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New Carbocyclic Ring Expansion of Cyclopentanones by Two and Three Carbons Based on Anionic Domino Transformations Cesium in Organic Synthesis
1-(2-Hydroxy-1-phenylethyl)-1,5-dihydropyrrol-2-one

1 5 11 12 13

a new polyvalent intermediate for asymmetric synthesis

Acros Organics journal for chemists

New applications of Lithium perchlorate

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Reactivity and Synthetic Applications of

May 1999

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

cts u d o r p w e n r o f e d See insi

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No 44 10-Deacetylbaccatin III , a starting material in semisynthetic production of Taxol and analogues. No 45 Calix[8]arene a tool for the recognition and purification of fullurenes No 46 Aminomalonaldehyde, an intermediate to build many unusual heterocyclic molecules. NEW No 47 Butadiene diepoxide, a versatile mutidisciplinar reagent NEW No 48 THAF, Tetrabutyl Ammonium Fluoride, a mild fluorination reagent.

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No 1 on Combinatorial Chemistry : Solid Phase synthesis of compound libraries and their application in drug discovery by Mark A. Gallop, Affimax Research Institute,USA No 2 on Asymmetric Catalysis : From homogeneous to heterogeneous catalysis, recent advantages in asymmetric synthesis with nitrogen containing ligands by F.Fache, P.Gamez, B.Dunjic and M. Lemaire, Institut de Recherches sur la Catalyse,UCBL-CPE,Villeurbanne, France. NEW No 3 on Carbocycles : 1-Hydroxycyclopropanecarboxylic acid a ready available and efficient precursor.
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Laboratoire RSo, Ractivit en Synthse Organique, UMR au CNRS 6516, Centre de St-Jrme, bote D12, 13397 Marseille cedex 20, France. E mail: Jean.Rodriguez@reso.u-3mrs.fr

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

New Carbocyclic Ring Expansion of Cyclopentanones by Two and Three Carbons Based on Anionic Domino Transformations
Sequential combinations of simple and well-known transformations such as Michael addition, aldolization, nucleophilic substitution, and retro-Dieckmann reaction have led to the proposal of new stereoselective anionic domino transformations, including up to five different steps, allowing the facile and efficient two- and threecarbon ring expansion of cyclopentanones. Among the growing number of useful sequential transformations used in organic chemistry, domino reactions,1 which are also widely involved in nature, emerge as powerful synthetic tools. This long time known concept allows both an economical and ecological access to complex molecules.2 Our goal was to access to the best efficiency in terms of selectivity, accessibility and cleanness in a project aimed at the selective synthesis of functionalized seven- and eight-membered rings, found in a multitude of natural and unnatural bioactive targets. We kept our interest to anionic domino reactions initiated by very simple and user friendly bases involved in simple and well-known transformations such as Michael addition, aldolization, nucleophilic substitution, and retro-Dieckmann reaction. The general pathway for the two-carbon ring expansion starts with a Michael addition of an activated cyclopentanone with an , -unsaturated aldehyde and involves an intramolecular aldolization giving rise to a highly functionalized bicyclo[3.2.1]octane ring system incorporating the required seven-membered ring, released by a retro-Dieckmann reaction3 (Scheme 1, Z = COOMe). The transformation showed a rather good generality under standard conditions using 0.5 eq of potasiumcarbonate in methanol and proved to 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 gave only one diastereomer of the desired cycloheptanol bearing four stereogenic centers. The substituent at the prostereogenic center can be an alkyl, an aryl, a furyl, and even a heteroatom or bearing a synthetically useful oxygenated function. More recently we have found gratifying to use DBU, which usually gave better yields in shorter reaction time.4 A mechanistic rationale, based on a comparative study of the fragmentation of two C-4-methyl isomeric bicyclooctanols, has been provided to account for the total diastereoselectivity.6 These results, clearly established the thermodynamic control of the cascade and the crucial influence of steric factors during the retro-Dieckmann ring cleavage.
Scheme 3
O COOMe + O R H 1 eq DBU , MeOH 62-96% MeOOC R = Me, E t, nB u, S iMe 3 , (CH 2)2OBn, (CH 2)2COOMe R COOH

Scheme 1
O R O H R Z R O Z
M

OZ
RO
-

R R R OOC

OO Z R R Z R O

OH

Re tro-Dieckmann

OH

Bic yclo[3.2.1]octanes

Scheme 2
Z COR 1 + O R 1 =OMe, OE t, Me R
2

O R
2

0.5 eq. K 2CO3 MeOH 40-94% R 1OC

= H, alkyl, aryl

OH

Interestingly enough, extention of the optimized experimental conditions (DBU, MeOH) to 2-substituted acroleins resulted in a synthetically important modification of the overall anionic cascade. The condensation of 2-methylpropenal (R = Me) with Dieckmann ester cleanly lead to functionalized a cycloheptene carboxylic acid in very good yield (Scheme 3).7 The overall transformation named MARDi cascade, involves a Michael addition, an intramolecular Aldol condensation, a RetroDieckmann reaction followed by dehydration and chemoselective ester saponification. The result is the facile five-step one-pot diastereoselective formation of highly functionalized and synthetically valuable cycloheptenes bearing two stereogenic centers, a potential Michael acceptor double bond and two chemically differentiated carboxylate groups. The generality of this new transformation was very good and has been applied to several 2-substituted ,-unsaturated aldehydes including propargylic or functionalized alkyl chains giving useful allylic intermediates ready for further inter- or intramolecular synthetic transformations by specific
Acros Organics Acta 6 - 1999

