Onda, Y. Sugama, H. Yokoyama, and F. Tada, Chem. and Pharm. Bull. (Japan), 1973, 21, 2359.

2

Saturated Heterocyclic Chemistry

(39)

(36), with intramolecular hydrogen-bonding as depicted in the formula, may depress the activation energy for ( 3 9 , leading to predominant formation of (36). The competitive reactions of (35) and (36) have also been examined.

The peroxy-acid oxidation of cyclo-octatetraene oxide2* yields the bis- oxirans (40), (41), and (42) and the trisoxiran (43), which is unchanged on heating at 255 "C for 20 h (Scheme 4). The oxirans (44) and (45) result on Do+ ,00+Q.. ..o

&- 0

0 m-ClC6H4COf (40) (41)

67 % 24 % (42) 9 %

(40) + (41) + (42) +

(43) Scheme 4

thermal treatment (200 "C) of (41) and (42) respectively. Despite the require- ment for high thermal activation, the bond relocations of (41) and (42) proceed entirely along symmetry-allowed pathways. The n.m.r. spectra of these compounds are discussed.

a4 A. G. Anastassiou and E. Reichmanis, J. Org. Chem., 1973, 38, 2421.

Thee-membered Rings 9

Me \ 7 Me

c=c / \ I

Et CHzC H2O( CH2)S- C- 0 / \ (46) 0 \ /!HZ

CH2

The epoxyoxatridecenoate (48), a pesticide,25 is obtained as a mixture of (E)- and (2)-isomers by treating the unsaturated ester (47) with rn-chloroperbenzoic acid. The acetal (46), prepared from (2)-4-methylhex-3-enol and 5-bromo-2,2-ethylenedioxypentane, on acid hydrolysis followed by reaction with dimethyl methoxycarbonylmethylphosphonate affords the unsaturated ester (47).

When @-unsaturated ketones are treated with peroxy-acids, attack usually occurs at the carbonyl group and epoxidation of the double bond is rare. However, it has recently been reported that oxidation of 2,3,4,5,6- hexamethylcyclohexa-2,5-dienone with m-chloroperbenzoic acid26 affords 2,3-epoxy-2,3,4,4,5,6-hexamethylcyclohex-5-enone (49) and on further oxidation cis-2,3 : 5,6-diepoxy-2,3,4,4,5,6-hexamethylcyclohexanone. Irradi- ation of the monoepoxy-ketone (49) through a Vycor filter affords the

(49) (50)

25 D. Hainaut and J. P. Demoute, Fr. Demande, 2 174 666/1973; ibid., No. 2 172 847/

26 H. Hart, M. Verma, and I. Wang, J. Org. Chem., 1973, 38, 3418. 1973 (Chem. A h . , 1974,80 , 82 617v; 82 618w).

10 Saturated Heterocyclic Chemistry single photoisomer 5-acetyl-2,3,4,4 ,Ppentamethylcyclopent-2-enone (50). Irradiation of the diepoxy-ketone gives only starting material.

The epoxidation of acid-sensitive olefins, or olefins yielding acid-sensitive epoxides, is typically conducted in the presence of a buffer such as sodium carbonate, sodium bicarbonate, or disodium hydrogen phosphate. Such solid buffer-solid systems have proved to be unsuitable for certain compounds. For example the epoxide (52), derived from 6-methylhept-Sen-2-one (51), is known to undergo very facile rearrangement to 1,3,3-trimethyl-2,7- dioxabicyclo [2,2,l]heptane (53) when heated or treated with acid. Thus

treatment of (5 1) with rn-chloroperbenzoic acid and sodium bicarbonate affords a mixture of (52) and (53). A simple procedure for the rn-chloroperbenzoic acid epoxidation of such acid-sensitive olefins2' has been reported. The method, which employs a biphasic solvent mixture of dichloromethane and 0.5M sodium bicarbonate solution, was used to epoxidize the yd- unsaturated ketone (Sl), affording 85% conversion into (52) with no concurrent formation of the bicyclo-compound (53). An olefinic acetal (54) and olefins containing enol-ester moieties, Me,~CHCH,CH,C(OAc)==CH, and Me,C=CHCH,CH=C(OAc)Me, were similarly epoxidized. The system can also be used to epoxidize less reactive olefins (e.g. hex-l-ene) and shows good selectivity in the epoxidation of a trisubstituted double bond in preference to a disubstituted double bond. Limonene with one equivalent of the peroxy-acid gave 1,2-epoxy-p-rnenth-8-ene in 85 % yield.

Epoxycyclopentanes (55) have been prepared by epoxidation of the appropriate cyclopentenes with monoperphthalic acid.28

(54) (55)

27 W. K. Anderson and T. Veysoglu, J . Org. Chem., 1973,38,2267. 28 S . A. Nesterenko, D. A. Pisanenko, and S. V. Zavgorodnii, Zhur. org. Khim., 1973,

9,758 (Chem. A h . , 1973,79,31 747j).


MeCH=CH-CH=CHCONRlR* (56)

Me 0x0 Me

Reagents : i, Phthalic anhydride-H,O,-NH,CONH,EtOH ; ii, Me,CO-FeCl,

Scheme 5

Substituted amides of sorbic acid (56) when treated with phthalic anhydride-hydrogen peroxide in ethanol containing urea afford29 the corresponding epoxyhexenamides (57) (Scheme 5). Hydrogenation of 4,5-epoxy- NN-diethylhex-2-enamide (57; R1 = R2 = Et) in the presence of Raney nickel gives NN-diethylhexanamide and 5-hydroxy-NN-diethylhexanamide. The epoxide (57; R1 = R2 = Et) condenses with acetone in the presence of ferric chloride to give the hexenamide cyclic acetal (58).

Syntheses30 for disparlure [cis-7,8-epoxy-2-methyloctadecane (61)], a sexual attractant of the gypsy moth (Purthetria dispar L.), have been reported by two independent groups. The syntheses differ only slightly in their routes from 1 - bromo-5-met hyl hexane to the key intermediate 2-me t hyloct adec-7- yne (59). In one, reaction is with dodec-1-yne in the presence of sodium hydride, in the other with lithium dodecylide. Oxidation of the olefin (60) to the oxiran (61) is achieved with perphthalic acid. Sheads and Beroza31 have synthesized a tritium-labelled disparlure (~is-7,8-epoxy-2-methy1[7,8-~H,]- octadecane) and report an improved method for preparing the intermediate 2-methyloctadec-7-yne.

Oxiran derivatives, (62) and (63), of p-aminoacetophenone which exhibit juvenile hormone activity2 have been prepared by the reaction of N-trifluoroacetyl-p-aminoacetophenone with geranyl bromide and citronellyl

29 L. P. Glushko, M. M. Kremlev, Yu. Yu. Samitov, and T. M. Malinovskaya, Ukrain. khim. Zhur., 1973,39, 807 (Chem. Abs., 1973,79, 126 173h). A. A. Shamshurin, M. A. Rekhter, and L. A. Vlad, Khim. prirod. Soedinenii, 1973, 9, 545 (Chem. Abs., 1974, 80, 36 927y); B. G. Kovalev, R. I. Ishchenko, V. A. Marchenko, and M. P. Filippova, Zhur. org. Khim., 1973,9,6 (Chem. Abs., 1973, 78, 84 127t).

31 R. E. Sheads and M. Beroza, J. Agric. Food Chem., 1973, 21, 751. xt2 Z. Machkova, L. Dolejs, and F. Sorm, Coil. Czech. Chem. Comm., 1973,38, 595.

Saturated Heterocyclic Chemistry Me(CH2)gC-CLi + Br(CH&CHMe2

Me(CH2)9C-C(CH&CHMe2 (59)

Me(CHB)sCH=CH(CH2)4CHMez (60)

!-HO.p CsH 4. CO,H

bromide respectively, followed by oxidation of the resulting unsaturated derivatives with perphthalic acid in diethyl ether. Masking of the amino- group of the intermediate N-(3,7-dimethylocta-2,6-dienyl)-p-aminoacetophenone and N-(3,7-dime t hyloct-6-enyl)-p-aminoacetophenone with the trifluoroacetyl group is essential for successful epoxidation of the alkenyl chain, since compounds with an unprotected amino-group afford mixtures of products which are difficult to resolve. The trifluoroacetyl group is readily removed with alcoholic sodium hydroxide at 35 "C affording (62) and (63) in 57 % and 72 % yields respectively.

(62) R = CH2CH=CMe(CH2)2CH-CMea

\o/

'0'

NHR (63) R = (CH&CHMe(CH2)2CH-CMeB

Carbon atom insertion. The reactions of various sulphur-stabilized carbanions with aldehydes and ketones continue to provide useful routes to epoxides. Dimethyl sulphoximine, prepared from dimethyl sulphoxide, on dialkylation affords NN-dimethylamino- and NN-diethylamino-dimethyloxosulphonium fluoroborates as stable, white, crystalline s0lids.3~ Treatment of the latter with sodium hydride in a variety of aprotic solvents, in particular dimethyl sulphoxide, gives the corresponding methylides (64; R = Et or Me). These

0 0 NaH-DMSO, -DMF, or -THF II

+ Me-S+CHI- II 1

NRt

Me-SLMe BF4- I NRB

C. R. Johnson and P. E. Rogers, J. Org. Chem., 1973, 38, 1793.


ylides have proved to be effective nucleophilic methylene-transfer reagents. Reactions with aldehydes and ketones afford epoxides, whereas reactions with c$-unsaturated ketones give cyclopropyl compounds as the major products. A certain degree of selectivity is observed: diethylaminomethyloxo- sulphonium methylide with 4-t-butylcyclohexanone gave only the (2)-epoxide, a similar stereospecificity having previously been reported for dimethyloxosulphonium methylide, whereas dimethylsulphonium methylide gave predominantly the (E)-epoxide.

A general procedure for the synthesis of epoxy-alkylated and -acylated heterocycles has been reported by Taylor et al.34 The oxirans (65) (R1 = 2-

quinolyl, 4-quinolyl , 1-isoquinolyl, 4-quinazolinyl, 2-benzoxazolyl, 1,3- dimethyl-2,4-dioxo-6-pyrimidinyl; R2 = Et or Ph, R3 = H; or R2 = R3 = Me) were prepared in 17-70 % yields by treating the appropriate aryl methyl sulphone (RISO,Me) or aryl chloride with diphenylmethylsulphonium tetrafluoroborate or diphenylmethylsulphonium perchlorate followed by reaction with the ketone (R2R3CO).

One disadvantage of base-promoted reactions of sulphur-stabilized carbanions with aldehydes or ketones is the possibility of side-reactions (hydrolysis of the sulphonium salt or Cannizzaro or aldol reactions etc.). However, it has been reported that if a biphasic system is used these side- reactions do not occur. Thus, by stirring a heterogeneous mixture of lauryl- dimethylsulphonium chloride (66) and a carbonyl compound in benzene- aqueous sodium hydroxide, oxirans have been synthesized in high yields.35 Typically, acetophenone gave an 85% yield of the oxiran (67). It has also been reported that trimethylsulphonium iodide reacts with benzaldehyde in a two-phase system (dichloromethane-aqueous sodium hydroxide) to form 2-phenyloxiran in excellent yield, but only if tetrabutylanimonium iodide is present.36 The latter is considered to be acting as a phase-transfer reagent, transferring the anionic reactant from the aqueous to the organic phase. Cinnamaldehyde afforded an equally smooth conversion into 2-styryloxiran, but ketones gave only low yields (18-36 %) of oxirans. Trimethyloxosul- phonium iodide and benzaldehyde afforded 2-phenyloxiran (in only 2 0 - 30 % yield) and 2,6-diphenyl-l,4-oxathian 4-oxide (68) (12 %). With ap- unsaturated ketones no oxirans were formed, but instead cis-trans mixtures of cyclopropane derivatives.

s4 E. C. Taylor, M. L. Chittenden, and S. F. Martin, Heterocycles, 1973, 1, 59. 35 Y. Yano, T. Okonogi, M. Sunaga, and W. Tagaki, J.C.S. Chem. Comm., 1973, 527. s6 A. Merz and G. Markl, Angew. Chem. Internat. Edn., 1973,12,845.


Me(CH ) S'CHa- Me(CH2)llS+Me&l- NaoH-C6H6+ 2 1 1 1 I

I

Me \ Ph\~/r2 + Me(CH2)11SMe Me /'O

(67) When 3-quin~clidinone~~ is treated with triphenyloxosulphonium iodide

and sodium hydride the spiro-oxiranquinuclidine (69) is formed.

(68) (69)

Treatment of (E)-butenylbis-sulphonium or (2)-butenylbis-sulphonium salts with a molar equivalent of an alkoxide afforded 1,3-butadienyIsul- phonium salts (70), which reacted with aldehydes in the presence of alkoxides at -78 O C to form mixtures of the stereoisomeric oxirans (71) and (72), with

NaOMe, -78'C

RCHO/

(71) (72) a1 J. R. Potaski and M. E. Freed, U.S.P. 3 775 419/1973.


a 1 -alkoxyprop-2-enyl ~ide-chain.~~ The diene sulphonium salt (73) did not add alcohol in the presence of alkoxide but lost a proton to give a stabilized ylide (74), which reacted with aldehydes to give the hitherto unknown oxiran derivative (75), and the diene (76), which gave a Diels-Alder reaction with tetracyanoet hylene.

Me2S+ Br’

\c/” II

I I Me

H

Me2S+ \

-Ht *+H+

/ (74)

(73)

(75) 70%

7 3.

(76) 30%

Although the nucleophilic alkylidene transfer from a sulphur ylide to a carbonyl group is a standard method for converting an aldehyde or ketone into an oxiran, such reactions may fail (i) if the substrate is readily enolizable or (ii) if the carbonyl group is sterically hindered.39 However, if such ketones are treated with phenylthiomet hyl-lit hium, methylthiomethyl-lithium , or a-lithiobenzyl phenyl sulphide, the corresponding p-hydroxysulphides are formed in yields of 41-100 %. Subsequent alkylation of the p-hydroxysulphides with methyl iodide or trimethyloxonium fluoroborate, followed by treatment of the resulting salts with base, affords oxirans in yields of 43-- 98% (Scheme 6). This sequence may also be worthy of consideration in those cases where a one-step ylide reagent would work, but where a mixture of diastereomeric epoxides results. These are often difficult to separate, but this is not usually true of the more polar diastereomeric alcohols. Thus resolution of the diastereomers may be achieved at the more convenient P-hydroxy- sulphide stage.

An alternative route to epoxides from carbonyl compounds involves reaction with diazoalkanes, a procedure which has not been very popular, possibly because of the hazardous nature of the reagents in some instances

a8 H. Braun, G. Huber, and G. Kreszc, Tetrahedron Letters, 1973, 4033. 39 J. R. Shanklin, C. R. Johnson, J. Ollinger, and R. M. Coates, J. Amer. Chem. Suc., 1973,95, 3429.


OH I \

/ I C---0 + PhSCH,Li % -C-- CIIpSph

i i i i

Reagents: i, THF; ii, H'; RX, iv, base

Scheme 6

and the low selectivity achieved in others. The latter point is illustrated by the reaction of diazomethane or diazoethane40 with 2,6-dichloro-p-benzoquinone (77) (Scheme 7). A diazoalkane molecule adds to each C=C group, one of the carbonyl groups is epoxidized, and both NH groups are alkylated to form (8la) and (81b). The intermediate products (78) and (79) or (80) can be isolated. Ethyl diazoacetate reacts with (77) to yield the epoxide (82), which on oxidative hydrolysis with nitric acid gives the dicarboxylic acid (83) which can be methylated with diazomethane to form the corresponding te t rame t hyl derivative. Cyclization of Halohydrin. The classical synthetic route to epoxidesfrom halohydrins and related compounds continues to be widely used, often with complete stereospecificity. 2-Chloro-1 -phenylpropan-1-01, MeCHClCHPhOH (84), formed by the Grignard reaction of phenylmagnesium bromide and 2-chloropropanol, when treated with potassium hydroxide in methanol yieIded trans-l,2-epoxy-l -pI~enylpropane,~~ whereas oxidation of (84) with chromic acid to the corresponding ketone followed by reduction with sodium borohydride gave a diastereomer of (84) which, when treated with methanol- potassium hydroxide, afforded cis-l,2-epoxy-l -phenylpropane.

A stereospecific synthesis for the cis- and trans-2,3-epoxybutanes from the benzaldehyde acetal of meso-butane-2,3-diol (85) has been reported.42 Treatment of the acetal(85) with N-bromosuccinimide in carbon tetrachloride containing a trace of hydrogen bromide, followed by treatment of the resulting bromohydrin ester with potassium hydroxide in ethylene glycol, gave cis-2,3-epoxybutane, isomerically pure by n.m.r. (Scheme 8). Treatment of the same acetal with N-bromosuccinimide in water followed by treatment with

40 B. Eistert, J. Riedinger, G . Kueffner, and W. Lazik, Chem. Ber., 1973, 106, 727. 41 K. K. Mathew, P. S. Raman, and T. G. B. Antharjanam, Current Sci., 1973, 42, 17

4 2 D. A. Seeley and J. McElwee, J . Org. Chem., 1973, 38, 1691. (Chem. A h . , 1973.78, 84 1281.1).


zt

u \


Ph

(8 5 )

i - O y O

Ph

Me% Me Ph

iii -

Reagents: i, NBS-HBr-CC&; ii, Br'; iii, OH' Scheme 8

toluene-p-sulphonyl chloride, and with potassium hydroxide in ethylene glycol and 1 ,Zdimethoxyethane, gave trans-2,3-epoxybutane (Scheme 9). These reactions and the treatment of other cyclic acetals with NBS showed the reaction to be ionic, kinetically regiospecific, and specific for the acetal carbon.

Golding, Hall, and Sakrikaf13 have investigated the mechanism, scope, and limitations of the reaction between vicinal diols and hydrogen bromide

Reagents : i,

a Me Me

H xe O&Ph

(59 %) NBS-H,O; ii, H,O; iii, TsCl; iv, OH-

Scheme 9 in acetic acid and have used the reaction as a route to chiral epoxides (Scheme 10). (S)-( +)-Propan-l,2-diol [prepared by reduction of commercial (5')-( -)- ethyl lactate] on treatment with hydrogen bromide in acetic acid gave a mixture of acetoxy-bromides (86) , which gave optically pure (S)-( +)- propylene oxide on reaction with one equivalent of potassium pentylate in pentyl alcohol. This method should also be applicable to the (R)-isomer.

