J. Org. Chem. 1983,48, 481-486
[l
48 1
+ 31 Cycloadditions of Isocyanides to Azomethine Ylides.
Synthesis and
Properties of 1-Phthalimidoazetidines Josiane Charrier, Andre Foucaud,* Herve Person, and Emile Loukakou Groupe de Chimie Structurale, Equipe de Recherche Associle au CNRS, Universitl de Rennes, Campus de Beaulieu, 35042 Rennes Cldex, France
Received May 21, 1982 Reactions of isocyanides with 1-phthalimidoaziridines 1, 5, and 11 gave 1-phthalimidoazetidines by [ l + 31 cycloaddition to the azomethine ylides that are in equilibrium with the aziridines. (tert-Buty1imino)azetidines and (tert-octy1imino)azetidinesrearranged into open-chain azadienes. Reactions of hydrazine hydrate with 1-phthalimidoazetidiesdid not give the corresponding N-aminoazetidines,but rather their decompositionproducts, nitrogen and enamino esters.
+
Few examples of [l 31 cycloadditions of isocyanides to 1,3-dipoles are known. Such cycloadditions to an azomethine,' an azomethine ylide,2a nitrile ylide? a thiirane imine: and an N-sulfinylamines have been reported. Deyrup6has reported the reaction of t-C4HgNCwith some 1-phenylaziridines. These latter reactions, which were probably acid catalyzed, gave ketenimines, and no cycloadditions were observed. 1-Phthalimidoaziridines bearing electronegative substituents form ylides readily.'OJ1 We here report the preparation of two new l-phthalimidoaziridines, 1 and 5, and the reactions of aziridines 1,5, and 11 with isocyanides to give 1-phthalimidoazetidines. Reactions of some 1-phthalimidoazetidines with hydrazine to give products resulting from decomposition of unstable 1-aminoazetidines are also discussed.
Results 1-Phthalimidoaziridines can be prepared by oxidation of N-aminophthalimide with lead tetraacetate in the presence of suitable 01efins.'~~We have prepared 1 and 5A stereospecifically by conducting this oxidation in the presence of tetracyanoethylene or dimethyl dicyanofumarate, respectively. The presence of their ylide isomers 2 and 6 was demonstrated by trapping with dimethyl acetylenedicarboxylate at room temperature to give 1phthalimidopyrrolines 3 and 7, respectively. We have previously reported the analogous trapping of ylide 12a at 25 "C to give pyrroline 14a (two diastereoisomers,85%), with concomitant formation of oxazole 13a (15%).11 In contrast, oxazole was not observed in the trapping of 5A. Ylide 2 reacted readily with t-C4HgNCto give the stable azetidine 4. Ylide 6 reacted with t-C4HgNC, tC,H9CH2C(CH3)2NC(tert-octyl isocyanide), or cyclohexyl (1)J. A. Deyrup, Tetrahedron Lett., 2191 (1971). (2)K. Burger, F. Manz, and A. Braun, Synthesis, 250 (1975). (3)K. Burger and J. Fehn, Angew. Chem.,Int. Ed. Engl., 11,47(1972). K. Burger, J. Fehn, and E. MCdler, Chem. Ber., 106,1 (1973). (4)G. L'Abbe, J. P. Dekerk, J. P. Declercq, G. Germain, and M. van Meersche, Tetrahedron Lett., 3213 (1979). (5)R. Beckert and A. Mayer, J.Prakt. Chem., 322, 273 (1980). (6)J. A. Deyrup and G. S. Kuta, J.Chem. SOC.,Chem. Commun., 34 (1975). (7)R. S.Atkinson and C. W. Rees, Chem. Commun., 1230 (1967);J. Chem. SOC.C,772 (1969). (8)H. Person, F. Tonnard, A. Foucaud, and C. Fayat, Tetrahedron Lett., 2495 (1973);Bull. SOC.Chim. Fr., 635 (1974). (9)H. Person, A. Foucaud, K. Lunglath. and C. Favat, J.0r.e. Chem., 41,2141 (1976). (10)R. Huisaen. - . W.Scheer. and H. Huber. J. A m . Chem. SOC.. . 89.. 1753 (1967). (11)H. Person, K. Luanglath, M. Baudru, and A. Foucaud, Bull. SOC. Chim. Fr., 1989 (1976).
Scheme Ia
I
1, R' 5A,R'
,
2
z
2 CH302CCECC02CH3
= CN = CO,CH,
2, 6
*
397
/ N /R It
CH,O,C'
NCy.cN CO,CH,
z 5B
4, R' = CN; R = t-C,H, 8, R' = CO,CH,; R = t-C,H, 9, R' = CO,CH,; R = t-C,H,CH,C(CH,), 10, R' = CO,CH,; R = C,Hll CH,C,H,-t
I
(a)CH,-C-CH,(b)
(a)CH3-C-CH,(b)
I1
N
CH
CH302C ,:+,. NC'
,
I
i
Z
9A
9B
isocyanide to give both diastereoisomers of the stable azetidines 8-10, which could be separated by chromatography on silica gel (Scheme I). The formation of oxazoles was not observed in these reactions. No epimerization of 8 or 9 was observed in CDC13 solution at 35-40 "C after 8 days. Again, these results differ from previously reported reactions of 11 with isocyanides (Scheme I1 and Table 1).l2 Reaction of 11 with i-C3H7NCor cyclohexyl isocyanide at (12)J. Charrier, H. Person, and A. Foucaud, TetrahedronLett., 1381 (1979).
0022-326318311948-0481$01.50/00 1983 American Chemical Society
482
J. Org. Chem., Vol. 48, No. 4, 1983
aziridine X
Table I. Reaction of Isocyanides with Aziridines 11 phthalazetidine imide oxazole 1 3 temp, time, "C ha (% yield) (% yield)b (% yield)b
isocyanide R
H
i-Pr i-Pr i-Pr i-Pr
a Me Me 0 H H
35 35 35 25 35 40 40 35 35 70
t-Bu t-Bu tert-octyl tert-octyl t-Bu
cl H
cl NO2
Charrier et al.