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: Jean.Rodriguez@reso.u-3mrs.fr

Scheme 4
COOMe O + O R = Me, (CH 2)2OBn COOH R H 1 eq DBU , MeOH 62-96% MeOOC R

manipulation of the diverse sites of reactivity. A bicyclic ketoester gave similar results allowing the facile construction of the corresponding functionalized bicyclo[5.4.0]undecene ring systems found in many natural products (Scheme 4). Concerning the mechanistic determination and the origin of the total diastereoselectivity two possible pathways have been proposed to rationalize these results which seem to be the conjuction of both a kinetic and a thermodynamic control. A related anionic three-carbon ring expansion cascade8 has been developed 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 of bicyclo[4.2.1]nonanes, which are rather rigid molecules, and could be included in a three-carbon ring expansion of cyclopentanone.10 ,Dialkylation of an easily enolizable 1,3-diactivated cyclopentanone with an 1,4-dielectrophile gave the properly functionalized bicyclo[4.2.1]nonane ready to be cleaved by an hydroxylic solvent such as MeOH.11 Interestingly enough, by a judicious choice of the electrophilic partners we could also access to other bridged compounds and especially the bicyclo[3.2.1]octane skeleton precursor of seven-membered rings (Scheme 5).

This methodology constitutes a new facile anionic domino ring expansion of cyclopentanones by two and three carbons for the flexible preparation of functionalized seven- and eight-membered rings (Scheme 6).12 The method was applied to several configurationally cis-fixed benzylic or allylic dihalides, and a total chemoselectivity was observed with both 1,3- and 1,4-dichlorides, dibromides or diodide. Alkylidenecycloheptanes could also be obtained in satisfactory yields by using simple 1,3-dihalides with a modest regioselectivity depending upon the bulkiness of the R substituent on the double bond. Similarly, new fused monocyclic and polycyclic structures incorporating an eight-membered ring were also easily accessible in good yields. For example the bicyclo[6.4.0]dodecane nucleus, present in many important naturally occurring cyclooctanoids, such as taxane, neolemnanes and parvifoline, could be obtained either directly from commercially available ,-O-dibromoxylene or by using the previously reported11 reactivity of the synthetically valuable 1,3-exocyclic diene arising from the condensation with 2,3-bis(iodomethyl)1,3-butadiene. Interestingly, in the case of the indole derivative the fragmentation proceeded with good regioselectivity to give the corresponding fused heterocycles as a 6:1 mixture of regioisomers. It is worthnoting that this fused indole substructure is found in caulerpin, a naturally occurring plant growth regulator pigment and

Scheme 5

R X 68-87% Z O Z Z = COOMe O Z 65-77% X X R

MeOH

Z X O Z R
B icyclo[4.2.1]nonanes

Z
MeOH

R Z COOMe

DBU MeOH

C-C-Dia lkylation

Re tro-Die ckma nn

Z R Z COOMe

Z R
Bi cyclo[3.2.1]octanes

Acros Organics Acta 6 - 1999

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: Jean.Rodriguez@reso.u-3mrs.fr

Scheme 6

Z R Z Z
X R

R = H, C5H11, P h E/Z = 1 to 1.8/1

Z Z

65-77% Z Z
Cl

X
X = Cl, B r I

Cl

87% Z O Z
Br Br

85%

Br N Br N

Z = COOMe

68%
Br

87%

Z N

81%
Br

N PhO 2 S

N Z Z

Z Z Z

N Z S O2P h Major regioisomer

constitutes also the basic skeleton of the non-natural potent tricyclic antidepressant iprindole. Another example of the synthetic potential of the method is the facile construction of an eight-membered ring present in the biologically important quinoxalines. In conclusion, from the few examples presented here, it is evident that anionic domino reactions are a powerful synthetic tool, which combine at a very low cost simplicity and efficiency in terms of selectivity, accessibility, and cleanness.

3 4 5 6 7 8 9 10 11 12

References
1 2 Tietze, L. F. Chem. Rev. 1996, 96, 242 and references cited therein. 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. For review on the synthesis and reactivity of bicyclo[3.2.1]octanes, see: Filippini, M. H.; Rodriguez, J. Chem. Rev. in press. Filippini, M. H. Ph D Thesis, Marseille 1996. Filippini, M. H.; Rodriguez, J. Santelli, M. J. Chem. Soc., Chem. Commun. 1993, 1647. Filippini, M. H.; Faure, R.; Rodriguez, J. J. Org. Chem. 1995, 60, 6872. Filippini, M. H.; Rodriguez, J. J. Org. Chem. 1997, 62, 3034. Lavoisier-Gallo, T. Ph D Thesis, Marseille 1996. For a review on eight-membered rings, see: Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. 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. Lavoisier, T.; Rodriguez, Synlett 1995, 1241. Lavoisier-Gallo, T.; Charonnet, E.; Rodriguez, J. J. Org. Chem. 1998, 63, 900.

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

Martina M. Hber

Cesium in Organic Synthesis

Cesium compounds are well known catalysts for a wide range of chemical reactions. Among these, CsFand Cs2CO3- promoted alkylation and cyclization reactions play an important role in the synthesis of pharmaceutical intermediates. In many cases, cesium compounds are superior to their Scheme 2 potassium analogs with respect to reaction time and yield; most reactions proceed under mild conditions in a variety of organic solvents. In particular when strong bases are needed, reactions are selective and MeOOC furthermore, compatible with a broad range of functional groups. In the following, examples are listed which provide information about the advantageous use of cesium compounds in manyfold organic reactions. The authors explained that the yield of 40 - 60 % of the key intermediates obtained under usual conditions (Pd(PPH3)4, Na2CO3, toluene-H2O) could be increased to 80 - 90 % using the milder conditions (Pd(PPh3)4, CsF, DME).

