Preparation of highly functionalized 1,5-disubstituted tetrazoles via palladium-catalyzed Suzuki coupling

Article abstract of DOI:10.1016/j.tetlet.2017.03.056

The preparation of a range of 1,5-disubstituted tetrazoles has been achieved through palladium-catalyzed Suzuki coupling. Using appropriately substituted 5-p-toluenesulfonyltetrazoles as substrates (obtained by cycloaddition of a substituted azide with p-toluenesulfonyl cyanide), this methodology provides access to a variety of highly substituted tetrazoles that would be difficult to access otherwise. The procedure is compatible with functional groups commonly found in drug-like molecules, and has been used to generate a number of compounds of potential biological interest.

Full text of DOI:10.1016/j.tetlet.2017.03.056

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of highly functionalized 1,5-disubstituted tetrazoles via
palladium-catalyzed Suzuki coupling
⇑
Edward J. Hennessy , Mark Cornebise, Lakshmaiah Gingipalli, Tyler Grebe, Sudhir Hande, Valerie Hoesch,
Hoan Huynh, Scott Throner, Jeffrey Varnes, Ye Wu
IMED Oncology, Innovative Medicines & Early Development, AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of a range of 1,5-disubstituted tetrazoles has been achieved through palladium-catalyzed
Suzuki coupling. Using appropriately substituted 5-p-toluenesulfonyltetrazoles as substrates (obtained
by cycloaddition of a substituted azide with p-toluenesulfonyl cyanide), this methodology provides
access to a variety of highly substituted tetrazoles that would be difficult to access otherwise. The pro-
cedure is compatible with functional groups commonly found in drug-like molecules, and has been used
to generate a number of compounds of potential biological interest.
Received 2 March 2017
Accepted 17 March 2017
Available online xxxx
Keywords:
Tetrazoles
Heterocycles
Ó 2017 Elsevier Ltd. All rights reserved.
Suzuki coupling
Biologically-active Molecules
Aromatic heterocycles are ubiquitous in synthetic compounds
designed to have biological activity, in large part due to the ability
of the heteroatoms within these ring systems to interact favorably
with functional groups in the biological target of interest. In addi-
tion, the ability to modulate the properties (such as lipophilicity,
aqueous solubility, etc.) of a scaffold through the inclusion of hete-
rocyclic rings is commonly exploited in the drug discovery process.
For example, the replacement of carbocyclic rings with hetero-
cyclic moieties in general results in quantifiably improved physical
properties, lowered risk of drug-drug interactions, and improved
overall developability.1
Amongst the heterocycles commonly encountered in medicinal
chemistry programs, tetrazoles are often used to modulate binding
affinity or physical properties of a series.2 NAH tetrazoles, by vir-
tue of the electron-deficient nature of the heterocyclic ring, are
ionized at physiological pH and are thus often employed as non-
classical carboxylic acid isosteres in the design of biologically
active compounds.3 Indeed, this ring system can be found in vari-
ous approved medicines, such as in a number of angiotensin II
receptor blockers (sartans).4
2,5-Disubstituted tetrazoles have similarly been utilized as compo-
nents of synthetic nucleotides and oligonucleotides.6
As part of a drug discovery program aimed at identifying com-
pounds with activity against a biological target of interest, we pos-
tulated that an ortho-disubstituted phenyl ring common to
compounds within the lead series could be replaced with a 1,5-dis-
ubstituted tetrazole ring, thus largely maintaining the overall
shape of the scaffold but with a substantial beneficial reduction
in lipophilicity. To test this hypothesis, we designed a series of
compounds containing such a disubstituted tetrazole ring to assess
whether this change would be compatible with the desired biolog-
ical activity. Synthetic access to many of these compounds proved
troublesome, however, as it has been established repeatedly
throughout the literature that the alkylation of NAH tetrazoles
proceeds to give mixtures of the 1,5- and 2,5-disubstituted iso-
mers, with product ratios largely dependent upon the nature of
the 5-substitutent.7 Thus, we sought a synthetic methodology that
would provide a reliable route to a variety of tetrazoles with the
desired substitution pattern.8
In devising a strategy to address this problem, we were inspired
Tetrazoles in which the carbon atom as well as one of the
nitrogen atoms are substituted have also found applications in
the construction of biologically-active motifs. For example, 1,5-dis-
ubstituted tetrazoles have been successfully employed as an
isosteric replacement for cis-amide bonds in peptidomimetics.5
by a publication from the Sharpless group describing the
regiospecific preparation of 1-substituted 5-sulfonyltetrazoles
through the cycloaddition of an organic azide with commercially
available p-toluenesulfonyl cyanide.9 This operationally-simple
reaction was shown to be high-yielding, providing access to a
relatively broad scope of substituted tetrazoles. Moreover, the
5-p-toluenesulfonyl group of these adducts can be readily
displaced by heteroatom-based nucleophiles, thus offering the
⇑
Corresponding author.
