Nickel-NHC-catalyzed cross-coupling of 2-methylsulfanylbenzofurans with alkyl grignard reagents

Article abstract of DOI:10.1055/s-0034-1378914

NiCl₂(PPh₃)(IPr) catalyzes cross-coupling reactions of 2-methylsulfanylbenzofurans with alkyl Grignard reagents. Other nickel complexes such as NiCl₂(dppe) failed to catalyze the same reaction. The alkylation is applicable to the synthesis of a couple of protein tyrosine phosphatase inhibitors, 3-(4-biphenylyl)-2-alkylbenzofurans.

Full text of DOI:10.1055/s-0034-1378914

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 327–330
cluster
327
A. Baralle et al.
Cluster
Synlett
Nickel–NHC-Catalyzed Cross-Coupling of 2-Methylsulfanylbenzo-
furans with Alkyl Grignard Reagents
Alexandre Barallea
Ph
Ph
Shinya Otsukaa
Vincent Guérina
Kei Murakamia,b
Hideki Yorimitsu*a,c
Atsuhiro Osukaa
NiCl2(PPh3)(IPr)
R
SMe
R
Alk
O
O
AlkMgX
a Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo-ku, Kyoto 606-8502, Japan
+
8
1
7
(
5
7
)
5
3
3
9
7
0
yori@kuchem.kyoto-u.ac.jp
b The Hakubi Center for Advanced Research, Kyoto University, Sakyo-ku,
Kyoto 606-8502, Japan
c ACT-C, JST, Sakyo-ku, Kyoto 606-8502, Japan
Received: 11.09.2014
Accepted after revision: 02.10.2014
Published online: 10.11.2014
anticancer agents.4g,h Along this line, we report herein that
a nickel–NHC (N-heterocyclic carbene) complex is an effec-
tive catalyst for cross-coupling alkylation8 of 2-methylsulfa-
nyl-substituted benzofurans, which was applied to efficient
synthesis of protein tyrosine phosphatase (PTP) 1B inhibi-
tors 6.
DOI: 10.1055/s-0034-1378914; Art ID: st-2014-r0756-c
Abstract NiCl2(PPh3)(IPr) catalyzes cross-coupling reactions of 2-methyl-
sulfanylbenzofurans with alkyl Grignard reagents. Other nickel com-
plexes such as NiCl2(dppe) failed to catalyze the same reaction. The
alkylation is applicable to the synthesis of a couple of protein tyrosine
phosphatase inhibitors, 3-(4-biphenylyl)-2-alkylbenzofurans.
R2
R2
acid anhydride
SMe
SMe
SMe
+
Key words nickel, alkylation, cross-coupling, sulfide, homogeneous
catalysis
R1
OH
O
R1
O
Ni or Pd cat.
ArMgX (or ZnX)
Ni–NHC cat.
AlkMgX
this work
Cross-coupling reactions of organosulfur compounds
date back to 1979, when Takei and Wenkert independently
reported the NiCl2(PPh3)2-catalyzed arylation of aryl or
alkenyl sulfides with Grignard reagents.1 Despite subse-
quent extensive studies since then,2–4 cross-coupling of aryl
sulfides still remains in its infancy compared with the ma-
ture cross-coupling of aryl halides. The immaturity would
be mostly attributable to 1) slow oxidative addition of their
rather strong C(sp2)–S bonds, 2) reluctant transmetalation
due to high affinity between a transition metal and sulfur
in an oxidative adduct, and 3) catalyst poisoning by sulfur
compounds. New reaction conditions for more efficient and
robust cross-coupling of aryl sulfides with a sustainable
metal catalyst have thus been awaited.
We have been interested in extended Pummerer reac-
tions5 of ketene dithioacetal monoxides4g,h,6,7 and recently
developed an efficient and modular access to multisubsti-
tuted benzofurans through Pummerer annulation4g,h,6e,f
(Scheme 1). Since our annulation always leads to the forma-
tion of 2-methylsulfanyl-substituted benzofurans, transfor-
mations of the sulfur moieties should dictate the usefulness
of our methodology. Indeed, with state-of-the-art transi-
tion-metal catalysis, cross-coupling arylation of the prod-
ucts yielded highly fluorescent compounds4g,h,6e,f as well as
previous work
R2
R2
Ar
Alk
O
O
R1
R1
Scheme 1 Pummerer annulation–cross-coupling strategy for tailor-
made synthesis of benzofurans
Cross-coupling butylation of benzofuran 1a was chosen
as a model reaction to probe a potent catalytic system. The
results of catalyst optimization are summarized in Table 1.