40 30 30 75 30 3 5
15a (46) 1 5 b (40)' 15c (47) 15d (35) 16a (48) 17a (49) 1 7 b (47)
30 32 25 61 33
10 11 24 29 13 9 3 4 5
14 15 33 33 40
25 25 30
azadiene (% yield)b
22a 22b 23a 23b 22e
(19) (38) (53) (51) (42)
* Required time for complete conversion of aziridine. Isolated product. Under these conditions, the yields of azetidines were optimized. Two diastereoisomers were purified. Scheme I1
Table 11. Thermolysis of Azetidine 17b CH30,C \c02cH3
p-XC H
;v:O2CH3
I
/
2
i
14a
lla, X = H b, X = C1 c , X = CH, d, X = CH,O e , X = NO,
time, h
solvent CDC1, CDCl, 6'
H6
6'
H6
3 30 1 3 3
MeCN a
recovered temp, azetidine 17b azadiene 22 "C (% yield)a (% yield) 40 40 80 80 40
83 36 56 23 7
15 62 26 60 82
Analyzed by NMR. Scheme I11 R
i
13a-e
I
20,21
Z
19a, R = C,H,O b, R = CH,
12a-e jRNC
ZCOCOC,H, 'CO,CH,
t 15a-d, R 16a, R 17a-b, R [18], R
= i-C,H, = C,H,, = t-C,H, = t-C,H,CH,C(CH,),
-
25a
22
3 23
35-40 "C gave azetidines 15 and 16 (two diastereoisomers) as well as smaller amounts of oxazoles 13. Reaction of 11 with t-C4HgNCgave azetidines 17, minor amounts of oxazoles 13, and significant quantities of azadiene esters 22. With t-C4HgCH2C(CH3)2NC no azetidines could be isolated, the principal products being azadiene esters 23 and minor amounts of oxazoles 13. The stability of the azetidines formed from 11 appears to decrease with increasing bulk of the R group derived from the isocyanide. Azetidines 15 (R = i-C3H7)and 16 (R = C6Hll) are stable. Azetidines 17 (R = t-C4H9)were transformed into 22, slowly at 35-40 "C and rapidly at 80 OC (Table II). The azetidines 18 (R = t-C4H&H2C(CH3)2) were evidently converted into 23 rapidly at 35-40 "C (Scheme 11). Attempts to prepare azetidines by reaction of t-C4HgNC with aziridines 19a and 19b were unsuccessful; only the oxazoles 20 and 21 were formed (Scheme 111). Structural assignments of products 15-17 and 22-23 were made on the basis of spectroscopic data. The mass
24b,e
spectra of 15-17 showed the molecular ion M+ and the ion fragments M+ - 147 and M+ - RNC. The mass spectra of azadiene esters 22 and 23 showed the molecular ion M+ and the ion fragments M+ - (CH3),C=CH2, M" - (CH3),C=CH2 - C02CH,, and the hydrolysis of 22a with 10 M HC1 at room temperature to 25. Treatment of azadienes 22 with NzH4or NaOH at room temperature gave azadiene? 24 (Scheme 111). Stereochemistry. After standing 3 h at 18 "C, aziridine 5A was partly converted into 5B, presumably through the isomerization of the ylide 6. The NMR spectrum of the mixture 5A-5B at room temperature exhibits two signals for the methyl protons. The signal of 5A (6 4.03) splits into two signals at -20 "C because of the slow inversion of the aziridine nitrogen atom. The rate of inversion was estimated at the coalescence temperature (263 K) from the equation k, = a A v / d / 2 , in which Av is the frequency separation of the two sites at slow exchange. The free energy of activation was found to be AGS = 15 kcal mol-' (Av = 7.5 Hz at 100 MHz). No splitting of the signal of the
J. Org. Chem., Vol. 48, No. 4, 1983 483
1-Phthalimidoazetidines
Scheme V
Scheme IV
1
~-XC,H,~HC=+NR
1
R ' N
2 GLH,
26
30
\
p-XC6H4C\H2
CN ,
;c=< RN\
/ p H 3
H-.-O
I
2
L
15b (A), R = i-C!,Ii, 16b (A), R = C,Hll 17b (A), R = t-C,H,
CH30H
CHC13
15b (B) 16b (B) 17b (B)
! f -C,H,f$
27
methyl protons of 5 B (6 3.94) was observed; even at -40 "C only one isomer was observed, probably for steric reasons, the phthalimido group and the ester groups being trans. A t low temperatures, the 'H NMR spectra of every diastereoisomer of the azetidines 8-10 indicated a reversible isomerization which is not the epimerization. Two possible pathways exist for the isomerization of 3-iminoazetidines: pyramidal inversion of the ring nitrogen atom, and syn-anti isomerization of the imine group. The first of these is known to be much more rapid than the second;l3J4the process observed is probably the second. A t room temperature, the NMR spectrum (at 100 MHz) of each of 9A and 9 B shows a single signal for the C02CH3 protons, which indicates a fast syn-anti isomerization of the imine group. This isomerization becomes slow at -30 "C. The coalescence temperature of the signals was 263 K for 9A and 273 K for 9 B (Au = 10 Hz at 100 MHz, AG* is about 15 kcal mol-'). At 20 "C, the CH3(a) and CH3(b) groups of 9A are magnetically equivalent and give one peak. At the same temperature, the analogous CH3groups of 9 B are magnetically nonequivalent and give two peaks. The isomers A and B of azetidine 15b were separated by crystallization. Solutions of each of the isomers in CDC13allowed to stand at room temperature for 30 h gave the same mixture of isomers A and B in a ratio of 70:30. This isomerization does not arise from exchange of the hydrogen atom in the ortho position of the p-C1C6H4group; isomerization in the presence of CH30D did not introduce a deuterium atom into the azetidine molecule. The isomerization probably results from cleavage of a C-C bond to give intermediate 26 (Scheme IV). Ring closure of 26 to the azetidine was fast when R = i-C3H7or CeHll but slow for steric reasons when R = t-C4H9or t-C4H9CH2C(CH3)2. In the latter cases, irreversible 1,3-migration of the phthalimido group gave azadienes 22 or 23. Evidence for intermediate 26 was provided by allowing a solution of isomeric azetidines 17b in dry 2:l CHC13/CH30Hto stand (13)J. B. Lambert, Top. Stereochem., 6, 19 (1971). (14)H.0.Kalinowski and H. Kessler, Top. Stereockm. 7,295(1973).
