I l l ep r in ted l rom the .k ru rna l o f Organ ic ( ' hemis t r l ' , , 14 , 2 ;169 (1979) .1(- 'opyr ight O 19?9 l tv the American ( lhemical Society and repr inted bv permissiot- r o l ' the copyr ight owner.

Slr2 Displacements and Reductive Coupling of Ketones with Olef ins in

N,N-Diethylacetamide and N-Ethylpyrrol idone

Allan F. Sowinski and George M. Whitesides*

Department of Chemistrt ' , Massachusetts Inst i tute of Technologt ' , Cambridge, Massachusetts 02139

Receiued March 8. 1979

N,l/-Diethylacetamide (DEA) and N-ethylpyrrolidone (NEP) are complementary to hexamethylphosphorictriamide (HMPA), dimethylformamide, and dimethyl sulfoxide as solvents in which to carry out several reactionscommonly conducted in polar, aprotic media. Reaction of neopentyl tosylates with lithium halides in DEA andNEP gives good yields of neopentyl hal ides. Ketones and terminal olef ins are reductively coupled to tert iary,alcohols in fair to good yields in mixtures containing NEP, sodium, and f erf -butyl alcohol; 1-hepten-6-one and1-octen-7-one are cleanly cyclized to five- and six-membered rings, respectively, in good yield by this same mixture.Terminal olefins are reduced to alkanes in fair yield by DEA sodium ferf-butyl alcohol mixtures; di- andtetrasubstituted olefins are resistant to reduction bv this mixture.

Hexamethylphosphoric triamide (HMPA) is a dipolaraprotic solventr'2 that is particularl5r valuable for suchreactions as SN2 displacement with anionic nucleophilesrr'aand dissolving-metal reductions.s The routine use ofHMPA has been discouraged by the announcement thatit may be carcinogenic.6 In the course of other studies,we required quantit ies of several neopentyl halides.Compounds of this type had proved in previous work tobe most rapidly prepared by displacement of tosylate ionby halide ion using HMPA as solvent.:r '? A recent paperby Young and Dewald reported that l{,.4/-diethylacetamide(DEA) and other tertiary amide solvents dissolved sodiummetal and gave blue solutions containing solvated electronsand metal anions.s Young and Dewald suggested inpassing that the high sodium cation solvating ability andchemical stability indicated by this observation might findapplication in other types of reactions.8 Here we describeexperiments confirming that DEA and l/-ethylpy'rrolidone(NEP) are comparable to HMPA as solvents for dis-placement reactions and that they are of significant, but

(1) For reviews of HMPA, see: Normant,H. Angeu. Chem., Int. Ed.Engl. 1967 ,6, 1046 S7; Normant, H. Bull. Chim. Soc. Fr. 1968, 791 826.

(2) Gutmann, Y. CHEMTECH 1977, 255 63.(3) Mosher, H. S.;Stephenson, B.;Solladie, G. J. Am. Chem. Soc.1972,

94,4t84-8.(4) Schlessinger, R. H. ; Richman, J. E. ; Lee C. S. ; Herrmann, J. L. ;

Cregge, R. J. Tetrahedron Lett. 1973,2425 28.(5) Ehmann, W.J. ; Whi tesides, G. M. J. Org. Chem.1970,35,3565 ?;

and references contained therein.(6) L loyd, J. W. J. Am.Ind. Hyg. Assoc.1975,36,917-9; Zapp, J. A. ,

Jr . Science 1975, 190,422 3.(7) Gutowski , F. D. ; Whi tesides, G. M. J. Org. Chem.1976, '11,2882 5.(8) Young, C. A. ; Dewald, R. R. J. Chem. Soc. , Chem. Commun.1977.

188 9.

more limited value than HMPA for dissolving-metal re-duction of olefins. In addition, we describe a useful newreaction which occurs in NEP (but not in HMPA) bvwhich ketones and terminal olefins are reductively coupledto tertiary alcohols by sodium-ferf-butyl alcohol mixtures.

Resul ts and Discussion

Bimolecular Substitution in DEA and NEP. TableI l ists the yields of alkyl halides detected following thetreatment of neopentyl and cyclohexyl tosylates with ca.2 equiv of lithium halide in various solvents. DEA, NBP,and ly'-acetylpyrrolidine (NAcP) afford marginally higheryields of neopentyl chloride than HMPA and significantlyimproved yields compared with yields obtained with thecommon dipolar aprotic solvents l/,1/-dimethylacetamide(DMA), DMF, and Me2SO. Several analogues of DEAlisted in this table proved to be less effective solvents fordisplacement than their parent structure. Although DEAis comparable to HMPA as a solvent for nucleophil icsubstitutions involving neopentyl tosylate and 2,2-di-methylpropanediyl 1,3-ditosylate, it is notably poorer thanHMPA for nucleophilic displacement of tosylate from2,2,3,3-tetramethylbutanediyl 1,4-ditosylate with lithiumchloride: in addition to lower yields, NEP and DEAappear to give products contaminated by monohalogenatedmaterials (ca. 10-15%); DMF and Me2SO are again muchless effective. The practical utility of DEA as a solventfor displacements at neopentyl centers is indicated by theisolation of good yields of neopentyl chloride, 1-chloro-2,2-diethylbutane, 1,4-dibromo-2,2-dimethylpropane, andpentaerythrityl tetrabromide from preparative-scale re-actions. The experimental procedures followed in DEA

2370 J. Org. Chem., Vol. 44, No. 14, 1979

Table I. Conversion of Alkyl Tosylates to the Corresponding Alkyl Halides byin Various Solventsd

Sowinski and Whitesides

Reaction with Lithium Halides

GC y ie ld , %solventb

structure abbrev( C H , ) , -CCH,C I

( c ,H , ) , - [ ( cH. . ) , -ccH,c l ccH,c l I ,

( cH. ) , -C(CH, I i r ) , C (CH,B r ) .

c - C o -H , , C l

t lCH,CH,CH,CONCH"CH. NEPcH.coN(cH,cH. ) , DEA

8 9 5 287 (69 )d ' n Q7 )d , f 68c 1 0 1 ( ? o y r ' r

Tab le I I . Reduc t ion o f O le f i ns to I { r ' c l roc 'a rbons u - i t hSod ium and 1 r , r l -Bu tv l A l coho l

r e a c t a n l s o l v e n t l '

V l r ' l ( 1 . ' ,

. ' . r : ' 1 i n (p r o d t t c t r n . r t , ' , , ' i a l .

' 7 )

1-hexene HN' lPA r i -hex i ineDEPDEBDEADPANEPNMPANAcP

cyc lohexene HMPA c1 'c loht 'xaneDEADEP

te l ramethy l - DEA 2,3-c l imethv le thy lene butat re

o Reac t ions were ca r r i ed ou t by v igo rc lus l v s t i r r i ng am i x t u r e o f s o d i u m s h o t ( c a . 0 . 3 g , 1 3 m m o l ) . o l e t i n r 1 . 2m m o l ) , a n d f e r f - b u t y l a l c o h o l ( 0 . 3 - m L a l i q u o t s ( c a . 3mmol ) added a t 6 -8 -h i n te rva ls ) i n the spec i f i ed so lven t(6 .0 mL) a t amb ien t tempera tu re ove r 17 -24 -h pe r ioc l s .D Abbrev ia t i ons a re the same as those used in Tab le I .c Reference 5.

tempts to improve the reducing medium were unsuccessful.For example, sodium -potassium alloy (78 wt % K) andlithium, sodium, and sodium-alumina dispersions appearto reduce DEA12 and afford only low conversions of 1-hexene to n-hexane. HMPA-sodium-ferf-but.vl alcoholmixtures are noticeably stabilized by the addition of THFas a cosolvent, although their reactivity toward reduciblesubstances seems undiminished.ll The addition of THFor TMBDA to DEA as cosolvents did not enhance thesolubility of sodium or stabilize the resultant blue solution

(12) Larcheveque, M.;Cuvigny, T. ;Normant, H. C. R. Hebd. SecncesAcad. Sci . , Ser. 1973, 276,209 12.

i q a

J D "