43 B. T. Golding, D. R. Hall, and S. Sakrikar, J.C.S. Perkin I , 1973, 1214.


Me H MC )-COIEt

HO

J AcO Br

Br \ H--m

Me OAc

'0' Reagents: i , LiAlH4; ii , HBr-HOAc

Scheme 10 Epoxyacetylenes containing groups which are unstable to base have been

prepared.44 For example, reaction of 2-methylbut-3-yn-2-01 with ethyl- magnesium bromide at -20 O C followed by addition of 2,3-dibromobutanal gave 2-bromo-7-methyl-3,4-epoxyoct-5-yn-7-o1, which when heated with potassium carbonate afforded 2-bromo-3,4-epoxyhex-5-yne.

Although the addition of mercuric salts to olefins in the presence of water to give p-hydroxyalkylmercuric salts was discovered at the turn of the century, these compounds have received little consideration as synthetic intermediates. Recently Kretchmer et al. studied the base-catalysed decomposition of #?-hydroxyalkylmercuric chlorides45 and found that the latter compounds undergo reactions analogous to those of the corresponding 1 ,2-halohydrins. Thus trans-2-hydroxycyclopentylmercuric chloride and trans-2-hydroxycyclo- hexylmercuric chloride, in the presence of a base, e.g. potassium t-butoxide, provide convenient and high-yield sources of cyclopentene oxide and cyclohexene oxide respectively. The cycloheptyl derivative, however, affords primarily cycloheptanone, the product of a 1,2-hydride shift. Acyclic mer- curials also afford the corresponding ketones. Darzens Reaction. The Darzens condensation of aldehydes and ketones may be one of the most convenient and common procedures for the one-step synthesis of 2,3-epoxyalkanoates, but little has been reported on the reactions of a-halogeno-aldehydes under such conditions. Takeda et aZ.46 have studied base-catalysed Darzens- type condensat ions of a-haIogeno-aldehydes with methyl chloroacetate and found that aliphatic a-chloro-aldehydes afford

44 Y . I. Kibina, Sh. Musantaeva, and A. V. Shchelkunov, Ref. Zhur., Khim., 1973,

46 R. A. Kretchmer, R. A. Conrad, and E. D. Mihelich, J . Org. Chem., 1973, 38, 1251. Abstr. No. 5Zh242 (Chem. Abs., 1973,79, 78 477m).

A. Takeda, S. Tsuboi, and T. Hongo, Bull. Chem. SOC. Japan, 1973, 46, 1844.

20 Saturated Heterocyclic Chemistry -

RIRzC-CHO + ClCH2C02Me NaoR-ether Or -THF, R'R2C - CH-C H-C02Me c1 '

I c1

trans-4-chloro-2,3-epoxyalkanoates (87) in somewhat variable yields. a- Bromo-aldehydes reacted differently: 2-bromo-Zmethylpropanal gave a-chloro-y,y-dimethyl-Aa*p-butenolide (88) as a major product, and other 2-bromo-n-alkanals yielded mixtures of several minor products.

1

0

Moraud and C ~ m b r e t ~ ~ have reported the preparation of a new class of epoxide, namely a-alkoxy-cc,B-epoxy-esters (90). These compounds, which are stable in alcohol unlike most epoxy-esters previously reported, are prepared in 43-58 % yield at room temperature by treatment of halogenopyruvate esters (89) with an alkoxide-alcohol mixture. These epoxides provide routes to new compounds and to others difficult to make by other methods. Thus acid hydrolysis of (90) gives quantitative conversion into a-hydroxypyruvates (91), and dry hydrogen chloride-ether in an alcohol (R20H) affords acetals (92).

OR2 I

I I RTH-C-C02R2 R1CH-C-C02R2

(9 1) (92)

OH OR2 I II OH 0

47 B. Moraud and J. C . Combret, Compt. rend., 1973,277, C, 523.

Three-membered Rings 21 NaOMe-MeCH(OMe)2

- 10°C + R1 COzR2

'0' COAr + CICH2COrR2 "' A!

(93) (94)

The base-catalysed reaction of a,@-epoxy aryl ketones (93) with alkyl chloroacetates4* affords diepoxy-esters (94). Usually only one isomer, which has the aryl and the ester groups cis to the 2,3-epoxy-group, is formed.

The reactiong9 of 2-nitrophenacyl bromide (95) and sodium methoxide in absolute methanol affords, via a Darzens reaction, the keto-epoxide (96) and the bis-epoxide (97). The bis-epoxide results from an attack by a methoxide anion on the carbonyl carbon of (96) and a subsequent rearrangement with displacement of a bromide ion.

G/lvBr NaOMe-MeOH, (-J: / O b

O2N (95)

(96)

+

(97)

The ability of diazomethyl ketones to undergo various base-catalysed condensation reactions similar to those of ordinary ketones is well established. However, the first example of a Darzens condensation of a diazo-ketone has only recently been reported.50 Thus reaction of 1 -chloro-3-diazopropane (98) with various aldehydes and sodium hydroxide in stoicheiometric amounts gave the Darzens-condensation products, 1 -diazo-3,4-epoxybutan-2-ones (99), in 44-88 % yield. With excess benzaldehyde and base a diastereomeric mixture of a diadduct, 2-diazo-l,5-diphenyl-4,5-epoxy-l-hydroxypentan-3- one (100) was also formed in addition to the monoadduct (99; R = Ph).

The esterification of (R)-( -)-3,3-dimethylbutan-l ,2-dio151 with 4-bromo- benzenesulphonyl chloride, followed by treatment with sodium methoxide- methanol at 0 "C, affords 3,3-dimethyl-l,2-epoxybutane, which on reaction

I* L. S. Stanishevskii, G. I. Tishchenko, V. I. Tyvorskii, V; Yu. Glazkov, V. A. Mashen- kov, and L. A. Khil'manovich, Vesrnik Beloruss. Inst., 1973, 2, 26 (Chem. Abs., 1974,80,82 522k).

I9 E. Campaigne and J. H. Hutchinson, J . Heterocyclic Chem., 1973, 10, 229. 50 N. F. Woolsey and M. H. Khalil, J. Org. Chem., 1973, 38, 4216. 51 M. Sepulchre and A. M. Sepulchre, Bull. SOC. chim. France, 1973, 1164.


with methoxide-methanol at 98 “C yields (R)-( -)-1 -methoxy-3,3-dimethyl- but an-2-01.

The preparation of a,b-epoxy-sulphones and -sulphoxides has been reported previously by Tavares et al. Now they have reported the preparation of a,~-epoxy-~ulphides,~~ a new class of sulphur-substituted oxirans. The Darzens condensation of chloromethyl p-tolyl sulphide and benzaldehyde in the presence of potassium t-butoxide affords a poor conversion into the a$-epoxy-sulphides (101) and (102). However, in the presence of ‘Dabco’

H SC6H4Me-p ’”*-A Ph SC6H4Me-p *H

(101) (102)

(174-diazabicyclo [2,2,2]octane) good yields of the a,!-epoxy-sulphides are obtained. Thus it would appear that, in the absence of ‘Dabco’, the con- centration of the p-tolylthiochloromethyl carbanion is low, a proposal sup- ported by the recovery of unreacted starting material. This procedure gives a general route to this class of compound, the only previously reported a,b-epoxy-sulphide being a spiro-derivative (103). The oxiran (102) rear- ranges in the presence of BF3,2Et,0, affording an a-thio-aldehyde (104).

0

(103)

The latter results from a migration

CHO PhCH-S-C6H4Me-p I

(104)

of the p-tolylthio-group similar to the rearrangement reported for the related sulphoxides and sulphones.

Metal-catalysed Epoxidation. The use of metals or metal complexes as catalysts in the preparation of oxirans continues to receive much attention in the industrial sphere.

68 D. F. Tavares and R. E. Estep, Tetrahedron Letters, 1973, 1229.


Silver of crystallite size -700-800 A, man~factured~~ by electrodeposition from aqueous solutions containing AgNO,, Na,B,O,,lOH,O, NaOH, NH,OH, and CM-cellulose as a protective colloid in an electrolytic cell, has been shown to be an effective catalyst for the oxidation of ethylene to ethylene oxide.

Another procedure, in which the epoxidation reaction is not accompanied by the formation of acetaldehyde, also involves a silver catalyst.54 In this instance, the oxidation reaction is carried out in the gas phase in a C-steel reaction tube coated on the inside with a nickel-phosphorus alloy.

Molybdenum catalysts are also being widely used. Propylene in benzene, in the presence of the complex (NH,),MoO,F, and oxygen, is oxidized in a stainless-steel reaction vessel to propylene oxide.55 Olefins can be epoxidized with >67% selectivity by carrying out the oxidation with a hydroperoxide in the presence of a molybdenum oxide catalyst containing a Group VIB metal oxide.66 Thus decene 1 ,Zoxide was obtained with 100 % selectivity and 92 % hydroperoxide conversion by oxidizing dec-1-ene with t-butyl hydroperoxide in toluene in the presence of Bi,PMol,O5, on SiO,.

The activity of various molybdenum-based catalysts5' has been studied for the reaction of cumene hydroperoxide with cyclohexene in cumene at 113 "C. MOO, [(NH,),MoO, ignited] alone or on carbon or aluminium oxide was only slightly active, but an active, selective, and homogeneous catalyst was prepared from MOO,-SO,. Molybdenum trioxide itself has been found to be an effective in toluene at 100 OC for the epoxidation of 1,2,3,6- tetrahydrophthalic anhydride by cumene hydroperoxide.

Complexes of copper, nickel, cobalt, ruthenium, or tungsten have also been successfully employed as catalysts in epoxidation reactions. Copper methoxychloride (CuClOMe) in pyridine59 effected the cyclodimerization of acetone and acetophenone to give 70% and 60% yields of the epoxides (105; R = Me) and (105; R = Ph) respectively. Cyclopentanone reacted similarly.

Me

R wcoR (195)

59 L. R. M. Piro and B. Notari, Ger. Offen 2 263 883/1973 (Chem. Abs., 1973, 79,

64 E. Ide, T. Kumazawa and 1. Kiguchi, Ger. Offen 2 136 979/1973 (Chem. Abs., 1973,

66A. A. Balepin, A. V. Bobolev, Yu. A. Buslaev, V. I. Chagin, N. M. Emanuel, and

56 J. Dahlman, E. Hoeft, H. F. Boeden, B. Castisella, and J. Scheve, Ger. Offen

57 L. Cerveny, A. Marhoul and V. Ruzicka, Chem. prrimysl, 1973,23, 299 (Chem. Abs.,

58 Y. M. Paushkin, D. V. Lopatik, I. P. Prokopovich, Doklady Akad. Nauk beloruss.

6a C. Neri and E. Perrotti, B.P. 1 331 856/1973 (Chem. Abs., 1974,80,27 081r).

91 974r).

78, 125 143).

A. I. Sergeev, Ger. Offen 2235 229/1973 (Chem. Abs., 1973, 78, 125 146u).

2 231 374/1973 (Chem. Abs., 1974,80,27 080q).

1973,79,91 850x).

S.S.R., 1973,17, 933 (Chem. Abs., 1974, 80, 14 791x).

3

24 Saturated Heterocyclic Chemistry The yields of the epoxides formed by oxidation of but-l-ene, cis-but-2-ene, and isobutene were increased60 by using complexes of thio-cr(or p)-diketones with nickel or cobalt as catalysts, e.g. tetrabutylammonium bis [bis-(3,4- toluenedithiolato)nickelate] (106; x = 1 or 2). Styrene in benzene at 25 *C

(106)

was oxidized by t-butyl hydroperoxide to styrene oxide in the presence of dichlorotris(triphenylphosphine)ruthenium.61 Oxidation of maleic acid or its anhydride to epoxysuccinic acid by hydrogen peroxide was achieved in the presence of W03, H2W04, or its salts.62 The activity of the catalyst can be increased if it is first pretreated with hydrogen peroxide.

Miscellaneous. It is well known that o-hydroxymethylphenols (107), which have at least one bulky substituent, can be oxidized by periodate to mono- meric spiroepoxy-2,4-cyclohexadienones (108). Recent studies.63 however, Rq OH OH R p A H 2

NaIO4 ~

\ /

R2 R2

(107) (108)

have shown that oxidation of benzyl-2-hydroxyphenylcarbinol (109) with sodium periodate affords the Diels-Alder dimer (1 lo), and oxidation of

6o H. Kawazura, Y. Yamamoto, and Y. Kariya, Japan. Kokai 73/15 808 (Chem. Abs., 1973,78, 147 768a). J. 0. Turner and J. E. Lyons, Ger. Offen 2 231 67811973 (Chem. Abs., 1973, 78, 1 1 1 925k).

62 M. Saotome, Y. Itoh and M. Terashi, Japan. Kokai 73/39 435,73139 436 (Chem. Abs., 1973,79, 78 591u, 78 592v).

63 H. D. Becker and T. Bremholt, Tetrahedron Letters, 1973, 197.

Three-membered Rings

OH R' I

25

R3

!.APh

o-hydroxy-substituted diarylcarbinols and triarylcarbinols (1 1 1) yields cyclic catechol benzaldehyde acetals (1 12).

Theoretically benzene is capable of forming five oxides, viz. benzene oxide, syn-benzene dioxide, anti-benzene dioxide, syn-benzene trioxide, and anti- benzene trioxide, of which all except the anti-benzene dioxide (116) have been prepared within the past few years. The latter has now been prepared64 by treatment of the trans-l,2-diacetate (1 15) with 5 % methanolic potassium hydroxide, The intermediate (115) is formed in small yield (1 %) when the dibromoepoxide (1 14) is treated with acetic anhydride and sulphuric acid at room temperature or by reaction of traizs-l,2-diacetoxycyclohex-4-ene (1 13) with N-bromosuccinimide. Reaction of (1 16) with diazomethane gave a

pyrazoliiie which on U.V. irradiation afforded anti-dioxatrishomobenzene (1 17), which remained unchanged when heated at 150 "C. The analogous reaction with cis-benzene dioxide (1 18) yielded the dioxatrishomobenzene (119), which was isomerized at 150 "C to the cyclononatriene (120) (Scheme 11). An antibiotic that had earlier been assigned an anti-benzene dioxide structure was shown, as a result of detailed n.m.r. investigations in conjunc- tion with these experiments, to have the syn-benzene dioxide structure (121).

64 E. Vogel, H. J. Altenbach, and E. Schmidbauer, Angew. Chem. Internat. Edn., 1973, 12, 838.


Reagents: i, CH,N,; ii, hv; iii, 15OOC

Scheme 11 It has been established that dio~quinone,~~ which occurs in the bark of

Diospyrus tricolor Hiern, is in fact an optically active naphthoquinone epoxide which must be one of the two enantiomers represented by structure (122).

0 L - (121) (122)

Synthetic diospyrin epoxide is the corresponding racemic compound. ( f)-2- cis-4-trans-Xanthoxin (1 23) has been in eight steps, from 1 ,3,3- t rimet hylcyclohex- 1 -en-Sone.

HO (123)

The racemic oxides (124) and (125) of methyl esters of octadec-6-enoic acids have been separated6' by the slow crystallization of the urea adducts of the racemic compound.

The condensation of 5-methyl-5-(glycidoxyethoxy)hex-l-en-3-yne (126) 65 T. J. Lillie, 0. C. Musgrave, and R. H. Thomson, J.C.S. Chem. Comm., 1973,463. 66 T. Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1973, 37, 1215. 6 7 I. L. Kuranova and L. V. Balykina, Zhur. priklad. Khim., 1973, 46 ,939 (Chem. Abs.,

1973 ,79 ,53 l05a).


with hexachloropenta-l,3-diene (127) or 5,5'-dimethoxytetrachlorocyclo- penta-1,3-diene leads to adducts with an endo configuration.6a Thus when a mixture of (126) and (127) was heated with hydroquinone at 100°C, the adduct (128) was formed.

CH20(CH&OCMe2C=C-CH= CH2

(126) IkG;i:;;ta-l,3-diene (127).

c1, ,Cl

b' (128)

The base-catalysed reactionsof epichlorohydrin with alkoxynaphthenic phen~lphthalein,~~, and 4-a~etoxy-3,5,6-trimethylphenol~~ have been

studied, and in each instance epoxy-groups were easily incorporated into the substrate.

An ethynyl group is essential for optimal anticancer activity of carbamate esters, and bisepoxides are more potent anticancer agents than monoepoxides. These observations led to the syntheses, by an acid-catalysed reaction between epichlorohydrin and the respective acetylenic alcohol, of a series of 2- [(2-propynyloxy)methyl]oxirans (129), ethynyl derivatives of ~xirans.'~ It

R2 I /*\

I .

R.'-C=C-C-O-CH2-CH-CHa I R3

(129) 68 I . M. Akhrnedov, M. G. Veliev, P. B. Akhundova, and M. M. Guseinov, Azerb.

khim. Zhur., 1973, 59 (Chem. Abs., 1974, 80, 47 717f). 69 R. A. Ismailova, S. I. Sadykh-Zade, and Sh. F. Sadygov, Azerb. khim. Zhur., 1973,

56 (Chem. Abs., 1974, 1974,80,47 716~) . 'O S. N. Satazkin, V. S. Vinogradova, and L. I. Komarova, Izvest. Akad. Nauk S.S.R.,

Ser. khim., 1973, 144 (Chem. Abs., 1973,78, 147 693x). L. Blaha, J. Weichet, and J. Stribrny, Czech. P. 150 020/1973 (Chem. Ahs., 1974, 80, 47 823n). R. B. Fugitt, G. S. Wu, and L. C. Martinelli, J . Pharm. Sci., 1973, 62, 1894.

28 Satiirated Heterocyclic Chemistry was hoped that the presence of both an ethynyl group and an oxiran group in the same molecule would lead to significant anticancer activity. The screening results, however, were inconclusive.

Reactions-Ring-opening. Elecfruphilic. The reactions of a series of epoxychalcones (130; R1 = PhCH, or MeOCH,; R2 = MeO, C1, or Me; R3 = H or MeO) with acidic reagents have been in~estigated.~~ The product distribution is rationalized in terms of the sigma value of the 5’-substituent. Thus, when 0 4 0, treatment with HCI or BF,-Et,O gives the flavanon-3-01 (131), through elimination of the protective R1 group and cyclization. When Q > 0, treatment with HCl results in opening of the oxiran ring without elimination of the protective group to give the chlorohydrin (132), whereas with BF3-Et20 the isoflavone (133) is obtained.

