Synthesis of tricyclic azetidinones by intramolecular

Synthesis of tricyclic azetidinones by intramolecular free radical cyclization GEORGEJUST

AND

GUERINO SACRIPANTE

Department of Chemistry, McGill University, Montreal, P.Q.,Canada H3A 2K6 Received June 6 , 1986

Can. J. Chem. Downloaded from www.nrcresearchpress.com by Renmin University of China on 05/28/13 For personal use only.

This paper is dedicated to Dr. 0.E. (Ted) Edwards

GEORGE JUSTand GUERINO SACRIPANTE. Can. J. Chem. 65, 104 (1987). The synthesis of strained tricyclic azetidinones was achieved by free radical cyclization of N-substituted azetidinones involving a tributyltin hydride/AIBN mediated chain reaction. The 5-exo cyclization led to benzo carbapenerns 10, 12, and 13, which were relatively unstable in solution. The 6-exo mode, however, afforded stable benzo carbacephems 20,22, 24, and 25. GEORGE JUSTet GUERINO SACRIPANTE. Can. J. Chem. 65, 104 (1987). On a rkalisk la synthkse d'azttidinones tricycliques tendues en faisant appel a une cyclisation radicalaire d'azktidinones N-substitukes qui implique une rtaction en chaine provoqute par le couple hydrure de tributylttainlAIBN.La cyclisation exo-5 conduit aux benzo carbapknernes 10, 12 et 13 qui sont relativement instables en solution. Toutefois, dans le mode exo-6, les cyclisations conduisent aux benzo carbackphkmes 20, 22,24 et 25 stables. [Traduit par la revue]

Introduction Since the discovery of the antibacterial drug thienamycin, 1, numerous modifications of its carbapenem structure have been carried out to determine the effect of the ring size on biological activity (1). Our interests in preparing nonclassical tricyclic azetidinones (2) prompted us to investigate the stabilities of the more strained tricyclic benzo carbapenem (n = 0) or carbacephem (n = 1) of type 2. The syntheses of carbapenems or carbacephems were previously achieved by ionic methods. In view of the known instability of tricyclic carbacephems towards acids and nucleophilic reagents, we sought a free radical method for their synthesis (3). As suitable precursors for the intramolecular free radical annelation yielding 2, the radicals were generated either P (n = 0) or y (n = 1) to the nitrogen atom of the azetidinone 3, and a phenyl substituent (R1)was chosen so that the exo mode of addition should be favoured over the endo process. Similar free radical cyclizations yielding bicyclic azetidinones have been described elsewhere (4, 5). Results and discussion The cis-azido azetidinones were prepared by known methods (2) involving the condensation of an appropriate Schiff base with azidoacetyl chloride in the presence of equimolar amounts of triethylamine. Reduction of the azide substituent using hydrogen sulfide and triethylamine followed by acylation of the amine intermediate with phenylacetyl chloride and triethylamine gave fair to good yields of the expected amido azetidinones 4-8. Free radical cyclization of 4 (0.02 M in refluxing benzene), with slow addition of tributyltin hydride and catalytic AIBN over a 20-h period under an inert atmosphere, gave the reduction product 9 (15%), tricyclic azetidinone 10 (5%), and the azepinone 11 (35%), together with some starting material, after separation using a neutral silica hplc column. The configuration of 10 was assigned, based on its coupling constant of 8 Hz (JH4-H5), by analogy with diastereomers 20 and 26 discussed below. When this tricyclic benzo carbapenam 10 was placed in an nmr tube (CDC13), it decomposed within a week, and 11 was isolated as the major product. Due to the instability of 10 in solution, the free radical annelation of 4 was repeated using 1.5 equiv. of tributyltin hydride over a shorter period of time

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'~uthorto whom correspondence may be addressed.

