J.Org. Chem., Vol. 42, No. 12, 1977 2137
?-Alkylation of cr,P-Unsaturated Carbonyl Compounds (15)T. T. Tchen and K. Bloch, J. Biol. Chem., 226, 931 (1957). (16)E. Caspi, J. J. Greig, (andJ. M. Zander, 8iochem. J., 109, 931 (1968). (17)J. M. Zander, J. E. Greig, and E. Caspi, J. 8lol. Chem., 245, 1247 (1970). (18) E. Caspi, J. M. Zander, J. B. Greig, F. B. Mallory, R. L. Conner, and J. R. Landrey, J. Am. Chern. SOC.,90, 3583 (1968). (19)E. Caspi, J. E. Greig, ,I. M. Zander, and A. Mandelbaum, Chem. Gommn., 28 (1969). (20)J. M. Zander and E. Caspi, Chem. Commun., 210 (1969). (21)D.H. R. Barton, A. F. Gosden, G. Mellows, arid D.A. Widdowson, Chem. Commun., 184 (1969). (22)0. Germain, M. M.Woolfson, and P. Main, Acta Crystallogr., Sect. A., 27, 368 (1971).
(23)D. A. Langs and G. T. DeTitta, Acta Crystallogr., Sect. A, submitted. (24)G. T. DeTitta, J. W. Edmonds, D.A. Langs, and H. Hauptman, Acta Crystallogr., Sect. A, 31, 472 (1975). (25)J. Karle and I. L. Karle, Acta Crystallogr., Sect. 8,21, 849 (1966). (26)T. Nakanishi, H. Yamauchi, T. Fujimara, and K. Tomita, TetrahedronLett., 1157 (1971). (27)The standard deviation of this average calculates as f0.017A when based upon the deviation of the individual observations from the average w f0.005A when based on the standard deviations of the individualobservations. Since the two observationsdiffer by greater than twice the lower of these values (0.005A), the standard deviations of the individualobservations must be slightly underestimated and the standard deviation of the average value probably lies somewhere between 0.006 and 0.017A.
y-Alkylation of a,B-Unsaturated Carbonyl Compounds Ernest Wenkert,* Thomas E. Goodwin, and Brindaban C. Ranu Department of Chemistry, Rice University, Houston, Texas 77001 Received November 19,1976 T h e copper-catalyzed reactions o f ethyl diazoacetate and diazoacetone w i t h the dienol derivatives l - m e t h o x y and l-trimethylsilyloxy-1,3-butadiene,3-acetoxymethylene- and 3-trimethylsilyloxymethylenecyclohexene,and l-methoxy-1,3-cyclohexadieneand i t s 4-methyl analogue are described. Hydrolysis o f the olefinic cyclopropane adducts is shown t o lead to a- and y-alkylated a,@-unsaturated aldehydes and ketones.
The simple, three-step scheme of conversion of aldehydes or ketones into enol ethers or esters, cyclopropanation of these olefinic intermediates with a-diazocarbonyl reagents over copper, and aqueous acid cleavage of the resultant 6-oxycyclopropylketo compounds has been shown to be the equivalent of cu-alkylation of aldehydo and keto substances as well as a useful procedure for the synthesis of 1,4-dicarbonyl compounds.1-4 As part of an attempt to broaden the scope of this method of synthesis it became of interest to explore the behavior of more highly functionalized enol derivatives and a-diazoketo systems in the cyclopropanation step. In this connection one study involved the copper-catalyzed interaction of ethyl diazoacetate as well as diazoacetone with conjugated dienyl ethers and esters, derived from a$-unsaturated aldehydes and ketones. As the following equations indicate, it was assumed that, were the cyclopropanation to take place
PMe la, R = M e b, R = SiMe,
2a,R=Ac b, R = SiMe,
3a,R=H b, R = M e
0-alkylation of the aldehyde with trimethylsilyl chloride in the presence of trieth~lamine.~Jl The decomposition of ethyl diazoacetate in cyclohexane or neat solutions of each of the six dienes over copper bronze a t 65-85 "C led to 55-80% yields of stereo- and regioisomer mixtures of olefinic cyclopropanecarboxylates, i.e., l a 4a 5a, lb 4b 5b,2a-+6a 7a,2b- 6b 7b,3a 8a 9a, and 3b 8b 9b. With the exception of the silyl ethers
+
-- + +
+
+
-+
-+
0
5 R = M e ; R' = OEt b, R = SiMe,; R = OEt c , R = R' = M e d, R = SiMe,; R' = M e
4
a,