1
J 31
28a-c, R = X , H , 29b, R = t-C,H,
at room temperature for 48 h, giving products 27 (31%) and 22b (67%). Under these conditions 22b was not transformed into 27. The syn-anti isomerization of azetidines 15 and 17 was observed by 'H NMR. The proton signals of the CH, of i-C3H7group of 15a (diastereoisomer A) coalesced at 363 K (Av = 23 Hz at 100 MHz, AG* = 19 kcal mol-'), and those of the tert-butyl group of 17b (one diastereoisomer) at 293 K (Av = 20 Hz at 100 MHz, AG* = 15 kcal mol-'). Azetidines 15 and 17 reacted with hydrazine hydrate at room temperature to give nitrogen, phthalhydrazide, and the enamino esters 28 and 29, respectively. These products are 2 isomers with an intramolecular hydrogen bond, which was detected by infrared. This reaction probably involves initial formation of a 1-aminoazetidine 30 which rearranges to the final products (Scheme V). However, this result is in contrast to the stability of l-aminoand 1-(dialazetidine,15l-amino-2,4-dimethylazetidine,16 kylamino)azetidines." The instability of 30 resembles that of certain l-aminoaziridines.'g20 The extrusion of aminonitrene from 30 would be expected to give some cyclopropane via the trimethylene intermediate.16 No cyclopropane was found, and we propose that the reaction proceeds by cleavage of the C-N bond in 30 to give the intermediate 31 (Scheme V), as in the Wolff-Kishner reduction. The transformation of 30 into 31 is similar to that of the transformation of azetidines 17 into 26. Experimental Section
Melting points (uncorrected)were determined on a Reichert apparatus. Mass spectra were obtained on a Varian MAT 311 mass spectrometer. 'H NMR (internal standard Me&) spectra were taken, unless stated otherwise, in CDC13,on a JEOL MH 100 instrument. Elemental analyses were performed by the analytical laboratory, Centre National de la Recherche Scientifique. Isocyanides were obtained by following the known procedure.21-22 l-Phthalimido-2,2,3,3-tetracyanoaziridine (1). Aziridine 1 was prepared according to the described procedure;7* mp 197 "C dec; IR (Nujol) 1759, 1769, 1804, 2212 cm-'; 'H NMR 6 8.0 (15)K. Kirste, W. Luttke, and P. Rademacher, Angew. Chem.,Int. Ed. Engl., 17, 680 (1978). (16)J. P.Freeman, D. G. Pucci, and G. Binsh, J.Org. Chem., 37,1894 (1972). (17)S. F. Nelsen, V. E. Peacock, G. R. Weisman, M. E. Landis, and J. A. Spencer, J.Am. Chem. SOC.,100, 2806 (1978). (18)L.A. Carpino and R. K. Kirkley, J . Am. Chem. SOC.,92, 1784 (1970). (19)D.Felix, R. K. Muller, U. Horn, R. Joos, J. Schreiber, and A. Eschenmoser, Helu. Chim. Acta, 66, 1276 (1972). (20)R. Annunziata, R. Fornassier, and F. Montanari, J. Org. Chem., 39, 3195 (1974). (21)W.P. Weber and G. W. Gokel, Tetrahedron Lett., 1637 (1972). (22)W. P.Weber, G. W. Gokel, and I. K. Ugi, Angew. Chem., Int. Ed. Engl., 11, 530 (1972).
484 J . Org. Chem., Vol. 48, No. 4, 1983 (m); mass spectrum, molecular ion peak at m/e 288. Anal. Calcd for Cl4H4N6O2:C, 58.33; H, 1.39; N, 29.16. Found: C, 58.18; H, 1.51; N, 29.18. 3,4-Bis(methoxycarbonyl)-l-phthalimido-2,2,5,5-tetracyano-A2-pyrroline (3). To a solution of aziridine 1 (1.44 g, 5 mmol) in 10 mL of dichloromethane was added dimethyl acetylenedicarboxylate (0.71 g, 5 mmol). The mixture was heated at reflux for 5 h and then cooled to room temperature. The pyrroline 3 was obtained in 46% yield; mp 275 "C (ethanol); IR (Nujol) 1671,1713,1757,1794,2238,2252 cm-'; mass spectrum, molecular ion peak at m/e 430; exact mass calcd for CpoHloN606m/e 430.0662, found 430.0663. 2,2,4,4-Tetracyano-3-(tert -butylimino)-1-phthalimidoazetidine (4). To a solution of aziridine 1 (2.59 g, 9 mmol) in 15 mL of CH2C12was added tert-butyl isocyanide (0.83 g, 10 mmol). The mixture was heated at reflux for 4 h and then concentrated under vacuum. Addition of ether (3 mL) to the residue gave crystals of azetidine 4 (0.95 g, 28.5% yield): mp 173-175 "C (benzene);IR (Nujol) 1758,1800,2240 cm-'; 'H NMR 6 1.56 (s,9 H), 7.9 (m, 4 H). Anal. Calcd for C1&I13N702:C, 61.45; H, 3.40; N, 26.41. Found: C, 61.61; H, 3.50; N, 26.23.