(3 h). After evaporation of the solvent, the crude residue was redissolved in carbon tetrachloride, and 10 precipitated as colorless crystals (24%). The infrared spectrum of 10 displayed the azetidinone carbonyl frequency at 1805 cm-I, which is considerably higher than for less strained bicyclic azetidinones such as cephalosporanic acid (1765 cm- I). The decomposition of 10 to 11 most likely resulted via proton abstraction at C 5 with a double bond formation at C4-C5 and ring opening at the C4-N position to give 11, which is closely related to diazepam (see arrows, 10). To avoid this decomposition, we decided to carry out the next experiment on a propargyl azetidinone 5, where the resulting product 12/13 lacks the C5 proton. Thus, the free radical cyclization of 5 gave two tricyclic azetidinones 12 and 13 in a 4:3 ratio as a crystalline mixture (3 I%), mp 140- 145°C. Also, the reduction product 14 (27%), some starting material, and several decomposition products were obtained. The mixture of 12 and 13 did not survive chromatography using various types of silica and only 13 was recovered partially when neutral silica gel was used. Attempts to recrystallize this mixture also failed, giving decomposition in solution within a few days. From this decomposed mixture was isolated the azepinone 15, which most likely resulted via proton abstraction at C3 forming a double bond at C3-C4 and ring opening at N-C4 of the azetidinone rings 12 and 13. The infrared spectra of 12 and 13 showed the azetidinone carbonyl frequency vibration at 1824 cm-'. Since the benzo carbapenems obtained were found to b e unstable in solution, we next investigated the formation of the somewhat less strained benzo carbacephems 2 (n = I). Desilylation of 6-8 using tetrabutylarnrnonium fluoride, followed by bromination of the corresponding alcohol with triphenylphosphine/carbon tetrabromide, gave good yields of the bromo azetidinones 16, 17, and 18 respectively. Free radical cyclization of 16 gave some reduction product 19 and 65% tricyclic benzo carbacephem, mp 256"C, exclusively, as the less crowded diastereomer 20. The infrared spectrum showed the azetidinone carbonyl absorption at 1755 cm- I. This tricyclic product resulting from a 6-exo addition was found to be highly stable in solution. Similarly, free radical cyclization of 17 gave the reduction product 21 and a good yield of the analogous tricyclic azetidinone 22 (70%), mp 273"C, which displayed the infrared carbonyl vibration at 1770 'cm- .

'


JUST AND SACRIPANTE

4

x - B r

9

X - H

Ph BnCONH

BnCONH

+

R

6

R - H

Hydrogenolysis of 22 using palladium on charcoal in DMF afforded an almost quantitative yield of the tricyclic phenol 23, which displayed the carbonyl frequency at lower wave numbers, 1715 cm-' , due to H-bonding of the phenol proton with the azetidinone carbonyl. The presence of the azetidinone was proven by silylation with Me3SiCl/Et3N, which gave a

-

16 X Br. R 17 X Br. R 19 x - H . R -

H

H OBn

20 22

R - H R

-

OBn

1

product for which the azetidinone frequency reverted to its expected position at 1773 cm-I. In both of the above cyclizations, no diastereomer of 20122 or 7-endocyclization product was detected. The free radical cyclization of 18 gave the 6-exointramolecular cyclization products as a 1:l mixture of geometic isomers


CAN. J. CHEM. VOL. 65, 1987

1 I

I I

1I

i

in over 75% combined yield. These tricyclic azetidinones 24 and 25 were easily separated by flash chromatography and their structures assigned unambiguously by nOe (nuclear Overhauser effect) nrnr experiments. The tricyclic azetidinones 24 and 25, m p 189 and 196°C respectively, were found to be soluble in most organic solvents and stable in solution. Interestingly, the more sterically crowded Z isomer 25 displayed a slightly higher azetidinone carbonyl frequency at 1753 cm-', as compared to 1748 cm-' for 24. Hydrogenation of either 24 or 25, using platinum black as catalyst, reduced the exocyclic double bond from the less hindered side to give the more crowded tricyclic benzo carbacephem 26 as the only product, mp 236-237°C. The coupling constant between H-4 and H-5 was found to be 3 Hz, distinctly smaller than for its diastereomer 20 (10 Hz). The infrared spectrum showed the carbonyl frequency at 1768 cm-' , which was, not surprisingly, 13 wave numbers higher than its less constrained diastereomer 20. Finally, a mixture of 24 and 25 was ozonolyzed to give the corresponding ketone 27 in good yield. Its infrared spectrum showed the azetidinone frequency at 1793cm- and the ketone absorption at 1722 cm-'. This ketone was considerably less stable than its olefinic precursor, and slowly decomposed on silica gel. Overall, the infrared data indicate a trend of higher instability as the azetidinone carbonyl frequency increases from 1755 to 1824 cm-'. The reactions carried out establish the usefulness of a radical process for the carbon-carbon bond formation in strained azetidinone. These free radical reactions also give good stereochemical control in the intramolecular cyclization onto an olefinic bond.

'

Experimental The nrnr spectra were recorded on a Varian XL-200 or XL-300 spectrometerusing TMS as internal standard, and the assignments were determined unambiguously by decoupling, nOe, or 2D experiments when necessary. The infrared spectra were recorded on Perkin Elmer 297 or Nicolet FT 7000 ir spectrometers. Mass spectra (ms) were