( 6S ;a ' H 26

1 0 2 ( 8 5 ) d 7 0 2 2 5.>^

l l

t t/ 1

a Unless specif ied otherwise, displacement reactions on neopentyl tosylates were cafie(l out a1 103-1 10 ( l () ! f . I i I l l lpe ods by emp loy ing app rox ima le l y 2equ i vo f l i t h i um ha l i de and t osy la te concen t ra t i ons o i ca -0 .26 l l I t h t ' s r r5 . r r r L r t r , r no tryclohexyl tosylate was conducted at 68-72 C over 20-h periods by employing approximately 2 equiv ol l i thrrrm rhlorir leand a tosylate concentrat ion of ca. 0.26 M. D Abbreviat ions: NEP, N.ethylpyrrol idone; DEA, N.N-dielhl l tc, ' : . ,mrrle.NAcP, N-acetylpyrrol idine; DEP, N,N'diethylpropionamide; HMPA, hexamethylphosphoric tr iamide: Dl l .- \ . \ \ ,r inr"thyl 'acetamide; NMP, N-methylpyrrol idone; NMPA, N-melhyl-N -acetylpiperazine; DMF, N,N-Cimethyl lof mami(:, : I )F- U. . \ . . \ 'diethyl isobutyramide I NAcM, N-acetylrnorpholine; Me, SO, dimethyl sulfoxide; DPA, N,N-di isopropvlacc l i inl i ( i . ( ] clo-hexene (66-70%) was the major product from the treatment of cyclohexyl tosylate with l i thiunl chlol ir i i ' in \ r fL{ 'u. solvents.Material balances were 90-99%. d The vield was determined bv isolat ion. " The concentrat ion ()t nt ()DFnlvr i ,) \ \ ' r f ,re was0 .3M. / - I t e

subs t i t t r t i on o f 2 ,2 -d ie thy l "bu l y l l - t osy la te was ca r r i ed ou t a t 150 -160 'C ove r u J r J . | l pe ' r , " 1 r ' r ,m ; , . . , r r r { 1 .4equiv of l i thium chloride. s The concenlrat ion of di losylate was 0.14 M. h The substi tut ion ol penlaer! ih,-Li!L r, . l ramesyl-ate $as carr ied out at 135-140 "C over a 48-h period by employing 1.5 equiv of l i thium bromide ancl l ln)f"\ l r , i , r( ,ncentla-t ion of 0,5 M. i Reference 3.

CH, (CH, ) ,NCOCH. NAcP 83cH .cH2coN(cH .cH . ) " DEP 79( (CH, ) ,N ) .P - O HMPA 78 (62 )d ' ici ,c9l(cx, ) , DMA i 4

cHrcH,cH,coNCH. NMP 70cH3coN(cH2cH' ) 'NCH3 NMPA 69HCON(CH, ) , DMF 61(cH, ) ,CHCON(CH,CH, ) , DEB 57CH.CON(CH,CH, ) ,O NAcM 46CH.SOCH, MerSO 45cH.coN(cH(cH3 ) ' ) ' DPA 37

preparations are analogous to those employed withHMPA.e Products are easily isolated by dilution of thereaction mixture with 1-2 volumes of water and extractionwith an immiscible solvent such as hexane.

Displacement reactions on cyclohexyl rings generally donot proceed well. lO Table I includes the yields of cy-clohexyl chloride obtained from the reaction of cyclohexyltosylate with lithium chloride in various solvents. Cy-clohexyl tosylate primarily undergoes elimination in all ofthe solvents tested, giving cyclohexene (65-67 %) andmodest yields of cyclohexyl chloride (14-33%). DEA andNEP appear to offer no special advantage to HMPA orDMF as solvents for this reaction.

Dissolving-Metal Reduction in DEA. Dilute bluesolutions are formed when DEA, NEP, and l/,l/-di-ethylpropionamide (DEP) are stirred vigorously withsodium shot. In comparison, DMA is rapidly decomposedunder these conditions and HMPA gives concentrated,almost opaque, blue-black solutions. The blue solutionsformed by these l{-ethylamides are considerably less stablethan that formed by HMPA,rr and persist at room tem-perature only 2-3 min after removal from the metal.Whereas HMPA-metal solutions are stable even to 1 equivof tert-butyl alcohol, N-ethylamide-metal solutions aredecolorized instantly by it. HMPA-sodium-terf-butylalcohol mixtures are effective for reducing nonconjugatedalkenes and polyalkylated aromatic compounds.s Weattempted analogous reactions with some simple olefins,and these results are summarized in Table II. Terminalolefins are reduced slowly in fair yield in DEA, DEP, andN,l[-diethylisobutyramide (DEB), but multiply alkyl-substituted double bonds resist reduction. Various at-

l . \

i ) : r r I I

t i j r 1 9 t- . . '

r . l I. i l r l t r Ij r r r l l t

I r I . , )

I r ( l - 1 t

! i l l ,

l i r r ( ) )

I r t r - ( l ( ) t

I r 1 U 0 )

Reductive Coupling of Ketones with Olefins

Scheme I

o o Hl l e - | n c H - c H z

-,^- | +

c H r - - l t E t

2 R o H c H 3 c N E t 2

O H

I r H lC H a - C - C H 2 C H R _ * +- I

N E t 2

OHI

C H 3 C C H 2 C H 2 R

l l r tt -

O H

IC H 3 C H C H 2 C H 2 R

J. Org. Chem., Vol. 44, No. 14, 1979 2371

Table III. Intermolecular Reductive Coupling ofCarbonyl Groups with Olefins in NEPa

Corbony I

Cm od .

hodJc t C o r b o n y l : G L C Y i e l d

O l e f i n R o t ; o ' c

nt lt l

c H 3 - c - c H 2 c H 2 R

5 %

c

R O H

oil

Ai l

t ' l

2 l

t 2

t , l

2 ' l

t , ?

t l

2 l

l , l

? ' l

t , ?

t ' l

2 l

t , ?

t , l

5 2

z s [ r s - s s ] d

5 l

5 5 -

6 5

8 l

6 3

5 I '

< 5

l l

6 2

5 9

4 ?

5 4

4 0

t l

57o

[ H ' ] = e

OH

n u - - L r 2 |

v 5

I

c H 2 c H 2 R

l r n tf '

'

O HII

C H 3 - C ( C H 2 C H 2 R ) 2

I0 -20vo

+ ROH or RH

toward tert-butyl alcohol; poor conversions of terminalolefin to reduced hydrocarbon resulted from use of thesemixed solvents. Attempts to employ proton donors lessacidic than tert-butyl alcohol (e.g., n-propylamine,ethylenediamine, morpholine) gave low yields of n-hexanefrom l-hexene. The incremental addition of alcohol to blueDEA-sodium-1-hexene mixtures also produced low yieldsof n-hexane.

Our qualitative observations indicate that the dissolutionof sodium in HMPA, l iquid ammonia, and ethylenedi-amine is considerably more facile than in l/-ethylamidesolvents and that HMPA is superior for the dissolving-metal reductions of olefins to saturated hydrocarbons.

Reductive Coupling of Ketones with Olefins inNEP. Examination of the side products formed duringreduct ion of l -hexene to n-hexane in DEA sodium-terf-butyl alcohol mixtures revealed small amounts ofchain-extended products such as 2-octanone (ca. 5To),2-octanol (35%), and 7-methyl-7-tridecanol (10-20%)(Scheme I). These and related products incorporatingsolvent moieties from DEA or other solvents make up themajor part of the mass balance not reported as n-hexaneor l-hexene in Table I. The C8 and C14 products observedin DEA are probably produced by the addition of a-aminoland a-hydroxy radicals (or DEA and 2-octanone radicalanions) to the terminal carbon of 1-hexene. The reductionof these intermediate radicals to saturated products canthen occur either by single-electron reduction and pro-tonation or by hydrogen atom abstraction from the solvent.The addition of a-hydroxy radicals generated from primaryor secondary alcohols under free-radical conditions toterminal olefins is well-known,lir but a-aminol additionshave not been reported. Development of this reactionestablished that moderate to good yields of tertiary al-cohols could be prepared by reductive coupling of ketonesand terminal alkenes on a small scale (1-5 mmol) in NBP,but other types of carbonyl compounds (e.g., amides, esters,aldehydes) did not result in significant yields of coupledproducts. Representative reactions are summarized inTable III. In a typical example, 1 equiv of 2-heptanoneand excess fert-butyl alcohol were added in portions to avigorously stirred 1-hexene sodium-NEP mixture at 25

