3474 J. Org. Chem., Vol. 40,No. 24,1975
Harmon and Hutchinson
(19) R. F. Zuercher, Helv. Chim. Acta, 48, 2054 (1963). (20) As the prototropic shifts are reverslble the reaction seems to be under thermodynamic control. Judging from models, the more stable structures have the 13P-H in the 14-ene and the 14a-H in the 12-ene. (21) J. Ramseyer, J. S. Williams, and H. Hirschmann, Steroids, 9, 347 (1967). (22) D. J. Pasto and F. M. Klein, J. Org. Chem., 33, 1468 (1968); D. J. Pasto, B. Lepeska, and T.4. Cheng, J. Am. Chem. Soo., 94,6083 (1972). (23) M. Pankova, J. Sicher. M. Tichjr and M C. Whiting, J. Chem. SOC. B, 365 (1968). Their compound is named according to rule d: Chemical Registry No.-lb, 1914-30-3;2b, 2270-04-4;3d, 56665-84-0;3e, Abstracts, 78, Index Guide, Section iV, 861 (left column) (1972). 56665-85-1;3f, 56665-86-2;4d, 56665-87-3;4e, 56665-88-4;4f, (24) N. C. G. Campbell, D. M. Muir, R. R. Hill, J. H. Parish, R. M. Southam, 56665-89-5;6b, 56665-90-8;7a isomer 1, 56665-91-9;7a isomer 2, and M. C. Whiting, J. Chem. SOC.6,355 (1968). 7b isomer 2, 56665-94-2;7c (25) This is borne out by measurements analogous to those reported by J. A. 56665-92-0;7b isomer 1, 56665-93-1; Marshall and R. D. Carroll, J. Org. Chem., 30, 2748 (1965), for axial hyisomer 1, 56665-95-3; 7c isomer 2, 56665-96-4;8a, 56665-97-5; 8c, drogens. At any fixed C-17-0 distance assumed for the transition state, 31751-19-6;9b, 56665-98-6;lob, 56665-99-7;llb, 56666-00-3;12b, the oxygen would be closer to a methyl group if it is on the /3 rather than 56666-01-4;13d, 56666-02-5;13e, 56666-03-6;13f, 56666-04-7;14e, on the a side. 56666-05-8;14f, 56666-06-9;15b, 56666-07-0;l7a920P-epoxy-5a- (26) S . Winstein and N. J. Holness, J. Am. Chem. Soc.,77, 5562 (1955). pregnan-3P-yl acetate, 56666-08-1;diborane, 18099-45-1; p-tolu(27) As this axial tosylate lacks a 1,3 interaction between the tosyloxy and a methyl group, some but possibly not all of the acceleration is to be atenesulfonyl chloride, 98-59-9;3&17a&dihydroxy-17a-methyl-Dtributed to the lessened strain between these groups in the transition homo-5a-androstan-l7-one, 3751-01-7;m-chloroperbenzoic acid, For the probable magnitude of this effect in acetic acid see S.Ni937-14-4; 17a,l7aa-epoxy-17a-methyl-~-homo-5~-androstan-3/3- state. shida, J. Am. Chem. SOC..82, 4290 (1960). y l acetate, 56666-09-2. (28) The high yield of the 16a isomer also argues abainst the possibility that the steric preference at C-17 could have been caused by a rapid equilibration between C-17 and C-16 open cations. If the "windshield wiper References and Notes effect" [H. C . Brown, K. J. Morgan, and F. J. Chloupek, J. Am. Chem. SOC.,87, 2137 (1965)] of the I6a-hydrogen were operatlve In our case (1) Supported by Grants AM 9105 and K6-AM-14367 of the National Instiwe would expect it to block a-attack about as effectively at C-16 as at tutes of Health. C-17. (2) H. Hlrschmann, F. 8. Hirschmann, and A. P. Zala, J. Org. Chem., 31, (29) G. Drefahl, K. Ponsold, and H. Schick, Chem. Ber., 98, 604 (1965). 375 (1966). (30) J. S. Baran, J. Org. Chem., 25, 257 (1960). (3) F. 8. Hirschmann and H. Hirschmann, J. Org. Chem., 38, 1270 (1973). (31) This value is disconcertingly close to the one reported for the more sta(4) S . S.Deshmane and H. Hirschmann. J. Org. Chem., 38, 748 (1973). ble 17a epimer (-51")5 and not in good accord with those reported by (5) F. Ramirez and S.Stafiej, J. Am. Chem. SOC.,77, 134 (1955); 78, 644 the same authors for 2a and 2c. (1956). (32) This upfield shift for the 19-H agrees with observations on 3b-acetoxy(6) K. I. H. Williams, M. Smulowitz, and D. K. Fukushima, J. Org. Chem., 30, 5a-steroids made by von Bruno Hampel and J. M. Kraemer, Tetrahe1447 (1965). dron. 22. 