E-mail address: edward.hennessy@astrazeneca.com (E.J. Hennessy).
http://dx.doi.org/10.1016/j.tetlet.2017.03.056
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
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E.J. Hennessy et al. / Tetrahedron Letters xxx (2017) xxx–xxx
opportunity to prepare a diverse array of 1,5-disubstituted tetra-
zoles. While this methodology was useful for the construction of
some of our designed targets, we also desired compounds in which
a carbon atom was bound to the 5-position of the tetrazole ring,
which would be derived from reaction with carbon-based nucle-
ophiles. At the time of our studies, however, there were only a
few reports of the use of activated carbon nucleophiles (such as
ethyl cyanoacetate) to displace a 5-sulfonyl group from a tetra-
zole.10 In addition, an aryl Grignard reagent has similarly been
shown to undergo this reaction.11 Given the modest reported yield
of this transformation, however, along with limited functional
group compatibility expected with the use of organomagnesium
reagents, we sought an alternative method to construct carbon–
carbon bonds within this scaffold that would be more generally
applicable to a range of functionalized substrates.
While palladium-catalyzed Suzuki couplings employing 5-
chloro or 5-bromotetrazole substrates have been described in the
literature,12 preparation of these substrates typically requires mul-
tiple synthetic steps, often using reagents incompatible with
Scheme 1. Preparation of 1-phenethyl-5-p-toluenesulfonyltetrazole (1) and cou-
pling with 4-fluorophenylboronic acid to yield tetrazole 2.
Table 1
Pd-catalyzed synthesis of 1,5-disubstituted tetrazoles.
aReported yields are for analytically pure material isolated following the reaction, and unless otherwise indicated are the average of two independent
runs. bNaHCO3 used as base. cAryl or heteroarylpinacolboronate ester used instead of boronic acid. dIsolated yield from single run. eAryl potassium
trifluoroborate used instead of arylboronic acid.
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E.J. Hennessy et al. / Tetrahedron Letters xxx (2017) xxx–xxx
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Scheme 2. Preparation of a 5-methyltetrazole derivative.
Scheme 5. Intramolecular displacement of p-toluenesulfonyl group under typical
coupling reaction conditions.
less active phosphine ligands (such as triphenylphosphine) did not
afford any observable product. Since Suzuki-Miyaura couplings are
often conducted with heating under biphasic conditions in the
presence of a stoichiometric excess of base, and the aforemen-
tioned precedent for facile nucleophilic displacement of the 5-sul-
fonyl group from the tetrazole ring, we were mindful of the
possibility of hydrolysis of the substrate competing with the
desired transformation. Indeed, hydrolysis products were com-
monly observed in our initial studies and were expected to accom-
pany the desired coupling in all cases. We therefore opted to use
RuPhos (2-dicyclohexylphosphino-20,60-diisopropoxybiphenyl) in
our continued work, since the use of this ligand seemed to give
the cleanest reaction mixtures, suggestive of the most rapid
cross-coupling. Thus, heating a mixture of 5-p-toluenesulfonyl
tetrazole substrate 1, 4-fluorophenylboronic acid, potassium car-
bonate, RuPhos, and palladium (II) acetate in a mixture of 1,4-diox-
ane and water provided a high isolated yield of the desired
coupling product 2. While we did not conduct exhaustive screen-
ing to identify the most optimal ligand for this reaction in a more
general sense, the conditions we developed for this particular cou-
pling were amenable to effecting the desired transformation across
a range of substrates (Table 1). Interestingly, the commercially-
available RuPhos Pd G3 precatalyst17 was similarly effective, fur-
ther simplifying the experimental setup for conducting this trans-
formation (see Supplementary content for experimental details).
Using this methodology, a range of functionalized tetrazoles can
be prepared from the appropriate choice of starting material and
boronic acid (Table 1). Isolated yields are generally high, particu-
larly for substrates lacking highly polar moieties or suitably pro-
tected functional groups. Thioethers, which are known to often
result in inhibition of palladium-catalyzed chemistry,18 are toler-
ated albeit with significantly reduced yields (examples 7 and 8).
Similarly, sterically-encumbered tetrazoles (such as 14) or tetra-
zoles containing polar functional groups (such as 15) are accessible
in more modest yields; in some cases these diminished yields
result from low recoveries following reverse-phase HPLC purifica-
tion rather than incomplete conversion of substrate during the
reaction.
Scheme 3. Preferential Suzuki coupling at an aryl bromide.
functionality commonly present in compounds designed to be bio-
logically active. A direct arylation of 1-substituted-5-H tetrazoles
has been reported that offers an alternative approach to the
desired substitution pattern, however the scope of this methodol-
ogy appears limited to aryl iodides.13 Given the ease of preparation
of a diverse array of 5-p-toluenesulfonyl tetrazoles, and recogniz-
ing that the p-toluenesulfonyl group appended to the 5-position
is an activated leaving group, we envisioned the possibility of con-
ducting palladium-catalyzed carbon–carbon bond formation at
this center. While alkyl or arylsulfonyl groups appended to acti-
vated positions of heterocycles have found widespread use as leav-
ing groups in nucleophilic aromatic substitution reactions,14 there
are only a few reports in the patent literature of their use in palla-
dium-catalyzed cross coupling reactions.15 To assess whether or
not our approach was feasible, we conducted exploratory studies
on the Suzuki-Miyaura type coupling of 1-phenethyl-5-p-toluene-
sulfonyltetrazole (1, prepared by cycloaddition of phenethyl azide
and p-toluenesulfonyl cyanide, Scheme 1) and 4-fluorophenyl-
boronic acid as a model system.