on the unoxygenated double bond, the new three-step scheme would be the equivalent of a y-alkylation of a,p-unsaturated keto system^,^ leading to 1,6-dicarbonyl compounds.6 The crotonaldehyde-based dienyl ethers 1-methoxy-1,3butadiene (la) and 1-trimethylsilyloxy-1,3-butadiene (lb),7.8 the enol acetate and trimethylsilyl ether from l-cyclohexenecarb~xaldehyde~ (2a and 2b, respectively), and the l-methoxy-1,3-cyclohexadienes103a and 3b served as starting materials for this investigation. Diene 2a was prepared by the acid-induced acetylation of 1-cyclohexenecarboxaldehyde with isopropenyl acetate, while diene 2b was the result of the
the regioisomers were separated into stereoisomer mixtures, no attempt having been made to fractionate the latter. Interaction of diazoacetone with each of the starting dienes under conditions similar to those of the diazoacetic ester reactions produced difficultly separable isomer mixtures of the ketone pairs 4c-5c, 4d-5d, 6c-7c, 6d-7d, 8c-9c, and 8d-9d, respectively. Mild treatment of cyclopropane 4a with aqueous acid caused the hydrolysis of its enol ether moiety leading to the aldehydo ester 10, whereas oxycyclopropane 5a remains un-
Wenkert, Goodwin, and Ranu
2138 J . Org. Chem., 1101. 42, No. 12, 1977
Similar treatment of ketones 813,8d, 9c, and 9d produced diketones 15c, 15d, 16c, and 16d (in addition to its 0 , y - u n s a t urated ketone isomer). The isolation of 1,6-diketo compounds 11,13, and 15 at the e n d of a two-step reaction scheme emanating from masked a$-unsaturated keto systems makes the procedure a new y-alkylation method. Furthermore, the ratios of cyclopropanation products (5040%total yields) favoring nonoxygenated cyclopropanes (2:l to 5 1 ) in most instances and the 1,6-diketo substances being the more preponderant, final products, irrespective of the 0 substituent of the initial conjugated diene, bodes well for this y-alkylation concept. More work will be necessary to improve the regioselectivity of t h e cyclopropa-
H
n
7
6
a, b, e, d,
R = Ac; R' = O E t FL = SiMe,; R = OEt R = Ac; R' = Me El = SiMe,; R' = Me
MvmR'
PMe
n a t i o n process.
Experimental Section
COR'
k
8
9
a, R = H; R = OEt b, R = Me; R = OEt C , R = H; R' = Me d,R=R=Me
perturbed under these conditions. Hydrolyses of 4a and 5a at elevated temperature produced the acyclic substances 1 l a and 12a, respectively.12 The same products result from the hydrolysis of t h e silyl e t h e r mixture, 4b and 5b, on heating. Finally, mild, aqueous acid hydrolysis of either the ketone mixture 4c and 5c or the 4d-5d mixture led to keto aldehydes l l b and 12b.
x H
R
COzEt
H
R' LCHO
CHzCHO
CHO 11
10
12
a , R = OEt b,R=Me Cyclopropanes 6 and 7 were hydrolyzable in both acid and base. Cleavage of the three-membered rings of 6a and 6b with alcoholic base yielded ester 13a, while 7a and 7b gave ester 14a. Similarly, compounds 6c and 6d produced aldehydo ketone 13b, while 7c and 7d led to 14b.
14
13
a , R = OEt b, R = Me Acid hydrolysis of esters 8 a , 8b, 9a, a n d 9b afforded cyclohexenone esters 15a, 15b, 16a, and 16b, respectively.
R 15
16
a , R = H; R' = O E t b, R = Me; R' = O E t c,R=H;R=Me d, R = R = Me
Boiling and melting points are uncorrected. Infrared spectra of neat liquids were recorded on a Perkin-Elmer 167 spectrophotometer and mass spectra obtained on a CEC 21-110 spectrometer. 'H NMR spectra were run on CDC13 solutions with Me4Si as internal standard (6 0 ppm) on a Varian A-60 spectrometer and the 13CNMR spectrum was recorded on a Varian XL-100-15spectrometer operating at 25.02 MHz in the Fourier transform mode. GPC runs were performed on a 10-ft 20% Carbowax on Chromosorb W column in a Varian Autoprep A-700 chromatograph, while preparative TLC utilized Merck silica gel HF 254 as adsorbant. 