A New Class of Amide Ligands Enable Cu-Catalyzed Coupling of Sodium Methanesulfinate with (Hetero)aryl Chlorides

Article abstract of DOI:10.1002/cjoc.201700477

((2S,4R)-4-Hydroxy-N-(2-methylnaphthalen-1-yl)pyrrolidine-2-carboxamide (HMNPC), an amide derived from 4-hydroxy-L-proline and 2-methyl naphthalen-1-amine, is a powerful ligand for Cu-catalyzed coupling of (hetero)aryl halides with sulfinic acid salts, allowing for first time the metal-catalyzed coupling of (hetero)aryl chlorides and NaSO₂Me. A considerable number of (hetero)aryl chlorides worked well, providing the pharmaceutically important (hetero)aryl methylsulfones in good to excellent yields.

Full text of DOI:10.1002/cjoc.201700477

A New Class of Amide Ligands Enable Cu-Catalyzed Coupling
of Sodium Methanesulfinate with (Hetero)aryl Chlorides
Dawei Ma,a* Songtao Niu,b Jinlong Zhao,b Xi Jiang,a Yongwen Jiang,a Xiaojing Zhang,b and
Tiemin Sunb
aState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
bShenyang Pharmaceutical University, 103 Wenhua Lu, Shenyang 110016, China
((2S,4R)-4-hydroxy-N-(2-methylnaphthalen-1-yl)pyrrolidine-2-carboxamide (HMNPC), an amide derived from
4-hydroxy-L-proline and 2-methyl naphthalen-1-amine, is a powerful ligand for Cu-catalyzed coupling of (het-
ero)aryl halides with sulfinic acid salts, allowing for first time the metal-catalyzed coupling of (hetero)aryl chlorides
and NaSO2Me. A considerable number of (hetero)aryl chlorides worked well, providing the pharmaceutically im-
portant (hetero)aryl methylsulfones in good to excellent yields.
Keywords (hetero)aryl methylsulfone, coupling reaction, (hetero)aryl halides, ligand, copper
Introduction
(Hetero)aryl methylsulfone scaffold has been fre-
quently used in pharmaceutical design.[1] The existing
drugs containing this unit include nonsteroidal an-
ti-inflammatory drug Rofecoxib (Figure 1),[2]
LFA-1/ICAM-1 antagonist Xiidra that was launched last
year for the treatment of signs and symptoms of dry eye
disease;[3] hedgehog pathway inhibitor Vismodegin that
has been approved recently for the treatment of metastic
or locally advanced basal cell carcinoma;[4] as well as
CS-3150, a mineralocorticoid receptor antagonist that
has entered phase III clinical trials for the treatment of
essential hypertension.[5] Consequently, efficient meth-
ods that allow diverse and efficient synthesis of aryl
methylsulfones are essential for drug development.[6-10]
Traditionally, aryl methylsulfones were prepared by
direct sulfonylation of arenes with methylsulfonyl chlo-
ride, which suffered from low regioselectivity and poor
functional group tolerance.[6] During the past decades,
two efficient and general methods have been developed,
namely, metal-catalyzed coupling of aryl halides with
thiols followed by oxidation[6,7] and metal-catalyzed
coupling of sodium methanesulfinate with suitable aro-
matic electrophiles.[6,8,9] Due to their broad substrate
scope, operational simplicity, and ready accessibility of
aryl halides, these two methods have become the pri-
mary choice for assembling designed (hetero)aryl me-
thylsulfones, particularly for late stage manipula-
tion.[3,7,11] Obviously, the direct coupling with sodium
methanesulfinate is more attractive and preferred than
the two-step thiol coupling/oxidation process, because
the former can avoid the use of unpleasant reagents and
the additional oxidation step.
Figure 1 Structures of some pharmaceutically important aryl
methylsulfones.
During the past decades, a considerable range of
aromatic electrophiles have been found to be able to
couple with sodium methanesulfinate under palladium
or copper catalysis.[8,9] However, aryl chlorides as the
cheapest and most abundant aromatic electrophiles re-
main inert substrates for either Pd- or Cu-catalyzed
coupling reactions (Figure 2).[6a] To address this chal-
lenging problem, we recently explored a variety of lig-
ands to promote Cu-catalyzed coupling of (hetero)aryl
chlorides with sodium methanesulfinate, and found that
a class of newly developed amides could make this cou-
pling reaction possible. Herein, we wish to disclose our
results.