N NTr N N (HO )2B

N NPr P d(P P h 3)4 (cat.) 2.3 eq. CsF , DME 100 oC, 18 h Tr = triphenylmethyl

MeOOC

N NPr

N NTr N N

Br

90 %

Amination
Several palladium-catalyzed coupling reactions need a strong base to proceed effectively. Here, cesium carbonate fulfills the desired criteria as demonstrated in manyfold applications (Schemes 3 - 5). In several publications Buchwald et al. 4-6 describe the effective amination of aryl halides and triflates carrying base sensitive groups in the presence of cesium carbonate. In Scheme 3 examples are given where the use of cesium carbonate in place of sodium-t-butoxide leads to improved functional group compatibility and higher yields, also in the amination of electron-deficient aryl triflates.
Scheme 3
ONa OTf NaOtBu + Y HN R 1 eq. 1.2 eq. R Pd( O-A c )2 , BINA P ( c at .) 1 .4 eq. Cs2 CO 3 80 o C, toluene R R N

C-C- Coupling Reactions Suzuki-Type Cross Coupling Reactions

Scheme 1
X R B (OH)2 + Br P d(P P h 3 )4 (ca t). 2.2 e q.CsF DME R X

e.g. R = C 6H 6, E -CH CH-n-C 6 H13 X = CH 2CO 2 CH 3, CH 2CN, NHCOCF 3, CH2CH 2OAc , CH 2CH 2 OTs , CHO

Y ield = 80 - 98 %

The palladium catalyzed cross coupling of aromatic- and alkenyl boronic acids with aryl halides is a powerful and popular method for the formation of C-C-carbon bonds. Recent efforts focused on circumventing 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 coupling reaction is to form a boronate anion that is capable of effecting boron to palladium transmetallation. Therefore fluorides seem to present an excellent alternative considering the high affinity of fluoride anions to boron and the stability of the product fluoroborate ion. As presented in Scheme 1, an extensive study by Wright et al.2 found that cesium fluoride represents the best fluoride source regarding reaction time and yield. A further advantage consists in the solubility of 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 selective angiotensin II (AII) receptor antagonists (Scheme 2). AII plays an important role in the regulation of blood pressure and volemia. The compounds are derivatives of Du Ponts Losartan, the first orally active AII antagonist that reached the market for the treatment of hypertension.

Triflate
O OTf Ph

Amine
HN HN HN O O

Yield A 92 % 86 % 84 %

Yield B* 49 % 47 % 28 %

NC

OTf

* se e ref. 7

Alkylation and Arylation

Under similar conditions the formation of allenic compounds from the reaction of aryl halides is reported by Miura et al.8 (Scheme 4). High yields and regioselectivity were observed for the palladiumcatalyzed cross-coupling of mono- and diarylation of aryl iodides reported by Satoh et al.9. An example is given in Scheme 5.

Acros Organics Acta 6 - 1999

Cesium in Organic Synthesis

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

Scheme 4
R2 R
3

+ Br

R5 C C

P d(OAc) 2 / P P h3 (ca t.) 1.5 e q. Cs 2 CO 3 DMF , 130 o C

R2 R
3 4

R1 C C C H R5

Me R 1, R 3: -Me ; R 2 : -H ; R 4: R 5: -iB u Me ; 70 % 27 % 67 %

R 1, R 3: -H ; R 2: -O-Me ; R 4 : -P r ; R 5 : -E t R 1- O-Me , R 2, R 3: -H ; R 4: -P r ; R 5: -E t

Scheme 5
Me Me Me

Pd(OAc) 2 (ca t .) H I + 3 OH 1 eq . Cs 2 CO 3 DMF , 10 0 o C OH

Whenever a strong base is needed to deprotonate a species with a high pka, e.g. alkylation reactions presented in Schemes 6 and 7, cesium carbonate is the compound of choice. Furthermore, the use of this compound offers a way for ring closure reactions, which are otherwise difficult to obtain. As displayed in Scheme 6, a pharmaceutical company takes advantage of this reactivity in preparing novel bis-indolemaleimide macrocycle derivatives of use for inhibiting Protein Kinase C in mammals10. Cesium carbonate does not only provide excellent yields, but also works, - as demonstrated earlier, - in cases where other functionalities are present.

+ H H OH H

A further example of an alkylation reaction with subsequent ring closure is shown in Scheme 7. Here, another 76 % 1 eq. 0.25 eq . pharmaceutical company describes the alkylation of substituted catechol derivatives11. In several steps, -bromoarylacetates are generated, which are then treated with 4-hydroxyAlkylation and Ring Closure benzene sulfonamide derivatives to form -bromoesters. O-alkylation Recent reports demonstrate that the application of synthetic methods of the phenolic hydroxyl group proceeds in the presence of cesium which take advantage of the classical cesium effect, are gaining carbonate yielding important intermediates in the synthesis of increased attention. phenoxyphenylacetic acids and derivatives. These compounds show endothelian antagonist activity Scheme 6 O V O V O O and are useful in the treatment of cardiovascular m(R ) (R )m (R )m m(R ) disorders. 4eq.Cs CO 3 2 L X
1