obtained on MP 5984A or LKB 9000 mass spectrometers, ion source 250°C and 70 eV electron impact, direct inlet (unless otherwise stated); mlz (assignment, relative intensity). Melting points were determined on a Gallenkamp block and are uncorrected. Column chromatography was performed using Woelm Silica, 32-63 p m size, and the hplc separations were performed using an Altex Ultrasphere-Si column. The cis-azetidinones 4, 5, and 8 were prepared by a procedure as described for 6 (2a) and 7 (2b). Bromo azetidinone 4 Prepared in 78% yield from its corresponding azide; mp 138- 139°C; ir (KBr) v,: 3300 (NH), 177 1 (azetidinone), 1654 (amide); 'H nrnr (CDC13)6: 3.51 (s, 2H, CH,), 5.31 (dd, lH, C3-H, J = 5.3,8), 5.45 (dd, lH, C4-H, J = 5.4, 8), 5.9 (dd, lH, C5-H, J = 8, 16), 6.15 (d, lH, N-H, J = 8), 6.52 (d, 1H,C6-H, J = 16),7.03-7.51 (m, 14H, Ar-H); I3C nmr (CDC13) 6: 43.4 (CH2), 59.9 (C3), 63.4 (C4), 117-136 (20 C, C5, C6 and Ar-C), 165.7 (C2), 171.4 (amide carbonyl); ms (150°C): 4601462 (M+, 0.6), 284 (M+ - CloHgNO2, 32), 263 (M+ - CI8Hl7NO,38.8), 197(40.7), 17 1 (72.6), 145 (67.6), 91 (100). Mol. Wt. (high resolution rns) calcd. for C25H2102N2Br: 460.0783; found: 460.0799. Free radical cyclization of 4 Tributyltin hydride (170 mg, 0.55 rnmol), AIBN (catalytic amount), and dry benzene (3 mL) were added to azetidinone 4 (213 mg, 0.46 mmol) and dry benzene (20 mL) at reflux temperature during 20 h (syringe pump) under an inert atmosphere. 'The mixture was cooled to room temperature and the solvent removed. The residual yellow oil was dissolved in acetonitrile (30 mL), washed with hexane (3 x 30 mL), and the solvent removed. High performance liquid chromatography (hplc) using isopropanol/hexane (15) as eluent gave starting material (same spectroscopic data as 4) and the following products: Reduction product 9 (15%); ir (KBr) v,,,: 1765 (azetidinone), 1657 (amide); 'H nmr (CDC13)6: 3.56 (s, 2H, CH,), 4.95 (dd, lH, C4-H, J = 5,8), 5.53 (dd, lH, C3-H, J = 5,8), 5.98 (dd, lH, C5-H, J = 8, 16),6.61 (d, 1H,C6-H, J = 16),7.01-7.44(m, 16H,N-Hand Ar-H). Tricyclic benzo carbapenem 10 (5%); mp 121°C: ir (KBr) v,,,: 3305 (NH), 1805 (azetidinone), 1664 (amide); 'H nmr (CDC13)6: 2.95 (dd, lH, C6-Hb, J = 13.8, 18), 3.18 (dd, lH, C6-Ha, J = 6.2, 13.8), 3.34-3.45 (m, IH, C5-H), 3.45 (dd, 2H, CH2, J = 4, 16), 4.32 (dd,

JUST AND SACRIPANTE

lH, C4-H, J = 5,8), 5.39 (dd, lH, C3-H, J = 5,8), 5.73 (d, IH, N-H, = 8). 7.05-7.32 (m, 14H, Ar-H); ms (260°C): 382 (M+, loo), 337 (M' - 45,56), 247 (M' - BnCONH2, 96), 207 (M' - CIOH9N02, 53.1). Mol. Wt. (high resolution ms) calcd. for C25H22N202: 382.1681; found: 382.1734. Azepinone 11(35%); ir (KBr) v,,: 3290 (NH), 1680 (lactarn), 1657 (amide); 'H nmr (CDC13) 6: 3.63 (s, 2H, CH2CO), 4.31 (dd, 2H, CH2Ar, J = 3,5), 4.56 (d, lH, C4-H, J = 5.2), 5.68 (dd, lH, C3-H, J = 5, 6), 6.78 (d, lH, N-H, J = 6), 6.93-8.0 (m, 15H, Ar-H); ms (1 11°C): 382 (M', 0.23), 291 (M' - Bn, 0.3), 207 (M' - Cl0HgNO2, 31.3), 206 (24.4), 130 (100). Repeating the above cyclization, except adding 1.5 equiv. of tributyltin hydride over a 3-h period, gave a precipitate, after evaporation of the solvent and trituration of the corresponding residue with carbon tetrachloride. The crystals were filtered off and washed with hexane to give 10 (24%) as colorless crystals, with identical spectroscopic data as before.