‘OR’

(133)

Somewhat analogous and complementary results have been reported by O’Sullivan and G ~ r r n l e y , ~ ~ who have studied the reaction of 2’-tosyloxy- chalcone epoxides (134) with boron trifluoride (Scheme 12). Treatment of (134; R = H) affords the flavononal(l35) and the flavonal(136), but reaction with (134; R = OMe) gives the cc-formyl-desoxybenzoin (137). Treatment of the epoxide (134; R = H) with alkali at room temperature also gives flavonol whereas the epoxide (134; R = OMe) on similar treatment, or in refluxing solvent, gives 4-methoxyaurone (138; R = OMe). The latter result

7s G. Litkei and R. Bognar, Acta Chim. Acad. Sci. Hung., 1973, 77, 93. 7 4 T. R. Gormley and W. I. O’Sullivan, Tetrahedron, 1973, 29, 369.


Ph

R O

(134)

i (R = H)

i ( R = OMe) -

OTs

OMe 0 Ph

(137)

(135) ( 1 36)

Scheme 12

indicates that an epoxide is not an intermediate in the production of flavonols from 2’-hydroxy-6’-methoxychalcones on treatment with alkaline hydrogen peroxide (Algar-Flynn-Oyamada reaction) at temperatures greater than 20 “c.

The benzothiazin-4(3H)-one 1,l-dioxide (1 39) on treatment with hydrogen peroxide and sodium hydroxide gives rise to the epoxide (140). The latter in the presence of boron trifluoride etherate75 does not yield the ring-expanded ketone (141), but the keto-aldehyde (142). The preference for phenyl migration as opposed to benzoyl migration has also been reported for the boron

Reagents: i , BF3-Et20; ii , refluxing solvent

NaOH-H202

0 2

(142) (141) 7 6 H. Zinnes and J. Shavel, jun., J . Heterocyclic Chem., 1973, 10, 95.

30 Saturated Heterocyclic Chemistry trifluoride-catalysed rearrangement of epoxides derived from benzalacenaph- thenone.

The acid-catalysed rearrangements of trans- and cis-1 -acetoxy-3,4-epoxy- pentanes and 1 -acetoxy-4,5-epoxyhexanes, epoxides having neighbouring groups capable of nucleophilic participation, have been studied.76 The reactions yield cis- and trans-2-methyl-3-acetoxytetrahydrofuran and threu- and erythru-2-( 1 -acetoxyethyl)tetrahydrofuran respectively with retention of configuration at the epoxide carbon atoms. Rearrangement of trans-l-acetoxy-3,4-epoxypentane (143) lSO-enriched at the acetate carbonyl gave cis-3- acetoxy-2-methyltetrahydrofuran (144) (21.5 % l80), which on hydrolysis

Me Me

%* OCOMe

(144) H

-BFs /O-CH2

to the alcohol showed no significant loss of the oxygen label (20% leg). The carbonyl oxygen of the starting acetate must therefore be present as the ether or the hydroxy oxygen in the product. The known stereochemistry of the products, coupled with the labelling experiments, points to a mechanism consistent with the intermediacy of orthoesters formed by the initial attack of acetate on the epoxide with inversion of configuration. The orthoester is then cleaved to give the more stable five-membered-ring acetonium ion, which undergoes intramolecular rearrangement to form the furan ring.

trans- and cis-4,5-Epoxyhexan-l-ols and 5,6-epoxyheptan-1 -oh, when treated with boron trifluoride etherate in ether, show a marked preference for

78 J. M. Coxon, M. P. Hartshorn, and W. H. Swallow, J.C.S. Chem. Comm., 1973,261.

Three-rnembered Rings 31 cyclic ether formation: tetrahydrofuran > tetrahydropyran > ~xepan. '~ The ether products arise by intramolecular hydroxyl displacement of the epoxide oxygen with inversion of configuration. Reactions of trans- and cis-epoxypentan-1-01s give a mixture of trans- and cis-2-methyltetrahydrofuran-3-01s. From each epoxide one methyltetrahydrofurar,ol must arise by nucleophilic displacement of the secondary epoxide oxygen with retention of configuration.

The effect of the reaction conditions on the direction of opening of the epoxy-ring of 1,2-epoxy-3-alkoxypropane (145) on treatment with various

\o/CH~OCH~CH=CH~ RC02H-A1C13 + RCO&HCHZOCHzCH=CH2 I

CHzCl (145)

carboxylic acids in the presence of Lewis acids has been investigated.'* A carboxylate group is substituted at the 2-position and a chloro-group at the l-position.

The opening of the or-oxide ring in 4,5-epoxy-3,6-diphenyl-NN'-diethoxy- carbonylhexahydropyrazine (146) in the presence of gaseous hydrogen chloride in methanol79 gives an unidentified product (35 %) and 3,5-diphenyl- 4-hydroxy-6-chloro-NN'-diethoxycarbonylhexahydropyridazine (1 47) (37 %).

Ph Ph

dry HCI-MeOH + Ho+T'cozEt Ph /u"\co,,,

c1 (147)

The oxiran (146), therefore, not only undergoes a ring-opening reaction but also the 645 migration of a phenyl group. Treatmentso of the nitroepoxy-

N0,C6H4) with hydrogen chloride gives the corresponding a-chloro-p- hydroxy-ketone (149) in excellent yield.

ketones (148; R = p-MeCsH4, p-PhC6H4, p-clccH4, m-PhC6H4, or p-

CMezNOz ?y RCOCHClCH(OH)CMe2N@2 Rco-iJ- (149)

(148)

7 7 J. M. Coxon, M. P. Hartshorn, and W. H. Swallow, Austral. J . Chem., 1973,26, 2521. 78 B. F. Pishnamazzade and A. Kh. Mamishov, Zhur. org. Khim., 1973, 9, 1365 (Chem.

79 Y. S . Shaborov and L. D. Sychkova, Zhur. obshchei Khim., 1973, 43,883 (Chern. Abs.,

8o V. F. Belyaev and V. P. Prokopovich, Vesti Akad. Navuk belarusk. S.S.R., Ser. khim.

Abs., 1973,79, 115 376a).

1973,79,66 281e).

Nauuk, 1973, No. 5, 78 (Chem. Abs., 1973, 79, 146 106s).

32 Saturated Heterocyclic Chemistry Ethylene oxide and 1,2-epoxycyclohexane each react with dichlorocar-

benesl to form the corresponding chloro-oxirans, which when treated with hydrogen bromide give 2-bromoethanal and 2-bromocyclohexanone respectively.

Sulphur trioxide is reporteds2 to react with perfluoropropylene oxide (150) at 150 "C in 10 h, affording a 1 :3 mixture of the dioxathiolan (151) and

(151) CF3COCF20S0,F (152), along with 5 % of CF3COCF,0S020S0,F. The dioxathiolan (151) is difficult to hydrolyse and is apparently unchanged by heating to 2OO0C or by contact with potassium fluoride, sulphur trioxide, or triethylamine. Therefore (1 52) must be formed independently, and not through (151), by opening of the epoxide ring by attack by sulphur trioxide at the C-F bond. If the reaction is conducted in the presence of sodium chloride, it also yields CF,COCF,Cl, confirming this proposal. Nucleophilic. Oxirans have been shown to be useful precursors in syntheses of heterocyclic compounds, Thus the epoxychalcones (1 53) reacts3 with toluene in the presence of aluminium chloride to give indenes (154), with monosubstituted hydrazines (R3NHNH2) to yield pyrazolines (1 55), and with hydroxyl- amine to afford isoxazoles (156) (Scheme 13). However, treatment with primary or secondary amines (R4R5NH) results in a nucleophilic substitution reaction at the carbon atom to the carbonyl group, with concurrent opening of the epoxide ring to give the compound (157). The epoxyvalerates (158; R1 = H or Me; RZN = NMe,, NEt2, piperidino, or morpholino), prepared by amination of the appropriate diepoxyvalerate, when reduced with lithium aluminium hydride afford ring-opened products (159) which can be cyclized with toluene-p-sulphonic acids4 to yield tetrahydrofuran derivatives (1 60). Diepoxyazabicyclononanes (161 ; R = S0,Ph or CHO) when heated with methylamine, 2,6-diaza-adamantadiols (162; R = S0,Ph or CHO).

Nitrogen-containing 2,3-dihydrobenzofuran derivatives (1 64, 165 ; R = Me,N or piperidino), sedatives, are formed when methylmerancin (1 63) is treated with dimethylamine or piperidine.86 The structure of the product

M. M. Movsumzade, A. L. Shavanov, A. S. Kyazimov and N. G. Kerimova, Ref. Zhur. Khim., 1973, Abstr. No. 10Zh262 (Chem. Abs., 1974,80,95 623u).

8a I. L. Knunyants, V. V. Shokina, and E. I. MYSOV, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 2725 (Chem. Abs., 1974, 80,95 151p).

83 A. Sammour, M. Selin, and A. A. Hamed, Egypt. J . Chem., 1973, 16, 101. 84 L. S. Stanishevskii, I. G. Tishchenko, V. I. Tyvorskii, L. A. Khil'manovich, A. S.

Zakharevskii, and A. V. Miklevich, Khim. geterotsikl. Soedinenii, 1973, 1443 (Chem. A h . , 1974,80,70 624g).

8 5 R. E. Portmann and C. Ganter, Helu. Chim. Acra, 1973, 56, 1986. 86 M. Murayama, H. Murai, K. Sempuku, T. Suminokura, and M. Ozaki, Japan. Kokai

73/00 822 (Chem. A h . , 1973,78, 136 047p).

Three-mernbered Riiigs 33

R1

i

(155)

p-R'CsHaCOCH(OH)CH3CijH4R2-p 1

NR4R5

(157) Reagents i , RSNHNH,; ii, MePh-AICI,; iii, NH,OH; iv, R4R6NH

Scheme 13

0 R$NCH,CRl(OH) ti COzCHMez

Me

LiAIH, (li8)

R~NCHKR1(OH)CMe(OH)CHzCHzOH

(159)

p-MeCaH4SOsH


Me*c$ OiMe

0

Me/

/

I OH

OMe

COR OH

(165)

reflects the reaction conditions. Thus (163) and excess 40 % aqueous dimethylamine in methanol at 40 O C for 30 h afford (164; R = NMe,), whereas (163) and dimethylamine in benzene at 125 O C for 7 h give (165; R = NMe2).

Some reactions of epoxides with nitrogen-containing compounds afford acyclic products. For example the amination reactionss7 of mono- and diepoxy-alcohols have been reported to give l-amino-2,4-diols as the major products.

The reactions of oxirans with alcohols have received little attention during this period. Treatment of b-chloroethyl glycidyl ether (1 66) with alcohols in the presence of SnC1,,ss followed by cyclization with sodium hydroxide, gives 2-alkoxymethyl-p-dioxans (1 67) in 55-93 % yield. Acyloxiranssa

E. F. Marchik, V. I. Pansevich-Kolyada, V. I. Makhnach, and G . S. Bychkova, Vesti Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1973, No. 2 , 106; I. A. Shnyp, V. I. Pansevich-Kolyada, N. A. Glazkova, and L. N. Falaleeva, ibid., 1973, No. 3 , 107 (Chern. Abs., 1973,79, 5184d; 66 106b).

8 8 B. F. Pishnamazzade and A. Kh. Mamishov, Khim. geterotsikl. Soedinenii, 1973, 161 (Chem. Abs., 1973,78, 124 518e).

s e I. G. Tishchenko, 0. N. Bubel, and G. S. Chertov, Vesti Akad. Navuk belarusk. S.S.R., Ser. khim. Navuk, 1973, No. 5, 82 (Chem. Abs., 1973,79, 137 0572).


are reported to give 2-acyl-p-dioxans on reaction with alcohols followed by cyclization with sodium. An interesting reaction is the alcoholysisgo of 2,3- epoxycyclohexan-l-one with ROH (R = Me, Et, or PhCH2), which affords 2-alkoxycyclohex-2-en- 1 -ones.

The reaction of Wittig-type reagents with oxirans to form cyclopropane- carboxylic acid derivatives has been well documented. Both ethoxycarbonyl- methylenephosphoranes and phosphonate anions have been successfully utilized. There has, however, been some disagreement concerning the overall mechanisms, mainly as to whether the products arise by a direct collapse of the phosphonate ester (169) or by a stepwise decomposition (Scheme 14).

(EtO)ePOCHCO,Et Rl** (168)

R4 R3

0 P( 0Et)s \

1 COzEt 3

major product

(EtO)2PO’

1

/(OEt)2 -0 P R4--v R2

6OzEt minor product

Scheme 14

In order to clarify the situation, Izydore and Ghirardelligl have studied the reaction of the triethylphosphonoacetate anion (1 68) with optically active trans-2,3-dimethyloxiran and with cis-2,3-dimethyloxiran. They conclude that the major products in each reaction must result from an even number of inversions of the initial epoxide, and are therefore consistent with Denney’s stepwise mechanism (process a). The minor products, which require only one inversion, arise by a direct collapse of the cyclophosphonate ester (1 69) (process 6).

so N. S. Kozlov and V. N. Kovaleva, Zhur. org. Khim., 1973, 9, 1984 (Chem. Abs.

O1 R. A. Izydore and R. G. Ghirardelli, J . Org. Chem., 1973, 38, 1790. 1974, 80, 26 803v).


HO 4Q The epoxy-p-bromobenzenesulphonate (170; n = 1) on reaction with

sodium sulphideg2 in DMSO affords exo-2-hydroxy-4-thiatricyclo [4,2,1 ,03*7]- nonane (172; n = 1) in 60% yield. The reaction is thought to proceed via the intermediate (171) which results from initial displacement of the p-bromo- benzenesulphonyl group. The other possible ring-opened product (1 73 ; n = 1) was not formed. Similarly the epoxy-p-bromobenzenesulphonate (170; It = 2) gave exo-2-hydroxy-4-thiatricyclo[4,3,1 ,03n7]decane (172; n = 2). Such conformationally rigid organosulphur molecules are extremely useful substrates in studies pertaining to stereochemistry and intramolecular interactions. Hydrogen sulphide, hydrogen cyanide, and 1 H-benzimidazole, nucleophiles containing a labile hydrogen, are reportedg3 to give a regiospecific cleavage of the oxiran ring of trans-2-ethoxy-3,4-epoxytetrahydropyran (174), affording (f)-threo-tetrahydropyranols (175; R = CN, SH, and

(174)

HR - 1H-benzimidazol-1 -yl) respectively. A new mild procedure for the conversion at room temperature of epoxides into allylic alcohols has been reported.94 The procedure is based on the observation that alkyl phenyl selenoxides

9 2 C. R. Johnson and W. D. Kingsbury, J. Org. Chem., 1973, 38, 1803. 93 V. B. Mochalin, A. N. Kornilov, and B. V. Unkovskii, Khim. geterotsikl. Soedinenii,

94 K. B. Sharpless and R. F. Lauer, J. Amer. Chem. SOC., 1973, 95, 2697. 1973, 867 (Chern. Abs., 1973,79, 126 233c).

Three-mernbered Rings 37

bearing a ,%hydrogen undergo syn-elimination to form olefins under much milder conditions than the corresponding sulphoxides. Thus 4,5-epoxyoctane reacted with PhSe- (prepared from diphenyl selenide and sodium borohydride) to give trans-oct-3-en-4-01 (Scheme 15). It is of note that elimination

Reagents: i , EtOH, 2h; ii, excess H202, 0-25 "C; i i i , room temp., 10 11

Scheme 15

occurs away from the hydroxy-group in the decomposition of the &hydroxy- selenide, a phenomenon which appears to be general from the examples studied .

The reactions of oxirans with organolithium compounds continue to attract much attention, a high degree of selectivity often being found. It has been shown that the epoxide bridge of epoxynitriles can be selectively opened tc to the nitrile group by using lithium dimethylcuprate-lithium iodide.95 Thus the dimethylepoxynitrile (176; R1 = R2 = Me) upon treatment in ether at - 1 O O C gave four products (178)-(lsl), in 5 % , 20%, SO%, and 25 % yield respectively. The product distribution can be manipulated by altering the cuprate : oxiran ratio or by the addition of acetone to the reaction mixture. If R1 or R2 is Ph, degradation also occurs, affording ketones (R1COR2), particularly when R1 = R2 = Ph. The key intermediate in the reaction is thought to be the complex (177).

1 (178) R'R2C=CHCN (179) RlR*C(OH)CH,CN (1 80) R1R2C(OH)CHMeCN (1 81) R'R2C(OH)CH(CN)CR'R20H

95 J. M. Normant, Compt. rend., 1973,277, C, 1045.


General synthetic routes for the preparation of a-hydroxyallenes are rare, considering their presence in a number of natural products and their value as a replacement for allylic and acetylenic alcohols in pharmaceuticals. There- fore, a recently reported reaction,96 in which a-acetylenic epoxides (1 82) when treated with lithium dialkylcuprate reagents afford a-hydroxyallenes (183) in good to moderate yield, should find a wide application. The addition

R4

of lithium acetylides to a-halogenocarbonyl compounds followed by epoxidation with m-chloroperbenzoic acid affords the acetylenic epoxides (1 82), which react with either lithium dimethylcuprate or di-n-butylcuprate in diethyl ether at -20 to -30 'C. The reaction is extremely sensitive to vari- ations in the reaction conditions, a change in temperature, for example, promoting the formation of side products. The reactions of lithium dimethylcuprate with a series of oxirans containing neighbouring oxygen-containing substituents (HO, MeO, AcO, or Et02C) have been studied.97 The results suggest that the degree of selectivity observed earlier with ethyl 2,3-epoxy- butyrate, which gives an a-methylated product in good yield, will not prove to be a generally useful feature of the reactions of glycidic esters and that the product distribution will largely be the result of conformational control. It is further suggested that substituent-metal complex formation is not a significant feature of these reactions.

Lithium trialkylvinylborates (1 84) react with oxiran~,~* affording complexes (185) which on oxidative work-up with alkaline hydrogen peroxide give, by a novel and convenient route, 1,4-diols (1 86) in excellent yields.

H202 RCH(CH&CHR1 4

I I OH OH

96 P. R. Ortiz de Montellano, J.C.S. Chem. Comnt., 1973, 709. 97 B. C. Hartman, T. Livinghouse, and B. Rickborn, J. Org. Chem., 1973, 38 ,4346. 98 K. Urimoto, K. Uchida, and H. Nozaki, Tetrahedron Letters, 1973, 4527.