*
E-mail: madw@sioc.ac.cn; Tel.: 86-021-54925130; Fax: 86-021-64166128
Received ((will be filled in by the editorial staff)); accepted ((will be filled in by the editorial staff)); published online XXXX, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.2013xxxxx or from the author.
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under the reactions conditions, leading to enhanced
yields. Some oxalic diamide ligands (L10-L13)[12] that
have showed excellent activity in other Cu-catalyzed
coupling reactions with (hetero)aryl chlorides were
examined under the same conditions. None of them
provided satisfactory conversions (entries 10-13). The
Previous work:
MeSO2Na
[Cu] or [Pd], ligand
X
SO2Me
SO2Me
Y
Y
Y
X = Br, I, OTf, B(OR)2
This work:
other
known
ligands
like
L-proline,[8b]
MeSO2Na
[Cu], ligand
Cl
N1,N2-dimethylethane-1,2-diamine (DMEDA)[8a] and
1,10-phenanthroline[8c] (L14-L16) that are workable for
Cu-catalyzed coupling of sulfinic acid salts with aryl
iodides and bromides did not promote this reaction
(entries 14-16). Thus, we concluded that HMNPC (L8)
is the best ligand for this coupling reaction.
Y
Figure 2 Metal-catalyzed coupling reactions for assembling
aryl methylsulfones.
Results and Discussion
Recently, we have found that a class of oxalic dia-
mides are effective ligands for promoting Cu-catalyzed
arylation of aryl chlorides.[12] The key for this success is
the electronic nature of these ligands could be finely
tuned by employing amides derived from different
amines, which makes possible the discovery of a ligand
with matched electron property for activating C-Cl bond.
To further investigate the structure-activity relationship
of such ligands, we decided to develop a new class of
ligands with hybrid structures of L-proline and oxalic
Table 1 CuI/ligand-catalyzed coupling of 4-chloroanisole and
sodium methanesulfinate.a
diamides
(Figure
3).
Accordingly,
pyrroli-
dine-2-carboxamide L1 was prepared and tested for
CuI-catalyzed coupling of 4-chloroanisole with sodium
methanesulfinate (Table 1). It was found that the desired
coupling product 2a was formed in 38% yield after the
mixture was stirred at 120 oC after 24 h (entry 1). Use of
2,6-dimethylaniline-dervied amide L2 as the ligand
gave an improved result (entry 2), while ligands L3-L5
prepared from mono-substituted anilines still provided
low yields (entries 3-5).
Entry
Ligand Yield (%)b
Entry
9
Ligand Yield (%)b
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
38
L9
55
11
16
43
37
trace
0
56
10
11
12
13
14
15
16
L10
L11
L12
L13
L14
L15
L16
36
16
50
72
34
Figure 3 Design of a new class of ligands for Cu-catalyzed
coupling reactions.
75 (85c, 54d)
0
To further improve this coupling reaction, we then
moved our attention to naphthalen-1-amine-derived
ligands. Pleasingly, (S)-N-(2-methylnaphthalen-1-yl)-
pyrrolidine-2-carboxamide (L6, MNPC) and its
hydroxyl analogue L8 ((2S,4R)-4-hydroxy-N-(2-methyl-
naphthalen-1-yl)pyrrolidine-2-carboxamide, HMNPC)
led to the formation of 2a in good yields (entries 6 and
8). Interestingly, reducing the amount of K3PO4 from
1.5 equiv to 1 equiv could further improve the yield to
85% when L8 was used as the ligand. However, further
reducing the amount of the base gave a decreased yield
(entry 8). The methyl group in both L6 and L8 plays an
important role for the activity, as evident from the
decreased yields being observed with the demethylated
ligands L7 and L9 (entries 7 and 9). Presumably, the
methyl group could block the hydrolysis of the ligands
aReaction conditions: 1a (1 mmol), MeSO2Na (1.3 mmol), CuI
(0.1 mmol), ligand (0.1 mmol), K3PO4 (1.5 mmol), DMSO (0.5
mL), 120 oC, 24 h. bThe yield was determined by 1H NMR analy-
c
sis of crude products using CH2Br2 as the internal standard. The
d
reaction was conducted with 1.0 mmol of K3PO4. The reaction
was conducted with 0.5 mmol of K3PO4.
