acros organics acta n°006

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Acros Organics journalfor chemists

Acros Organics

New Carbocyclic Ring Expansion of Cyclopentanones by Twoand Three Carbons Based on Anionic Domino Transformations 1

Cesium in Organic Synthesis 5

1-(2-Hydroxy-1-phenylethyl)-1,5-dihydropyrrol-2-one

a new polyvalent intermediate for asymmetric synthesis 11

New applications of Lithium perchlorate

and Lithium tetrafluoroborate 12

Reactivity and Synthetic Applications of(Z) or (E)-1,2-Dichloroethylene in Organic Synthesis 13

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Sequential combinations of simple and well-knowntransformations such as Michael addition, aldolization,nucleophilic substitution, and retro-Dieckmann reactionhave led to the proposal of new stereoselective anionicdomino transformations, including up to five differentsteps, allowing the facile and efficient two- and three-carbon ring expansion of cyclopentanones.

Among the growing number of useful sequential transformations usedin organic chemistry, domino reactions,1 which are also widelyinvolved in nature, emerge as powerful synthetic tools. This long timeknown concept allows both an economical and ecological access tocomplex molecules.2

Our goal was to access to the best efficiency in terms of selectivity,accessibility and cleanness in a project aimed at the selectivesynthesis of functionalized seven- and eight-membered rings, foundin a multitude of natural and unnatural bioactive targets. We kept ourinterest to anionic domino reactions initiated by very simple and userfriendly bases involved in simple and well-known transformationssuch as Michael addition, aldolization, nucleophilic substitution,and retro-Dieckmann reaction.

The general pathway for the two-carbon ring expansion starts witha Michael addition of an activated cyclopentanone with an ,-unsaturated aldehyde and involves an intramolecular aldolizationgiving rise to a highly functionalized bicyclo[3.2.1]octane ring system

incorporating the required seven-membered ring, released by aretro-Dieckmann reaction3 (Scheme 1, Z = COOMe).

The transformation showed a rather good generality under standardconditions using 0.5 eq of potasiumcarbonate in methanol and provedto be totally diastereoselective using either the reactivity of -ketoesters or 2-acetylcyclopentan-1-one with several 3-substituted-,-unsaturated aldehydes (Scheme 2).5 The overall sequence gaveonly one diastereomer of the desired cycloheptanol bearing fourstereogenic centers. The substituent at the prostereogenic center canbe an alkyl, an aryl, a furyl, and even a heteroatom or bearing a synthet-

ically useful oxygenated function. More recently we have found gratify-ing to use DBU, which usually gave better yields in shorter reaction time.4

A mechanistic rationale, based on a comparative study of thefragmentation of two C-4-methyl isomeric bicyclooctanols, has beenprovided to account for the total diastereoselectivity.6 These results,clearly established the thermodynamic control of the cascade andthe crucial influence of steric factors during the retro-Dieckmannring cleavage.

Interestingly enough, extention of the optimizedexperimental conditions (DBU, MeOH) to 2-substi-tuted acroleins resulted in a synthetically importantmodification of the overall anionic cascade. Thecondensation of 2-methylpropenal (R = Me) withDieckmann ester cleanly lead to functionalized a

cycloheptene carboxylic acid in very good yield(Scheme 3).7 The overall transformation namedMARDi cascade, involves a Michael addition,an intramolecular Aldol condensation, a Retro-Dieckmann reaction followed by dehydration andchemoselective ester saponification. The result isthe facile five-step one-pot diastereoselectiveformation of highly functionalized and synthetically

valuable cycloheptenes bearing two stereogeniccenters, a potential Michael acceptor double bondand two chemically differentiated carboxylate

groups. The generality of this new transformationwas very good and has been applied to several2-substituted ,-unsaturated aldehydes includingpropargylic or functionalized alkyl chains givinguseful allylic intermediates ready for further inter- orintramolecular synthetic transformations by specific

Acros Organics Acta 6 - 1999 3

New Carbocyclic Ring Expansion of Cyclopentanones by Twoand Three Carbons Based on Anionic Domino Transformations

RO

-

Re tro-Dieckmann

O

R H

+

O

Z

R

M

ROOC

Z

R

OH

R

Bicyclo[3.2.1]octanesO

Z

O-

R

R

O-

Z

O

R

R O Z

OH

R

R

Scheme 1

0.5 eq. K2CO3MeOH

R1

=OMe, OEt, Me

O

HR 2

+

Z

R 1OC OH

R2

40-94%

R2 = H, alkyl, aryl

O

COR 1

Scheme 2

R = Me, E t, nBu, , (CH2)2OBn, (CH2)2COOMe

1 eq DBU, MeOH

62-96%

COOH

MeOOC

R

O

COOMe

+

O

HR

S iMe3

Scheme 3

Laboratoire RSo, Ractivit en Synthse Organique,UMR au CNRS 6516, Centre de St-Jrme, bote D12, 13397

Marseille cedex 20, France. E mail: [email protected]

M. H. Filippini, T. Lavoisier-Gallo,E. Charonnet, J. Rodriguez*


4/20

manipulation of the diverse sites of reactivity. A bicyclic ketoestergave similar results allowing the facile construction of the correspon-ding functionalized bicyclo[5.4.0]undecene ring systems found inmany natural products (Scheme 4). Concerning the mechanisticdetermination and the origin of the total diastereoselectivity twopossible pathways have been proposed to rationalize these results

which seem to be the conjuction of both a kinetic and a thermody-namic control.

A related anionic three-carbon ring expansion cascade8 has beendeveloped to access with the same facility, to eight-membered rings,

which are common structural elements in numerous natural products.9

The new methodologie is based on the known fragmentation ofbicyclo[4.2.1]nonanes, which are rather rigid molecules, and could beincluded in a three-carbon ring expansion of cyclopentanone.10 ,-

Dialkylation of an easily enolizable 1,3-diactivated cyclopentanonewith an 1,4-dielectrophile gave the properly functionalized bicy-clo[4.2.1]nonane ready to be cleaved by an hydroxylic solvent suchas MeOH.11 Interestingly enough, by a judicious choice of the elec-trophilic partners we could also access to other bridged compoundsand especially the bicyclo[3.2.1]octane skeleton precursor ofseven-membered rings (Scheme 5).

