Cross coupling of 3-bromopyridine and sulfonamides (R1NHSO2R2·R1 = H, Me, alkyl; R2 = alkyl and aryl) catalyzed by CuI/1,3-di(pyridin-2-yl)propane-1,3-dione

Article abstract of DOI:10.1016/j.tetlet.2009.11.037

N-(3-Pyridinyl)-substituted secondary and tertiary sulfonamides have been synthesized in good to excellent yields by the reaction of 3-bromopyridine with primary and secondary alkyl and aryl sulfonamides (MeSO₂NH₂, MeSO₂NHMe, TolSO₂NH₂, TolSO₂NHMe, 1,3-propanesultam, and 1,4-butanesultam), catalyzed by CuI (20 mol %) and 1,3-di(pyridin-2-yl)propane-1,3-dione (20 mol %) with K₂CO₃ (200 mol %) in DMF (0.17 M for ArBr) at 110-120 °C over 36-40 h. 2-Bromopyridine, 4-bromopyridine, and a wide variety of substituted phenyl bromides can also be successfully coupled with sulfonamides under these reaction conditions.

Full text of DOI:10.1016/j.tetlet.2009.11.037

Tetrahedron Letters 51 (2010) 360–362
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cross coupling of 3-bromopyridine and sulfonamides (R1NHSO2R2ꢀR1 = H, Me,
alkyl; R2 = alkyl and aryl) catalyzed by CuI/1,3-di(pyridin-2-yl)propane-1,3-dione
*
Xiaojun Han
Neuroscience Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
N-(3-Pyridinyl)-substituted secondary and tertiary sulfonamides have been synthesized in good to excel-
lent yields by the reaction of 3-bromopyridine with primary and secondary alkyl and aryl sulfonamides
(MeSO2NH2, MeSO2NHMe, TolSO2NH2, TolSO2NHMe, 1,3-propanesultam, and 1,4-butanesultam), cata-
lyzed by CuI (20 mol %) and 1,3-di(pyridin-2-yl)propane-1,3-dione (20 mol %) with K2CO3 (200 mol %)
in DMF (0.17 M for ArBr) at 110–120 °C over 36–40 h. 2-Bromopyridine, 4-bromopyridine, and a wide
variety of substituted phenyl bromides can also be successfully coupled with sulfonamides under these
reaction conditions.
Received 28 September 2009
Revised 30 October 2009
Accepted 9 November 2009
Available online 13 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
N-Arylated sulfonamides have been of interest to medicinal
chemists in recent years as b-secretase inhibitors for Alzheimer’s
disease,1a,b dipeptidyl peptidase IV inhibitors for diabetes,1c insu-
lin-like growth factor receptor (IGF-IR) inhibitors for cancer,1d
HCV NS5B polymerase inhibitors for acute hepatitis and chronic li-
ver disease,1e and as antibacterial agents.1f One of the most direct
ways of preparing them is the coupling of (hetero)aryl halides with
primary or secondary sulfonamides, generally using palladium or
copper catalysis. In the Pd-catalyzed reactions, Pd/Xantphos com-
bination2 has been employed most frequently. However, other
Pd/ligand combinations have also been reported.3 CuI has been
used as a catalyst without any ligand,4 or in the following combi-
nations: Cu2O/2,2-bipyridine,2c CuI/trans-N,N0-dimethyl-1,2-cyclo-
hexanediamine,5a and CuI/N,N0-dimethylglycine.5b Very recently,
newer ligands have also been coupled with Cu(I) salts for the prep-
aration of N-arylated heterocycles and amides. These include the
use of CuBr/b-ketoester,6a CuI/(S)-pyrrolidinylmethylimidazole,6b
CuI/oxazolidin-2-one,6c and CuI/1,3-di(pyridin-2-yl)propane-1,3-
dione.6d
During the course of a medicinal chemistry effort, we desired an
efficient method to access compound 2 in order to study the SAR
and to modulate the pharmacokinetic properties of these hetero-
arylated sulfonamides in comparison with the corresponding
amides. In our hands, Pd/Xantphos2 gave only reduced product 3.