Although nickel–phosphine complexes are known to pro-
mote cross-coupling of aryl sulfides,1,2a–e the transforma-
tion of 1a is not trivial. Attempted butylation with nickel
diphosphine complexes resulted in no conversions (Table 1,
entries 1–3). As 1a is regarded as a bulky aryl sulfide due to
the neighboring phenyl group, we envisioned a nickel–NHC
complex bearing a bulky NHC to be suitable in analogy with
the relevant palladium chemistry.9,10 Indeed, a commercial-
ly available nickel complex NiCl2(PPh3)(IPr)11 [IPr = 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene]
the desired alkylation very smoothly to afford 2a in 95%
yield (Table 1, entry 4). Finally, replacing toluene with THF
catalyzed
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 327–330

328
A. Baralle et al.
Cluster
Synlett
as a solvent led to quantitative formation of 2a in 30 min-
utes (Table 1, entry 5). In the absence of any catalysts, no
reaction took place (Table 1, entry 6).
NiCl2(PPh3)(IPr)
(3 mol%)
R2
R2
R1
R1
R3MgX (1.3 equiv)
SMe
R3
THF, 25 °C
O
O
Table 1 Optimization of Catalyst for Alkylation
1
2
Ph
Ph
Ni cat. (3 mol%)
BuMgBr (1.3 equiv)
Ph
Ph
R1
R1 = H
2a 97%
1 = OMe 2b 97%
1 = CF3 2c 94%
SMe
Bu
Bu
Me
2d >99%
solvent, 25 °C, 0.5 h
R
O
O
O
O
R
2a
Resultsa
1a
BuMgBr, 0.5 h
Ph
MeMgCl (2 equiv), 2 h
Ph
Entry
Catalyst
Solvent
1
2
3
4
5
6
NiCl2(PPh3)2
NiCl2(dppe)
NiCl2(dppp)
NiCl2(PPh3)(IPr)
NiCl2(PPh3)(IPr)
none
toluene
toluene
toluene
toluene
THF
no conversion
no conversion
no conversion
95% yield of 2a
>99% yield of 2a
no conversion
Bn
O
(CH2)9CH=CH2
O
2e 95%
2f 94%
BnMgCl, 4 h (in toluene) CH2=CH(CH2)9MgBr (2 equiv), 2 h, 5 mol% cat.
Ph Ph
CH2SiMe3
(CH2)11OTHP
THF
O
O
a By NMR analyses.
2g 65%
2h 94%
Me3SiCH2MgCl, 24 h
(50 °C in toluene)
THPO(CH2)11MgBr (2 equiv), 1.5 h, 5 mol% cat.
The scope of the alkylation is summarized in Scheme
2.12 Electronically biased substituents at the 6-position
have virtually no influence on the efficiency of the reaction
(2b and 2c). The smallest methyl (2d), unsaturated 10-un-
decenyl (2f), and THP-protected 11-hydroxyundecyl (2h)
groups were installed easily. Benzylmagnesium chloride
was less reactive and required four hours to reach comple-
tion (2e). Trimethylsilylmethylmagnesium chloride was
much more reluctant to afford 2g in 24 hours even at 50 °C.
It is worth noting that 2-methylsulfanylbenzofuran, which
has no substituent at the 3-position, totally resisted alkyla-
tion with NiCl2(dppe) but underwent very smooth alkyla-
tion with NiCl2(PPh3)(IPr) to yield 2i.13 Secondary alkyl
Grignard reagents underwent the cross-coupling with
much less efficiency. Cyclohexylation required sequential
additions of totally four equivalents of a cyclohexyl Gri-
gnard reagent to afford 2j in 65% yield, along with a reduced
byproduct where the SMe was replaced with H atom.