+ N H N H L Y

DM F T = 0 oC - reflux

N X W

N Y

Michael-Type Reaction
In the presence of the system CsF/Si(OEt)4, the 1,4addition of ketones and phenylacetonitriles to , unsaturated ketones, esters, and nitriles proceeds selectively and efficiently. Several examples using this type of Michael reaction are reported by Corriu et al.12. More recently, K. H. Ahn and S. J. Lee13 report the conjugate addition of -valerolactam to an , unsaturated ester supported by CsF Si(OEt)4. The reaction usually proceeds instantly at ambient temperature to afford the corresponding N-substituted R4 lactam in high yields, as demonstrated in Scheme 8. Solvents such as toluene O and THF can be employed when C OOE t necessary. The role of CsF involves the nucleophilic activation of Si(OEt)4 yielding the

V = O, or N-CH

L = Cl, Br, I, mesyl, tosyl W = e.g.-O-, -S -, -S O-, -S O -, -CO-, 2 -C 2 -C6 -, -NR 3-, -CONH-, -NHCOX, Y = C 1-C 4 alkylene or substituted alkylene

Yield ~ 20 - 50 %

R 1= e.g.H, Hal, C 1-C4 alkyl, or alkoxy, OH, NO 2 m = 0, 1,2, or 3

Scheme 7
HO HO R2 R1 C OOMe Br (C H2 )m Br (C H2 ) m Cs 2 CO 3 , DMF O R2 R1 O C OOMe

R 1 , R 2 = e. g. Hal, NO 2 , NH 2 , CF 3 , (C 1 -C6 )-alkyl, N HCO-(C 1 -C 6 )-alkyl, COOR m = 2, 3,or 4

R1 O (C H2 )m O R2

Br C OOE t + R3

S O 2 NH 2 Cs 2 CO 3 R4 DMF , heat OH

H 2NO 2S R3 R1 O (C H2 ) m O

R2 R 3 , R 4 = e .g. Hal, NO 2 , NH 2 , CF 3 , (C 1-C 6 )-alkyl, NH CO-(C 1 -C 6 )-alkyl, COOR

Acros Organics Acta 6 - 1999

Cesium in Organic Synthesis

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

Scheme 8
O NH + C OOE t 25 oC 98 % Si(OEt)4 / CsF (1 eq. / 0.1 eq.) O COOE t N

Scheme 9

OH R

OS O 2 CH3

4 e q. Cs F N-methylformamide 60 o C

F + R 1 ee (%) a) b) KF: b) 9 6.2 9 6.4 9 6.4 R atio 1: R 2 2

OH

R = a) 4-CN, b) 4-NO2 , c) 4-COOE t, d) 4-Br, e) 2-F , f) 4-(4-NO2 phenyl), g) 4-H

8 1 : 19 75 : 24 25 : 75

basic species which promotes enolate formation. In many cases this method allows the formation of pure cyclic compounds in a one pot process, where usually hydrolysis would be observed and stepwise reactions would be necessary.

References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. A. Suzuki; Acc. Chem. Res. 1982, 15, 178 - 184. S. W. Wright, D. L. Hageman, and L. D. McClure; J. Org. Chem. 1994, 59, 6095 - 6097. 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. J. P. Wolfe and S. L. Buchwald; Tetrahedron Lett. 1997, 38, 6359 - 6362. J. Ahmann and S. L. Buchwald; Tetrahedron Lett. 1997, 38, 6363 - 6366. J. P. Wolfe, J. Ahmann, J. P. Sadighi, R. A. Singer, and S. L. Buchwald; Tetrahedron Lett. 1997, 38, 6367 - 6370. J. P. Wolfe, S. L. Buchwald; J. Org. Chem. 1997, 62, 1264 - 1267. S. Picsa-Art, T. Satoh, M. Miura, and M. Nomura; Chem. Lett. 1997, 823 - 824. T. Satoh, Y. Kawamura, M. Miura, and M. Nomura; Angew. Chem. 1997, 109, 1820 - 1822. W. F. Heath, Jr., M. R. Jirousek, J. H. McDonald, III, and C. R. Rito; Eli Lilly and Company 1997, United States Patent, US 005624949 A. S. W. Bagley et al., Merck & Co. Inc. 1997, United States Patent, US 005668176 A. R. J. P. Corriu and R. Perz; Tetrahedron Lett. 1985, 26, 1311 - 1314. K.H. Ahn and S. J. Lee; Tetrahedron Lett. 1994, 35, 1875 - 1878. E. Fritz-Langhals; Tetrahedron Lett. 1994, 35, 1851 - 1854.

Fluorination
Cesium fluoride is well known as a good source of fluoride. A recent example where it is used to generate optically active 1-fluoro benzenes with high enantiomeric excess is shown in Scheme 914. As shown, potasium fluoride fails to generate the desired product. The method is useful for the synthesis of 1-fluoroalkyl benzenes with electron withdrawing substituents such as cyano, nitro, carboxy, etc. The alcohol 2 is formed as a byproduct, probably in a competing reaction with the solvent; however, it can be easily removed by distillation or chromatography.

PRODUCTS AVAILABLE FROM ACROS ORGANICS

Cesium Carbonate 99.5 % . . . . . . . . . . . . . . . . . . . . Cesium bicarbonate 99.9 % . . . . . . . . . . . . . . . . . . . Cesium acetate 99 % . . . . . . . . . . . . . . . . . . . . . . . . Cesium fluoride 99 % . . . . . . . . . . . . . . . . . . . . . . . . 4 Bromobenzaldehyde 99 % . . . . . . . . . . . . . . . . . . 4 Bromophenylacetonitrile 99 % . . . . . . . . . . . . . . . Tetrakis - (Triphenylphosphine) - palladium (0) 99 % . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19204 . . . . . . . . 20360 . . . . . . . . 19104 . . . . . . . . 18951 . . . . . . . . 10667 . . . . . . . . 15448 . . . . . . . . 20238

Acros Organics Acta 6 - 1999

and hints Tips and hints

Structure search on the web
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

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 draw a bond.Click again to start a new bond

STEP 2 A : to change a molecule, point your mouse at the molecule and right-click the molecule until you obtain a Nitrogen.