After screening a number of the above-mentioned Cu(I)/ligand
combinations, we were delighted to find that compound 2 was
formed in 35% yield along with 35% of reduced product 3 using
the CuI7/1,3-di(pyridin-2-yl)propane-1,3-dione combination (Eq.
1):6d
R1
R1
R1
Br
N
H
Pd or Cu
catalyst
S
O
R2
R2
R2
O
+
ð1Þ
N
N
N
R3
R3
R3
1
2
3
Having successfully applied these conditions to a molecule with the
complexity of compound 1 (polycyclic with a molecular weight of
350–400, containing two amide-like NH groups), we were
prompted to explore the application of these conditions to the cou-
pling of sulfonamides with bromopyridines. The resulting pyridines
would not only be more drug-like than the corresponding electron-
rich pyrroles, but reaction conditions developed for these more
challenging substrates would also be more likely to accommodate
other medicinally relevant heteroaryl halides. Although 2-bromo-
pyridine2c,f,8 has been reported to be a good substrate for this type
of coupling reaction, 3-bromo3a,9 and 4-bromopyridine10 are not.
For example, 2-bromopyridine was reacted with SES-NH2 under
Pd/Xantphos conditions to afford the coupled product in 85% yield.2f
It was also coupled with 1,4-butanesultam under Cu2O/bipyridine
conditions (93% yield)2c and under Pd/Xantphos conditions (62%
yield).2c However, when 3-chloropyridine was reacted with phen-
ylmethanesulfonamide under Pd catalysis, only 8% of coupled prod-
uct was formed.3a When pre-complexed to Et3B, 4-bromopyridine
reacts smoothly with 4-methylbenzenesulfonamide under Pd/Xant-
phos conditions to afford the N-arylated product in 91% yield. How-
ever, without pre-complexation the same product was formed in
only 41% yield.10
Reaction of 2-, 3-, or 4-bromopyridine with 1,4-butanesultam or
1,3-propanesultam at 110 °C for 40 h in the presence of 20 mol % of
CuI, 20 mol % of 1,3-di(pyridin-2-yl)propane-1,3-dione, and
200 mol % of K2CO3 afforded the corresponding pyridinyl-substi-
* Tel.: +1 2036777879; fax: +1 2036777702.
E-mail address: xiaojun.han@bms.com
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.037

X. Han / Tetrahedron Letters 51 (2010) 360–362
361
Table 2
tuted sulfonamides in good to excellent yields (60–86%, Table 1).
Among the three halopyridine regioisomers, 3-halopyridines are
the most challenging substrates toward transition metal-catalyzed
C–N coupling reactions.2,3,8–10 Therefore, to further explore the
scope of these conditions, 3-bromopyridine was reacted with a
number of primary and secondary alkyl and aryl sulfonamides under
similar reaction conditions (120 °C for 36 h vs 110 °C for 40 h).
