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HIGHLY STEREOSELECTIVESYNTHESIS OF DIALKYL 2-ALKYLIDENE GLUTARATESAli Samarat a , Jacques Lebreton b & Hassen Amric

a Universitaire-1060 Tunis , Tunisiab Faculté des Sciences et des Techniques ,Laboratoire de Synthésé Organique UMR-CNRS6513 , BP. 92208, 2 rue de la Houssinierè, 44322,Nautes Cedex-03, Francec Universitaire-1060 Tunis , TunisiaPublished online: 09 Nov 2006.

To cite this article: Ali Samarat , Jacques Lebreton & Hassen Amri (2001) HIGHLYSTEREOSELECTIVE SYNTHESIS OF DIALKYL 2-ALKYLIDENE GLUTARATES, SyntheticCommunications: An International Journal for Rapid Communication of SyntheticOrganic Chemistry, 31:11, 1675-1682, DOI: 10.1081/SCC-100103986

To link to this article: http://dx.doi.org/10.1081/SCC-100103986

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HIGHLY STEREOSELECTIVE SYNTHESIS

OF DIALKYL 2-ALKYLIDENE GLUTARATES

Ali Samarat,1 Jacques Lebreton,2 and Hassen Amri1,*

1Laboratoire de Chimie Organique et Organometallique,Faculte des Sciences Campus, Universitaire-1060 Tunis-

Tunisia2Laboratoire de Synthese Organique UMR-CNRS 6513,

Faculte des Sciences et des Techniques, BP. 92208,2 rue de la Houssiniere 44322 Nautes Cedex-03 France

ABSTRACT

Nucleophelic substitution of dialkyl (E)-2-bromomethyleneglutarates 2 by magnesium dialkyl cuprates generated in situprovided a regio and highly stereoselective methodology forthe synthesis of dialkyl 2-alkylidene glutarates 3 in good yields.

Nucleophilic substitution reactions on vinylic halides have gainedincreasing interest1. It is also known that ethylenic halides activated byelectron withdrawing groups are much more generally reactive and givemainly nucleophilic substitution products2–7 (Scheme 1).

Displacement reaction of vinyl halides using organometallic species8

as nucleophilic reagents is a successful pathway for C-C bond formation.In this area, and in continuation of our interest in the direct substitution ofa,b-unsaturated vinyl halides by organocuprates reagents,9,10 dialkyl (E)-2-

1675

Copyright & 2001 by Marcel Dekker, Inc. www.dekker.com

SYNTHETIC COMMUNICATIONS, 31(11), 1675–1682 (2001)

*Corresponding author. Fax: 216(1)885 008; E-mail: hassen.Amri@fst.rnu.tn

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bromomethylene glutarates 2 prepared in a simple tandem: bromination-dehydrobromination of dialkyl-2-methylene glutarates 1 according toreference,11 constituted the ideal intermediates for the synthesis of dialkyl2-alkylidene glutarates 3 which has been recently described by Basavaiahand Co-workers.12

As shown in scheme 2, the conjugate addition of dialkyl organocup-rates, generated ‘‘in situ’’ at low temperature from Grignard reagents in thepresence of catalytic amount of LiCuBr2 to dialkyl (E)-2-bromomethyleneglutarates 2 leads to the corresponding dialkyl 2-alkylidene glutarates 3 inhigh stereoselectivity (E/Z: 91–100/9–0) and good yields.

It has been reported13,14 that displacement of the vinylic halogen atomby various nucleophiles gave products with partial inversion of configura-tion in direct substitution mechanism. However, the mechanism proposedby Miller and Yonan,1 in which they postulate the inversion at a carbonatom adjacent to the reaction site involving an elimination-additionmechanism5 cannot be excluded. Indeed, it seems that the addition-elim-ination mechanism afforded products with a retained geometric configura-tion (<9% inversion) (scheme 3). All the reactions occurred in anhydrouscondition. The results are summarized in Table 1.