This methodology constitutes a new facile anionic domino ringexpansion of cyclopentanones by two and three carbons for theflexible preparation of functionalized seven- and eight-memberedrings (Scheme 6).12 The method was applied to several configura-tionally cis-fixed benzylic or allylic dihalides, and a total chemoselec-tivity was observed with both 1,3- and 1,4-dichlorides, dibromides ordiodide. Alkylidenecycloheptanes could also be obtained in satisfac-tory yields by using simple 1,3-dihalides with a modest regioselectiv-ity depending upon the bulkiness of the R substituent on the doublebond. Similarly, new fused monocyclic and polycyclic structuresincorporating an eight-membered ring were also easily accessible ingood yields. For example the bicyclo[6.4.0]dodecane nucleus, presentin many important naturally occurring cyclooctanoids, such as taxane,neolemnanes and parvifoline, could be obtained either directly fromcommercially available ,-O-dibromoxylene or by using the

previously reported11 reactivity of the synthetically valuable 1,3-exo-cyclic diene arising from the condensation with 2,3-bis(iodomethyl)-1,3-butadiene. Interestingly, in the case of the indole derivative thefragmentation proceeded with good regioselectivity to give thecorresponding fused heterocycles as a 6:1 mixture of regioisomers.It is worthnoting that this fused indole substructure is found in cauler-pin, a naturally occurring plant growth regulator pigment and

Acros Organics Acta 6 - 19992

R = Me, (CH2)2OBn

O

COOMe

O

HR

+

COOH

MeOOC

R

1 eq DBU , MeOH

62-96%

Scheme 4

New Carbocyclic Ring Expansion of Cyclopentanones by Two and Three Carbons

M. H. Filippini, T. Lavoisier-Gallo, E. Charonnet, J. Rodriguez*Laboratoire RSo, Ractivit en Synthse Organique, UMR au CNRS 6516,Centre de St-Jrme, bote D12, 13397 Marseille cedex 20, France.E mail: [email protected]

Z = COOMe

O

Z

Z

DBU

MeOH

R

MeOH

Z

Z

COOMe

R

O Z

Z

MeOH

O Z

Z

R

XX

R

X

X

R

Z

Z COOMe

R65-77%

68-87%

C-C-Dialkylation Re tro-Dieckmann

B icyclo[4.2.1]nonanes

Bicyclo[3.2.1]octanes

Scheme 5


5/20

DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16061

Ethyl 2-cyclopentanonecarboxylate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17359

Methyl 2-cyclopentanonecarboxylate - available soon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17358

Dimethyl 2,5-cyclopentanonedicarboxylate- available soon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34209

PRODUCTS AVAILABLE FROM ACROS ORGANICS

New Carbocyclic Ring Expansion of Cyclopentanones by Two and Three Carbons

M. H. Filippini, T. Lavoisier-Gallo, E. Charonnet, J. Rodriguez*Laboratoire RSo, Ractivit en Synthse Organique, UMR au CNRS 6516,

Centre de St-Jrme, bote D12, 13397 Marseille cedex 20, France.E mail: [email protected]

constitutes also the basic skeleton of the non-natural potenttricyclic antidepressant iprindole. Another example of the syntheticpotential of the method is the facile construction of an eight-memberedring present in the biologically important quinoxalines.

In conclusion, from the few examples presented here, it is evident thatanionic domino reactions are a powerful synthetic tool, which com-bine at a very low cost simplicity and efficiency in terms of selectivi-ty, accessibility, and cleanness.

References

1 Tietze, L. F. Chem. Rev. 1996, 96, 242 and references cited therein.

2 Hall, N. Science 1994, 266, 32; Bradley, D. Chem. Ind. 1996, 46. Ho, T.-L.

Tandem Organic Reactions, Wiley, New York, 1992; Tietze, L. F.; Beifuss, U.

Angew. Chem. 1993, 105, 137; Angew. Chem., Int. Ed. Engl. 1993, 32, 131;

Trost, B. M. Angew. Chem. 1995, 107, 285; Angew. Chem., Int. Ed. Engl.

1995, 34, 259-281; Bunce, R. A. Tetrahedron 1995, 51, 13103; see also a spe-

cial issues: Chem. Rev. 1996, 96, 1 and Tetrahedron Symposia in Print n 62,

1996; Trost, B. M.; Krische M. J. Synlett 1998, 1. Neuschtz, K.; Velker, J.;

Neier, R. Synthesis, 1998, 227.

3 For review on the synthesis and reactivity of bicyclo[3.2.1]octanes, see:

Filippini, M. H.; Rodriguez, J. Chem. Rev. in press.

4 Filippini, M. H. Ph D Thesis, Marseille 1996.

5 Filippini, M. H.; Rodriguez, J. Santelli, M. J. Chem. Soc., Chem. Commun.

1993, 1647.

6 Filippini, M. H.; Faure, R.; Rodriguez, J. J. Org. Chem. 1995, 60, 6872.

7 Filippini, M. H.; Rodriguez, J. J. Org. Chem. 1997, 62, 3034.

8 Lavoisier-Gallo, T. Ph D Thesis, Marseille 1996.

9 For a review on eight-membered rings, see: Petasis, N. A.; Patane, M. A.

Tetrahedron 1992, 48, 5757.

10 For a review on the synthesis and reactivity of bicyclo[4.2.1]nonanes, see:

Casanova, J; Koukoua, G.; Waegell, B. Bull. Soc. Chim. Fr. 1990, 127, 528.

11 Lavoisier, T.; Rodriguez, Synlett 1995, 1241.

12 Lavoisier-Gallo, T.; Charonnet, E.; Rodriguez, J. J. Org. Chem. 1998, 63, 900.

Z Z

Z

Z Z

Z

Cl

Cl

B r

B r

N

N

Br

Br

N

Br

Br

PhO 2S

I

I

Z

R

ZZ

Z Z

Z

N

N

Z Z

Z

O

Z

Z

X

X

R

87%

68%

81%

87%

85%

65-77%

Z = COOMe

R = H, C5H11, Ph

X = Cl, Br

E/Z = 1 to 1.8/1

Major regioisomer

Z

Z

N

Z

S O2P h

Scheme 6



6/20

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Cesium compounds are well known catalysts for a

wide range of chemical reactions. Among these, CsF-and Cs2CO3- promoted alkylation and cyclizationreactions play an important role in the synthesis ofpharmaceutical intermediates. In many cases,cesium compounds are superior to theirpotassium analogs with respect to reactiontime and yield; most reactions proceedunder mild conditions in a variety of organ-ic solvents. In particular when strong basesare needed, reactions are selective and

furthermore, compatible with a broadrange of functional groups.