After identifying HMNPC as the optimized ligand,
we next examined the CuI/HMNPC-catalyzed coupling
reaction with a series of (hetero)aryl chlorides. As
summarized in Scheme 1, a considerable number of aryl
chlorides with substituents at the para- and me-
ta-positions were compatible with these conditions,
providing the corresponding aryl methylsulfones 2b-2m
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in 70-96% yields. When 4-iodoaniline was used, the
aniline moiety did not influence the reaction course,
leading to the formation of 2e in a good yield, which has
been used for assembling anti-hypertension drug
CS-3150.[5] Regioselective coupling at the less sterically
hindered site was observed in the case of
2,4-dichloro-1-methylbenzene as a substrate, and the
corresponding coupling product 2k is a key intermediate
for preparing 2-chloro-4-(methylsulfonyl)benzoic acid
that has been used for manufacturing anti-tumor drug
Vismodegin.[4] Additionally, several electron-poor and
electron-rich heteroaryl chlorides worked well, leading
to the formation of heteroaryl methylsulfones 2n-2s in
good yields. These heterocycles include quinoline (2n)
pyridine (2o), thiophene (2p), benzothiophene (2q), and
indole (2r and 2s). It is notable that the product 2s has
been used for preparing anti-inflammatory agent
LM-1685.[2] The success in coupling of (hetero)aryl
chlorides with sodium methanesulfinate provides an
inexpensive and alternative approach for preparing these
synthetically useful (hetero)aryl methylsulfones.
this problem.
When aryl bromides were used as the coupling part-
ners, CuI/HMNPC catalyzed coupling still needed heat-
o
ing at 90 C to get complete conversion, which is simi-
lar with the reaction catalyzed by CuI/L-proline,[8b] alt-
hough the catalytic loading could be reduced to 2 mol%
(Scheme 2).
Scheme 2 CuI/HMNPC catalyzed coupling reaction of
(4-bromo-phenyl)methanol with sodium methanesulfinate
Based on the previous studies on ligand promoted
copper-catalyzed coupling reactions,[13] we proposed a
possible mechanism for the present transformation
(Scheme 3). Under the assistance of K3PO4, HMNPC
might undergo deprotenation at the amide site and then
react with CuI to form Cu(I) complex A, which would
able to activate the C-Cl bond to give the oxidative ad-
dition product B. Direct reaction of the Cu(III) complex
B with sodium methanesulfinate might provide ligand
exchange product C. Reductive elimination of C would
deliver the coupling product and regenerate the catalytic
species A.
Scheme 1 CuI/HMNPC catalyzed coupling of (hetero)aryl
chlorides with sodium methanesulfinate
MeSO2Na
10 mol% CuI
10 mol% L8
HO
H
N
N
(hetero)ArSO2Me
(hetero)ArCl
H
K3PO4, DMSO
O
Me
L8 (HMNPC)
Scheme 3 Possible mechanism
1
2
120 o
C
SO2Me
MeS
SO2Me
SO2Me
SO2Me
Ph
Me
H2N
2c
(81%)
2b (80%)
SO2Me
2d (83%)
2e (76%)
SO2Me
SO2Me
MeO
N
F3C
2g
(96%)
2f (80%)
O
2h (74%)
SO2Me
O
SO2Me
F3C
SO2Me
SO2Me
OMe
Me
H2N
O
Cl
F
2i (76%)
2k (74%)
2j (74%)
2l (72%)
O
S
MeO2S
N
Me
N
MeO2S
SO2Me
Conclusions
2o
(82%)
2n (88%)
2m (75%)
In conclusion, we have demonstrated that coupling
of (hetero)aryl chlorides and sodium methanesulfinate is
possible by employing the combination of CuI and
HMNPC as the catalytic system. A wide range of (het-
ero)aryl chlorides worked well under the catalysis of
CuI/HMNPC to afford the corresponding (hetero)aryl
methylsulfones in good to excellent yields. This proto-
col has provided an alternative and valuable tool for
assembling pharmaceutically important (hetero)aryl
sulfones. Additionally, the excellent performance dis-
played by pyrrolidine-2-carboxamide ligands will stim-
ulate further ligand design for greater applicability of
Cu-catalyzed coupling reactions.