2,5-Dicyano-l-phthalimido-2,3,4,5-tetrakis(methoxycarbonyl)-A3-pyrroline (7). To a solution of aziridine 59 (5A or mixture 5A, 5B, 3.54 g, 10 mmol) in 20 mL of dichloromethane was added dimethyl acetylenedicarboxylate (1.42 g, 10 mmol). The solution was heated at reflux for 5 h. The dichloromethane was evaporated to yield 4.2 g (8.5 mmol, 85%) of a 1:l mixture of the diastereoisomeric pyrrolines 7. The product mixture was separated by column chromatography over silica gel (3:2 ether/ benzene). Pyrroline 7A: mp 220 "C; IR (Nujol) 1662,1720,1734,1794 cm-'; 'H NMR 6 3.96 (s, 6 H), 3.98 (s, 6 H), 7.96 (m, 4 H). Anal. Calcd for C22H16N4010:C, 53.22; H, 3.22; N, 11.29. Found: C, 53.23; H, 3.48; N, 11.51. Pyrroline 7B: mp 228 "C (ethanol); IR (Nujol) 1662, 1720, 1734, 1796, 2240 cm-'; 'H NMR 6 3.82 (s, 6 H), 3.93 (9, 6 H), 7.9 (m, 4 H). Anal. Calcd for C22H16N4010: C, 53.22; H, 3.22; N, 11.29. Found: C, 53.24; H, 3.22; N, 11.02. 3 4 Alkylimino)-2,4-dicyano-2,4-bis( methoxycarbony1)- 1phthalimidoazetidines: General Procedure. To a solution of aziridine 5 (7.43 g, 21 mmol) in 30 mL of dichloromethane was added 42 mmol of isocyanide. The solution was heated at reflux for 8 h and then concentrated under vacuum. Addition of ether (3-5 mL) to the residue gave crystals of azetidine. Azetidines SA and 8B: yield 40%. The diastereoisomeric azetidine mixture (50:50) was separated by column chromatography over silica gel (3:2 ether/benzene). SA: 0.18 g; mp 173 "C dec (MeOH);IR (Nujol) 1738,1773,1798, 2237 cm-'; 'H NMR 6 1.40 (s, 9 H), 4.03 (s, 6 H), 7.88 (9, 4 H). Anal. Calcd for CZ1HlgN5O6:C, 57.66; H, 4.35; N, 16.02. Found: C, 57.64; H, 4.32; N, 16.30. 8B: 0.17 g, mp 148 "C; IR (Nujol) 1738,1773,1798,2237 cm-'; 'H NMR 6 1.42 (9, 9 H), 3.94 (s,6 H), 7.90 (m, 4 H). Anal. Calcd for C21H19N506:C, 57.66; H, 4.35. Found: C, 57.50; H, 4.41. Azetidines 9: yield 60%; IR (Nujol) 1746, 1758, 1800 cm-'. The diastereoisomers (50:50) were separated by column chromatography on silica gel (9:l benzene/ether). 9B: mp 157 "C; 'H NMR 6 1.03 (s, 9 H), 1.39 (s, 3 H), 1.44 (s, 3 H), 1.75 (s, 2 H), 4.06 (9, 6 H), 7.99 (s, 4 H). Anal. Calcd for CZ5H2,N5O6:C, 60.85; H, 5.47; N, 14.20. Found: C, 60.58; H, 5.33; N, 14.46. 9A: mp 160 "C (MeOH); 'H NMR 6 1.02 ( s , 9 H), 1.44 (s, 6 H), 1.77 (s, 2 H), 3.93 (9, 6 H), 7.9 (m, 4 H). Anal. Calcd for CzHnNbO6: C, 60.85; H, 5.47; N, 14.20. Found: C, 60.60; H, 5.53; N, 14.40. Azetidine 10 yield 35%; mp 177 "C (MeOH);IR (Nujol) 1752, 1800 cm-'; 'H NMR 6 1.7 (br, 10 H), 3.7 (br, 1H), 4.00 (s, 6 H), 7.87 (s, 4 H); mass spectrum, molecular ion peak at m/e 463; exact mass calcd for C23H21N506 463.1492, found 463.1482. Reaction of Aziridines 11 with Isopropyl Isocyanide and Cyclohexyl Isocyanide: General Procedure. To a suspension of aziridine 11 (5 mmol) in CHzClz(25 mL) was added isocyanide (7.5 mmol), and the mixture was heated a t 35 "C for 30 h and then cooled to 15-20 "C to give phthalimide, which was collected by filtration. The dichloromethane was evaporated, and ether was added to the residue to precipitate the azetidine, which was
Charrier et al. collected by filtration (a mixture of diastereoisomers; only one diastereoisomer was purified, except in the case of 15b). Concentration of the solution gave oxazole 13, identified by comparison with an authentic sample." 2-Cyano-3-(isopropylimino)-2-( methoxycarbony1)-4phenyl-1-phthalimidoazetidine(15a). Syn-anti isomers: 0.95 g (46%);mp 148 "C (MeOH); IR (Nujol) 2243, 1796, 1768, 1740 cm-'; 'H NMR 6 0.70 (d, J = 6 Hz), 1.09 (d, J = 6 Hz), 1.17 (d, J = 6 Hz), 1.28 (d, J = 6 Hz, 6 H, (CH3)2CH),3.6 (m, 1 H), 3.93 (s, 3 H), 6.99, 7.05 (s, 5, 1 H), 7.4 (m, 9 H). mass spectrum, molecular ion peak at m/e 416. Anal. Calcd for CZ3Hz0N4O4: C, 66.34; H, 4.80; N, 13.46. Found: C, 66.41; H, 4.83; N, 13.31. 