A manganese-catalyzed cross-coupling reaction

Article abstract of DOI:10.1055/s-2007-968013

A manganese-catalyzed cross-coupling reaction of heterocyclic chlorides with aryl- as well as alkylmagnesium halides has been developed. The reaction provides a variety of heterocyclic compounds under mild and practical reaction conditions using low amounts of manganese chloride as catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-968013

LETTER
247
A Manganese-Catalyzed Cross-Coupling Reaction
Manganese-Catalyzed
a
Cross-Coup
g
ling Reactio
n
n
us Rueping,* Winai Ieawsuwan
Degussa Endowed Professorship, Institute of Organic Chemistry and Chemical Biology, Johann-Wolfgang Goethe University Frankfurt,
Max-von-Laue Straße 7, 60438 Frankfurt, Germany
Fax +49(69)79829248; E-mail: M.Rueping@chemie.uni-frankfurt.de
Received 20 October 2006
R
R
R'–MgX 2
Abstract: A manganese-catalyzed cross-coupling reaction of
heterocyclic chlorides with aryl- as well as alkylmagnesium halides
has been developed. The reaction provides a variety of heterocyclic
compounds under mild and practical reaction conditions using low
amounts of manganese chloride as catalyst.
Cl
R'
MnCl2 (2–5 mol%)
N
N
1
3
Scheme 2 Manganese-catalyzed cross-coupling reaction of chloro-
quinoline and Grignard reagents
Key words: manganese catalysis, cross-coupling, arylation, alkyla-
tion, heterocycles, pyridine, quinoline
Our initial experiments of the manganese-catalyzed cross-
coupling reaction of chloroquinolines with aryl- and
alkylmagnesium chlorides 2 concentrated on the evalua-
tion of reaction parameters, such as solvent, temperature,
catalyst loading and manganese salt. From these first ex-
periments, we found that the test cross-coupling reaction
of 4-chloroquinoline (1a) with phenyl magnesium chlo-
ride (2a) could best be performed in THF as solvent. The
use of other solvents such as diethyl ether or DME also led
to product formation, but yields of the corresponding iso-
lated 4-phenyl quinoline (3a) were considerably lower.
Among the commercially available manganese salts ex-
amined, manganese(II) chloride9 showed the best catalyt-
ic activity and the use of 1 or 2 mol% resulted in complete
conversion of the substrate 1a after a short reaction time
(1.5 h) at 0 °C. The corresponding product 4-phenyl quin-
oline (3a) was obtained in either 86% or 91% isolated
yield, respectively, after column chromatography
(Table 1, entry 1). Using these optimized reaction condi-
tions, we explored the reaction of 1a with different alkyl-
magnesium chlorides 2b–e (Table 1, entry 2–7). The 4-
alkyl-substituted quinolinines were again isolated in good
yields (65–83%), however, in some cases we had to use 5
mol% of catalyst. The manganese-catalyzed cross-cou-
pling reaction could also be performed with 2-chloro-, 2-
chloro-4-alkyl-, and 4-chloro-2-phenylquinoline deriva-
tives 1b–d, as well as the 4,7-dichloroquinoline (1e). In
the latter case the 4-substituted product 3l was the major
isolated product. However, some formation of double
substituted product was additionally observed. Further ex-
amination of the reaction focused on variation of the het-
erocyclic system. Hence, performing the cross coupling of
1-chloroisoquinoline (1f) with phenyl- or n-butyl-magne-
sium chloride, the corresponding 2-alkyl- and 2-aryliso-
quinolines 3n–o were obtained in satisfactory 77% and
84% yield, respectively (entry 17 and 18). Similarly, the
manganese-catalyzed reaction of quinazoline, benzo-
thiazole, purine, pyrimidine, quinoxaline, and pyridine
derivatives 1g–l resulted in the corresponding alkylated
or arylated heterocyclic products 3p–v (entry 19–25),
although lower yields were obtained with the more
Transition-metal-catalyzed carbon–carbon bond-forming
reactions are of great significance in the preparation of
polyfunctional heterocylces.1 This is especially true for
cross-coupling reactions of chloro-substituted hetero-
cycles with readily available alkyl- and aryl-Grignard
reagents.2 So far, these reactions have been performed
with toxic or expensive nickel3 and palladium4 complexes
or using more effective iron5 or cobalt6 catalysts.
