A practical, one-pot synthesis of sulfonylated pyridines

Article abstract of DOI:10.1021/ol102629c

A concise and efficient one-pot synthesis of functionalized sulfonylated pyridines via an S_NAr reaction of readily available pyridines and sodium sulfinate salts in the presence of tetrabutylammonium chloride is presented.

Full text of DOI:10.1021/ol102629c

ORGANIC
LETTERS
2011
Vol. 13, No. 1
102-105
A Practical, One-Pot Synthesis of
Sulfonylated Pyridines
Kevin M. Maloney,* Jeffrey T. Kuethe,* and Kathleen Linn
Department of Process Research, Merck & Co., Inc., Rahway,
New Jersey 07065, United States
keVin_maloney@merck.com; Jeffrey_kuethe@merck.com
Received October 29, 2010
ABSTRACT
A concise and efficient one-pot synthesis of functionalized sulfonylated pyridines via an SNAr reaction of readily available pyridines and
sodium sulfinate salts in the presence of tetrabutylammonium chloride is presented.
The pyridyl sulfone moiety has proven to be a valuable
building block in both medicinal1 and agricultural chemistry.2
Sulfonylated pyridines have been shown to be anti-inflam-
matory,3 antihyperglycemic,4 and immunosuppressive5 agents
as well as inhibitors of HIV-1 reverse transcriptase.6 In
addition to their medicinal importance, sulfonylpyridines are
useful intermediates in organic synthesis7 and exhibit
interesting chemical properties.8 Due to their unique physical
properties and promising biological activities, sulfonylated
pyridines have emerged in recent years as important synthetic
targets and central pharmacophores in a large number of
biologically active medicinal agents.
The most common approach for the preparation of
sulfonylated pyridines has typically involved displacement
of a halopyridine with a thiol followed by oxidation of the
corresponding sulfide (eq 1).9 Limitations of this protocol
include the use of odoriferous thiols and problematic
oxidations that can generate large quantities of hazardous
waste.10 In addition to the high environmental burden, the
two-step protocol suffers from poor atom economy. Recently,
metal-catalyzed cross-coupling of sulfinate salts with ha-
(1) For leading references, see: (a) Furukawa, A.; Fukuzaki, T.; Onishi,
Y.; Kobayashi, H.; Matsufuji, T.; Honda, T. WO 2010082601, July 22,
2010. (b) Harris, J. M.; Neustadt, B. R.; Stamford, A.; Liu, H. WO
2010075271, July 1, 2010. (c) Smith, N. D.; Bonnefous, C.; Kahraman,
M.; Noble, S. A.; Payne, J. E.; Govek, S. P. WO 2010048149, April 29,
2010. (d) Hussain, I.; Yawer, M. A.; Lalk, M.; Lindequist, U.; Villinger,
A.; Fischer, C.; Langer, P. Bioorg. Med. Chem. Lett. 2008, 16, 9898. (e)
Galambos, J.; Keseru, G.; Gal, K.; Bobok, A. A.; Weber, C.; Prauda, L.;
Wagner, G. A. WO 2008155588, December 24, 2008. (f) Harz, R. A.;
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2006, 16, 934.
(5) (a) Nicholas, B. ; Harcken, C.; Lee, T.; Liu, P.; Mao, C.; Lord, J.;
Mao, W.; Denbush, B. C.; Razavi, H.; Sarko, C. R. WO 2009/137338,
November 12, 2009. (b) Gilligan, M.; Humphries, A. C.; Ladduwahetty,
T.; Merchant, K. J. WO 2006095205, September 14, 2006.
(6) Wassmundt, F. W. Preparation of aryl and heteroaryl compounds
having anti-retrovirus activity. WO 9206683, 1992.
(2) For leading references, see: (a) Adams, J. B. US 4456469, 1984.
(b) Taylor, J. B.; Wailes, J. S.; Jeanmart, S. A. M.; Govenkar, M. WO
2010069834, June, 24, 2010. (c) Selby, T. P.; Smith, B. T.; Stevenson,
T. M. WO 2008100426, August 21, 2008. (d) Doweyko, A. M. P.; Regis,
R. R.; Bell, A. R. US 4360677, November 23, 1982. (e) Nakagawa, T.;
Tejima, I.; Okuma, N. JP 62181260, August 8, 1987.
(7) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press:
Oxford, 1993.
(3) (a) Cheng, H.; Li, J.; Lundy, K. M.; Minich, M. L.; Sakya, S. M.;
Uchida, C. WO 01/30216, June 7, 2001. (b) Reitz, D. B.; Manning, R. E.;
Huang, H. C.; Li, J. US 5393790, February, 28, 1995.
(8) For leading references, see: (a) Hama, F.; Kondo, F. JP 61271271,
1986. (b) Sato, F.; Ogoshi, T.; Shimizu, A. JP 04120050, 1992.
(9) For a leading reference, see: Trankle, W. G.; Kopach, M. E. Org.
Process Res. DeV 2007, 11, 913.
(4) (a) Xia, Y.; Boyle, C. D.; Greenlee, W. J.; Chackalamannil, S.; Jayne,
C. L.; Stamford, A. W.; Dai, X.; Harris, J. M.; Neustadt, B. R.; Neelamkavil,
S. F.; Shah, U. G.; Lankin, C. M.; Liu, H. WO 2009055331, April, 30,
2009. (b) Asakawa, K. Sawada, N.; Tsuritani, T. Itoh, T.; Mase, T.;
Takahashi, K. Xu, F. WO 2009041475, April 2, 2009.
(10) (a) Scalone, M.; Waldmeier, F. Org. Process Res. DeV. 2003, 7,
418. (b) Yang, D.; Yip, Y. C.; Jiao, G. S.; Wong, M. K. J. Org. Chem.
1998, 63, 8952.
10.1021/ol102629c  2011 American Chemical Society
Published on Web 12/02/2010

