New synthesis of 2-methyleneaziridines and 2-methyleneazetidines by dimethyl titanocene mediated methylenation of α- and β-lactams

Article abstract of DOI:10.1016/S0040-4039(00)00076-9

2-Methyleneaziridines and 2-methyleneazetidines were synthesized via a titanium mediated olefination procedure starting from the corresponding α- lactams and β-lactams. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00076-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1975–1978
New synthesis of 2-methyleneaziridines and
2-methyleneazetidines by dimethyl titanocene mediated
methylenation of α- and β-lactams
Kourosch Abbaspour Tehrani † and Norbert De Kimpe ∗
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, University of Gent,
Coupure Links 653, B-9000 Gent, Belgium
Received 9 November 1999; accepted 11 January 2000
Abstract
2-Methyleneaziridines and 2-methyleneazetidines were synthesized via a titanium mediated olefination proce-
dure starting from the corresponding α-lactams and β-lactams. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: azetidines; aziridines; olefination.
2-Methyleneazetidines and 2-methyleneaziridines belong to a group of strained cyclic enamines for
which little information is available. The unique combination of functionalities, i.e. a reactive enamine
and an exocyclic double bond, offers possibilities for further manipulation. To explore their reactivity
and utility, ready access to 2-alkylideneazetidines and -aziridines is necessary. Only a few routes to
functionalized 2-methyleneazetidines have been described, most of them being of little generality.1–6
The fact that until now only three fundamentally different synthetic approaches for the synthesis of 2-
methyleneaziridines are available, combined with the increasing use of these reactive building blocks in
organic synthesis, makes these compounds important synthetic targets.7,8 An elementary retrosynthetic
analysis would suggest connecting a β-lactam or α-lactam and an appropriate alkylidene equivalent
(Fig. 1). Because the Wittig reaction of an ylid with a β-lactam is only possible in some isolated cases,5
another method was required for the methylenation of the carbonyl compounds. Therefore, in this paper
a novel application of Petasis’ alkylidenation chemistry9–11 for the conversion of N-aryl-2-azetidinones
and 2-aziridinones to N-aryl-2-methyleneazetidines and 2-methyleneaziridines is disclosed.
A suitable reagent for the methylenation of heteroatom-substituted carbonyl compounds is dimethyl
titanocene (Cp2TiMe2) 1.9–11 This compound was originally prepared by reaction of dicyclopentadie-
nyltitanium dichloride with methyllithium in toluene.9 For our purposes, 1 was synthesized by reaction
of methylmagnesium chloride in THF with titanocene dichloride.12 Because of the lower stability and
∗
†
Corresponding author. Tel +00 32 9 264 59 51; fax +00 32 9 264 62 43.
Postdoctoral Fellow of the F.W.O.-Flanders (Belgium).
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00076-9
tetl 16355