Recently, we became interested in the synthesis of
1,2,3,4-tetrahydroquinoline derivatives, which are of
great synthetic importance in the preparation of pharma-
ceuticals and agrochemicals, as well as in material scienc-
es. In addition, many natural occurring alkaloids consist
of this structural key element. Given the importance of
this class of molecules, we recently developed a new
Brønsted acid catalyzed partial reduction of quinolines
(Scheme 1).7
O
O
EtO
OEt
R
R
N
H
R'
R'
N
H
N
Brønsted acid
Scheme 1 Brønsted acid catalyzed transfer hydrogenation
During the development of this hydrogenation procedure
we required a practical, efficient and fast access to various
substituted quinolines. Here we wish to report our results
on the development of such a process, a manganese-cata-
lyzed cross-coupling reaction of chloroquinolines with
aryl- and alkylmagnesium halides (Scheme 2),8 and the
extension of this coupling procedure to other chloro-sub-
stituted heterocycles.
SYNLETT 2007, No. 2, pp 0247–0250
0
1.
0
2.
2
0
0
7
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-968013; Art ID: G31806ST
© Georg Thieme Verlag Stuttgart · New York

248
M. Rueping, W. Ieawsuwan
LETTER
electron-rich substrates. Interestingly, when comparing faster transmetalation step and formation of the alkyl-
the manganese-catalyzed cross-coupling reactions of aryl- manganese intermediates in the catalytic cycle.
with alkylmagnesium chlorides, we found that the latter
reactions generally proceeded more rapidly pointing to a
Table 1 Manganese-Catalyzed Cross-Coupling Reaction of Various Heterocyclic Chlorides with Aryl- and Alkylmagnesium Chlorides10
Entry
Ar–Cl
RMgCl 2
(equiv)
Catalyst amount Temp (°C) Time (h)
(mol%)
Product 3
Yield (%)a
R
1
2
PhMgCl (2) 2a
1
2
0
1.5
86
91
Cl
N
N
3a: R = Ph
1a
1a
3
MeMgCl (2) 2b
i-PrMgCl (2) 2c
5
0
0
1.5
1.5
3b: R = Me
3c: R = i-Pr
83
4
5
1a
1
2
78
89
6
7
8
1a
1a
n-BuMgCl (2) 2d
i-BuMgCl (2) 2e
PhMgCl (2) 2a
5
5
5
0
1.5
5.0
12
3d: R = n-Bu
3e: R = i-Bu
65
87
64
0
0 to r.t.
N
Cl
N
3f: R = Ph
3g: R = i-Pr
R
1b
1b
9
i-PrMgCl (1.2) 2c
PhMgCl (4) 2a
5
5
0
1.5
12
78
71
10
0 to r.t.
Me
Me
N
N
R
Cl
3h: R = Ph
1c
1c
11
12
i-PrMgCl (1.5) 2c
PhMgCl (4) 2a
2
5
0
4
4
3i: R = i-Pr
74
69
13
5
0 to r.t.
82
R
Cl
N
N
Ph
Ph
1d
1d
3j: R = Ph
14
15
i-PrMgCl (1.5) 2c
PhMgCl (2) 2a
2
5
0
4
3k: R = i-Pr
81
53
0 to r.t.
