The reaction of dimethyltitanocene with N-substituted-β-lactams

Article abstract of DOI:10.1016/S0040-4039(00)00919-9

2-Methyleneazetidines have been synthesized and isolated by the reaction of β-lactams with dimethyltitanocene, followed by chromatography on deactivated silica. Efficient conversion required that the lactam nitrogen be strongly deactivated. Methyl transfe

Full text of DOI:10.1016/S0040-4039(00)00919-9

Tetrahedron Letters 41 (2000) 5607±5611
The reaction of dimethyltitanocene with
N-substituted-b-lactams
Isamir Martõnez and Amy R. Howell*
Department of Chemistry, The University of Connecticut, Storrs, Connecticut 06269-3060, USA
Received 1 May 2000; revised 2 June 2000; accepted 5 June 2000
Abstract
2-Methyleneazetidines have been synthesized and isolated by the reaction of b-lactams with dimethyl-
titanocene, followed by chromatography on deactivated silica. Ecient conversion required that the lac-
tam nitrogen be strongly deactivated. Methyl transfer predominated in reactions with phenyl and benzyl
on the lactam nitrogen. # 2000 Elsevier Science Ltd. All rights reserved.
Our interest in strained heterocycles as versatile templates for the construction of more complex
synthetic intermediates and molecular targets has recently centered on the exploitation of 2-
methyleneoxetanes 1. We developed a straightforward entry into this class of compounds by the
methylenation of b-lactones with dimethyltitanocene.1 Our anticipation of the ¯exibility of 2-
methyleneoxetanes has already been con®rmed by their conversion to homopropargylic alcohols,2
fused ketals,3 functionalized ketones4 and 1,5-dioxaspiro[3.2]hexanes,5 the latter themselves being
fascinating and useful strained heterocyclic systems.6 Further, a 2-methyleneoxetane analog of
Orlistat, a b-lactone-containing pancreatic lipase inhibitor currently marketed as an anti-obesity
agent, was found to be a potent pancreatic lipase inhibitor.7 Because of the diverse reactivity and
biological promise of 2-methyleneoxetanes, we became interested in exploring 2-methyleneaze-
tidines 2.
There are few examples of simple 2-methyleneazetidines in the literature.8 11 The only reports
describing the preparation of multiple 2-methyleneazetidines come from the groups of Reinhoudt11
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00919-9

5608
and De Kimpe.9 The former reported the isolation of four examples when four-membered cyclic
nitrones 3 were treated with acetyl chloride in the absence of water. De Kimpe and co-workers
employed the base-promoted cyclization of N-aryl-b-chloro ketimines 4. The requirement for
a-disubstitution in this case limits the versatility of this approach. Because of our success in pre-
paring 2-methyleneoxetanes by the reaction of b-lactones with dimethyltitanocene, we decided to
pursue a similar strategy and to examine the methylenation of b-lactams. Herdeis and Heller
reported the methylenation of d-lactams with dimethyltitanocene.12 In this communication a
footnote stated that it was also possible to methylenate b-lactams, although no speci®c examples
or characterization data were provided. Baldwin et al. found that the Wittig reaction of stabilized
ylides with b-lactams proceeded only if strongly electron withdrawing groups were placed on the
nitrogen,13 thus restricting mesomeric resonance. Herdeis had also found that this was important
for the methylenation of d-lactams. Thus, we anticipated that the choice of functionality attached
to the nitrogen would be crucial. We decided to examine the e€ect of a range of substituents to
determine which were compatible with successful methylenation of the b-lactam carbonyl.
While we were preparing this manuscript, De Kimpe and co-workers reported the use of
dimethyltitanocene for the methylenation of two N-aryl-b-lactams 5.14 Successful isolation of the
resultant 2-methyleneazetidine was achieved by vacuum distillation for 5a, but in 20% yield. It
was reported that hydrolysis product 6 resulted when silica gel chromatography was employed
for puri®cation. Since our results with a 1-phenylazetidin-2-one were di€erent from those of De
Kimpe, and, since we were able to isolate a range of 2-methyleneazetidines under chromato-
graphic conditions which we have previously described for 2-methyleneoxetanes,15 we thought it
worthwhile to communicate our results.
The precursor b-lactams were prepared by standard methods. Thus, 4-phenylazetidin-2-one (7),16
benzyl 4-oxoazetidine-2-carboxylate (8)17 and b-lactam 918 were converted by known procedures19
to Boc-protected lactams 10a, 10c, and 10e,20 respectively. Compounds 7 and 8 were also trans-
formed by standard procedures21 to Cbz-protected lactams 10b and 10d (see Table 1).20 b-Lactam
7 was tosylated under conditions described22 by Adlington et al. to give 10f23 and was treated
with acetyl chloride24 to provide 10h.23 Lactams 10g25 and 10i26 were prepared by literature
procedures, and 7 was converted to 10j27 under conditions described by Murayama et al.28
The b-lactams 10 were dissolved in a solution of dimethyltitanocene in toluene (0.25 M, 5
equiv.) and heated under nitrogen in the dark until the starting material had disappeared, based
on 1H NMR.29 Although reactions conducted with fewer equivalents of dimethyltitanocene gave
similar yields, they tended to be slower. The best yields, not surprisingly,12,13 were observed with
the strongly electron withdrawing carbamates (10a±10e). There were, however, a number of
unexpected results and interesting observations.
The lack of reactivity of dimethyltitanocene with the carbamate carbonyls is not surprising;
however, dimethyltitanocene is known to methylenate esters.30 With ester-containing lactams
10c±e, we did not observe methylenation of the ester moieties as long as the reaction was quenched
upon initial consumption of the b-lactams. This chemoselectivity was gratifying. With lactam
1
10h, we were unable to isolate any pure product. Based on the crude H NMRs and the impure

