Room temperature cross-coupling of highly functionalized organozinc reagents with thiomethylated N-heterocycles by nickel catalysis

Article abstract of DOI:10.1021/jo1001615

Chemical Equation Presented A variety of thiomethyl-substituted N-heterocycles such as pyridines, isoquinolines, pyrimidines, pyrazines, pyridazines, quinazolines, triazines, benzothiazoles, or benzoxazoles undergo smooth Ni-catalyzed cross-coupling reactions with functionalized aryl-, heteroaryl-, alkyl-, and benzylic zinc reagents using an inexpensive Ni(acac)₂/ DPE-Phos catalytic system at 25^°C.

Full text of DOI:10.1021/jo1001615

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TABLE 1. Catalyst and Ligand Screening in the Cross-Coupling
Reaction of 2-Thiomethylpyridine (1) with 4-Methylphenylzinc Iodide (2)
Room Temperature Cross-Coupling of Highly
Functionalized Organozinc Reagents with
Thiomethylated N-Heterocycles by Nickel Catalysis
Laurin Melzig, Albrecht Metzger, and Paul Knochel*
Department Chemie, Ludwig-Maximilians-University,
Butenandtstr. 5-13, Munich, Germany
paul.knochel@cup.uni-muenchen.de
Received January 29, 2010
entry
metal
ligand
yield (%)a
1
2
3
4
5
6
7
8
Ni(PPh3)2Br2
NiCl2 DME
14
16
16
18
20
21
23
62
71
83
92
100
H3CC(CH2PPh2)3
IMes HCl
P(o-Tol)3
1,10-P(t-Bu)2-ferrocene
H3CC(CH2PPh2)3
(R)-QUINAP
3
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
3
9
NiCl2 DME
Ni(acac)2
3
10
11
12
PPh3
DPE-Phos
DPE-Phos
NiCl2 DME
3
Ni(acac)2
aGC yield using tridecane as internal standard.
groups are now readily available.7 We wish to report herein a
general cross-coupling reaction between various thiomethyl-
substituted N-heterocycles and functionalized aryl-, hetero-
aryl-, benzylic- and alkylzinc halides using a cheap Ni catalyst.
In preliminary studies, we have screened several common nickel
salts and phosphine ligands in the model reaction between 2-
thiomethylpyridine (1) and 4-methylphenylzinc iodide (2). Inthe
absence of a Pd or Ni catalyst system, no cross-coupling was
observed.8 Initial attemps with 1 mol % Ni(PPh3)2Br29 without
any added ligand gave only 14% yield of the cross-coupling
A variety of thiomethyl-substituted N-heterocycles such as
pyridines, isoquinolines, pyrimidines, pyrazines, pyrida-
zines, quinazolines, triazines, benzothiazoles, or benzoxa-
zoles undergo smooth Ni-catalyzed cross-coupling reac-
tions with functionalized aryl-, heteroaryl-, alkyl-, and
benzylic zinc reagents using an inexpensive Ni(acac)2/
DPE-Phos catalytic system at 25 °C.
product 3 after 9 h at 25 °C (Table 1, entry 1). NiCl2 DME10
The first cross-coupling reactions of thioethers with Grignard
reagents, catalyzed by transition metals, were independently
reported by Takei and Wenkert in 1979.1 This method allows
direct conversion of a carbon-sulfur bond into a carbon-
carbon bond. Liebeskind described a Ni-catalyzed cross-
coupling reaction using various sulfur functionalities as leaving
groups.2 Stambuli has prepared functionalized oxazoles with a
Ni cross-coupling at higher temperatures.3 Recently, we have
reported that thiomethyl-substituted heterocycles undergo effi-
cient cross-couplings with various zinc reagents using the
Pd(OAc)2/S-Phos catalytic system.4 Although some progress
has been reported,5,6 an improvement of the functional group
tolerance and a lowering of the catalyst system cost would still
be desirable. Organozinc reagents bearing sensitive functional
3
furnished the 2-arylated pyridine 3 in 71% yield under these
conditions (entry 9). This yield dropped dramatically when 2 mol
SCHEME 1. Ni-Catalyzed Cross-Coupling Reaction of Thio-
methyl-Substituted Heterocycles with Functionalized Organozinc
Reagents
(7) (a) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org.
React. 2001, 58, 417. (b) Knochel, P.; Leuser, H.; Gong, L.-Z.; Perrone, S.;
Kneisel, F. F. Handbook of Functionalized Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005; Vol. 1, p 251. (c) Manolikakes, G.; Munoz
Hernandez, C.; Schade, M. A.; Metzger, A.; Knochel, P. J. Org. Chem. 2008,
73, 8422. (d) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10, 1107.
(e) Dong, Z.; Clososki, G. C.; Wunderlich, S. H.; Unsinn, A.; Li, J.; Knochel, P.
Chem.;Eur. J. 2009, 15, 457. (f) Mosrin, M.; Monzon, G.; Bresser, T.; Knochel,
P. Chem. Commun. 2009, 37, 5615. (g) Piller, F. M.; Metzger, A.; Schade, M. A.;
Haag, B. A.; Gavryushin, A.; Knochel, P. Chem.;Eur. J. 2009, 15, 7192.
(8) We have also verified that the pyridine moiety does not act as a ligand.
(9) Miyaura, N.; Tanabe, Y.; Suginome, H.; Suzuki, A. J. Organomet.
Chem. 1982, 233, C13.
(1) (a) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 1, 43.
(b) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc, Chem.
Commun. 1979, 637. (c) Wenkert, E.; Ferreira, T. W. J. Chem. Soc. Chem.
Commun. 1982, 840. (d) Wenkert, E.; Shepard, M. E.; McPhail, A. T.
J. Chem. Soc., Chem. Commun. 1986, 1390.
(2) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J. Am. Chem. Soc.
1999, 121, 9449.
(3) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett. 2009, 11, 1457.
(4) Metzger, A.; Melzig, L.; Despotopoulou, C.; Knochel, P. Org. Lett.
2009, 11, 4228.
(5) Itami, K.; Higashi, S.; Mineno, M.; Yoshida, J.-i. Org. Lett. 2005, 7,
1219.
(6) Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett 2000, 905.
(10) Gonzalez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360.
DOI: 10.1021/jo1001615
r
Published on Web 03/01/2010
J. Org. Chem. 2010, 75, 2131–2133 2131
2010 American Chemical Society