MeO2S
MeO2S
MeO2S
SO2Me
2p (75%)
CO2Et
S
N
N
Bn
2s (72%)
S
Bn
2r (76%)
2q (87%)
aReaction conditions: 1 (5 mmol), sodium methanesulfinate (6.5
mmol), CuI (0.5 mmol), HMNPC (0.5 mmol), K3PO4 (5 mmol),
solvent (2.5 mL), 120 oC, 24-36 h. bIsolated yield.
Under the same conditions, coupling reactions of ar-
yl chlorides with more sterically hindered sodium ben-
zenesulfinate gave rather poor conversions. Further in-
vestigations on ligand screening are required to solve
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Chem. 2015, 13, 1592-1599.
Experimental
[7] Sakauchi, N. Kohara, Y.; Sato, A.; Suzuki, T.; Imai, Y.; Okabe, Y.;
Imai, S.; Saikawa, R.; Nagabukuro, H.; Kuno, H.; Fujita, H.; Kano,
I.; Yodhida, M. J. Med. Chem. 2016, 59, 2989-3002.
[8] For Cu-catalyzed coupling reactions with aryl halides, see: (a)
Baskin, J. M.; Wang, Z. Org. Lett. 2002, 4, 4423-4425. (b) Zhu, W.;
Ma, D. J. Org. Chem. 2005, 70, 2696-2700. (c) Bian, M.; Xu, F.; Ma,
C. Synthesis 2007, 2951-2956. (d) Ma, D.; Cai, Q. Acc. Chem. Res.
2008, 41, 1450-1460. (e) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054-3131.
[9] For Pd and Cu-catalyzed coupling reactions with other aromatic
electrophiles, see: (a) Beaulieu, C.; Guay, D.; Wang, Z.; Evans, D. A.
Tetrahedron Lett. 2004, 45, 3233-3236. (b) Kir, A.; Sayyed, I. A.;
Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse, M. K. Org. Lett. 2007, 9,
3405-3408. (c) Huang, F.; Batey, R. A. Tetrahedron 2007, 63,
7667-7672. (d) Yang, H.; Li, Y.; Jiang, M.; Wang, J.; Fu, H. Chem.
Eur. J. 2011, 17, 5652-5660.
[10] For other related studies, see: (a) Yuan, G.; Zheng, J.; Gao, X.; Li,
X.; Huang, L.; Chen, H.; Jiang, H. Chem. Commun. 2012, 48,
7513-7515. (e) Liang, S.; Zhang, R.-Y.; Xi, L.-Y.; Chen, S.-Y.; Yu,
X.-Q. J. Org. Chem. 2013, 78, 11874-11880. (f) Wu, Z.; Song, H.;
Cui, X.; Pi, C.; Du, W.; Wu, Y. Org. Lett. 2013, 15, 1270-1273. (h)
Du, B.; Qian, P.; Wang, Y.; Mei, H.; Han, J.; Pan, Y. Org. Lett.
2016, 18, 4144-4147.
General procedure for CuI/HMNPC catalyzed
coupling reaction of (hetero)aryl chlorides with so-
dium methanesulfinate: A 25 mL resealable screw-cap
test tube equipped with a Teflon-coated magnetic stir
bar was charged with CuI (95.2 mg), HMNPC (135.1
mg), (hetero)aryl chloride (if solid) (5.0 mmol), Me-
SO2Na (6.5 mmol) and K3PO4 (5 mmol). The tube was
then evacuated and backfilled with argon (this sequence
was repeated three times), and (hetero)aryl chloride (if
liquid) (5.0 mmol) and DMSO (3 mL) were then added
into the tube via syringe. The reaction mixture was
stirred at 120 °C in an oil bath for 24-36 h. After cool-
ing to room temperature, the crude product was diluted
with ethyl acetate, and filtrated through silica gel and
kieselguhr. Then the filtrate was concentrated in vacuo.
The residue was purified by flash chromatography
(eluting with ethyl acetate/hexanes or dichloro-
methane/methanol) to afford the corresponding (het-
ero)aryl sulfone products.
[11] Haile, P. A.; Votta, B. J.;. Marquis, R. W.; Bury, M. J.; Mehlmann, J.
F.; Singhaus Jr., R.; Charnley, A. K.; Lakdawala, A. S.; Convery, M.
