J.Org. Chem., Vol. 40,No. 10,1975
Notes lization from methanol afforded 95% colorless crystals, mp 110111', [a]D 33.76' (2.14 g/100 ml CHC13). Anal. Calcd for C28H460:C, 84.36; H, 11.63. Found: C, 84.28; H, 11.69. This mixture of 2a- and 2~-methylcholest-4-en-3-one (150 mg) was treated with 50 mg of potassium hydroxide in 25 ml of methanol for 3 hr at 25'. The usual work-up gave 2a-methylcholest-4-en%one (3, R = CH3; R = H) in 98% yield, mp 122-124' ( l k 2 mp 122-1241, [ a ] D 89' (lit.294'). B. 2-Methylcholest-4-en-3-one.The yield of crude 2,2-dimethylcholest-4-en-3-one (3, R = R' = CH3) was 97%. Recrystallization from methanol afforded 93% of pure material, mp 94-95' (lit.3 mp 94-95'), molecular ion (70 eV) m / e 412. C. 2-Methyl- d3-cholest-4-en-3-one. A mixture of diastereoisomers (3, R = CH3; R' = CD3 and R = CD3; R' = CH3) was obtained in 90% yield: mp 86-87'; ir (KBr) 2220 cm-l (C-D stretch); molecular ion (70 eV) m / e 415. Results of Specific Methylation with CD3I. A. Cholest-4was en-3-one. The yield of crude 2-methyl-d3-cholest-4-en-3-one 75%, mp 98-loo', ir (KBr) 2220 cm-l. B. 2-Methyloholest-4-en-3-one. A mixture of diastereoisomers (3, R = CD3; R' = CH3 and R = CH3; R' = CD3) was obtained in 40% yield after preparative TLC on a 2-mm silica gel plate eluent 9:l cyclohexane-ethyl acetate): mp 80-82'; ir (KBr) 2220 cm-l; molecular ion (70 eV) m / e 415. Analysis of the diastereoisomeric mixtures of deuterium-labeled 2,2-dimethylcholest-4-en-3-ones was effected by observing the relative intensities of the resonance signals at 6 1.06 and 1.12 ppm in the 100-MHz spectra of these mixtures.
Acknowledgments. We thank the National Institutes of Health for their support of this work (Grant 2 R01 AM 10849-08), Mrs. Lorraine Guile for her assistance in obtaining mass spectra, and Dr. D. N. Kirk of Westfield College, London, for his interest in and helpful comments regarding this work. Registry No.-1 (R = H), 601-57-0: 3 (R = H; R' = CH3), 54446-37-6; 3 (R = CH3; R' = H), 54446-38-7; 3 (R = R' = CH3), 17305-84-9; 3 (Rv= H; R' = CD3), 54446-39-8; 3 (R = CD3; R' = H), 54446-40-1; 3 (R = CH3; R' = CD3), 54515-22-9; 3 (R = CD3; R' = CH3), 54515-23-0; CH3I, 74-88-4; CDaI, 865-50-9.
References and Notes (1) R. A. Lee, C. McAndrews, K. M. Patel, and W. Reusch, Tetrahedron Lett., 965 (1973). ( 2 ) (a)Y. Mazur and F. Sondheimer, J. Am. Chem. Soc. 80, 5220 (1958);(b) 0. Engelfried and M. Schenck, Chem. Abstr., 58, 11669a (1962). ( 3 ) S. R. Pathak and G. H. Whitham, J. Chem. Soc., 193 (1968). ( 4 ) S.K. Malhotra and H. J. Ringold, J. Am. Chem. SOC.,86, 1997 (1964). ( 5 ) P. Beak and T. L. Chaffin, J. Org. Chem., 3 5 , 2275 (1970). ( 6 ) M. E. Kuehne. J. Org. Chem., 35, 171 (1970). ( 7 ) C. Girard and J. Conia, Tetrahedron Lett., 3327 (1974).