2-Cyano-3-(isopropylimino)-2-(methoxycarbonyl)-4-(p chloropheny1)-1-phthalimidoazetidine(15b). One diastereoisomer (A, mp 175 "C), insoluble in ether, was collected by filtration. The second diastereoisomer (B, mp 140 "C) was obtained mixed with oxazole, by concentration of the mother liquor, and was purified by recrystallization. Isomer A: 0.36 g (16%);mp 175 "C (MeOH, syn-anti isomers); IR (Nujol) 2240, 1793, 1764, 1742 cm-'; 'H NMR 6 0.72 (d, J = 6 Hz), 1.10 (d, J = 6 Hz), 1.20 (d, J = 6 Hz), 1.30 (d, J = 6 Hz, 6 H, (CH3)&H), 3.6 (m, 1 H), 3.98, 7.13 (s, 1 H), 7.6 (m, 8 H); mass spectrum, molecular ion peak at m/e 450. Anal. Calcd for CZ3Hl9N4O4C1: C, 61.26; H, 4.21; N, 12.43. Found: C, 61.33; H, 4.31; N, 12.23. Isomer B: 0.54 g (24%);mp 140 "C (CHC13/ether, syn-anti isomers); IR (Nujol) 2230, 1788, 1752, 1736 cm-'; 'H NMR 6 0.80 (d, J = 6 Hz), 1.20 (m), (6 H, (CH3)2CH),3.85 (s, 3 H), 3.95 (m, 1 H), 6.90, 6.94 (s, s, 1H), 7.5 (m, 8 H); mass spectrum, exact mass calcd for C23H19N40435C1 m/e 450.1095, found m/e 450.1099. 2-Cyano-3-(isopropylimino)-2-(methoxycarbonyl)-4-(p methylpheny1)-1-phthalimidoazetidine (15c). Syn-anti isomers: 1.01 g (47%);mp 155-157 "C (MeOH);IR (Nujol) 2239, 1793, 1765, 1739, cm-'; 'H NMR 6 0.78 (d, J = 6 Hz), 1.12 (d, J = 6 Hz), 1.18 (d, J = 6 Hz), 1.30 (d, J = 6 Hz, 6 H, (CH3)2CH), 2.32 (s, 3 H), 3.6 (m, 1 H), 3.94 (s, 3 H), 7.22 (s, 1 H), 7.5 (m, 8 H); mass spectrum, molecular ion peak at m/e 430. Anal. Calcd for CZ4Hz2N4O4: C, 66.98; H, 5.12; N, 13.02. Found: C, 67.32; H, 5.10; N, 13.17. 2-Cyano-3-(isopropylimino)-2-(methoxycarbonyl)-4-(p methoxypheny1)-1-phthalimidoazetidine(15d). Syn-anti isomers: 0.78 g (35%);mp 149-151 "C (MeOH);IR (Nujol) 2240, 1792, 1752, 1738 cm-'; 'H NMR 6 0.76 (d, J = 6 Hz), 1.12 (d, J = 6 Hz), 1.18 (d, J = 6 Hz), 1.30 (d, J = 6 Hz, 6 H, (CH3)2CH), 3.68 (m, 1 H), 3.76 (s, 3 H), 3.98 (s, 3 H), 7.15 (s, 1 H), 7.5 (m, 8 H). Anal. Calcd for CZ4Hz2N4O5: C, 64.57; H, 4.93; N, 12.56. Found: C, 64.59; H, 4.91; N, 12.38. 2-Cyano-3-(cyclohexylimino)-2-(methoxycarbonyl)-4phenyl-1-phthalimidoazetidine(16a). Syn-anti isomers: 1.09 g (48%); mp 134 "C (MeOH); IR (Nujol) 2238, 1796, 1768,1740 cm-'; 'H NMR 6 1.5 (m, 10 H), 3.3 (br, 1 H), 4.01 (s, 3 H), 7.27 (s, 1 H), 7.6 (m, 9 H).Anal. Calcd for Cz6HZ4N4o4: C, 68.42; H, 5.26; N, 12.28. Found: C, 67.90; H, 5.34; N, 11.79. Reaction of Aziridines 11 with tert-Butyl Isocyanide. To a solution of aziridine 11 (6.5 mmol) in CH2C12(10 mL) was added tert-butyl isocyanide (1g, 12 mmol). The mixture was refluxed for 5 h and then cooled to room temperature. The insoluble phthalimide was collected by filtration. The dichloromethane was evaporated, and ether was added to the residue to give a precipitate of azetidine (17) and azadiene (22). The solution was concentrated at room temperature to give the oxazole 13 (identified by IR and 'H NMR spectra"). The mixture of azetidine and azadiene was dissolved in warm CHCl3; the warm solution was filtered, and ether was added (1:2 CHC13/ether). The mixture was cooled to 20 "C to give a precipitate of pure azetidine. Evaporation of the solvent gave a mixture of azetidine and azadiene. The azetidine was purified by recrystallization (1:2 CHCl,/ether). 2-Cyano-2-(methoxycarbonyl)-4-phenyl-l-phthalimido3 4 tert-buty1imino)azetidine(17a). Mixture of diastereoisomers A and B: 1.05 g (49%);mp 140-144 "C; IR (Nujol) 2238, 1798, 1767, 1749, 1735 cm-'; 'H NMR, diastereoisomer A (60%), syn-anti isomers, 6 1.02 (s, br, 9 H), 3.93 (s, 3 H); 'H NMR diastereoisomer B (40%), syn-anti isomers, F 1.48, 1.62 (s, s, 9 C, 66.98; H, 5.12; H), 3.83 (s, 3 H). Anal. Calcd for CZ4Hz2N4O4: N, 13.02. Found: C, 66.96; H, 5.15; N, 12.91.