A series of 3-(4-biphenylyl)-2-alkylbenzofurans are at-
tracting significant attention since they serve as potent in-
hibitors of PTP 1B.14 In the previous report, each
alkylbenzofuran in the library was prepared via a lengthy
linear route. Advantageously, our approach to 2-alkylben-
zofurans has proved to be more efficient for the synthesis of
3-(4-biphenylyl)-2-alkylbenzofurans bearing variety in the
alkyl chain. Ketene dithioacetal monoxide 3 was prepared
H
Ph
Bu
O
2i 94%
O
2j 65%
C6H11MgBr (1.0 equiv each
at 0 h, 0.5 h, 2 h, 4 h), 6 h
BuMgBr, 0.5 h
Scheme 2 Scope of alkylation
through the Knoevenagel condensation in one step accord-
ing to the literature procedure.7a Phenol underwent the
Pummerer annulation4g,h with 3 by means of trifluoroacetic
anhydride to afford 2-methylsulfanylbenzofuran 4 in 61%
yield. The following cross-coupling butylation and benzyla-
tion were successful, yielding intermediates 5a and 5b, re-
spectively, in a diversity-oriented fashion. Benzofurans 5a
and 5b are key intermediates that should undergo demeth-
ylation as the last step to yield potent PTP 1B inhibitors 6
(Scheme 3).14
In summary, we have developed a highly efficient cross-
coupling alkylation of benzofuryl sulfides with a nickel–
NHC catalyst and applied it to the formal synthesis of PTP
1B inhibitors. Investigations to find efficient transforma-
tions of organosulfur compounds with a sustainable transi-
tion-metal catalyst are underway in our laboratory.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 327–330

329
A. Baralle et al.
Cluster
Synlett
OMe
(3) Very recent selected examples: (a) Hooper, J. F.; Young, R. D.;
Pernik, I.; Weller, A. S.; Willis, M. C. Chem. Sci. 2013, 4, 1568.
(b) Pan, F.; Wang, H.; Shen, P.-X.; Zhao, J.; Shi, Z.-J. Chem. Sci.
2013, 4, 1573. (c) Creech, G. S.; Kwon, O. Chem. Sci. 2013, 4,
2670. (d) Higashino, T.; Rodríguez-Morgade, M. S.; Osuka, A.;
Torres, T. Chem. Eur. J. 2013, 19, 10353. (e) Liu, J.-X.; Liu, Y.-J.;
Du, W.-T.; Dong, Y.; Liu, J.; Wang, M. J. Org. Chem. 2013, 78,
7293. (f) Quan, Z.-J.; Lv, Y.; Jing, F.-Q.; Jia, X.-D.; Huo, C.-D.;
Wang, X.-C. Adv. Synth. Catal. 2014, 356, 325. (g) Sugahara, T.;
Murakami, K.; Yorimitsu, H.; Osuka, A. Angew. Chem. Int. Ed.
2014, 53, 9329. (h) Otsuka, S.; Fujino, D.; Murakami, K.;
Yorimitsu, H.; Osuka, A. Chem. Eur. J. 2014, 20, 13146.
(4) Recent examples of nickel-catalyzed cross-coupling of sulfides:
(a) Melzig, L.; Metzger, A.; Knochel, P. Chem. Eur. J. 2011, 17,
2948. (b) Hintermann, L.; Schmitz, M.; Chen, Y. Adv. Synth. Catal.
2010, 352, 2411. (c) Eberhart, A. J.; Imbriglio, J. E.; Procter, D. J.
Org. Lett. 2011, 13, 5882. (d) Ma, J.; Peng, L.; Zhang, X.; Zhang, Z.;
Campbell, M.; Wang, J. Chem. Asian J. 2010, 5, 2214. (e) Lee, K.;
Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009, 11, 1457.
(f) Ishizuka, K.; Seike, H.; Hatakeyama, T.; Nakamura, M. J. Am.
Chem. Soc. 2010, 132, 13117. (g) Murakami, K.; Yorimitsu, H.;
Osuka, A. Angew. Chem. Int. Ed. 2014, 53, 7510. (h) Murakami,
K.; Yorimitsu, H.; Osuka, A. Bull. Chem. Soc. Jpn. 2014, in press;
DOI: 10.1246/bcsj.20140241.
(5) Reviews: (a) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401.
(b) Feldman, K. S. Tetrahedron 2006, 62, 5003. (c) Smith, L. H. S.;
Coote, S. C.; Sneddon, H. F.; Procter, D. J. Angew. Chem. Int. Ed.