12
Cl
R
Cl
N
Cl
N
1e
3l: R = Ph
16
17
1e
i-PrMgCl (1.2) 2c
PhMgCl (4) 2a
5
5
0
0
2
3m: R = i-Pr
52
84
1.5
N
N
Cl
R
1f
1f
3n: R = Ph
18
n-BuMgCl (2) 2d
5
0
2
3o: R = n-Bu
77
Synlett 2007, No. 2, 247–250 © Thieme Stuttgart · New York

LETTER
Manganese-Catalyzed Cross-Coupling Reaction
249
Table 1 Manganese-Catalyzed Cross-Coupling Reaction of Various Heterocyclic Chlorides with Aryl- and Alkylmagnesium Chlorides10
(continued)
Entry
19
Ar–Cl
RMgCl 2
(equiv)
Catalyst amount Temp (°C) Time (h)
(mol%)
Product 3
Yield (%)a
71
Cl
N
PhMgCl (4) 2a
5
0
1.5
R
N
N
Ph
N
Ph
Ph
1g
1g
3p: R = Ph
20
21
i-PrMgCl (2) 2c
PhMgCl (5) 2a
5
5
0
3
3
3q: R = i-Pr
50
47
0 to r.t.
S
N
S
N
Cl
1h
3r
22
i-PrMgCl (2.4) 2c
5
0
2
46
i-Pr
Cl
N
N
N
N
N
N
N
H
N
H
1i
3s
23
24
25
PhMgCl (3) 2a
PhMgCl (4) 2a
PhMgCl (2) 2a
5
5
5
0
3
40
58
58
N
N
N
Cl
N
N
Ph
N
1j
1k
1l
3t
–20
0 to r.t.
0.5
4
Ph
Cl
N
N
3u
3v
N
Cl
N
R
a Isolated yield after flash chromatography.
After having developed an efficient manganese-catalyzed gen-containing heteroaryl chlorides with aryl- as well as
cross-coupling reaction of aryl- and alkyl-Grignard re- alkylmagnesium halides. Additionally, we were able to
agents with a range of chloro-substituted heterocycles, we demonstrate that this transformation can be easily per-
wondered whether it would be possible to extend this formed in a one-pot procedure to give the corresponding
transformation to a one-pot procedure. Hence, we pre- heterocyclic products in good to excellent isolated yields.
pared the corresponding Grignard reagents and added The mild reaction conditions, the operational simplicity
subsequently a solution of 4-chloroquinoline (1a) and and practicability, as well as the low catalyst loading and
MnCl2 to this mixture (Scheme 3). Following this proto- the lower cost of manganese chloride, as compared to
col we were able to isolate the corresponding 4-substitut- palladium or nickel salts, render this transformation an
ed quinoline derivatives in good to excellent yields (63– attractive alternative approach to various alkylated and
92%).
arylated heterocycles.
In summary we have developed an efficient manganese-
catalyzed cross-coupling reaction of a wide range of nitro-
Acknowledgment
Financial support by Degussa AG is gratefully acknowledged.
Ar
1) Mg, THF
2) 4-chloroquinoline
Ar Br
References and Notes
3) 2–5 mol% MnCl2, 0 °C
N
(1) (a) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, 1998.
(b) Miyaura, N. Cross-Coupling Reactions. A Practical
Guide; Springer: Berlin, 2002. (c) Knochel, P. Handbook of
Functionalized Organometallics; Wiley-VCH: Weinheim,
2005.
3a: Ar = Ph, 92%
3y: Ar = p-Tol, 85%
3z: Ar = 1-Naphthyl, 63%
Scheme 3 One-pot cross-coupling reaction of 4-chloroquinoline
with aryl-Grignard reagents
Synlett 2007, No. 2, 247–250 © Thieme Stuttgart · New York

250
M. Rueping, W. Ieawsuwan
LETTER
(10) Typical Procedure: Preparation of 4-Isopropyl-2-
(2) Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081.
(3) (a) Takahashi, T.; Kanno, K. Modern Organonickel
Chemistry; Wiley-VCH: Weinheim, 2005. (b) Tamao, K.;
Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94,
4374. (c) Kiso, Y.; Tamao, K.; Kumada, M. J. Organomet.
Chem. 1973, 50, C12. (d) Erdelmeier, I.; Gais, H. J. J. Am.