1976
Fig. 1.
even pyrophoric properties of 1 in the solid phase, a 1.1 M solution in toluene:THF (ratio 95:5) was
always used for the olefination reactions. The starting 1-aryl-2-azetidinones 4 were synthesized in a two-
step procedure starting from 3-chloro-2,2-dimethylpropanoyl chloride 2. This compound was reacted
with 2 equivalents of an aromatic amine in dichloromethane, giving rise to β-chloro propanamides
3, which could be cyclized to the required 1-aryl-2-azetidinones 4 by means of a phase transfer
catalyzed reaction of benzyltriethylammonium chloride (BTEA) and sodium hydroxide.13 In the case
of 3-chloro-2,2-dimethyl-N-isopropylpropanamide 3c, a much longer reaction time of 72 hours was
necessary for complete cyclization to 4c. In our first attempts to methylenate 4a, 1.5 equivalents of
a 0.6 M Cp2TiMe2 solution in toluene was heated at 80°C for several hours (6–24 h), thus affording
mixtures of starting material 4a (40–50%) and 2-methyleneazetidine 5a (40–60%). If 2-azetidinone 4a
was heated under reflux for 14 hours with 1.5 equivalents of a 1.1 M Cp2TiMe2 solution, a mixture of 93%
methyleneazetidine 5a and 7% starting material 4a was obtained (as observed by 1H NMR). Attempted
separation of both compounds by flash chromatography on silica gel (EtOAc:n-hexane: 1:4; Rf=0.15) or
preparative gas chromatography (160°C) gave rise to complete hydrolysis of 3,3-dimethyl-2-methylene-
1-phenylazetidine 5a to the corresponding 3,3-dimethyl-4-(phenylamino)-2-butanone 6 (Scheme 1).
By means of a Kugelrohr distillation (40–60°C/2.5 mmHg), the pure methyleneazetidine 5a could be
obtained in 20% yield.14 This low yield is due to degradation during the distillation. The reaction of 1-(4-
chlorophenyl)-3,3-dimethyl-2-azetidinone 4b with 1.5 equivalents of Cp2TiMe2 in toluene for 14 hours at
80°C gave 100% conversion to the exocyclic enamine 5b (Scheme 1).15 In all cases the reaction mixtures
were evaporated in vacuo, the residue suspended in pentane and the insoluble titanium salts removed
by filtration over Celite. This procedure was repeated until no further precipitation occurred of titanium
salts. Of course, such a workup procedure lowered the yields drastically. Finally, the reaction of 3,3-
dimethyl-1-isopropyl-2-azetidinone 4c with titanocene 1 under several circumstances gave either rise to
starting material or to complex reaction mixtures, which were not further analyzed. This last experiment
clearly demonstrates the need for an electron-withdrawing N-substituent in the methyleneazetidines to
stabilize the electron-rich exocyclic enamine moiety.
Because of the success of the above described methylenation procedure, the same reaction was
performed on a 2-aziridinone. As the methylenation reaction occurs at rather high temperatures and due
to the known instability of α-lactams, 1,3-ditert-butyl-2-aziridinone 7, was chosen as a model compound
(decomposition starts at 140°C).16 Compound 7 was heated with 1.5 equivalents Cp2TiMe2 1 (1.1 M in
toluene) for 6 hours under reflux. After non-aqueous workup, 1,2-ditert-butyl-3-methyleneaziridine 8 was
isolated as a yellow oil in 56% yield (Scheme 2). An analytically pure sample of 8 could be obtained by
preparative gas chromatography (140°C). Column chromatography on neutral alumina (EtOAc:n-hexane:
1:4; Rf=0.1) or vacuum distillation (24–26°C/1.3 mmHg) also afforded the pure methyleneaziridine
8.17 On the other hand, by column chromatography on silica gel, the labile enamine 8 was completely
hydrolyzed to 3-(tert-butylamino)-4,4-dimethyl-2-pentanone 9 (Scheme 2).

1977
Scheme 1.
Scheme 2.
In summary, an easy method was developed to convert strained α- and β-lactams into the correspon-
ding 2-methyleneaziridines and 2-methyleneazetidines by means of an organotitanium reagent.
Acknowledgements
The authors are indebted to the ‘Fund for Scientific Research-Flanders (Belgium)’ (F.W.O.-
Vlaanderen) and the I.W.T. for financial support.
References
1. (a) Del’tsova, D. P.; Gambaryan, N. P. Izv. Akad. Nauk. SSSR, Ser. Khim. 1976, 858–862; Chem. Abstr. 1976, 85, 123732.
(b) Zeifman, Y. V.; Ter-Gabrielyan, E. G.; Simonyan, L. A.; Gambaryan, N. P.; Knunyants, I. L. Izv. Akad. Nauk. SSSR, Ser.
Khim. 1976, 1813–1817; Chem. Abstr. 1977, 86, 16466.
2. (a) Wasserman, H. H.; Lipshutz, B. H.; Tremper, A. W.; Wu, J. S. J. Org. Chem. 1981, 46, 2991–2999. (b) Wasserman, H.
H.; Lipshutz, B. H.; Wu, J. S. Heterocycles 1977, 7, 321–326. (c) Raap, R. Can. J. Chem. 1971, 49, 1792–1798.
3. (a) Pifferi, G.; Consonni, P.; Testa, E. Ann. Chim. (Rome) 1968, 58, 1283–1293; Chem. Abstr. 1969, 70, 68015. (b) Pifferi,
G.; Vigevani, A.; Consonni, P. Ann. Chim. (Rome) 1969, 59, 658–670; Chem. Abstr. 1970, 72, 90159.