1505
Scheme I 0 RCHCOOEt
+
x
HO
-78e, CHIClz
7I
NHCHCOOEt
IaR=H b, R = CH, C, R = (CH&CH d, R (CHJ2CHCH2 e, R = PhCHz
I1
3
R
I11
As outlined in Scheme I, the method involves addition of an equimolar amount of the amino acid ester to a purified solution of cycl~propanone~ (or a suitable cyclopropanone in methylene precursor such as 1-acetoxycyclopropan~l)~ chloride at -78'. The resulting carbinolamine (11) in methylene chloride-acetonitrile (1:l) is then treated with 1 equiv of tert-butyl hypochlorite at ca. -loo, followed by addition of a threefold excess of silver nitrate. The reaction mixture is worked up in a manner identical with that reported for the simple alkyl primary amines.2,6 The @-lactamswere characterized by NMR, ir, and mass spectra, as well as by the hydrolytic procedure described below. The NMR spectra show characteristic multiplets for the 0-lactam ring protons7 near 6 3.2 (2 H) and 2.9 (2 H), while the ir spectra exhibit the expected lactam carbonyl peaks a t 1745 cm-1.8 Table I lists 0-lactams derived from the ethyl esters of glycine, alanine, phenylalanine, valine, and leucine. Chemical confirmation of the presence of the 0-lactam ring in these systems was obtained by ethanolysis of IIIb with dry hydrogen chloride gas in absolute ethanol. The structure of the acyclic amino diester IV was established by its synthesis from ethyl acrylate and the ethyl ester of alanine as shown in Scheme 11.
Scheme I1
CH3
PHCOOEt
Conversion of Amino Acids to /3-Lactam Derivatives via Cyclopropanone Haryy H. Wasserman* and Edward Glazer'
Department of Chemistry, Yale University, New Haven, Connecticut 06520 Received November 4.1974
During studies on ring-enlargement reactions of cyclopropanones2s3 we have recently reported a convenient synthesis of N-alk.yl 0-lactams via the silver ion catalyzed rearrangement of the corresponding N-chloro cyclopropylcarbinolamines.2 We now report the extension of this procedure to the preparation of novel derivatives of amino acids. In particular, the method may be used as a simple route to @-lactamsrelated to the penicillins, such as IIIc.
HCI EtOH
CH3CHNHCH2CH2COOEt I COOEt
IIIb
Iv
CHSCHNHZ
I COOEt
+
CH,=CHCOOEt
f
Ib
Experimental Section Preparation of Cyclopropanone Solutions. Solutions of cyclopropanone in methylene chloride were prepared by the reaction at -78' of ketene with diazomethane, according to established procedure^.^^ Best results were obtained by using doubly distilled ketene and rigorously dried solvent. 1-Acetoxycyclopropanol. To a solution of cyclopropanone (50 mmol) in methylene chloride at -78' was added glacial acetic acid (2.3 9). Removal of solvent on the rotary evaporator at 0' gave 1-
1506 J. Org. Chem., Vol. 40, No. 10, 1975
Notes
Table I Ester
a. NH2CHZCO2Et
56-40-6
33"
54643-14-0
56-41-7
47
34094 -43 -4
72-18-4
65
54643 -15-1
61-90-5
65
54643-16-2
CH3
I
b. NHZCHC02Et CH(CH,),
I
NHZCHCOzEt CHzCH(CH,),
C.
I
d. NHzCHCOzEt CHzPh
I
63-91-2 70 54643 -17 -3 Yield based on the carbinolamine intermediate (IIa).
e. NH2CHCO2Et a
acetoxycyclopropanol (50-70%), showing properties identical with those previously reported for this compound.4bThe alcohol could be stored for several weeks at Oo without serious decompositioh. Conversion of Amino Acid Esters to 0-Lactams. In a typical experiment, 35 mmol of the appropriate amino acid ethyl ester was added at once to the cyclopropanone solution and the resulting mixture was stirred for 45 min at -78O and 30 min at 0'. The solution was then treated with 0.5 g of sodium bicarbonate, followed by the addition of 3.8 g (35 mmol) of tert-butyl hypochlorite at -15 to -loo in the dark. The resulting mixture was stirred for an additional 40 min followed by dilution with 200 ml of dry acetonitrile and then treatment