Go to our catalogue search page by selecting catalogue /search

CLICK SEARCH

2b

3b

1b
STEP 1 B : Open ChemdrawNET together with the Acros website. Draw your 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

Tips and hints Tips and hints Tips and h

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.

w Interview Interview Interview

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

ELNBs and Organic Chemistry

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 ?

This sounds quite theoretical could you give us a reallife example ?

The computer is indeed a very welcome tool for the organic chemistry community. And in its early years it is certain that many chemists suffered the frustrations arising from lost or smudged data. The potential of computer- based recording systems for laboratory information had to wait to be exploited untill some recent developments.
You mean more powerful computers ?

Expereact is one such electronic notebook and is now being used by over 100 researchers at the UCL university in Belgium. Products, reactions and stock-keeping records of the chemicals are logged in a logical and secure manner. Scientists are able to share their experiences, by feeding and questioning the program with all the experience they and their colleagues have gained from reactions they have performed. Users can consult the prorgam for a reaction , check the availablity of the necessary products in the lab and calculate automatically the quantities necessary for this reaction. The program can 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 like this. Patents linked to data have to be respected, the data authenticated and a way of preventing data being altered by unauthorized people has to be established, especially if you make these systems available on the Internet to the whole scientific community.
And what about people ?

No not necessarily , it has more to do with motivation from academics and industrialists. While a number of innovative specialist systems have been individually developed, the focus is on establishing standards and protocols to be used in electronic laboratory notebooks. These ELNBs should provide scientists with a unified working environment.

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 people or those that have worked in a laboratory for less than a couple of years find it easy to change their note-taking practice.

Announcement Announcement
SFC Acros Organics award in France
During the JCO98 meeting in France which brought together over 700 participants, Jean-Rodriguez (Universit Aix-Marseille III) received the SFC Acros Organics award from J-P Genet ( President of the Organic Chemistry Division) and Louis Ciorra (Director, Acros Organics France). The SFC award is presented annually to motivate organic chemists under the age 40 in their research. See Mr Rodriguez's article in this edition of Acta

from left to right : Jean Rodriguez, Louis Ciorra, J-P Genet

Centre National de La Recherche Scientifique Jacques Royer - Directeur de recherche avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, France E-Mail: royer@icsn.enrs-gif.fr

Jacques Royer

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

a new polyvalent intermediate for asymmetric synthesis

Scheme 1

Ph N

OH O 1) 2)

H N

O R1 R2 H2N

H N R1 R2 COOH
R1 R2

7) H N HO H HO OH 3) 5) HO N HO H HO OH R2 R1 H N 4)

6) R

H N

H N

6)

H2N
R1

COOH

R1

H N

O R2

H2N
R1 R2

COOH

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 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 Asymmetric Routes Towards Polyfunctionalized Pyrrolidines:Synthesis and Reactivity of a Chiral Silyloxypyrrole I. BAUSSANNE, J. ROYER.Tetraliedron Lett., 1996, 37, 1213-1216 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 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 Asymmetric Synthesis of 5-Substituted Pyrrolidones via a Chiral NAcyliminium equivalent. I.BAUSSANNE, J. ROYER, not published 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

PRODUCTS AVAILABLE FROM ACROS ORGANICS

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

Acros Organics Acta 6 - 1999

13

Institute of Technology, Madras, India

Prof K.K. Balasubramanian

New applications of Lithium perchlorate and Lithium tetrafluoroborate

Selected by Prof K.K. Balasubramanian, Indian Institute of Technology, Madras, India

