440 J . Org. Chem., Vol. 58,No. 5,1 W S
CUBHMAN AND CASTAGNOLI
was extracted (CHzClz, 3 X 60 ml) and the extract was concentrated. The residue was partitioned between 2 N HC1 and ether. The 2 N HC1 fraction was basified (20% KOH) and reextracted (ether). Removal of the ether gave an oil (3.34 g, 527&),which was essentially 14 (R = CH,) from nmr spectroscop;. This was characterized as the biscyclamate: mp 126128 ; vmax 3240 (m), 1584 (m), 1290 (s), 1270 (s) 1208 (s), 1170 (s), 1030 cm-l (s); ' : : :A benzenoid absorption; nmr (free base) 6 7.10 (q,4), 3.64 (s, 2), 2.24 ( s , 3), 2.04 (s, 3). Anal. Calcd for C14H22iTz*2C6HlaN0&3: C, 54.15; H , 8.39; N , 9.72. Found: C, 53.89; H , 8.66; N, 9.60. Attempted Catalytic Reduction of 6 (R = H) to 5.-Compound 6 (R = H ) (2.07 g, 0.011 mol) was hydrogenated (room temperature and pressure) in ethanol over PtOz (100 mg). Hydrogen was consumed (410 ml), the reaction mixture was filtered through Celite, and the ethanol was removed. The residue was an oil (0.02 g), identical (nmr, ir) with 2-(3-aminopropyl)-l,2,3,4-tetrahydroisoquinoline (4) prepared by NaBHl reduction of 1 (n = 2 ) . The dihydrochloride melting point (283-265') was identical with that of material above. Attempted Reduction of 6 (R = H ) to 5.-Compound 6 (R = H ) (3.74 g, 0.02 mol) was dissolved in dry T H F (30 ml) and added to a well-stirred slurry of LiAlH4 (1.9 g) in T H F (100 ml) under nitrogen. The mixture was refluxed overnight. The excess reagent was decomposed with saturated sodium potassium tartrate and the mixture was filtered through Celite. The filtrate was diluted with ether, well wnshed (saturated salt solution), dried (MgSOa), and concentrated to yield an oil (3.31 g) identical (ir, nmr) with the starting material 6 (R = H).
Mercuric Acetate-EDTA Oxidation of Compound 9.-Compound 9 (700 mg, 0.0035 mol) was added to a solution of mercuric acetate (1.14 g, 0.0035 mol) and EDTA disodium salt (1.3 g, 0.0035 mol) in 2% aqueous acetic acid (60 ml). After 2 days at room temperature, the mixture was made basic (20% KOH) and extracted (ether). The ether was washed (saturated NaCl solution), dried (RlgSOd), and removed. The resulting oil (420 mg) was distilled in a hot box (0.05 mm). The distilled material (380 mg) was examined: vmsx 1650 cm-' (m), 1620 (m); nmr 6 8.34 (d, -0.25), 6.18 (d, w O . S ) , 5.34 (d, -0.5); mass spectrum m/e 216, 200, 187, 157, 129; 200 + 157 is loss of .CH2=NCH2, linked by a metastable peak a t 123.2; 157 + 129 is loss of CzHa linked by a metastable peak ai 106.0.
Registry No.-1 (n -= l ) , 37384-28-4; 1 (n = 2)) 37384-29-5; 3 (n = l ) , 37394-04-0; 3 (n = 2), 2113996-8; 4, 5596-87-2; 5, 37393-84-3; 6 (R = H, biscyclamate), 37393-83-2; 7, 37413-11-9; 8, 37393-85-4; 10,37393-86-5; 13 (R = H), 37393-87-6; 14 (R = H, biscyclamate), 37393-88-7; 14 (R = CH3, biscyclamate) , 37393-89-8. Acknowledgment. -We wish to acknowledge the support and encouragement of Dr. George deStevens and helpful discussions of the spectral data with Mr. L. Dorfman, whose staff we thank for the microanalyses and spectra.