1601 (1966). (7) Williams et al.' isolated 3 % of thls epoxide but accounted only for 53% (33) R. N. Jones and F. Heriing, J. Org. Chem., 19, 1252 (1954); J. Am. of their product. They used alumina for its separation which at least in Chem. SOC..78. 1152 (1956). our hands caused some destruction of the epoxide (34) D. K. Fukushima, S.Dobriner, M. S . Heffier, T. H. Kritchevsky, F. Herl(8) H. S. Aaron and C. P. Rader, J. Am. Chem. SOC.,85, 3046 (1963). ing, and G. Roberts, J. Am. Chem. SOC..77, 6585 (1955). (9) D. H. Williams and N. S. Bhacca, J. Am. Chem. SOC.,88, 2742 (1964). (35) D. N. Klrk and A. Mudd, J. Chem. SOC.12,2045 (1970). (IO) P. V. Demarco, E. Farkas, D. Doddreli, B. L. Mylari, and E. Wenkert, J. (36) R. B. Turner, R. Anliker. R. Heibiing, J. Meier, and H. Heusser. Helv Am. Chem. SOC.,90,5480 (1968). Chim. Acta, 38, 41 1 (1955). (1 1) To permit these and other studies of the 3-monoacetates, the conditions (37) C. W. Shoppee and D. A. Prins, Helv. Chim. Acta, 26, 185 (1943). of hydroboration were modified for an improved preservation of the (38) L. Ruzicka and H. F. Meldahl, Helv. Chim. Acta, 24, 1321 (1941). ester group of lob. (39) R. J. W. Cremiyn, D. L. Garmaise, and C. W. Shoppee, J. Chem. Soc., (12) For references see J. E. Page, J. Chem. SOC.,2017 (1955). 1847 (1953). (13) J. Schreiber and A. Eschenmoser, Helv. Chim. Acta, 38, 1529 (1955). (40) There is a wide discrepancy between the differences in molecular rota(14) As a result, the formolysis of 9b would be a far more suitable object ~~~~ the ' tions of various 17a-methyi-Dhomo-l7a. 1 7 a a - e p o x i d e ~ .and than that of androsterone tosylate15 for the precise determination of the standard values for transformations in the A and B rings of steroids as effect of isotopic substitution of a neighboring hydrogen on the rate of given by D. H. R. Barton and W. Klyne. Chem. lnd. (London),755 formation of the individual formolysis products. (1948). Our measurement is in reasonable accord with the rotation re(15) J. Ramseyer and H. Hirschmann, J. Org. Chem., 32, 1850 (1967). ported by Ruzicka et ai.41 (16) C. Monneret and Q. Khuong-Huu, Bull. SOC.Chim. Fr., 623 (1971). (41) L. Ruzicka, N. Wahba, P. T. Herzig, and H. Heusser, Chem. Ber., 85, (17) R. T Aplin, H. E. Browning, and P. Chamberiain,-Cbem. Comrnun., 1071 491 (1952). (1967). 142) E. Hardeooer and C. Schoiz. Helv. Chim. Acta. 28. 1355 11945) (18) F B. Hlrschmann, D. M. Kautz, S. S. Deshmane, and H. Hirschmann, (43) A. Bowe; T. G. Halsali, E. k. H. Jones, and A.J. 'Lemin,'J. Ch'em. SOC., Tetrahedron, 27, 2041 (1971). 2546 (1953).
for recording the lH NMR spectra; to Dr. Rodger L. Foltz, Batelle High Resolution Mass Spectrometer Center, Pittsburgh, Pa., for the mass spectrum; to Mr. A. W. Spang, Ann Arbor, Mich., for the microanalyses; and to Dr. Miklos Bodanszky for the use of the polarimeter.
Synthesis of a-Methylene Lactones by Reductive Amination of a-Formyl Lactones. Scope and Limitations Alan D. Harmon1 and C. Richard Hutchinson*2 School of Pharmacy, U n i v e r s i t y of Connecticut, Storrs, Connecticut 06268 Received J u n e
19,1975
T h e synthesis o f a-methylene lactones by reductive amination o f a - f o r m y l lactones w i t h sodium cyanoborohydride a n d dimethylamine i s described with regard t o i t s scope a n d limitations. T h e a-methylene lactones a-methacid y-lactone (13),a-methylene-cisylene-6-valerolactone (lo),a-methylene-trans-2-hydroxycyclohexaneacetic 2-hydroxycyclohexaneacetic acid y-lactone (161,a n d 3-methylene-3,4-dihydrocoumarin (23) are prepared f r o m t h e i r a - f o r m y l lactones. T h e a-methylene lactone of 2-coumaranone could n o t be synthesized by t h i s procedure.