Melzig et al.
JOCNote
TABLE 2. Reaction of Thiomethyl-Substituted Heterocycles (4) with Organozinc Reagents (5)
aYield of analytically pure product.
% of 1,1,1-tris(diphenylphosphino)ethane was added (entry 2)
but increased to 92% in the presence of 2 mol % of bis[2-(di-
phenylphosphino)phenyl]ether (DPE-Phos) (entry 11).11
The use of inexpensive Ni(acac)2 led to further improvements,
and after testing different ligands, including QUINAP,12 1,10-bis-
(di-tert-butylphosphino)ferrocene,13 and also carbene ligands
2132 J. Org. Chem. Vol. 75, No. 6, 2010

Melzig et al.
JOCNote
such as IMes HCl,14 we have found that the most efficient and
alkylzinc bromide underwent also a smooth cross-coupling
with the 2,4,6-trisubstituted triazine 4e, affording the func-
tionalized triazine 6o in 68% yield (entry 15). Finally, the
reaction of 2-(methylthio)-1,3-benzoxazole (4c) with 5-cyano-
5-methylhexylzinc bromide (5m) provided the alkylated
benzoxazole 6p in 82% yield (entry 16).
3
robust system is Ni(acac)2 (1 mol %) associated with DPE-Phos
(2 mol %), giving quantitative yield of 3 after 9 h at 25 °C (entry
12).15 Using Ni(acac)2 (2.5 mol %) and DPE-Phos (5.0 mol %)16
a broad reaction scope was achieved and most cross-couplings
could be completed in 3-48 h at 25 °C (Scheme 1).
Thus, the cross-coupling proceeds well with a range of
functionalized aryl- and heteroarylzinc reagents.17 The reac-
tion of 6,7-dimethoxy-4-(methylthio)quinazoline (4a) with
4-ethoxycarbonylphenylzinc iodide (5a) provided the func-
tionalized quinazoline 6a in 82% yield (entry 1 of Table 2).
The thiomethyl-substituted pyrazine (4b) reacted with 3-
ethoxycarbonylphenylzinc iodide (5b), providing pyrazine
6b in 74% yield (entry 2). Electron-rich zinc reagents (5c,d)
reacted smoothly with benzoxazole 4c and the disubstituted
pyrimidine 4d, leading to the polyfunctional heterocycles 6c
and 6d in 81-96% yield (entries 3 and 4). The reaction of
trifluoromethylated pyrimidine 4d with 2-thienylzinc iodide
(5e) gave the pyrimidine 6e in 94% yield (entry 5). This
heteroarylic zinc reagent also underwent cross-coupling with
dimethoxy-substituted triazine (4e), yielding the trisubsti-
tuted product 6f in 87% yield (entry 6).
The reaction protocol could be applied to benzylic zinc
reagents.18 The thiomethylated pyridazine 4f reacted with 4-
fluorobenzylzinc chloride (5f), furnishing the pyridazine 6g in
74% yield (entry 7). Similarly, the pyrimidine 4g, pyridine 4h,
benzothiazole 4i, and isoquinoline 4j could be cross-coupled
with benzylic zinc reagents bearing sensitive functional groups
such as an ester, a nitrile, a ketone, or a trifluoromethyl group,
leading to the heterocyclic diarylmethanes 6h-l in 70-94%
yield (entries 8-12). Also, 4-(2-furyl)-2-methylthio-6-trifluoro-
methylpyrimidine (4k) could readily be functionalized using
the electron-rich benzylic zinc reagent 5k, providing the pyri-
midine 6m in 89% yield (entry 13).
In summary, we have developed a novel Ni-catalyzed
cross-coupling reaction that uses the inexpensive and com-
mercially available Ni(acac)2/DPE-Phos system (2.5 and 5
mol %) and takes place at room temperature, furnishing the
expected heterocyclic products in 68-96% yield. A wide
range of functional groups is tolerated, and various kinds of
zinc reagents (alkyl, aryl, heteroaryl, and benzylic) can be