lopyridines11 and pyridyl boronic acids12 have been reported;
however, yields are generally low (<50%) for the preparation
of sulfonylated pyridines. While the nucleophilic SNAr
reaction of activated aryl halides with sulfinic acid salts has
been reported,13 application of this protocol for the prepara-
tion of sulfonylated pyridines has been limited to a single
report which utilized microwave heating in refluxing DMSO
behind a blast shield.14 In order to fully define biological
profiles, strategies which provide rapid and efficient access
to sulfonylated pyridines are important synthetic tools. In
this paper, we describe the development of a practical, one-
pot synthesis of sulfonylated pyridines via the direct SNAr
displacement of readily available chloropyridines with
sulfinic acid salts.
of 3 in analytically pure form was achieved by addition of
water at the end of the reaction and filtration of the resulting
slurry to give analytically pure 3 avoiding the need for
chromatography.
Having identified optimal conditions for the sulfonylation
of chloropyridine 1, we set out to explore the scope and
generality of the procedure. As shown in Table 1, electron-
Table 1. Sulfonylation of Electron-Deficient Chloropyridines
Our investigations began by examining the preparation of
sulfonylpyridine 3 (eq 2). After conducting a thorough
catalysis screen exploring Pd sources, Cu sources, ligands,
additives, and solvents, we observed that tetrabutylammo-
nium chloride (TBACl) as an additive11a and dimethylac-
etamide (DMAc) as solvent afforded moderate yields of 3
irrelevant of the metal source or ligand. Intrigued by these
results, we decided to explore the feasibility of a simple
phase-transfer-catalyzed (PTC) SNAr approach to pyridine
3. As shown in eq 2, simply heating chloropyridine 1 with
sulfinate 215 in the presence of a catalytic amount TBACl
in DMAc at 100 °C for 3 h afforded pyridine 3 in 93%
isolated yield.16 In the absence of TBACl, conversion was
<20% at the same time point.17 We speculated that the
significant rate increase in the presence of TBACl could be
explained by the formation of n-Bu4NSO2Tol from TBACl
and NaSO2Tol.18,19 In order to probe this possibility, we
prepared n-Bu4NSO2Tol and subjected it to the reaction with
1. This gave complete conversion to 3. The fact that
n-Bu4NSO2Tol is more soluble than NaSO2Tol in DMAc
nicely accounts for the increased reaction rates.20 Isolation
(11) (a) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M.; Bernini,
R. J. Org. Chem. 2004, 69, 5608. (b) Zhu, W.; Ma, D. J. Org. Chem. 2005,
70, 2696.
(12) (a) Kar, A.; Sayyed, I. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.;
Tse, M. K. Org. Lett. 2007, 9, 3405. (b) Huang, F.; Batey, R. A. Tetrahedron
2007, 63, 7667.
a Isolated yields.
(13) Ulman, A.; Urankar, E. J. Org. Chem. 1989, 54, 4691.
(14) Zou, J.; Feng, L.; Feng, G. T. Chin. J. Chem. 2009, 20, 17.
(15) Both commercially available sodium p-toluenesulfinate and sodium
p-toluenesulfinate hydrate could be employed with equal success.
(16) DMAc was found to be the superior solvent for this reaction;
nonpolar aprotic solvents resulted in no reaction.
deficient chloropyridines afforded an array of highly func-
tionalized sulfonylated pyridines in excellent yields. Of
particular importance is entry 5, where the inherently less
reactive 3-postion of 12 underwent successful sulfonylation.
Attempts to apply our standard procedure (A) to electron-
neutral chloropyridines proved unsuccessful as shown in
(17) For a related transformation on a chloropyridine in the absence of
TBACl, see: Caron, S.; Do, N. M.; Sieser, J. E.; Whritenour, D. C.; Hill,
P. D. Org. Process Res. DeV 2009, 13, 324.
(18) Vennstra, G. E.; Zwaneburg, B. Synthesis 1975, 519
.
(19) The solubility of sodium p-toluenesulfinate in DMAC at rt was
measured to be 1.0 mg/mL and at 100 °C was 1.5 mg/mL by HPLC anal-
ysis.
(20) N-Bu4NSO2Tol was completely soluble in DMAc at 100 °C.
Org. Lett., Vol. 13, No. 1, 2011
103