As a counterpart to our development of a synthesis of amethylene-y- or -&lactones by reductive amination of the corresponding a-formyl lactones,3a which enabled an efficient synthesis of tulipalin A and pentaacetyl tuliposide A,3b we decided to examine the scope and limitations of this method. In view of the continued great interest in syn-
thetic methods for construction of a-methylene-y- and &lactone units: which are found in a variety of biologically active natural product^,^ such a study was felt to be necessary to truly define the generality of our synthetic approach, We now report the successes and failures of our investigation.
J. Org. Chem., Vol. 40,No. 24,1975 3475
Synthesis of a-Methylene Lactones Results Our general synthetic format for the preparation of amethylene-y- and -&lactones is shown in Scheme I. Since it involves the addition of an a-methylene unit to a preformed y- or &lactone, we investigated the “a-methylenation” of lactones 1-4 as representative of the a-methylene lactone systems found in certain natural products,5 and 5 and 6, whose “a-methylenation” had been attempted by
amine to a-formyl butyrolactone and the reaction solvent seemed to be somewhat less critical. The synthesis of a-methylene-b-valerolactone3a (10) could be achieved in only a 41% overall yield from 2. As with 1, the lowest yield was obtained in step I1 of the reaction sequence. A similar study (vide supra) of the yield of a-dimethylaminomethyl-6-valerolactone(8) was done; the
&NGHd2
1
5
3
4
Ho
8
2
6
Martin et a1.6 but with unsuccessful results using an amethylation method based on methyl methoxymagnesium carbonate carboxylation of lactones. For comparative purposes we chose to look at our reductive amination method as comprised of three basic steps: I, lactone formylation; 11, reductive amination; and 111, quaternization and elimination, although the latter was a trivial distinction. The synthesis of tulipalin A, the a-methylene analog of 1, has been d e ~ c r i b e d .Since ~ ~ , ~steps I and I11 of its synthesis were carried out essentially quantitatively whereas the yield of a-dimethylaminomethyl-y-butyrolactone (7)3bin step I1 of the reaction sequence appeared to be variable, a brief study of the effect of experimental conditions on the yield of 7 was undertaken. The results of this study are shown in Table I. Control of the initial pH of the reaction mixture between 5 and 7 by addition of absolute methanolic HC1 favorably affected the yield of 7 and lessened the amount of the principal by-product, 2-dimethylaminomethyl-4-hydroxybutanoic acid dimethylamide (formed in less than ca. 10% yield7), whereas the ratio of dimethylTable I Reductive Amination of Sodium a-Formyl-pbutyrolactone
9
10
results are shown in Table 11. The amount of dimethylamide by-product (9) always represented a greater percentage of the consumed a-formyl-2 than with 1, appearing with 8 in a 1:lratio when the reaction solvent was DME. Although the methiodide of 8 could not be obtained crystalline, step I11 of the reaction sequence could be carried out to give an 80-85% yield of 10. The method of Newman and VanderwerfB was used to obtain trans-2-hydroxycyclohexaneacetic acid y-lactone (3).This was converted in 90% yield t o its a-formyl derivative (11,sodium salt) when diethyl ether was the reaction solvent in step I, and 73% yield when DME was used. Step I1 of the reaction sequence was shown to be much.less variable than for 1 or 2; the yield of 12 ranged from 43% (MeOH) to 57% (DME). Step I11 was carried out in high yield to give a-methylene-trans- 2-hydroxycyclohexaneacetic acid y-lactone (13) in an overall yield of 48% from 3.