In the following, examples are listed whichprovide information about the advanta-geous use of cesium compounds in manyfold organicreactions.

C-C- Coupling Reactions

Suzuki-Type Cross Coupling Reactions

The palladium catalyzed cross coupling of aromatic- and alkenylboronic acids with aryl halides is a powerful and popular methodfor the formation of C-C-carbon bonds. Recent efforts focused oncircumventing the use of bases like aqueous carbonate which tend to

react with functional groups present in the desired reactants.According to Suzuki1, the function of the base in the couplingreaction is to form a boronate anion that is capable of effecting boronto palladium transmetallation. Therefore fluorides seem to presentan excellent alternative considering the high affinity of fluorideanions to boron and the stability of the product fluoroborate ion.

As presented in Scheme 1, an extensive study by Wright et al.2 foundthat cesium fluoride represents the best fluoride source regardingreaction time and yield. A further advantage consists in the solubilityof cesium fluoride in many organic solvents.

Almansa et al.3 report the application of CsF assisted boronic acid

cross coupling in the synthesis of a series of potent AT1 selectiveangiotensin II (AII) receptor antagonists (Scheme 2). AII plays animportant role in the regulation of blood pressure and volemia. Thecompounds are derivatives of Du Ponts Losartan, the first orallyactive AII antagonist that reached the market for the treatmentof hypertension.

The authors explained that the yield of 40 - 60 % of the key inter-

mediates obtained under usual conditions (Pd(PPH3)4, Na2CO3,toluene-H2O) could be increased to 80 - 90 % using the milderconditions (Pd(PPh3)4, CsF, DME).

Amination

Several palladium-catalyzed coupling reactions need a strong baseto proceed effectively. Here, cesium carbonate fulfills the desiredcriteria as demonstrated in manyfold applications (Schemes 3 - 5).In several publications Buchwald et al.4-6 describe the effectiveamination of aryl halides and triflates carrying base sensitive groupsin the presence of cesium carbonate. In Scheme 3 examples are given

where the use of cesium carbonate in place of sodium-t-butoxideleads to improved functional group compatibility and higher yields,also in the amination of electron-deficient aryl triflates.

Alkylation and ArylationUnder similar conditions the formation of allenic compounds fromthe reaction of aryl halides is reported by Miura et al. 8 (Scheme 4).

High yields and regioselectivity were observed for the palladium-catalyzed cross-coupling of mono- and diarylation of aryl iodidesreported by Satoh et al.9. An example is given in Scheme 5.


Cesium in Organic Synthesis

R B(OH)2 + 2.2 eq.CsF

Pd(PPh3)4 (cat).

R

X

e.g. R = C6H6, E -CH

X = CH2CO2CH3, CH2CN, NHCOCF 3,

CH2CH2OAc, CH2CH2OTs, CHO

CH-n-C 6H13

DMEBr

X

Y ield = 80 - 98 %

Scheme 1

(cat.)

100 oC, 18 h

90 %Tr = triphenylmethyl

Pd(PPh3)4

2.3 eq. CsF , DME

Br

MeOOCNPr

N

N N

N NTr

(HO)2B

N N

N NTr

N

NPrMeOOC

Scheme 2

NaOtBu

Y

ONa

84 % 28 %

86 % 47 %

92 % 49 %

Yield

NC OTf HN O

HN O

HN

Amine

O

PhOTf

Triflate

Y

NR R

Pd(O-Ac)2,BINAP(cat.)

1. 4eq .Cs2CO3

HN

R

R

+

Y

OTf

1 eq. 1.2 eq.

80 oC,tolueneB

A

A B*

Yield

* see ref. 7

Scheme 3

Chemetall GmbH, Trakehner Strae 3,D-60487 Frankfurt am Main, Germany

Martina M. Hber


8/20

Alkylation and Ring Closure

Recent reports demonstrate that the application of synthetic methodswhich take advantage of the classical cesium effect, are gainingincreased attention.

Whenever a strong base is needed todeprotonate a species with a high pka,e.g. alkylation reactions presented inSchemes 6 and 7, cesium carbonate isthe compound of choice. Furthermore,the use of this compound offers a wayfor ring closure reactions, which areotherwise difficult to obtain. As dis-played in Scheme 6, a pharmaceuticalcompany takes advantage of this reac-tivity in preparing novel bis-indolema-leimide macrocycle derivatives of usefor inhibiting Protein Kinase C in mam-mals10. Cesium carbonate does not only

provide excellent yields, but also works,- as demonstrated earlier, - in cases

where other functionalities are present.

A further example of an alkylationreaction with subsequent ring closureis shown in Scheme 7. Here, anotherpharmaceutical company describes thealkylation of substituted catecholderivatives11. In several steps, -bro-

moarylacetates are generated, which are then treated with 4-hydroxy-benzene sulfonamide derivatives to form -bromoesters. O-alkylation

of the phenolic hydroxyl group proceeds in the presence of cesiumcarbonate yielding important intermediates in the synthesis of

phenoxyphenylacetic acids and derivatives. Thesecompounds show endothelian antagonist activityand are useful in the treatment of cardiovasculardisorders.

Michael-Type Reaction

In the presence of the system CsF/Si(OEt)4, the 1,4-addition of ketones and phenylacetonitriles to , -

unsaturated ketones, esters, and nitriles

proceeds selectively and efficiently.Several examples using this type ofMichael reaction are reported byCorriu et al.12. More recently, K. H. Ahnand S. J. Lee13 report the conjugateaddition of-valerolactam to an , -unsaturated ester supported by CsF -Si(OEt)4. The reaction usually proceedsinstantly at ambient temperature toafford the corresponding N-substitutedlactam in high yields, as demonstrated

in Scheme 8. Solvents such as tolueneand THF can be employed whennecessary.

The role of CsF involves the nucleo-philic activation of Si(OEt)4yielding the



Martina M. HberChemetall GmbH, Trakehner Strae 3,D-60487 Frankfurt am Main,Germany

DMF, 130 oC

C

67 %R 1- O-Me, R 2, R 3: -H ; R 4: -Pr ; R5: -Et

27 %R1, R 3: -H ; R 2: -O-Me ; R 4: -P r ; R5: -E t

70 %R 5: -iBu;Me

Me

R1, R 3: -Me ; R2: -H ; R 4:

R 5

H4

R

RR

R C C

12

3

RR

R Br

12

3

Pd(OAc) 2 / PP h3 (cat.)

1.5 eq. Cs2CO3

54

R

CR C+

Scheme 4

H I +

Me

OH

Pd(OAc) 2 (cat.)