Lithium perchlorate/ Diethyl ether induced rearrangement of epimeric endo- and exodicyclopentadienyl vinyl ethers. N. Palani and K.K. Balasubramanian Tetrahedron Letters, 34, 1993, 5001. Formal [1,3] rearrangement of 2-Furyl methyl and 2-thienylmethyl vinyl ether N. Palani and K.K. Balasubramanian, Tetrahedron. Lett. 36, 1995, 9527 Mechanism of Lithium perchlorate /Diethyl etherCatalysed rearrangement of - and - endo and exodicyclopentadienyl vinyl ether: Use of deuterium labelling and a chiral probe. N. Palani., A. Chada and K.K. Balasubramanian J Org. Chem, 63, 5318, 1998 Mild and Efficient Tetrahydropyranylation of Alcohols- Catalysis by Lithium Perchlorate in Diethyl Ether. B. Sobhana Babu and K.K. Balasubramanian (Tetrahedron Lett, 1998) Rearrangement of Dicyclopentadienyl vinyl ethers in Lithium perchlorate/diethyl ether. Effect of V- substitution. Palani and K.K. Balasubramanian 15 th. International IUPAC conference on organic synthesis held at Indian Institute of Science Bangalore, India, December 11-16, 1994 Facile 1,3-Claisen rearrangement of 2-Furyl and 2Thienylmethyl vinyl ethers in Lithium perchlorate/ diethyl ether medium N. Palani and K.K. Balasubramanian 15th International Congress of Heterocyclic Chemistry held at Taper, August 6-11, 1995 LPDE induced Ferrier reaction -Synthesis of 2,3-unsaturated C-aryl glycosides. B. Sobhana Babu and K. K. Balasubramanian. XVM International carbohydrate symposium held at Milan, Italy, July 21-26, 1996. A Facile Ferrier rearrangement of Tri-0-acetyl-D-glucal with Thio-Phenol, Phenols and aromatic-tert-amines in LPDE medium - A convenient entry to C-aryl glycosides. B. Sobhana Babu, K.K. Balasubramanian. Xlth carbohydrate conference held at Indian Institute of Chemical Biology, 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 Carbohydrate Symposium held at Utrecht, Netherlands, July 6-11, 1997. Lithium tetrafluoroborate catalysed Ferrier rearrangement of triO-O-acetyl-D-galactal - Facile synthesis of alky2,3-unsaturated glycopyranosides. B. Sobhana Babu and K. K. Balasubramanian 215th ACS National meeting, held at Dallas, USA, March 29th -April 2nd, 1998. Aromatic (1,3)-Claisen rearrangement in Lithium perchlorate / Nitro methane medium. N. Geetha and K.K. Balasubramanian 215th ACS National meeting held at Dallas, USA, March29April 2nd, 1998. Mild and Efficient Tetrahydropyranylation of Alcohols- Catalysis by Lithium Perchlorate in Diethyl Ether, B. Sobhana Babu and K.K. Balasubramanian XVIRth European Coloquium on Heterocyclic Chemistry (ECHC), IRCOF-INSA, held at Rouen, Cedex, France. Oct 47th 1998. LTAN catalysed synthesis of 2,3-unsaturated thio glucopyranosides. B. Sobhana Babu and K.K. Balasubramanian. XM Carbohydrate Conference held at Dehra Dun, India, Nov 19-20, 1998.

PRODUCTS AVAILABLE FROM ACROS ORGANICS

Lithium Lithium Lithium Lithium perchlorate, p.a. . . . . . . . . . . perchlorate trihydrate, p.a. . . perchlorate, reagent ACS . . . tetrafluoroborate, anhydrous, ..... ..... ..... 98% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19471 . . . . . 19472 . . . . . 42386 . . . . . 22377

12

Acros Organics Acta 6 - 1999

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

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

Reactivity and Synthetic Applications of

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

Abstract : (Z) or (E)-1,2-dichloroethylene has proved to be an efficient reagent for the stereoselective introduction of a Carbon-Carbon double bond since its coupling with organometallic species allows efficiently the synthesis of various unsaturated compounds suitable for the stereoselective construction of polyene derivatives. with alkenylalanes affords stereoselectively chlorodiene derivatives 34. It is noteworthy that the nature of the nickel catalyst shows a critical influence for the success of the reaction. Thus when using a Ni(II) complex, only symmetrical disubstituted products 4 were obtained5. The coupling reaction of 1,2-dichloroethylenes to form unsymmetrical disubstituted products 2 is also of interest. Thus sequential substitution of (Z) or (E)-1,2-dichloroethylene with Grignard reagents under Ni(0)-catalysis affords in good yields stereodefined (E) or (Z)-olefins 2 having an excellent stereoisomeric purity (Scheme 1)6. This

The stereoselective introduction of a Carbon-Carbon double bond into a molecule is a problem familiar to many organic chemists. In recent years, several novel synthetic methods have been developed in the literature. Among them, the tranScheme 2 sition metal catalyzed coupling reaction of organometallic derivatives with vinyl halides and related electrophiles is an attractive alternative to the Wittig-type reaction. The Cl Cl potential of this approach has attracted the attention of chemists worldwide and currently represents one of the 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-Carbon double bond. This article will consider the synthetic applications of 1,2-dichloroethylenes towards the construction of unsaturated compounds. In the presence of a catalytic amount of Ni(PPh3)4, the cross coupling of an excess of (Z) or (E)-1,2-dichloroethylene with alkyl Grignard reagents allows efficiently the stereoselective synthesis of (Z) or (E)-1-chloroalkenes 1 (Scheme 1)3. Under similar conditions, the coupling
Scheme 1
RMgCl, Ni(0) C 8H17 Cl Z-1 C 8H17MgCl Ni(PPh 3)4
C 5H11

1/

BrMg

OTHP

Ni(0) OAc 2/ 3/ H3O+ 4/ Ac2O

MgBr

Pd(0)

Scheme 3
Cl Cl

R Cl E -6
1

R1

Pd-Cu, piperidine 80-95%

PdCl 2(PhCN) 2 CuI, piperidine 78-95%

E -7

R1

R, R

= C5H11, C6H5, Me3Si, (CH 2)3Cl, (CH 2)3COOMe CH 2OH, (CH2)2OH, CH 2NMe2, CH 2C(Me)2NH2

Cl

Cl

Cl R Z-6

R1

Pd-Cu, BuNH 2 80-90%

PdCl 2(PhCN) 2 CuI, piperidine 78-93%

Z-7

R1

C 8H17 Z-2

approach was used successfuly for the synthesis of monoenic pheromones as well as dienic pheromones for instance lobesia botrana 5 which has a conjugated diene system of E, Z-configuration (Scheme 2)3. On the other hand, the reaction of (E) or (Z)-1,2-dichloroethylene with terminal alkynes under palladiumcopper catalysis occurs in a stereospecific manner ( 99.5% isomeric purity) thus providing an efficient access to stereodefined (E) or (Z)chloroenynes 6 (Scheme 3)3, 7. This procedure is of great interest since the preparation of organometallic
Acros Organics Acta 6 - 1999