(13) Sosnovsky, G. "Free Radical Reactions in Preparative OrganicChemistry" ; Macmi l lan: New York, N.Y. , 1964;pp 121 5:and referencesincluded therein.

otl

t\N'/

I

t ' l

3 , 1

g "

t 8

H o I.<

Ho a}

d_'

d_xo\A

d_''? ir-,.<1( |I

" o Ak)t l

xo r.\

,4, )(-/

x o A

y< ')

H O | |

Y2

ao

- ) -trr.r-t

t

il

tl

tl/^ ri'-\t t l t ll l r /

otl

a\I I

2372 J. Org. Chem., Vol. 44, No. 14, 1979

oC over a 1-h period. The mixture was worked up bycautiously quenching the supernatant solution with anequal volume of water and extracting with pentane; theextract was found to contain n-hexane (5%), l-hexene(17 Vo), 2-heptanol (16%), and 6-methyl-6-dodecanol(66%). Employing a two- or threefold excess of 2-hep-tanone increased the yield of coupled product to 75-8lTo,based on the Iimiting reactant l-hexene; using an excessof l-hexene with various ketones generally did not improvethe yield over that of the 1:1 stoichiometry. The pro-portion of ketone reduction to alcohol and reductivecoupling with l-hexene depends on the solvent used: thereduction of 2-heptanone and l-hexene in liquid ammo-nia-ether affords no 6-methyl-6-dodecanol (<l%), butmodest yields are obtained in ethylenediamine--ether (6%),HMPA (ca.I0%), and the l{-ethylamides DEB (9%), DEP(2L%), and DEA (40To). The coupling procedure fails ifthe ketone is converted to enolate by the accumulatingstrong bases arising from amide or Iactam decomposi-tions,12 and a relatively acidic proton source, like ferf-butylalcohol, is required in moderate excess. Warming a 2-heptanone-l-hexene-NBP mixture to 48 oC resulted inlowered yields of coupled products (56%), and cooling amixture to -20 oC slowed the reaction to an impracticalrate. The presence of cosolvents such as HMPA or EDAhad no influence on the yield.

The reductive coupling reaction proceeded in lower yieldin larger scale trials (0.03-0.12 mol (ca. 0.6 M) 1-hexene)and isolated yields of product following chromatographyover silica gel and distillation were only 20-30%. Controlexperiments established that reduction of ketone to alcoholbecomes more important relative to coupling of ketone andolefin when the reaction is scaled up. It is possible thatchanges in the surface to volume ratio of the sodium metalare responsible for the decreased yields of coupled product.Vigorous stirring of these larger preparations beats thesodium shot into a large, smooth lump, once the particlesurfaces have become chemically clean in the presence ofthe solvent. A Hershberg type of stirrer (braided wirestrands) was no more effective than a Teflon paddle fordispersing the soft metal lump. The inclusion of diluentparticles such as fine sand (ca. 15 wt To), glass powder, orpolyacrylamide polymer particles (ca.25 wt Vo) did notalleviate the problem noticeably or improve the yield ofcoupled product. The presence of the dispersing agentoleic acid (4 wt % ) had no effect on the reaction course.We attempted to reduce the malleability of the sodium bypreparing a high-melting 25% bismuth alloy in situ fromsodium-NEP and bismuth tribromide.la The reductionof bismuth tribromide produced a fine, gray suspension,but this mixture had low reactivity: 2-heptanone in thepresence of 1-hexene and tert-butyl alcohol was incom-pletely reduced and a mixture of 2-heptanone 1o9%),2-heptanol (21%), and couple (6-methyl-6-dodecanol, 47o)was obtained. We are continuing to investigate the effectsof other amide solvents and the composition and form ofdissolving metals such as sodium on carbonyl-olefin re-ductive coupling.

The proportion of ketone-olefin coupling and ketonereduction in NEP decreases as the steric bulk of the alkylsubstituents around either functional group increases.Acetone, 2-heptanone, and 3-pentanone gave 50 65%yields of coupled product with 1-hexene, but pinacolonegave a very low yield (10%). The terminal olefin 1-hexeneand ethylene reacted with 2-heptanone (50-65% yield of

(1a) (a) Hansen, M.; Anderko, K. "Constitution of Binary Alloys";McGraw-Hi l l : New York, N.Y. , 1958;pp 321 2. (b) Zint l , E. ; Goubeau,J. ; Dul lenkopf, W. Z. Phys. Chem., A 1931, 154, | 46.

Sowinski and Whitesides

coupled product), but the geminally disubstituted olefin2-methyl-1-pentene underwent addition poorly (20Vo), andvicinal di- and trisubstituted olefins gave only traces(<5%) of coupled products.

Extension of the reductive addition reaction to othercarbonyl compounds was not successful. Heptanal andother aldehydes containing a protons appeared to sufferbase-catalyzed condensation before reduction took place;pivaldehyde, which does not bear a protons, did undergoreduction to neopentanol but afforded only traces ofcoupled product with l-hexene ((5%). The addition ofanhydrous formaldehyde to 1-hexene in an NEP-sodi-um-ferf-butyl alcohol mixture did not produce l-heptanol(<I%). Acyl derivatives may react with 1-hexene to giveproducts incorporating one or two olefin units: a threefoldexcess of DMA relative to l-hexene affored both 2-octanol(18%) and traces of ?-methyl-7-tridecanol (5%), but ethylacetate, acetyl chloride, and acetic anhydride did not givecoupled products. A ketimine (acetone l/-propylimine)and an aldimine (acetaldehyde l/-propylimine) did notundergo addition to 1-hexene to give secondary aminesunder the conditions we examined. Reductive couplingof acetone with either 1,3-butadiene or isoprene in thesemixtures did not take place (traces of materials wereisolated that had spectroscopic properties consistent withl/-pentenyl- and l/-hexenylpyrrolidone from l,3-butadieneand isoprene, respectively, suggesting the trapping ofsolvent-derived radicals by the diene reactant). Terminalacetylenes appeared to undergo predominantly reductionto terminal alkenes, which then underwent reductivecoupling with acetone to give fully saturated tertiary al-cohols. Internal alkynes were unreactive: 4-octyne wasrecovered in 80% yield from reaction with acetone underthese reductive coupling conditions.

Intramolecular ketone-olefin15 and ketone-alkynel6reductive coupling b1- dissolving-metal mixtures has beenobserved previously only in stereochemically rigid systems,but five- and six-membered tertiary alcohols have beenprepared by electrochemical cyclization -of nonconjugated.non.r in either diethyl ether or DMF.1? We found thatnonconjugated enones can also be reductively cyclized tofive- and six-membered rings in good yield by NEP-so-dium-terf-butyl alcohol mixtures, and representativeexamples are summarized in Table IV. For example,1-hepten-6-one afforded a diasteromeric mixture of 1,2-dimethylcyclopentanols accompanied by only traces of1-methylcyclohexanol and noncyclized alcohol (s3%).

Similarly, l-octen-7-one cyclized to a mixture of 1,2-di-methylcyclohexanols (80%), attended by traces of 1-oc-ten-7-ol (33%). The regioselective exo closure of theseprecursors to five- or six-membered 1,2-dimethylcyclo-alkanols is in accord with numerous observations in theIiterature.l8'1e Intramolecular cyclization of 1-hexen-5-oneapparently did not compete with intermolecular coupling,and only low yields of l-methylcyclopentanol and 1,2-dimethylcyclobutanols (<5% ) and 1-hexen-5-oI (5%) weredetected. Modest yields of intermediate rings were ob-tained from l-nonen-8-one by this method: both endoproduct l-methylcyclooctanol (L2Vo) and exo product1,2-dimethylcycloheptanol (67o) were formed; l-nonen-8-ol

(15) Eakin, M.; Mart in, , I . ; Parker. W. J. Chem. Soc. . Chem. Commun.1965. 206.

(16) Stork, G.; Malhotra, S. ;Thompson, H. ; Uchibayashi ,M. J. Am'Chem. Soc . 1965 ,87 . 11 '18 9 .

(17) Shono, T. : Nishiguchi , I . ; Ohmizu, H' ; Mi tani . M. . / . Am. Chem.Soc . 1978 , 100 .515 50 .