1978
4. Danion-Bougot, R.; Danion, D.; Carrié, R. Tetrahedron 1985, 41, 1953–1958.
5. Baldwin, J. E.; Edwards, A. J.; Farthing, C. N.; Russell, A. T. Synlett 1993, 49–50.
6. Sulmon, P.; De Kimpe, N.; Schamp, N. J. Org. Chem. 1988, 53, 4462–4465.
7. For a leading reference on the preparation and chemistry of methyleneaziridines, see: De Kimpe, N.; De Smaele, D.; Sakonyi,
Z. J. Org. Chem. 1997, 62, 2448–2452.
8. (a) Ince, J.; Shipman, M.; Ennis, D. S. Tetrahedron Lett. 1997, 38, 5887–5890. (b) Shipman, M.; Ross, T. R.; Slawin, A. M.
Z. Tetrahedron Lett. 1999, 40, 6091–6092.
9. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–6394.
10. Petasis, N. A.; Akritopoulou, I. Synlett 1992, 665–667.
11. Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1995, 36, 2393–2396.
12. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrel, I. F.; Verhoeven, T. R. Org. Prep. Proced. Int. 1995, 27, 707–709.
13. (a) Mori, M.; Chiba, K.; Okita, M.; Kayo, I.; Ban, Y. Tetrahedron 1985, 41, 375–385. (b) Bartholomew, D.; Stocks, M. J.
Tetrahedron Lett. 1991, 32, 4795–4798.
14. The spectrometric data of compound 5a are identical with those reported in Ref. 6.
15. As an example, the spectral data of 1-(4-chlorophenyl)-3,3-dimethyl-2-methyleneazetidine 5b are given; H NMR (270
1
MHz, CDCl3): δ 1.32 (6H, s, Me2C); 3.61 (2H, s, CH2N); 3.81 and 4.07 (2×1H, 2×d, J=3.1 Hz, C_CH2); 6.68 and 7.20
(2×2H, 2×d, J=8.90 Hz, HCmeta and HCortho resp.). 13C NMR (68 MHz, CDCl3): δ 25.52 (CMe2); 39.69 (CMe2); 60.39
(CH2N); 74.61 (CH2_C); 114.28 (HCmeta); 128.91 (HCortho); 129.00 and 129.13 (2×Cquat); 159.42 (CH2_C). IR (NaCl,
cm−1): νmax=3410, 3010, 1690, 1620, 1520, 1410, 1390, 1114, 930, 835. MS (70 eV) m/z (%): 207/209 (M+, 80); 206/208
(13); 192 (7); 181 (6); 180 (10); 179 (13); 178 (9); 172 (6); 170 (7); 166 (11); 154 (17); 153 (14); 152 (27); 151 (34); 142
(14); 139/141 (100); 138 (23); 127 (9); 111/113 (23); 75 (18); 66 (15); 65 (6); 51 (11); 44 (12); 41 (13); 40 (70).
16. Sheehan, J. C.; Beeson, J. H. J. Am. Chem. Soc. 1967, 89, 362–366.
17. As an example, the spectral data of 1,3-ditert-butyl-2-methyleneaziridine 8 are given; 1H NMR (270 MHz, CDCl3): δ 0.91
and 1.07 (2×9H, 2×s, 2×Me3C); 1.90 (1H, t, J=0.65 Hz, CH); 4.43 (1H, t, J=1.1 Hz, (H)CH_); 4.46 (1H, d, J=0.65 Hz,
(H)CH_). 13C NMR (68 MHz, CDCl3): δ 26.76 and 27.12 (2×CMe3); 30.65 (CHCMe3); 45.23 (CH); 54.41 (NCMe3);
79.78 (CH2_C); 137.32 (CH2_C). MS (70 eV) m/z (%): 167 (M+, 5); 152 (6); 124 (2); 112 (7); 111 (11); 110 (19); 108 (1);
98 (1); 96 (44); 95 (3); 94 (4); 93 (2); 83 (5); 82 (5); 81 (3); 80 (2); 79 (3); 71 (7); 70 (35); 69 (100); 68 (8); 67 (4); 58 (8);
57 (81); 56 (10); 55 (31); 54 (9); 53 (6); 43 (9); 42 (29); 41 (69). Bp 24–26°C/1.3 mmHg.