A Novel Approach to the Synthesis of Nitrogen Analogs of the Tetrahydrocannabinols MARKCUSHMAN~ AND NEALCASTAGKOLL, JR.* Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, Sun Francisco, California 9412% Received August 50, 1972 An approach to the synthesis of nitrogen analogs of the tetrahydrocannabinols which preserves the integrity of the trans ring fusion and a natural location of the double bond is reported in the present study. The condensation of 0-anisylidenemethylamine (10)and glutaric anhydride yic lded trans- and cis-I-methyl-6-carboxy6-(0-methoxyphenyl)-2-piperidones(11 and 12). Subsequent 0-demethylation and cyclodehydration of the trans diastereomer provided the tricyclic lactone 16, which was converted into the corresponding gem-dimethyl alcohol 18. Cyclodehydration of 18 gave the key tricyclic intermediate 23, which was also obtained independently via the methyl ester 13 of 11. Treatment of the trans esier 13 with CH8MgBr yielded the tertiary alcohol 24, which on treatment with BBr8 gave the trans bromide 25. Dehydrohalogenation of 25 provided a mixture of olefins 26 and 27, which could be cyclized to the key intermediate 23 in CFaCOOH. Configtirational and conformational assignments were made by nmr spectroscopy. Subsequent methylations and reductions of 23 provided the corresponding carbinolamines, enamines, and amines.
It has been shown that the biologically active constituents of Cannabis are A1-tmns-tetrahydrocannabinol (A1-THC) 1 and A'@)-truns-tetrahydrocannabinol
2 (monoterpenoid numbering)
1
(Al(@-THC)2.3 The absolute configurations of ,A1THC and A1@)-THC at C-3 and C-4 are R S 4 (1) NDEA Predoctoral Fellow and American Foundation for Pharmaceutical Education Fellow. (2) Y. Gaoni and R. Mechoulam, J. Amer. Chem. Soc., 86, 1646 (1964). (3) R. L. Hively, W. A. Mosher, and F. W. Hoffmann, ibid., 88, 1832 (1966). (4) R. Mechoulam and Y. Gaoni, Tetrahedron Lett., 1109 (1967).
In view of the generally recognized psychotropic activity of the THC'S,~a striking structural fcaturc of these molecules is the absence of nitrogen. However, a number of THC nitrogen analogs have been reported. Thus far, the synthesis of most of these nitrogen analogs has been based on the early work of Adams and Todd and their collaborators,6 who con( 5 ) I,. E . Hoilister, Ann. N . Y.Acad. Sa., 191, 132 (1971). (6) R . Adams and B. R . Baker, J. Amer. Chem. Soc., 62, 2405 (1940); R . Ghouh, A. R. Todd, and S. Wilkinson, J . Chem. Soc., 1121 (1940).
NITROGEN ANALOGSOF THE TETRAHYDROCANNABINOLS dcnsed ethyl 5-mothylcyclohcxanone-2-carboxylate (3) with olivctol (4) in thc prcscncc of phosphorus oxychloride to givo the bcnzopyronc 5. Treatment of 5 with mcthylmagncsium iodide providcd the unnatural arid 1css physiologically activc A3-THC 6. By conOH
5
J. Org. Chem., Vol. 38, N o . 3, 1973 441
mers 1 and 2, it may be concluded that the stereochemistry of the terpene ring is an important factor in terms of any physiological response. Therefore, we have undertaken a new approach to the synthesis of nitrogen analogs of the THC's in which the integrity of tho trans ring fusion and a natural location of the double bond are preserved. An additional factor which should be considorcd in the design of a synthetic route to these cornpounds is its potcntial versatility toward structural modification, sincc tho preparation of a scrim of structurally related compounds should prove of value in the elucidation of parameters associated with thc biological activity. With these considerations in mind, we chose dl-tl.ans-1,5,j-trimcthyl-2-oxo - 1,2,3,4,4a,5,10b- heptahydro [llbenzopyrano[4,3-b]pyridinc (23) as our first objective. The condensation of o-anisylidencmethylamine (10)
'b NCH,
6
I
0
densation of appropriatrly substituted piperidones Lvith olivctol undw similar conditions followed by Grignard rncthylation, aza analogs 7,' 8,*and ggahave been prrparcld.gb