1 eq . Cs 2CO 3

+

Me

H H

Me

H OH

1 eq. 0.25 eq . 76 %

DMF, 100 oC

OH

3

Scheme 5

m(R1) (R1 )m

L = Cl, Br , I, mesyl, tosyl

(R1)mm(R

1)

N

H

OO V

H

N

L X

WYL

+

4eq.Cs 2CO3

DMF

V = O, or N-CH 3

R1= e.g. H, Hal, C -C4 alkyl,or alkoxy, OH, NO

m = 0, 1, 2, or 3

W = e.g.-O-, -S-, -S O-, -SO -, -CO-,-C -C6-, -NR 3-, -CONH-, -NHCO-

X, Y = C -C4alkylene or substituted alkylene

T = 0 oC - reflux

Yield ~ 20 - 50 %

2

1

122

N

YW

X

N

VO OScheme 6

HO

HO

C OOMeR1

R 2

Br (CH2)m Br

Cs 2 CO 3, DMF

R 1, R 2 = e. g. Hal, NO 2, NH2, CF 3, (C 1-C6)-alkyl,

N HCO-(C1-C6)-alkyl, COOR

m = 2,3,or 4

R 2

R 1COOMe

O

(CH2)m

O

O(CH2)m

OCOOE t

BrR1

R2

SO2NH

2

OH

R 3 R4+

R 3, R 4 = e .g. Hal, NO 2, NH2, CF 3, (C 1-C6)-alkyl,

NH CO-(C 1-C6)-alkyl, CO OR

Cs 2CO 3

DMF , heat

R 2

R 1

COOEt

O

H2NO

2S

O

(CH2)m

O

R4

R 3

Scheme 7


9/20

basic species which promotes enolate formation. In many cases thismethod allows the formation of pure cyclic compounds in a one potprocess, where usually hydrolysis would be observed andstepwise reactions would be necessary.

Fluorination

Cesium fluoride is well known as a good source of fluoride. A recentexample where it is used to generate optically active 1-fluorobenzenes with high enantiomeric excess is shown in Scheme 9 14. Asshown, potasium fluoride fails to generate the desired product. Themethod is useful for the synthesis of 1-fluoroalkyl benzenes withelectron withdrawing substituents such as cyano, nitro, carboxy, etc.The alcohol 2 is formed as a byproduct, probably in a competingreaction with the solvent; however, it can be easily removedby distillation or chromatography.

References

1. A. Suzuki; Acc. Chem. Res. 1982, 15, 178 - 184.

2. S. W. Wright, D. L. Hageman, and L. D. McClure; J. Org. Chem. 1994, 59,

6095 - 6097.

3. C. Almansa, L. A. Gomez, F. L. Cavalcanti, A. F. de Arriba, J. Garcia-Rafanell,

and J. Forn; J. Med. Chem. 1997, 40, 574 - 558.

4. J. P. Wolfe and S. L. Buchwald; Tetrahedron Lett. 1997, 38, 6359 - 6362.

5. J. Ahmann and S. L. Buchwald; Tetrahedron Lett. 1997, 38, 6363 - 6366.

6. J. P. Wolfe, J. Ahmann, J. P. Sadighi, R. A. Singer, and S. L. Buchwald;

Tetrahedron Lett. 1997, 38, 6367 - 6370.

7. J. P. Wolfe, S. L. Buchwald; J. Org. Chem. 1997, 62, 1264 - 1267.

8. S. Picsa-Art, T. Satoh, M. Miura, and M. Nomura; Chem. Lett. 1997, 823 - 824.

9. T. Satoh, Y. Kawamura, M. Miura, and M. Nomura; Angew. Chem.1997, 109,

1820 - 1822.

10. W. F. Heath, Jr., M. R. Jirousek, J. H. McDonald, III, and C. R. Rito; Eli Lilly

and Company1997, United States Patent, US 005624949 A.

11. S. W. Bagley et al., Merck & Co. Inc. 1997, United States Patent,

US 005668176 A.

12. R. J. P. Corriu and R. Perz; Tetrahedron Lett. 1985, 26, 1311 - 1314.

13. K.H. Ahn and S. J. Lee; Tetrahedron Lett. 1994, 35, 1875 - 1878.

14. E. Fritz-Langhals; Tetrahedron Lett. 1994, 35, 1851 - 1854.



Martina M. HberChemetall GmbH, Trakehner Strae 3,

D-60487 Frankfurt am Main,Germany

25 oC

98 %

(1 eq. / 0.1 eq.)N

O

COOEt

Si(OEt)4/ CsF

COOEt+NH

O

Scheme 8

N-methyl-

formamide

60 oC

KF:

a) 96.2 8 1 : 19b) 96.4 75 : 24

b) 96.4 25 : 75

ee (%) R atio 1: 2

21

R =a) 4-CN, b) 4-NO2,

c) 4-COOEt, d) 4-Br,e) 2-F , f) 4-(4 -NO2 phenyl),

g) 4-H

R

OH

+

R

F4e q.CsF

OS O2CH3

RR

OHScheme 9

Cesium Carbonate 99.5% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19204

Cesium bicarbonate 99.9% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20360

Cesium acetate 99% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19104

Cesium fluoride 99 % . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18951

4 Bromobenzaldehyde 99% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10667

4 Bromophenylacetonitrile 99% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15448

Tetrakis - (Triphenylphosphine)- palladium (0) 99% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20238



10/20

nd hints Tips and hints

Go to our catalogue search page by selecting catalogue /search

The new Acros Organics website offers 2 strategies to perform structure search.

For quick and easy searching just draw a free-hand structure in the left hand box.If you are used to working with ISIS or Chemdraw you can import your queries

using the universal SMILES format in the text search box.

1a 2a

1b

2b 3b

Structure search on the web

STEP 1 A :

you can start drawing once you

see a C in the middle of the box

Point with your mouse at

the C Leftclick and drag to drawa bond.Click again to start

a new bond

STEP 2 A :

to change a molecule, point

your mouse at the molecule andright-click the molecule until

you obtain a Nitrogen.

CLICK SEARCH

STEP 1 B :

Open ChemdrawNET together

with the Acros website. Drawyour structure using, select your

molecule by choosing select all,

then select copy as SMILE.

STEP 2 B :

select the SMILES option

on the search page.

STEP 3 B :

paste the SMILE structure

by pushing the control key and

the V key simultaneously


11/20

Tips and hints Tips and hints Tips and

4

5

6

STEP 5 :

Select the molecule of

your choice. The product

screen appears.