utilized.
Experimental Section
Representative Preparation of 2-(3-pentanoylbenzyl)nico-
tinonitrile (6j). In a dry argon-flushed Schlenk flask equipped
with a septum and a magnetic stirring bar were dissolved
2-(methylthio)nicotinonitrile (4h) (150 mg, 1.00 mmol), Ni(acac)2
(6.4 mg, 2.5 mol %), and DPE-Phos (27 mg, 5.0 mol %) in THF (1
mL). After 10 min of stirring, (3-pentanoylbenzyl)zinc chloride (5i)
(3.41 mL, 1.50 mmol, 0.44 M in THF) was added dropwise, and the
reaction mixture was stirred for 5 h at room temperature until GC
analysis of a hydrolyzed aliquot showed full conversion of the
electrophile. The reaction mixture was quenched with saturated
aqueous K2CO3 solution (15 mL) and extracted with EtOAc (3 ꢀ
25 mL). The combined organic layers were dried (Na2SO4), andthe
solvent was removed in vacuo. Purification by flash chromato-
graphy (silica gel, pentane/Et2O 4:6) afforded the pyridine 6j (221
mg, 79%) as a clear oil. 1H NMR (CDCl3, 600 MHz) δ (ppm) 0.92
(t, J = 7.31 Hz, 3H), 1.32-1.44 (m, 2H), 1.63-1.73 (m, 2H), 2.93
(t, J = 7.43 Hz, 2H), 4.43 (s, 2H), 7.28 (dd, J = 7.80, 4.83 Hz, 1H),
7.36-7.41 (m, 1H), 7.53-7.57 (m, 1H), 7.79-7.83 (m, 1H),
7.91-7.96 (m, 2H), 8.73 (dd, J = 4.83, 1.36 Hz, 1H). 13C NMR
(CDCl3, 150 MHz) δ (ppm) 13.9 (CH3), 22.4 (CH2), 26.4 (CH2),
38.3 (CH2), 42.8 (CH2), 109.2, 116.7, 121.5 (CH), 126.6 (CH),
128.7 (CH), 128.9 (CH), 133.5 (CH), 137.5, 137.8, 140.7 (CH),
152.6 (CH), 162.9, 200.3. IR (Diamond-ATR, neat) ν~/cm-1 2956
(m), 2931 (m), 2870 (w), 2227 (w), 1680 (vs), 1580 (m), 1564 (m),
1429 (s), 1265 (m), 1255 (m), 1225 (m), 1174 (m), 1157 (m), 1093
(m), 804 (s), 776 (m), 712 (m), 691 (s). MS (EI, 70 eV) m/z (%) 278
(Mþ, 13), 237 (7), 236 (40), 235 (11), 222 (15), 221 (100), 219 (7),
194 (6), 193 (23), 192 (32). HRMS (EI) calcd for C18H18N2O,
278.1419; found, 278.1417 (Mþ).
Furthermore, this Ni-catalyzed cross-coupling reaction
also takes place with alkylzinc reagents.17 Hence pyrimidine
4l reacted with 4-cyanopropylzinc bromide (5l), furnishing
the alkylated product 6n in 84% yield (entry 14). This
(11) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; Goubitz,
K.; Fraanje, J.; van Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081.
(12) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry
1993, 4, 743.
(13) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369.
(14) Arduengo, A. J. III; Rasika Dias, H. V.; Harlow, R. L.; Kline, M.
J. Am. Chem. Soc. 1992, 114, 5530.
(15) Melzig, L.; Gavryushin, A.; Knochel, P. Org. Lett. 2007, 9, 5529.
(16) The catalyst and ligand loading was raised from 1 mol % Ni(acac)2 to
2.5 mol % to decrease the reaction time especially in the case of unreactive
zinc reagents such as 5j or 5l.
(17) All aryl- and alkylzinc reagents were prepared according to
Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 6040.
Acknowledgment. We thank the DFG and the European
Research Council (ERC) for financial support. We thank
Chemetall GmbH(Frankfurt) and BASF SE (Ludwigshafen)
for the generous gift of chemicals.
Supporting Information Available: Experimental proce-
dures and full characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) All benzylic zinc reagents were prepared according to Metzger, A.;
Schade, M. A.; Manolikakes, G.; Knochel, P. Chem. Asian J. 2008, 3, 1678.
J. Org. Chem. Vol. 75, No. 6, 2010 2133