3-Acetoxymethylenecyclohexene(2a).A stirring solution of 1.52 g of 1-cyclohexenecarboxaldehyde9['H NMR 6 1.65 (m, 4, methylenes), 2.21 (m, 4, allyl methylenes), 6.66 (m, l , olefinic H), 9.35 (s, l , CHO); 13CNMR (CDC13) 6 21.06 (C-4, C-5), 21.78 (C-6), 26.19 (C-3), 141.12 (C-I), 150.95 (C-2), 193.72 (CO)] and 19 mg of p-toluenesulfonic acid in 12 mL of isopropenyl acetate was refluxed under nitrogen with slow removal of the solvent for 5.5 h. Fractional, vacuum distillation yielded 2.09 g of colorless, liquid diene 2a: bp 55-58 OC (1.25 Torr); IR C=O 1752 cm-' (s); 'H NMR 6 1.61 (m, 2, CHz), 2.06,2.39 (m, 2 each, allyl methylenes), 2.12 (s, 3, Me) 5.68 (dt, 1, J = 10,3 Hz, H-l), 5.93 (dt, 1,J = 10, 1 Hz, H-2), 6.92 (broad s, 1, OCH); mass spectrum mle 152 (M+), 110 (base), 95, 81, 79; exact mass mle 152.0842 (calcd for CSH1202, 152.0836). 3-Trimethylsilyloxymethylenecyclohexene (2b). A stirring solution of 1.78 g of 1-cyclohexenecarboxaldehyde? 2.71 g of trimethylsilyl chloride, and 3.28 g of triethylamine in 7 mL of dimethylformamide was refluxed under nitrogen for 21 h. After cooling the brown solution was diluted with 50 mL of hexane, washed with 30 mL of 5% sodium bicarbonate solution, 30 mL of water, and 30 mL of saturated brine solution, and dried (Na2S04). Upon removal of the solvent the liquid was distilled, yielding 1.73g of liquid diene 2 b bp 33-34 "C (0.25 Torr); IR C=C 1643 (m), 1609 cm-' (m); 'H NMR 6 0.19 (s, 9 Mes), 1.56 (m, 2, CHz), 2.04, 2.35 (m, 2 each, allyl methylenes), 5.48 (dt, l , J = 10,4 Hz, H-l), 5.98 (dt, l , J = 10,2 Hz, H-2), 6.12 (broad s, 1, OCH); mass spectrum mle 182 (M+),167,93,92,75, 73 (base); exact mass mle 182.1132 (calcd for CloHlaOSi, 182.1126). 1-Dimethoxymethylcyclohexene.A stirring mixture of 1.20 g of 1-cyclohexenecarboxaldehyde: 0.60 g of Amberlite IR-120-H ion exchange resin (medium porosity, washed three times with methanol), and 5 mL of trimethyl orthoformate in 5 mL of methanol was refluxed under nitrogen for 5 h. Sodium sulfate was added and the cooled mixture filtered through Celite and evaporated. An ether solution (50 mL) of the residue was washed with 100 mL of 5% sodium bicarbonate solution and 50 mL of brine solution, dried (NaZSOd),and evaporated. Distillation (0.2 Torr, bath temperature 31 "C) of the residue (1.45 g) on a Vigreux column (1.7 X 13 mm) yielded 1.21 g of colorless, liquid 1-cyclohexenecarboxaldehyde dimethyl acetal: 'H NMR 6 1.58 (m, 4, methylenes), 1.96 (m, 4, allyl methylenes), 3.23 [s, 6, (OMe)z],4.40 (s, 1, OzCH), 5.75 (broad s, 1, olefinic H); mass spectrum mle 156 (M+),128 (base), 94,78; exact mass mle 156.1146 (calcd for C9H1602, 156.1149). Ethyl 2-(~-Methoxyvinyl)cyclopropanecarboxylate (4a) and Ethyl 2-Methoxy-3-vinylcyclopropanecarboxylate (5a).All cyclopropanations followed an earlier procedure.'I2 Ethyl diazoacetate (3.15 g) was added dropwise over a 4-h period to a stirring suspension of 300 mg of copper bronze13 and 2.10 g of l-methoxy-1,3-butadiene (la)in 10 mL of cyclohexane kept at 80 "C under nitrogen. Thereafter the mixture was stirred at 80 "C for an additional 0.5 h and filtered. The catalyst was washed with 15 mL of ether and the combined filtrate and washings evaporated. Distillation of the residue gave 2.60
y-Alkylation of a,&Unsaturated Carbonyl Compounds g of an ester mixture, bp 50-55 "C (0.1 Torr), which was separated by GPC (column temperature 120 "C) and led to two fractions of 10 and 20 min retention times. The first fraction consisted of 350 mg of 5a: IR C=O 1730 (s),C=C 1640 cm-' (m); 'H NMR 6 1.25 (t, 3, J = 7 Hz, Me), 1.7-2.6 (m, 2, c-Pr H), 3.31 (s, 3, OMe), 3.4-3.6 (m, 1, OCH), 4.18 (q, 2, J = 7 Hz, OCHz), 4.8-6.0 (m, 3, olefinic H); mass spectrum rnle 170 (M+),169,131,119,97 (base),69; exact mass rnle 170.0942 (calcd for C&1403, 170.0943). The second fraction contained 1.60 g of 4a: IR C=O 1730 (s), C=C 1670 (s), 1655 cm-' (SI; 'H NMR 6 0.7-2.1 (m, 4, c-Pr H), 1.22 (t, 3, J = 7 Hz, Me), 3.45,3.69 (s, 3 total, OMe), 4.12 (q,2,J = 7 Hz, OCH2), 4.4-4.9 (m, 1, olefinic I145 "C (0.5 Torr), predominating in the biscyclopropanation product: IR C=O 1760-1700 cm-' (s); 'H NMR 6 1.24 (t, 6, J = 7 Hz, Men), 2.03 (s, 3, COMe), 3.8-4.3 [m, 4, (OCH2)2],4.48 (d,