1-Phthalimidoazetidines
2-Cyano-2-(methoxycarbonyl)-4-(p -chlorophenyl)-1phthalimido-3-(tert -butylimino)azetidine (17b). Mixture of diastereoisomers A and B: 1.09 g (47%); mp 147-150 "C; IR (Nujol) 2236,1796,1762,1747,1733 cm-'; 'H NMR (recorded at 60 "C; the syn-anti isomerization is fast a t this temperdture) diastereoisomer A (70%) 6 1.20 ( 8 , 9 H), 3.93 ( 8 , 3 H), 7.11 (s, 1 H); 'H NMR diastereoisomer B (30%) 6 1.50 (s,9 H), 3.84 (s, 3 H), 6.90 (s, 1H); mass spectrum, molecular ion peak at m/e 464. Anal. Calcd for C24H21N404C1: C, 62.00, H, 4.52; N,12.05. Found: C, 62.36; H, 4.57; N, 11.81. Azadienes 22 and 23: General Procedure. To a suspension in 4 mL of dichloromethane was added of aziridine 11 (5.76 "01) tert-butyl isocyanide or tert-octyl isocyanide (8.6 mmol). The resulting mixture was stirred at 35 "C for 24 h and then cooled to room temperature to give a precipitate of phthalimide, which was collected by filtration. The solvent was evaporated to give an oil. Addition of ether to the oil gave yellow crystals, which on recrystallization from 1:l MeOH/ether yielded the azadiene (mixture of two isomers a t room temperature). 1-( Methoxycarbonyl)-2-aza-l-cyano-3-phenyl-4-phthalimido-4-(tert-buty1amino)buta-l,J-diene (22a): 0.40 g (19%1; mp 190 "C; 'H NMR 6 1.49 (8, 9 H), 3.22, 3.97 (8, s, 3 H), 7.5 (m, 9 H); IR (Nujol) 1600, 1701, 1723, 1787, 2200, 3323 cm-'; mass spectrum, molecular ion peak a t m/e 430. Anal. Calcd for CaHPN404: C, 66.98; H, 5.12; N, 13.02. Found C, 66.96; H, 5.15; N, 12.91. l-(Methoxycarbonyl)-2-aza-l-cyano-3-(p -chlorophenyl)-4-phthalimido-4-( tert -butylamino)buta-1,3-diene (22b): 0.88 g (38%); mp 214 "C; 'H NMR 6 1.38 (e, 9 H), 3.20, 3.87 ( 8 , s, 3 H), 7.5 (m, 8 H); IR (CC14) 1596, 1700, 1725, 1788, 2198,3390 cm-'; mass spectrum, molecular ion peak at m/e 464. Anal. Calcd for CaHzlN404C1: C, 62.00; H, 4.52; N, 12.05. Found: C, 61.76; H, 4.25; N, 12.03. l-(Methoxycarbonyl)-2-aza-l-cyano-3-(p -nitrophenyl)-4phthalimido-4-( tert -butylamino)buta-l,3-diene (22e): 1.00 g (42%); mp 235 "C; 'H NMR 6 1.42 (s, 9 H), 3.26, 3.91 (s, s, 3 H), 7.7 (m, 8 H); IR (CCl,) 1598,1705,1732,1790,2196,3295cm-'; mass spectrum, molecular ion peak at m/e 475. Anal. Calcd for CaHPN506: C, 60.63; H, 4.42; N, 14.73. Found C, 60.94; H, 4.36; N, 14.92. 1-( Methoxycarbonyl)-2-aza-l-cyano-3-phenyl-4-pht halimido-4-(tert-octy1amino)buta-lf-diene(23a): 1.28 g (53%); yellow crystals, mp 156-158 "C; 'H NMR 6 0.84,1.14 (s, s, 9 H), 1.38, 1.41 (s, s, 6 H), 1.51, 1.69 (s, s, 2 H), 3.17, 3.84 (s, s, 3 H), 7.5 (m, 9 H); IR (Nujol) 1600,1702, 1736,1790,2195,3336 cm-'. Anal. Calcd for C&&404: C, 69.13; H, 6.17; N, 11.52. Found: C, 68.80; H, 6.13; N, 11.71. l-(Methoxycarbonyl)-2-aza-l-cyano-3-(p -chlorophenyl)-a-phthalimido-4-( tert -0cty1amino)buta-1,3-diene (23b): 1.32 g (51%); red crystals, mp 166 "C; 'H NMR 6 0.92, 1.14 (s, s, 9 H), 1.42 (s, 6 H), 1.54, 1.70 ( 8 , s, 2 H), 3.19, 3.88 (8, s, 3 H), 7.6 (m, 8 H); IR (Nujol) 1601,1716,1734,1788,2191,3257 cm-'. Anal. Calcd for CBHBN404C1:C, 64.55; H, 5.57; N, 10.76. Found: C, 64.89; H, 5.49; N, 10.83. Hydrolysis of Azadiene 22a. A suspension of azadiene 22a (1g, 2.3 mmol) in concentrated hydrochloric acid (13 mL) was stirred for 20 h at room temperature. A white solid, collected by filtration and washed with water, gave 25 as colorless crystals: 0.42 g (65%); mp 214 "C (CHCl,); IR (Nujol) 1680, 1704, 1744, 1800 cm-'; mass spectrum, exact mass calcd for Cl6H9No4 279.0531, found 279.0528. Anal. Calcd for Cl6H9No4: c , 68.22; H, 3.22; N, 5.02. Found: C, 68.60; H, 3.24; N, 5.37. Reaction of Aziridines 19 with tert-Butyl Isocyanide. To in CH3CN (10 mL) was added a solution of aziridine 19 (6.5 "01) tert-butyl isocyanide (1g, 12 mmol). The mixture was refluxed for 4 h and then cooled to room temperature. Insoluble phthalimide was collected by filtration. The acetonitrile and isocyanide was evaporated, and ether was added to the residue to give oxazoles 20 (mp 73 "C (98%)) or 21 (mp 78 "C (80%)), respectively. The 'H NMR spectra of 20 and 21 were identical with the 'H NMR spectra of the corresponding oxazoles obtained by thermolysis of aziridines 19." Reaction of Azadiene 22e with Hydrazine. To a suspension of azadiene 22e (0.4 g, 0.84 mmol) in methanol (5 mL) was added hydrazine hydrate (0.84 g, 3.4 mmol), and the mixture was stirred at room temperature for 2 h. The azadiene 24e was collected by
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Chem., Vol. 48, No. 4, 1983 485