Table 2. Sulfonylation of Electron-Neutral or -Rich
Table 3. Sulfonylation of Nitrogen Heterocycles
Chloropyridines
a Isolated yields.
entry 1 (Table 2). Realizing we needed to activate the
pyridine ring for SNAr displacement, we explored the
possibility of an acid-promoted sulfonylation. After screening
several acids, we discovered that addition of 1 equiv of concd
HCl to our standard reaction conditions facilitated the
reaction of electron-neutral chloropyridines presumably via
protonation of the pyridine nitrogen (entry 1).21 With a
modified procedure in hand (procedure B), electron-neutral
chloropyridines 18 and 20 were successfully sulfonylated to
give 19 and 21 in excellent yields. In the case of 3-chloro-
pyridine 22 (entry 4), no identifiable product was obtained
and represents the only limitation to the present methodol-
ogy.22 Even more exciting was the successful sulfonylation
of the electron rich chloropyridine 24 to give 25 in 88% yield
as shown in entry 5. In should be mentioned that under the
acidic conditions of procedure B we identified small amounts
of ester 2623 as a byproduct.
a Isolated yields.
the sulfonylation with respect to other halopyridines, het-
erocycles, and sulfinate salts. As shown in entries 1-3 (Table
3), the sulfonylation worked equally as well with iodopy-
ridines, bromopyridines, and pyridine triflates to afford the
products in good to excellent yield. However, in the case of
triflate 31, we did observe ca. 15% hydrolysis to give the
corresponding 2-hydroxypyridine by product. It should be
mentioned that hydrolysis was not seen in any of the
(21) While protonation of sodium p-toluenesulfinate is a possibility in
the presence of HCl, the fact that these reactions proceed to completion
and in high yield suggest that protonation of the pyridine nitrogen is
faster.
(22) 3-Bromopyridine, 3-fluoropyridine, and 3-iodopyridine also failed
to react with sulfinate 2.
(23) For the preparation of compound 26 under similar conditions, see:
(a) Smiles, G. J. Chem. Soc. 1924, 125, 181. (b) Freeman, F.; Bartosik,
L. G.; Van Bui, N.; Keindl, M. C.; Nelson, E. L. Phosphorus Sulfur 1988,
53, 375.
Having identified general conditions for the sulfonylation
of a variety of chloropyridines, we investigated the scope of
104
Org. Lett., Vol. 13, No. 1, 2011