Ar 4

ArMgBr Ar Ni(acac) 2 or NiCl2(dppe) or NiCl2(dppp)

Cl

Cl

Al(i-Bu) 2

C 5H11 Cl 3

Z or E

Ni(0)

C 8H17MgCl Ni(PPh 3)4 RMgCl, Ni(0) Cl E -1 E -2

C 8H17

C 8H17 R

15

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

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

acetylide species is not required and allows a huge range of functionalized 1-alkynes to couple chemoselectively under very mild conditions.
Scheme 4
LAH or Red-Al R OH (E,E )-9 or (E,Z )-9 Cl R OH (E )-8 or (Z)-8 OH R Cl (Z,E )-9 or (Z,Z )-9 OH Bu 3SnH, Pd(II) R SnBu 3 R = H, Me, C 5H11 (E,E )-10 or (E,Z )-10 Cl MnO2 R SnBu 3 (E,E )-12 or (E,Z )-12 O Cl Cl MnO2 R Cl O (E,E )-11 or (E,Z )-11

Selective reduction of the Carbon-Carbon triple bond of chloroenynes 8 allows efficiently the synthesis of all isomers of hydroxychlorodienes 911. If the reduction is performed with tributyltin hydride, it provides an efficient stereo and regioselective route to 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 the palladium mediated rearrangement of bis-allylic acetates 1313 and the second one, is based on the stereoselective reduction of homopropargylic alcohols 15 into the corresponding (E)-homoallylic alcohols followed by an elimination reaction14 as described in scheme 5.
Scheme 6
Cl n-BuLi, -100c then E + 63-91% Cl R R 20 E E -6 R2 n-BuLi, -30c then E + 51-95% E = COOEt, CH(OH)R, CONHPh, SnBu
3,

Sia 2BH then AcOH

Further coupling of 6 with a different 1-alkyne in the presence of PdCl2(PhCN)2 affords stereospecifically enediynes 78, an interesting class of unsaturated systems which are found in various biologically active compounds. The use of PdCl2(PhCN)2 as catalyst in piperidine for such coupling reaction have been shown to be much more effective catalysts than Pd(PPh3)4 or PdCl2(PPh3)2 since large rate enhancements were observed reducing the reaction time to 0.5-2h at room
Scheme 5
R OAc (E,E,E )-13 or(E,E,Z) -13 1/ Red-Al 2/ MsCl 3/ DBU 15 R = H, Me, Pr R1 R1 16 = C5H11, C6H5, p-MeOC6H4, p-i-PrC 6H4 Cl Pd(II) R OAc (E,E,E )-14 or(E,E,Z) -14 Cl

R 1MgX, PdCl2(PPh 3)2 THF-Et 3N 51-95% R 17

R1

R 19

R 2MgX, MnCl 22LiCl THF-DMPU 51-96% SiMe 3, PPh 2 R 1 = Aryl, alkenyl

18

R 2 = 1, 2 or 3 alkyl

OH R1

Cl

Cl

temperature compared to 4-9h with Pd(PPh3)4 9. The efficiency of this catalyst was demonstrated by the synthesis of the triene framework of leukotriene B4 (LTB4) which is an important metabolite of the arachidonic acid 10. Scheme 7 Chloroenynes readily obtained from 1,2-dichloroethylenes are also suitable synthetic intermediates for the preparation of functionalized chlorodiene and chlorotriene compounds having stereodefined geometry. These compounds are of interest in organic synthesis since they are not photosensitive and they are more stable than the corresponding iodides or bromides.
R

The remaining chloro group in unsaturated vinyl chlorides (chloroenynes, chlorodienes and chlorotrienes) is not inert to further coupling. For instance, reaction of (E)-chloroenynes 6 with aryl or alkenyl Grignard reagents in the presence of Pd(II)-catalyst allows efficiently the synthesis of various enyne compounds 17 (scheme 6) 15. With alkyl Grignard reagents containing -hydrogen(s), the coupling is less successful and -elimination reactions occur. Carrying out the reaction in THF-DMPU in the presence of soluble complex MnCl22LiCl the cross coupling with alkyl Grignard reagents affords stereoselectively enynes 18 in good yields16. Finally when treated with n-BuLi, (E)-chloroenynes 6 can be readily converted into substituted chloroenynes 19 or into terminal or internal 1,3diynes 20 (Scheme 6)17.

Zn (Cu/Ag) MeOH, H 2O, 20C R1 80% Zn (Cu/Ag) R R1 R = n-Bu MeOH, H 2O, 20C 75% R 1 = (CH2)7COOMe R

R1

R1

14

Acros Organics Acta 6 - 1999

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

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

Scheme 8
R Zn (Cu/Ag) MeOH, H 2O, 20C R1 80% Zn (Cu/Ag) R R1 R = n-Bu MeOH, H 2O, 20C 75% R 1 = (CH2)7COOMe R1 R R1

coupling reaction between terminal dienyne 22 with chlorotriene 21 under Pd-catalysis and subsequent stereoselective reduction of the triple bonds furnished the polyene containing one Z-double bond which is not stable at room temperature and isomerized readily into 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. C5H11 2 4. Ratovelomanana, V.; Linstrumelle, G. Bull. Soc. Chim. Fr. 1986, 174. 5. Corriu, R.J.P.; Masse, J.P. J. Chem. Soc. Chem. Comm. C5H11 1972, 144. 2 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.