Three-membered Rings 39 Koebrich et aLg9 have studied the behaviour of 2-chloro-1-t-butyl-1 -phenyl-

oxiran towards nucleophiles. The oxiran is inert to secondary amines and lithium methoxide but reacts with several organolithiums (R = Bun, But, Ph, or BuCH,CPh,) to afford the corresponding 2-alkyl-1 -t-butyl-1 -phenyloxiran. Lithium piperidide, however, opens the oxiran ring, affording 3,3- dimethyl-2-phenylbutan-2-01-1 -al. A new synthesis for the dihydro-y-pyrone system (187) which involves the addition of 2-lithio-2-(2,2-dimethoxyethyl)- 1,3-dithian to epoxides has been reported.loO The near quantitative addition to the epoxide occurs at the least hindered carbon. Conversion of (187a) into (187b) involves three further steps.

( I 37a) (187b)

When 2-lithiated isocyanides (1 S9), prepared from alkyl isocyanides (1 88) and butyl-lithium, are treated with epoxides (190), 5,6-dihydro-4H- 1,3-oxazines (193), without a substituent at position 2, or 8-amino-alcohols

R1CH2NC R'CHNC (-CdH1O) I

(188) Li

NC OH

RICH-CH R2- CHR3 * R* CH-CH R2- C HR3

(IS9) \ I I

I I NC OLi

(191)

HNX

(194) X = CHO (195) X = H

H R2 (193)

Reagents: i , BuLi; i i , R 2 (190); iii, Y'; iv,H30+-HeO; v, CuzO-NaOEt; vi, MeOH )"( H R3

Scheme 16

99 G. Koebrich, W. Werner, and J. Grosser, Chem. Ber., 1973, 106,2620. l o o F. Sher, J. L. Isidor, H. R. Taneja, and R. M. Carlson, Tetrahedron Letters, 1973, 577.

4

40 Saturated Heterocyclic Chemistry are formed in good yield (Scheme 1 6).lo1 Unsymmetrically substituted epoxides are attacked preferentially or exclusively at the least hindered carbon atom. The primary product (191) of the reaction can be isolated as an 8- cyano-alcohol (192) by addition of one equivalent of acetic acid. Depending upon the experimental conditions, acid hydrolysis of these products yields either y-formylamino-alcohols (1 94) or p-amino-alcohols (1 95). 5,6-Dihydro- 4H-1,3-oxazines are formed by allowing ethanolic solutions of the primary adducts (191) to stand or by warming the p-isocyano-alcohol (192) with cuprous oxide and sodium ethoxide. Dipolar cycloaddition. On heating equimolar amounts of 1,l -dicyano-2- aryloxirans (196; R = CN) or l-cyano-l-ethoxy-2-aryloxirans (196; R = C0,Et) with substituted benzylideneanilines (1 97), oxazolidines (1 98) are

formed102 in yields of ca. 60%. With the former only one stereoisomer is formed, whereas with the latter two isomers which do not epimerize under the reaction conditions are isolated. It is proposed that the products must arise by a regiospecific addition of an epoxide-derived ylide to the imine. The influence of ylide substituents and imine substituents on the reaction may be rationalized on the basis of frontier orbital analysis. The reaction of thiourea with 1 ,l-dicyano-2-aryloxirans (196; R = CN) at room temperature affordslo3 a useful route to 2-amino-4-thiazolines (1 99). Spectral data show that the latter exist predominantly in the amino-form. Reaction with 1,l- dicyano-2-alkyl-2-aryIoxirans, as one would expect, does not result in ring- opening but yields 1 -cyano-1 -thiocarbamyl-2-alkyl-2-aryloxirans.

The treatment of oxirans with phenyl isocyanate or methyl isocyanate in the presence of lithium chloride affords a high-yield synthesislog of N-alkyl- and N-aryl-2-oxazolidinones (200) in one step. Although the isocyanate oxiran reaction is known to produce both C-4 and C-5 substitution products 101 U. Schollkopf and R. Jentsch, Angew. Chem. Internat. Edn., 1973,12, 323. lorA. Robert, J. J. Pommeret, E. Marchand, and A. Foucard, Tetrahedron, 1973, 29,

l op R. B. Fugitt and C. L. Martinelli, J . Pharm. Sci., 1973, 62, 1013.

463. M. Ferrey, A. Robert, and A. Foucard, Compt. rend., 1973, 277, C, 1153.

Three-membered Rirgs 41 R2

I I /O\

R1C-C-C-O-CH,-CiI-cIr2 + PhNCO

k3

(200) through the breaking of either the C-1-0 or C-2-0 epoxide bonds, only the C-5 product was formed in these reactions.

1,3-Dioxolans (202; R = Ph, C&&k, C6H4Cl, or Me,C6H,) can be preparedlo5 in 46-81 % yield by condensation of the appropriate epoxide (201) with acetone in the presence of boron trifluoride etherate.

Me CHZR \ /

The use of triphenylphosphine and its derivatives as deoxygenating reagents is well established. The versatility of these reagents has recently been extended by the discovery that triphenylphosphine selenide and trifluoroacetic acid constitute an effective and mild combination of reagents for carrying out a stereospecific deoxygenation of epoxides to olefins.lo6 The olefin is thought to arise by the extrusion of selenium from the corresponding episelenide (Scheme 17), an unusual process for which, however, there is precedent in the stereospecific thermolyses of episulphides.

Scheme 17 Rearrangement. The Julia-Johnson rearrangement of cyclopropylcarbinols is a most useful reaction for the stereoselective synthesis of trisubstituted olefins. One disadvantage of the sequence, however, is the formation of a terminally functionalized homoallylic system, which is unsuited for the synthesis of 2- or 3-methylalk-2-en-1-01s (the terminal unit of isoprene).

lo5 M. M. Guseinov, M. S. Salakhov, 0. A. Zutitkova, and S. Yu. Mamedalieva, Arerb.

lo6 D. L. Clive and C. V. Denyer, J.C.S. Cliem. Comm., 1973, 253. Nefr. Khoz., 1973, 53, 32 (Chem. Abs., 1973, 79, 53 206j).


A novel adaptation of this synthesis which overcomes this disadvantage has now been reported.lo7 Treatment of the cyclopropyloxiran (203; R1 = H, R2 = Me) with 48 % hydrobromic acid at 0 "C affords (E)-5-bromo-2-methyl- pent-2-en-1-01 with 96 % stereoselectivity, whilst treatment with sodium iodide in acetic acid-propionic acid-sodium acetate at -18 OC affords the corresponding (E)-iodo-compound. The isomeric oxiran (203 ; R1 = Me, R2 = H) on reaction with zinc bromide in ether gives (E)-5-bromo-3-methyl- pent-2-en-1-01. The stereoselectivity of these reactions is rationalized on the basis of a concerted process via the transition state (204).

X -

H +

(203) (204)

Addition of dicyanoacetylene or dimethyl acetylenedicarboxylate to the oxiran (205) affords the adducts (206) and (207), respectively.1°8 When (206) is treated with sodium iodide in acetone at room temperature the adduct (208) (53%) and the isomer (209) (25%) are formed. In the dehalogenation of (207) the only product formed corresponds to the isomer (209). Contrary to expectation, thermolysis of (208) does not lead to liberation of benz- oxiren by Alder-Rickert cleavage. Instead, a quantitative arene oxide-arene oxide rearrangement takes place quantitatively at 80-100 "C, yielding (209). The isomerization of (208) to (209), constituting a suprafacial 1,5-sigma- tropic shift, is symmetry-allowed.

RC-CR 7

Br

(206) R = CN (207) R = COzMe

(208) (209) lo' H. Nakamura, H. Yamamoto, and H. Nozaki, Tetrahedron Letters, 1973, 1 1 1 . loB F. G. Flaerner and E. Vogel, Angew. Chem. Znternat. Edn., 1973, 12, 840.

Three-membered Rings 43 Reaction of trans-1-benzoyl-2-phenylcyclopropanes with dimethylsul-

phonium methylide results in an inseparable mixture of two cyclopropyl epoxide isomers (210). When these are heated,lo9 alone or in toluene, at 100 O C for 10-15 min, a novel rearrangement occurs affording 3,6-dihydro- 2H-pyrans (21 1) quantitatively. The mechanism of this rearrangement is thought to involve adventitious acid-catalysed opening of the epoxide ring, followed by intramolecular attack on the resulting homoallyl cation (Scheme 18). This procedure should prove a most useful synthetic route to 2-aryl-3,6- dihydro-2H-p yrans.

(21 1) Scheme 18

A re-examinationl10 of the isomerization of 1 , 1 '-epoxybicyclohexyl-2-one (212) to spiro-diketones has confirmed that reaction with antimony pentachlo- ride in liquid sulphur dioxide affords cycloheptanespirohexa-2 ,ir-dione as previously reported. However, in earlier work there was some doubt as to the identity of the thermal-rearrangement product. This has now been shown to be cycloheptanespirocyclohexane-2,2'-dione (21 3). The isomerization probably involves a radical reaction, similar to that suggested for the p ho t olytic conversion of a, /3-epoxy-ket ones into spiro- 1,3 -diket ones (Scheme 19).

(2 13) Scheme 19

looJ. O'Grady, J.C.S. Perkin I , 1973, 2030. G. E. Hawkins and R. Large, J.C.S. Perkin I , 1973, 2169.


The photolysis of phenanthrene oxide (214) is wavelength-dependent.lll Irradiation at 300-350 nm in dichloromethanc affords 9-phenanthrol (50%), phenanthrene (1 1 %), and the oxepin (215) (0.5%). At 207-235 nm 9-phenanthrol is still the major product (56%); the yield of phenanthrene drops to 0.2% whilst that of the oxepin increases to 3 %, and a small amount of fluorene (0.2 %) is isolated. Irradiation at 250-290 nm affords 9-phenanthrol (8 %), the oxepin (2&30%), fluorene (3 %), and a dimer (25 %).

In contrast to the extensive investigation of the photochemistry of u,P- epoxy-ketones, p, y-epoxy-ketones have received relatively little at tent ion. One point which is emerging, however, is that photodecarbonylation to a greater or lesser extent is a typical reaction of such compounds. Treatment of hexamethylbenzobicyclo [2,2,2]octadienone (216; R = Me) with m-chloroperbenzoic acid gives the epoxy-ketone (217; R = Me), which on irradiation in ether112 througha Corex filter affords the unsaturated oxiran (218 ; R = Me) in 95 % yield. Irradiation of (217; R = H) also results in photodecarbonylation and gives (218; R = H) in 75 % yield. The photoproducts are thought to result from the biradical (219) followed by formal 1,6-hydrogen shifts.

CH2=CH R (2 18)

U

(219)

K. Shudo and T. Okamoto, Chem. and Pharm. Bull. (Japan), 1973,21,2809. 112 R. K. Murray, jun., T. K. Morgan, H. Hart, and J. V.Hul1, J . Org. Chem., 1973,38,3805.

Three-membered Rings 45 Irradiation113 of an ether solution of 2,2,4,4-tetramethyl-7-oxabicyclo-

[4,1 ,O]heptan-3-one (220), however, in striking contrast to the previous report ,112 does not lead to photodecarbonylation, but photoisomerization occurs to give 2,2-dimethyl-4- (2-me thylprop- 1 -enyl) butanolide (22 1) and 2,2,6-trimethyl-4-oxohept-5-enal (222) The photoproducts are readily accounted for by initial Norrish Type I bond cleavage of (220) to give the biradical (223), which undergoes subsequent ring-opening to provide the biradical (224). Ring closure of (224) affords (221), and a 1,4-hydrogen shift in (224) gives (222).

1

The photoproducts resulting from the irradiation of (220) are analogous to those obtained in the photoisomerizations of 2-0xiranyl-cycloalkanones.~~~ The latter (225), like their cyclopropyl counterparts, undergo a three-atom photochemical ring expansion via the sequence (225) +(226), affording macrolides, in good yield, as the major products. Indeed, these results suggest that such photoisomerizations are the characteristic reactions of 7-oxabicyclo [4,1 ,O]heptane-3-ones and that photodecarbonylation only becomes a major process in such systems when specific skeletal constraints prevent similar photoisomerizations from occurring.

Ring Retention. It is well known that organomagnesium compounds always attack epoxy-nitriles at the nitrile group. It has recently been shown,l15 however, that selective attack at either the nitrile or the epoxide group can be achieved using organolithium compounds at -78°C. The position of attack depends on the ‘basicity’ of the lithium reagent. Weakly basic compounds attack the nitrile group whereas strongly basic compounds remove the

na R. K. Murray, jun. and D. L. Goff, J.C.S. Chem. Comm., 1973, 881. 11* R. G. Carlson, J. H.-A. Huber, and D. E. Henton, J.C.S. Chem. Comm., 1973, 223. 116 J. M. Normant, Tetrahedron Letters, 1973, 4253.


proton a to the nitrile group. Thus the dimethyl epoxy-nitrile (227) with RLi (R = Me, Ph, or CH,CN) at -78 "C gave in 7 0 4 3 0 % yield the oxirans (228; R = Me or Ph). The corresponding imines can be prepared if a non- acidic hydrolysis of the intermediate lithium complexes is employed. The strongly basic lithium reagents RLi (R = Bu, CH,CI, CHCI,, or CH=CH,) afford in 15-70% yield in the diepoxide (229). This results from reaction of the intermediate carbanion with a further molecule of the epoxide (227), reaction occurring at the nitrile group. Butyl-lithium and 3-cyano-2,2- diphenyloxiran give the diepoxy-ketimine (230) in 80 % yield.

Me RLi-HzO, Me wHc,R II Me 0

(228)

0

(227)-H20

Ph H

Miscellaneous. Soluble low-valence transition-metal complexes are now well recognized as important agents for effecting structural transformations in

Three-mem bered Rings 47

organic substrates. Numerous catalytic reactions have been reported in- volving transition-metal activation of organic substrates containing carbon- halogen bonds, carbon r-bonds, and strained a-bonds, but little has been reported about similar reactions with carbon-oxygen bonds. It has recently been shown,l16 however, that nickel(0) complexes are excellent catalysts for the formation of alkylene carbonates from epoxides and carbon dioxide. Thus epoxyethane and carbon dioxide at 100°C in benzene containing (Ph,P),Ni gave ethylene carbonate in >95 % selectivity. 2-Methyl-l,2- epoxypropane and 1 -chloro-2,3-epoxypropane reacted similarly. Bis(tri- cy d o hex ylp ho sp hine) nickel a1 so cat a1 y se d a1 k ylene carbonate formation.

The photochemical bromination of oxiranY1l7 methyloxiran, trimethyloxiran (23 l), tetramethyloxiran, and epoxycyclohexane (232) with N-bromosuccinimide in CCI, at 15 "C yields bromo-oxiran, l-bromo-2,3-epoxypropane, 1 -bromo3 -me t hyl-2,3 -epoxybutane, 1 -bromo-2,3 -dimet hyl-2,3 -epoxybu tane , and l-bromo-2,3-epoxycyclohexane respectively. Bromotrichloromethane in CCl, at 0 "C with (231) and (232) afforded the a-bromo-ketones 2-bromo- 2-methylbutan-2-one and 2-bromocyclohexan-l-one respectively. Mono- bromourea and (232) at 0 "C also gave 1 -bromo-2,3-epoxycyclohexane,

The bromochlorination of olefin-oxiran mixtures has been studied.ll8 Oxiran and bromine chloride in carbon tetrachloride at -30 "C, on treatment with ethene, cyclohexene, and cyclopentene, give the ethers [233; R1 = R2 = H; R1R2 = (CH2)4; and R1R2 = (CH,),] respectively. Similarly 1,2-epoxycyclohexane and bromine chloride with ethene, propene, cyclohexene, and cyclopentene yielded the chlorocyclohexanes [234; R1 = R2 = H; R1 = Me, R2 = H; R1R2 = (CH2)4; and R1R2 = (CH,),] respectively.

A, B,.Cy C1CH2CH20CHRTHR?Br

(233)

(234)

u6 R. J. De Pasquale, J.C.S. Chem. Comm., 1973, 157. u7 M. M. Movsumzade, A. L. Shabanov, and N. V. Petrova, Azerb. khim. Zhur., 1973,

11* M. M. Movsumzade, A. L. Shabanov, R. A. Garbanov, and R. G. MovsuIn-Zade, 35 (Chem. Abs., 1974,80, 108 268j).

Zhur. org. Khim., 1973, 9, 1998 (Chem. Abs., 1974,80,47 721c).


OH O H I I

OR OH I I

RlR2R3C-C=_C-CrC-C-C-R4 I t R5 H

(237)

The reaction of magnesium derivatives of diacetylenic alcohols with chloro-ketones, followed by alkaline dehydrochlorination, affords a general route119 to diacetylenic epoxides (235). Thermal decomposition of (235) is reported to afford monosubstituted diacetylenic epoxides. Hydration of the epoxides (235) yields a-diols (236), whilst treatment with alcohols and boron trifluoride e therat e gives a1 koxydiace tylenes (23 7).

A new route to functionalized allenes has been reported by Brown et ~1.120 They found that 3,4-epoxybut-l-yne derivatives (238; R = H or Me) give, when treated with organoboranes (239; R1 = Et or cyclopropyl) in the presence of oxygen, allenic alcohols (240) by a free-radical mechanism. Thus, tricyclopentylborane and (238; R = H) were mixed in benzene under nitrogen, air was introduced at 0.5 ml mi&, and the solution was stirred for 6 h at room temperature, affording, after alkaline hydrolysis, (240; R1 = cyclopentyl) in 62% yield.

3,4-Epoxy-2,3,4,5-tetrahydrothiophen 1,l -dioxide reacts121 with sulphur tetrafluoride in dichloromethane at 100 “C to give 3,4-difluoro-2,3,4,5- tetrahydrothiophen 1 ,l-dioxide, which on treatment with aqueous sodium carbonate affords 3-fluoro-2,3-dihydrothiophen 1 ,l-dioxide. The mass

119T. I. Kupriyanov and V. Tatarchuk, Ref. Zhur. Khim., 1973, Abstr. No. 4Zh279 (Chem. Abs., 1973, 78, 91 849d); ibid., 1973, Abstr. No. 9Zh308 (Chem. Abs., 1974, 80,70 61 2b).

12oA. Suzuki, N. hliyaura, M. Itoh, H. C. Brown, and P. Jacob, tert., Synthesis, 1973, 305.

1ZlV. I. Golikov, A. M. Aleksandrov, L. A. Alekseeva, T. E. Bezmenova, and L. M. Yagupol’skil, Zhur. org. Khim., 1973,9,2428 (Chem. Abs., 1974,80,47 745p).