In conclusion, the nucleophilic substitution of activated vinyl bromideby organomagnesium reagents in the presence of amounts of Cu(I) consti-tute an interesting alternative for the cuprous catalyzed reaction in the syn-thesis of functional vinyl compounds. In addition to its low cost and thehigh stereoselectivity of the reaction, the method described above is favor-ably compared to the recently cross-coupling reactions using manganesechloride16 or iron complexes.17,18

1676 SAMARAT, LEBRETON, AND AMRI

Scheme 1.

Scheme 2.

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EXPERIMENTAL

All reactions were conducted in dry glassware under nitrogen atmos-phere. Solvents were previously dried. Grignard reagents were prepared bythe known methods and stored under inert atmosphere. They were titratedprior to use, i.e. with 1M solution of benzyl alcohol in anhydrous tolueneand in presence of 2,20-bipyridil as indicator.

DIALKYL 2-ALKYLIDENE GLUTARATES 1677

Table 1. Dialkyl 2-Alkylidene Glutarates 3a-l Synthesized

Enty Product R R0MgX (equiv.) E:Z (%)* Yield**

1 3a CH3iC3H7MgBr (2,3) 98:2 70

2 3b CH3nC4H9MgBr (2) 92:8 73

3 3c C2H5iC3H7MgBr (2,2) 94:6 72

4 3d C2H5nC4H9MgBr (2) 93:7 71

5 3e C2H5tC4H9MgCl (3) 100:0 84

6 3f C2H5cC6H11MgCl (2,9) 93:7 72

7 3g C2H5 PhCH2MgBr (2,8) 98:2 648 3h tC4H9

iC3H7MgBr (2) 100:0 72

9 3itC4H9

nC4H9MgBr (2,5) 91:9 6510 3j tC4H9

tC4H9MgCl (3) 100:0 7411 3k tC4H9

cC6H11MgCl (3) 94:6 6612 3l tC4H9 PhCH2MgBr (3) 92:8 62

(*) Sterochemical assignments and isomeric purities were based on the difference inchemical shifts and integration ratios of vinylic protons of 2-Alkylidene group in 1HNMR analysis. The latter protons appeared at downfield for E isomer whereas the

same protons appeared at upfiled for the Z isomer according to the reference 15.(**) Yields refer to isolate pure products characterized by IR, 1H, 13C NMR andmass spectrometry.

Scheme 3.

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Typical Experimental Procedure

An ether or THF solution of alkylmagnesium halide R0MgX (2 to 3equiv.) was added dropwise over a period of 15–20min to a mixture ofdialkyl (E)-2-bromomethylene glutarate 2 (5mmol) and 1M solution ofLiCuBr2 (0,15mL) diluted in dry THF (20mL) at �20�C under nitrogenatmosphere. A magnetic stirring was maintained at �20�C. After a fewminutes (TLC), the reaction mixture was quenched with a saturated NH4Clsolution (15mL) then extractedwith ether (3� 20mL). The combined organiclayers were dried over MgSO4, filtered and evaporated under reduced press-ure. The crude product was purified by column chromatography on silica gel(AcOEt/Hexane, 1/9) to afford (E, Z)-dialkyl-2-alkylidene glutarates 3a–l.

Spectral Data of Products 3a–l

(E,Z)-2-(2-Methylpropylidene) pentanedioıc acid dimethyl ester 3a

�max neat/cm�1 1738, 1713, and 1644; 1H NMR(300MHz, CDCl3):1.03(6H, d, J¼ 7.7Hz), 2.42–2.65(4H, 2m), 2.73(1H, m), 3.66(3H, s),3.73(3H, s), 5.78(1H, d, J¼ 10.8Hz, Z), 6.64(1H, d, J¼ 10Hz, E);13C-NMR(75MHz, CDCl3): 22.1( CH3-CH), 22.2( CH3-CH), 22.4( CH2-COO), 27.7( CH2-C¼ ), 33.6( CH-CH¼ ), 51.4( CH3-O), 51.5( CH3-O),127.8( CH¼C), 150.7(CH¼ C), 167.9( COO), 173.1( COO); MS (70 eV,m/z); 214(Mþ, 1), 182(100), 154(95), 125(48), 122(38), 108(31), 95(71),81(56), 41(29).