Chem. Soc. 1989, 111, 1125. (e) Li, G. Y. Angew. Chem.
Int. Ed. 2001, 40, 1513; Angew. Chem. 2001, 113, 1561.
(f) Li, G. Y.; Marshall, W. J. Organometallics 2002, 21,
590. (g) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D.
Angew. Chem. Int. Ed. 2005, 44, 7216; Angew. Chem. 2005,
117, 7382.
phenylquinoline (3k).
A two-necked round-bottomed flask was charged under Ar
with 4-chloro-2-phenylquinoline (0.2397 g, 1.00 mmol),
MnCl2 (6.3 mg, 50 mmol) and THF (5mL) and cooled to
0 °C. The Grignard reagent i-PrMgCl (1.25 mL, 1.20 M in
THF, 1.50 mmol) was added slowly via a syringe and the
reaction mixture was stirred at 0 °C for 4 h. The reaction
mixture was quenched with sat. NH4Cl (5 mL) and H2O (5
mL) at 0 °C, extracted with EtOAc (3 × 25 mL), and dried
over Mg(SO4). After removal of solvents in vacuo, the crude
product was purified by column chromatography (hexane–
EtOAc, 50:1) to give the product as a pale yellow oil (0.1887
g, 81%). 1H NMR (250 MHz, CDCl3): d = 8.12 (d, J = 8.5
Hz, 1 H, ArH), 8.10–8.02 (m, 2 H, ArH), 7.99 (d, J = 8.3 Hz,
1 H, ArH), 7.68 (s, 1 H, ArH), 7.64–7.55 (m, 1 H, ArH),
7.47–7.32 (m, 4 H, ArH), 3.68 [sept, J = 6.8 Hz, 1 H,
CH(CH3)2], 1.35 [d, J = 6.8 Hz, 6 H, CH(CH3)2]. 13C NMR
(63 MHz, CDCl3): d = 157.4 (C), 155.0 (C), 148.6 (C), 140.3
(C), 130.7 (CH), 129.2 (CH), 129.1 (CH), 128.8 (CH), 127.7
(CH), 126.0 (CH), 125.9 (C), 123.0 (CH), 115.0 (CH), 28.6
(CH), 23.1 (CH3). IR (neat): n = 3061 (m), 2865 (s), 2930
(m), 2871 (w), 1596 (s), 1551 (s), 1508 (m), 1494 (s), 1460
(m), 1445 (m), 1414 (w), 1385 (m), 1364 (w), 1347 (s), 1234
(w), 1181 (w), 1071 (w), 1029 (w), 907 (w), 879 (m), 838
(w), 792 (m), 770 (s), 694 (s) cm–1. ESI-MS: m/z = 248 [M +
H]+. Anal. Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66.
Found: C, 87.59; H, 7.04; N, 5.45.
(4) (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176. (b) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E.
Tetrahedron 2001, 57, 7449. (c) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(5) (a) Fürstner, A.; Leitner, A.; Méndez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856. (b) Quintin, J.; Frank, X.;
Hocquemiller, R.; Figadère, B. Tetrahedron Lett. 2002, 43,
3547. (c) Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P.
Synlett 2001, 1901. (d) Cahiez, G.; Avedissian, H. Synthesis
1998, 1199. (e) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc.
1971, 93, 1487. (f) Tamura, M.; Kochi, J. K. Synthesis 1971,
303. (g) Neumann, S. M.; Kochi, J. K. J. Org. Chem. 1975,
40, 599. (h) Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976,
41, 502. (i) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351.
(6) (a) Cahiez, G.; Avedissian, H. Tetrahedron Lett. 1998, 39,
6159. (b) Avedissian, H.; Bérillon, L.; Cahiez, G.; Knochel,
P. Tetrahedron Lett. 1998, 39, 6163. (c) Korn, T.; Cahiez,
G.; Knochel, P. Synlett 2003, 1892.
Preparation of 4-(p-Tolyl)quinoline (3y).