J

Bromo azetidinone 5 Prepared in 7 1% yield from its corresponding azide; mp 151- 152°C as colorless crystals; ir (KBr) v,,,: 2280 (C=C), 1741 (azetidinone), 1647 (amide); 'H nmr (CDC1,) 6: 3.65 (s, 2H, CH,), 5.48 (d, lH, C4-H, J = 5.4), 5.75 (dd, lH, C3-H, J = 5.4,9), 6.78 (d, lH, N-H, J = 9), 7.1 1-7.6 (m, 14H, Ar-H); 13Cnmr (CDC13) 6: 43.46 (CH2), 53.62 (C4), 59.22 (C3), 81.34 ((25); 90.07 (C6), 118-133 (18C, Ar-C), 165.5 (C2), 171.22 (amide carbonyl); ms (195°C): 4581460 (M', 5.7), 2831285 (M' - CI0H9NO2,20.8), 175 (M' - 283,5.7). Free radical cyclization of 5 Tributyltin hydride (150 mg, 0.5 mmol), AIBN (cat.), and dry benzene (1 mL) were added to azetidinone 5 (193 mg, 0.42 mrnol) and dry benzene (20 mL) at reflux temperature during 5 h (syringe pump) under an inert atmosphere. The mixture was cooled to room temperature and the solvent removed. The residue was dissolved in acetonitrile (30 mL), washed with hexanes (3 x 30 mL), and the solvent removed. Trituration of the residue with carbon tetrachloride/acetonitrile gave the tricyclic azetidinones 12 and 13 as a yellow precipitate (4:3 ratio respectively, 31%), mp 140-145°C. From the filtrate was isolated starting material (5%), reduction product 14 (1 I%), and the azepinone 15 (27%), after separation by column chromatography using ethyl acetatelhexane as eluent (1:1). Tricyclic azetidinone 12; 'H nmr (CDCI3) 6: 3.60 (dd, lH, CH2, J = 2.5, 17), 5.79 (dd, lH, C3-H, J = 5.9, 9.2), 6.00 (d, lH, N-H, J = 9.2), 6.32 (d, lH, C6-H, J = 2.5), 7.07-7.54 (m, 14H, Ar-H); 13C nmr (CDC13) 6: 43.42 (CH2), 58.34 (C4), 62.13 (C3), 126.01 (C6), 122-144 (Ar-C and C5), 171.OO (Cl), 175.87 (amide carbonyl). Tricyclic azetidinone 13; 'H nmr (CDC13) 6: 3.06 (dd, 2H, CH2, J = 17, 34), 5.51 (dd, lH, C4-H, J = 3.3, 6), 5.66 (d, IH, N-H,

467 (M' - tert-butyl, 1.9), 349 (M' (M' - C2C3 - tert-butvl, . . 26.1).

107 - CIOH9N02,1.7), 292

Silyl azetidinone 16 Tetrabutylamrnonium fluoride (4.69 g, 17 mmol) and THF (5 mL) were added to azetidinone 6 (5.0 g, 9.5 mmol) and 150 mL of dry THF at 0°C under a nitrogen atmosphere. After 30 min, water (2 mL) was added and the solvent removed. The residue was then purified by flash chromatography using ethyl acetatelhexane (1:l) as eluent to give the alcohol as colorless crystals (72%); mp 174-175°C; ir (KBr) v,,,,: 1756 (azetidinone), 1660 (amide); 'H nrnr (DMSO-d6)6: 3.34 (s, 2H, CH2CO), 4.52-4.56 (bs, lH, 0-H), 4.53 (s, 2H, CH2-0), 4.82 (dd, lH, C4-H, J = 5, 86), 5.25 (dd, lH, CH3-H, J = 5, 8), 6.05 (dd, lH, C5-H, J = 8, 16), 6.40 (d, lH, C6-H, J = 16), 6.8-7.28 (m, 19H, Ar-H), 8.26 (d, lH, N-H, J = 8); ms (230°C): 410 (M' - 2H', 2.6), 333 (410 - Ph, 3.3), 320 (M' - Bn - H', 50.1). To the above alcohol (700 mg, 1.7 mmol) and dry methylene chloride (100 mL) at O°C under a nitrogen atmosphere were added carbon tetrabromide (560 mg) followed by slow addition of triphenylphosphine (430 mg, 1.97 mmol). After 3 h of stirring, the solution was allowed to warm up to room temperature, and purified by column chromatography using ethyl acetatelhexane (1:3) to give the azetidinone 16 as colorless crystals (62.5%) after recrystallization from ethyl acetatelhexane; mp 123-124°C; ir (KBr) v,,: 3310 (NH), 1744 (azetidinone), 1644 (amide); 'H nmr (CDC13) 6: 3.60 (s, 2H, CH2-0), 4.72 (dd, 2H, CH2Br, J = 10.4,22), 5.02 (dd, lH, C4-H, J = 5, 8.2), 5.55 (dd, lH, C3-H, J = 5, 8), 6.08 (dd, lH, C5-H, J=8.2,16),6.38(d,lH,N-H,J=8),6.64(d,lH,C6-H,J=16), 7.1-7.34 (m, 14H, Ar-H); ms (305°C): 4741476 (M' , 4/3.9), 395 (M" - Br', 33), 394 (M' - HBr, loo), 317(M' - Ph - HBr, 70.5), 275 (M' - HBr - BnCO, 43.7), 220 (M" - C10H9N02- Br', 4 9 , 263 (M' - CI8Hl7NO,17).

