Copper-mediated n-heteroarylation of primary sulfonamides: Synthesis of mono-n-heteroaryl sulfonamides

Article abstract of DOI:10.1021/ol100263r

"Figure Presented" We describe the coupling of primary sulfonamides and various halogenated heterocyclic cores, with an emphasis on 2-heteroaryl halides, via copper catalysis. These studies enabled the synthesis of many new mono-N-heteroaryl sulfonamides.

Full text of DOI:10.1021/ol100263r

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1532-1535
Copper-Mediated N-Heteroarylation of
Primary Sulfonamides: Synthesis of
Mono-N-heteroaryl Sulfonamides
Jonathan Baffoe, Madelene Y. Hoe, and B. Barry Toure´*
NoVartis Institutes for Biomedical Research, Inc. Oncology, Global DiscoVery
Chemistry, 250 Massachusetts AVenue, Cambridge, Massachusetts 02139
barry.toure@noVartis.com
Received February 1, 2010
ABSTRACT
We describe the coupling of primary sulfonamides and various halogenated heterocyclic cores, with an emphasis on 2-heteroaryl halides, via
copper catalysis. These studies enabled the synthesis of many new mono-N-heteroaryl sulfonamides. The electronic factors that influence the
course of the reaction have also been investigated.
The sulfonamide functional group is a key feature in drug
design. It is encountered in a multitude of marketed drugs
and countless drug candidates.1 During the course of a lead
optimization process, we became interested in attenuating
the pKa of primary sulfonamides via N-heteroarylation
(sulfonamides as carboxylic acid isosteres) (Figure 1). We
sought a broad, practical, and predictable route to this class
of targets based on the union of primary sulfonamides and
Figure 1. An example of an N-heteroaryl sulfonamide drug.
heteroaryl halides (with an emphasis on 2-heteroaryl halides
to accentuate electron withdrawing effects) via metal ca-
talysis.
studies. The mono-N-heteroarylation of primary sulfonamides
using a small set of heteroaryl halides has been achieved
under palladium-catalyzed conditions.4 However, the results
were highly variable, and differences in reactivity between
The challenges inherent to the catalytic reaction of basic
heteroaromatic reagents have been outlined by Shen and
Hartwig, who have introduced a route for their use in
palladium-catalyzed N-heteroarylation reactions based on the
precomplexation with triethyl borane.2 The N-amidation of
a series of unmasked heteroaryl donors with palladium as
well as copper catalysts has also been described by the
Buchwald group.3 However, 2-heteroaryl halides, with the
exception of 2-halo thiophenes, were not included in these
(3) Paladium catalyst: (a) Ikawa, T.; Barder, T. E.; Biscoe, M. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 13001–13007. (b) Fors,
B. P.; Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. Tetrahedron 2006, 62,
6042–6049. (c) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727–7729. (d) Klapars, A.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421–7428. (e) Enguehard-
Gueiffier, C.; Thery, I.; Gueiffier, A.; Buchwald, S. L. Tetrahedron 2009,
65, 6576–6583.
(1) See the table of sulfonamide drugs in: (a) Smith, D. A.; Jones, R. M.
Curr. Opin. Drug DiscoVery DeV. 2008, 11, 72–79. (b) Also see ref 8 for
other medicinal uses of sulfonamides.
(2) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734–7735.
(4) (a) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org, Lett. 2003, 23, 4373–
4376. (b) Steinhuebel, D.; Palucki, M.; Askin, D.; Dolling, U. Tetrahedron
Lett. 2004, 45, 3305–3307. (c) Anjanappa, P.; Mullick, D.; Selvakumar,
K.; Sivakumar, M. Tetrahedron Lett. 2008, 49, 4585–4587.
10.1021/ol100263r  2010 American Chemical Society
Published on Web 03/02/2010

heterocyclic cores, the nature of the halide, and/or its position
on the ring have been observed. The copper-catalyzed mono-
N-arylation of primary sulfonamides is known;5 however,
the use of heteroaryl donors in these reactions still remains
uncharted ground,6 and the potential for product inhibition
is a major concern.7 Indeed, the conjugate base of the
N-heteroarylation product, formed easily as a result of the
increased acidity of the sulfonamide NH, may form a stable
complex with the catalyst, thus impeding its turnover.7b In
general, a N-heteroarylation procedure that covers a broad
spectrum of heteroaryl halides (many have not been explored)
is still needed.