A.; Lipshutz, D. B.; Desai, B. M.; Swift, B.; Capriotti, C. A.; Berger,
S. B.; Mahajan, M. K.; Reilly, M. A.; Rivera, E. J.; Sun, H. H.;
Nagilla, R.; Beal, A. M.; Finger, J. N.; Cook, M. N.; King, B. W.;
Ouellette, M. T.; Totoritis, R. D.; Pierdomenico, M.; Negroni, A.;
Stronati, L.; Cucchiara, S.; Ziółkowski, B.; Vossenkämper, A.;
MacDonald, T. T.; Gough, P. J.; Bertin, J.; Casillas, L. N. J. Med.
Chem. 2016, 59, 4867-4880.
[12] (a) Zhou, W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. J. Am. Chem. Soc.
2015, 137, 11942-11946. (b) Fan, M.; Zhou, W.; Jiang, Y.; Ma, D.
Org. Lett. 2015, 17, 5934-5937. (c) Fan, M.; Zhou, W.; Jiang, Y.; Ma,
D. Angew. Chem. Int. Ed. 2016, 55, 6211-6215. (d) Xia, S.; Gan, L.;
Wang, K.; Li, Z.; Ma, D. J. Am. Chem. Soc. 2016, 138, 13493-13496.
(e) De, S.; Yin, J.; Ma, D. Org. Lett. 2017, 19, 4854-4857.
[13] (a) Zhang, S.-L.; Liu, L.; Fu, Y.; Guo, Q.-X. Organometallics, 2007,
26, 4546-4554. (b) Altman, R. A.; Hyde, A. M.; Huang, X.; Buch-
wald, S. L. J. Am. Chem. Soc. 2008, 130, 9613-9620. (c) Tye, J. W.;
Wang, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem.
Soc. 2008, 130, 9971-9983. (d) Strieter, E. R.; Bhayana, B.; Buch-
wald, S. L. J. Am. Chem. Soc. 2009, 131, 78-88. (e) Casitas, A.;
King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.; Ribas, X. Chem. Sci.
2010, 1, 326-330. For a review, see: (f) Alicia, C.; Xavi, R. Chem.
Sci. 2013, 4, 2301-2318.
Acknowledgement
The authors are grateful to Chinese Academy of
Sciences (sup-ported by the Strategic Priority Research
Program,
grant
XDB20020200
&
QYZDJ-SSW-SLH029) and the National Natural Sci-
ence Foundation of China (grant 21621002) for their
financial support.
References
[1] Wang, J.; Hou, T. J. Chem. Inf. Model. 2010, 50, 55-67.
[2] Paloner, A.; Cabré, F.; Pascual, J.; Campos, J.; Trujillo, M. A.;
Entrena, A.; Gallo, M. A.; García, L.; Mauleón, D.; Espinosa, A. J.
Med. Chem. 2002, 45, 1402-1411.
[3] Zhong, M.; Gadek, T. R.; Bui, M.; Shen, W.; Burnier, J.; Barr, K. J.;
Hanan, E. J.; Oslob, J. D.; Yu, C. H.; Zhu, J.; Arkin, M. R.;
Evanchik, M. J.; Flanagan, W. M.; Hoch, U.; Hyde, J.; Prabhu, S.;
Silverman, J. A.; Wright, J. ACS Med. Chem. Lett. 2012, 3, 203-206.
[4] Angelaud, R.; Reynolds, M.; Venkatramani, C.; Savage, S.; Trafelet,
H.; Landmesser, T.; Denel, P.; Levis, M.; Ruha, O.; Ruechert, B.;
Jaeggi, H. Org. Process Res. Dev. 2016, 20, 1509-1519.
[5] Arai, K.; Homma, T.; Morikawa, Y.; Ubukata, N.; Tsuruoka, H.;
Aoki, K.; Ishikawa, H.; Mizuno, M.; Sada, T. Eur. J. Pharmacol.
2015, 716, 226-234
[6] For reviews, see: (a) Liu, N.-W.; Liang, S.; Manolikakes, G. Synthe-
sis, 2016, 48, 1939-1973. (b) Liu, G.; Fan, C.; Wu, J. Org. Biomol.
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Entry for the Table of Contents
Page No.
A New Class of Amide Ligands Enable
Cu-Catalyzed Coupling of Sodium
Methanesulfinate with (Hetero)aryl
Chlorides
Dawei Ma,* Songtao Niu, Jinlong Zhao,
Xi Jiang, Yongwen Jiang, Xiaojing
Zhang, and Tiemin Sun
This article is protected by copyright. All rights reserved.