Silyl azetidinone 17 Prepared as described for 16. The alcohol was obtained in 65% yield from 9 as colorless crystals, mp 163°C; I H nmr (CDC1,) 6: 3.50 (s, 2H, CH2CO), 4.12 (dd, lH, 0-H, J = 4,8),4.64and 4.82 (dd, 2H, CH2-0, J = 8 , 12and4, 12),5.08(s, 1H,PhCH2Ar),5.13(dd, lH, C4-H, J = 5,8), 5.24 (dd, lH, C3-H, J = 5,8), 6.07 (dd, lH, C5-H, J = 8, 16), 6.40 (d, lH, C6-H, J = 16), 6.80 (d, IH, N-H, J = 8), 6.9-7.39 (m, 13H, Ar-H); ms (200°C): 518 (M', O.1), 343 (M' C10H9N02,0.9), 263 (M' - Cl5HI3NO3,42.7), 175 (Mf - NC4, 3.0). Azetidinone 17 was obtained as colorless crystals in 8 1%yield from 3270 (NH), 1758 the above alcohol; mp 145-146°C; ir (KBr) v,: (azetidinone), 1656 (amide); 'H nmr (CDC13)6: 3.56 (s, 2H, CH2CO), 4.66 (dd, 2H, CH2Br, J = 10, 10. l ) , 5.05 (s, 2H, PhCH2Ar), 5.12 (dd, lH, C4-H, J = 5, 8), 5.41 (dd, IH, C3-H, J = 5.8), 5.96 (bd, lH, N-H, J = 8), 6.09 (dd, lH, C5-H, J = 8, 16), 6.42 (d, lH, J=10),6.10(dd,1H,C3-H,J=6,10),6.99(d,1H,C6-H,J=3.3), C6-H, J = 16), 6.88-7.39 (m, 18H, Ar-H); ms (285°C): 5801582 7.07-7.54 (m, 14H, Ar-H); I3C nmr (CDCI3)6: 42.79 (CH,), 58.02 (M', 0.8/0.7), 501 (M" - Br, 38.4), 500 (M' - HBr, loo), 423 (C4), 61.86 (C3), 123.42 (C6), 122-144 (Ar-C and C5), 170.32 (C2), (M' - HBr - Ph, 30), 381 (M' - HBr - BnCON, 19.9). 175.77 (amide carbonyl); ir of 14 and 15 (KBr) v,,: 3290-3310 (NH), Silyl azetidinone 18 1824 (azetidinone), 1640- 1647 (amide). Prepared as described for 17. The alcohol was obtained in 5 1% yield Reduction product 14; ir (KBr) v,,: 3300 (NH), 1745 (azetidifrom 8 as colorless crystals; mp 184- 185°C; ir (KBr) v,,,: 3305 (NH), none), 1649 (amide); 'H nmr (CDC13) 6: 3.65 (s, 2H, CH2), 5.03 1768 (azetidinone), 1650 (amide); 'H nmr (DMSO-d6)6: 3.29 (s, IH, (d, lH, C4-H, J = 5), 5.72 (dd, lH, C3-H, J = 5, 8), 6.26 (d, lH, 0-H), 3.61 (s, 2H, CH2CO), 4.69 (s, 2H, CH2-O), 5.23 (d, lH, N-H, J = 8), 7.05-7.59 (m, 15H, Ar-H); ms (1 11°C) chemical C4-H, J = 5), 5.50 (dd, lH, C3-H, J = 5, 8), 7.08-7.46 (m, 15H, ionization, isobutane: 381 (M' + 1, 22. I), 363 (M' - BnCO, 15.8), Ar-H and N-H); ms (208°C) chemical ionization, isobutane: 411 353 (381 - CO, 10.1), 206 (M' - CI0H9NO2,loo), 176 (M' - 206, (M' + 1, 19.4), 319 (M' + 1 - CloH9NOr,9.1). Mol. Wt. (high 65.7). resolution ms (208°C)) calcd. for C26H22N203:410.1629; found: Azepinone 15; 'H nmr (CDC13)6: 4.19 (s, 2H, CH,CO), 6.86-7.50 410.1685. (m, 1lH, Ar-H and C=CH), 8.85 (bs, lH, NH). Azetidinone 18 was obtained in 63% yield from the above alcohol as Bromo azetidinone 8 colorless crystals; mp 135-136°C; ir (KBr) v,: 3290 (NH), 1755 Prepared in 49% yield from its corresponding azide; mp 123- 124°C (azetidinone), 1666 (amide); 'H nmr (CDC13)6: 3.69 (s, 2H, CH,CO), (colorless crystals); ir (KBr) v,,,: 3210 (NH), 1768 (azetidinone), 4.64 (dd, 2H, CH2Br, J = 10, 18), 5.21 (d, lH, C4-H, J = 5), 5.75 1645 (amide); 'H nmr (CDC13) 6: 0.048 and 0.056 (s, 6H, SiMe2), (dd, lH, C3-H, J = 5, 8), 6.30 (d, lH, N-H, J = 8), 7.05-7.51 0.907 (s, 9H, tert-butyl), 3.67 (s, 2H, CH2CO), 5.18 (2, 1H, C4-H, (m, 14H, Ar-H); ms (195°C): 4721474 (M', 0.3), 343 (M" - Br', J=8),5.7(~,2H,CH~0),5.71(dd,lH,C3-H,J=5,10),6.3(d,lH, 1 4 , 392 (M' - Bn, 1.8), 392 (M' - HBr, 5.8), 218 (M" - Br' N-H, J = lo), 7.1-7.5 (m, 14H, Ar-H); ms (175°C): 524 (M', 0.1) CloH9N02,56.8), 217 (41.2), 175 (28.2).