Table 1. Reaction Scope with Respect to Heteroaryl Halides
The recent mechanistic insights that enabled the Hiyama
and Suzuki couplings of 2-pyridyl nucleophiles,8 along with
the N-amidation works reported in the literature,3 gave us
greater confidence that copper catalysts may be applied for
the N-sulfonamidation of 2-heteroaryl halides.9 We also
believed that a solution to the coupling of this capricious
subclass of heteroaryl donors may be broadly applicable to
other systems. Herein, we detail the reduction of these
hypotheses to practice.
We initiated our investigations by examining conditions
under which 4-toluene sulfonamide and 2-bromopyridine
can be coupled. We examined the effect of ligand, base,
solvent, and copper salts.10 The initial screening experi-
ments were performed in dioxane with CuI (5 mol %),
and cesium carbonate as base, and the best parameter was
included in the next round of optimization. We observed
(5) For the coupling between aryl boronic acids and sulfonamides see:
(a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron
Lett. 1998, 39, 2933–2936. (b) Combs, A. P.; Rafalski, M. J. Comb. Chem.
2000, 2, 29–32. (c) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. For the coupling of
aryl halides and sulfonamides under the classic Goldberg reaction conditions
see: (d) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385–3386. For
examples of catalytic coupling of aryl halides and sulfonamides see: (e)
Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett.
2004, 45, 2311–2315. (f) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-
X. Tetrahedron Lett. 2005, 46, 7295–7298.
(6) During the course of the preparation of this manuscript, the coupling
of pyridine derivatives and sulfonamides was reported: Han, X. Tetrahedron
Lett. 2010, 51, 360–362.
(7) For examples of use of 2-aminopyridine as ligands in copper
catalysis, see: (a) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A.
J. Am. Chem. Soc. 2000, 122, 5043–505. For an example of product
inhibition associated with the use of primary sulfonamides see: (b) Toto,
P.; Gesquiere, J.-C.; Cousaert, N.; Deprez, B.; Willand, N. Tetrahedron
Lett. 2006, 47, 4973–497. For an example of sulfonamide chromium ligand
see: (c) Liu, X.; Henderson, J. A.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc.
2009, 131, 16678–16680.
a Isolated yield after silica gel chromatography. b Reaction was heated
to 130 °C. c Purified by tritutation.
(8) CuI as additives in the Hiyama and Suzuki cross-coupling of
2-borono and trimethylsilane pyridine, see: (a) Pierrat, P.; Gros, P.; Fort,
Y. Org. Lett. 2005, 7, 697–700. (b) Jones, N. A.; Antoon, J. W.; Bowie,
A. L., Jr.; Borak, J. B.; Stevens, E. P. J. Heterocycl. Chem. 2007, 44, 363–
367. (c) Deng, J. Z.; Paone, D. V.; Ginetti, A. T.; Kurihara, H.; Dreher,
S. D.; Weissman, S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11,
345–347. (d) Gutz, C.; Lutzen, A. Synthesis 2010, 1, 85–90.
that glycine,11 N,N′-dimethylethane-1,2-diamine, and trans-
N,N′-dimethylcyclohexane-1,2-diamine12 ligands afforded
the desired product in 5%, 20%, and 26% yield, respec-
tively. Phenanthroline,13 2-pyrrole carboxylic acid,14 and
(benzotriazol-1-yl)methanol15 ligands did not afford any
(9) For recent reviews on copper catalysis, see: (a) Monnier, F.; Taillefer,
M. Angew. Chem., Int. Ed. 2009, 48, 6954–6971. (b) Carril, M.; SanMartin,
R.; Dominguez, E. Chem. Soc. ReV. 2008, 37, 639–647. (c) Ma, D. W.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450–1460. (d) Kienle, M.; Dubbaka,
S. R.; Brade, K.; Knochel, P. Eur. J. Org. Chem. 2007, 4166–4176. (e)
Frlan, R.; Kikelj, D. Synthesis 2006, 2271–2285. Corbet, J.-P.; Mignani,
G. Chem. ReV. 2006, 106, 2651–2710. (f) Beletskaya, I. P.; Cheprakov,
A. V. Coord. Chem. ReV. 2004, 248, 2337–2364. (g) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449. (h) Kunz, K.; Scholz,
U.; Ganzer, D. Synlett 2003, 2428–2439.