with 17.0 g of silver nitrate. Immediately after the addition of silver ion a copious white precipitate was observed, and the solution was allowed to warm to room temperature. After stirring for an additional 1.5 hr the solution was filtered, and the solvent was removed in vacuo at 35O. The residue was treated with 200 ml of 15% ammonium hydroxide and extracted with ether (3 X 100 ml). The extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure to afford the desired p-lactam as a yellow liquid. The method of purification, along with physical and spectroscopic data, is given below for each p-lactam. l-(a-Carbethoxy)ethylazetidin-2-0ne (IIIb). The P-lactam (3.6 g, 47%) was purified by preparative VPC (12 f t X 0.75 in. 9% SE-30 column at 140O): ir (film) 3.38-3.50 (split), 5.75, 6.90, 7.15, 8.25, 8.40, 9.40, 10.85 p ; NMR (CDCl3) 6 1.30 (6 H, m) 2.96 (2 H, t, J = 4 Hz), 3.40 (2 H, m), 4.20 (2 H, q, J = 7 Hz), 4.50 (1H, q, J = 7 Hz); mass spectrum m/e (re1 intensity) 171 (M+, 5.5), 40 (291, 44 (26), 56 (96), 70 (14),98 (100). Anal. Calcd for C~H13N03:C, 56.13; H, 7.65; N, 8.18. Found C, 56.30; H, 7.72; N, 8.26. l-(a-Carbethoxy-p-phenyl)ethylazetidin-2-one(IIIe). The product (70%)was subjected to preparative thick layer chromatography on silica gel (15% CH*C12-85% ether): ir (film) 3.22-3.45 (split), 5.75, 7.25 (split), 7.95, 8.20, 8.40, 9.75, 13.40, 14.40 p; NMR (CDC13) 6 1.28 (3 H , t, J = 7 Hz), 2.90 (2 H, m), 3.00-3.60 (4 H, m), 4.20 ( 2 H, q , J = 7 Hz), 4.66 (1,H, d of d, J = 6 and 8 Hz), 7.48 (5 H, m); mass spectrum m / e (re1 intensity) 247 (M+, 14), 91 (861,114 (95), 132 (loo), 156 (46), 174 (74), 176 (96). Anal. Calcd for C14H17N03: C, 68.00; H, 6.93; N, 5.66. Found: C, 68.28; H, 6.94; N, 5.85. l-(cu-Carbethoxy)isoamylazetidin-2-one(IIId). The crude product (65%) was purified by VPC (12 ft X 0.75 in. 9% SE-30 column at 145O):ir (film) 3.28-3.50 (split), 5.75, 6.80,7.20 (split), 7.40, 7.92, 8.15, 8.43, 9.73, 10.80 p ; NMR (CDC13) 6 1.00 (6 H, m), 1.32 (3 H, t, J = 7.5 Hz), 1.72 (3 H, m), 3.04 (2 H, t, J = 4 Hz), 3.30 (1 H, m), 3.52 (1 H, m), 4.25 (2 H, q, J = 7.5 Hz), 4.56 (1 H, t, J = 7.5 Hz); mass spectrum m/e re1 intensity 213 (M', l), 58 (511, 98 (35), 140 (100). Anal. Calcd for CllH19N03: C, 61.95; H, 8.98; N, 6.57. Found: C, 61.81; H, 8.75; N, 6.51. l-(cu-Carbethoxy)isobutylazetidin-2-one(IIIc). The crude addition product (65%) was purified by VPC (12 f t X 0.75 in. 9% SE-30 column at 140O): ir (film) 3.34-3.50 (split), 5.75, 6.65, 7.17 (split), 7.35, 8.00, 8.30, 8.45, 9.75 p; NMR (CDC13) 6 1.04 (6 H, d, J = 6 Hz), 1.32 (t, 3 H, J = 7.5 Hz), 2.28 (br septet, 1 H, J = 6 Hz), 3.10 (2 H, t, J = 4 Hz), 3.52 (1 H, m), 3.72 (1H, m), 4.36 (3 H, m); mass spectrum mle (re1 intensity) 199 (M', 5.6), 4 1 (111, 84 (79), 114 (13), 126 (100).
Anal. Calcd for C10H17N03: C, 60.28; H, 8.60; N, 7.03. Found: C, 60.30; H, 8.63; N, 7.21. 1-Carbethoxymethylazetidin-2-one (IIIa). 1-Acetoxycyclopropanol (2.32 g, 15 mmol) in 15 ml of methylene chloride was added dropwise to a solution of ethyl glycinate (3.09 g, 30 mmol) in 100 ml of methylene chloride at -5O under nitrogen. The mixture was stirred for 1 hr and allowed to warm to Oo, followed by addition with vigorous stirring of 50 ml of cold saturated aqueous sodium bicarbonate. The phases were separated, and the organic layer was dried over magnesium sulfate. Removal of the solvent below 20' on the rotary evaporator gave 1.43 g (60%)of the carbinolamine as a clear oil: ir (film) 2.95, 3.45, 5.75, 7.25, 8.30, 9.85, 10.2 p ; NMR (CDC13) 6 0.78 (4 H, m), 1.22 (3 H, t, J = 7.5 Hz), 3.40 and 3.46 (4 H, two singlets), 4.20 (2 H, q, J = 7.5 Hz). To a solution of the carbinolamine (1.39 g, 8.8 mmol) in 100 ml of acetonitrilemethylene chloride (1:l)at -15O