A two-necked round-bottomed flask, equipped with a reflux
condenser and dropping funnel, was charged with Mg (63.2
mg, 2.60 mmol) and THF (8 mL) under Ar and a solution of
p-bromotoluene (0.4276 g, 2.50 mmol) in THF (5 mL) was
added dropwise (15 min). Subsequently, the reaction
mixture was refluxed for 1 h and cooled to 0 °C. A solution
of 4-chloroquinoline (0.1636 g, 1.00 mmol) in THF (3 mL)
was added via syringe to the reaction mixture and MnCl2
(2.5 mg, 20 mmol) was quickly added. The resulting solution
was stirred at 0 °C for 2 h, quenched with sat. NH4Cl (5 mL)
and H2O (5 mL) at 0 °C, extracted with EtOAc (3 × 25 mL),
and dried over Mg(SO4). After removal of solvents in vacuo,
the crude product was purified by silica gel column
chromatography (hexane–EtOAc, 5:1) to provide the
product as a pale yellow oil (0.1857 g, 85%). 1H NMR (250
MHz, CDCl3): d = 8.05 (d, J = 8.5 Hz, 1 H, ArH), 8.79 (d,
J = 4.5 Hz, 1 H, ArH), 7.81 (d, J = 8.3 Hz, 1 H, ArH), 7.61–
7.78 (m, 1 H, ArH), 7.37–7.28 (m, 1 H, ArH), 7.28–7.14 (m,
5 H, ArH), 2.31 (s, 3 H, CH3). 13C NMR (63 MHz, CDCl3):
d = 150.0 (CH), 148.8 (C), 148.5 (C), 138.4 (C), 135.1 (C),
129.9 (CH), 129.5 (CH), 129.3 (CH), 129.2 (CH), 126.9 (C),
126.5 (CH), 126.0 (CH), 121.3 (CH), 21.3 (CH3). IR (neat):
n = 3027 (m), 2920 (m), 1614 (m), 1586 (s), 1569 (s), 1501
(s), 1459 (w), 1421 (m), 1389 (m), 1275 (w), 1112 (w), 1021
(w), 872 (w), 819 (s), 765 (s), 721 (w), 674 (m), 661 (w)
cm–1. ESI-MS: m/z = 220 [M + H]+. Anal. Calcd for
C16H13N: C, 87.64; H, 5.98; N, 6.39. Found: C, 87.53; H,
6.15; N, 6.29.
(7) Organocatalytic reductions of quinolines and imines:
(a) Rueping, M.; Theissmann, T.; Antonchick, A. P. Synlett
2006, 1071. (b) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem. Int. Ed. 2006, 45, 3683;
Angew. Chem. 2006, 118, 3765. (c) Rueping, M.; Azap, C.;
Sugiono, E.; Theissmann, T. Synlett 2005, 2367.
(d) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (e) Rueping, M.;
Sugiono, E.; Azap, C. Angew. Chem. Int. Ed. 2006, 45, 2617;
Angew. Chem. 2006, 118, 2679. (f) Rueping, M.;
Antonchick, A. P.; Theissmann, T. Angew. Chem. Int. Ed.
2006, 45, 6751; Angew. Chem. 2006, 118, 6903.
(g) Rueping, M.; Azap, C. Angew. Chem. Int. Ed. 2006, 45,
7832; Angew. Chem. 2006, 118, 7996.
(8) For an earlier report on functional-group-directed
manganese-catalyzed cross-coupling with activated aryl
chlorides, see: Cahiez, G.; Lepifre, F.; Ramiandrasoa, P.
Synthesis 1999, 2138.
(9) For the reactions reported commercially available MnCl2
salts were applied. MnCl2 anhyd (Aldrich 99.999%),
MnCl2·4H2O (Strem 99.999%) and MnCl2 (Aldrich 98%)
gave the same results in the cross-coupling reactions.
Synlett 2007, No. 2, 247–250 © Thieme Stuttgart · New York

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