(18 ) (a )Ju l i a , M . Acc .Chem' Res . 1971 , ' 1 .386 92 . (b )Ju l i a , M . PureAppl . Chem. 1967, 15, 167-83.

i t g t Ba ld * in . . 1 . E . J . Chem. S r . ,< ' . . Chem. Commt tn - 1976 ' 734 6 .

o H o H o H}{- + \(Lr \2 Lr

< 5

#II

r R////t . .l L H . lI

O H

l lt l \

[H ' ] = e - + ROH o r RH

< 5

\2

o H o H o H

kfd\f

LYo H o H o H

tfdsn

-\ l l\ t (

\ , dbu

Reductive Coupling of Ketones with Olefins

Table IV. Intramolecular Reductive Coupling ofKetoolefins in NEPd

J. Org. Chem., Vol. 44, No. 14, 1979 2373

Scheme II

O _ O HI no,r I l r . l

.'+\

aprotic conditions (anhydrous DMF-tetraethylammoniump-toluenesulfonate).17 Thus either reactive species iscapable of facile olefin addition, and it is not possible todistinguish which is involved in reductive coupling insodium-ferf-butyl alcohol-NEP mixtures on this basis. Amechanism involving the addition of olefin radical anionsor sodium alkyls to the ketone carbonyl in reductivecoupling by NEP-sodium-tert-butyl alcohol does notappear probable. The reduction of terminal olefins byl/-ethylamide-sodium-fert-butyl alcohol mixtures pro-ceeds to 50To completion after 5-10 h, and olefins do notvisibly react with blue l[-ethylamide-sodium solutions. Incontrast, ketones instantly decolorize these blue solutions,and the reductive coupling reaction is complete within 1h. Thus, the rate of reaction of olefins in NEP-sodi-um-ferf-butyl alcohol is not fast enough to account for theobserved rate of formation of coupled product.

Conclusions

DEA and NEP are comparable to HMPA, and superiorto other polar aprotic solvents, as media in which to carryout nucleophil ic displacement reactions at neopentylcenters. Both are sufficiently stable toward reduction thatthey allow the reductive coupling of ketones with olefinsin the presence of sodium and tert-butyl alcohol (SchemeII). Reductions of olefins to hydrocarbons can also beaccomplished by these solvents in the absence of ketones,but this reaction is unlikely to prove useful in synthesisin other than unusual circumstances.

Several characteristics of the interesting reductivecoupling reaction deserve brief comment. First, DEA andNEP are considerably more stable toward dissolved sodiumthan dimethylformamide, dimethylacetamide, and ly'-methylpyrrolidone. The relatively low stabil ity of DMFin the presence of strong bases is well-known and seemsto be a result of rapid base-catalyzed decarbonylation. Themechanistic origin of the difference in stability between(di)nrethylamides and (di)ethylamides (and higher (di)-alkylamides) is not presently clear but is important inchoosing amide-containing solvents for these stronglyreducing reactions. Second, it is unclear whether thereductive coupling reaction occurs at the sodium surfaceor in solution. DEA and NEP do dissolve sodium and giveblue solutions, but reaction mixtures are colorless duringthe reductive coupling reaction. Further, HMPA formsmuch more concentrated solutions of sodium than do DEAand NEP, but only the latter solvents yield the tertiaryalcohols derived from reductive coupling: in HMPA,reduction of ketone to alcohol is the only important re-action. Although this difference might simply reflect thepartitioning of an intermediate ketyl or protonated ketylbetween addition to olefin and reduction to alcohol(ate),it may also indicate some more major difference in

ol l e

O HI

4-r

VL

6 5

\------>'--l

< 3

< 3<r8 0

O HO H

6 < 2 0

o

T h e k e t o o l e f i n ( 2 " 0 m m o l ) w o s o l l o w e d i o r e o c i w i t h v i q o r o u s l y s t i r r e d s o d i m s h o i

F;1"1i;"i1#J:: ' ' ond teri-buhvr orcohor (1'B mL' e mmor) in NEP (6 l mL)

and 2-nonanol (520%) and intermolecular couplingproducts presumably completed the material balance.

Some suggestions about the essential mechanistic fea-tures of the reductive coupling of ketones with terminalolefins can be drawn from these observations. The C-Cbond-forming step probably involves the addition of theintermediate ketyl radical anion or a-hydroxy radicalderived from one-electron reduction of the ketone to theexo carbon of the terminal olefinl3'l8 (Scheme II). Thisintermediate alkyl radical could undergo subsequent re-duction by single-electron transfer and protonation or byhydrogen atom abstraction from any one of several goodhydrogen donors that are present. The ketyl anion ora-hydroxy radical that does not add appears to sufferreduction to the secondary alcohol by these same se-quences. Examples of C-C bond formation by the additionof either reactive intermediate to a terminal olefin haveappeared. Generating a-hydroxy radicals from primaryor secondary alcohols and init iators in the presence ofterminal olefins gives preparatively useful yields of thecoupled product.l:r The eiectrochemical reductive cycli-zation of 1-octen-7-one gives comparable yields of 1,2-dimethylcyclohexanol under protic (1:9 (v/v) methanol/dioxane-tetraethylammonium p-toluenesulfonate) or

2374 J. Org. Chem., VoL 44, No. 14, 1979

mechanism. Third, in a practical sense, this reaction ispresently only useful for the preparation of small quantities((5 mmol) of products: yields decrease significanr"ly whenthe reaction is scaled up. Our qualitative observationssuggest that the aggregation of sodium during the reaction,and the consequent decrease in sodium surface, is animportant contributor to this decrease in yield. It may bepossible to circumvent this problem by high-speed stirringor by other mechanical or chemical means of maintaininga high sodium surface area. Alternatively, electrochemicalreductions in DEA or NEP might prove valuable. Untilthese possibil i t ies have been tested experimentally,however, the reaction should be considered only forsmall-scale preparations.

Although toxicity data regarding DEA and other amidesare scarce,2o these solvents have the combination of highsolvent power and miscibility with both organic solventsand water which would be expected to make them effectivein facilitating passive transport of both organic and in-organic materials through the skin and cell walls. Solutionsof toxic substances in these solvents should be handledwith care.

Experimental Section

General Methods. Melting points were determined on aThomas-Hoover capillary melting point apparatus and are un-corrected. Boiling points are uncorrected. Infrared spectra (IR)were recorded on a Perkin-Elmer Model 567 grating infraredspectrometer and are reported in wavenumbers. Proton NMRspectra were determined on a Varian Associates Model T-60spectrometer and are reported in parts per million downfield fromMeaSi. Mass spectra were obtained on a Varian Model MAT 44instrument at an ionizing voltage of 70 eV. Elemental analyseswere performed by Robertson Laboratory, Florham Park, N.J.GLC analyses were carried out on a Perkin-Elmer Model 990 or39208 gas chromatograph equipped with a flame ionizationdetector. Neopentyl and cyclohexyl halides were analyzed by usinga 9-ft column of 20% SE-30 on 80-100 Chrom P; hydrocarbonswere analyzed with a 30-ft column of l0To TCEP on 80 100Chrom P; secondary alcohols and ketones were separated on a9-ft column of 5To Carbowax 20M on 80-100 Chrom W; tertiaryalcohols were detected following chromatography on a12-ft HiPakcolumn of UC-W98 on 80-100 WHP. Products were identifiedby peak-height enhancement resulting from coinjection of anauthentic sample and by mass spectroscopy on a Hewlett-Packard59924 GC/MS. Reagent grade HMPA, DMA, NMP, DEA, NEP,DEP, Me2SO, and DMF were obtained from commercial sourcesand were purified by distillation from calcium hydride througha 26-cm column at reduced pressure. HMPA (bp 88.9-89.0 oC

(8 torr)), DEA (bp 105.0-107.0 'C (61 torr)), NEP (bp 78.0-78.5"C (90 torr)), and DEP (bp 81.3-82.0'C (10 torr)) were redistilledthrough the same column from molten sodium.2r Reagent gradefert-butyl alcohol was distilled from sodium metal under nitrogen.Reactants such as olefins and ketones were purified immediatelybefore use by passage through a 2-in. column of grade I alumina.Dissolving-metal reductions and couplings were performed in15-mL polymerization tubes (Lab Glass) that were sealed with0.25-in. butyl rubber septa and crown caps. All reactions werecarried out in flame-dried glassware under an inert atmosphereof prepurified nitrogen or argon by using routine techniques forhandling oxygen- and moisture-sensitive materials.22

General Preparation of Ethylamides. Additional amideswere prepared by routine methods.B N-Acetylmorpholine (79%):bp 139.0-139.8 "C (26 tor r ) ( l i t .24 117-118 (13 tor r ) ) ; lH NMR

(20) Christenson, H. E., Ed., "Toxic Substances List, 1973 Ed."; NIOSH:Rockvi l le , Md., 1973; p 3.

