Room-temperature chromium(II)-catalyzed direct arylation of pyridines, aryl oxazolines, and imines using arylmagnesium reagents

Article abstract of DOI:10.1021/ol502623v

We report a CrCl₂-catalyzed oxidative arylation of various pyridines, aryl oxazolines, and aryl imines using aromatic Grignard reagents in the presence of 2,3-dichlorobutane (DCB). Most of the reactions proceed rapidly at 25 °C and do not requi

Full text of DOI:10.1021/ol502623v

Letter
pubs.acs.org/OrgLett
Room-Temperature Chromium(II)-Catalyzed Direct Arylation of
Pyridines, Aryl Oxazolines, and Imines Using Arylmagnesium
Reagents
Olesya M. Kuzmina and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstr. 5-13, 81377 Munich, Germany
̈
S
* Supporting Information
ABSTRACT: We report a CrCl2-catalyzed oxidative arylation
of various pyridines, aryl oxazolines, and aryl imines using
aromatic Grignard reagents in the presence of 2,3-dichlor-
obutane (DCB). Most of the reactions proceed rapidly at 25
°C and do not require any additional ligand. Benzo[h]-
quinoline, 2-arylpyridine, aryl oxazoline, and imines were
successfully arylated in good yields under these conditions. A TMS-substituent was used to prevent double arylation. After
oxidative cross-coupling the TMS-group was further converted to a second ortho-aryl substituent. Remarkably, inexpensive aryl
N-butylimine derivatives are excellent substrates for this oxidative arylation.
Table 1. Optimization of the Reaction of Benzo[h]quinoline
(1) with PhMgBr (2a) Catalyzed by CrCl2
he formation of C−C bonds involving a transition-metal
Tcatalyzed C−H activation has been widely developed in
recent years.1 A range of transition metals such as Pd,2 Ru,3 Rh,4
Co,5 and Fe6,7 catalyze such cross-couplings. Iron and to some
extent cobalt complexes are of special interest due to the
moderate price and toxicity of these metals. The pioneering
work of Nakamura and Yoshikai involving iron6a,b,e or cobalt
catalysis5a−f,h,j−l and the recent modification of Wang and Shi5g
have attracted much attention. Although very attractive, the
large amounts of Grignard reagents required to reach full
conversion, the long reaction times,5g,6a,d and the need for
appropriate ligands (such as cis-1,2-bis(diphenylphosphino)-
ethylene, 1,10-phenanthroline, 4,4′-di-tert-2,2-bipyridyl or N-
heterocyclic carbenes)5h−k,6a,b,7b are drawbacks that make
improvements still desirable.7 Previously, we reported that
CrCl2 is an excellent catalyst for performing cross-couplings
between aryl or heteroaryl halides and Grignard reagents.8 The
key feature of this cross-coupling is the very small amount of
homocoupling product formed, implying that almost no excess
of Grignard reagent is required. Furthermore, these chromium-
(II)-catalyzed cross-couplings are very fast reactions. These
interesting features led us to examine directed C−H bond
activation reactions involving CrCl2.9 Herein, we report the first
Cr-catalyzed directed arylation of N-heterocycles,2b,3c,5b,g,6a,7a−c
aryl oxazolines,3c,e and aryl imines,5d,h,j,k,7a,c which proceed
usually rapidly at 25 °C and do not require any additional ligand.
Thus, we have treated benzo[h]quinoline (1) with PhMgBr (2a,
CrCl2
PhMgBr
yield of 3a
a
entry
1
(mol %)
(2a; equiv)
oxidant
(%)
0
4
2,3-dichlorobutane
(DCB)
0
2
3
4
5
6
7
5
10
10
10
10
10
4
DCB
57
b
4
DCB
98 (95)
1.5
2.5
4
DCB
19
63
45
87
DCB
1,2-dichloroethane
4
1,2-dichloro-2-
methylpropane
8
10
4
without
10
a
Yield determined after 24 h by integration of a GC chromatogram
b
and comparison with undecane as a calibrated internal standart. Yield
of isolated product.
to 19% and 63% (entries 4 and 5).11 Changing the nature of the
oxidant from DCB5g to 1,2-dichloroethane or 1,2-dichloro-2-
methylpropane6a,7 led to lower yields (45−87%; entries 6 and
7). In the absence of an oxidant, only 10% of 3a was obtained
(entry 8). Treatment of benzo[h]quinoline (1) with PhMgBr
(2a; 4 equiv) under the optimized conditions provided the
arylated heterocycle 3a in 95% isolated yield (entry 3). Similarly,
other arylmagnesium reagents bearing either donor or acceptor
substituents undergo a high yield arylation at position 10
furnishing the arylated benzo[h]quinolines 3b−f in 66−90%
10
1.5−4 equiv) in the presence of catalytic amounts of CrCl2
and a 1,2-dichloroalkane acting as an oxidant at 25 °C for 24 h
(Table 1). The use of 5 mol % of CrCl2 led to the desired
phenylated product in 57% yield, in the presence of 2,3-
dichlorobutane (DCB)5g as an oxidant (entry 2). Using 10 mol
% of CrCl2 increased the yield of 3a to 98% (calibrated GC-
yield; entry 3). Lowering the amount of Grignard reagent to 1.5
or 2.5 equiv (instead of 4 equiv) decreased the yield respectively
Received: September 4, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
yield (entries 2−6 of Table 2). Using the same conditions, it was