Tlree-membered Rings 49

spectrometry of 3-fluoro-5,6-epoxy-steroids has been studied.122 The influence of the fluorine atom on the fragmentation pattern could not be precisely defined, but it is certain that the stereochemistry of the epoxide plays a promi- nent role in the fragmentation. Hexafluoropropylene oxide is known to form difluorocarbene and tetrafluoroacetaldehyde on pyrolysis. It has now been found that this reaction is re~ersib1e.l~~ Related polfluorinated epoxides (241; X = H or Cl; n = 2 - 4 , when heated for 4-8 h at 100-150 "C in the presence of antimony pentafluoride, i s o m e r i ~ e , ~ ~ ~ via an ionic mechanism, to the corresponding fluoro-ketones (242) in 85-96 % yield.

3 Aziridines

Formation.-Direct Insertion of Nitrogen or Carbon Atoms. The reactions of amino-nitrenes with olefins to form N-aminoaziridines still attracts some attention. The reaction of N-aminonaphthalimide with cyclob~tene'~~ and with cis-3,4-dichlorocyclobutene in the presence of lead tetra-acetate gives 2-phthalimidyl-(243) and 2-phthaIimidyl-4,5-dichloro-(244) 5-azabicyclo-

(243) R = H (244) R = C1

[2,1 ,O]pentane in yields of 18-22 % and 9-12 % respectively. The lH n.m.r. spectrum of (244) indicated the presence of the exo- (245) and the endo- (246) isomers in the ratio 4 : 1. The isomer ratio is consistent with the expectation

N-N :@tJJJ 34-N /

CI 0 0

/ c1

H

(245) (246)

lz2 J. L. Borgna, A. Guida, and L. Fonzes, Org. Mass Spectrometry, 1973, 7 , 133 . laS W. Mahler and P. R. Resnick, J . Fluorine Chem., 1973, 3 , 451 (Chem. Abs., 1974,

80, 47 370n). lZ4 A. Ya. Zapevalov, I. P. Kolenko, V. S. Plashkin, and P. G. Niefel'd, Zhur. Vsesoyuz.

Khim, obshch. im D. I . Mendeleeua, 1973, 18, 592 (Chem. Abs., 1974, 80, 26 713m). A. G. Anderson, jun. and D. R. Fagerburg, Tetrahedron, 1973,29,2973.


that steric repulsion between the chlorine substituents and the amino- phthalimide in the transition state for the formation of (246) would favour (245) as the major product.

Stable l-alkoxyaziridine invertonxrs have been reported by Ioffee and Koroleva.126 A series of alkoxy-amines (247; R = Me, Et, or Pri) was oxidized with lead tetra-acetate in the presence of olefins, affording, by way of the respective O-nitrene, l-alkoxyaziridines (248)-(251) in yields of

R' R3

O R (348) R1 = R2 = H, R3 = Me (239) R1 = Me, R2 = Rz = H (250) R1 = R? = Me, K3 = H (251) R1 = Rz = R3 = fine

9-35 %. The l-alkoxy-2,2,3-trimethylaziridines (250) were mixtures of two stereoisomers which did not interconvert at room temperature. The mixtures (250) were separated by g.1.c. and the configurations of these invertomers assigned from IH n.m.r. data.

N-Unsubstituted aziridines (254) can be prepared12' by the reaction of 3,3-pentamethyleneoxaziridine (252) with olefins (253). Treatment of cyclohexanone with ammonia and sodium hypochlorite affords the oxaziridine (252). Thus indene and (252) when refluxed in chlorobenzene gave the N- phenylcarbamoyl derivative (254; R1 = R2 = o-C,H,CH,, R8 = H).

(252) (253) (254)

Dichlorocarbene, generated by treatment of chloroform in hexane with potassium t-butoxide, reacts12* with azomethines (255) to afford diphenyl- ethyleneimines (256).

(256) (255)

12s B. V. Ioffee and E. V. Koroleva, TefruhedronLetters, 1973,619. le7 E. Schmitz and K. Jachnisch, Ger. Offen 230952911973 (Chem. Abs., 1973, 79,

12* N. S. Kozlov, V. D. Pak, V. V. Mashevskii, and P. N. Plaksina, Khim. Farm. Zhur., 136 973h).

1973,7, 15 (Chem. As., 1973,79,78 47811).


Cyclizatian. Brown and Levy129 have reported that 2-iodoalkyl azides (257), which are now readily available with known stereochemistry, undergo a facile reaction with aryl- and alkyl-dichlsroboranes, affording 8-iodo secondary amines. These amines without isolation undergo a ring-closure reaction with base, providing the corresponding N-aryl- and N-alkyl-aziridines (258) in good yields (73-94 %). Significantly, the stereochemistry of the original 2-iodoalkyl azide is maintained, providing for the first time a synthesis of N-aryl- and N-alkyl-aziridines in which the stereochemistry of the ring substituents may be easily defined. Furthermore, as previous work has the N-alkyl groups must retain the original stereochemistry of the group attached to boron. This procedure, therefore, shows exceptional promise as a relatively simple direct route to aziridines with well defined stereochemistry.

(257) (258) Ring closure of organo-azides can also be achieved with cobalt dibromide.131

Thus the 10-mesylate derivative of methyl 1 l-azido-l0-hydroxy-7-ethyl-3,11- dimet hyltrideca-2,6-dienoate gave methyl lO,ll-imino-7-ethyl-3,11 -dimethyl trideca-2,6-dienoate.

Cromwell et al. have extended their investigation of the reaction of 2,3- dibromo-3-phenylindanone (259) with cyclohexyl- and methyl-amine, which affords 1 -alkyl-6-(alkylimino)-l, 1 a,6,6a-tetrahydro-l a-phenylindeno [ 1,241- azirines (261), to reactions with ethyl-, isopropyl-, t-butyl-, and benzyl- arnine.l3, All of these, with the exception of t-butylamine, which results only in the dehalogenation of (259) to 2-bromo-3-phenylindenone (260), gave the respective polycyclic aziridine (261 ; R = Et, Pri, or PhCH,). The behaviour of t-butylamine is attributed to the steric bulk of the t-butyl group, particularly in light of the fact that benzylamine, a weaker base, did react readily to produce an aziridinyl Schiff base. It has also been established that the Schiff- base formation is catalysed by the presence of the amine hydrobromide in the reaction mixture. Methods which may be used for hydrolysis of the imino- group are severely limited by the reactivity and facile opening of the aziridine ring. However, in this instance, column chromatography on silica gel of the Schiff base (261) afforded an almost quantitative conversion into the previously unknown tricyclic aziridinyl ketones (262), a class of ketone characterized by great instability to air and light. The ethyl aziridinyl ketone (262; R = Et) undergoes a thermally disallowed valence tautomerism. This was shown by trapping the carbonyl ylide in a 1,3-dipolar cycloaddition reaction la@ A. B. Levy and H. C. Brown, J. Amer. Chem. SOC., 1973,95,4067. lgO H. C. Brown, M. M. Midland, and A. B. Levy, J . Amer. Chem. SOC., 1973,95,2394. lal R. J. Anderson, C. A. Henrick, and J. B. Siddall, U.S.P. 3 179 666/1973 (Chem. A h . ,

lga D. L. Garling and N. H. Cromwell, J. Org. Chem., 1973,38,654. 1973,78,136 03911).


(259)

(263) R1 = C02Me

with dimethyl fumarate. A mixture of isomers is obtained in which the endo- product (263) appears to predominate. Ethyleneimine has been prepared, by a somewhat analogous procedure,l= by heating 1 ,ZdichIoroethane and ammonia for 30 min at 80 *C in the presence of 1,8-diazabicyclo[5,4,O]undec- 7-ene. Conversely, instead of treating an c+dihalogeno-alkane with an amine, it is possible to use NN-dihalogeno-amides and electron-deficient olefins. Thus, a series of sulphonamides (264) was brominated and the resulting NN-dibromo-compounds were heated with acrylic or methacrylic compounds in chloroform.l= Treatment of the resultant bromo-derivatives (265) with sodium hydroxide gave the respective aziridines (266). 133 F. Matsuda, T. Takahashi, and N. Ogiya, Japan. Kokai 74/14 456 (Chern. A h . , 1974,

134 M. Kojima and T. Kawakita, Japan. Kokai 73/36 148 (Chern. Abs., 1973,79,42 320r). 80, 95 702u).


R'

R2CI-I=CR3 Y 1 R1 ~ ( C H 2 h S 0 , N H C H R 2 C R 3 B r Y

(265)

The cis- and trans-aziridinylphosphonates (268; R = H), related to phosphonomycin, have been prepared135 by heating diethyl 1 -bromopropene- 1-phosphonate (267) with liquid ammonia in a sealed tube. Treatment of (268; R = H) with phenyl isocyanate gave the corresponding aziridine (268; R = PhNHCO). Attempts to hydrolyse either cis- or trans-(268; R = H or PhNHCO) to the exact nitrogen analogue of phosphonomycin resulted in extensive polymerization. R

I N

MeCH=CBrP(0)(OEt)z a Me

(267) (268) Oxirans can sometimes be used with advantage in the synthesis of aziri-

dines, For example, cis-Zbutylene oxide on treatment with ammonia in methanol gives threo-3-aminobutan-2-01, which reacts with sodium hydro- oxide to give ~is-2,3-dimethylaziridine.~~~ trans-Dimethylaziridine can be similarly prepared. Ethylene oxide137 reacts with l-(N-methylamino)-3-aryl- propanes (269) to afford ,9-hydroxy-amines (270), which on chlorination with thionyl chloride give N-(p-halogenoalky1)-N,a-dimethylarylethylamines (271). These on treatment with sodium hydroxide and sodium 2,4,6-tri- nitrobenzenesulphonate or silver perchlorate give the aziridinium salts [272 ; R = H, C1, or F; X = 2,4,6-(O,N),C6H,S0; or ClOa].

/"\ p-RCGH4CH2CHMeNHMe CH2CH2 + p-RCdhCH&HMeN( Me)CH2CH20H

(269) (270)

n A

R-( \ t C H 2 C H M e 6 ( l X- B- ~ - R C B H ~ C H ~ C H M ~ N ( M ~ ) C H ~ C H ~ C ~ I

Me (272) (271)

185

ias 187

D. K. Berlin and S. Rengaraju, Proc. Oklahoma Acad. Sci., 1973,53,73 (Chem. Abs., 1973,79, 136 9181.1). C. A. Rowe, jun. and E. L. Stagryn, U.S.P. 3 717 628/1973, E. Zara-Kaczian, G. Deak, J. Hasko-Breur, and A. Neszmelyi, Acta Chim. h a d . Sci. Hung., 1973,79,433 (Chem. Abs., 1974,80, 82 524n).


(273) 0

(274) R = H,Br, or Cl

A new synthesis for N-acylated aziridones (274) which have a chiral centre at C-3, from the corresponding L-acylamino-acids, has been described.13* The 3-substituted-1-benzyloxycarbonylaziridin-2-ones (274) and related compounds are prepared from the corresponding benzyloxycarbonyl L-

amino-acids (273) by using a dehydrating agent, such as phosgene, thionyl chloride, or phosphorus oxychloride. The reaction must be carried out in THF at -20 to -30 OC, using triethylamine to neutralize the reaction solution exactly. A reaction mechanism is discussed. An advantage of this route is the fact that it does not involve abstraction from the asymmetric carbon during the cyclization reaction; therefore optical activity is retained in the product. With optically active aziridinones obtained by dehydrohalogenation of a-halogeno-amides, abstraction of halide occurs from the asymmetric carbon atom, and therefore partial racemization is possible. A somewhzt similar procedure, which does not utilize a dehydrating agent, has been used to prepare peptides containing an aziridine ring.139 Thus the peptide (275; Tos = 4-MeOC,H,S02) was cyclized, by heating it for 21 h at 60 OC with triethylamine in THF, to give the aziridine (276) in 94% yield.

PhCH202CNHCH2CO-NH XH-CONHCHXC02CHd'h I I

(275)

H - C - O T o s

Me

Et3N-THF 60 "C, 21 h I

PhCH202CNHCHeCO-N-CH-CONHCHKO2CH2Ph \ /

(276)

Lithium aluminium hydride is known to reduce certain substituted cyclohexanone oximes to amines. However, it has been reported140 that 2-benzyl- idenecyclohexanone oximes (277), on reduction with lithium aluminium hydride, afford the corresponding 1 -benzyl-l,2-epiminocyclohexanes (278),

138 M. Miyoshi, Bull. Chem. SOC. Japan, 1973, 46, 212. 13# K. Okawa, Japan. Kokai 73/36 158 (Cliem. Abs., 1973,79,42 848u). 140 J. R. Dimock, W. A. Turner, P. J. Smith, and R. G. Sutherland, Cunud. J . Chern.,

1973, 51,427.


'OH (279) a; R = H

LiAID4 \ (R = H)

(277) a; R = H b; R = 2-CI c; R = 4-C1 d; R = 4-NMe2

I H

(283)

not the corresponding amines (279). Similarly reduction of 2-benzylidene- cyclohexanone oxime (277a) with lithium aluminium deuteride gives the epiminocyclohexane (280), which contains two deuterium atoms. A possible reaction mechanism for the synthesis of the deuteriated product (280) is depicted in Scheme 20. Attempts to prepare the N-acetylaziridine (281) by acetylation of (278) with acetic anhydride gave 3-acetamido-2-benzylcyclohex- l-ene (283). Formation of (283) from (278) presumably arises by pyrolytic cis elimination of the N-acetylaziridine via the transition state (282).

The stereochemistry of the reduction of ap-unsaturated cyclohexene oximes by lithium aluminium hydride has been studied:" to establish (a) whether the formation of aziridines occurs when the olefinic bond is not substituted by

L. Ferrero, M. Decouzon, and M. Azzaro, Tetrahedron Letters, 1973,4151.

6


I (277; R = H)

(280) Scheme 20

a phenyl group (as was the case in all previous investigations) and (b) whether the configuration of the hydroxy-group of the oxime with respect to the conjugated system is a contributory factor. Reduction of E-2-methylcyclohex- 2-en-1-one oxime (284) gave the aziridine (285) (58%) as the major product, the azacycloheptane (286) (10 %), 1-methyl-6-aminocyclohex-1-ene (287) (19 %), and 7-aminoheptan-2-one (289) (13 %), which presumably arises by

Me c=o I

- + I (CH2)5

I NH2

(285) (286) (287) (288) (289)

hydrolysis of the enamine (288). Reduction of Z-3-methylcyclohex-2-en-l-one oxime (290) gave the aziridines (291) (35%), (292) (35%), l-methyl-3- aminocyclohex-1-ene (293) (13 %), and saturated amines (17 %). A 1 : 1 mixture of the 2- and E-oximes (290), since the E-oxime could not be isolated on its own, also gave a mixture of the aziridines (291) (27 %) and (292) (27 %), the amine (293) (17%), and saturated amines (29%). Thus it was concluded that in the reaction of lithium aluminium hydride with up-unsaturated cyclo- hexenone oximes (a) aziridine formation predominates over amine formation

Three-membered Rings OH I

57

'ON (290)

LiAIH1-THF - (290) + ".i'

+ saturated amines

(293)

+

H

'H (292)

and (b) ring closure to form the aziridine occurs in the direction of the carbon- carbon double bond. It would also appear that the stereochemistry of the hydroxy group with respect to the C=C-C=N system is only of minor significance, a slightly increased yield of aziridines being obtained when the hydroxy-group was cis to the carbon-carbon double bond.

A similar study has been made of the lithium aluminium hydride reduction of oximes of a-ethylenic carbonyl compounds.142 Reduction of the Z-transoid- oximes of pent-3-en-2-one (294; R = Me) and 4-phenylbut-3-en-2-one (294; R = Ph) gives the corresponding aziridines (295) and the amines (296). Reduction of the E-transoid-oximes (297; R = Me or Ph) gives in addition the corresponding aziridines (298) and the saturated amines (299). E-cisoid-2-

(294) (295) (296) R R

C-N - (295) + (296) +

(297) (298) (299)

+R\NH2 / \ NH

OH

Cyclopentylidenecyclopentanone oxime (300) also gives an aziridine reduction product (301), as well as a ring-expanded 2-cyclopentyl-3,4,5,6-tetrahydropy- ridine and 2-cyclopentylpiperidine. The formation of aziridines fromZ-oximes

+w (30 1 )

/N Ho (300)

142 G. Ricart, D. Couturier, and C. Glacet, Compt. rend., 1973,277, C, 519.

58 Saturated Heterocyclic Chemistry was found to be independent of solvent polarity and temperature, but aziridine formation from E-oximes increased with temperature and solvent polarity.

The preparation of fatty-acid derivatives containing an internal aziridine function continues to be a subject of interest. A procedure utilizing the stereospecific addition of iodine azide to the unsaturated compound, followed by reductive cyclization to the aziridine, has been r e ~ 0 r t e d . l ~ ~ For the latter step, unlike the work of Brown and Levy129 discussed earlier in this section, several hydride reducing agents and also direct hydrogenation over metal catalysts were investigated as ways of forming the aziridine. A comparison of the various reagents studied, namely lithium aluminium hydride, sodium bis-(2-methoxyethoxy)aluminium hydride, diborane, and catalytic hydrogenation, showed that the best yields (59 %) of epimino-derivatives were obtained with lithium aluminium hydride. Direct hydrogenation gave the poorest yield (2 %). Thus reduction of methyl threo-9-azido-10-iodo-octadecanoate with lithium aluminium hydride produced the cis-9,lO-epimino-derivative of octadecanol by concomitant reduction of the ester function. The versatility of the b-iodo-azides as precursors in organic chemistry is illustrated by their reactions with trialkyl phosphites. The iodo-azides (302) react immediately with trimethyl phosphite in hexane, affording the dimethylphosphonoazirid- ines (303). Since this rearrangement involves one inversion at carbon, the aziridines (303) have a cis geometry.

I

M e 0 OMe (303) a; R1 = R2 = C8H17

b; R1 = C8HI7, R2 = C7HI4CO2Me

Treatment of exo-lY4-dihydro-l ,4-methanonaphthalene with nitrosyl chloride yields the dimer (304), which is reducedlM with lithium aluminium hydride to the em-cis- 1 a , 2,7 ,7a-tet rahydro- 1 H-2,7-methano [2,3 -b]aziridino- naphthalene (305; R = H). Treatment of (305; R = H) with toluene-p- sulphonyl chloride gives both the exo- and endo-l,2,3,4-tetrahydro-2-@- tosylamido)-l,4-methanonaphthalenes and the aziridine (305; R = p- MeC,H,SO,).