(E,Z)-2-Pentylidene pentanedioıc acid dimethyl ester 3b

�max neat/cm�1 1731, 1706 and 1644; 1H NMR(300MHz, CDCl3):0.91(3H, t, J¼ 6.9Hz), 1.38(4H, m), 2.21(2H, q, J¼ 7.4Hz), 2.41–2.65(4H, 2m), 3.66(3H, s), 3.73(3H, s), 6.00(1H, t, J¼ 8.2Hz, Z), 6.82(1H, t,J¼ 7.7Hz, E); 13C-NMR(75MHz, CDCl3): 13.7( CH3-CH2), 22.1(CH3-CH2), 28.1( CH2-CH2), 28.9( CH2-COO), 30.7( CH2-C¼ ), 33.2( CH2¼CH),51.0( CH3-O), 51.5( CH3-O), 130.0( CH¼C), 144.4(CH¼ C), 167.7( COO),173.2( COO); MS (70 eV, m/z): 228(Mþ, 1), 196(100), 167(70), 154(77),139(50), 125(61), 107(50), 95(76), 67(58).

(E,Z)-2-(2-Methylpropylidene) pentanedioıc acid diethyl ester 3c

�max neat/cm�1 1727, 1698 and 1644; 1H NMR(300MHz, CDCl3):1.01(6H, d, J¼ 6.6Hz), 1.23–1.32(6H, 2t), 2.40–2.62(4H, 2m), 2.72(1H,

1678 SAMARAT, LEBRETON, AND AMRI

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m), 5.73(1H, d, J¼ 9.7Hz, Z), 6.61(1H, d, J¼ 10.3Hz, E); 13C-NMR(75MHz, CDCl3): 13.9( CH3-CH2), 14.0( CH3-CH2), 22.0( CH3-CH-), 22.1( CH2-COO), 27.5( CH-CH¼ ), 33.7( CH2-C¼ ), 60.0( CH2-O),60.1( CH2-O), 128.0( CH¼C), 150.0(CH¼ C), 167.3( COO), 172.6( COO);MS (70 eV, m/z): 242(Mþ, 1), 196(100), 168(83), 139(56), 125(44), 122(40),95(75), 81(50), 29(41).

(E,Z)-2-Pentylidene pentanedioıc acid diethyl ester 3d

�max neat/cm�1 1724, 1706 and 1643; 1H NMR(300MHz, CDCl3):0.91(3H, t, J¼ 6.9Hz), 1.22–1.32(6H, 2t), 1.38(4H, 2m), 4.01–4.2(4H, 2q),6.01(1H, t, J¼ 9.5Hz, Z), 6.81(1H, t, J¼ 9Hz, E); 13C-NMR(75MHz,CDCl3): 13.7( CH3-CH2), 14.0( CH2-CH2), 14.1(CH2-CH2), 22.1( CH3-CH2O), 22.3( CH3-CH2O), 28.1( CH2-COO), 30.7( CH2-CH¼ ), 33.5( CH2-C¼ ), 60.2( CH2-O), 60.3( CH2-O), 130.3( CH¼C), 143.9(CH¼C),167.2( COO), 172.2( COO); MS (70 eV, m/z): 256(Mþ, 1), 210(100),182(56), 168(37), 153(73), 137(39), 95(44), 29(40).

(E)-2-(2,2-Dimethylpropylidene) pentanedioıc acid diethyl ester 3e

�max neat/cm�1 1724, 1700 and 1636; 1H NMR (300MHz, CDCl3):1.19(9H, s), 1.23–;1.32(6H, 2t), 2.44–2.74(4H, 2m), 4.10–4.22(4H, 2q),6.84(1H, s, E); 13C-NMR(75MHz, CDCl3): 14.0( CH3-CH2O), 14.1( CH3-CH2O), 22.6( CH2-COO), 30.3(( CH3)3C-), 33.1( CH2-C¼ ), 33.9((CH3)3C-),60.1( CH2-O), 60.4( CH2-O), 129.5( CH¼C), 152.3(CH¼ C), 168.1( COO),172.7( COO); MS (70 eV, m/z): 256(Mþ, 2), 210(100), 211(93), 182(62),169(48), 137(49), 121(78), 109(64), 95(85), 29(68).