(21) Burf ie ld, D. R. ; Lee, K.-H.; Smithers, R. H. J. Org. Chem.1977,42,3060 5,

(22) Shriver, D. F. "The Manipulation of Air-Sensitive Compounds";McGraw-Hill: New York, N.Y., 1969; pp 145 205.

(23) Hilgetag, G.; Martini, A., Eds., "Preparative Organic Chemistrv";Wi ley: New York, N.Y. , 19?2; pp 484 8.

Sowinski and Whitesides

(CDCI3) 6 3.60 (8 H, broadened. spl i t s), 2.1 (3 H, s). N-methyl-N'-acetylpiperazine (39%): bp 129.0 129.8 oC (19.5 torr)( l i t .25 168 'c (760 tor r ) ) ; lH NMR (CDCI3) 6 3 .50 (4 H, m) , ca.2.3 (7 H, superimposed s and m), 2.10 (3 H, s). l /-Acetyl-py'rrol idine (51%): bp 111.0 113.0'C (15 torr); tH NMR (CDCI3)6 3.21 (4 H, t), 2.0 (7 H, superimposed s and m). N,N-Diiso-propylacetamide (85%): bp 97.5-99.0'C (24 torr) ( l i t .2a 80 oC

(13 tor r ) ) ; 1H NMR (CDCI3) 6 3 .6 (2 H. broad m),2 .05 (3 H, s) ,1.25 (12 H, "t"). N,N-Diethylisobutyramide was prepared fromisobutyric acid by conversion to its acid chloride (63%) withthionyl chloride and treatment with 2 equiv of diethylamine indiethyl ether:23 bp 90.0-92.0 "C (19 torr) ( l i t .26 ?5.0-76.0 "C (8tor r ) ) ; IH NMR (CDCI3) 6 3 .38 (4 H, q) ,3 .70 (1 H, sep) , 1 .1 ( fZH, superimposed d and t).

Preparation of Authentic Samples of Alcohol Products.Samples of various tertiary alcohols were prepared in routinefashion from ketones and Grignard or lithium reagentsu and werecharacterized by standard spectroscopic techniques and com-parison of physical properties with literature values, whenavailable, The boiling points and mass spectral data of a seriesof alcohols that were prepared from n-hexylmagnesium chlorideand the appropriate ketone are listed as follows. 7-Methyl-7-tridecanol: bp 156 158 oC (19 torr); mass spectrum mf e (relativei n t e n s i t y ) 1 9 9 ( 7 ) , 1 3 0 ( 1 1 ) , 1 1 9 ( 1 0 0 ) , 1 1 1 ( 6 ) , 7 I ( 7 ) , 6 9 ( 4 2 ) , 5 8(5) , 57(6) , 55 (11) ,45 (5) ,43 (15) ,41 (8) . 6-Methy l -6-dodecanol :bp 118-122'C (5 torr); mass spectrum mf e (relat ive intensity)1 8 5 ( 6 ) , 1 3 0 ( 7 ) , 1 2 9 ( 7 0 ) , 1 1 6 ( 8 ) , 1 1 5 ( 1 0 0 ) , 1 1 4 ( 5 ) , 1 1 1 ( 6 ) , 9 9(7 ) , 97 (20 ) ,85 (6 ) , 83 (6 ) , 71 (2 t ) , 70 (6 ) , 69 (57 ) ,59 (10 ) ,58 (19 ) ,57 (15) , 56 (14) , 55 (54) , 45 (32) ,44 (9) ,43 (83) , 42 (13) ,41 (43) .3-Ethyl-3-nonanol: bp 123.5 125.0 oC (30 torr); mass spectrummf e (relat ive intensitv) 144 (8), 143 (80).88 (6),87 (100),85 (10),83 (27) , 73 (6) , 70 (5) , 69 (63) , 59 (18) , 57 (33) , 55 (22) ,45 (28) ,43 (24) ,41 Q4\ ,39 (6) . 2-Methy l -2-octanol : bp 127.0-128.5 "C(87 torr) ( l i t .28 80'C (12.5 torr)); mass spectrum mf e (relat ivein tens i ty ) 129 (13) ,69 (17) ,59 (100) ,58 (5) ,55 (6) ,43 (14) ,41 (10) .1-n-Hexylcyclohexanol: bp 125.0-L27.0 oC (7 torr) (1ft .2e 172'C(100 torr)): mass spectrum mf e (relat ive intensity) 141 (8), 114(4 ) , 113 (12 ) , 100 (7 ) , 99 (100 ) , 81 (34 ) , 72 (6 ) , 71 (9 ) , 67 (8 ) , 58( 8 ) , 5 7 ( 1 6 ) , 5 5 ( 1 7 ) , 4 3 ( i 3 ) , 4 1 ( 1 3 ) , 2 9 ( 7 ) . A s a m p l e o f 2 , 2 , 3 -tr imethyl-3-nonanol was prepared from 1-l i thiohexane and pi-nacolone: bp 122.0-123.0 "C (24 torr); mass spectrum mf e( re la t ive in tens i ty ) 130 (6) , 129 (75) ,102 (6) ,101 (79) ,85 (13) ,83( 3 6 ) , 7 1 ( 1 9 ) , 7 0 ( 7 ) , 6 9 ( 1 0 0 ) , 5 9 ( 2 7 ) , 5 8 ( 1 2 ) , 5 7 ( 3 3 ) , 5 5 ( 3 8 ) , 4 5(20), 43 (57),41(43), 39 (9), 29 (30). 2,2-Dimethyl-3-nonanol wasprepared from pivaldehyde and n-hexylmagnesium chloride: bp145.0-146.0 "C (92 torr) ( l i t .30 90 oC (13 torr)); mass spectrummle ( re la t ive in tens i ty ) 115 (11) ,97 (45) ,96 (8) ,87 (16) ,71 (10) ,70 (7) , 69 (25) , 58 (6) , 57 (68) , 55 (100) , 54 (7) ,45 (13) , 44 (L5) ,43 (52) , 42 ( l i \ ,41 (75) , 40 (10) , 39 (21) . A sample o f 4 ,6-d i -methyl-6-undecanol was prepared from 2-heptanone and 2-methylpentyl-1-magnesium bromide: bp 174.0-175.0 oC (98 torr);mass spectrum mf e (relative intensity) 129 (54),116 (7), 115 (100),111 (9 ) , 97 (16 ) ,85 (18 ) ,83 (8 ) , 71 (29 ) ,70 (10 ) ,69 (33 ) , 59 (27 ) ,5 8 ( 1 1 ) , 5 7 ( 1 8 ) , 5 6 ( 1 1 ) , 5 5 ( 4 4 ) , 4 5 ( 1 6 ) , 4 3 ( 5 9 ) , 4 1 ( 3 0 ) , 3 9 ( 7 ) ,29 (22). The addition of ethylmagnesium bromide to heptanoneafforded 3-methyl-3-octanol: bp 113.0 114.5 oC (58 torr) ( l i t .3t80-81 'C (15 torr)); mass spectrum m/e (relat ive intensity) 129( 1 3 ) , 1 1 5 ( 4 0 ) , 9 7 ( 9 ) , i 4 ( 1 1 ) , 7 3 ( 1 0 0 ) , ? l ( 8 ) , 7 0 ( 8 ) , 6 9 ( 1 0 ) , 5 9(13 ) ,57 (8 ) , 55 (33 ) ,45 (9 ) , 43 (17 ) ,41 (11 ) . 2 -Me thy l -2 -bu tano lwas obtained commercial ly.

Authentic samples of cyclic tertiarv alcohols were prepared fromthe appropriate cycloalkanone and methyllithium. A sample of2-methylcyclooctanone was synthesized according to a literatureprocedure;32 al l other ketones were obtained commercial ly.