148 T. A. Foglia, P. A. Barr, and 1. Schmeltz, J. Amer. Oil. Chemists’ SOC., 1973,50, 290. S. J. Dominianni, U.S.P. 3 715 262/1973 (Chem. A h . , 1973,78,136 040f).


(306) (307)

Reaction of cyclohexene with ethyl NN-dibromoaminoformate affords a mixture of the trans-bromocyclohexylaminoformate (306) and its cis-isomer. Reduction of this mixture145 with lithium aluminium hydride gives the N- methylaziridine (307) (90 %) and cyclohexylmethylamine (10 %). Cycloheptene gives a similar series of reactions.

Ring Contraction. Organic azides often undergo 173-dipolar cycloaddition to strained cyclic olefins to give A2-triazolines, which on decomposition yield aziridines. For example, the photodecompositions of the exo-A2-triazoline adducts derived from a series of bicyclo[2,2,1]heptenes are known to result in the loss of nitrogen with stereospecific formation of the corresponding exo-3-azatricyclo-octanes. The reactions of a series of bicyclo[2,2,l]hepta- dienes (308) with phenyl azide have now been examined146 and the resultant A2-triazolines (309) and (3 10) characterized. Photolysis of these compounds, (309) and (310), provides a convenient route, with good yields, to several exo- and endo-azatricyclo-octenes (3 11) and (3 12).

(309)

ihV R'

1".

lP6 0. Cervinka, V. Dudek, and V. Senft, 2. Chem., 1973,13, 176. lP6 B. Halton and A. D. Woolhouse, Austral. J . Chern., 1973,26, 619.

60 Saturated Heterocyc Zic Chemistry A more convenient synthesis of the indano [1,2-b]aziridin-6-one system (3 15)

has been re~0rted.l~' The key intermediate is an indano [2,1-d]triazoline, which can be easily converted into aziridines. Indenone (313), prepared by an improved method, was treated with phenyl azide at 0 *C in the dark for 3 days and gave the A2-1,2,3-triazoline (314). Triazolines of this type containing an electron-withdrawing group in the 4-position are frequently unstable or exist in an equilibrium with the isomeric amino-azo-compound, but no such difficulties were experienced with the adduct (314). Photolysis in benzene gave the aziridine (315) (65 %).

Ph

(3 13) (3 14) (315) lY2-Diphenylazaspiro [2,2]pentane (3 17), a nitrogen analogue of the oxa-

spiropentanes that have been the subject of much interest, has been prepared148 by irradiation at 3100 in dichIoromethane of the A2-1,2,3-triazoline (316), the thermal adduct of phenyl azide and benzylidenecyclopane. Although (317) is stable at 0 'C, thermal rearrangement occurs at 100 O , affording the imine (3 18), a process which is analogous to the oxaspiropentane-cyclobutanone isomerization. The spiroaziridine (317) reacts readily with methanol to give the solvent adduct (319). ?[ hv : TAPh h a t , <::

Ph Ph Ph

(316) (3 17) (3 1 8)

Ph (3 19)

Formation via Azirines. The 3-phenyl-2H-azirines (321; R = Ph or H) undergo 1,3-dipolar cycloaddition reactions with N-(pnitrobenzy1)benzimi- doyl chloride (320) in benzene, at 0 "C in the dark under nitrogen, yielding149 14' P. E. Hansen and K. Undheim, Acta Chem. Scand., 1973,27,1112.

J. K. Crandall and W. W. Conover, J.C.S. Chem. Comm., 1973,33. 149 N. S. Narasimhan, H. Heimgartner, J. H. Hansen, and H. Schmid, Helu. Chim. Actu,

1973,56, 1351.

Three-membered Rings 61 c1

+

P h F ’-NH

C‘H

O I N C L ‘NHCOPh

2- ( p i t rophenyl)-4 , 5-diphenyl- 1 , 3 -diazabicyclo [3 , 1 ,O] hex-3-enes (322). Under the basic conditions of the reaction, (322; R = Ph) and (322; R = H) are partially converted into 2- (p-ni t rophenyl)-4 , 5-diphenyl- 1,6-dihydro - pyrimidines (323), which are oxidized to the corresponding pyrimidines (324). Only when R = Ph is the aziridine (325) also formed. The 3-phenyl-2H- azirines (321), on heating with 2,4-diphenyl-A2-oxazolin-5-one (326) in xylene at 145 *C, give 4-(aziridin-2’-yl)-2,4-diphenyl-A2-oxazolin-5-ones (327). The aziridines (327) arise by an ene reaction of the enol form of (326) with the azirine (321).

(327)

It is well known that the reaction of Grignard reagents with oximes usually affords aziridines, and it has been postulated that such reactions proceed by way of azirine intermediates. In the case of acetophenone oxime Laurent et claim to have isolated the intermediate 2-phenylazirines. They have

160 R. Chaabouni, A. Laurent, and P. Mison, Tetrahedron Letters, 1973, 1343.


/ cis

cis-(329) a; 75% b; 60%

P /

trans trans-(330) a; 25% b; 40%

(328) a; R = Ph b; R = Me

(331)

also the reactions of E-2-phenyl- and E-2-methyl-cyclohexanone oximes (328; R = Ph or Me) with methylmagnesium bromide. Each reaction gave only two major products, the cis- and the trans- bycyclic aziridines (329) and (330). No aziridines of the type (331) were detected, thus confirming the regiospecificity and stereospecificity of this reaction. The configurations and conformations of (329) and (330) were determined from their lH and lSC n.m.r. spectra. Treatment of cyclohexanone oxime with methyl- or ethyl- magnesium bromide affords the corresponding 1 -methyl- or 1 -et hyl-7-azabicyclo [4,1 ,O]heptane, but treatment with phenylmagnesium bromide gives only cyclohexanone and aniline.151 However, when cyclohexanone oxime is treated with phenyl-lithium, 1-phenyl-7-azabicyclo [4,1 ,O]heptane (332) (59 %) and N-phenyl-(l-pheny1)cyclohexylamine (334) (33 %) are formed. The products are thought to arise by two competitive reactions (Scheme 21). The intermediate ketimine (333) would explain both the formation of the amine (334) and that of aniline in the reaction with phenylmagnesium bromide, hydrolysis of the imine affording cyclohexanone and aniline.

Reactions.-Ring-opening. Electrophilic and nucleophilic. Dichlorocarbene, prepared in situ from chloroform and potassium t-butoxide, is reportedls2 to react with N-benzylaziridine to give l-(t-butoxy)-2-(N-benzylamino)ethane and its N-formyl derivative. No N to C rearrangement products were detected. The products are rationalized in terms of reactions subsequent to ylide lS1 R. Chaabouni and A. Laurent, BUN. SOC. chim. France, 1973,2680. lS2 A. G . Giumanini, Boll. Chim. Farm., 1973, 112, 6.


1 (332)

uN’ph (333) (334)

Reagents: i, 2PhLi; ii, PhLi; iii, Ha0 Scheme 21

formation. N-Cyclohexyl-1-alkylaziridines (335; R = Me or H) on the other hand153 react with dichlorocarbene, generated by refluxing sodium trichloro- . acetate in glyme, to give dichloromethanimine (336) (30-40 %).

R

(335) 0 3 6 ) Vaultier et aZ.lM have reported that the reactions of nucleophiles with

aziridines, potential azomethine ylides, may in some instances be catalysed by acid. For example, the aziridine (337; R1 = R2 = C02Me) when treated with trifluoroacetic acid ring-opened to give the immonium salt (338), but the aziridine (R1 = H, R2 = C02Me) gave the amine (341). The immonium salts, which were not isolated but detected by lH n.m.r., reacted readily with potassium cyanide, methylmagnesium iodide, or potassium borohydride to give the amino-esters (340; R = CN, Me, or H). Formation of the immonium salt (338) or the amino-ester (339) depended on the strength of the nucleophile A-. Two ring-opening reactions are therefore possible when aziridines are treated with acid and these are summarized in the sequence (337)-(341).

The selective methylation of 2,2-dimethyl-4-phenyl-6-p-nitrophenyl-1,3- diazabicyclo [3,1 ,O]hex3-ene (342) by trimethyloxonium tetrafluoroborate to form 2 , 2,3 - t rime t hy l4p hen yl-6 -p -ni t rop hen yl- 1 -aza-3 -azoniabicy clo [3,1,0]- hex-3-ene tetrafluoroborate (343) has been achieved.155 When the tetrafluoroborate (343) is treated with diazomethane a novel transformation occurs, 153 V. I. Markov and A. E. Polyakov, Zhur. org. Khim. 1973,9,1759 (Chem. Abs., 1973,

15* M. Vaultier, R. Danion-Bougot, D. Danion, J. Hamelin, and R. Carrib, Tetrahedron

ls6 H. W. Heine, T. A. Newton, G. J. Blosick, K. C. Irving, C. Meyer, and G. B. Cor-

79, 126 175k).

Letters, 1973, 2883.

coran, tert., J., Org. Chem., 1973,38,651.

64 Saturated Heterocyclic Chemistry PhCH-CR'R2 . PhCH CR'RB \b/ -

I 'N'

I Pi1 Ph

(337)

Hf PhCH-CR1R2, A- \&/

/ \ Ph H

1

PhCH CHR1R2, A' \&I

I Ph

(338)

J/' \- PhCH-CRlR2 PhCH-NAHR'R' PhCH-NAHR'R*

I I R Ph

I t A Ph

I I A NHPh

(341) (339) (340)

affording the ring-opened compound (345), presumably via the intermediate aziridinium ion (344). The intermediacy of (344) seems quite reasonable, since it is well known that addition of diazomethane to ternary iminium salts is a general method for the preparation of aziridinium salts.

H

(342)

c- /Ph

\ Ye ArCH=NCH=C

CH2y=CMe2 BF;

(345)

H

(343)

(344) The novel tricyclic system 2-azatricyclo[2,2,1 ,01a6]heptane (346) is formed156

when 4- (aminomethyl)cyclopent ene is oxidized with lead tetra-acet ate in refluxing benzene. The aziridine (346) is rather unstable and is best converted

156 P. S . Portoghese and D. T. Sepp, Tetrahedron, 1973,29,2253.

Three-membered Rings 65 hl\e

Pb(OAc)4- bznzene , 8 + Me1

H (349)

I I H OAc

(348)

without isolation into its methiodide salt (347) which is quite stable. Reaction of (347) with potassium acetate in refluxing ethanol gives N-methyl-exo-6- acetoxy-2-azabicyclo[2,2,l]heptane (348), which on reduction with lithium aluminium hydride gives the exo-alcohol (349). Equilibration of (349) with aluminium isopropoxide gives an exo:endo ratio (83 : 17) similar to that obtained with norborneol (80: 20), indicating that the steric requirements of the N lone pair are similar to those of CH. DipoZar cydoaddition. 2 , 2-Dimet hyl-4-phenyl-6-p-ni trophenyl- 1 ,3-diazabicyclo [3,1 ,O]hex3-ene 3-oxide (350), formed when 2,2-dimethyl-4-pheny1-6- p-nitrophenyl-l,3-diazabicyclo [3,1,0]hex-3-ene, (342) is treated with rn- chloroperbenzoic acid in benzene at room temperature, forms an azomethine ylide when heated.155 In refluxing toluene with N-phenylmaleimide and diethyl azodicarboxylate, (350) gives the cycloadducts (351) and (352), respectively. Interestingly, irradiation of a benzene solution of (350) and

66 Saturated Heterocyclic Chemistry diethyl azodicarboxylate also gives (352) identical in all respects to the product from the thermal reaction.

It has been reported15' that N-alkoxyaziridines react with nitriles in the presence of boron trifluoride etherate, thus affording a new route to 2- imidazolines. The N-alkoxycarbonylaziridines (353a) and (353b) with acetonitrile or benzonitrile give the corresponding l-alkoxycarbonyl-2-imidazolines, (354ax), (354ay), and 354bx). The imidazolines obtained by the reaction of N-ethoxycarbonyl-2,3-tetramethyleneaziridine (353c) with acetonitrile or benzonitrile are labile and are readily hydrolysed to trans-cyclohexan-l,2- diamine derivatives (355cx) or (355cy). The mechanism of the reaction, since

C02R3 R1 R1 I \ ''> N --COzR3 R4CN-BF3,Et20

R2

(355) 82% (354) (353) a; R* = H, R2 = Ph, R3 = Me, b; R1,R2 = +CH2CH2CH=CHCH&H2)-,

C;

v; R4 = Ph

R3 = Et R',R2 = dCH&-, R3 = Et

x; RJ = Me

the presence of a Lewis acid is necessary, is not thought to involve direct nucleophilic attack by the nitriles. Boron trifluoride is thought to co-ordinate to the oxygen atom of the carbonyl group, whilst the nitrile attacks the aziridine ring to afford a zwitterion, which subsequently cyclizes to the 2-imidazo- line (Scheme 22). The stereochemistry suggests an S,Ztype mechanism.

COzEt I

0 BF3 IJ- i.

Scheme 22 By contrast, N-tosylaziridine reacts with methyl or ethyl 2-cyanoacetates

(356; R = Me or Et), in the presence of the corresponding alkoxide, affording the 3-alkoxycarbonyl-2-amino-1-tosyl-2-pyrrolines (357; R = Me or Et) in yields of 42 and 23 %, respective1y.lm 15' T. Hiyama, H. Koide, S. Fujita, and H. Nozaki, Tetrahedron, 1973,29,3137. lS8 J. Lehmann and H. Wamhoff, Synthesis, 1973, 546.

Three-membered Rings

Gco2" C82R I v+ ((Ha RO',

NH2 I 40s N fl Tos

(356) (357)

67

Texier et al. have studied the cycloaddition reactions of 2-cyano-3-phenyl- aziridines to some alkynes and activated a l k e n e ~ . ~ ~ ~ The erythro-aziridines (358 ; R = cyclohexyl or PhCH,) reacted with dimethyl acetylenedicarboxylate in boiling toluene to give pyrrolines which spontaneously eliminated hydrogen cyanide to afford the pyrroles (359) in quantitative yield. Under similar conditions the aziridines (358) reacted stereospecifically with activated

w 0 2 M e

Ph---\-/--CN MeO2C-CEC--CO2Me ~

N

R Ph I I R

(358) (359) olefins (360; X = H, CN or C0,Me; Y = C0,Me or CN; Z = CO,Me, CN, Ph, p-ClC6H4, or p-MeOC6H,) to give pyrrolidines, primarily (361)

Ph, ,cN ,

XYC=CHZ f 'v' toluene

(358)

(360)

C02Me CO2Me

Meo2ck-F Ph Meo23 Ph

r3 b (366) (365) 16@ F. Texier, J. Guenzet, and B. Merah, Compt. rend., 1973,277, C, 1371.


and (362), with smaller amounts, if any, of (363) and (364). The pyrrolidines (361) and (362) when R = cyclohexyl, X = H, and Y = 2 = C02Me eliminated hydrogen cyanide during their purification to give (365) and (366) respectively.

Aziridines are known to react with alkylidenephosphoranes, yielding 3- pyrrolines. It has now been shown160 that such reactions are kinetically con- trolled, and that the mechanism of a reaction depends on the structure of the phosphorane, which can behave either as a reactive nucleophile or as a di- polarophile. The type of product formed also depends, as one might expect, on the class of ylideused. When the aziridine (367), dissolved in either benzene, THF, or a THF-DMSO mixture, is treated at room temperature with sulphide or sulphoxide ylides (368 and 369; R1 = H, R2 = H, CO,Me, CO,Et, Bz; R1, R2 = fluorenyl) the isomeric azetidines (370) and (371) are formed in

N

Ph I

(367) (370)

/R1

R2 \

(368) Me2S=C

(371)

'R2

quantitative yield.161 The reaction is immediate and accompanied by the formation of dimethyl sulphide or dimethyl sulphoxide. The azetidines are thought to be formed (Scheme 23) by the addition of the sulphur ylide to the azo-

R1 $Me2 PhkH C(C02Me)? \I3 \" w R2-;: 7

I Ph x y N , C ( C02Me)2 (367)

Ph

(3 72) I

J J;:73, (370) + (371)

Scheme 23 l60 M. Vaultier, R. Danion-Bougot, D. Danion, J. Hamelin, and R. Carrie, Compr. rend.,

1973,277, C, 1041. M. Vaultier, R. Danion-Bougot, D. Danion, J. Hamelin, and R. Carrib, Tetrahedron Letters, 1973, 1923.

Three-membered Rings 69 methine ylide (372), which is in equilibrium with the aziridine (367) at room temperature. The betaine (373) thus formed cyclizes with elimination of dimethyl sulphide or dimethyl sulphoxide, depending on the ylide used.

Although several a-lactams have been prepared, few reactions of these compounds have been studied in detail. Previous studies have shown that the thermal decomposition of all a-lactams involves fragmentation to a carbonyl compound and an isocyanide, and, depending on the conditions, other unidentified products have also been observed. A detailed study has now been made162 of the pyrolysis of 1,3-di-( 1 -adamantyl)aziridin-2-one (374; R = 1-adamantyl) in a sealed tube at 115-160 "C. The ring-expansion product, 1,3-di-(l-adamantyl)4-( l-adamantylimino)-2-azetidinone (378), was the major product isolated but the aldehyde (376) and the isocyanide (377) were also detected. When equimolar mixtures of (374) and (377) were heated, the same ring-expanded product (378) was produced. This observation suggests that the azetidinone is produced by cycloaddition of (377) to either (374) or an isomer obtained by thermal rearrangement of (374), which may be the elusive imino-oxiran (375).

(374)

1

(375)

(376) (378)

Rearrangement. The acetolysis reactions of a series of benzenesulphonyl- benzobicycloheptaneaziridines, prepared by the action of benzenesulphonyl azide on the corresponding substituted benzobicycloheptanes, have been studied.ls3 For example the aziridine (380), prepared by treating the benzonor- bornene (379) with benzenesulphonyl azide in anhydrous benzene, although a somewhat unstable oil gave spectral data consistent with its structure and the expected exo stereochemistry. Acetolysis was accomplished by heating the compound to 100°C in glacial acetic acid. Under these conditions the ring opened with rearrangement to afford the products (381) and (382) in the ratio 94:6. For these products to be formed the aziridine ring must open

162 E. R. Talaty, A. E. Dupuy, jun., C. M. Utermoehlen, and L. H. Stekol1,J.C.S. Chern.

le3 K. Wiesner, Ho Pak-Tsun, R. C. Jain, S. F. Lee, S. Oida, and A. Philipp, Cunad. J . Comm., 1973,48.