STEP 4 :

The program will now search the Acros Organics database

which contains the latest product additions. The screen now

shows all molecules matching your query.

STEP 6 :

MSDS datasheets are available

by selecting MSDS on this

product screen.


12/20

Announcement Announcement

The computer is omnipresent in life today. Not only when you

surf the net, but also when you use your credit card, receive a

detailed phone bill , cross a traffic light in the street. Bits and bytes

are involved in all this.

But what about the laboratory environment and

especially the organic chemistry lab ?

The computer is indeed a very welcome tool for the organic chemistrycommunity.

And in its early years it is certain that many chemists suffered thefrustrations arising from lost or smudged data. The potential ofcomputer- based recording systems for laboratory information hadto wait to be exploited untill some recent developments.

You mean more powerful computers?

No not necessarily , it has more to do with motivation from academicsand industrialists.

While a number of innovative specialist systems have been individually

developed, the focus is on establishing standards and protocols to beused in electronic laboratory notebooks.These ELNBs should provide scientists with a unified workingenvironment.

This sounds quite theoretical could you give us a real-

life example?

Expereact is one such electronic notebook and is now being usedby over 100 researchers at the UCL university in Belgium. Products,reactions and stock-keeping records of the chemicals are logged in alogical and secure manner. Scientists are able to share their experi-ences, by feeding and questioning the program with all the experi-ence they and their colleagues have gained from reactions theyhave performed. Users can consult the prorgam for a reaction , checkthe availablity of the necessary products in the lab and calculateautomatically the quantities necessary for this reaction. The programcan be linked to any databases of interest e.g. NMR spectra.

Could such an ELNB be used on a larger scale?

Yes, but the biggest obstacle is the legal acceptancs a notebook likethis. Patents linked to data have to be respected, the data authenticatedand a way of preventing data being altered by unauthorized peoplehas to be established, especially if you make these systems availableon the Internet to the whole scientific community.

And what about people ?

Even though scientists are spending more than half a day a week

consulting and copying data from one manual notebook to another,not everyone is eager to fully exploit the system. Only younger peopleor those that have worked in a laboratory for less than a coupleof years find it easy to change their note-taking practice.

Interview Interview Interview

ELNBs andOrganic Chemistry

During the JCO98 meeting in France which broughttogether over 700 participants, Jean-Rodriguez (Uni-

versit Aix-Marseille III) received the SFC AcrosOrganics award from J-P Genet ( President of theOrganic Chemistry Division) and Louis Ciorra(Director, Acros Organics France). The SFC awardis presented annually to motivate organic chemistsunder the age 40 in their research. See Mr Rodriguez'sarticle in this edition of Acta

SFC Acros Organics award in France

from left to right :

Jean Rodriguez, Louis Ciorra, J-P Genet

Interview with Dr. Luc Patiny, organic chemist, creator of Expereact


13/20Acros Organics Acta 6 - 1999 13

References

1 Diastereoselective bis-alkylation of chiral non-racemic , -unsaturated

-lactams.I. BAUSSANNE, A. CHIARONI, C. RICHE, J. ROYER and H.-P. HUSSON

Tetrahedron Lett., 1994, 35, 3931-3934

2 Asymmetric synthesis of 3-substituted pyrrolidones via -alkylation of a chiral

non-racemic -lactam I. BAUSSANNE, C. TRAVERS, J. ROYER

Tetrahedron Asym. 1998, 9, 797-804

3 Asymmetric Routes Towards Polyfunctionalized Pyrrolidines:Synthesis and

Reactivity of a Chiral Silyloxypyrrole

I. BAUSSANNE, J. ROYER.Tetraliedron Lett., 1996, 37, 1213-1216

4 Synthesis of (-)-Aza-Muricatacin : an Analogue of the Bioactive Muricatacin,

an Acetogenin of Annonaceae

I.BAUSSANNE, 0. SCHWARDT, J. ROYER, M. PICHON, B. FIGADERE, A.

CAVE,Tetrahedron Lett., 1997, 38, 2259-2262

5 Stereoselective Synthesis of 4,5-disubstituted pyrrolidin-2-ones by cuprate

addition to chiral , -unsaturated --lactams

I. BAUSSANNE, J. ROYER,Tetrahedron Lett. 1998, 39, 845-848

6 Asymmetric Synthesis of 5-Substituted Pyrrolidones via a Chiral N-

Acyliminium equivalent.

I.BAUSSANNE, J. ROYER, not published

7 Asymmetric Routes Towards Polyfunctionalized Pyrrolidines: A Short

Diastereoselective Synthesis of Polyhydroxylated Pyrrolidines and an

Indolizidine.

B. DUDOT, L. MICOUIN, I. BAUSSANNE and J. ROYER, submitted to Synthesis

1-(2-Hydroxy-1-phenylethyl)-1,5-dihydropyrrol-2-one

a new polyvalent intermediate for asymmetric synthesis

NO

OHPh

N

R2

O

R1

N

R2

R1

NH2

R1 R2

COOH

NR O NR

NH2

COOH

R1

NH2

COOH

R1 R2

N OR1

R2

NR1

OH H

R2

N

OHOH

HOH

N

OHH

OH OH

H H

H HH

HH

1)2)

6)

6)3)

5)

4)

7)

Scheme 1

1-(2-Hydroxy-1-phenylethyl)-1,5-dihydropyrrol-2-one . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33529


Centre National de La Recherche ScientifiqueJacques Royer - Directeur de recherche

avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, FranceE-Mail: [email protected]

Jacques Royer


14/20Acros Organics Acta 6 - 199912

Lithium perchlorate/ Diethyl ether induced rearrangement ofepimeric endo- and exodicyclopentadienyl vinyl ethers.N. Palani and K.K. Balasubramanian TetrahedronLetters, 34, 1993, 5001.

Formal [1,3] rearrangement of 2-Furyl methyl and2-thienylmethyl vinyl ether N. Palani and K.K.Balasubramanian, Tetrahedron. Lett. 36, 1995,9527

Mechanism of Lithium perchlorate /Diethyl ether-Catalysed rearrangement of - and - endo and exo-dicyclopentadienyl vinyl ether: Use of deuterium labelling anda chiral probe. N. Palani., A. Chada and K.K. Balasubramanian

J Org. Chem, 63, 5318, 1998

Mild and Efficient Tetrahydropyranylation of Alcohols- Catalysisby Lithium Perchlorate in Diethyl Ether. B. Sobhana Babu andK.K. Balasubramanian (Tetrahedron Lett, 1998)

Rearrangement of Dicyclopentadienyl vinyl ethers in Lithiumperchlorate/diethyl ether. Effect of V- substitution. Palani and K.K.