7
8
CH, 10
and glutaric anhydride in refluxing xylene proceeded smoot'hly to yield a diastercomcric mixture of pipcridoncs 11 and 12, which could be separated by fractional crystallization, These trans and cis diastcreomcrs were converted into their methyl esters 13 and 14 by treatment with diazomethane. By analogy with the condcnsation of Schiff bascs and succinic a n h y d r i d c ~ , ' ~thc . ' ~ maior diastereomer would be cxpcctcd to have the trans configuration while that of the minor diastereomer would be cis. In addition, the aromatic ring in both trans and cis diastereomers may be expected to occupy' the axial conformation in
c, HI1 9
hnltw and Cook synthesizctd compound 8 in 1940 and roportctd it to have no analgesic activity.* Razdan, et al., rcpciatad tho synthcfiis of compound 8 and rcportcd in 196s that it is an activc CNS agent similar to compound 7,IO rctportod by Pars, et al.' Both compound* w ( w found to dcpross spontaneous activity and producc: analgesia in micn. The pharmacologic activity of thosr nitrogttn analogs cncouragcd the syntlicsis of thc quinuclidino dorivativc: 9, which was also rrportc.d to bo a n activc CSS agcmt.l' Sinw thc unnatural A 3 isomcr 6 is considcrably lcss potorit in animals'2 and in than the trans iso(7) 11. G . Pars, F. E. Granclielli, J. I
CUSHMAN AND CASTANOGLI compound 16. Attempted conversionla of the methyl ether 11 into 16 via the phenol intermediate 15 with HI in acetic acid gave unexpectedly the coumarin 17.
m
12, RI = COOI-I, R2 = CH, 14, 111 = COOCH3, R2 = CH3
tons of the methyl cstcr of tho major trans diastcrcomcr 13 appears at 6 3.75 ppm whoreas tho corrosponding signal of thc minor diastercomctr 14 appears a t 6 3.56 ppm. Irispctction of Dreiding models reveals that thc mcthoxycarbonyl protoris of the cyuatorial cstcr group of 14 may c>xpcricnccthc shiclding cff cct of thc: aromatic x cloud whcrcas those of the axial wtcr group of 13 may not. Furthcr support of thcsc assignmcmts is providcd by tho coupling constant of HAin 11 ( J = 2.,5 Hz) in comparison with the coupling cwistant of HA in 12 ( J = .5 He). This is as cxpcct,c:d sincc: in comparablc systcms the cwupling wnstants for diequatorial protoris arc: invariably significantly smaller than those of axial-oquatorial protons. l 7 Finally, tho trans lactonc: 16, a ltcy iritcrmediatct in our overall
16
synthotic plan (sce below), ctxists as a rigid dicquatorial conformer. This conversion from t'hc diaxial arrangcmcnt in thc ring o p ~ nsystcm, e.y., 11 to dicquatorial 16 was ac:c:ompaiiicd by a ohangc: in coupling constant for HAfrom 2.5 Hz for 11 t o 13 He for 16. It is firmly ctstablished that tho rimr spectra of compounds containing six-mcmborcd rings show coupling constants for diaxial protons i r i the range of 8-13 Hz and dicquatorial protons in the rang(?1-5 Hz.I7 The rctlativo amounts of 11 and 12 present in thc crude reaction product could be ostimatcd by intcgration of the O-CI-13 singlets in tho nmr spectrum. Based on thcsc valucs, the mixturc contairicd 8Syo of the trans diastcrcomcr and 12% of the cis. I n order to dctcrmitic tho thormodynaniic equilibrium for the mc:tliyl cstcrs 13 and 14, each diastcreomctr \vas hcatcd in JlcOH in the prcuenco of an cquivalcnt of CHD-. The mixture obtained in this way starting from cithor pure trans or pure cis contained 92% of thc trans isomer and 8% of thc cis, dotcrmiricd by integration of mothoxycarbonyl proton sigrials in nmr spectra. Comparable rcsults were obtained by pyrolysis of the trans acid 11. The ncxt stop in our approach to thc model aza arialogs of T H C involved formation of t h c tricyclic (17) I,. M. Jackrnan and 8.Sternliell. "Applications of Siiclear bfapnetic Resonance Spectroscopy in Organic Chemistry," 2nd ed, I'ergamon Press, Elinsford, N . Y . , 1969, p 288.
