Spiro-aziridine and bislactam formation from bisketene-imine cycloadditions

Article abstract of DOI:10.1021/ja077623y

1,2-Bisketenes 6 react with imines PhCH=NAr, (E)-2, forming spiro-aziridines 7. DFT computations indicate that this occurs by nucleophilic attack of the imine on the carbonyl carbon of the more reactive arylketene moiety, followed by cyclization, and not by prior cyclization of the 1,2-bisketene forming a carbene lactone intermediate. Computations also indicate that the previously studied bisketene 10 from benzocyclobutadiene 9 is 4.0 kcal/mol less stable than carbene lactone 12 that would result from cyclization but that the failure to observe 12 results from a lower barrier for 10 to instead revert to 9. 1,2-, 1,3-, and 1,4-Bisketenylbenzenes 16, 19, and 22 react with imines forming bis(β-lactams), with a preference for formation of mixtures of trans, trans chiral (±) and achiral diastereomeric products. Copyright

Full text of DOI:10.1021/ja077623y

Published on Web 02/02/2008
Spiro-Aziridine and Bislactam Formation from Bisketene-Imine
Cycloadditions
Annette D. Allen, Jazmin Godoy, Nanyan Fu,† Michelle Nagy, Sandra Spadaro,
Thomas T. Tidwell,* and Sinisa Vukovic
Department of Chemistry, UniVersity of Toronto, Toronto, Ontario M5S 3H6, Canada
Received October 3, 2007; E-mail: ttidwell@chem.utoronto.ca
Reaction of diphenylketene (1) with imine 2a forming 3 reported
100 years ago (eq 1) was the first synthesis of a â-lactam and,
with the reaction of 1 with aldehydes forming â-lactones and with
alkenes forming cyclobutanones, was the first example of [2 + 2]
cycloaddition.1 This reaction took on great interest after the
discovery of penicillin in 1928 and its identification as the first
â-lactam antibiotic.2a-c The â-lactam structure of the penicillins
was proposed in the 1940s,2c and synthesis of penam 4, which
differs from the natural penicillins by the presence of the 9-phenyl
group, was achieved in 1950 by using ketene-imine cycload-
dition.2d,e
Figure 1. X-ray structure of aziridine 7a.
than thermal reversion to 5 (eq 3). However, B3LYP/6-31G(d)
computations4 of interconversion of 5a, 6a, and 8a show the carbene
lactone 8a is 30.7 kcal/mol higher in energy than 6a, with a 36.7
kcal/mol barrier for reaction, showing that formation of 8a is not
a viable route to 7a.
Subsequently, there has been immense effort devoted to â-lactam
synthesis,2f,g including preparation of bis(â-lactams) by ketene
reactions with bis(imines),3a-c photolysis of bis(carbene) complexes
in the presence of imidazolines,3d,e and dehydration of diacids with
Mukaiyama’s reagent in the presence of imines.3f The presence of
bisketene intermediates in these reactions was, however, not
established, and the goal of the current research is to study imine-
bisketene reactions in circumstances where bisketenes are proven
to be intermediates, so that the course of the reactions can be
followed with certainty.
Photolysis of cyclobutenedione 5a formed bisketene 6a, which
with imine 2a gave aziridine trans-(()-7a in 78% yield (eq 2).
The stereochemistry was proven by X-ray (Figure 1). Imine 2b
with 6a gave trans-(()-7b, also characterized by X-ray. Generation
of 6b (R ) Me) and reaction with imine 2a gave the aziridine 7c,
which was unstable to chromatography but was identified by
NMR.
Lactone derivatives analogous to 7 have been formed previously
in the reactions of 1,2-bisketenes,5,6 originally in the reactions of
bisketene 10 formed by photolysis of benzocyclobutadienone (9),
which for example reacts with pyridine to form the zwitterion 11
(eq 4).6g Computations4 now show the unobserved carbene lactone
12 to be 4.0 kcal/mol more stable than the bisketene 10, but the
barrier calculated for return of the bisketene 10 to cyclobutene-