Although the product obtained using methanesulfonamide was
formed in only modest yield (42%), the other three sulfonamides
afforded excellent yields of the N-arylated products (90–99%, Table
2). We hypothesized that this catalytic system works well with 3-
and 4-bromopyridines because of the very stable complex that
forms between CuI and 1,3-di(pyridin-2-yl)propane-1,3-dione.11
Therefore, the unproductive coordination of the nitrogen atom of
the halopyridine and Cu+ is prevented, allowing the catalytic reac-
tion to proceed smoothly to product.10
CuI-catalyzed cross coupling of 3-bromopyridine with primary and secondary alkyl
and aryl sulfonamides
R1
0.2 equiv CuI
R1
N
R2
0.2 equiv ligand
HN
O
Br
+
R2
S
N
N
S
3.0 equiv K2CO3,
DMF (3 mL)
120 °C, 36 h
O
O
O
(ArBr, 0.5 mmol)
1.5 equiv
90%
99%
91%
NH
S
N
N
N
N
N
S
S
O
O
O
O
O
NH
S
N
42%
O
O
O
These reaction conditions were also applied to the reaction of
substituted phenyl bromides with 1,4-butanesultam and 1,3-pro-
panesultam (Table 3). Methyl 4-bromobenzoate underwent clean
conversion to afford 4 in 85% yield, while methyl 3-bromobenzoate
produced 5 in 60% yield and methyl 2-bromobenzoate gave none of
the desired product 6 (even upon complete consumption of the
bromide starting material). This failure was likely due to intramo-
lecular interaction of the ester functionality with C–Cu bond of the
formed intermediates after oxidative addition but before reductive
elimination. Both 4- and 3-methoxphenyl bromides afforded the
desired product in modest yields (7–8, 43%). Yields were higher
when based on recovered starting material (brsm), improving the
yields to 60% and 65%, respectively. 2-Methoxyphenyl bromide
afforded 9 in poor yield (10% isolated; 40% brsm). Although the
yields of 7–9 were low to moderate, the reaction of 4-methyoxy-
phenyl bromide with SES-NH2 did not afford any of the desired
coupling product using the Pd/Xantphos conditions.2f When the
phenylbromide contained both an electron-donating group (EDG)
at the para position and an electron-withdrawing group (EWG),
the substrate reacted well (10, 64%). 2-Bromotoluene afforded 11
in low yield (14% isolated; 38% brsm), and there was no desired
product formed from the very hindered 2,6-dimethyl phenyl bro-
mide (12). These bromides were also reacted with 1,3-propanesul-
tam under the same reaction conditions. These reactions showed
trends similar to the aforementioned results (i.e., 4 vs 13, 7 vs
14, 10 vs 15). These findings are in good agreement with the
well-established notion that Cu-catalyzed carbon–nitrogen bond-
forming reactions of aryl halides are particularly sensitive to steric
hindrance at the electrophile, and that EWG-substituted phenyl
bromides are better substrates than EDG-substituted bromides in
these types of reactions.2,3,12
Substituted phenyl bromides also performed well in reactions
with primary and secondary alkyl and aryl sulfonamides. For
example, methyl 4-bromobenzoate underwent reaction with 4-
methylbenzenesulfonamide,
N,4-dimethylbenzenesulfonamide,
methanesulfonamide, and N-methylmethanesulfonamide to afford
the coupling products in modest to good yields (51–78%) (see Table
4).
To study the electronic effects of sulfonamides on CuI/1,3-
di(pyridin-2-yl)propane-1,3-dione-catalyzed coupling reactions,
3-bromopyrine and 4-nitrobenzenesulfonamide were reacted
and the coupling product was formed in 33% yield. In compari-
son, there was no coupling product formed between 4-chloro-
quinoline and 4-nitrobenzenesulfonamide under palladium
catalysis, although other sulfonamides worked fine.3a 4-Chloro-
and 4-methoxybenzenesulfonamide were also coupled with 3-
bromopyridine to afford desired coupling products in modest
yields (Eq. 2):13
X
0.2 equiv CuI
X
Br
0.2 equiv ligand
H2N
O
NH
S
+
S
2.0 equiv K2CO3,
DMF (3 mL)
ð2Þ
N
O
N
O
O
(0.5 mmol)
1.5 equiv
120 °C, 36 h
X = NO2, 33%; X = Cl, 55%; X = OMe, 54%
Table 1
N-Arylation of 1,4-butanesultam by aryl bromides catalyzed by copper
O
O
0.2 equiv CuI
0.2 equiv ligand
O
S
O
S
ArBr
HN
+
N
Ar
2.0 equiv K2CO3,
DMF (3 mL)
110 °C, 40 h
(0.5 mmol)
0,1
0,1
1.5 equiv
O
O
Ligand:
N
N
86%a
N
N
N
70%
85%
61%
70%
S
S
S
S
S
S
O
O
O
O
O
O
N
N
N
N
N
N
N
N
60%a
O
O
O
O
O
O
N
a
4-Bromopyridine hydrochloride salt was used, and 3 equiv of K2CO3 was used.

