protocols have been devised to access their general struc-
tures.6 However, far fewer methods are available for the
regioselective preparation of compounds substituted at both
the 4 and 5 positions.7 As part of a medicinal chemistry
project, we required an expedient method of preparing a
library of such privileged substructures. We envisaged this
could be achieved in flow via the addition of an alkyl
isocyanoacetate to an acyl chloride with a base-catalyzed
intramolecular cyclization (Scheme 1).6,8 The chemistry
Aliquots of the reaction stream can also be sampled at any
stage of the process and profiled through an LC-MS system.
Furthermore, in-line preparative HPLC can be applied to
purify intermediates or products if necessary in a fully
automated fashion. Finally, the system is connected to a
second liquid handler enabling sorting (fraction collection
in the case of prep-HPLC) and easy collection of the various
products. The entire process is completely computer con-
trolled for repeatability, ease of use, and importantly as-
similation and correlation of the information-rich experi-
ments.
The Synthesis: Initially, we focused on using ethyl
isocyanoacetate as the starting isocyanide and aimed to
introduce diversity by varying the acyl chloride component.
Hence, when equimolar mixtures of ethyl isocyanoacetate
and 3-nitrobenzoyl chloride (10 mM in acetonitrile) were
combined (variable residence time mixing chip from 274 µL
to 1 mL) in a stream of acetonitrile at a flow rate of 0.2
mL/min, automated analysis of the reaction stream indicated
the formation of an intermediate addition adduct. Progressing
this combined reaction stream through a packed cartridge
of base (PS-BEMP9) facilitated a rapid base-catalyzed
intramolecular cyclization yielding the 4,5-disubstituted
oxazole as the sole product after 20-30 min. In these initial
experiments, direct automated collection and evaporation of
the solvent stream yielded the oxazole products in >80%
isolated yield and in 90% purity as determined by HPLC
Scheme 1. 4,5-Disubstituted Oxazoles
described was successfully optimized, and a small compound
collection was prepared using a bespoke small-footprint
automated flow reactor (schematic presented in Supporting
Information).
The Reactor: The current dual channel flow reactor is
driven by two variable delivery pumps, each responsible for
the independent supply of a solvent and reagent stream. The
pumps are integrated with a multiposition liquid handler
enabling the required starting materials and reagents to be
selected and dispensed into two separate queuing ports which
act as temporary reagent stores. Following aspiration into
the reactor, the starting materials flow into a glass T-
configured mixing chip where precise blending can be
achieved. A modified hot plate heating block allows different
reaction temperatures to be established and rapidly cycled
to facilitate condition screening. Next, a highly flexible valve
selection arrangement directs the reacting flow stream
through a predetermined sequence of “reactor” cartridges
containing solid-supported reagents, scavengers, or catalysts.
An auxiliary heating or cooling system for these packed
columns controls the reaction temperatures, easily allowing
variable reaction parameters at each step of the process. The
entire reaction progress is monitored in real time via a
tuneable wavelength UV detection unit, permitting feedback
of reaction information to earlier stages of the sequence.
1
and H NMR.
Interestingly, the overall isolated yield and kinetics of the
transformation were found to be dependent on the specific
period of mixing prior to contact with the immobilized base.
The reason for this is not entirely evident from the implied
mechanism, and repeated attempts to isolate the precycliza-
tion intermediate have proven unsuccessful. However, in situ
NMR analysis of a reaction performed in the reactor using
d3-MeCN prior to base contact indicated formation of an
adduct where acylation had occurred exclusively at the
methylene site. Such an intermediate would then undergo a
very facile base-catalyzed formal 5-enol-endo-dig cyclization.
This is in contrast to the work carried out by Huang et al.8a
who reported the chemoselective addition of the same
isocyanide functional group directly to the acid chloride
furnishing the intermediate R-ketoimidoyl chlorides (albeit
under basic conditions) which spontaneously cyclized to the
alternative 2,5-disubstituted oxazoles. We were unable to
prepare such intermediates or the correspondingly derived
products despite extensive screening of the reaction condi-
tions even in the presence of added base (K2CO3, DBU,
BEMP, Et3N); in all our reactions, only the 4,5-disubstituted
oxazole was detected.
(6) For a review of classical methods of preparing oxazoles, see: (a)
Turchi, I. J. Oxazoles in Heterocyclic Compounds;Turchi, I. J., Ed.; Wiley:
New York, 1986; Vol. 45. (b) Hartner, F. W. Oxazoles in ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F.
V., Eds.; Pergamon Press: Oxford, 1996; Vol. 6, pp 262 and references
cited therein.
(7) (a) Scho¨llkopf, U.; Schro¨der, R. Angew. Chem. 1971, 83, 358. (b)
Suzuki, M.; Iwasaki, T.; Miyoshi, M.; Okumura, K.; Matsumoto, K. J. Syn.
Commun. 1972, 2, 237. (c) Suzuki, M.; Iwasaki, T.; Miyoshi, M.; Okumura,
K.; Matsumoto, K. J. Org. Chem. 1973, 38, 3571. (d) Scho¨llkopf, U.; Porsch,
P.-H.; Chem. Ber. 1973, 106, 3382. (e) Scho¨llkopf, U.; Schro¨der, R. Liebigs
Ann. Chem. 1975, 533. (f) Henneke, K.-W.; Scho¨llkopf, U.; Neudecker, T.
Liebigs Ann. Chem. 1979, 1370. (g) Racho´n, J.; Scho¨llkopf, U. Liebigs Ann.
Chem. 1981, 1186. (h) Maeda, S.; Suzuki, M.; Iwasaki, T.; Matsumoto,
K.; Iwasawa, Y. Chem. Pharm. Bull. 1984, 32, 2536. (i) Armarego, W. L.
F.; Taguchi, H.; Cotton, R. G. H.; Battiston, S.; Leong, L. Eur. J. Med.
Chem. (Chim. Ther.) 1987, 22, 283.
For additional comparative purposes, we also ran the same
reactions as a standard batch process at ambient temperature
as well as at 40 and 70 °C in both MeCN and DCM (sealed
tubes). We found such conditions gave comparatively poor
conversions (50-70%) and much lower purities (<70%) for
both solvents and all temperatures, even after a 10 h reaction.
At present, we are unable to conclusively identify any reason
for the enhanced conversions or kinetics attained in the flow
(8) (a) Huang, W.-S.; Zhang, Y.-X.; Yuan, C.-Y. Syn. Commun. 1996,
26, 1149. (b) Tian, W.-S.; Livinghouse, T. J. Chem. Soc., Chem. Commun.
1989, 819. (c) Tang, J.; Verkade, J. G. J. Org. Chem. 1994, 59, 7793.
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