(241 Chem. Abstr . 1956,50, i112.(25 ) Naka j ima . K . Ru l l Chem. Soc . Jpn . ,1961 , 3 .1 , 651-4 .(26 ) M i l l e r , L . L . ; Johnson , J . R . J . Org . Chem.1936 , / , 135 -40 .(27) Reference 2l ) , pp 879 81.(28) Will iams, F. E.; Whitmore, F. C. J. Am. Chem.Soc. 1933, 55, 406-11.(29) Wi l l iams, H. B. , Edwards W. R., Jr . J . Am. Chem. Soc. 1947,69,

3 3 6 , 8 .(30) Zavada.,J.; Pdnkova, I\{.; Sicher, J. CoLlect. Czech. Chem. Commun.

1972. ,37,2414 35.( i l l ) Jamison . M. M. ; Less l i e , M . S . ;Tu rne r , E . E . J . I ns t . Pe t .1949 ,

,r5. 590 620.( l l2) Girard. C. ; Conia, ,J . M. Tetrahedron Let t . 1973,2767 70.

Reductive Coupling of Ketones with Olefins

Spectral and physical properties of this series of compounds areas follows. l-Methylcyclopentanol bp 74.0-75.5 oC (64 torr) (lit.m134 oC (760 torr)); mass spectrum mf e (relative intensity) 85 (14),8 4 ( 6 ) , 7 2 ( 8 ) , 7 1 ( 1 0 0 ) , 7 0 ( 7 ) , 6 7 ( 1 4 ) , 5 9 ( 6 ) , 5 8 ( 7 1 ) , 5 7 ( 2 7 ) , 5 6(8) , 55 (27) ,53 (5) , 45 (8) , 44 (5) , 43 (96) ,42 12\ ,41 (29) ,40 (7) ,39 (19). Racemic 1,2-dimethylcyclopentanol: bp 83.0 86.0 "C(65 torr) (lit.34 70 "C (25 torr)); mass spectrum mf e (relativein tens i t y ) 99 (5 ) , 86 (12 ) ,85 (21 ) ,84 (19 ) ,83 (5 ) , 81 (9 ) , 72 (18 ) ,7 1 ( 8 4 ) , 7 0 ( 1 0 ) , 6 9 ( 7 ) , 5 9 ( 5 3 ) , 5 8 ( 5 0 ) , 5 7 ( 2 6 ) , 5 6 ( 9 ) , 5 5 ( 2 6 ) ,53 (6 ) , 51 (15 ) , 49 (44 ) ,48 (6 ) , 47 (8 ) , 45 (11 ) , 44 (6 ) , 43 (100 ) ,42(26),41(36), 40 (11), 39 (20). 1-Methylcyclohexanol: bp 87.0-89.0"C (61 torr) (lit.s 69 70 'C (30 torr)); mass spectrvm m f e (relativein tens i t y ) 99 (12 ) ,98 (9 ) , 86 (14 ) ,85 (10 ) ,84 (23 ) ,83 (6 ) , 81 (15 ) ,72 (13 ) ,71 (100 ) ,70 (14 ) ,69 (11 ) ,59 (17 ) ,58 (41 ) , 57 ( r2 ) , 56 (7 ) ,55 (51) , 54 (8) , 53 (7) , 5 t (22) ,50 (6) , 49 (65) , 48 (10) , 47 ( t2) ,45(7) , 43 (73) , 42 (41) , 40 (18) , 39 (23) . Racemic 1 ,2-d imethy l -cyclohexanol: bp 94.5-95.0 "C (60 torr) ( l i t .3a 83 oC (25 torr));mass spectrum mf e (relat ive intensity) 728 (7, M*), 113 (8), 86( 1 7 ) , 8 5 ( 2 6 ) , 8 4 ( 2 3 ) , 8 3 ( 6 ) , 8 t ( 7 ) , 7 2 ( 1 5 ) , 7 1 ( 1 0 0 ) , 7 0 ( 1 1 ) , 6 9( 1 0 ) , 6 8 ( 1 5 ) , 6 7 ( 8 ) , 5 9 ( 1 2 ) , 5 8 ( 3 9 ) , 5 7 ( 2 1 ) , 5 6 ( 7 ) , 5 5 ( 2 1 ) , 5 3(7 ) ,4 t ( 21 ) , 50 (5 ) , 49 (65 ) , 48 (10 ) , 47 ( t 2 ) , 45 $2 ) ,44 (16 ) , 43(83) , 42 (19) , 41 (38) , 40 (17) , 39 (21) . l -Methy lcyc loheptanol :bp 60.5-62.0 'C (3 torr) ( l i t .36 75 "C (12 torr)); mass spectrummle ( re la t ive in tens i ty ) 113 (19) ,95 (10) ,86 (5) ,85 (12) ,72(10) ,7 1 ( 1 0 0 ) , 6 9 ( 6 ) , 6 8 ( 1 0 ) , 6 ? ( 6 ) , 5 9 ( 6 ) , 5 8 ( 2 5 ) , 5 7 ( 6 ) , 5 5 ( 7 ) , 4 3(29),4L (13). l-Methylcyclooctanol: bp72.0-7a.0 "C (3 torr);massspectrum mf e (relative intensity) I27 (12), 99 (7\,82 (10), 72 (7),7 1 ( 1 0 0 ) , 6 7 ( 9 ) , 5 9 ( i 0 ) , 5 8 ( 4 2 ) , 5 7 ( 8 ) , 5 5 ( 1 1 ) , 4 3 ( 3 1 ) , 4 1 ( 1 5 ) ,39 (8). 1,2-Dimethylcycloheptanol: bp 103.0-103.5 "C (34 torr)(lit.37 83-86 oC (8 torr)); mass spectrum mf e (relative intensity)t42 (6) , r27 (12) ,109 (9) , 99 (10) ,86 (10) ,85 (49) , 83 (18) , 82 (10) ,7 2 ( 2 0 ) , 7 1 ( 1 0 0 ) , 6 9 ( 1 6 ) , 6 8 ( 6 ) , 6 7 ( r 2 ) , 5 9 ( 9 ) , 5 8 ( 2 5 ) , 5 7 ( 1 9 ) ,55 (15 ) , 45 (7 ) , 43 (43 ) , 42 (6 ) , 41 (20 ) , 39 (10 ) .

The nonconjugated enones 1-hexen-5-one, 1-hepten-6-one,l-octen-7-one, and 1-nonen-8-one were prepared satisfactorilyby ethyl acetoacetate alkylation with a,c^r-haloolefins,38 base-catalyzed hydrolysis,3e and acid-catalyzed decarboxylation.3s

A Sample of N-propylpropionaldimine was prepared by theusual reaction:ao bp 98.0-100.0 oC (?60 torr); lH NMR (CDCI3)6 7 .63 (1 H, t ) , 3 .25 (2 H, t ) , 2 .2 (2 H, m) , I .4 (2 H, m) , ca. 1 .0 (6H, two superimposed t); IR (neat) 1675 (s). A sample of l /-propyl-2-propanone imine was prepared as reported elsewhere:atbp 107.0-107.5'C (760 torr) ( l i t .41 107.0 "C (760 torr)); lH NMR(CDCI3) 6 3 .20 (2 H, t ) , 2 .02 (3 H, s) , 1 .87 (3 H, s) , ca. 1 .6 (2 H,m), 0.97 (3 H, t); IR (neat) 1667 (vs).

Reductive Coupling of 2-Heptanone with 1-Hexene.Representative Procedure. A 15-mL polymerization tubecontaining ca. 0.1 g of washed, ignited sand and a Teflon-coatedstirring bar was capped with a No-Air septum and flame driedunder a nitrogen stream. A suspension of sodium sand (0.22 g,9 mmol) in xylene was transferred to the tube by using a disposablepipet. Solvent was decanted by cannula, and the sodium waswashed with three 6-mL portions of degassed pentane. Gentlywarming the tube while purging with nitrogen removed thepentane. The tube was then capped with a butyl rubber septumand crown cap. NEP (5 mL) was added and vigorous stirring forseveral minutes gave a deep blue color and conglomerated thesodium sand. The l-hexene (0.22mL,0.15 g, 1.8 mmol) was addeddirectly by syringe and stirred for several minutes. The 2-heptanone (0.24 mL,0.19 g, 1.7 mmol) and tert-butyl alcohol (0.65mL) were added in three aliquots to the vigorously stirred mixtureover a 1-h period, and the mixture was stirred an additional0.5h. Cyclohexane (0.16 mL, 0.12 g) and n-tridecane (0.25 mL, 0.19g) were added as internal standards. The supernatant was de-

(33) Mclel lan, C. R. ;Edwards, Jr . , W. R. J. Am. Chem. Soc. 1944,66,409-12.