362
X. Han / Tetrahedron Letters 51 (2010) 360–362
Table 3
Acknowledgments
N-Arylation of 1,3-propanesultam and 1,4-butanesultam by aryl bromides catalyzed
by copper
I thank Drs. John E. Macor and Gene M. Dubowchik for support
during the course of this research, and Dr. Andrew P. Degnan for
critical reading of this manuscript.
O
O
0.2 equiv CuI
O
S
N
S
0.2 equiv ligand
O
ArBr
HN
+
2.0 equiv K2CO3,
DMF (3 mL)
110 °C, 40 h
(0.5 mmol)
Ar
0,1
0,1
1.5 equiv
85%
Supplementary data
Supplementary data (1H, 13C NMR spectra for all synthesized
compounds) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.11.037.
N
N
S
S
60%
O
0
O
O
O
MeO2C
MeO2C
4
5
CO2Me
References and notes
N
N
1. (a) Stanton, M. G.; Stauffer, S. R.; Gregro, A. R.; Steinbeiser, M.; Nantermet, P.;
Sankaranarayanan, S.; Price, E. A.; Wu, G.; Crouthamel, M.; Ellis, J.; Lai, M.;
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Nantermet, P. G.; Barrow, J. C.; Rittle, K. E.; Collusi, D.; Espeseth, A. S.; Lai, M.;
Pietrak, B. L.; Holloway, M. K.; McGaughey, G. B.; Munshi, S. K.; Hochman, J. H.;
Simon, A. J.; Selnick, H. G.; Graham, S. L.; Vacca, J. P. Bioorg. Med. Chem. Lett.
2007, 17, 1788–1792; (c) Duffy, J. L.; Kirk, B. A.; Wang, L.; Eiermann, G. J.; He,
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K.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett. 2007, 17, 2879–2885;
(d) Mayer, S. C.; Banker, A. L.; Boschelli, F.; Di, L.; Johnson, M.; Kenny, C. H.;
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H.; Xu, W. Bioorg. Med. Chem. Lett. 2008, 18, 3641–3645; (e) Dragovich, P. S.;
Blazel, J. K.; Ellis, D. A.; Han, Q.; Kamran, R.; Kissinger, C. R.; LeBrun, L. A.; Li, L.;
Murphy, D. E.; Noble, M.; Patel, R. A.; Ruebsam, F.; Sergeeva, M. V.; Shah, A. M.;
Showalter, R. E.; Tran, C. V.; Tsan, M.; Webber, S. E.; Kirkovsky, L.; Zhou, Y.
Bioorg. Med. Chem. Lett. 2008, 18, 5635–5639; (f) Namba, K.; Zheng, X.;
Motoshima, K.; Kobayashi, H.; Tai, A.; Takahashi, E.; Sasaki, K.; Okamoto, K.;
Kakuta, H. Bioorg. Med. Chem. 2008, 16, 6131–6144.
S
N
S
O
O
43%
O
O
MeO
6
7
MeO
MeO
N
S
S
43%
64%
10%
O
O
O
O
8
9
N
N
S
S
14%
O
O
O
O
H2N
10
11
NO2
N
N
S
O
S
O
0
83%
O
O
MeO2C
2. (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104; (b) Yin, J.; Buchwald, S.
L. J. Am. Chem. Soc. 2002, 124, 6043–6048; (c) Stinbuebel, D.; Palucki, M.; Askin,
D.; Dolling, U. Tetrahedron Lett. 2004, 45, 3305–3307; (d) Audisio, D.;
Messaoudi, S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2007, 48,
6928–6932; (e) Messaoudi, S.; Audisio, D.; Brion, J.-D.; Alami, M. Tetrahedron
2007, 63, 10202–10210; (f) Anjanappa, P.; Mullick, D.; Selvakumar, K.;
Sivakumar, M. Tetrahedron Lett. 2008, 49, 4585–4587.
12
13
N
N
S
S
O
O
40%
75%
O
O
MeO
H2N
14
15
NO2
3. (a) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373–4376; (b) Ikawa,
T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
13001–13007.
4. (a) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385–3386; (b) Okano, K.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987–4990.