also possible to arylate 2-(2-trimethylsilylphenyl)pyridine (4)
with various arylmagnesium reagents, affording the expected
pyridines 5a−e in 79−92% yield (entries 7−11 of Table 2).
Interestingly, these chromium(II)-catalyzed arylations pro-
ceed within a few hours at 25 °C. The role of the TMS-group
(TMS = trimethylsilyl) at position 2 is to avoid a double
arylation. This group can be further used to introduce a second
different aryl substituent as shown in Scheme 1.
Scheme 1. Selective Bis-arylation of Phenylpyridine 4 Using
Chromium and Palladium Catalysts
Table 2. Chromium-Catalyzed Arylation of
Benzo[h]quinoline (1) and 2-(2-
Trimethylsilylphenyl)pyridine (4)
Thus, the treatment of 4 with 3-tolylmagnesium bromide
(2h) in the presence of CrCl2 (10 mol %; 97% purity) and DCB
(1.5 equiv) afforded the arylated product 5f in 89% yield.
Treatment with ICl in refluxing CH2Cl2 for 12 h, followed by
Negishi cross-coupling12 with the cyano-substituted phenylzinc
derivative 6 in the presence of 3 mol % Pd(dba)2 (dba =
dibenzylideneacetone) and 6 mol % tfp (tfp = tris(2-
furyl)phosphine)13 at 50 °C for 15 h, furnished the bis-arylated
pyridine 7 in 63% yield over two steps (Scheme 1).
Aryl oxazolines are very popular substituents for directed C−
H bond activation. Using the 2-TMS-phenyl oxazoline 8, we
have achieved an efficient C−H activation and arylation with
various Grignard reagents as shown in Scheme 2. Functional
groups such as a methoxy, a dimethylamino, or an OTBS group
were well tolerated, and the ortho-arylated oxazolines 9a−d were
obtained in 72−91% yield (Scheme 2).
Scheme 2. Chromium-Catalyzed Arylation of 2-(2-
Trimethylsilyl)phenyl)oxazoline (8) with Grignard Reagents
2
To convert the TMS group into a second aryl substituent, we
have first arylated 8 with the Grignard reagent 2f using 10 mol %
CrCl2 and DCB (1.5 equiv) and have obtained oxazoline 9e in
87% yield (Scheme 3).
Treatment of 9e with ICl in refluxing CH2Cl2 for 6 h, and
subsequent Negishi cross-coupling with the ester-substituted
phenylzinc derivative 10 in the presence of 3 mol % Pd(dba)2
and 6 mol % tfp, furnishes the bis-arylated pyridine 11 in 89%
yield over two steps (Scheme 3).
Also, we have found that imine-protected aldehydes 12 and
13 undergo this chromium-catalyzed C−H activation, furnishing
the aldehydes 14a−f in 61−88% yield (Scheme 4). Remarkably,
the reaction time is strongly dependent on the nature of an aryl
imine of type 12 or 13. When the aryl N-(p-methoxy)phenyl
a
Yield of isolated product after purification by flash column
b
chromatography. For entry 1, CrCl2 (99.99%) was used. In all
further experiments, CrCl2 of 97% purity was used. Reaction run for
38 h. Reaction run for 4 h.
c
d
B
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Organic Letters
Letter
unsymmetrically bis-arylated aldehyde 17 in 65% yield (Scheme
5).
Scheme 3. Selective Bis-Arylation of the 2-(2-
Trimethylsilyl)phenyl)oxazoline (8) Using Chromium and
Palladium Catalysts
In conclusion, we have shown that CrCl2 is a very efficient
catalyst for the performance of C−H activations of benzo[h]-
quinoline, 2-phenylpyridine, phenyl oxazoline, and aryl imines
using DCB as an oxidant. All these direct arylations proceed at
25 °C. The high catalytic activity of CrCl2 avoids the use of
additional ligands, and a broad reaction scope is achieved. Also,
in the case of the direct arylation of imines, the use of N-butyl
imines is possible for the first time (usually N-aryl imines are
required). Further extensions of these Cr-catalyzed arylations
are underway in our laboratories.
Scheme 4. Chromium-Catalyzed Arylation of Imines 12 and
13 with Grignard Reagents 2
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details, 1H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank DFG (Deutsche Forschungsgemein-
schaft) for financial support. We also thank BASF SE and
Rockwood Lithium GmbH for the generous gift of chemicals.
imine 12 was used, the chromium-catalyzed arylation reactions
using Grignard reagents 2c, 2f, 2d, and (3-chloro-4-(trifluoro-
methyl)phenyl)magnesium bromide (2i) proceeded with
reaction times of 16−25 h. On the other hand, the aryl N-
butyl imine 13 reacted with Grignard reagents 2c, 2f, (4-
(trifluoromethoxy)phenyl)magnesium bromide (2j) and (4-
(tert-butyl)phenyl)magnesium bromide (2k) with much faster
rates (1.5−3 h) giving after acidic workup the arylated aldehydes
14a−b and 14e−f in 73−88% yield (Scheme 4).
To show the practicability of this chromium C−H activation
method, we have performed an unsymmetrical bis-arylation of
the imine 15 derived from 2-chlorobenzaldehyde, via a one-pot
Cr-catalyzed cross-coupling followed by a Cr-catalyzed oxidative
arylation (Scheme 5).
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