(E,Z)-2-Cyclohexylmethyene pentanedioıc acid diethyl ester 3f

�max neat/cm�1 1714, 1698 and 1643; 1H NMR(300MHz, CDCl3):1.13–1.35(6H, m), 1.26–1.30(6H, 2t), 1.59–1.71(4H, m), 2.35(1H, m), 2.40–2.64(4H, 2m), 5.75(1H, d, J¼ 9.8Hz, Z), 6.61(1H, d, J¼ 10Hz, E);13C-NMR(75MHz, CDCl3): 14.0( CH3-CH2O), 14.1( CH3-CH2O), 22.3–25.6( CH2-CH2-CH2), 32.0( CH2-COO), 32.5( CH2-CH), 33.9( CH-CH¼ ),37.4( CH2-C¼ ), 60.1( CH2-O), 60.2( CH2-O), 128.4( CH¼C), 148.7(CH¼ C), 167.5( COO), 172.8( COO); MS (70 eV, m/z): 282(Mþ, 1),236(100), 190(48), 162(36), 148(38), 135(61), 81(30).

DIALKYL 2-ALKYLIDENE GLUTARATES 1679

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(E,Z)-2-Benzylidene pentanedioıc acid diethyl ester 3g

�max neat/cm�1 1724, 1704 and 1644; 1H NMR(300MHz, CDCl3):1.21–1.29(6H, 2t), 2.41–2.78(4H, 2m), 3.56(2H, d, J¼ 7.7Hz), 6.1(1H, t,J¼ 7.1Hz, Z), 7.16(1H, t, J¼ 7.7Hz, E), 7.16–7.33(5H, m); 13C-NMR(75MHz, CDCl3): 14.0( CH3-CH2), 14.1( CH3-CH2), 22.2( CH2-COO), 33.3( CH2-C¼ ), 34.5( CH2-CH¼ ), 60.2( CH2-O), 60.5( CH2-O),126.3–131.0( Carom), 138.6( CH¼C), 141.6(CH¼ C), 167.0( COO);172.7( COO); MS (70 eV, m/z): 290(Mþ, 1), 244(11), 198(100), 170(55),156(41), 129(81), 91(27), 29(26).

(E)-2-(2-Methylpropylidene) pentanedioıc acid di-tert-butyl ester 3h

�max neat/cm�1 1726, 1714 and 1644; 1H NMR(300MHz, CDCl3):1.01(6H, d, J¼ 6.6Hz), 1.44(9H, s), 1.49(9H, s), 2.29–2.55(4H, 2m),2.69(1H, m), 6.50(1H, d, J¼ 10.1Hz, E); 13C-NMR(75MHz, CDCl3):22.2(( CH3)3C), 27.6(( CH3)3C), 28.1( CH2-COO), 33.6( CH2-C¼ ),35.1( CH-CH¼ ), 80.0( C-O), 81.5( C-O), 129.6( CH¼C), 149.0(CH¼ C),166.8( COO), 172.2( COO); MS (70 eV, m/z): 298(Mþ, 1), 186(38), 169(67),168(100), 140(49), 57(81), 41(39).