(34) Trevoy, L. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71,1675-8.(35) Mosher, W. A. J. Am. Chem. Soc. 1940. 62,552-4.(36) Olesch, B.; von Borsdorf, R. J. Praht. Chem. 1967, 36, 165 9.(37) Chr ist l , M.; Roberts, J. D. J. Org. Chem.1972,37,3443 52.(38) Ravid, U.; Ikan, R. J. Org. Chem. 1974, 39,2637 9.(39) Vogel, A.I. "Practical Organic Chemistry";Wiley: New York, N.Y.,

1966; pp 481-3.(40) Reference 23, pp 504-7.(41) Norton, D.G.; Haury, V. E. ;Davis, F.C.;Mi tchel l , L. J . ;Bal lard,

S. A. J. Org. Chem. 1954, 19,1054 66.

J. Org. Chem., Vol. 44, No. 14, 1979 2375

canted from the unreacted sodium and cautiously treated withwater (10 mL). The mixture was extracted with three 15-mLvolumes of pentane (98%), and the combined extracts werewashed with three 15-mL volumes of water. The solution wasdried over magnesium sulfate. GLC analysis revealed 6-methyl-6- dodecanol (65 % ), 2-heptanol (37 % ), 2-heptanon e (<I % ),n-hexane (5%), and l-hexene (177o), based on 2-heptanone.

Preparative Reductive Coupling of Acetone and l-Hexene.A three-necked, 100-mL flask was equipped with a mechanicalstirrer and a 10-mL addition funnel. A xylene slurry of sodiumshot (4.22 g, 0.184 g atom) and washed, ignited sand (1.26 g) wereadded. The solvent was decanted by cannula and the solids werewashed with four 20-mL volumes of pentane; solvent traces wereremoved by gently warming while flushing with nitrogen. NEP(50 mL) was added, and the mixture was cooled to ca. 15 oC ina dry ice 2-propanol bath. A deep blue solution formed after 25min of vig<lrous stirring, and the sodium shot agglomerated intoa faceted lump. Neat l-hexene (2.26 g,27 mmol) was added,discoloring the solution slightly. Neat terf-butyl alcohol (2.4Ig, 21 mmol) was added, instantly dispelling the color. A solutionof acetone (3.14 g, 54 mmol) and fert-butyl alcohol (3.87 g, 52mmol) was added over a 50-min period to the vigorously stirredmixture. Addit ional terf-butyl alcohol (1.57 g,21 mmol, wasintroduced, and the mixture was allowed to stir for 2 h. The liquidwas cautiously decanted onto water (100 mL) at 0 oC. The mixturewas extracted with four 30-mL volumes of pentane. The combinedextracts were washed with water (50 mL) and two 50-mL volumesof saturated sodium chloride solution and were dried overpowdered sodium sulfate. The solution was concentrated to ca.10 mL by distillation of solvent through al2-in. Holtzman column.The yellow residue was subjected to chromatography over silicagel (60 g, 0.2-0.5 mm), with diethyl ether-pentane (40:60 (v/v),600 mL) as elutant. The solution was reduced to a 50-mL volumeby distillation of solvent through a 24-in. column packed withglass hel ices and then to 3 mL by dist i l lat ion with a 12-in.Holtzman column. The product was distilled through a short-pathapparatus, giving 2-methyl-2-octanol (0.72 g, t9%): bp 115.5-117.0'C (79 torr). Elemental analysis for this compound was acceptable.

Preparation of Neopentyl Chloride in DEA. Neopentyltosylate (26.2 g,0.11 mol), anhydrous l i thium chloride (6.5 g,0.15mol), and DEA (50 mL) were combined in a 200-mL f laskcontaining a Teflon-coated stirring bar. The No-Air stopper wasreplaced with a condenser, and the mixture was warmed to 110'C. The solids dissolved readily at this temperature. The solutionwas stirred at 110 + 4 oC for 14 h. A trace of white precipitateappeared by the end of this period. The mixture was poured into100 mL of water in a 250-mL separatory funnel and extractedwith four 50-mL volumes of diethyl ether. The combined etherfractions were washed with four 50-mL volumes of water and weredried over anhydrous MgSOa. Solvent was effectively removedby a rapid distillation through a 22-in. Teflon spinning bandcolumn. The residue was distilled through an 8-in. stainless steelspinning band column, giving 7.5 S $9n) of neopentyl chloride:bp 84.0-85.5 oc ( l i t .42 84.3 "c); lH NMR (cDCl3) 6 3.30 (2 H, s),1.00 (9 H, s). Elemental analysis was acceptable.

Diethyl 2,2,3,3-Tetramethylsuccinate was prepared fromethyl isobutyrate by oxidation of the lithium enolate with iodineas reported by Brocksom and co-workers:a3 bp 12?.0-129.0 'C (20torr) (lit.44 125-127 "C (20 torr)); tH NMR (CDCls) 6 4.L (2 H,e), ca. 1.15 (9 H, superimposed t and s).

Preparation of 2,2,3,}-Tetramethylbutane-1,4-diol. Aflame-dried, nitrogen-flushed, 3-L flask containing 150 mL ofdiethyl ether and a Teflon-coated stirring bar was chilled to 0oC, and 25.0 g (0.66 mol) of lithium aluminum hydride was slowlyadded. A solution of 152 g (0.659 mol) of diethyl tetramethyl-succinate in ca. 500 mL of ether was added over a 60-min periodto the vigorously stirred slurry at 0 oC. The viscous mixture wasallowed to warm to ambient temperature and was stirred for 12h. The mixture was treated with 25 mL of water. 25 mL of 15Vo

(42) Weast, R. C., Ed. "Handbook of Chemistry and Physics"; TheChemical Rubber Co: Cleveland, Ohio, 1970; p C-44I.

(43) Brocksom, T. J.; Petragnani, N.; Rodriques, R.; La Scala Teixeira,H. Synthesi.s 1975, 396-7.

(44) Ausell, M. F.; Hickinbottom. W. J.: Holton. P. G. J. Chem. Soc.1 9 5 5 , 3 4 9 5 1 .

2376 J. Org. Chem., Vol. 44, No. 14, 1979

sodium hydroxide, and 75 mL of water at 0 oC over a 60-minperiod. The flocculant white precipitate was collected on a 18.5-cmdiameter Buechner funnel and was triturated with three 300-mLportions of ether; the solids were extracted for 12 h in a Soxhletapparatus and the ether fractions were combined. Solvent wasremoved on a rotary evaporator giving ca. 100 mL of a slurry ofwhite crystals. The diol was conveniently recrystallized from 4L of hot hexane, giving 59.2 g (62Vo) of white, feathery crystals:mp 209.5-211.5 "C; IR (KBr) ca. 3300 (br, s), 2940 (s), 2880 (s),1480 (s), 1378 (m), 13?0 (m), 1152 (m), 1150 (s);rH NMR (CDCI3)6 5 .55 (2 H, s) ,3 .39 (4 H, s) ,0 .89 (12 H, s) ; mass spect rum mf e( re la t ive in tens i ty ) 98 (12) , 83 (22) ,73 (11) ,72 ( I2) ,71 (12) ,69(13) , 58 (8) , 57 (100) , 56 (50) , 55 (53) , 54 (6) , 53 (7) , 45 ( r2) ,44(6) ,43 (46) ,42 (11) ,41 (60) ,40 (10) ,39 (21) . E lementa l ana lys iswas acceptable.