(11) Ma, D. W.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453–2455.
(12) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684–11688.
(13) (a) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2657–2660. (b) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem.
1999, 64, 670–674.
(14) Altman, R. A.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2008, 73, 5167–5169.
(10) The screening results are summarized in Table 1 in the SI.
Org. Lett., Vol. 12, No. 7, 2010
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products. Many bases including K3PO4 (24%), Cs2CO3
(26%), NaH (19%), KOH (22%), Et3N (15%), and
LiHMDS (16%) can be used in the reaction; the best result
was obtained with K2CO3 (38%). A variety of copper salts
can effect this transformation (Cu(OAc)2, CuBr,
Cu(CF3SO3)2, CuO, afforded the desired product in 21%,
24%, 33%, and 34% yield, respectively), but CuI (38%)
was selected for the subsequent optimization studies.
Finally, the reaction can be performed in dioxane (21%),
DMSO (23%), DMA (19%), and toluene (17%). Superior
results were observed with DMF (43%). Further optimiza-
tion of the reaction parameters (stoichiometry of reagents,
concentration, temperature, time, data not shown) resulted
in marginal improvement, and ultimately increasing
catalyst loading to 15 mol % was essential to achieve
complete conversion. This optimal procedure closely
mirrors the copper-catalyzed N-arylation conditions previ-
ously described in the literature.3c-e
Table 2. Reaction Scope with Respect to Sulfonamides
With these successful conditions in hand,16 we explored
the generality of this copper coupling process. The results
are summarized in Table 1. 2-Bromopyridine was coupled
to 4-toluene sulfonamide in 75% yield (entry 1). This
reaction can also be performed under microwave condi-
tions, although we noted a slight decrease in the yield
(data not shown). To increase the acidity of the newly
formed sulfonamide in this series, electron-withdrawing
groups (EWGs) were attached to the pyridine ring.
2-Bromo-5-nitropyridine yielded product 5 in 72% yield
(entry 2). Similarly, product 6 was obtained in 91% yield
when methyl 6-bromonicotinate was used as the aryl donor
(entry 3). The latter result represents a clear improvement
over the use of 2-bromopyridine (entry 1), and indicates
that the modulation of the pKa of the NH (product) through
the use of EWGs does not negatively impact the perfor-
mance of the catalyst. Next, we explored the use of more
electron deficient heteroarene cores starting with 2-bro-
moquinoline, which afforded the corresponding product
7 in 65% yield (entry 4). 2-Bromopyrazine also underwent
coupling with 4-toluene sulfonamide to afford the expected
product 8 in 41% yield (entry 5). Switching to 2-iodopy-
razine resulted in a marginal improvement of the yield of
the reaction (50%, entry 5). In both cases, the halide
starting materials were completely consumed. We also
confirmed that the low coupling yield was not due to
product stability issues (8 was quantitatively recovered
upon heating under the reaction conditions for 20 h).
Taken together, these results suggest that product inhibi-
a Isolated yield after silica gel chromatography. b Percent conversion
as determined by HPLC.
tion was not significantly operative. Thus, the lower yield
of the reaction may be attributed to the instability of the
heteroaryl-metal catalytic intermediates.17 The origin of
this instability appears to be of electronic nature; the more
electron deficient the heteroarene, the higher the instability
(entry 1 versus entry 5). This experimental observation
may be applied predictively. For instance, the yield of
the coupling process declined further when 2-bromopy-
rimidine was employed as aryl donor (35%, entry 6). In
contrast, 5-bromopyrimidine afforded the coupling product
in 60% yield (entry 7). Thus, for heteroarenes that are
less electron deficient than pyrazine and pyrimidine,
copper may prove a judicious choice of catalyst. In the
5-membered azole series, 4-bromo-1-methylpyrazole af-
forded 60% yield of the coupling product 11 (entry 8). In
this instance, the reaction was perfomed at 130 °C to
ensure complete conversion of the bromide starting
material. Benzothiazole derivatives, represented by 2-bro-
mobenzothiazole, are tolerated under the reaction condi-
tions (64%, entry 9). The product of this reaction was
purified by trituration to circumvent potential issues of
(15) Verrna, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C.