B 11
13
12
cis-2-Hydroxycyclohexaneacetic acid y-lactone (4) was prepared according to Klein? Formylation of 4 was accomplished in either diethyl ether or DME as the reaction solvent to give 14 in a 97-100% yield. Two C-2 epimers of 15
H
7
Ratio of (CH,),” to Na Initial Expt enolateb pH
Time,
Yield of 7,
hr
%
96 96
50 69
MeOH MeOH MeOH
1 1 18
MeOH
18
C
DME DME DME-HMPA
18 24 18
42 32 68 64 68 81 66
-6
DME-MeOH
18
63
C
2a
7:l 6:l
3 4 5 6 7 8 9
1:l 2:l 2:l 2:l 2:l 2:l 2:l
-4 -4 -4 -6
10
2:l
1
c
Solvent MeOH THF-MeOH (3:l)
c
-6
(9:l) (15:l)
Using purified NaCNBH,;I6 all other runs were done with the commercially available NaCNBH, used as received. b NaCNBH, always was used in at least 50% excess molar equiv. CInitial pH not adjusted. a
16
15
14
were obtained in step I1 of the reaction sequence in a combined yield of 33-50% when the sodium enolate of 14 was used as starting material to 57% when 14 itself was used. Although the chromatographically separable epimers of 15 Table I1 Reductive Amination of Sodium &-Formyl-y-valerolactone Ratio of (CH,),” to Na Initial Expt enolatea DH 1 2 3 4 5 6
6:l 5:l 2:l 2:l 2:l 2:l
b b b -6 b -6
Solvent MeOH
MeOH MeOH MeOH DME DME-MeOH
Yield
Time, hr
of 8,c
96 24 24 20 24 20
64 30 35 49 32 33
%
(1O:l) a NaCNBH, always was used in at least 50% excess molar equiv. b Initial pH not adjusted. C Accompanied by varying
amounts of 9 (10-20%), which appeared in significant amounts ( - 32%)in run 5.
3476 J. Org. Chem., Vol. 40,No. 24,1975
Harmon and Hutchinson Scheme IK
Scheme K
5
17
18
Base, HC02C2Hj. NaCNBH3, (CH&NH. NaHC03.
19
CH$, aqueous
gave distinctly different methiodides (Experimental Section), their structural distinction spectroscopically was not done largely owing to the close proximity of the resonances from the carbocyclic ring to those of the C-2 hydrogen in the 100-MHz NMR spectra. Each of the epimers of 15, or their mixture, was carried through step I1 to give 16 in an overall yield of 50% from 14. 3-Formyl-3,4-dihydrocoumarin(17) was prepared in 45% yield essentially as described by Korte and Buchel,lo although several alternative approaches were examined. Numerous bases and formylating reagents were examined in the hope of finding a combination which would favor the formation of 17 rather than ring-opened products. The combination of lithium 2,2,6,6-tetramethylpiperidideand acetic-formic anhydride’l produced a 30% yield of 17. The same base with formic-pivalic anhydride gave only a 27% yield of 17. Sodium hydride and lithium diisopropylamide produced less satisfactory results. Numerous uncharacterized products were formed in all instances. The reductive amination of 5 (Scheme 11) was carried out more successfully than with 2-4 in that the yield of the adimethylaminomethyl derivative was as high as 72%. It i s unfortunate that the amino lactone was not the reaction product. In all cases the ring-opened methyl ester (19) was obtained as the major product, with the corresponding dimethylamide (18) as a minor product. In one instance when DME was used as the solvent a nearly 1:l mixture of 18 and 19 was obtained, 19 arising from initial acidification of the reaction mixture with methanolic hydrogen chloride. Conversion of 19 to its methiodide (20) resulted in the formation of a yellow, amorphous solid. TLC analysis of the reaction mixture after 5 min a t room temperature in the dark indicated the presence of unreacted 19 as well as 20. Two other spots were observed which were not amines, one corresponding to 21. Treatment of the mixture by shaking with 5% aqueous sodium bicarbonate gave a 62% isolated yield of the a-methylene ester (21) based on 17. Hydrolysis with barium hydroxide and neutralization with 1 N sulfuric acid afforded 22, which was lactonized with p toluenesulfonic acid in refluxing toluene to %methylene3,4-dihydrocoumarin (23). A 55% overall yield of 23 was obtained from 17. The structure given as 23 was assigned on the basis of the following spectral and analytical data. The ir spectrum contained a strong peak a t 1740 cm-l. When compared with the 1773-cm-l peak observed with 5 it was seen that the observed shift of carbonyl absorption corresponded to that observed between other a,P-unsaturated esters and lactones when compared to their saturated analogs.12Peaks at 1639 and 810 cm-l suggest a vinylidene group. The NMR spectrum (60 MHz) contained a four-proton multiplet a t S 6.9-7.4 for the aromatic system. A pair of finely split multiplets a t 6 5.77 and 6.40 represented the a-methylene protons which were split by the two P protons and by
20
21
22 23 MgiN(i-i’r)&, HCOZC~HS. NaCNBH3, (CH&NH, (CHdzNH2C1. CHd. Aqueous NaHC03. e Ba(0H)Z. f p-TSA, a
A.
the magnetically nonequivalent vinylogous twin. Both ,I values are