Preparat ion o f 2 ,2 ,3 ,3-Tet ramethy lbutanediy l 1 ,4-Ditosylate. In a 3-L flask containing a Teflon-coated stirringbar were combined 50.2 g (0.34 mol) of 2,2,3,3-tetramethyl-butane-1,4-diol and 1.0 L of pyridine that had been freshly distilledfrom barium oxide under nitrogen. Tosyl chloride (mp 66.5-68.5oC) was ground into a fine powder and 189 g (0.99 mol) was addedover a 40-min period to the stirred solution at 0 oC. The resultingyellow solution was stored for 7 days in a freezer, during whichtime a large quantity of plnidinrhydrochloride precipitated. Theyellow mixture was poured onto 1.0 L of ice in a 4-L beaker and2 L of chloroform was added. The mixture was separated in a6-L funnel, and the aqueous layer was extracted with two 700-mLportions of chloroform. The combined organic extracts werewashed with four 500-mL portions of a 3:1 solution of water andconcentrated hydrochloric acid and with two 1.5-L portions ofwater. The chloroform solution was dried over powdered sodiumsulfate, and solvent was removed on a rotary evaporator. Theresultant yellow oil (100 mL) crystallized upon standing for 12h and the product was recrystallized from ca. 1.0 L of hot 1:1chloroform-hexane. Filtration gave 110 g (7lTo) of irridescentwhite f lakes: mp 109.5-111.0'C; IR (KBr) 2950 (m), 2870 (m),1600 (m) , 1493 (m) , 1475 (m) , 1455 (m) , 1380 (w) , 1350 (s) , 1190(s ) , 1165 ( s ) , 1100 (m) ,963 ( s ) , 855 ( s ) , 820 (m) ,668 ( s ) , 660 (m) ,558 (s), 483 (m); tH NMR (CDCI3) 6 7.80 (2 H, d, Jo,thu = 9 Hz),7.35 (2 H, d, 4,*,o = 9 Hz), 3.80 (2 H, s), 2.30 (3 H, s), 0.84 (6 H,s). Elemental analysis was acceptable.

Preparation of 1,4-Dichlo ro-2,2,3,3-tetramethylbutane inHMPA. In a 1-L flask containing a Teflon-coated stirring barwere combined 2,2,3,3-tetramethylbutanediyl 1,4-ditosylate (130g, 0.066 mol), anhydrous lithium chloride (7.3 g,0.174 mol), andHMPA (500 mL). The mixture was warmed to 105 * 4 oC for12 h. The yellow solution was poured into 600 mL of water ina 3-L separatory funnel and the resulting mixture was extractedwith three 300-mL volumes of hexane. The hexane fractions werewashed with five 200-mL volumes of water and dried over MgSOa.Solvent was removed at reduced pressure on a rotary evaporator.Distillation afforded 10.6 g (85%) of dihalide: bp 88.0 91.0 'C

(6 torr); mp 44.0-46.0 oC; IR (CCl4) 2980 (br, s), 2890 (s), 1470(s), 1438 (m), 1400 (m), 1385 (s), 1373 (m), 1300 (s),1292 (s), 1138(s), 1130 (s),940 (w),897 (w); 'H NMR (CCl4) 6 3.53 (4 H, s), 1.03(12 H, s);mass spectrum mf e (relat ive intensity) 133 (5),97 (6),

91 (9 ) , 90 (5 ) , 69 (7 ) , 63 (7 ) , 57 (61 ) , 56 (100 ) , 55 (89 ) , 54 (8 ) , 53(12), 49 (16), 43 (32), 41 (70), 39 (42). Elemental analysis wassatisfactory.

Sowinski and Whitesides

Reduction of l-Hexene. Representative Procedure. A15-mL polyrnerization tube containing ca. 0.1 g of washed, ignitedsand and a Teflon-coated stirring bar was capped with a No-Airseptum and flame dried under a nitrogen stream. A suspensionof sodium sand (0.216 g, 9.4 mg atom) in xylene was transferredto the tube by disposable pipet. Solvent was decanted by cannula,and the metal was washed with three 5-mL aliquots of degassedpentane. The pentane was removed by gently warming undera nitrogen stream. The tube was capped with a butyl rubberseptum. DEA (2.0 mL) was added to the mixture, and vigorousstirring produced a deep blue color after several minutes. Asolut ion of l-hexene (0.147 g, 1.80 mmol) in DEA (5 mL) wasadded in drops over 2 min, maintaining the color. An aliquot offerf-butyl alcohol (0.3 mL, ca. 0.2 g, 3 mmol) was introduced,instantly dispelling the color. The mixture was vigorously stirredfor 11 h under 5 psi of nitrogen. A second aliquot of tert-butylalcohol (0.3 mL) was added to the resulting colorless solution,and the mixture was stirred at ambient temperature for anaddit ional 13 h. Cyclohexane (0.20 mL, 0.165 g) was added asan internal standard, and GLC analysis showed the presence of0 .0?? g (51%) of n-hexane and 0.0015 g ( I%) o f 1-hexene.

Acknowledgments. This work was supported by the

National Science Foundation Grant 771I282-CHE.

Registry No. DEA, 685-91-6; NEP, 2687-91-4; N-acetylmorpholine,1696-20-4; N-methyl-N'-acetylpiperazine, 60787-05-5; N-acetyl-pyrrolidine, 4030- 18-6; N,N-diisopropylacetamide, 7 59-22-8; N,N -

diethylisobutyramide, 3393 1 -44- 1 ; 7-methyl-7-tridecanol, 19016-75-2;3-ethyl-3-nonanol, 51246-24-3; 2-methyl-2-octanol, 628- 44- 4; l-n-hexylcyclohexanol, 3964-63-4; 2,2,3-trimethyl-3-nonanol, 70178-78-8;2, 2 - d imet h-v-l- l3- nonan ol, 25966 -6 4 -7 ; 4,6- d imethyl- 6-undecanol,701?8-79-9; 3-methyl-3-octanol, 5340-36-3; 1-methylcyclopentanol,1462-03-9; cis-1,2-dimethylcyclopentanol, 16467-13-3; 1-methyl-cyclohexanol, 590-67-0; cl .s-1,2-dimethylcyclohexanol, 19879-11-9;1-methylcycloheptanol, 37 61 -94-2; 1-methylcyclooctanol, 59123-41-0;cis- 1,2-dimethylcvcloheptanol, ?01 78-80-2; l{-propylpropionaldimine,i 7 07 -7 0-2; N-propyl- 2-propanon e imine, 289 1 6- 23-6; 1 -hexene, 592- 4l-6;2-heptanone, 1 10-43-0; 6-methyl-6-dodecanol, 62958-40-1; 2-heptanol,543-49-7 ; n-hexane, 1 10-54-3; acetone, 6i -64-l; neopentyl tosylate,2346-07-8; neopentyl chloride, 753-89-9; diethyl 2,2,3,S-letra-methylsuccinate, 33367-54-3; 2,2,3,3-tetramethylbutane-1,4-diol,1051 9-69-4: 2,2,3,3-tetramethylbutanediyl 1,4-ditosylate, 70178-81-3;1,4-dichloro -2,2,3,3-tntramethylbutane, 70178-83 -5;2,2-diethylbutaneyl

1-tosylate, 70178-84-6; 2,2-dimethylpropanediyl 1,3-ditosylate,22308-72-9; cyclohexane tosylate, 953-9 1-3; 2,2-diethyl- 1 -chlorobutane,

7 017 8-82-4; 2,2-dimethyl-1,3-dibromopropane, 5434-27'5; 1,3-di-bromo-2,2-dibromomethylpropane, 3229-00-3; bromocyclohexane,108-85-0; cyclohexene, 110-83-8; cyclohexane, 110-82-7; tetra-methylethylene, 563- 79- 1 ; 2,3-dimethylbutane, 79- 29-8; ethene, 7 4-85-l;2-methyl- 2-butanol, ?5-85-4; 2-methyl- 1 -pent,ene, 763-29- 1 ; 2-hexene,592-43-8; 3-pentanone, 96-22-0; cyclohexanone, 108-94-1; 3,3-di-methyl-2-butanone, 7 5-97 -8; ly',N-dimethylacetami de, 1'27 -I9-5; 2-octanol, i23-96-6; 1-hexen-5-one, 109-49-9; cis-1,2-dimethylcyclo-butanol, 1 594-23-6; 1 -hexen-5-ol, 626-94-8; 1 -hepten-6-one, 21889-88-3;1-hepten-6-ol, 1331 1,-7 6-7 ; 1-octen-?-one, 3664-60-6; 1-octen-7-ol,39546-75-3; 1-nonen-8-one, 5009-32-5; 1-nonen-8-ol, 65727-63-1;trans-I,2-dimethylcyclopentanol, 16467'04-2; trans-I,2'dimethyl-cyclohexanol, 19879-12-0; trans-I,2-dimethylcyclobutanol, 1551-58-2;t rans-7,2-d imethy lcyc loheptanol , 35099-39-9; 2 ,2-d ihydroxy-methyl- 1,3-propanediol tetratosyla Le, 1522-89-0; C 13H4O, 7 0f7 8-7 7 -7'