1473
A. Hafner, S. V. Ley
Letter
Synlett
Notably, phenyl ketene 2d was prepared starting from
the corresponding acyl chloride instead of the acyl bro-
mide. While we found that the α-bromo functionality was
important for the smooth and stable generation of the cor-
responding ketene through zinc-mediated dehalogenation,
both acyl chlorides and bromides reacted the same way.
When α-chloro-2-phenylacetyl chloride was used instead,
ketene formation only occurred when a heated zinc column
with freshly prepared activated zinc was used. However, it
was difficult to achieve reliable and stable ketene forma-
tion.
Furthermore, we investigated a full flow protocol for the
[2+2] cycloaddition reaction between ketenes and imines.16
A stream of generated ketene 2a was directly reacted in-
line with a stream of benzylideneaniline. However, because
pumping of different streams of low-boiling solvent is chal-
lenging, the solvent system was switched. Optimum results
were obtained by using ethyl acetate as the solvent. Here,
the desired β-lactam 6b could be obtained in 50% yield af-
ter a residence time of just 5 minutes (Scheme 4).
In conclusion, we report the generation of monoalkyl-
and phenyl ketenes by using a simple dehalogenation pro-
cedure under flow conditions.17 The generation of these
highly reactive species could be followed by using in-line IR
analysis, and the ketenes were obtained in high yields, al-
lowing the preparation of different β-lactams by a [2+2] cy-
cloaddition reaction at room temperature.
To compare the reaction with a classical batch-mode re-
action, the reaction was also studied in one pot. Thus, zinc
and benzylideneaniline were placed in a flask under argon
in Et2O and the α-butyryl bromide (1b) was added slowly.
However, after 2 h stirring at room temperature and com-
1
plete consumption of starting material, the crude H NMR
spectrum showed no desired product 6h, and N-phenylbu-
tyramide (7) could be isolated in 67% as the major product
(Scheme 3). This clearly demonstrates the advantage of
translocation of a reactive species, which can be achieved
by using flow chemistry.
Acknowledgment
We gratefully acknowledge the EPSRC (Award No. EP/K009494/1) for
funding (SVL) and the Alexander-von-Humboldt Foundation for a Feodor
Lynen Research Fellowship (AH).
O
Supporting Information
Br
Ph
Br
H
O
Ph
Ph
N
N
Supporting information for this article is available online at
N
Et
Zn, Et2O, r.t., 2 h
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
+
Ph
O
Et
6h
not observed
7
References and Notes
(67%)
Scheme 3 Test reaction of β-lactam formation under the same condi-
tions in the batch mode. Isolated yield of 7 is given.
(1) (a) Allen, A. D.; Tidwell, T. T. Chem. Rev. 2013, 113, 7287.
(b) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563.
(2) (a) Cossío, F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41,
925. (b) Pitts, C. R.; Lectka, T. Chem. Rev. 2014, 114, 7930.
(c) Mehta, P. D.; Sengar, N. P. S.; Pathak, A. K. Eur. J. Med. Chem.
2010, 45, 5541. (d) Rasik, C. M.; Brown, M. K. J. Am. Chem. Soc.
2013, 135, 1673.
Br
Br
Zn
(3 equiv)
Ph
1a
O
N
O
(3) For selected recent examples, see: (a) Lee, S. Y.; Neufeind, S.; Fu,
G. C. J. Am. Chem. Soc. 2014, 136, 8899. (b) Zhang, H.-M.; Gao, Z.-
H.; Ye, S. Org. Lett. 2014, 16, 3079. (c) Chen, S.; Mondal, M.;
Ibrahim, A. A.; Wheeler, K. A.; Kerrigan, N. J. J. Org. Chem. 2014,
79, 4920.
(4) For selected recent examples, see: (a) Ibrahim, A. A.; Nalla, D.;
Van Raaphorst, M.; Kerrigan, N. J. J. Am. Chem. Soc. 2012, 134,
2942. (b) Paull, D. H.; Scerba, M. T.; Alden-Danforth, E.; Widger,
L. R.; Lectka, T. J. Am. Chem. Soc. 2008, 130, 17260. (c) Tiseni, P.
S.; Peters, R. Angew. Chem. Int. Ed. 2007, 46, 5325. (d) Purohit, V.
C.; Richardson, R. D.; Smith, J. W.; Romo, D. J. Org. Chem. 2006,
71, 4549.
flow-IR
Ph
r.t.
H
0.1 M in EtOAc
1 ml/min
0.05M in EtOAc
1 ml/min
5 min, r.t.
(5) (a) Allen, A. D.; Andraos, J.; Tidwell, T. T.; Vukovic, S. J. Org.
Chem. 2014, 79, 679. (b) Hafez, A. M.; Taggi, A. E.; Wack, H.;
Drury, W. J.; Lectka, T. Org. Lett. 2000, 2, 3963. (c) Hafez, A. M.;
Taggi, A. E.; Lectka, T. Chemistry 2002, 8, 4114.
O
Ph
N
Ph
6b
50%
(6) Staudinger, H. Chem. Ber. 1911, 44, 533.
(7) McCarney, C. C.; Ward, R. S. J. Chem. Soc., Perkin Trans. 1 1975,
1600.
Scheme 4 Synthesis of β-lactam 6b by using reactive ketenes in flow.
Isolated yield of 6b is given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1470–1474