Early in our explorations, we quickly found that a number of
biaryl phosphine ligands popularized for a range of palladium
chemistry over recent years were highly effective at promoting
the desired transformation.16 For example, ligands such as S-Phos,
BrettPhos, and RuPhos provided high conversions of the starting
sulfonyltetrazole to afford the desired product, while traditionally
Scheme 4. Coupling of 1-benzylic tetrazole substrates results in two major products.
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E.J. Hennessy et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Scheme 6. Preparation of 5-aryltetrazole-containing oxazolidinone analogs.
Both the desired transformation and the competing hydrolysis
plagued by higher amounts of competing hydrolysis, resulting in
lower isolated yields. Moreover, substrates bearing nucleophilic
heteroatoms capable of addition into the tetrazole ring may
require suitable protection to avoid intramolecular cyclization that
can occur under the reaction conditions. For example, while no
cyclization byproduct was observed in the coupling reaction to
generate compound 10, complicated reaction mixtures were
obtained in the attempted couplings of substrates poised to
undergo more geometrically-favorable cyclization to generate 5-
or 6-membered rings. Indeed, such cyclizations readily occur under
the milder reaction conditions developed for hydrolytically-sensi-
tive substrates (Scheme 5).
In line with our original motivations to develop this chemistry,
we have been able to successfully use this reaction to prepare com-
pounds of potential interest to our drug discovery programs. For
example, a series of analogs based on the oxazolidinone scaffold
common to a number of antibacterial agents19 were prepared in
high yield using this methodology (Scheme 6).
In conclusion, we have developed a novel synthetic protocol to
access a range of 1,5-disubstituted tetrazoles through palladium-
catalyzed coupling of readily-prepared 5-p-toluenesulfonyltetra-
zole substrates with boron-based nucleophiles. This methodology
is compatible with a variety of functional groups commonly found
in medicinal chemistry programs, and has been successfully
applied to the preparation of a number of compounds of potential
interest to ongoing drug discovery programs.
reaction result in the release of p-toluenesulfinate anion; this
material can be observed when monitoring reaction progress by
HPLC, and is readily removed by aqueous workup following com-
pletion of the reaction. In couplings employing more electron-defi-
cient substrates (such a 1-phenyl-substituted tetrazole 3), we
found that the competing hydrolysis reaction seemed to occur
more quickly, resulting in greater amounts of undesired side prod-
ucts. Gratifyingly, when a weaker base was used (such as NaHCO3)
in the reaction mixture, we found that while the desired coupling
proceeded more slowly, the hydrolysis of the substrate occurs to a
negligible extent thus resulting in higher yields of the desired
product.
In order to broaden the utility of this reaction, we surveyed
whether nucleophiles other than boronic acids could employed
in this transformation. We were pleased to find that the use of
pinacolboronate esters (examples 6, 12, and 13) and potassium tri-
fluoroborate salts (example 16) was well-tolerated under these
conditions, providing access to moderate to high yields of the
desired products. While we didn’t exhaustively optimize the reac-
tion parameters for non-aromatic nucleophiles, we found that the
use of trimethylboroxine under the standard reaction conditions
allowed for the introduction of a methyl group at the 5-position
in reasonable yield (Scheme 2).
Given the failure of less active catalyst systems to activate the
5-p-toluenesulfonyl group observed in our initial studies, we con-
sidered whether the judicious choice of reaction conditions would
allow for palladium-catalyzed chemistry to be conducted on other
functional groups that may be present within a substrate, while
leaving the 5-sulfonyltetrazole moiety intact. For example, Suzuki
coupling occurs exclusively at an aryl bromide moiety when
PdCl2(PPh3)2 is used as catalyst, with no reaction derived from acti-
vation of the sulfonyl group observed (Scheme 3). This selectivity
could theoretically allow for the preparation of a diverse array of
compounds based on this scaffold, with the Suzuki reaction as
the penultimate step prior to displacement of the sulfonyl group
with a suitable nucleophile.
While were able to utilize the procedure described in this paper
to prepare a variety of interesting compounds, the methodology is
not without notable limitations. In particular, presumably because
of the electron-deficient nature of 5-p-toluenesulfonyltetrazole
ring common to all substrates, this group itself can behave as a
leaving group under certain situations at the expense of the desired
chemistry occurring at the tetrazole 5-position. For example, in
attempted couplings of 5-p-toluenesulfonyltetrazoles containing
benzyl or substituted benzyl groups at the 1-position, Suzuki prod-
ucts derived from oxidative addition at both the tetrazole 5-posi-
tion (with p-toluenesulfinic acid as leaving group) as well as at
the benzylic position (with the entire 5-p-toluenesulfonyltetrazole
as leaving group) were observed (Scheme 4). Similar observations
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.03.
056.
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