108

CAN. J. CHEF

Radical cyclizarion of 16 Tributyltin hydride (442 mg, 1.52 mmol), AIBN (cat.), and benzene (5 mL) were added to azetidinone 16 (600 mg, 1.27 mmol) and dry benzene (55 mL) at reflux temperature during 10 h under an inert atmosphere. The mixture was cooled to room temperature and the precipitate filtered off and washed with hexane to give the azetidinone 20 (340 mg, 68%) as colorless crystals. From the filtrate, after the usual work-up and column chromatography, was recovered the reduction product 19 (12%) using ethyl acetatelhexane as eluent. Benzo carbacephem 20; mp 256°C; ir (KBr) v,,,: 3290 (NH), 1755 (azetidinone), 1642 (amide); 'H nmr (pyridine-d5, 60°C) 6: 1.95 (m, lH,C5),2.19(dd, 1H,C6-Hc, J = 10, 13),2.32(dd, lH,C7-Ha, J = 15, 13), 2.59 (dd, lH, C7-Hb, J = 4, 15), 2.97 (dd, lH, C6-Hd, J = 4, 13), 3.74 (dd, lH, C4-H, J = 5, lo), 3.82 (s, 2H, CH2CO), 5.96 (dd, lH, C3-H, J = 5, 9), 6.99-7.63 (m, 14H, Ar-H), 9.91 (d, 1H, N-H, J = 9); I3cnmr (DMSO-d6) 6: 30.45 (C7), 32.32 (C5), 36.85 (C6), 42.11 (CH2Ph), 56.77 (C4), 58.56 (C3), 117-138.3 (Ar-C), 165.68 (C2), 170.57 (amide carbonyl); ms (225°C): 396 (M+, 2.2), 305 (M+ - Bn, 2.1), 277 (M+ - BnCO, 6.6), 222 (M+ + 1 - Cl&19N02,35.7), 175 (1.9), 77 (100). Mol. WI. (high resolution ms) calcd. for C26H2402N2:396.1837; found: 396.1830. Reduction product 19; ir (KBr) v,,,: 3305 (NH), 1740 (azetidinone), 1675 (amide); 'H nrnr (CDC13) 6: 2.32 (s, 3H, CH,), 3.50 (s, 2H, CHzCO), 4.92 (dd, lH, C4-H, J = 5, 8), 5.56 (dd, lH, C3-H, J = 5 , 8 ) , 6 . 1 5 ( d d , lH,C5-H, J = 8 , 16),6.56(d, lH,C5-H,J= 16), 6.92-7.57 (m, 15H, Ar-H and N-H); ms (100°C): 396 (M+, 3.2), 395 (5.7), 305 (M+ - Bn, 1.8), 277 (M+ - BnCO, 6.0), 221 (M+ - CloH9N02,33), 222 (100).

'OL. 65, 1987

(dd, lH, C3-H, J = 5, 9), 6.87-7.49 (m, 14H, Ar-H), 9.98 (d, l H , N-H, J = 9); ms (220°C): 412 (M+,2.9), 293 (M+ - BnCO, 5 3 , 2 3 7 (M+ - CI0H9NO2,15.5), 238 (100). Mol. Wr. (high resolution ms 412.1786; found: 412.1835. (260°C) ) calcd. for C26H2403N2: Free radical cyclization of 18 Tributyltin hydride (125 mg, 0.42 mmol), AIBN (cat.), and benzene (2 mL) were added to azetidinone 18 (170 mg, 0.36 mmol) and dry benzene (18 mL) at reflux temperature during 12 h (syringe pump) under an inert atmosphere. The mixture was cooled to room temperature and the solvent removed. The residue was dissolved in acetonitrile (30 mL), washed with hexane (3 x 30 mL), and the solvent removed. Column chromatography using ethyl acetatelhexane as eluent gave the following products: Tricyclic azetidinone 24 (37%); E isomer; mp 189°C (colorless 3305 (NH), 1748 (azetidinone), 1690(amide); crystals); ir (KBr) v,,: 'H nmr (CDC13) 6: 3.30 (dd, 2H, C7-H, J = 16, 30), 3.47 (s, 2H, CH2CO), 4.78 (d, lH, C4-H, J = 5), 5.77 (d, lH, N-H, J = 8), 5.78 (dd, IH, C3-H, J = 5, 8), 6.60 (s, l H , C6-H), 6.96-7.41 (m, 14H, Ar-H); ms (270°C): 394 (M+, 0.7), 275 (M+ - BnCO, 0.6), 260 (M+ - BnCONH, 0.93), 221 (M+ - CI0H9NO2,18.2), 220 (100). Mol. Wt. (high resolution ms (270°C)) calcd. for C26H2602N2: 394.1681; found: 394.1695. Tricyclic azetidinone 25 (38%): Z isomer: mp 196.C: ir (KBr) v,,,: 3260 (NH), 1753 (azetidinone), 1655 (amide); H nmr (CDC13)6: 3.60 (s, 2H, CH2CO),3.63 (dd, 2H, C7-H, J = 19,28), 4.62 (d, lH, C4-H,