17
The ir snectrum of tho solid rcvcals strong lactone arid ami& carbonyl bands as w l l as an K-H band at 3380 cm-I which shifts to 2425 cm-l after deutorium cxchangc with D20, consistctnt with the proposed sccoridary aniidc structure.l 9 The nrnr chemical shift valuc: (6 7.85 ppm) of the olefinic proton singlet agrees well with tho 6 7.72 ppm valuc rcportcd for tho corresponding doublot in coumarin.20 Thr remaining nmr signals as n.cll as thc mass spoctral, uv, arid microanalytical data also support this structure (see Exporimctntal Section for details). Synthesis of the dcsircd tricyclic lactone 16 was finally accomplishcd by a txo-stop scquencct. The mothy1 ether 11 was converted into the phenol 15 by treatment with boron tribromidc in methylene dichloride. 21 The phenol underwent cyclodchydration smoothly t o compound 16 in the presence of dicyclohexylcarbodiimide. Attempted thermal cyclization of phenol 15 to 16 ga,vo instead the same coumarin 17 isolated by HI treatment of compound 11. Since both 11 and 16 could not be converted into 17 by heating, it would appear that compound 15 is an obligatory intermediate in the formation of thc coumarin. Trcittmctnt of 16 with cxccss methylmagnesium bromidc in tctrahydrofuran at, 0" providcd tho lactani 18 as thc solo isolable product. Whon thc lactone 16 was treated wit'h mcthylmagncsium broniidc in refluxing xylene for 6 hr, glpc analysis showed tho isolatcd product to bo a 3 : 1 mixturc of two components which could bc separated by column chromatography on neutral alumina. Although the chemical ionization mass spectrum and clcmclntal analysis of the major component could be intcrprctod in terms of the cnaminc 19, the nrnr spectrum could not be
. . .. ..
. ....-
19
(18) R . .\darns and It. 13. Carlin, J . Amer. Chetn. S O ~ .65, , ,760 (1943). (19) I,. J. I3ellamy, "The Infrared Spectra of Complex Molecules," 2nd cd, Wiley, New York, N . Y., 1058, p 207. (20) Varian High Resolution NMIl Spectra Catalog, No. 228. (21) J. I'. W. McOmie, &I. L. Watts, and 11. IC. West, Tetrahedron, 2 4 , 2289 (1968).
NITROGEN ANALOGS OF THE TETRAHYDROCANNABINOLS rationalized on the basis of this structure. In particular, the signal for the C-CH3 a to nitrogen appeared a t 6 1.26 ppm as a sharp singlet, which is a t a higher field than expected for an olefinic methyl signal. Furthermore, the olefinic proton Hn of 19 should appear near 6 4.4 ppm.22 The only signal in this area appeared as a singlet a t 6 4.15 ppni which may be assigned to a benzylic proton. A review of the T H C literature revealed that a compound originally thought to be A1@)-3,4-cis-THCmas reassigned structure 20 on the basis of its nrnr ~pectrum.~3Consideration of the arguments for this reassignment led to the realization that the corresponding structure 2 1 was consistent
J. Org. Chem., Vob. 38. No. 3, 19’78
443
gave a crystalline solid material which proved to be the amide hydrobromide 28.24 Comparison of the
27 H,
0 69
Bre 7
3
HEc-+r--r2
Y 28
20
21
with our spectral data. The chemical shift value of the benzylic proton HAof 21 of 6 4.18 compares favorably with the 6 4.19 reported for the allylic benzylic proton HA of 20. The 6 1.26 value for the C-methyl a to nitrogen in 21 also compares favorably with the 6 1.36 for the corresponding methyl group of 20. The second minor component of the reaction mixture proved to be the product resulting from the addition of four methyl groups to 16 yielding the diequatorially = 10.5 Hz) amine 22. Mixtures of substituted (JA,B