Balasubramanian 15 th. International IUPAC conference onorganic synthesis held at Indian Institute of Science Bangalore,India, December 11-16, 1994

Facile 1,3-Claisen rearrangement of 2-Furyl and 2-Thienylmethyl vinyl ethers in Lithium perchlorate/diethyl ether medium N. Palani and K.K. Balasubra-manian 15th International Congress of Hete-rocyclic Chemistryheld at Taper, August 6-11,1995

LPDE induced Ferrier reaction -Synthesis of 2,3-unsat-urated C-aryl glycosides. B. Sobhana Babu and K. K.

Balasubramanian.XVM International carbohydrate sympo-siumheld at Milan, Italy, July 21-26, 1996.

A Facile Ferrier rearrangement of Tri-0-acetyl-D-glucal withThio-Phenol, Phenols and aromatic-tert-amines in LPDE

medium - A convenient entry to C-aryl glycosides. B.Sobhana Babu, K.K. Balasubramanian.Xlth carbohy-drate conference held at Indian Institute of ChemicalBiology, Calcutta, India, November 21-22, 1996.

Behaviour of Ferrier systems in LPDE medium:Synthesis of 2-deoxy-galactosides B. Sobhana Babu,

K. K. Balasubramanian. 9th European CarbohydrateSymposiumheld at Utrecht, Netherlands, July 6-11, 1997.

Lithium tetrafluoroborate catalysed Ferrier rearrangementof triO-O-acetyl-D-galactal - Facile synthesis of alky2,3-unsaturatedglycopyranosides. B. Sobhana Babu and K. K. Balasubramanian215th ACS National meeting, held at Dallas, USA, March 29th -April2nd, 1998.

Aromatic (1,3)-Claisen rearrangement in Lithium perchlorate /Nitro methane medium. N. Geetha and K.K. Balasubramanian215th ACS National meeting held at Dallas, USA, March29-

April 2nd, 1998.

Mild and Efficient Tetrahydropyranylation of Alcohols- Catalysisby Lithium Perchlorate in Diethyl Ether, B. Sobhana Babu

and K.K. Balasubramanian XVIRth EuropeanColoquium on Heterocyclic Chemistry (ECHC),IRCOF-INSA, held at Rouen, Cedex, France. Oct 4-7th 1998.

LTAN catalysed synthesis of 2,3-unsaturated thioglucopyranosides. B. Sobhana Babu and K.K. Bala-

subramanian. XM Carbohydrate Conference heldat Dehra Dun, India, Nov 19-20, 1998.

New applications of Lithium perchlorate and Lithium tetrafluoroborate

Selected by Prof K.K. Balasubramanian, Indian

Institute of Technology, Madras, India

Lithium perchlorate, p.a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19471

Lithium perchlorate trihydrate, p.a. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19472

Lithium perchlorate, reagent ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42386

Lithium tetrafluoroborate, anhydrous, 98% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22377


Institute of Technology, Madras, India Prof K.K. Balasubramanian


15/20

Abstract : (Z) or (E)-1,2-dichloroethylene has provedto be an efficient reagent for the stereoselective intro-duction of a Carbon-Carbon double bond since its cou-pling with organometallic species allows efficiently thesynthesis of various unsaturated compoundssuitable for the stereoselective construction ofpolyene derivatives.

The stereoselective introduction of a Carbon-Carbon double bondinto a molecule is a problem familiar to many organic chemists.

In recent years, several novel synthetic methods havebeen developed in the literature. Among them, the tran-sition metal catalyzed coupling reaction of organometallicderivatives with vinyl halides and related electrophiles isan attractive alternative to the Wittig-type reaction. Thepotential of this approach has attracted the attention ofchemists worldwide and currently represents one ofthe more general routes to stereodefined olefins1,2.

Owing to the presence of two reactive terminal functions,much attention has recently been focused on the use of(Z) and (E)-1,2-dichloroethylenes as useful reagents for

the stereoselective introduction of a Carbon-Carbondouble bond. This article will consider the syntheticapplications of 1,2-dichloroethylenes towards the con-struction of unsaturated compounds.

In the presence of a catalytic amount of Ni(PPh3)4, thecross coupling of an excess of (Z) or (E)-1,2-dichloro-ethylene with alkyl Grignard reagents allows efficientlythe stereoselective synthesis of (Z) or (E)-1-chloroalkenes1 (Scheme 1)3. Under similar conditions, the coupling

with alkenylalanes affords stereoselectively chlorodiene derivatives 34.It is noteworthy that the nature of the nickel catalyst shows a criticalinfluence for the success of the reaction. Thus when using a Ni(II)complex, only symmetrical disubstituted products 4were obtained5.

The coupling reaction of 1,2-dichloroethylenes to form unsymmetricaldisubstituted products 2 is also of interest. Thus sequential substitu-tion of (Z) or (E)-1,2-dichloroethylene with Grignard reagents underNi(0)-catalysis affords in good yields stereodefined (E) or (Z)-olefins2 having an excellent stereoisomeric purity (Scheme 1)6. This

approach was used successfuly forthe synthesis of monoenic phero-mones as well as dienic pheromonesfor instance lobesia botrana 5whichhas a conjugated diene system of E,Z-configuration (Scheme 2)3.

On the other hand, the reaction of(E) or (Z)-1,2-dichloroethylene withterminal alkynes under palladium-copper catalysis occurs in a stereo-specific manner ( 99.5% isomeric

purity) thus providing an efficientaccess to stereodefined (E) or (Z)-chloroenynes 6 (Scheme 3)3, 7. Thisprocedure is of great interest sincethe preparation of organometallic


Reactivity and Synthetic Applications of(Z) or (E) - 1,2-Dichloroethylene in Organic Synthesis

Moud AlamiEcole Suprieure de Chimie Organique et Minrale, Dpartement de Chimie associ au CNRS,

13, bd de lHautil, 95092 Cergy Pontoise Cedex, FranceFax: (+33) 01 30 75 60 21

Reactivity and Synthetic Applications of

(Z) or (E) -1,2-Dichloroethylene in Organic Synthesis

ClCl

C8H17Cl

C8H17 Cl C8H17 R

C8H17R

C5H11Cl

ArAr

C5H11Al(i-Bu)2

Z or E

C8H17MgCl

Ni(PPh 3)4

RMgCl, Ni(0)

