DOI: 10.1002/anie.201006272
Microreactors
Safe and Efficient Tetrazole Synthesis in a Continuous-Flow
Microreactor**
Prakash B. Palde and Timothy F. Jamison*
Tetrazoles are an important class of heterocycles in a wide
range of applications, such as, organocatalysis and transition-
metal catalysis, propellants, explosives, and perhaps most
commonly, as non-classical isosteres of carboxylic acids in
medicinal chemistry.[1,2] This broad utility has prompted
significant effort toward tetrazole synthesis,[3] and notable
among these is that of Sharpless, in which aqueous zinc
bromide (ZnBr2) facilitates the assembly of tetrazoles from
nitriles and sodium azide (NaN3).[3e] Nevertheless, the major-
ity of reported methods are either less straightforward or
generally not suited for large-scale synthesis; they require
explosive and/or expensive reagents, toxic metal-containing
compounds, or excess azide. The most significant hazard is the
generation of hydrazoic acid (HN3), particularly in reactions
conducted in the presence of even trace amounts of Brønsted
acids.[4]
Continuous-flow synthesis is emerging as a powerful
technology complementary in several contexts to batch
synthesis in flasks or vessel reactors.[5] As only small
quantities of reagents and products are exposed to the
reaction conditions at a given time, the risks associated with
hazardous materials are minimized, and transformations
using them are thus rendered much safer. Flow would thus
appear to be an appropriate reaction format for the synthesis
of tetrazoles from nitriles and an azide source. During the
preparation of this manuscript a collaborative effort between
Kappe and Lonza reported an exquisitely engineered system
for the continuous-flow synthesis of tetrazoles using HN3.[6]
Generated in situ from NaN3 and acetic acid, HN3 (approx-
imately 2.5 equiv at 1.6m) may be used at elevated temper-
atures and pressures to prepare a range of tetrazoles from the
corresponding nitriles.
our method: avoid the use and generation of HN3,[7] require
only a slight excess of azide (in any form), develop a system
that can be assembled easily such that it may be implemented
both in the laboratory (education and research) and, with
straightforward modification, on manufacturing scale. In
addition to being safer (no HN3, minimal azide usage),
easily assembled (see video provided in Supporting Informa-
tion) and less expensive (syringes, syringe pumps, oil bath,
standard tubing and fittings), this method is, perhaps unex-
pectedly, faster and higher yielding in many cases. Other
features include the fact that neither a metal catalyst nor
promoter is required and the inclusion of a simple in-line,
post-reaction treatment with NaNO2 to quench the vanish-
ingly small traces of remaining azide.
We began our investigations by evaluating several
reported methods of tetrazole synthesis with the aim of
finding one that would be amenable to the requirements listed
above. In early stages, small-scale microwave reactions
provided a useful and informative bridging basis of compar-
ison between batch and flow[8] (Table S1, Supporting Infor-
mation). Nitrile 1 (Figure 1, R = p-anisyl) was chosen as the
starting point as it is of moderate reactivity in most tetrazole
syntheses, largely due to the electron-donating effect of the
methoxy group.[9] The conditions reported by Sharpless
et al.[3e] and later shown to be effective under microwave
irradiation by Fang et al.[3h] (Table S1, entries 4–6) showed the
greatest promise for development of a flow process. With
nitrile 1 a reaction temperature of 1408C provided the highest
From the outset of our investigations, described herein, we
took a conceptually and technically different approach,
establishing the following as fundamental requirements of
[*] Dr. P. B. Palde, Prof. Dr. T. F. Jamison
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-0253
E-mail: tfj@mit.edu
[**] We are grateful to the Novartis-MIT Center for Continuous
Manufacturing for financial support and to several colleagues at
MIT (Stephen L. Buchwald, Klavs F. Jensen, and their co-workers)
and Novartis (Gerhard Penn, Berthold Schenkel, Oljan Repic,
Thierry Schlama, Mike Girgis, Lukas Padeste, and Felix Kollmer) for
insightful discussions.
Figure 1. A) Continuous-flow synthesis of tetrazoles using our micro-
reactor. See Supporting Information for parts list and instructions for
assembly and operation (video). B) Summary of the function of each
reactor feature. NMP=N-methyl-2-pyrrolidone.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 3525 –3528
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3525