J=5),5.64(dd,lH,C3-H,J=5,8),6.04(d,lH,N-H,J=8), (s, lH, C6-H), 7.06-7.44 (m, 14H, Ar-H); ms (269°C): 394 (1.6), 260 ( l l ) , 275 (0.9), 221 (21.7), 220 (loo), 219 (19.6). Mol. Wr. (high resolution ms) calcd. 394.168 1; found: 394.171 0.

Radical cyclizarion of 17 ~ribuGltinhydride (72 mg, 0.25 mmol), AIBN (cat.), and benzene Tricyclic benzo carbacephem 26 (1.5 mL) were added to azetidinone 17 and dry benzene (10 mL) at To a mixture of azetidinones 24 (10 mg) and 25 (10 mg), ethyl reflux temperature during 5 h (syringe pump) under an inert atmosacetate (5 mL), and ethanol (3 mL) was added platinum black (3 mg). phere. After a further 3 h at the same temperature, the reaction mixture The mixture was stirred overnight at room temperature under a was cooled to room temperature, whereby a white precipitate formed. hydrogen atmosphere, was then filtered off, and the solvent removed. The precipitate was filtered off and washed with hexane to give The residue was purified by flash chromatography using ethyl aceazetidinone 22 (39 mg, 70%) as colorless crystals. The solvent was tatelhexane as eluent to give, after recrystallization from chlororemoved to give an oily residue, which after the usual work-up and form/carbon tetrachloride, the tricyclic azetidinone 26 as colorless purification by column chromatography (ethyl acetatelhexane 1:l) crystals (25%); mp 237°C; ir (KBr) v,,,: 3305 (NH), 1768 (azetidigave the reduction product 21 (12%). none), 1641 (amide); 'H nmr (CDC13) 6: 1.91-2.04 and 2.36-2.65 Tricyclic benzo carbacephem 22; mp 273-274°C; ir (KBr) v,,: (m, 5H, C5-H, C6-H, and C7-H), 3.65 (dd, 2H, CH2C0,J = 2.5,6), 3282 (NH), 1770 (azetidinone), 1655 (amide); 'H nmr (pyridine-d5)6: 4.25 (dd, IH, C4-H, J = 3, 5), 5.41 (dd, l H , C3-H, J = 5, 6), 2.25-2.4 (m, 3H, C5-H, C7-Ha, and C6-Hc), 2.63 (dd, IH, C7-H6, 6.01 (d, l H , N-H, J = 6), 6.7-7.5 (m, 14H, Ar-H); ms (220°C): J = 1.2, 14),2.98(dd, 1H,C6-Hd, J = 1.2, lo), 3,69(dd,2H,C4-H, 396 (M+, 2.1), 305 (M+ - Bn, 1.7), 277 (M+ - BnCO, 23.1), J = 5 , 10.2), 3.81 (s, 2H, CH2CO), 5.17(dd,2H,CH2-0, J = 12, 262 (M+ - BnCONH2, 20), 222 (M+ + H - C10H9N02,14.2), 22), 5.97 (dd, lH, C3-H, J = 5, 9), 6.84-7.7 (m, 14H, Ar-H), 9.97 175 (14.4). Mol. Wt. (high resolution ms) calcd. for C26H2402N2: (d, lH, N-H, J = 9); ms (273°C): 502 (M+, 0.96), 41 1 (M+ - Bn, 396.1837; found: 396.1758. 4.5). 383 (M+ - BnCO, 1.6), 328 (M+ + 1 - CIOH9N02', loo), 148 (M' - 328, 0.5). Mol. ~ t . ( h i g hresolution ms~(27o0c))calcd. for Tricyclic keroazetidinone 27 M+ - Bn, C26H2303N2: 411.171; found: 411.171. A mixture of azetidinones 24 (10 mg) and 2 5 (10 mg), methanol Reduction product 21; ir (KBr) v,,,: 3278 (NH), 1748 (azetidi(2 mL), and dichloromethane (2 mL) at - 7g°C was ozonized for 5 min. none), 1650 (amide); 'H nmr (CDCI3) 6: 2.33 (s, 3H, CH3), 3.50 The light blue solution was stirred for 15 min, and a stream of nitrogen (s, 2H, CH2CO), 4.95 (dd, lH, CH4-H, J = 5 , 8), 5.06 (dd, 2H, was passed through the solution for 15 min. Dimethylsulfide (excess) PhCH2-O,J= 12, 16),5.38(dd,lH,C3-H,J=5,8),5.95(dd,lH, was added and the mixture left overnight at room temperature. The C5-H, J = 8, 16), 6.17(d, lH, N-H, J = 8), 6.44(d, lH, C6-H, solvents were removed and the residue purified by column chromatogJ = 16), 6.75-7.39 (m, 18H, Ar-H); ms (282°C): 502 (M+, 2.7), raphy using ethyl acetatelhexane (1 :1) to give the ketone 27 as a yellow 41 1 (M+ - Bn, 4 . 9 , 327 (M+ - CLOH9NO2, 21.3), 328 (41.9), 237 oil (75% yield); ir (neat) v:, 3160 (NH), 1793 (azetidinone), 1722 (17.1). (ketone), 1647 (arnide); 'H nrnr (CDCI3) 6: 3.55 (dd, lH, C6-Ha, J = 1.8, 22), 3.56 (s, 2H, CH2CO), 4.06 (d, lH, C6-Hb, J = 22), 4.06 Phenol carbacephem 23 (dd, 1H,C4-H, J = 1.8,5.7),4.74(dd, 1H,C3-H, J=5.7,7.2), 6.05 Azetidinone 22 (25 mg), ethanol (5 mL), and dimethylfomarnide (d, lH, N-H, J = 7.2). 7.17-7.39 (m, 9H, Ar-H); ms (148°C) (2.5 mL) were hydrogenated with palladium on charcoal (2.5 mg, chemical ionization, isobutane: 321 (M+ + 1, 48.4), 320 (M+, 2.7), 10%) until 2.5 mL of hydrogen had been absorbed. The mixture was 319 (14.7), 304 (321 - 17, 38.8), 303 (321 - 18,48.3), 176 (14.6), filtered and the solvent removed. Recrystallization from hot ethyl 146 (M+ + 1 - Cl&I9NO2,100). acetate and precipitation with hexane gave quantitative yield of azetidinone 23 as colorless crystals; mp 282-283"~; ir ( K B ~:,v) Acknowledgements 3420 (b, OH), 3280 (NH), 1715 (azetidinone), 1658 (amide); 'H nmr We wish to thank Drs. John Finkenbine and Orval Mamer of (pyridine-d5) 6: 2.35-2.47 (m, 3H, c ~ - H ,c ~ - H ~ and , ~ 7 - H ~2.71 ), (d, lH, C7-Hb, J = 12), 3.01 (d, I H , c 6 - ~ dJ, = lo), 3.78 (dd, 1 ~ , the Biomedical Mass Spectrometry Unit, McGill University, for mass spectra, Dr. Werner Hin? for helpful discussions, and C4-H, J = 5, 9.2), 3.85 (s, 2H, CH2CO), 5.02 (bs, I H , OH), 5.95

