COMMUNICATION
DOI: 10.1002/chem.201100768
In Situ Generation and Intramolecular Schmidt Reaction of Keto Azides in a
Microwave-Assisted Flow Format
Thomas O. Painter,[a] Paul D. Thornton,[a] Mario Orestano,[a, b] Conrad Santini,[a]
Michael G. Organ,[a, b] and Jeffrey Aubꢀ*[a, c]
It is now well appreciated that flow techniques offer much
in the area of fine organic synthesis.[1] In particular, they
permit the utilization of even highly reactive intermediates
in a relatively safe setting and offer a convenient means of
preparing large quantities of compounds by extending the
time of the flow reaction (“scaling out”) and thus avoiding
issues with “scaling up” of batch reactions. Since some alkyl
azides are known to pose potential explosion hazards, the
adoption of flow techniques for alkyl azide reactions is at-
tractive. Previously, the in situ generation of azides and their
utilization in Curtius rearrangement,[2] Staudinger aza-
Scheme 1. General reaction sequence. (MWI=microwave irradiation)
Wittig,[3] and 1,3-dipolar cycloaddition[4] reactions have been
reported.[5] In this communication, we report the use of mi-
crowave-assisted flow reaction conditions in the context of
the intramolecular Schmidt reaction of alkyl azides, a useful
method for the generation of lactams.[6]
We used keto chloride 1 as a model substrate for develop-
ing the two-step MACOS sequence depicted in Scheme 1.[7]
Using a syringe pump an equimolar solution of N,N,N,N-tet-
rabutylammonium azide (TBAA) and the halide in DMF
was flowed (10 mLminÀ1) through a glass capillary posi-
tioned inside the reaction chamber of a microwave reactor
set to operate at 300 W. The solution exited the chamber
and reached a connection point joined to a second glass cap-
tered the microwave chamber through the second capillary
and was collected upon exiting. To prevent possible in-line
cavitation the experiment was performed under 70 psi argon
pressure, which was applied through a needle inlet into the
receiving vial.
Conversion to the lactam was determined by extractive
workup and examination of the derived products by
1H NMR spectroscopy. While reasonable conversion
(ꢀ70%) was attained, improvement was clearly required. In
addition, the elimination of dead volume from the system
was desired to facilitate yield determination.
Several modifications were introduced that improved the
outcome. The replacement of DMF by CH3CN afforded
complete conversion of the intermediate azide to the
lactam, even at reduced power (125 W), presumably because
CH3CN does not attenuate the acidity of TFA.[8] The re-
ACHTUNGTRENNUNGillary that was also positioned inside the microwave cham-
ber. Trifluoroacetic acid (TFA, 20 mLminÀ1) was introduced
to the flowing stream at the connection point by using a
second syringe pump. The combined reaction mixture re-en-
AHCTUNGTREGUNaNN ction mixture was loaded into a sample loop made of
PEEK (polyether ether ketone) tubing that was introduced
into the beginning of the flow path. The first syringe pump
delivered only solvent, removing any possibility that reac-
tants would remain in the system uncollected. Instead of
using fragile glass capillaries within the microwave chamber,
mechanically robust, flexible, fused silica tubing (700 mm di-
ameter) was used (see the Supporting Information for a
schematic diagram). A reduced pressure of 40 psi was both
effective in preventing cavitation and resulted in less la-
borous flow. To improve the throughput, the flow rate was
increased to 50 mLminÀ1 from each syringe pump. The resi-
dence time was calculated to be about 60 s for the azide dis-
placement and 30 s for conversion to the lactam, assuming
that the length of the irradiated flow path was 2–3 cm (ca.
45–50 mL irradiated volume). Given the absence of direct in-
strumental measurement, the reaction temperature was esti-
[a] Dr. T. O. Painter, Dr. P. D. Thornton, M. Orestano, Dr. C. Santini,
Prof. M. G. Organ, Prof. J. Aubꢀ
Chemical Methodology and Library Development Center
University of Kansas
Delbert M. Shankel Structural Biology Center
2034 Becker Drive, Lawrence, KS 66047-3761 (USA)
Fax : (+1)785-864-8179
[b] M. Orestano, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele St., Ontario (Canada)
[c] Prof. J. Aubꢀ
Department of Medicinal Chemistry
University of Kansas
Delbert M. Shankel Structural Biology Center
2034 Becker Drive, Lawrence, KS 66047-3761 (USA)
Supporting information for this article is available on the WWW
Chem. Eur. J. 2011, 17, 9595 – 9598
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9595