Alternatively, sulfonylation of dichloropyridine 41 afforded
exclusively the monosulfonylated pyridine 42 in 91% yield
(entry 2). Analysis of the crude reaction mixture by both
HPLC and 1H NMR analysis revealed no detectable sign of
the expected disulfonylated pyridine. In a similar fashion,
reaction of dichloropyridines 43 and 45 also gave the
monosulfonylated pyridines 44 and 46 as the exclusive
products in excellent yields. In stark contrast to entry 5 of
Table 1 bearing similar activation products 42, 44, and 46,
this reaction remained resistant to further displacement of
the second chlorine atom even upon prolonged heating.
Mechanistically, this suggested that the sulfonyl group at C-2
(entries 2 and 3, Table 4) and C-4 (entry 4, Table 4) is more
reactive toward SNAr than the chloro substituent. Therefore,
the monosulfonylated products are continually reacting at
C-2 and C-4 and never at the carbon bearing the second
chlorine atom. To support this hypothesis, we subjected
sulfonylated pyridine 11 to our standard sulfonylation
conditions with a different sulfinate salt as shown in eq 3.
As predicted, MeSO2Na underwent addition at the C-2
sulfonyl group to give sulfonylated pyridine 47 in >95%
conversion.
Table 4. Sufonylation of Dichloropyridines
a Isolated yields.
halopyridines cases. As shown in entries 4 and 5 (Table 3),
we were able to extend the methodology to other nitrogen
heterocycles. Chloropyrazine 33 afforded the desired sulfone
34 in 90% yield under our standard conditions. Interestingly,
subjecting chloroquinoline 35 to general procedure B af-
forded predominantly the hydrolysis by product 2-hydrox-
yquinoline. However, switching to anhydrous HCl instead
of concd HCl reduced the hydrolysis product from 70% to
<8% and afforded the desired sulfone 36 in 90% isolated
yield. Finally, we explored the sulfonylation procedure
utilizing other sodium sulfinate salts. As shown in entries 6
and 7, our sulfonation procedure afforded methyl sulfone
37 and p-chlorophenyl 38 in 80% and 90% yields, respec-
tively.24
In conclusion, a concise, one-pot protocol has been
developed for the rapid preparation of highly functionalized
sulfonylated pyridines. This efficient and high-yielding
procedure is operationally simple and generally requires no
chromatographic purification. The use of TBACl imparts a
significant rate acceleration through the in situ formation of
n-Bu4NSO2Tol. From a mechanistic standpoint, displacement
of the sulfonyl group is a continuous process and potentially
allows for a switchable procedure to evaluate alternative
sulfonyl moieties. Finally, the method is safe, scalable, and
significantly greener than current alternatives.
Acknowledgment. We thank Dr. Jingjun Yin (Merck &
Co., Inc.) for valuable experimental assistance.
Next, we set out to explore the reactivity of several
dichloropyridines utilizing general procedure B. As shown
in Table 4, treatment of dichloropyridine 39 with 3 equiv of
sulfinate 2 afforded disulfonylated pyridine 40 in 92% yield.
Supporting Information Available: Experimental details
and characterization of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) Although not investigated in the present study, the methodology
should be applicable to other types of alkyl and aryl sulfinate salts.
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