JUST AND SACRIPANTE

the Natural Sciences and Engineering Research Council of Canada, Lederle Laboratories, and Fonds FCAR, Province de Qukbec, for generous financial support. 1. ( a ) J. H. BATESON, P. M. ROBERTS, T. C. SMALE,and R. SOUTHGATE. J. Chem. Soc. Chem. Cornmun. 185 (1980); (b)


I

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3 . J. FINKELSTEIN, K. G. HOLDEN,and C. C. PERCHONOCK. Tetrahedron Lett. 19, 1629 (1978). 4. ( a ) M . D. BACHIand C. HOORNAERT. Tetrahedron Lett. 22,2689 (1981); ( b ) 22, 2693 (1981); ( c ) 22, 2505 (1981); ( d ) M . D.

BACHI,F. FROWLOW, and C. HOORNAERT. J. Org. Chem. 48,

1841 (1983). 5 . ( a ) J. KNIGHT, P. J. PARSONS, and R. SOUTHGATE. J. Chem. Soc. N. T. SALZMANN, R. W. RATCLIFFE, and B. G . CHRISTENSEN. Chem. Cornmun. 788 (1986); ( 6 ) A. L. J. BECKWITH and R. D. Tetrahedron Lett. 21, 1193 (1980). BOATHE. Tetrahedron Lett. 26, 1761 (1985). 2. ( a ) G. JUSTand R. ZAMBONI. Can. J. Chem. 56, 2720 (1978); ( 6 ) 5 6 , 2725 (1978); ( c ) G. JUST,Y . S. TSANTRIZOS, and A. UGOLINI. Can. J. Chem. 59, 2781 (198 1).