5. (a) Toto, P.; Gesquiere, J.-C.; Cousaert, N.; Deprez, B.; Willand, N. Tetrahedron
Lett. 2006, 47, 4973–4978; (b) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.
Tetrahedron Lett. 2005, 46, 7295–7298.
6. (a) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863–3867; (b) Zhu, L.; Cheng, L.;
Zhang, Y.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 2737–2743; (c) Ma, H. C.; Jiang,
X. Z. Synlett 2008, 1335–1340; (d) Xi, Z.; Liu, F.; Zhou, Y.; Chen, W. Tetrahedron
2008, 64, 4254–4259.
7. CuI was purified by a literature procedure: Kauffman, G. B.; Fang, L. Y. Inorg.
Synth. 1983, 22, 101–103.
Table 4
CuI-catalyzed cross coupling of aryl bromides with primary and secondary alkyl and
aryl sulfonamides
R1
0.2 equiv CuI
R1
N
R2
0.2 equiv ligand
HN
O
MeO2C
Br
+
Ar
R2
S
3.0 equiv K2CO3,
DMF (3 mL)
110 °C, 40 h
S
O
O
O
(ArBr, 0.5 mmol)
1.5 equiv
8. Kandzia, C.; Steckhan, E.; Knoch, F. Tetrahedron: Asymmetry 1993, 4, 39–42.
9. (a) Sugahara, M.; Ukita, T. Chem. Pharm. Bull. 1997, 45, 719–721; (b) Li, C. S.;
Dixon, D. D. Tetrahedron Lett. 2004, 45, 4257–4260; (c) St. Jean, D., Jr; Poon, S. F.;
Schwarzbach, J. L. Org. Lett. 2007, 9, 4893–4896.
10. Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734–7735.
11. Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586–6596. In our
reactions, when the reaction mixtures were extracted with EtOAc and 6 N
NH4OH, the aqueous layer was almost colorless, lacking the blue color
indicative of no complexation of ammonia with copper. This further supports
51%
73%
78%
MeO2C
MeO2C
NH
S
MeO2C
MeO2C
N
S
O
O
O
O
O
O
NH
S
N
S
62%
O
O
the hypothesis that
a stable complex was formed between CuI and 1,3-
di(pyridin-2-yl)propane-1,3-dione.
12. Altman, R. A.; Buchwald, S. L. Org. Lett. 2007, 9, 643–646.
In conclusion, we have found that CuI/1,3-di(pyridin-2-yl)propane-
1,3-dione, first developed by Chen,6d successfully catalyzed the
coupling of primary and secondary alkyl and aryl sulfonamides with
2-, 3-, and 4-bromopyridines and other substituted phenyl bro-
mides.14 This is the first catalytic system to afford modest to excel-
lent yields of coupling products between 3-bromopyridine and
various primary and secondary sulfonamides. We anticipate that
this catalytic system will find wide application in the medicinal
chemistry community for the coupling of nitrogen-containing het-
eroaromatic bromides and varied primary and secondary
sulfonamides.
13. I acknowledge that one of the referees suggested these three experiments to
study electronic effects of sulfonamides on the coupling reactions.
14. General reaction procedure is as follows: A 10 mL microwave vial was charged
with aryl bromide (0.50 mmol), substituted sulfonamide (0.75 mmol), 1,3-
di(pyridin-2-yl)propane-1,3-dione (0.023 g, 0.10 mmol), copper(I) iodide
(0.019 g, 0.10 mmol), and potassium carbonate (0.138 g, 1.0 mmol). After the
reaction vessel was degassed under
a flow of N2 for 5 min, DMF (3 mL,
degassed by a flow of N2 for 30 min) was added. The resulting mixture was
further degassed by a flow of N2 for 5 min and heated at 120 °C for 36 h. All
volatiles were removed and the resulting residue was extracted with EtOAc
(twice) and washed with brine. The combined organic layers were dried over
Na2SO4, filtered, concentrated, and purified by flash chromatography (EtOAc/
hexanes or 2 M NH3–MeOH/CH2Cl2).