(E,Z)-2-Pentylidene pentanedioıc acid di-tert-butyl ester 3i

�max neat/cm�1 1714, 1706 and 1643; 1H NMR(300MHz, CDCl3):0.91(3H, t, J¼ 6.9Hz), 1.33�1.37(4H, m), 1.43(9H, s), 1.50(9H, s),2.17(2H, q, J¼ 7.4Hz), 2.22�2.56(4H, 2m), 5.85(1H, t, J¼ 8.6Hz, Z),6.68(1H, t, J¼ 7.7Hz, E); 13C-NMR(75MHz, CDCl3): 3.7( CH3-CH2),22.3(CH3-CH2), 22.4(CH2-CH2), 22.7(( CH3)3C), 23.9(( CH3)3C), 28.0( CH2-COO), 30.8( CH2-C¼ ), 34.7( CH2-CH¼ ), 79.9( C-O), 80.7( C-O),131.8( CH¼C), 142.6(CH¼ C), 166.6( COO), 172.2( COO); MS (70 eV,m/z): 312(Mþ, 1), 200(30), 182(97), 183(70), 153(28), 140(46), 57(100),41(42).

(E)-2-(2,2-Dimethylpropylidene) pentanedioıc acid di-tert-butyl ester3j

�max neat/cm�1 1716, 1704 and 1636; 1HNMR(300MHz,CDCl3): 1.18(9H, s), 1.44(9H, s), 1.50(9H, s), 2.33–2.66(4H, 2m), 6.75(1H,s, E); 13C-NMR(75MHz, CDCl3): 2.9(( CH3)3C), 28.0(( CH3)3C), 30.4

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(( CH3)3C), 31.2( CH2-COO), 32.9( CH2-C¼ ), 35.2( C-CH¼ ), 80.0( C-O),80.1( C-O), 131.1( CH¼C), 151.1(CH¼ C), 167.4( COO), 172.2( COO);MS (70 eV, m/z): 312(Mþ, 1), 200(78), 183(95), 182(87), 154(44), 57(100),41(47).

(E,Z)-2-Cyclohexylmethyene pentanedioıc acid di-tert-butyl ester 3k

�max neat/cm�1 1715, 1697 and 1642; 1H NMR(300MHz, CDCl3):0.81(2H, m), 1.05–1.13(4H, m), 1.38(9H, s), 1.42(9H, s), 1.52–1.63(4H, m),2.22(1H, m), 2.24–2.48(4H, 2m), 5.58(1H, d, J¼ 9.8Hz, Z), 6.43(1H, d,J¼ 10.1Hz, E); 13C-NMR(75MHz, CDCl3): 14.0(CH2-CH2-CH2), 22.5,22.6( CH2-CH2-CH2), 25.4, 25.7( CH2-CH-CH2), 26.8(( CH3)3C), 28.0(( CH3)3C), 30.0( CH2-COO), 32.2( CH2-C¼ ), 37.4( CH-CH¼ ), 166.0( COO), 172.3( COO); MS (70 eV, m/z): 338(Mþ, 3), 226(42), 209(50),208(100), 135(27), 57(60), 41(33).

(E,Z)-2-Benzylidene pentanedioıc acid di-tert-butyl ester 3l

�max neat/cm�1 1715, 1698 and 1644; 1H NMR(300MHz,CDCl3): 1.50(9H, s), 1.53(9H, s), 2.37–2.70(4H, 2m), 3.62(2H, d,J¼ 7.7Hz), 6.20(1H, t, J¼ 7.7Hz, Z), 6.90(1H, t, J¼ 7.6Hz, E),7.22�7.35(m, 5H); 13C-NMR(75MHz, CDCl3): 22.5(( CH3)3C), 27.9( CH2-COO), 28.0( CH2-C¼ ), 34.5( CH2-CH¼ ), 80.3( C-O), 126.2( CH¼C),128.4–138.9( Carom), 140.2(CH¼ C), 166.4( COO), 172.2( COO); MS(70 eV, m/z): 290(Mþ, 1), 234(39), 217(37), 216(48), 198(87), 170(40),129(48), 57(100).

ACKNOWLEDGMENT

Authors thank Pr. T. Labassi for his help and English discussions.

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91, 620.

DIALKYL 2-ALKYLIDENE GLUTARATES 1681

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4. Patai, S.; Rappoport, Z.; The Chemistry of alkenes (Edited by Patai, S.)

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Accepted in the Netherlands August 3, 2000

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