2010, 49, 5832. (d) Akai, S.; Kita, Y. Top. Curr. Chem. 2007, 274,
35. (e) Sulfur-Mediated Rearrangements I; Schaumann, E., Ed.;
Springer: Berlin, Heidelberg, 2007. (f) Yorimitsu, H. J. Synth. Org.
Chem. Jpn. 2013, 71, 341.
(6) (a) Yoshida, S.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 5573.
(b) Yoshida, S.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2008, 37,
786. (c) Kobatake, T.; Yoshida, S.; Yorimitsu, H.; Oshima, K.
Angew. Chem. Int. Ed. 2010, 49, 2340. (d) Murakami, K.; Imoto, J.;
Matsubara, H.; Yoshida, S.; Yorimitsu, H.; Oshima, K. Chem. Eur.
J. 2013, 19, 5625. (e) Kobatake, T.; Fujino, D.; Yoshida, S.;
Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2010, 132, 11838.
(f) Ookubo, Y.; Wakamiya, A.; Yorimitsu, H.; Osuka, A. Chem.
Eur. J. 2012, 18, 12690.
OMe
(CF3CO)2O (1.3 equiv)
CH2Cl2, 25 °C, 1 h
+
OH
SMe
SMe
SMe
O
O
4 61%
3
OR1
NiCl2(PPh3)(IPr) (3 mol%)
BuMgBr (1.3 equiv)
THF, 25 °C, 0.5 h 95%
or
NiCl2(PPh3)(IPr) (3 mol%)
BnMgCl (1.3 equiv)
toluene, 25 °C, 4 h >99%
R2
O
5a R1, R2 = Me, Bu
5b R1, R2 = Me, Bn
BBr3
ref. 14
6a R1, R2 = H, Bu
6b R1, R2 = H, Bn
Scheme 3 Formal synthesis of PTP inhibitors
Acknowledgment
This work was supported by Grants-in-Aid from MEXT (Nos.:
24106721 ‘Reaction Integration’ and 25107002 ‘Science of Atomic
Layers’) and from JSPS {Nos.: 24685007 [Young Scientists (A)] and
26620081 (Exploratory Research)}. A.B. and K.M. acknowledge JSPS
for financial support. V.G. thanks Ecole Nationale Supérieure de
Chimie de Rennes for Overseas Student Training Program.
(7) Facile preparation of ketene dithioacetal monoxides:
(a) Murakami, K.; Yorimitsu, H.; Osuka, A. Bull. Chem. Soc. Jpn.
2013, 86, 1193. (b) Murakami, K.; Yorimitsu, H.; Osuka, A. Bull.
Chem. Soc. Jpn. 2014, 87, 441. (c) Ogura, K.; Tsuchihashi, G. Tet-
rahedron Lett. 1972, 13, 1383. (d) Ogura, K.; Ito, Y.; Tsuchihashi,
G. Bull. Chem. Soc. Jpn. 1979, 52, 2013.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378914.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(8) Ni–NHC catalysts are known to be more effective than Ni–phos-
phine catalysts for cross-coupling arylation of organosulfur
compounds with aryl Grignard reagents. See ref. 4b,g,h.
(9) Representative reviews on transition metal–carbene com-
plexes: (a) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41,
1440. (b) Diez-Gonzalez, S.; Nolan, S. P. Coord. Chem. Rev. 2007,
251, 874. (c) Fortman, G. C.; Nolan, S. P. Chem. Soc. Rev. 2011, 40,
5151. (d) Wuertz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523.
(e) Weskamp, T.; Bohm, V. P. W.; Herrmann, W. A. J. Organomet.
Chem. 2000, 600, 12. (f) Valente, C.; Çalimsiz, S.; Hoi, K. H.;
Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed. 2012,
51, 3314.
References and Notes
(1) (a) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 20,
43. (b) Takei, H.; Miura, M.; Sugimura, H.; Okamura, H. Chem.
Lett. 1979, 1447. (c) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L.
J. Chem. Soc., Chem. Commun. 1979, 637.
(2) Reviews: (a) Sugimura, H.; Okamura, H.; Miura, M.; Yoshida, M.;
Takei, H. Nippon Kagaku Kaishi 1985, 416. (b) Naso, F. Pure Appl.