RMgCl, Ni(0)

Ni(0)

ArMgBr

Ni(acac)2 or

NiCl2(dppe) or

NiCl2(dppp)

C8H17MgCl

Ni(PPh 3)4

Z-1

3

E-1

Z-2

4

E-2

Scheme 1

ClCl

MgBr

BrMgOTHP

OAc

1/

2/

4/ Ac2O

3/ H3O+

5

Ni(0)

Pd(0)

Scheme 2

Cl

R

R 1

R

R R 1

Cl

R

R

R 1

PdCl2(PhCN)2CuI, piperidine

78-93%

R 1

PdCl2(PhCN)2CuI, piperidine

78-95%

ClCl

ClCl

Pd-Cu, piperidine80-95%

Pd-Cu, BuNH 280-90%

E-6 E-7

Z-6 Z-7

R, R 1 = C5H11, C6H5, Me3Si, (CH 2)3Cl, (CH2)3COOMe

CH2OH, (CH2)2OH, CH2NMe2, CH2C(Me)2NH2

Scheme 3


16/20

acetylide species is not required and allows a huge range of func-tionalized 1-alkynes to couple chemoselectively under very mildconditions.

Further coupling of 6 with a different 1-alkyne in the presence ofPdCl2(PhCN)2 affords stereospecifically enediynes 7

8, an interestingclass of unsaturated systems which are found in various biologicallyactive compounds. The use of PdCl2(PhCN)2 as catalyst in piperidinefor such coupling reaction have been shown to be much more effectivecatalysts than Pd(PPh3)4 or PdCl2(PPh3)2 since large rate enhance-ments were observed reducing the reaction time to 0.5-2h at room

temperature compared to 4-9h with Pd(PPh3)49

. The efficiency ofthis catalyst was demonstrated by the synthesis of the trieneframework of leukotriene B4 (LTB4)

which is an important metabolite ofthe arachidonic acid 10.

Chloroenynes readily obtained from1,2-dichloroethylenes are also suitablesynthetic intermediates for the pre-paration of functionalized chlorodieneand chlorotriene compounds havingstereodefined geometry. These com-

pounds are of interest in organicsynthesis since they are not photo-sensitive and they are more stable thanthe corresponding iodides or bromides.

Selective reduction of the Carbon-Carbon triple bond of chloroenynes8 allows efficiently the synthesis of all isomers of hydroxy-chlorodienes 911. If the reduction is performed with tributyltinhydride, it provides an efficient stereo and regioselective routeto chlorodienyl stannanes 10 (Scheme 4)12.

Concerning the synthesis of stereodefined chlorotrienes 14 and 16,two different synthetic approaches were developed. The first one,

which leads to functionalized chlorotrienes 14, is based on thepalladium mediated rearrangement of bis-allylic acetates 1313 andthe second one, is based on the stereoselective reduction of homo-propargylic alcohols 15 into the corresponding (E)-homoallylic alco-hols followed by an elimination reaction14 as described in scheme 5.

The remaining chloro group in unsaturated vinyl chlorides (chloro-enynes, chlorodienes and chlorotrienes) is not inert to furthercoupling. For instance, reaction of (E)-chloroenynes 6 with aryl oralkenyl Grignard reagents in the presence of Pd(II)-catalyst allowsefficiently the synthesis of various enyne compounds 17 (scheme 6) 15.

With alkyl Grignard reagents containing -hydrogen(s), thecoupling is less successful and -elimination reactions occur.Carrying out the reaction in THF-DMPU in the presence of solublecomplex MnCl22LiCl the cross coupling with alkyl Grignardreagents affords stereoselectively enynes 18 in good yields16. Finally

when treated with n-BuLi, (E)-chloroenynes 6 can be readily convertedinto substituted chloroenynes 19 or into terminal or internal 1,3-

diynes 20 (Scheme 6)17.



Moud AlamiEcole Suprieure de Chimie Organique et Minrale, Dpartement de Chimie associ au CNRS,13, bd de lHautil, 95092 Cergy Pontoise Cedex, FranceFax: (+33) 01 30 75 60 21

Cl

OH

R

R Cl

OH

R

OH

Cl

Cl

OH

R

SnBu 3

Cl

O

R

SnBu 3

R Cl

O

(E,E)-9 or (E,Z)-9

(E)-8 or (Z)-8

(Z,E)-9 or (Z,Z)-9

(E,E)-10 or (E,Z)-10

LAH or Red-Al

Sia 2BH then

AcOH

Bu3SnH, Pd(II)

MnO2

MnO2

(E,E)-11 or (E,Z)-11

(E,E)-12 or (E,Z)-12R = H, Me, C 5H11

Scheme 4

Cl

R Cl R

OAc

Cl

OAc

R 1

OH

R 1Cl

16

R = H, Me, Pr R 1 = C5H11, C6H5, p-MeOC6H4, p-i-PrC6H4

Pd(II)

1/ Red-Al2/ MsCl

3/ DBU

15

(E,E,E )-14 or(E,E,Z) -14(E,E,E )-13 or(E,E,Z) -13

Scheme 5

Cl

R

R 2MgX, MnCl22LiCl

THF-DMPU

R 1

R

R 2

R

Cl

R

R E

E

R 1MgX, PdCl2(PPh 3)2THF-Et 3N

n-BuLi, -100c

then E+

n-BuLi, -30c

then E+

E-6

17

18

19

20

51-95%

51-96%

63-91%

51-95%

R 1 = Aryl, alkenyl R 2 = 1, 2 or 3 alkylE = COOEt, CH(OH)R, CONHPh, SnBu 3, SiMe3, PPh 2

Scheme 6

R1R

R

R1

R R1

R1R

Zn (Cu/Ag)

MeOH, H2O, 20C

Zn (Cu/Ag)

MeOH, H2O, 20C

R = n-Bu R1 = (CH2)7COOMe

80%

75%

Scheme 7


17/20

The palladium-catalyzed sequential stereospecific substitution of (E)or (Z)-1,2-dichloroethylenes by terminal alkynes or polyenynesfollowed by stereoselective reduction of the triple bonds has provedto be a reliable method for the synthesis of molecules having longpolyenic chains. For instance, pure (Z,Z,Z) and (Z,E,Z)-conjugatedtrienes have been produced through zinc reduction of enediynederivatives (Scheme 7)18.