nmr spectrum in CDC13 of this material with that of the corresponding amide 23 reveals downfield shifts for the N-methyl group and all protons in the nitrogencontaining heterocyclic ring, Furthermore, the magnitude of this effect is greatest for thc protons nearest the positive charge. Treatment of the nmr samples with a few drops of Py-da or DzO instantaneously generated the spectrum of thc amide 23. Except for the appearance of HBr, the electron impact mass spectrum of the hydrobromide 28 was identical \*ith that of the amide 23. The empirical formula of the base peak in both spectra was established as CsH9N0by high resolution, which is consistent with structure 29. Radical
t NHCH, 22
21 and 22 could be converted completely into 22 by repeated subjection of the mixture to the Grignard conditions in refluxing xylene. The tricyclic amide 23 was obtained in 40y0 yield by cyclization of the tertiary alcohol 18 in CF3COOH. As in the conversion of 15 into 16, this reaction was accompanied by a conformational conversion from a diaxial to a rigid diequatorial ring system, as indicated by a change in the coupling constant J A , Bfrom 2.5 to 9.5 Hz. An alternative route to the tricyclic amide 23 was also established. Treatment of the trans ester 13 with methylmagnesium bromide in tetrahydrofuran provided the corresponding tertiary alcohol 24, which was converted with boron tribromide into the trans bromide 25. Dehydrohalogenation of this bromide 25 gave a mixture of the olefins 26 and 27, which were shown by nmr to be present in a 19: 1ratio, respectively. In addition to the above two olefins, concentration of the aqueous HBr solution of this reaction mixture
(24) Houben-Weyl, “Die Mothoden der organischen Chemie,” l l P , Georg Thieme, Leiwig, 1958, p 568. (25) B. Wilhalm. A. F. Thomas, and F. Gautsohi, Tetrokedvon, 20, 1185
(22) G. Stork, A. Brissolara, H. Landesman, J. Samusskovicz, and R . Terreil, J. Amer. Chem. Soc.. 86, 207 (1963). ( 2 3 ) Y. Gaoni and R. Meohoulam, %bad.,88, 5673 (1966).
(1964). (26) €1. Budsikiewioz, C.Djerassi, and D. H. Williams, “Mass Speotrometry of Organic Compounds,” Holden-Day, San Francisco, Calif., 1967, pp 340-346.
29
23a
ion 29 may be formed by ring opening of the pyranz5 followed by a cleavage of the amide 23a with loss of a carbene.26 The ir spectrum of hydrobromide 28 contained a broad absorption at 1650 em-’, near the VC=O (1660 cm-l) of amide 23. The amide 23 was obtained after extraction of CHC13 suspensions of 28 with water. The 19 : 1mixture of olefins 26 and 27 was t,reated with boiling CFaCOOH for 35 min and the nonphenolic material isolated in 70Oj, yield. Integration of the KCH3 groups at 6 3.15 and 3.35 ppm of the crude isolate indicated that the trans amide 23 and cis amide 30
444
J. Org. Chem., Vol. 38,N o . 4, 1973
were present in a 17:3 ratio, respectively. During separation of 23 and 30 by fractional crystallization, a trace impurity was detected by glpc on SE-30 which cocrystallized and cosublimed with the desired trans amide 23. Column chromatography led to the separation of the trans and cis amides 23 and 30 from the impurity. As had becri observed with the coumarin 17, the N-methyl doublet ( J = 5 Hz) in the nmr spectrum of the "impurity" collapsed to a singlet after addition of DzO, suggesting the chromene 31. Although thc appearance of the signal for the four methylene protons as a sharp singlet was somewhat surprising, examples of other unsymmetrically