Scheme 9

+
Cl 21 22
2

PdLn, CuI
C5H11

Zn

23

C5H11

The palladium-catalyzed sequential stereospecific substitution of (E) or (Z)-1,2-dichloroethylenes by terminal alkynes or polyenynes followed by stereoselective reduction of the triple bonds has proved to be a reliable method for the synthesis of molecules having long polyenic chains. For instance, pure (Z,Z,Z) and (Z,E,Z)-conjugated trienes have been produced through zinc reduction of enediyne derivatives (Scheme 7)18. The efficiency of this procedure was demonstrated by a convergent total synthesis of lipoxin B4 (LXB4) which is a metabolite of the arachidonic acid19. This approach allows chemoselectively the construction of the conjugated tetraene framework (E,Z,E,E) of LXB4 in a limited number of steps and without any protection deprotection sequence of the alcohol functions (Scheme 8). Following this synthetic strategy, various polyene compounds containing 5, 6 or 7 double bonds can be prepared stereoselectively in good yield20. Carrying out the reaction from chlorotriene derivatives, conjugated polyene compounds containing up to 6 double bonds with all-E configuration can also be prepared. Thus, the

PRODUCTS AVAILABLE FROM ACROS ORGANICS

trans-1,2 - Dichloroethylene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40684 cis-1,2 - Dichloroethylene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11338

Acros Organics Acta 6 - 1999

17

s and hints Tips and hints

Acros Organics extra dry solvents meet the necessary quality standards for synthesis in anhydrous environments and for some column chromatography applications. The water content of the Acros Organics Extra Dry solvents is lower than 50 ppm.( Batches of these solvents with even lower water contents are routinely available, for more information contact your Acros Organics distributor. Acros Organics Extra Dry Solvents are packaged under an inert gas and placed in double-sealed double-layer aluminum bags. This eliminates indefinitely any risk of water, light and dust contamination of the solvent during storage. How to use :

Extra dry solvents from Acros Organics

Aluminum bags should therefore only be opened just before using the product. To withdraw required amounts of solvent we recommend following procedure: Prepare smaller diameter dry syringes to pierce the septum. Fill it with a dry inert gas (example nitrogen). Choose a new injection site very time you pierce the septum. Push the inert gas into the bottle and finally withdraw the required amount of solvent. Store the bottle in a dry environment.

PRODUCTS AVAILABLE AT ACROS ORGANICS

Acetone, extra dry, water <50 ppm . . . . . . . . . . . Acetonitrile, extra dry, water <10 ppm . . . . . . . . . Chloroform, extra dry, water <10 ppm . . . . . . . . . Cyclohexane, extra dry, water <10 ppm . . . . . . . . 1,2-Dichloroethane, extra dry, water <30 ppm . . . Dichloromethane, extra dry, water <30 ppm . . . . Dimethylformamide, extra dry, water <50 ppm . . 1,4-Dioxane, extra dry, water <30 ppm . . . . . . . . Ether, extra dry, water <50 ppm . . . . . . . . . . . . . Ethyl acetate, extra dry, water <50 ppm . . . . . . . n-Heptane, extra dry, water <20 ppm . . . . . . . . . n-Hexane, extra dry, water <20 ppm . . . . . . . . . . Isopropanol, extra dry, water <50 ppm . . . . . . . . . Methyl alcohol, extra dry, water <50 ppm . . . . . . N-Methylpyrrolidinone, extra dry, water <50 ppm Methyl sulfoxide, extra dry, water <50 ppm . . . . . Tetrahydrofuran, extra dry, water <50 ppm . . . . . Toluene, extra dry, water <10 ppm . . . . . . . . . . . . 2,2,4-Trimethylpentane, extra dry, water <30 ppm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 . . . .250 ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml ml . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326802500 326812500 326822500 326832500 326842500 326852500 326872500 326892500 326862500 326902500 326912500 326922500 326962500 326952500 326932500 326882500 326972500 326982500 326942500

FAX back form:

NAME: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INSTITUTE/COMPANY: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DEPT: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDRESS: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fax this form for additional information !

Acros Organics FAX 0032 14 59 34 34

.................................................... COUNTRY: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TEL: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FAX: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E-MAIL: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yes, send me a free copy Electronic Acros Organics Catalogue on CD-ROM Acros Organics Sub-Structure Searchable Catalogue on CD-ROM Information Acros Organics Information Sheet No /Review No Acros Organics Catalogue Acros Organics Company Information Acros Organics Software Brochure Put my name on your mailing list

Moleko
The Molecule Game
The winner of this challenging and educational game is the first to build a chemical molecule by collecting and assembling the necessary bonds and atoms during play. 2 - 4 players 10 years and up 1 hour of exciting play

Box containing : 1 board 1 dice 4 counters 174 cards 1 manual including background information on the 99 molecules in the game. 589 atoms and bonds Warning : contains small parts, not suitable for children 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 discover the 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

Middle East Israel Jordan Oman Saudi Arabia United Arab Emirates Africa Egypt Morocco South-Afrika Tunesia North America Australia New-Zealand

Europe Austria Belgium Denmark Finland France Germany Italy Malta Netherlands Norway Portugal Spain Sweden Switzerland United Kingdom

Far East Bangladesh China Hong-Kong India Japan Malaysia Singapore South-Korea Eastern Europe Czech Republic Estonia Hungary Latvia Poland Roumenia Slovakia Ukraine

For more information, please contact your local dealer

ACROS ORGANICS N.V. Geel West Zone 2 Janssen Pharmaceuticalaan 3a B-2440 Geel Belgium Tel.: +32(0)14/57.52.11 Fax: +32(0)14/59.34.34 Internet: http://www.acros.be