filtration and washed with ether to give 260 mg (90%) of yellow crystals: mp 247 "C (acetone); IR (Nujol) 1498,1598,1628,2159, 3240,3296,3338,3427 cm-l; 'H NMR (CD3COCD3)6 1.48 (s, 9 H), 3.63 (s, 3 H), 7.51, 8.18 (AB, J = 9 Hz, 4 H), 8.56 (br, 1 H), 9.46 (br, 2 H); mass spectrum, molecular ion peak a t m/e 345. Anal. Calcd for C16H19N504:C, 55.65; H, 5.50; N, 20.28. Found: C, 55.51; H, 5.26; N, 20.18. Reaction of Azadiene 22b with Sodium Hydroxide. To a solution of azadiene 22b (1g, 2.1 mmol) in CH2C12(50 mL) was added sodium hydroxide (4 M, 25 mL). The mixture was stirred at room temperature for 17 h and then neutralized with 4 M HCl. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 24b: mp 229-231 "C (acetone);yield 80%;IR (Nujol) 1498,1590,1629,1664,2159,3276, 3337 cm-'; 'H NMR [(CD3),SO] 6 1.41 (s, 9 H), 3.47 (s, 3 H), 7.4 (m, 7 H). Anal. Calcd for Cl6Hl9N4O2C1:C, 54.40; H, 5.68, N, 16.74. Found: C, 57.33; H, 5.69; N, 16.85. Isomerization of Azetidine 17b into Azadiene 22b Typical Procedure. A solution of azetidine (0.2 g, 0.43 mmol) in acetonitrile (40 mL) was heated at 40 "C for 3 h. The solvent was evaporated and the residue was analyzed by NMR (Table 11). Isomerization of Azetidines 15b (Diastereoisomer A or B). A solution of a pure diastereoisomer 15b (A or B; 0.5 g, 1 mmol) in 2 1 CHC13/MeOH or CHC13/MeOD (10 mL) was stirred at room temperature for 30 h. The solvent was evaporated, and the residue was analyzed by NMR. Synthesis of Azadiene 27. A solution of azetidine 17b (0.93 g, 2 mmol) in 24 mL of dry 2:l chloroform/methanol was stirred at room temperature for 48 h. The solution was concentrated under reduced pressure to give azadiene 27 as yellow crystals 216 mg (31%);mp 175 "C dec (ether); IR (Nujol) 1618, 1648,2154, 3100 cm-'; 'H NMR 6 1.40 (s, 9 H), 3.75 (s, 3 H),3.88 (s, 3 H), 7.2 (m, 4 H), 7.7 (br, 1 H); mass spectrum, molecular ion peak at m/e 349; exact mass calcd for C17HzoN3033SC1 349.1193, found 349.1186. Phthalimide and azadiene 22b was obtained by evaporation of the mother liquor. Synthesis of Enamino Esters 28 and 29: General Procedure. To a solution of azetidine 15 or 17 (3 mmol) in methanol (15 mL) was added dropwise hydrazine hydrate (0.6 g, 12 mmol). The mixture was stirred at room temperature for 2 h. Nitrogen was evolved; phthalhydrazide separated out and was removed by filtration. The filtrate was evaporated to leave the enamino ester. Methyl 2-Cyano-3-(isopropylamino)-4-phenylbut-2-enoate (28a): colorless crystals, mp 118 "C (ether); 0.76 g (98%); IR (Nujol) 1601,1668,2203,3138,3220 cm-'; IR (CC14) 1664,2207, 3137,3216 cm-'; 'H NMR 6 1.09 (d, 6 H), 3.81 (s, 3 H), 3.92 (m, 1 H), 4.04 (s, 2 H), 7.4 (m, 5 H), 10.14 (br, 1H). Anal. Calcd for CiSHiBN202: C, 69.77; H, 6.98; N, 10.85. Found: C, 69.57; H, 6.88; N, 10.70. Methyl 2-Cyano-3-(isopropylamino)-4-(p-chlorophenyl)-but-2-enoate (28b): colorless crystals, mp 89 "C; 0.83 g (95%); IR (Nujol) 1600,1663,2203,3138,3217 cm-'; IR (CC14) 1666, 2209, 3136, 3215 cm-'; 'H NMR 6 1.13 (d, 6 H), 3.80 (s, 3 H), 3.82 (m, 1H), 3.98 (s, 2 H), 7.3 (m, 4 H), 10.05 (br, 1 H); mass spectrum, exact mass calcd for C15H17N2025 C1,292.0978, found 292.0974. Anal. Calcd for ClSHl7N2O2C1:C, 61.54; H, 5.81; N, 9.57. Found C, 61.73; H, 5.81; N, 9.55. Methyl 2-Cyano-3-(isopropylamino)-4-(p-methylphenyl)-but-2enoate (2812): colorless crystals, mp 105 "C (ether); 0.77 g (95%); IR (Nujol) 1586, 1676, 2200, 3134, 3214 cm-'; IR (CCl,) 1666,2209,3135,3218 cm-'; 'H NMR 6 1.09 (d, 6 H), 2.29 ( 8 , 3 H), 3.74 (s, 3 H), 3.84 (m, 1 H), 3.92 (s, 2 H), 7.1 (m, 4 H), 9.94 (br, 1 €3). Anal. Calcd for C16H20N202:C, 70.59; H, 7.35; N, 10.29. Found: C, 70.40; H, 7.44; N, 10.20. Methyl 2-Cyano-3-(tert -butylamine)-4-(p -chloropheny1)but-2-enoate (29b): colorless crystals, mp 149 "C (1:2 MeOH/CHC13);0.83 g (95%); IR (Nujol) 1605, 1664, 2201, 3110, 3234 cm-'; IR (CC14)1670,2210,3104,3237 cm-'; 'H NMR 6 1.38 (s, 9 H), 3.75 (s, 3 H), 4.10 (s, 2 H), 7.3 (m, 4 H). Anal. Calcd for Cl5Hl7NzO2C1:C, 62.64; H, 6.20; N, 9.13. Found: C, 62.96; H, 6.38; N, 9.32.
Registry No. 1,84130-25-6;3,84118-08-1;4,84118-09-2; 5A, 58747-24-3; 5B, 84118-11-6; 7A, 84118-10-5; 7B, 84118-12-7; SA, 84118-13-8; 8B, 84118-14-9; 9A, 84118-15-0; 9B, 84118-16-1; LO,
486
J. Org. Chem. 1983, 48, 486-491
84118285; lla, 49678-72-0; l l b , 4967879-7; l l c , 72011-34-8; l l d , 49678-66-2; l l e , 49678-81-1; E a , 72011-35-9; 15bA (isomer l ) , 84171-42-6; 15bA (isomer 21, 84171-43-7; 15bB (isomer l ) , 84171-44-8; 15bB (isomer 2), 84171-45-9; 15c, 72011-38-2; 15d, 84118-17-2; 16a, 72011-39-3; 17aA (isomer l ) , 84171-46-0; 17aA (isomer 2), 84171-47-1; 17aB (isomer l), 8423486-6; 17aB (isomer 2), 84171-48-2; 17bA, 84118-18-3; 17bB, 84118-19-4; 19a, 3241796-2; 19b, 63066-09-1; 20, 32418-03-4; 21, 2940-19-4; 22a, 7201141-7; 22b, 72011-42-8; 22e, 84118-20-7; 23a, 72011-43-9; 23b, 72011-44-0; 24b, 84118-23-0; 24e, 84118-22-9; 25, 84118-21-8; 27,
84118-24-1;28a, 84118-25-2; 28b, 84118-26-3;28c, 84118-27-4;29b, 84130-26-7;dimethyl acetylenedicarboxylate, 762-42-5; tert-butyl isocyanide, 7188-38-7; 1,1,33-tetramethylbutyl isocyanide, 14542-93-9;cyclohexyl isocyanide, 931-53-3; isopropyl isocyanide, 598-45-8; hydrazine, 302-01-2. Supplementary Material Available: Table containing mass spectral data of azetidines 4,8-10,15a-c, and 17b and azadienes 22 (1 page). Ordering information is given on any current masthead page.
