Tetrahedron Letters 51 (2010) 1404–1406
Tetrahedron Letters
Improved conditions for converting sterically hindered amides to
1,5-disubstituted tetrazoles
*
Gretchen M. Schroeder , Sydney Marshall, Honghe Wan, Ashok V. Purandare
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Improved conditions for converting amides into 1,5-disubstituted tetrazoles are described. The optimum
reaction conditions [diisopropyl azodicarboxylate (DIAD), diphenylphosphoryl azide (DPPA), and diphe-
nyl-2-pyridyl phosphine in THF at 45 °C] converted sterically hindered amides to their corresponding tet-
razoles in good yield.
Received 15 December 2009
Revised 5 January 2010
Accepted 7 January 2010
Available online 13 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Tetrazoles, while not found in nature, have gained considerable
popularity in drug discovery efforts.1 5-Substituted (1H)-tetrazoles
possess an acidic hydrogen at the N-1 position and have thus found
use as carboxylic acid bioisosteres. While maintaining similar pKa
values to carboxylic acids, 5-substituted (1H)-tetrazoles can bene-
fit from improved cell permeability, bioavailability, and metabolic
stability. Substitution of the N-1 nitrogen to give 1,5-disubstituted
tetrazoles has also proven beneficial in drug discovery as cis-amide
isosteres.2
4–6). Diphenyl-2-pyridyl phosphine has been reported as a viable
triphenylphosphine surrogate in the Mitsunobu reaction.7,8 While
reaction at room temperature gave very low conversion (5%) after
stirring for 2 h, the use of diphenyl-2-pyridyl phosphine at slightly
elevated temperatures gave enhanced conversion (40%) to the de-
sired tetrazole 2a (entries 7 and 8). The use of diphenyl-2-pyridyl
phosphine was also advantageous with respect to reaction work-
up and purification. We frequently found it difficult to remove
the triphenylphosphine oxide by-product from the desired com-
pounds by column chromatography. As polymer-bound triphenyl-
phosphine failed in our hands, we turned to diphenyl-2-pyridyl
phosphine to provide complimentary affinity for silica gel which
facilitated our purifications. Such a benefit has been reported
previously.9
Next, we examined trimethylsilylazide alternatives and found
diphenylphosphoryl azide (DPPA) to be a suitable replacement in
forming tetrazole 2a.10 In the presence of diphenyl-2-pyridyl phos-
phine and DPPA, 25% conversion of amide 1a to tetrazole 2a could
be achieved after stirring at room temperature for 2 h (entry 9).
The previously described temperature effect could then be
exploited to give nearly 50% conversion after 2 h at 45 °C (entry
10). In contrast to reactions with trimethylsilyl azide, reactions
with DPPA were homogeneous. We believe that the generation of
a homogeneous reaction solution contributes to the increased con-
version achieved with DPPA.
Alternative solvents such as 1,2-dimethoxyethane and 1,4-diox-
ane failed to give improved results (data not shown). Finally, we
explored increasing the number of equivalents of all three reagents
(diphenyl-2-pyridyl phosphine, DIAD, and DPPA) relative to the
substrate. A steady increase in the conversion was observed as
the equivalent was increased from two to five (entries 11–13). At
45 °C, it was found that 4 equiv of the reagents was sufficient to
drive the reaction to complete conversion after stirring overnight.
Under these conditions, tetrazole 2a could be isolated in 85% yield
following column chromatography. To conclude, the use of DPPA,
diphenyl-2-pyridyl phosphine, and DIAD (4 equiv each) in THF at
In the context of our medicinal chemistry efforts, we sought to
convert sterically hindered amides into their corresponding 1,5-
disubstituted tetrazoles using the conditions described in the liter-
ature [triphenylphosphine, diethyl azodicaboxylate (DEAD), TMS-
azide].3 Unfortunately, these conditions gave only trace amounts
of the desired tetrazoles. Conversion of the primary amide into
the (1H)-tetrazole followed by alkylation was deemed undesirable
as regiochemical mixtures of N-alkylated products are frequently
obtained. In this Letter we describe improved reaction conditions
for the generation of 1,5-disubstituted tetrazoles from amides.4,5
Isopropyl amide 1a was chosen as a model system to investigate
improved tetrazole-forming reaction conditions. We recognized
the similarity between the previously reported conditions for con-
verting an amide to a tetrazole3 to the conditions typically used in
a Mitsunobu reaction. We therefore turned to the Mitsunobu liter-
ature to guide our efforts and began by exploring a variety of phos-
phines in the place of triphenylphosphine (Table 1). Polymer-
bound triphenylphosphine failed to give the desired product even
when less sterically hindered amides were employed (entry 2). It
has been reported that electron-rich alkyl phosphine ylides are
more reactive than those generated with triphenylphosphine.6
Unfortunately, phosphines such as diphenylmethyl phosphine
gave, not surprisingly, the reduction of TMS-azide (entry 3). Elec-
tron-deficient phosphines simply gave no or trace reaction (entries
* Corresponding author. Tel.: +1 609 252 3965; fax: +1 609 252 7410.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.