Chem., 1973, 51, 1448.


COpMe I

COzMe

-

AcOH (379)

P h S 0 2 N H m

AcO

(381) 947;

A c O m +

PhS02NH-

(382) 6%

with rearrangement and the resulting carbonium ion react with acetic acid. This process is depicted by arrows in formula (380) and leads to the product (381). An exactly analogous process initiated by opening of the second carbon-nitrogen bond yields the product (382). Product (381) predominates since the formation of compound (382) requires the development of a carbonium ion adjacent to a carbonyl group, a situation known to be energeti- cally unfavourable. The influence of various substitution patterns on the direction of the aziridine rearrangement is also discussed, and it is shown that the rearrangements may be used as a suitable approach to the synthesis of ring B-bridged di t erpeno id a1 kaloids .

In the presence of small amounts of ammonium bromide, the cyclic imidic ester 3,4,5,6-tetrahydro-7-methoxy-2H-azepine (383 ; It = 3) undergoes a mild exothermic reaction with the aziridines (384; R = H or Me) to yield l-iminomethyl-substituted aziridines (385).f64 When heated with iodine in acetone, the aziridines (385; R = H or Me) rearrange to 1,8-diazabicyclo- [5,3,0]dec-7-enes (386). These strongly basic compounds can be used as dehydrohalogenation reagents. Ring Retention. 2-Methoxy-l-pyrroline (383 ; n = 1) and ethyl N-phenyl- forminidate, in the presence of ammonium bromide,ls4 also give exothermic reactions with aziridine (see previous section), yielding the aziridines (387) and (388) respectively. No rearrangement reactions were reported.

The carbamate (389), prepared by reaction of p-methoxycarbonylphenyl chloroformate with an excess of p-aminophenol, gives the phosphorodi- chloridate (390) in almost quantitative yield when treated with equivalent amounts of phosphorus oxychloride and triethylamine. The aziridines (391 ; R = H or Me) couple with the dichloridate (390) at - 10 to - 15 *C to givels6 bis-(l-aziridiny1)phosphinyl alkylating agents (392) which contain O-phenyl N-phenylcarbamate side-chains. By conducting the reactions at these low temperatures transamidation of the carbamyl groups, a major side- reaction at 0 "C, is avoided. 1 G 4 D. Bormann, Angew. Chern. Internut. Edn., 1973, 12,768. 1e6 Y. Y. Hsiao and T. J. Bardos,J. Medicin. Chem., 1973,16,391.


(383)

= 1 (384; R = H) I - MeOH

/ (384; R = H) / Ph-N=C, -&OH ' Ph-N=C,

'OEt

(389)

\

P

6


Carboxylic acid P-(N-ethy1eneimino)ethylamides (394; n = 0, 1-4, or 8 ) are reported to be formed166 when the corresponding diallyl dicarboxylates (393) are treated with ethyleneimine at 50-95 "C in the presence of triethylamine or sodium ethoxide. The diamides (394) polymerize at their melting point owing to opening of the aziridine ring.

H~C=CHCH202C(CH&COzCHzCH=CHa

(393)

0 0

3 ~-CH2CHpNflC(CH2),CNHCH&Hp-N II I I

(394)

The photochemical or thermal reactions of the hexacarbonyls of chromium, molybdenum, and tungsten with aziridine (in), in THF, yield the complexes (395; n = 1 , 2, or 3).ls7 The cis-bis(aziridine)tetracarbonylmetal compounds

M(CO)s + nHN 3 M(CO)s-n(HN 3 )n

(395) (395; n = 2) in the presence of protic solvents yield the chelate complexes (396) with N-(2-aminoethyl)aziridine (diin) as the ligand. A possible sequence of events which would account for the formation of the complexes (396) is depicted in Scheme 24.

H H

/o. -.NJ /

/

(c0)4M,q / '.3 + / N \ 4 H (CO),M 'a NHzCHzCHz 7

/ H

(395; n = 2)

(396) Scheme 24

lB6 V. N. Andronov, V. A. Aleksandrova, V. G. Avakyan, and D. S. Zhuk, Zzuest. Akad. Nauk S.S.S.R., Ser. khim., 1973,140 (Chem.Abs., 1973,78,147 696a).

16' R. Hoefer, W. Beck, and A. Engelmann, Chem. Ber., 1973,106,2590.

Three-membered Rings 73 The preparation of (r-MeC,H,)Mn(CO),(in) and of (m-MeC,H,)(CO),Mn-

(diin)Mn(CO),(r-MeC,H,) is also reported, and the structure and bonding of each complex are discussed on the basis of its i.r. spectrum.

2-Methylaziridine is reported to react with paraforma1dehydel6* in the presence of Triton B to give (N-2-methylaziridiny1)methanol (397; R = OH)

(86 %). In the presence of potassium carbonate, the reaction yields the same aziridine (397; R = OH) (77 %) and di-(2-methylaziridinyl)methane (5 %). The aziridine (412; R = OH) reacts with amines to give the amino-deriva- t ives (3 97 ; R = piperidino , 2,6-dimet hylpiperidino , 2,2,6,6-tet ramet hylpiperidino, morpholino, or ;dicyclohexylamino), of which (397; R = 2,6- dimethylpiperidino or dicyclohexylamino) react with acetyl chloride to give 1 -acetyl-2-met hylaziridine and] RCH,CI, whereas 2,2,2-trichloro-l -(N-aziridinyl)ethanol(398) reacts with dialkyl chlorophosphites16g in the presence of triethylamine to form the corresponding esters (399; R = Et, Pr”, Pri, or Bu).

cc13

(398) (399)

4 Thiirans

Formation.-Carbon Atom Insertion. Compounds which contain a thiocar- bony1 group can often be converted into the corresponding thiiran when treated with diazoalkanes. The scope of this reaction has been investigated and a reaction mechanism proposed.

With diazomethane170 in ether at - 5 ‘C, aliphatic thioketones give thiirans as the principal products, plus methylthioalkenes which, interestingly, have the least substituted double bond. For example, 3-methylbutan-2- thione (400) affords the thiiran (401) and the methylthioalkene (402). The latter must arise via 3-methylbut-l-ene-2-thiol. Under the same conditions 3-methylbut-2-ene-2-thiol yields almost quantitatively 3-methyl-2-(methyl- thio)but-2-ene. When the thioketone cannot enolize, a thiiran is the only

16* G. Zinner and W. Kilwing, Chem.-Ztg., 1973, 97, 156. 160 N. P. Grechkin and N. L. Grishina, Izvest. Akad. Nauk S.S.S.R., Ser. khim., 1973,

170 J. M. Beiner, D. Lecadet, D. Paquer, A. Thuillier, and J. Vialle, Bull. SOC. chirn. 1883 (Chem. A h . , 1974,80,47 725g).

France, 1973, 1979.


Me SMe Me

Me--C--C-Me CH%N2, &/-Me I Me

S H I I I hk,,c>\7 \H

(400) (401) 70% (402) 25%

product. For example phenyl t-butyl thioketone yields 2-phenyl-2-t-butyl- thiiran, which decomposes readily on heating to 2,2-dimethyl-3-phenyIbut-3- ene. The aliphatic dithioesters (403; R = Me, Et, or Pr') afford the methylthiothiirans (404; R1 = R2 = H), which on heating lose sulphur to yield methylthioalkenes (405; R1 = R2 = H). Methyl dithiobenzoate and thionoesters, however, give cis- and trans-lY3-dithiolans and 1 ,2,3-thiadiazolinesY respectively, as the principal products, no thiirans being detected.

S R

MeS MeS R d - S M e R1R2cN2, "x,h:l

(403) (404) (405)

With diazoethane and 2-diazopropane,171 3,3-dimethylbutan-2-thione affords the thiirans (406; R = H or Me) and the alkylthioalkenes (407; R =

H or Me). With the non-enolizable thioketone t-butyl phenyl thioketone (408), the thiirans (409; R = H or Me) and their decomposition products (410; R = H or Me) are formed. With diazoethane the aliphatic dithioesters (403; R = Me, Et, Pr', or Bu:) yield the methylthiothiirans (404; R1 = Me, R2 = H) and their decomposition products (405; R1 = Me, R2 = H); analogous products are obtained when the dithioesters (403; R = Me or But) are treated with 2-diazopropane. In contrast to the results obtained with

171 J. M. Beiner, D. Lecadet, D. Paquer, and A. Thuillier, Bull. SOC. chim. France, 1973, 1983.

Three-membered Rings 75 H S I II R 2 0

R1-C--OR2 - lhTA:e + R 1 - C - C 4 R 2 I I R I

Me S

\ (when R1 = Ra = Me)

R 2 0 \

R' /c=cHMe

Scheme 25

diazomethane, both diazoethane and 2-diazopropane react with thionoesters to give thiirans. For example, the thionoesters (411; R1 = R2 = Me; R1 = Ph, R2 = Me) afford the corresponding thiirans plus decomposition products (Scheme 25).

Although it is possible to rationalize the formation of the thiirans in terms of carbene cycloaddition reactions, this possibility was ruled out by the isolation and/or detection of thiadiazolines in many of the reactions; especially when the reactions were carried out at -70 "C rather than the usual -5 "C. Therefore it was concluded that the formation of thiirans, by the action of diazoalkanes on thiocarbonyl derivatives, proceeds via intermediate A2-1 ,2,3- thiadiazolines and/or A3-l ,3,4-thiadiazoliies

S

R' 4-R2 II

(Scheme 26).

.R3

.1" R2

R1 W R 4 Scheme 26

Met~nerl'~ has studied the reactions of up-ethylenic thioketones with diazoalkanesin ether. The typeof product formed depends on the diazoalkane, the reaction temperature, and the order of addition of the reactants. When 3,6,6-trimethylcyclohex-2-en-l-thione (412) was treated with diazodiphenylmethane and diazophenylmethane at 20 OC the spiro-thiirans (413; R = Ph

179 P. Metzner, Bull. SOC. chim. France, 1973, 2297.


(4 12) (413)

or H) were formed in 70% and 50% yields, respectively. SimiIarly 3,5,5- trimethylcyclohex-2-en-1-thione (414) gave, when treated at 20 "C with diazodiphenylmethane, the thiiran (415; R = Ph) (75 %). However, at 20 "C the thione (414) gave the dithiolan (417) (85%) when treated with diazomethane. The thiiran (415; R = H) (45%) and the olefin (416) (20%) were formed when a reaction temperature of -60 "C was used.

P A (R (R = = RzCNz Ph, H, -60°C) 20 "C) , dR+ A (414)

I CHzN2,20 "C I

s-s

Perchlorothiiran (418; R = C1) can be prepared by the reaction of phenylmercury bromodichloromethane with sulphur or thiophosgene, in benzene at 70 "C under an atmosphere of nitrogen.173 Thiophosgene is thought to be an intermediate in the reaction with sulphur. Similarly, diphenyl thioketone gave the thiiran (418; R = Ph). A cycloaddition reaction of dichlorocarbene, formed by thermolysis of the phenylmercury trihalogenomethane, would account for the products formed. wi + PhHgBr

C1

or C1 csc12

or

PhHgCClzBr + S '$$"+

(418) R = C1 or Ph Ph&=S

173 D. Seyferth and W. Tronich, U.S.P. 3 717 660/1973 (Chern. A h . , 1973,78,125 128q).

Three-membered Rings 77 Sulphur Atom Insertion. A unique and useful route to thiirans involves the reaction of an oxiran with thiocyanate ion. Thus, the insecticidal thiiran (419), ethyl 10,l l-epithio-3,7,1 l-trimethyldodeca-2,4-dienoate, was pre-

=M: Et O2CCH=CMeCH=CHCH2CHMeCHzCHz

(4 19)

pared174 by treating the corresponding oxiran with aqueous potassium thiocyanate. The oxiran was synthesized by epoxidizing ethyl lrans-3,7,11- t rimet hyldodeca-2,4,1 O-trienoate with m-chloroperbenzoic acid.

Cyclization. The addition of acetyl chlorosulphide to the unsaturated esters or amides (420; R1, R2, RS = H or Me; X = OMe, NHPh, OH, or OEt) is reported175 to afford mixtures of the p-halogeno-a-S-acetyl disulphides (421) and (422). The isomer (422) was predominant except in reactions with anilides of methacrylic acid and esters of 3-methylbut-2-enoic acid, which gave only isomer (421). Removal of the acetyl groups from isomer (421) with alcoholic hydrogen chloride gave a p-chloromercaptan and free sulphur. With sodium bicarbonate the mercaptan cyclized to the thiiran (423).

R2

\ /R3 AcSCl - AcS2CR'R2CCIR3COX

R' /"="\ cox (422)

(420) + CICR1R2CR3(COX)SpAc

(j;l&Aic HCl

1

(423)

Miscellaneous. The cycloadduct (424; R = Ph), obtained from methyl iso- t hiocyanate and 3-benzyl-4-methyl-5- (2-hydroxy)et hyl t hiazolium ylide, with liquid ammonia in a sealed tube at room temperature for 20 h yields the t hiiran 3-phenyl-6,8-dimethyl-2,9-dithia-4,6,8-triazatricyclo [3,3,0, 11*5]o~t-3- ene (425; R = Ph) (83%).176 The reaction of the p-nitrobenzyl derivative (424; R = p-N0,C,H4) with liquid ammonia is complete within 3 h, but the 174 J. B. Siddall and C. A. Henrick; (a) U.S.P. 3 723 462/1973; (b) U.S.P. 3 775 432/1973

(Chem. A h . , 1974,80,59 849p). 175 N. M. Karimova, M. G . Lin'kova, 0. V. Kil'disheva, and I. L. Knunyants; (a)

U.S.S.R.P. 376 378/1973 (Chem. A h . , 1973, 79, 78 594x); (b) Zzuest. Akad. Nauk S.S.S.R., Ser. khim., 1973, 1788 (Chem. Abs., 1974,80, 70 619j).

176 A. Takamizawa and S. Matsumoto, Chem. and Pharm. Bull. (Japan), 1973,21,1300.

78 Saturated Heterocyc Zic Chemistry

"'Q.

isolated yield of the thiiran (425; R =p-NO,C,H,) varies from 15 to 30% because of the unstable nature of the product. In this case the 5'4mino- derivative (426; R = p-N0,C6H4) is also formed. The imino-compound (426) is the only product when the cycloadduct (424; R = H) is treated with ammonia. Reaction of liquid ammonia with the p-methoxybenzyl derivative (424; R =p-MeOC,H,) gives only a trace amount of the thiiran (425; R =p-MeOC,H,). When the thiirans (425) are heated in toluene at 100 O C , sulphur is readily lost to give quantitatively the corresponding 2-aryl-4,6- dimethyldihydroimidazo [4,5-d]thiazole-5-thiones (427). A possibIe mechanism for this unique decomposition is depicted in Scheme 27.

-H+,

R /C"

Three- mem bered Rings 79

Alkyl thioglycidyl sulphides (428; R = C4-ro n-alkyl) can be prepared1'' in 34-53 % yields by treatment of thioepichlorohydrin with n-alkanethiols at 60 O C in the presence of 27 % aqueous sodium hydroxide.

Episufphoxides. Methods for the synthesis of episulphoxides using metaperiod- ate or perbenzoic acids in dichloromethane, the thermal decomposition of episulphoxides and the trapping of sulphur monoxide with conjugated olefins, the addition reactions of episulphoxides with thioketones, and the thermal decomposition of episulphoxides substituted with alkyl groups have been re~iewed?'~

The normal reaction of sulphines with diazoalkanes is reported to involve a concerted 1,3-dipolar cycloaddition to give A3-1 ,3,4thiadiazoline 1-oxides. However, the introduction of bulky substituents into either of the reactants appears to hinder this cyclization sterically and gives rise to alternative reaction routes, of which the non-stereospecific formation of episulphoxides is the most interesting Thus, the isomeric mesityl phenylsulphonyl sulphines (429a) and (429b) reacted easily with 2-diazopropane in benzeneether (1 : 1) at - 10 *C to give a 1 : 1 mixture of diastereomeric episulphoxides in 72.5 % yield, irrespective of which sulphine isomer was used. The product mixture

0

\S a \S02Ph MezCN2, PhS02,

\

(429) [or the Z-isomer (429b)I

t \

Scheme 28

177 A. M. Kuliev, K. Byashimov, and F. N. Mamedov, Doklady Akad. Nauk Azerb.

176 A, Negishi, Yuki Gosei Kagaku Kyokai Shi, 1973, 31, 331 (Chem. Abs., 1974, 80,

17@ L. Thijs, A. Wagenaar, E. M. M. van Rens, and B. Zwanenburg, Tetrahedron Letters,

S.S.R., 1973, 29, 33 (Chem. Abs., 1973, 79, 91 854b).

59 804v).

1973, 3589.


could not be separated as the compounds would not withstand extensive chromatography. Oxidation of the products with rn-chloroperbenzoic acid in ether at 20 "C gave 1 -mesi tyl-Zmethyl-1 -phenylsulphon ylprop- 1 -ene (oxidation to the episulphone with subsequent loss of SO,). It is suggested that the episulphoxides are formed as the result of a two-step process. An initial nucleophilic attack of the diazo-carbon at the sulphine sulphur provides a zwitterionic diazonium compound and an internal 1,3-displacement of nitrogen then produces the episulphoxide (Scheme 28).

Bonini and Maccagnanilgo have reported a similar series of reactions. They found that aromatic sulphines such as diphenyl sulphine and t hiofluorenone S-oxide react with phenyl- and p-tolyl-diazomethanes to give triaryl-substituted episulphoxides as a mixture of diastereomers (2: E ratio ranging from 1:4 to 2:3 depending on the aryl substituents). Once again a non- stereospecific formation of the three-membered ring was observed. Any attempt to separate the two components by normal chromatographic methods resulted in the loss of sulphur monoxide to give the olefinic derivatives.

Reactions.-Ring-opening. Sulphurated sodium borohydride has been found to react with thiiranslS1 in a manner similar to that observed for oxiran, to give polymeric disulphide dithiols, which on treatment with lithium aluminium hydride afford lY2-dithiols. The yield of the 1 ,Zdithiol can vary rather widely, depending mainly upon the structure and stability of the starting thiiran. For example, with (430; R1 = H, R2 = Ph or PhOCH,) the sulphuration reactions took place as expected, affording the lY2-dithiols (431). The thiiran (430; R1 = R2 = H) gave only polymeric material whilst trans-2,3-diphenyl- thiiran (430; R1 = R2 = Ph) afforded trans-stilbene as the only product.