Angew. Chem., Int. Ed. 2009, 48, 1138–1143.
(16) Typical experimental procedure: A dry vial was cooled to rt under
nitrogen, and was charged with copper(I) iodide (43.0 mg, 0.23 mmol),
potassium carbonate (415 mg, 3.0 mmol), and p-toluene sulfonamide (257
mg, 1.50 mmol). Dry DMF (10 mL) was added, followed by ligand 1 (0.071
mL, 0.45 mmol) and 2-bromopyridine (286 mg, 1.80 mmol). The resulting
blue suspension was stirred at rt for 5 min, then heated to 100 °C for 16 h.
The reaction mixture was then cooled to rt, diluted with ethyl acetate (75
mL), then transferred to a separatory funnel and washed with 10% aqueous
ammonium chloride. The aqueous phase was extracted with ethyl acetate
(3 times 60 mL). The combined organic phases were washed with water (3
times 75 mL) and brine then dried over magnesium sulfate. All the volatiles
were evaporated, and the resulting residue was purified by silica gel
chromatography with a DCM/MeOH gradient.
(17) Recent experimental and theoretical studies have indicated that the
rate-determining step of the arylation of amides with copper is the oxidative
addition. We assumed that a similar reaction mechanism is operative: (a)
Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 4120–4125. (b) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organo-
metallics 2007, 26, 4546–4554. (c) Strieter, E. R.; Bhayana, B.; Buchwald,
S. L. J. Am. Chem. Soc. 2009, 131, 16720–16734.
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Org. Lett., Vol. 12, No. 7, 2010

tautomerization.18 Thiazole and oxazole derivatives failed
under the reaction conditions (entries 10 and 11).
In summary, we have investigated the coupling of primary
sulfonamides and 2-heteroaryl halides. The procedure is
broadly applicable to other heterocyclic systems, and allowed
access to many novel N-heteroaryl sulfonamides that will
be difficult to access otherwise. The predictability of this
method is a significant advantage over the reported pal-
ladium-catalyzed protocols. However, the limitations of this
methodology are also apparent (oxazole and thiazoles deriva-
tives failed, while the highly electron deficient heteroarenes
are low yielding). The effective N-sulfonamidation of these
heteroarenes may require the development of even milder
reaction conditions.
We also explored the generality of the reaction with respect
to the sulfonamide component. As shown in Table 2, 2-tolyl
sulfonamide, a sterically hindered substrate, is tolerated under
the reaction conditions (65%, entry 1). Phenyl methane-
sulfonamide, bearing R-acidic protons, also performed well
(74%, entry 2). The smaller aliphatic methylsulfonamide
underwent coupling with 2-bromopyridine in moderate yield
(62%, entry 3). Camphor sulfonamide can also be employed
in the reaction without the need to protect the ketone
functionality (84%, entry 4). In this instance, the bis-arylation
biproduct was also isolated in 9% yield. Finally, we also
observed that aliphatic sulfinamides, exemplified by Ellman’s
auxiliary,19 can be used under the reaction conditions. This
exciting preliminary result opens the door to the rapid
synthesis of many aryl and heteroaryl amines from their
halide precursors by exploiting the relative lability of the
Ellman’s auxiliary after the coupling process (Ellman’s
auxiliary as ammonia surrogate). Additionally, this offers an
alternative strategy for further fine-tuning the pKa of the
sulfonamide NH while allowing for chiral discrimination.
Acknowledgment. We thank the Novartis Diversity
Program and Jen Megules (HR, Novartis) for a summer
internship support (J.B.). The authors also would like to thank
Drs. Tim Ramsey and Chris Brain (Novartis, Oncology) for
their support.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Forlani, L. Gazz. Chim. Ital. 1981, 111, 159–162.
(19) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119,
9913–9914.
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