Simple sulfinate synthesis enables C-H trifluoromethylcyclopropanation

Article abstract of DOI:10.1002/anie.201406622

A simple method to convert readily available carboxylic acids into sulfinate salts by employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent, TFCS-Na. The reactivity of six of these salts towards C-H functionalization was field-tested using several different classes of heterocycles.

Full text of DOI:10.1002/anie.201406622

Angewandte
Chemie
DOI: 10.1002/anie.201406622
CÀH Functionalization
À
Simple Sulfinate Synthesis Enables C H
Trifluoromethylcyclopropanation**
Ryan Gianatassio, Shuhei Kawamura, Cecil L Eprile, Klement Foo, Jason Ge, Aaron C. Burns,
Michael R. Collins, and Phil S. Baran*
In memory of Carlos F. Barbas, III
Abstract: A simple method to convert readily available
carboxylic acids into sulfinate salts by employing an inter-
rupted Barton decarboxylation reaction is reported. A medic-
inally oriented panel of ten new sulfinate reagents was created
using this method, including a key trifluoromethylcyclopropa-
nation reagent, TFCS-Na. The reactivity of six of these salts
towards CÀH functionalization was field-tested using several
different classes of heterocycles.
T
he decoration of CÀH bonds on heteroarenes by using
radicals generated from sulfinate salts has emerged as
a predictable and chemoselective method for both the early
[1]
and late stages of a synthesis, for the prediction and
[
2]
prevention of drug metabolism, and for the native chemical
[
3]
tagging of complex molecules. In a recent report, a sulfinate
salt was used to append a trifluoromethyl group onto (À)-
agelastatin A, which led to the synthesis of the most potent
[
4]
derivative of this natural product. The surging commercial
demand for sulfinate reagents pointed to a clear drawback in
that only a limited set are currently available. In contrast to
their more widely available relatives, carboxylic acids, sulfi-
nates have a significantly weaker energy barrier for homolysis
leading to alkyl radicals (as judged by bond dissociation
energies (BDEs), Scheme 1A). The relatively weak CÀS
bond in sulfinates makes them ideal radical precursors as
compared to carboxylic acids, which often require strong
oxidants, heat, light, specialized transition-metal catalysts, or
further functionalization. Herein, we report a simple pro-
cedure for the conversion of a variety of carboxylic acids into
Scheme 1. A) Logic behind the conversion of carboxylic acids into
sulfinates; ubiquitous but less reactive carboxylic acids could be used
as precursors to rare but useful sulfinates. B) The “interrupted” Barton
reaction allows for the development of a high-value reagent for the
introduction of isosteric units for medicinal chemistry. CSA=camphor-
sulfonic acid.
[5]
[*] R. Gianatassio, Dr. S. Kawamura, C. L. Eprile, Dr. K. Foo, J. Ge,
Prof. Dr. P. S. Baran
Department of Chemistry, The Scripps Research Institute
sulfinate salts, thus enabling the direct synthesis of a variety of
important bioisosteres and setting the stage for significant
expansion of the commercially available sulfinate toolkit.
The invention of a route to sulfinate salts from carboxylic
acids was actually prompted by a recent report from a research
group at Novartis, where the trifluoromethylcyclopropyl
group was found to function as a metabolically stable
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: pbaran@scripps.edu
Dr. A. C. Burns, Dr. M. R. Collins
Department of Chemistry, Pfizer Pharmaceuticals
La Jolla Laboratories
1
0770 Science Center Drive, La Jolla, CA 92121 (USA)
**] Financial support for this work was provided by the NIH/NIGMS
GM-106210), Sigma–Aldrich, Inc., Pfizer, Inc., Uehara Memorial
[
(
[6]
replacement for a tert-butyl moiety. The introduction of
Foundation (postdoctoral fellowship for S.K.), and A*STAR (pre-
doctoral fellowship for K.F.). We are grateful to Prof. A. L. Rheingold
and Dr. C. E. Moore (UCSD) for X-ray crystallographic analysis, Dr.