was added 0.5 g of solid sodium bicarbonate, followed by tert-butyl hypochlorite (1.05 g, 9.7 mmol) in the dark under nitrogen. The mixture was stirred for 1.5 hr and 5.0 g of silver nitrate was added at once. After stirring for 1.5 hr, the reaction mixture was worked up in the usual way to give the product (33%), purified by VPC (5 f t X 0.75 in. 9% SE-30 column at 130O):ir (film) 3.45, 5.74, 7.10, 8.20,9.60, 10.7 p; NMR (CDCla) 6 1.24 (3 H, t, J = 7 Hz), 3.00 (2 H, t, J = 4 Hz), 3.40 (2 H, t, J = 4 Hz), 3.92 ( 2 H, s), 4.18 (2 H, q, J = 7 Hz); mass spectrum m/e (re1 intensity) 157 (M+, 2), 42 (100),56 (12), 69 (25), 84 (77), 129 (22). Anal. Calcd for C7HllN03: C, 53.49; H, 7.05; N, 8.91. Found: C, 53.29; H, 7.13; N, 8.93. Ethanolysis of t h e 8-Lactam Derived from Ethyl Alanate. A solution containing 500 mg (2.92 mmol) of the p-lactam in 15 ml of absolute ethanol was treated with dry hydrogen chloride gas for 30 min and the resulting mixture was heated at 72' for 6 hr. The solvent was removed under reduced pressure, the residue was taken up in 40 ml of chloroform, and ammonia gas was bubbled through the solution for 15 min. The white precipitate was filtered and the solvent was removed in vacuo to give 470 mg (74%) of a light yellow liquid, purified by VPC (5 ft X 0.25 in. 20% SE-30 column at 145O): ir (film) 3.00, 3.37 (5.80, 6.95, 7.30, 8.45-8.76 (split), 9.80 p ; NMR (CDC13) d 1.22 (9 H, m), 1.82 (1 H, s), 2.38 (2 H, t, J = 6 Hz), 2.70 (2 H, m), 3.24 (1 H, q, J = 7.5 Hz), 4.02 (4 H, m); mass spectrum m/e (re1 intensity) 217 (M+, l ) , 42 ( l l ) , 44 (17), 55 (12), 56 (83), 98 (44), 130 (30), 144 (100). Anal. Calcd for CIoH19N04: C, 55.28; H, 8.81; N, 6.45. Found: C, 55.50; H, 8.86; N, 6.45. Chemical confirmation of this structure was provided by its synthesis from ethyl acrylate and ethyl alanate. A solution containing 2.0 g (20 mmol) of ethyl acrylate and 2.92 g (25 mmol) of ethyl alanate in 25 ml of absolute ethanol was stirred at room temperature for 18 hr and for an additional 4 hr at 35-40°. The solvent was removed on the rotary evaporator and excess starting material was removed by evacuation at 20° (2 mm) to give a liquid (3.8 g, 88%). The product was purified by VPC and was shown to be identical (by ir, NMR, and GLC retention time) with the product obtained upon ethanolysis of the 0-lactam.
Acknowledgment. This work was supported by Grant GM-07874 from the National Institutes of Health. Registry No.-IV, 79-3.
54643-18-4; 1-acetoxycyclopropanol, 16223-
References a n d Notes National Institutes of Health Postdoctoral Fellow, 1972-1973. H. H. Wasserman, H. W. Adickes, and 0. Espejo de Ochoa, J. Am. Chem. Soc., 93,5566 (1971). H. H. Wasserman, E. A. Glazer, and M.J. Hearn, Tetrahedron Lett., 4855 (1973). (a)N . J. Turro and W. E. Hammond. J. Am. Chem. Soc., 88, 3672 (1966); (b) W. J. M. van Tilborg. Thesis, University of Amsterdam, 1971. W. J. M. van Tilborg, S.E. Schaafsma, H. Steinberg, and T. J. de Boer, Red. Trav. Chim. Pays-Bas, 86, 419 (1967). With ethyl glycinate, little p-iactam was initially detected in the mixture of
products, since the monomeric carbinolamine (Ila) undergoes reaction with a second molecule of cyclopropanone to give a bis adduct.4bReverse addition of cyciopropanone (in the form of l-acetoxycyclopropan0 1 ) ~ to a 50% excess of ethyl glycinate gave the monomeric carbinolamhe (Iia),which could then be readily converted to the p-lactam (Illa). H. B. Kagan, J. d. Basseller, and J. L. Lucke, Tetrahedron Lett., 941 (1964): A. K. Bose, V. Sudarsanam, V. Anjaneyulu, and M. S. Manhas, Tetrahedron, 25, 1191 (1969):R. M. Moriarty and J. M. Kliegman, Tetrahedron Lett., 891 (1966). K. Nakanishi, "Infrared Absorption Spectroscopy", Holden-Day, San Francisco. Calif., 1964.