dione 9 is lower than that for formation of the more stable carbene
lactone 12 by 4.5 kcal/mol, thereby accounting for the failure to
observe 12.
Two reaction paths have been calculated4 for reaction of
bisketene 6a with imine (E)-2a, which is more stable than
(Z)-2a by 6.6 kcal/mol. These include the possibility that reaction
occurs by initial conversion of (E)-2a to (Z)-2a followed by re-
action with the ketene, as reported7 for other such reactions. The
rate-limiting step for bisketene 6a reaction with (E)-2a giving
aziridine 7a is calculated to be formation of zwitterionic inter-
mediate (E)-13, followed by cyclization to lower energy intermedi-
ate (E)-14 (eq 5). This is less than the corresponding barrier
for reaction via (Z)-2a by 1.0 kcal/mol, but within the accuracy
of the computations, reaction by one or the other route, or both,
is not proven.
A conceivable pathway for formation of aziridines 7 is cyclization
of bisketenes 6 to highly reactive carbene lactones 8 in low
concentration, so that reaction proceeds through this channel rather
† Current address: Department of Chemistry, Fuzhou University, Fuzhou, Fujian
350002, China.
9
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J. AM. CHEM. SOC. 2008, 130, 2386-2387
10.1021/ja077623y CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Experimental demonstration of bislactam formation by reaction
of the observable 1,3-bisketenylbenzene 168 generated by Wolff
rearrangement of 1,3-bis(diazoacetyl)benzene (15) by continuous
photolysis, followed by addition of imine (E)-2a, led to a product
identified by the characteristic trans H,H NMR couplings as the
chiral (() and achiral trans,trans-diastereomers of bislactam 17a
as a 1:1 mixture (eq 6). trans-Stereochemistry has been reported
for the â-lactam from imine (E)-2a and phenylketene generated
photochemically or by dehydrochlorination.9
Figure 2. X-ray structure of chiral bis(â-lactam) 20a.
as well as new structural types. A mechanism involving stepwise
imine addition to the bisketene is proposed based on DFT
computational studies. This argues against formation of carbene
lactones in this process and against previous suggestions of carbene
lactone 12 in the reactions of bisketene 10 from benzocyclobutene-
dione (9), even though 12 is calculated to be more stable than
bisketene 10. Bisketenylbenzenes 16, 19, and 22 react with imines
2 forming unique bis(â-lactams), including 17 and 20, providing
simple routes to these structurally interesting compounds.
Acknowledgment. Financial support by the Natural and Sci-
ences Engineering Research Council of Canada is gratefully
acknowledged.
Supporting Information Available: Experimental procedures,
spectra, and computational details, and cif files. This material is
available free of charge via the Internet at http://pubs.acs.org.
Observable 1,2-bisketenylbenzene 198 generated by dehydro-
chlorination of bis(acyl chloride) 18 with 1,8-bis(dimethylamino)-
naphthalene and catalytic Et3N in toluene (eq 7) was captured by
imine (E)-2a, giving four isolated products, identified as chiral (()
and meso trans,trans-bis(â-lactams) 20a,b, cis/trans-isomer 20c,
and (()-lactam 21, in a 73:12:4:11 ratio by NMR analysis (eq 8).
Similar methodology gave 16 from the 1,3-bis(acyl chloride), which
with (E)-2a formed 17a, while 16 and PhCHdNBn (E)-2c, gave
17b (R1 ) Bn) as two diastereomers in a 2:1 ratio. 1,4-
Bisketenylbenzene 22, also generated by this protocol, reacted
similarly with 2a forming bis(â-lactams).4a
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In summary, reaction of 1,2-bisketenes 6 with imines (E)-2a,b
forms aziridines 7, providing a new method of aziridine synthesis,
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