Chem. 1988, 60, 79. (c) Luh, T.-Y.; Ni, Z.-J. Synthesis 1990, 89.
(d) Luh, T.-Y. Acc. Chem. Res. 1991, 24, 257. (e) Fiandanese, V.
Pure Appl. Chem. 1990, 62, 1987. (f) Liebeskind, L. S.; Srogl, J.;
Savarin, C.; Polanco, C. Pure Appl. Chem. 2002, 74, 115.
(g) Dubbaka, S. R.; Vogel, P. Angew. Chem. Int. Ed. 2005, 44, 7674.
(h) Prokopcová, H.; Kappe, C. O. Angew. Chem. Int. Ed. 2008, 47,
3674. (i) Wang, L.; He, W.; Yu, Z. Chem. Soc. Rev. 2013, 42, 599.
(j) Modha, S. G.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc.
Rev. 2013, 42, 5042. (k) Pan, F.; Shi, Z.-J. ACS Catal. 2014, 4, 280.
(10) For Ni–NHC complexes: (a) Gu, S.; Ni, P.; Chen, W. Chin. J. Catal.
2010, 31, 875. (b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.;
Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev.
2011, 111, 1346. (c) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 327–330

330
A. Baralle et al.
Cluster
Synlett
(11) (a) Matsubara, K.; Ueno, K.; Shibata, Y. Organometallics 2006,
25, 3422. (b) Tanaka, S.; Tanaka, D.; Tatsuta, G.; Murakami, K.;
Tamba, S.; Sugie, A.; Mori, A. Chem. Eur. J. 2013, 19, 1658.
(c) Iglesias, M. J.; Prieto, A.; Nicasio, M. C. Org. Lett. 2012, 14,
4318.
2-Butyl-3-phenylbenzo[b]furan (2a)
1H NMR (600 MHz, CDCl3): δ = 7.60 (d, 1 H, J = 7.8 Hz), 7.54–7.50
(m, 5 H), 7.40 (t, 1 H, J = 6.6 Hz), 7.30 (t, 1 H, J = 6.6 Hz), 7.25 (t, 1
H, J = 7.8 Hz), 2.90 (t, 2 H, J = 7.8 Hz), 1.81 (quint, 2 H, J = 7.2 Hz),
1.44 (sext, 2 H, J = 7.2 Hz), 0.95 (t, 3 H, J = 7.2 Hz) ppm. 13C NMR
(150 MHz, CDCl3): δ = 155.46, 154.18, 133.07, 129.25, 129.06,
128.86, 127.12, 123.66, 122.68, 119.57, 116.93, 110.97, 30.68,
26.66, 22.61, 13.95 ppm. IR: 2956, 2928, 2871, 1610, 1496,
1454, 1255, 1219, 1174, 1012, 969, 769, 700 cm–1. ESI-HRMS:
m/z calcd for C18H18OH [M + H]+: 281.1536; found: 281.1538.
(13) The scope of benzofuran substrates in the alkylation seems to
be narrower than that in our previous arylation at present. For
instance, 3-CF3-substituted benzofuran resisted the butylation
whereas it underwent smooth arylation in ref. 6f.
(12) Butylation of 1a – Representative Procedure
NiCl2(PPh3)(IPr) (11.7 mg, 0.015 mmol) was placed in a dry
Schlenk tube equipped with a magnetic stir bar and a rubber
septum under argon. A solution of methylsulfanylbenzofuran
(1a, 120 mg, 0.50 mmol) in THF (5.0 mL) was then added. Butyl-
magnesium bromide (0.60 M in THF, 1.0 mL, 0.60 mmol) was
then added to the mixture, and the resulting mixture was
stirred for 30 min at 25 °C. The mixture was filtered through a
pad of silica gel with copious washings with CH2Cl2. The filtrate
1
was evaporated to leave a crude oil. H NMR analysis of the oil
(14) Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W.;
McDevitt, R.; Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.;
Sullivan, D.; Taylor, J. R. J. Med. Chem. 2000, 43, 1293.
revealed the yield of 2a was quantitative. Silica gel column puri-
fication (n-hexane) afforded butylated benzofuran 2a (121 mg,
0.48 mmol) in 97% yield as a colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 327–330

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.