Chemistry of Four-Membered Cyclic Nitrones. 4. Reaction with Electrophilic Reagents and Conversion into P-Lactam Derivatives' Marcel L. M. Pennings and David N. Reinhoudt* Laboratory of Organic Chemistry, Twente University of Technology, Enschede, The Netherlands
Sybolt Harkema and Gerrit J. van Hummel Laboratory of Chemical Physics, Twente University of Technology, Enschede, The Netherlands Received June 7, 1982
The conversion of the four-membered cyclic nitrone la into a P-lactam has been investigated by using several electrophilic reagents. With methanesulfonyl chloride or with acetic acid, la reacts to give the oxime 2. In acetic acid this oxime undergoes cyclization at room temperature to yield the 6H-1,L-oxazinone 3. Reaction of nitrones la and l b with acetyl chloride a t 0 O C , followed by an aqueous workup leads to the formation of the aldehyde 8a and ketone 8b, respectively. Aldehyde 8a is rather unstable and rearranges in chloroform solution a t room temperature via the aziridine 9 to the 2,5-dihydrooxazole 12. Reaction of both 8a and 8b with sodium hydroxide causes saponification of the acetoxy group and subsequent cyclization to give the 5-hydroxyisoxazolidines 14a and 14b, respectively. Reaction of the nitrones l b and IC with acetyl chloride a t room temperature gives the 3-chloroazetidine 15 and the 3-chlorodihydroazete 16, respectively. The structure of 16 has been elucidated with single-crystal X-ray analysis. Oxidation of nitrone la with 1 equiv of lead tetraacetate in benzene yields the 1-acetoxy-2-azetidinone 26a which can be converted into the 1-hydroxy-2-azetidinone 26b either by hydrolysis with aqueous sodium carbonate or catalytic reduction with palladium on charcoal catalyst. Reduction of 26b with titanium(II1) chloride in tetrahydrofuran-water gives the p-lactam derivative 27. 1-Acetoxy-2-azetidinone 26a is also prepared by oxidation of the corresponding 1-hydroxyazetidine 28, obtained by reduction of la with sodium borohydride, with 2 equiu of lead tetraacetate.
Recently we described the synthesis of a number of four-membered cyclic nitrones (2,3-dihydroazete1-oxides) by the reaction of nitro(cyc1o)alkenes with ynamines.2 Since these four-membered cyclic nitrones belong to a class of virtually unknown heterocycle^,^ we are currently investigating the chemical reactivity of the nitrone moiety of these compounds. In previous papers we have described the l,&dipolar cycloadditions4of these nitrones and their reactions with nucleophile^.^ Since four-membered cyclic nitrones are isomeric with 8-lactams, a heterocyclic ring system that is present in a number of biologically important compounds like cephalosporins and penicillins? we have investigated the possibility of converting these four-membered cyclic nitrones into 8-lactams. In general, the conversion of nitrones into amides is a well-known reaction and can be achieved b y (1) Part of the forthcoming thesis of M.L.M.P. (2) Penninps, M. L. M.; Reinhoudt, D. N . J. Org. Chem. 1982,47,1816. (3) Other examples of four-memberedcyclic nitrones: Black, D. St. C.; Brown, R. F. C.; Dunstan, B. F.; Sternhell, S. Tetrahedron Lett. 1974, 4283. Harnisch, J.; Szeimies, G. Chem. Ber. 1979, 112, 3914. Reinhoudt, D. N.; Harkema, S.; van (4) Pennings, M. L. M.; Okay, G.; Hummel, G. J. J. Org. Chem. 1982, 47, 4413. (5) Pennings, M. L. M.; Reinhoudt, D. N . ; Harkema, S.;van Hummel, G.J. J. Org. Chem. 1982, 47, 4419. (6) (a) Mukerjee, A. K.; Singh, A. K. Tetrahedron 1978,34,1731. (b) Heueler, K. 'Cephalosporins and Penicillins, Chemistry and Biochemistry";Flynn, E. H., Ed.; Academic Press: New York, 1972; p 255.
Scheme I
4 X Y = MeCCOI-,
? Cl S O r M e
a number of electrophilic reagents such as acetyl chloride, phosphorus chlorides, acetic anhydride, and thionyl chloIn this paper we describe the results of reactions of four-membered cyclic nitrones 1 with several of these electrophilic reagents.I3
Results and Discussion Reaction of la with mesyl chloride gave a product isomeric with la in 40% yield which was shown, b y com(7) Rundel W. In 'Methoden der Organischen Chemie (HoubenWeyl)";Mueller, E., Ed.;Georg Thieme Verlag: Stuttgart, 1968 Vol. X/4, p 310. (8) Hamer, J.; Macaluso, A. Chem. Reu. 1964, 64, 473. (9) Delpierre, G. R.; Lamchen, M. Q.Rev., Chem. SOC.1965,19, 329. (10) Korte, F. Ed. 'Methodicum Chimicum"; Georg Thieme Verlag: Stuttgart, 1974; Vol. 6, p 341. (11) Krohnke, F. Justus Liebigs Ann. Chem. 1957, 604, 203 and references cited therein. (12) Breuer, E. In "The Chemistry of Functional Groups";Patai, S., Ed.; Interscience: New York, 1982; Supplement F, Part 1, p 459. (13) Some of these results have been described in a preliminary publication: Pennings, M. L. M.; Reinhoudt, D. N. Tetrahedron Lett. 1981, 22, 1153.
0022-3263/83/1948-0486$01.50/00 1983 American Chemical Society