5609
Table 1
products isolated in multiple reactions, it appeared that methylenation was occurring almost
equally at the lactam and acetyl carbonyls, but not at both. The methylenation of O-benzyl lactam
1
10g was successful, based on crude H NMR; however, repeated puri®cation attempts did not
result in any clearly identi®able product related to 2g. The isolated yield of 2f was low, and it was
dicult to ascertain whether this re¯ected actual conversion. Of all of the reactions in which

5610
methylenation was successful, this was the messiest. It did not appear that methyl transfer (vide
infra) was occurring, and other than 2f, no identi®able product was isolated. In spite of the low
yield, 2f is a particularly interesting product because a number of tosylated b-lactams are known
inhibitors of elastases, and we are anxious to determine whether 2-methyleneazetidines can serve
as isosteres for b-lactams.
The results with N-phenyllactam 10i and N-benzyllactam 10j were divergent from the other
lactams we studied and from those reported for N-aryl-b-lactams by De Kimpe.14 In our initial
attempt to methylenate 10i, ring-opened product 11a was isolated in 55% yield. Assuming this
resulted from inadvertent hydrolysis, the reaction was repeated; the result was the same. Exam-
ination of the crude 1H NMRs of both reactions showed that 11a appeared to be the only lactam-
related material prior to puri®cation. The reaction was repeated with extensive monitoring of the
1
reaction by H NMR. At no point did we observe any 2-methyleneazetidine; the only lactam-
related materials throughout the course of the reaction were 10i and 11a. These results were
mirrored by 10j.31 The outcomes of these reactions suggest that the nitrogens in 10i and 10j are
Lewis basic enough to allow for their coordination with the titanium, leading to methyl transfer
to the carbonyl moieties, rather than metathesis. Interestingly, in recent preparations of 2a on a
1
larger scale than our initial studies, we isolated 11c (15%). Examination of the crude H NMRs
of these reactions con®rmed the presence of 11c prior to work-up. Thus, it appears that at least
some of the material balance in these reactions may be accounted for by methyl transfer.
In summary, we have demonstrated that 2-methyleneazetidines can be prepared and isolated in
good yields by the reaction of b-lactams with dimethyltitanocene, as long as the lactams are
properly activated. It appears that methyl transfer represents an alternative pathway of reaction
that predominates in cases where the Lewis basicity of the lactam nitrogen is not suciently
dampened. We are currently investigating the potential of 2-methyleneazetidines as b-lactam
isosteres and as novel molecular sca€olds.
Acknowledgements
Helpful discussions with Nicos Petasis and Claude Herdeis are gratefully acknowledged. We
thank Lisa Dollinger and Lisa Le Blanc for preliminary studies on the methylenation of 10g.
ARH thanks the NSF for a CAREER Award.
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18. We thank Dr Preston Conrad of Eli Lilly for generously providing a sample of 9.
19. Palomo, C.; Alzpurua, J. M.; Garcia, J. M.; Iturburu, M.; Odriozola, J. M. J. Org. Chem. 1994, 59, 5184±5188.
20. All new compounds are fully characterized.
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29. General procedure for methylenation. N-(tert-Butoxycarbonyl)-4-phenyl-2-methyleneazetidine (2a). A solution of
dimethyltitanocene (0.25 M in toluene, 6.6 mL), N-(tert-butoxycarbonyl)-4-phenyl-2-azetidinone (10a) (0.10 g,
0.40 mmol), and pyridine (0.13 g, 1.6 mmol) was stirred in the dark at 70ꢀC under nitrogen. The reaction was
1
followed over a period of 1±3 hours by H NMR. The cooled reaction mixture was added to petroleum ether (50
mL) and stirred for 1 h. The reaction mixture was ®ltered through celite and washed with petroleum ether until the
®ltrate was colorless. The ®ltrate was concentrated in vacuo and the residue puri®ed by ¯ash chromatography on
silica gel (petroleum ether/EtOAc/NEt3 94:5:1), a€ording the product as a pale yellow solid (74 mg, 76%): IR
1
(KBr) 2978, 2929, 1713, 1632, 1456, 1153, 1101 cm^1; H NMR (400 MHz, CDCl3) ꢀ 7.32 (m, 5H), 5.11 (broad s,
1H), 5.03 (broad s, 0.5H), 4.73 (broad s, 0.5H), 4.22 (s, 1H), 3.19 (m, 1H), 2.65 (broad d, J=13.6, 1H), 1.24 (broad
s, 9H); 13C NMR (100 MHz, CDCl3) ꢀ 146.0, 141.2, 129.0, 128.3, 126.5, 87.5, 62.3, 36.3, 30.2, 28.7; MS (EI) m/z
245 (M+), 200, 189, 174, 144 (M+-Boc) (100), 129, 104; Anal. calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71.
Found: C, 73.04; H, 7.94; N, 5.43.
30. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392±6394.
31. Compound 11b not isolated; only product observed by 1H NMR.