D.-H. Huang and Dr. L. Pasternack for assistance with NMR
spectroscopy, and M. A. Ornelas for technical assistance.
this group was problematic, and the reported method requires
a multistep synthesis (using diazomethane), thus making it an
excellent candidate for a CÀH functionalization strategy
using sulfinates. The commercial availability of acid 1 con-
veniently allowed us to determine if it was even necessary to
invent such a reagent bearing this motif (2). As shown in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406622.
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Scheme 1B, classic Minisci conditions were screened using
a variety of acids and temperatures with caffeine as the test
substrate, and no product (2A) was detected by LC/MS.
These findings are consistent with our previous studies, where
Minisci conditions generally fail when using fluorinated
at 608C, significant amounts of 2 A were observed by LC/MS.
After screening various solvents and temperatures, a mixture
of diethyl carbonate and water (3:2) at 908C led to a 71%
yield of 2 A after only one hour. The elevated temperature
relative to other sulfinate additions is presumably required
to generate the radical and forge the quaternary carbon
center.
As illustrated in Table 1, this procedure for the net
conversion of carboxylic acids into sulfinate salts is simple and
general. The sequence involves only one isolated intermedi-
ate (sulfone), with the intermediate Barton ester carried on
crude after aqueous workup, and the rearranged sulfide
[
1]
[
1]
acids. We then turned to Bartonꢀs classic work on visible
light mediated photolytic radical formation from O-esters of
[7]
thiohydroxamic acids. Acid 1 was converted into ester 3,
which was subjected to Bartonꢀs conditions for the generation
of alkyl radicals and a Minisci-type addition in the presence of
[8]
a Brønsted acid. Although we were able to reproduce the
reported addition of an adamantyl radical to caffeine, the
identical conditions using 3 as the radical donor in either
DMF or CH Cl led to less than 1% conversion by LC/MS.
submitted directly to the RuCl -catalyzed oxidation. Ten
3
different sulfinate reagents were prepared using this route
and ranged in structural complexity, fluorine content, and
2
2
Further analysis by LC-MS showed that the attempted
homolysis of 3 led to small quantities of thiopyridyl substrate
[
9]
heteroatom presence.
4
, an intermediate that represented a possible pathway to
In addition to TFCS-Na 2, several other salts may find use
in medicinal chemistry programs (Table 2). It is important to
note that difluorinated congeners of common cyclic ethers
were synthesized as isosteric replacements of oxygen (e.g.,
14). Azetidine 23 could be used to increase the solubility of
medicinally relevant compounds, and removal of the Boc
group could lead to further derivatization. Other sulfinates
such as 17, 20, and 29 contain motifs popular in medicinal
sulfinate 2. After extensive solvent screening, ethyl acetate
was found to be the optimal medium to obtain synthetically
useful yields of 4. This empirical finding is useful given the
reported inefficiency of the “interrupted” Barton decarbox-
ylation on small-sized ring systems.
using RuCl was facile and cleavage of pyridine with NaOEt
led to the coveted trifluoromethylcyclopropyl sulfinate salt in
7
lography, CCDC 1010780). To our delight, when caffeine was
[7o–q]
Subsequent oxidation
3
[
10]
5% yield (TFCS-Na, 2, structure verified by X-ray crystal-
chemistry and they were selected for commercialization.
As such, their synthesis was conducted on multigram scales.
exposed to sulfinate salt 2 (3.0 equiv) and TBHP (5.0 equiv)
[
a]
Table 1: Conversion of readily available carboxylic acids into sulfinate reagents.
[
a] Conditions: carboxylic acid (1 equiv), (COCl) (1.5 equiv), DMF (0.1 equiv), 0 to 238C; 250 W or 600 W tungsten lamp, EtOAc; RuCl (5 mol%),
2
3
NaIO (6 equiv), EtOAc/H O; NaOEt (1.1 equiv), DMA, 0 to 308C or NaSEt, THF, 0 to 238C. Boc=tert-butoxycarbonyl, DMA=N,N-
4
2
dimethylacetamide.
2
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[
a]
Table 2: Reactions of newly designed sodium alkanesulfinate salts and heteroarenes.
[a] Reactions were performed on a 0.1 or 0.2 mmol scale. Standard conditions: Heterocycle (1 equiv), sulfinate salt (3 equiv), tert-butyl hydroperoxide
(
TBHP, 5.0 equiv), 0 to 908C. Yields of chromatographically pure products are displayed. [b] Sigma–Aldrich Catalog number. [c] 6.0 equiv of the
sulfinate salt and 10 equiv of TBHP were used.