The efficiency of this procedure was demonstrated by a convergenttotal synthesis of lipoxin B4 (LXB4) which is a metabolite of thearachidonic acid19. This approach allows chemoselectively theconstruction of the conjugated tetraene framework (E,Z,E,E) of LXB4in a limited number of steps and without any protectiondeprotection sequence of the alcohol functions (Scheme 8).

Following this synthetic strategy, various polyene compoundscontaining 5, 6 or 7 double bonds can be prepared stereoselectivelyin good yield20. Carrying out the reaction from chlorotrienederivatives, conjugated polyene compounds containing up to 6 doublebonds with all-E configuration can also be prepared. Thus, the

coupling reaction between terminal dienyne 22with chlorotriene 21 under Pd-catalysis andsubsequent stereoselective reduction of thetriple bonds furnished the polyene containingone Z-double bond which is not stable atroom temperature and isomerized readilyinto pure all-E hexaene 23 (Scheme 9)14.

References

1. Tamao, K. in Comprehensive Organic Synthesis, Vol.

3; Trost, B.M.; Fleming, I.; Pattenden, G. Ed.;

Pergamon Press: Oxford, 1991, pp 435.

2. Knight, D.W. in Comprehensive Organic Synthesis,

Vol. 3; Trost, B.M.; Fleming, I.; Pattenden, G. Ed.;

Pergamon Press: Oxford, 1991, pp 481.

3. Ratovelomanana, V.; Linstrumelle, G. Tetrahedron

Lett. 1981, 22, 315.

4. Ratovelomanana, V.; Linstrumelle, G. Bull. Soc. Chim.

Fr. 1986, 174.

5. Corriu, R.J.P.; Masse, J.P. J. Chem. Soc. Chem. Comm.

1972, 144.

6. Ratovelomanana, V.; Linstrumelle, G. Synth. Commun.

1984, 14, 179.

7. Chemin, D.; Linstrumelle, G. Tetrahedron 1994, 50,

5335.8. Alami, M.; Gueugnot, S.; Domingues, E.; Linstrumelle, G. Tetrahedron 1995, 51,

1209.

9. Alami, M.; Linstrumelle, G. Tetrahedron Lett. 1991, 32, 6109.

10. Chemin, D.; Linstrumelle, G. Tetrahedron 1992, 48, 1943.

11. Guillerm, D.; Linstrumelle, G. Tetrahedron Lett. 1986, 27, 5857.

12. Alami, M.; Ferri, F. Synlett. 1996, 755.

13. Mladenova, M.; Alami, M.; Linstrumelle, G. Tetrahedron Lett. 1996, 37, 6547.

14. Crousse, B.; Alami, M.; Linstrumelle, G. Tetrahedron Lett. 1997, 38, 5297.

15. Ramiandrasoa, P.; Brhon, B.; Thivet, A.; Alami, M.; Cahiez, G. Tetrahedron

Lett. 1997, 38, 2447.

16. Alami, M.; Ramiandrasoa, P.; Cahiez, G. Synlett. 1998, 325.17. Alami, M.; Crousse, B.; Linstrumelle, G. Tetrahedron Lett. 1995, 36, 3687.

18. Alami, M.; Crousse, B.; Linstrumelle, G. Tetrahedron Lett. 1994, 35, 3543.

19. Alami, M.; Crousse, B.; Linstrumelle, G.; Mambu, L.; Larchevque, M.

Tetrahedron Asym. 1997, 8, 2949.

20. Crousse, B.; Alami, M.; Linstrumelle, G. Tetrahedron Lett. 1995, 36, 4245.



Moud AlamiEcole Suprieure de Chimie Organique et Minrale, Dpartement de Chimie associ au CNRS,

13, bd de lHautil, 95092 Cergy Pontoise Cedex, FranceFax: (+33) 01 30 75 60 21

R1R

R

R1

R R1

R1R

Zn (Cu/Ag)

MeOH, H2O, 20C

Zn (Cu/Ag)

MeOH, H2O, 20C

R = n-Bu R1 = (CH2)7COOMe

80%

75%

Scheme 8

C5H11

C5H11Cl

C5H11

C5H11

+

2

PdLn, CuI

2

22

Zn21 22

23

Scheme 9

trans-1,2 - Dichloroethylene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40684

cis-1,2 - Dichloroethylene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11338



18/20

Acros Organics extra dry solvents meet the necessary quality standardsfor synthesis in anhydrous environments and for some column chroma-tography applications.

The water content of the Acros Organics Extra Dry solvents is lowerthan 50 ppm.( Batches of these solvents with even lower water

contents are routinely available, for more information contact yourAcros Organics distributor.

Acros Organics Extra Dry Solvents are packaged under an inert gas andplaced in double-sealed double-layer aluminum bags. This eliminatesindefinitely any risk of water, light and dust contamination of the solventduring storage.

How to use :

Aluminum bags should therefore only be opened just before usingthe product. To withdraw required amounts of solvent we recommend

following procedure: Prepare smaller diameter dry syringes to piercethe septum.

Fill it with a dry inert gas (example nitrogen). Choose a new injectionsite very time you pierce the septum. Push the inert gas into thebottle and finally withdraw the required amount of solvent. Store thebottle in a dry environment.

and hints Tips and hints

Acetone, extra dry, water


19/20

Box containing :

1 board

1 dice

4 counters

174 cards

1 manual including background informa-

tion on the 99 molecules in the game.

589 atoms and bonds

Warning :

contains small parts, not suitable for chil-

dren under age of 3

Gameplay :

Each player draws a card showing

the molecule he or she has to build.

By throwing the dice the player moves

around the board.

He can win or lose bonds or molecules

from the bank or even from another

player. Will you be the first

to build your molecule ?

Order Moleko from your Acros Organics

distributor today.

Code 97968

Play the molecule game and discoverthe fun of chemistry, even at home

1998, Jean-Marie Lehn, Prix Nobel de Chimie Universit - Louis Pasteur, Strasbourg, France

CNRS/CNRS EDITIONS - 15, rue Malebranche - 75005 PARIS FRANCE

The Molecule Game

Moleko

The winner of thischallenging andeducational game isthe first to build a chemicalmolecule by collectingand assembling thenecessary bondsand atoms during play.

2 - 4 players10 years and up1 hour of exciting play


20/20

ACROS ORGANICS N.V.

Geel West Zone 2

Janssen Pharmaceuticalaan 3aB-2440 Geel Belgium

Tel.: +32(0)14/57.52.11

For more information, please contact your local dealer

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