The thioglycidic acid derivatives (432; X = OMe, NH,, NHPh, or NMe,) undergo ring-opening at -30 to -40 OC in the presence of methyl chlorosulphide or acetyl chlorosulphide to give mixtures of the corresponding #.I-halogenodisulphides (433) and (435) in 85-96 % total yield,ls2 with (433) predominating. The /?-halogenodisulphides (433; R = Me, X = NH,, NHPh, or NMe,) undergo partial isomerization to the respective (435) after 10h at 100°C, eia the intermediate episulphonium ion (434). The rate of isomerization decreases in the stated order of X.

loo B. F. Bonini and G. Maccagnani, Tetrahedron Letters, 1973, 3585. 181 J. M. Lalancette and M. LalibertC, Tetrahedron Letters, 1973, 1401. la' N. M. Karimova, M. G. Lin'kova, 0. V. Kildisheva, and I. L. Knunyants, Khim.

geterotsikl. Soedinenii, 1973, 8 (Chem. Abs., 1973, 78, 123 970j).

Three-mem bered Rings 81

yAcrx RSSCHoCMeCICOX (435)

(432) ClCH2CMe(SSR)COX (433) +

(434) Desulphurization. The desulphurization of cis- and trans-2,3-dimethyl- t hiirans with n-butyl-lithium, nonacarbonyldi-iron, and dodecacarbonyltri- iron has been studied.183 The reactions proceed with complete stereospecificity : for example, the trans-isomer with n-butyl-lithium produced only trans-but- 2-ene in 83 % yield, a 2-6 % crossover in the cases of the iron carbonyls being attributable to subsequent alkene isomerization. Approximately 15 years ago, Bordwell suggested two possible mechanisms for the n-butyl- lithium reaction (Scheme 29). In the first, the concerted process (a), fragmentation occurs via a sulphurane (436). The second, the carbanion mechanism (b), requires that elimination must be 30-60 times faster than inversion and bond-rotation. The intermediacy of 2-lithio-3-alkylthiobutanes (437)

H\ISIIMe + RLi Me' 'H

RSLi Li+ -

H -?

I

crythro-(437) threo-(437)

'y / 1 + RSLi > -t RSLi

(R=Bu") Scheme 29

u3 B. M. Trost and S. D. Ziman, J . Org. Chem., 1973,38,932.

82 Saturated Heterocyclic Chemistry for the n-butyl-lithium reaction can now be excluded, as independent genera- tion of these species shows considerable loss of stereochemistry under the conditions of the thiiran desulphurizations. The loss of stereochemistry is a function of the thioether leaving group, the loss being considerably less for thiophenoxide than for ethyl thiolate.

The major process in the photolytic decomposition of thiiran is desulphurization. The photolysis of 2,2,3,3-tetraphenylthiiran (438) has recently been investigatedlS4 in order to discover what effect uic aryl substitution, a parameter known to alter the photochemical behaviour of oxirans and cyclo- propanes, might have on the photolytic reactions of thiirans. Photolysis of the thiiran (438) in pentane until decomposition is complete (ca. 30 h) gives 9,lO-diphenylphenanthrene (440) (98 %), hydrogen sulphide, and sulphur. A possible transition state for the conversion of (438) into (440) is depicted in diagram (439). From this study it would appear that tetraphenyl substitution

Ph

(438) (439)

in thiiran does not alter the photolytic behaviour of thiiran; the decomposition is characterized by sulphur elimination. This conforms to the general behaviour of organosulphur compounds which exhibit a marked reluctance to undergo transformations in which the carbon-sulphur single bond is converted into a double bond. Ring Expansion. The methylthiothiirans (441; R = Me or Et) undergo a cycloaddition reaction with carbon disulphide in the presence of potassium methoxide to afford 1,3-dithiolan-2-thiones (442) and 1,3-dithiolen-2-thiones (443).”0

n 8

5 Rings containing More than One Heteroatom

Formation.-Diaziridines. The addition of alkanals to chloramine in methanolic ammonia, the Schmitz reaction, affords 2,4,6-trialkyl-1,3,5-triazabicyclo- [3,1,0]hexanes (445; R = alkyl or Ph) with trans stereochemistry of the (2-2,

R. C. Petterson, A. L. Hebert, G. W. Griffin, I. Sarkar, 0. P. Strausz, and J. Font,J. Heterocyclic Chem., 1973, 10, 879.

Three-membered Rirrgs 83

C-4 substituents, whereas oxidation of the 2,4,6-trialkyl-1,3,5-hexahydrotri- azines (444) with t-butyl hypochlorite in methanol at -40 "C gives the corresponding cis-diaziridines (445; R = Me, Et, or Pr) and trans-diaziridines (445; R = alkyl group larger than Pr).lS5 Similarly (444; R = Pr') gives a mixture of cis- and trans-(445). The cis-isomers are quantitatively epirnerized to the trans-isomers when heated in methanol at 25 "C for 48 h. The epirneriza- tion is believed to occur so rapidly in compounds having larger alkyl groups (larger than isopropyl) that the cis-isomers cannot be isolated under the reaction conditions used.

The reaction of benzylideneaniline or benzylidine-p-toluidine with hydroxy- amino-O-sulphonic acid in the presence of aniline or p-toluidine does not yield the expected diaziridines but benzaldehyde phenyl- or p-tolyl-hydra- zones.lS6 Under the same conditions, however, Schiff bases of non-aromatic amines do give diaziridines. Although the existence of stereoisomers of such diaziridines, due to slow nitrogen inversion, has previously been reported, the stereochemistry has not bsen fully investigated. Thus an X-ray crystal- structure analysis of an invertomer was undertaken and the configuration of 1 -cyclohexyl-3-(p-bromophenyl)diaziridine found to be trans with respect to the 1 -cyclohexyl and the 3-@-bromopheny1)groups. Treatment of several of the l-cyclohexyl-3-aryldiaziridines with phenyl isocyanate afforded l-cyclohexyl-2-(anilinoformyl)-3-aryldiaziridines.

A series of diaziridines (447) having antibacterial properties has been prepared by treating substituted guanidines (446) with base.ls7 For example, the guanidine (446; R1 = R2 = Me) on treatment with methanolic sodium hydroxide gave the diaziridine Schiff base (447; R1 = R2 = Me).

lE6 A. T. Nielsen, R. L. Atkins, D. W. Moore, D. Mallory, and J. M. La Berge, Tetra- hedron Letters, 1973, 1167. A. Nabeya, Y. Tamura, I. Kodama, and Y. Iwakura, J . Org. Chern., 1973,38,3758.

lE7 T. Konotsune, T. Yauchi, and M. Suzuki, Japan. Kokai 73/85 565 (Chern. A h . , 1974, 80,47 968p).

84 Saturated Heterocyclic Chemistry Oxaziridines. Oxidation of unstrained imino-ethers (448; R = H or But), readily prepared by the alkylation of amides with trimethyloxonium fluoroborate, with rn-chloroperbenzoic acid in dichloromethane at -20 "C affords188 oxaziridines (449; R = H or But). These are hydrolysed in aqueous acid to give esters (450; R = H or But) and N-t-butylhydroxylamine. With strained imino-ethers the type of product depends on the ring size. 1-Aza-2ethoxy- cyclopentene (451) affords 5-ethoxy-1 -aza-6-oxabicyclo [3,1 ,O]hexane (452) (66%), which decomposes on heating to give the trimer of ethyl 4-imino- butanoate (453), probably by way of a radical chain mechanism. With 2-

R \C/OMe %Of, 1 1 + BU~NHOH

R yoMe 0

I0 N'

m-CICsH 4CO3 H

R

I1 /

But /N But (448) (449) (450)

\

COiEt I

methoxyazetines the novel 1-aza-5-oxabicyclo [2,1 ,O]pentanes can not be isolated, but l-aza-5-oxa-2,2-dimethylbicyclo [2,1 ,O]pentane can be detected by low-temperature n.m.r.

It has been reported189 that N-unsubstituted oxaziridines, which tend to be rather unstable, can be stabilized by saturating an ethereal solution of the oxaziridine with carbon dioxide.

Azaphosphiridines. The 1 ,2L5-azaphosphiridines (455; R = MeO, EtO, or MqN) have been synthesizedlW in 57-96 % yield by treating hexafluoroace- toneazine (454) with phosphorous esters or tris(dimethy1amino)phosphine in

(455) D. Thomas and D. H. Aue, Tetrahedron Letters, 1973, 1807.

lEs Y . Kobayashi, Japan. Kokai 73/10 062 (Chem. Abs., 1973, 78, 11 1 284a). no K. Burger, J. Fehn, and W. Thenn, Angew. Chem. Internat. Edn., 1973,12,502.

Three-membered Rings 85 anhydrous hexane at 0 "C. These compounds (455) have considerable thermal stability and werecharacterized bytheir1H,19F, and 13Cn.m.r. andmassspectra.

Thiadiaziridine 1,l Dioxides. The second example of a stable three-membered ring system composed entirely of heteroatoms, the thiadiaziridine dioxides (458), has been reported.lg1-lg3 The oxadiaziridines were the first system of this type. Although the thiadiaziridine dioxides (458) are not strictly organic heterocyclic compounds, their novel structure merits their inclusion in this Report. The thiadiaziridine dioxides (458; R1 = R2 = But, ButCH2CMe,, or adamantyl; or R1 = But, R2 = ButCH,CMe2) are conveniently prepared in good yield by treating the corresponding dialkylsulphamide (456) with sodium hydride in pentane to give the sodium salt (457), which on treatment with t-butyl hypochlorite yields the thiadiaziridine dioxide. These compounds show remarkable thermal and chemical stability.

Reactions.-Diaziridines. It has been observed that in contrast to aziridines, which have been shown to addto anumber of acetylenes to give N-vinylazirid- ines, diaziridines usually react with electrophilic acetylenes to give products in which the diaziridine ring is no longer For example, addition of lY3-dialkyl- and 1,3,3-trialkyl-diaziridines (459) to dibenzoylacetylene in benzene at room temperature affords 2-(alkylidenehydrazino)-l,4-diphenyl- but-2-en-174-diones (460). Only the 1,2-unsubstituted diaziridine 3,3-pentamethylenediaziridine [459; R1 = H, R2,R3 = -(CH,),-] reacted with dibenzoylacetylene or ethyl propiolate to give addition products in which the

Bz =CHBz F

diaziridine ring was still intact. The adduct with dibenzoylacetylene, however, on gentle heating in 95% ethanol rapidly rearranged to [460; R1 = H, R2,R3 = -(CH2),--]. The products (460), formed when the 1,3-dialkyl- and 1,3,3-trialkyl-diaziridines (459) react with dibenzoylacetylene, are thought

lS1 J. W. Timberlake and M. L. Hodges, J . Amer. Chem. SOC., 1973,95,634. lea J. W. Timberlake, M. L. Hodges, and A. W. Garner, Tetrahedron Letters, 1973, 3843. lg3 H. Quast and F. Kees, Tetrahedron Letters, 1973, 1655. lD4 H. W. Heine,T. R. Hoye, P. G. Williard, and R. C. Hoye,J. Org. Chem., 1973,38,2984.


(460) t-

Scheme 30 to arise by a Michael-type addition of the N-alkylated nitrogen of the diaziridine to the alkyne linkage (Scheme 30). 3,3-Pentamethylenediaziridine [459; R1 = H, R2,R3 = -(CH,),-] is also

reported to undergo a Ugi four-component condensation reaction,ls5 with formaldehyde, cyclohexyl isocyanide, and ammonia as the nucleophilic compound, to give the tetrazolyl derivative (461) (13 %). The latter, on acid hydrolysis with hydrochloric acid, ring-opened to give the salt (462). Under the same reaction conditions, the less stable N-methyl derivative [459; R1 = Me, R2,RS = -(CH&-] gave the hydrazine (463) as the only product, but with water as the nucleophilic compound the hydrazine (464) and 1 -hydroxy-N-cyclohexylcyclohexanamide (465) were produced, possibly by way of N-methylhydrazine and cyclohexanone.

4 Me \N-N<cH2R4+ wH <> R4

C-NH

0 CHzR4

/ R4CH2

(464) (465) G. Zinner and W. Bock, Arch. Pharm., 1973, 306,94.


n

The reactions of 1-cyclohexyl-2-(anilinoformyl)-3-phenyldiaziridines (466 ; R = Me or H) with p-phenetidine at 100 "C under nitrogen have been investigated.186 The diaziridine (466; R = H) afforded a mixture of l-cyclohexyl-4-phenylsemicarbazide, benzylidene-p-phenetidine, and a small amount of l-(p-ethoxyphenyl)-3-phenylurea. Similarly (466; R = Me) gave the same semicarbazide and a-methylbenzylidene-p-phenetidine, plus an appreciable amount of an unknown compound (467). Thesamecompound wasalso formed when (466; R = Me) was heated at 100°C for 1 h. Analysis showed (466; R = Me) and (467) to be isomeric. The structure of (467) is tentatively proposed as l-cyclohexyl-4,5-diphenyl-5-methyl-l,2,4-triazolidin-3-one, which would be formed as the result of the cleavage of the C-N bond of the diazir- ine ring of (466; R = Me), possibly via the intermediacy of a stabilized 1,3- dipole. The formation of the benzylidene-p-phenetidines and lcyclohexyl-4- phenylsemicarbazide by the reaction of p-phenetidine with (466; R = H or Me) may be considered to proceed via the ring-opened addition product as shown in Scheme 3 1.

A study has been made of the reduction of di-t-butyldiaziridinone under electron-transfer conditions.1s6 Reduction by both electrochemical and chemical methods (t-butyl-lithium or sodium naphthalenide) gave 1,3-di-t- butylurea, indicating that the preferred mode of reduction of the diaziridinone under such conditions is cleavage of the N-N bond. Mechanisms for the reactions are discussed.

Oxuziridines. As a starting point in a search for synthetic routes to thiaziridines, Black and WatsonlQ7 treated oxaziridines with sulphur-containing nucleophiles, an analogous procedure to that used for the mild conversion of oxirans into thiirans. The stable bicyclic oxaziridines (468; R = Ph, Me, H, or But) each gave the corresponding pyrroline (469) when treated with thiourea in refluxing ethanol ; no thiaziridines were isolated. Similarly the monocyclic oxaziridines (470; R = Ph or p-C,H,NO,) were deoxygenated to give the

ls8 A. J. Fry, W. E. Britton, R. Wilson, F. D. Greene, and J. G. Pacifici, J . Org. Chem.,

lS7 D. St. C. Black and K. G. Watson, Austral. J . Chem., 1973,26,2159. 1973, 38,2620.

7


+ E t O O N k h Ph

- \C-N R’\N’

I CONHPh

I

Scheme 31

’ NH~CSNHZ-E~OH Me

Me Me

+ s But

But -N=C \ /H NHtCSNHZ-EtOM, N-C ‘0’ \R ‘R (470) (471)

R = Ph or p-CsH,NOz

imines (471) and sulphur. Treatment of the oxaziridine (468; R = Ph) with potassium t hiocyanate, potassium ethylxant hate, potassium selenocyanate, or triphenylphosphine sulphidetrifluoroaoetic acid afforded the pyrroline (469; R = Ph) with about the same facility as did thiourea. The results obtained from these studies would support the proposal that the deoxygenation is effected by conversion of the oxaziridines into thiaziridines, followed by rapid loss of sulphur. A mechanism for the reaction of oxaziridines with thiocyanate ion which invakes such a proposal is depicted in Scheme 32.


Scheme 32

IrradiatioxP of the cis-oxaziridine (472) at 254nm in benzene afforded 5,5-dimethyl4-phenylpyrrolidin-2-one (473) and 2,2-dimet hyl-3-phenyl-l- pivaloylazet idine (474). The rearrangement of the oxaziridine (472) probably proceeds with homolytic cleavage of the N-0 bond to form a biradical which can then rearrange via two alternative pathways as shown. In all previously reported photo-rearrangements of analogous oxaziridines the ringcontraction pathway was preferred. In this instance the t-butyl radical must be sufficiently stable to allow its formation to compete successfully with ring contraction, and also to be able to provide a hydrogen atom necessary for the formation

Ph

M e p b , B u t A M e b y - Me Me N-c-BUt

II Me k 0 . o

\ I (472) 1 \

Ph

Me2C=CH2

(468; R = H) (473)

108 D. St. C. Black and K. G. Watson, Austral. J . Chem., 1973,26,2505.


(477)

I

\ H (476)

of the pyrrolidin-Zone (473). It is of note that 2-methylpropene has been observed as a product in related reactions of other oxaziridines. Under similar conditions, photochemical irradiation of the oxaziridine (475) gave solely 2,2,4,4-tetramethylazetidine-l-carbaldehyde (476). Once again the homolytic cleavage of the N-0 bond must be the first step of the rearrangement reaction, followed, rather surprisingly, it would appear by a cleavage of the C4-C-5 bond to give a tertiary alkyl radical. This is the only reported example of this type of reaction in which carbon-carbon bond cleavage is preferred to carbon-hydrogen bond cleavage. Irradiation of 3,3-pentamethyleneoxaziridine,lgg in ether at 0 "C in the presence of benzyl phenyl ketone, with a 250 W high-pressure mercury lamp afforded hexanamide (54 %) with 89 % selectivity.

The ferrous-ion-catalysed reactions of five oxaziridines have been reported.20° The oxaziridines (470; R = But or Me) were converted into N-t- butylfomamide and N-t-butylacetamide, respectively. The bicyclic oxaziridines (468; R = H) and (472) both gave the lactam (473), whilst the bicyclic oxaziridine (475) afforded the lactam (477) together with other, unidentified products. The reactions are discussed in terms of three mechanisms postulated by Emmons, some years ago, in the first major report on the reactions of oxazir idines . Thiadiaziridine 1.1-Dioxides. The thermal and chemical properties of the thiadiaziridine 1 ,l-dioxides (478a-c) are discussed in the papers of Timber- lake et uZ?91*192 Of particular interest is the chemical reactivity of (478) towards lithium and Grignard reagents. These reactions are depicted in Scheme 33 and proably reflect the differences in nucleophilicity versus the complexing ability of the reagents. A complete mechanistic interpretation, however, must await further experimental results.

lQU Y. Kobayashi, Japan. Kokai 73/05 711 (Chem. Abs., 1973, 78, 124 077k). D. St. C. Black and K. G. Watson, Austral. J . Chern., 1973, 26, 2515.


(478) a; R.= But b; R = ButCH2CMe2 c; . R = adamantyl

R I

*

R-w N-R eRMgX [ :+ ]

hc9780851865621-00001

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