The CÀH functionalization of four different classes of
heterocycles A–D was explored with these six newly com-
mercialized sulfinate salts (Table 2). All of these sulfinates
gave products in good to moderate yields. As can be expected
with sulfinate chemistry, these reactions are conducted
under air, in the presence of water, and without using
transition metals, which makes them very practical and
operationally simple. Similarly to 1 (Scheme 1B), standard
Minisci reaction conditions were screened with caffeine
and can be converted into other functional groups such as
sulfonamides.
[13]
This method compares well with other state-of-the-art
routes to introduce medicinally important functional groups
onto heteroarenes. For example, sulfinate salt 14 allows for
the facile attachment of a difluorinated isostere of a tetrahy-
dropyran ring onto a heterocycle, which would otherwise
require four steps to install starting from the corresponding
[
1]
[
14]
carboxylic acid.
Another method to directly append
(
RCO H, AgNO , (NH ) S O , and H SO in H O at 908C)
tetrahydropyran, tetrahydrofuran, azetidine, and cyclobutane
rings onto heteroarenes has been developed by Molander and
co-workers. Also, a trifluoropropyl group can be incorpo-
2
3
4
2
2
8
2
4
2
using 12, 15, 18, 21, and 27, but zero or slight conversion (less
than 5%) was observed.
[
11]
[15]
Although we only tested the
potential of some of these new salts for CÀH functionaliza-
rated into a heteroarene through a condensation reaction with
4,4,4-trifluorobutanal, 2-oxopropanal, and ammonium hy-
[12]
tion, sulfinate salts have shown reactivity in cross-coupling
[16]
droxide.
However, the only method to directly append
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[
[
2
Scheme 2. Comparison of conventional and CÀH functionalization
routes to 35. Reagents and conditions: 36 (1 equiv), 2 (3.0 equiv), tert-
butylhydroperoxide (TBHP, 5.0 equiv), 0 to 908C; then 2-bromo-5-
cyanopyridine (1.1 equiv), [Pd(PPh ) ], DME/H O (3:1), reflux. Reac-
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dioxaborolane, DME=dimethoxyethane.
2
720.
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achieved using sulfinate radical chemistry.
Lastly, our attention was turned to one of the highlighted
[6]
substrates in the Novartis report: bispyridine 35 (Scheme 2).
The reported synthesis started from 33, a compound with
limited availability but easily prepared from 2,5-dibromopyr-
idine. Three steps are required to convert 33 into the
trifluoromethylcyclopropylpyridine 34. A final (presumably
unoptimized) Suzuki coupling proceeded in 3% yield to
furnish 35. In stark contrast, commercially available pyridine
3
6 bearing a C-3 boron functionality could be trifluorome-
thylcyclopropanated using 2 to chemoselectively furnish 37.
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purification in a Suzuki coupling to afford 35 in a 37% yield of
the isolated product over the two-step, one-pot operation.
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classic Barton chemistry. Several of these salts were commer-
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[
oxidant, simple solvent, and no metals) is a clear advantage
over other radical donors. Judging from the demonstrated
utility of these and other sulfinate salts at Pfizer, we anticipate
their rapid adoption for use in drug discovery.
6
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Received: June 26, 2014
Published online: && &&, &&&&
Keywords: analogue synthesis · bioisosteres ·
.
CÀH functionalization · heterocycles · sulfinate salts
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Communications
Communications
CÀH Functionalization
An interrupted Barton decarboxylation
reaction has been used to convert readily
available carboxylic acids into sulfinate
salts (see scheme). Ten new sulfinate
reagents were created and the reactivity
of six of them towards CÀH functionali-
R. Gianatassio, S. Kawamura, C. L. Eprile,
K. Foo, J. Ge, A. C. Burns, M. R. Collins,
P. S. Baran*
&&&& — &&&&
Simple Sulfinate Synthesis Enables CÀH
zation was tested on a range of hetero-
cycles. The simplicity of this approach (a
cheap industrial oxidant, simple solvent,
and no metals) is a clear advantage over
other radical donors.
Trifluoromethylcyclopropanation
6
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