l12-disubstituted ethylenes in which the four methylene protons appear as a singlet have been r ~ p o r t e d . ~ 'The ir characteristics of 31 werc similar to those observed for the coumarin 17. When the CF&OOH reaction period was extended to 24 hr, the cis amide 30 (JA,B= 5 Hz) was the only isolable product, and none of 23 or 31 could be detected. Since the chromene 31 is a symmetrical molecule, our attention was directed to the possibility that it is an intermediate in the epimerization of 23 to 30. Therefore a solution of 31 in C$'al'aCOOH was heated a t the boiling point and the reaction progrcss followed by nmr. Essentially complete conversion of thc chromcno 31 to the cis amide 30 was observed within 3 hr. Evidently the epimerization of 23 to 30 proceeds by cleavage of the benzylic carbon-nitrogen bond to form intermediate 32a +-+ 32b,which then deprotonates to generate thc chromcne
CUSHMAN AND CASTAGNOLI drofuran. The corresponding amino aldehyde 34 and enamine 35 str'uctures can be excluded due to the lack of any aldehyde or enamine double bond absorbance in the solid state ir spectrum. Broad multiplets were observed in the nmr spectrum for the mcthine and methylene protons. The nmr spectrum recorded 16 hr after dissolution of the carbinolamine 33 showed substantial conversion (>60%) into the enamine 35. The signal for the benzylic proton HA appeared as a distinct doublet (JA,B= 10 Hz) at 6 4.00 ppm. The signal for the olefinic proton H r has been assigned to a doublet (JE,F= 7 Hz) at 6 6.19 ppm and the signal for the remaining proton HE corresponds to a multiplet a t 6 4.95 ppm.28 This change in the nmr spectrum was paralleled by the appearance of the enamine double bond (1650 cm-l) in the ir ~ p e c t r u m . ~ ~This ,~~J~
37 (m/e 230)
L
k
NHCH,
31
30
31 or cyclizcs to the cis amidc 30. Similar rewlts were also observed on trcatment of the tertiary alcohol 18 with boiling CI:,COOH.
Thc carbinolamine 33 was isolatcd as a, stable solid in 63% yield aftcr reduction of the amide 23 with a large cxcess of lithium aluminum hydride in tetrahy(27) Varian High Resolution NMR Spectra Catalog No. 106 a n d 129.
36 (m/e 229)
facile dehydration was also evident in thc chemical ionization mass spcctrum of the carbinolamine 33 which showed no ion at m l e 248 corresporlding to protonated 33, but did show the iminium ion 37 (m/e 230) as the base peak along with the enamine radical ion 36 (m/e 229,47%). Treatment of the trans amide 23 with an excess of methylmagnesium bromide in boiling tetrahydrofuran yielded thc carbinolamine 38 as a stable solid in 86% yield. As with carbinolamine 33, the corresponding amino aldehyde and enamine structures could be ruled out due to lack of any aldehyde or enamine double bond absorbance in the solid state ir spectrum. In contrast to carbinolamine 33, the nmr and ir spectra recorded at 10-min intervals aftcr dissolution of carbinolamine 38 indicated essentially complete conversion into the enamine 39 plus water within 1 hr. The olefinic proton in the nmr spectrum of the enamine 39 appeared as a multiplet at 6 4-87 ppm and the ir spectrum displayed an absorbance at 1650 crn-l, corresponding to an enamine double bond.22 The enamine 39 could be isolated and characterized as an oil after (28) H. Diekmann, G. Englert, and K. Wallenfela, Tetrahedron, 20, 281 (1964). (29) N . J. Lnonard a n d V. W.Gash, J . Amer. Chem. Soe., 76, 2781 (1954). (80) N. J. Leonard, P. D. Thomas, and V. W. Gash, ibid., 77, 1552 (1955).
NITROGENANALOGE, OF
THE
TETRAHYDROCANNABIKOLS
dehydration of the carbinolamine 38. Unlike other members in this series, the signal for proton HA appeared as a multiplet instead of the expected doublet, presumably due to virtual long-range coupling.31 Addition of DnO to CDCL solutions of enamine 39 resulted in disappearance of the olefinic proton HE and the olefinic methyl group in the nmr spectrum yielding the deuterated enamine 4032333(tt,, for ex-
J . Org. Chem., Vol. 38, N o . 3, 1973 44.5 Experimental Section34
o-Anisylidenemethylamine (lo).-0-Anisaldehyde (136.15 g, 1 mol) and methylamine (34.17 g, 1.1 mol) were stirred for 5 hr at room temp in 200 ml of CGHG in the presence of molecular sieves (3.4, 200 g). Following filtration and washing of the sieves with benzene, the solvent was removed and the residue distilled a t 70" (0.2 nim) t o give the Schiff base as a pale yellow oil (132.47 g, 89y0): nmr 6 8.68 (9, J = 1.5 Hz, imino H), 7.92-6.91 (m, Ar), 3.77 (s, OCH,), 3.48 (d, J = 1.5 Hz, NCH3). Anal. Calcd for CgHllNO: C, 72.46; H , 7.43; N , 9.39. Found: C, 72.22; H , 7.38; N,9.41.
trans-l-Methyl-5-carboxy-6-(o-methoxyphenyl)-2-piperidone (ll).-o-Anisylidenemethylamine (74.60 g, 0.5 mol) and glutaric anhydride (57.05 g, 0.5 mol) were heated in refluxing xylene (100 ml) for 24 hr. Crystallization of a light yellow solid (109.92 g, 83%), mp 155-173"' was induced by scratching the hot solution. Analytically pure trans acid (71.68 g, 55%) was obtained from the diastereomeric mixture by fractional crystallization from 2-butanone (1 1.): mp 182-183; ir (KBr) 3400 (broad), 2900, 1715 (carboxylic acid V C - o ) , 1605 (lactam V C - 0 ) ; nmr 6 11.99 (s, COOH, exchangeable with DzO), 7.14 (m, Ar), 5.37 (d, J = 2.5 Hz, H A ) ,3.86 (s, OCH,), 3.02 (m, HB), 2.89 (s, NCHs), 2.65 (m, HE,F)2.01 (m, Hc,D). Anal. Calcd for ClaH17NOI: C, 63.87; H , 6.51; N, 5.32. Found: C,63.70; H , 6.47; N , 5.46.
cis-l-Methyl-5-carboxy-6-(o-methoxyphenyl)-2-piperidone
change approximately 15 min). In order to establish that an exchange process had occurred rather than dccomposition, the reversibility of the reaction was tested by back-exchange of deuterium in 40 with HzO. Addition of HzO to CDCL solutions of 40 resulted in regeneration of the nrnr gpectrum of 39. Proton HA in the amine 41, obtained by catalytic reduction of 38, appearcd as a doublet ( J A , B = 11 Hz). The presence of a single diastereomer was indicated by the sharp melting point, the presence of single signals for the N-CH3 and C-CHa groups in the nnir spectrum, and obscrvation of a single peak on glpc. The relative configuration at C-2 was not assigned. Compound 42 was obtained by diborane reduction of amide 23.
(12).-The filtrate left after separation of the above trans isomer was concentrated to a volume of 150 ml. After standing overnight, the white solid (7.03 g), mp 170-204', was collected. The pure cis acid (12) (0.73 g, 0.67,) was obtained after three recrystallizations from EtOH: mp 215-216"; ir (KBr) 3383 (b, OH), 2890, 1710 (carboxylic acid V C - O ) , 1595 (lactam U C - 0 ) ; nmr 6 10.27 (s, COOIS, exchangeable with DzO), 7.08 (Ar), 5.36 ( d , J = 5 Hz, H ~ ) , 3 . 6 2( s , O C H ~ )3.24 , (m,HB), 2.81 (s,NCHI), 2.19 (m, CHz-CHz). Anal. Calcd for CldHI7NO: C. 63.87: H . 6.51: N , 5.32. Found: C,64.11; H,6.53; N,5.40. trans-l-Methyl-5-methoxycarbonyl-6-(o-methoxyphenyl)-2-piperidone (13).-An excess of CHzNS in EtOH-Et20 was added to the piperidone 11 (52.66 g, 0.2 mol). Evaporation of solvent from the resulting solution left the methyl ester as a glassy residue which crystallized from EtzO-pentane (100:55 ml) as a rolorless solid (46.52 g), mp 77-78". An additional 4.06 g, mp 77-78', was obtained after concentrating the filtrate to a volume of
