Chemoselective chromium(II)-catalyzed cross-coupling reactions of dichlorinated heteroaromatics with functionalized aryl Grignard reagents

Article abstract of DOI:10.1002/chem.201405275

Chromium(II) chloride catalyzes the chemoselective cross-coupling reaction of dichloropyridines with a range of functionalized (hetero)aromatic Grignard reagents at room temperature. Functional groups, such as esters and acetals, are well tolerated in this transformation. Previously challenging substrates, quinolines and isoquinolines, participate in the selective Cr-catalyzed cross-coupling in cyclopentyl methyl ether (CPME) as the solvent. The effective purging of Cr salts is demonstrated by using various solid supports.

Full text of DOI:10.1002/chem.201405275

DOI: 10.1002/chem.201405275
Full Paper
&
Synthetic Methods
Chemoselective Chromium(II)-Catalyzed Cross-Coupling Reactions
of Dichlorinated Heteroaromatics with Functionalized Aryl
Grignard Reagents
Andreas K. Steib,[a] Olesya M. Kuzmina,[a] Sarah Fernandez,[a] Sushant Malhotra,*[b] and
Paul Knochel*[a]
Abstract: Chromium(II) chloride catalyzes the chemo-
selective cross-coupling reaction of dichloropyridines with
a range of functionalized (hetero)aromatic Grignard reagents
at room temperature. Functional groups, such as esters and
acetals, are well tolerated in this transformation. Previously
challenging substrates, quinolines and isoquinolines, partici-
pate in the selective Cr-catalyzed cross-coupling in cyclo-
pentyl methyl ether (CPME) as the solvent. The effective
purging of Cr salts is demonstrated by using various solid
supports.
Introduction
using catalytic CrCl2, in which the cross-coupling reaction be-
tween N-heterocyclic monochlorides and (hetero)aromatic
Grignard reagents leads to the formation of the desired prod-
uct with only trace amounts of homocoupled product.[6,7] The
advantage of low oxidation state chromium salts is that they
are more economical compared to palladium salts, but are also
less toxic. According to the International Conference on Har-
monization (ICH) guidelines, the permitted daily oral exposure
for chromium(III) picolinate is approximately 10.7 mgdayÀ1
compared to PdIICl2 at 0.1 mgdayÀ1 and soluble Ni at
Nitrogen-containing heterocyclic compounds are of significant
interest to the pharmaceutical and agrochemical industries.
Transition-metal-catalyzed cross-coupling reactions have
become a cornerstone in the functionalization of such com-
pounds. In general, cross-coupling-based methods to access
complex molecules employ palladium or nickel catalysts.[1] The
high cost of palladium and comparably higher toxicology of
nickel salts have motivated the development of cross-coupling
methods employing economical and readily available transition
metals. Over the last few decades, iron salts have proven to be
viable catalysts for cross-coupling reactions to form both
sp2–sp2 and sp2–sp3 bonds.[2] Despite the promise of Fe-
based cross-coupling reactions, the facility, with which certain
aryl nucleophiles, such as aryl Grignard reagents, undergo
homocoupling (to form symmetrical biaryls), has attenuated
the utility of this transformation.[3] To address this challenge,
Nakamura and co-workers have reported the use of N-hetero-
cyclic carbene ligands for efficient biaryl formation.[4] Further-
more, isoquinoline can accelerate analogous Fe-catalyzed
cross-coupling reactions, producing 2-arylated N-heterocyclic
biaryls with low amounts of undesired homocoupled prod-
ucts.[5] To further improve this transformation, we have recently
reported that unsymmetrical biaryls can be efficiently accessed
0.6 mgdayÀ1 [8]
.
An effective strategy to obtain highly functionalized hetero-
aromatic structural motifs involves the use of polyhalogenated
starting materials that can be subsequently functionalized.
Challenges in product selectivity with such systems have been
addressed by utilizing differentially halogenated rings. Recent-
ly, high control in the differentiation of dihaloaromatics by
using Fe(acac)3 (acac=acetylacetonate) to form a range of
alkylated N-heterocycles (sp2–sp3 coupling) has been demon-
strated.[9] Unfortunately, employing this strategy in the forma-
tion of unsymmetrical biaryls led to the formation of significant
amounts of homocoupled products employing various Fe, Co,
and Mn catalysts. Given the utility of the transformation, we
embarked on studying the chemoselective differentiation of di-
chloropyridines, quinolines, and isoquinolines in the context of
biaryl coupling due to the prevalence of such motifs in drug-
discovery programs. Herein, we report the development of
a highly chemoselective Cr-catalyzed cross-coupling reaction
and demonstrate the effective purging of chromium salts from
the desired product using various solid supports.
[a] Dr. A. K. Steib, Dr. O. M. Kuzmina, S. Fernandez, Prof. P. Knochel
Department of Chemistry, Ludwig-Maximilians-Universitꢀt
Butenandtstrasse 5–13, 81377 Munich (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[b] Dr. S. Malhotra
Discovery Chemistry, Genentech Inc.
1 DNA Way, South San Francisco, California 94080 (USA)
E-mail: malhotra.sushant@gene.com
Results and Discussion
Initial work utilizing 2,4-dichloropyridine (1a) with PhMgCl (2a)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405275.
through
a
previously optimized Fe-catalysis protocol[5]
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in which 2,4-dichloropyridines 1d–e react rapidly with 2a to
give phenylated products 3d–e in high yields (85% for 3d and
88% for 3e, entries 3, 4). The sterically more demanding and
coordinating acetal-containing 2,4-dichloropyridines 1 f–g also
react rapidly to give products 3 f–g in 67% and 76% yields,
respectively (entries 5–6).
Chromium-catalyzed biaryl formation on 1,3-dichloroiso-
quinoline 1h and 2,4-dichloroquinoline 1i proved to be chal-
lenging. Although selective, the optimal conditions illustrated
in Table 1 resulted in attenuated reactivity. Evaluation of coor-
dinating and non-coordinating solvents with these fused aro-
matics revealed the superiority of cyclopentyl methyl ether
(CPME) in the CrCl2-catalyzed cross-coupling reaction. The de-
sired coupling product 3h was obtained in 71% yield after
only 1 h reaction time at room temperature by using 3 mol%
of CrCl2 in CPME as solvent. The phenylation regioselectivity of
1h at position one can be explained by formation of the more
stable intermediate A that retains aromaticity. The competing
arylation at position three does not occur because of loss of ar-
omaticity in intermediate B. Analogously, the chemoselective
coupling between quinoline 1i and Grignard reagent 2a gave
the desired 2-arylated quinoline 3i in 70% yield by using
CPME (Scheme 2).
Scheme 1. Cross-coupling of 2,4-dichloropyridine (1a) with PhMgCl (2a): Fe
versus Cr.
exclusively gave the 2-arylated product 3a in 58% yield. In
comparison, the chromium(II) chloride-catalyzed reaction
using lower levels of 2a (1.2 instead of 2 equiv) selectively
gave pyridine 3a in 80% yield with only trace amounts of the
homocoupled product (Scheme 1).[10,11]
Evaluation of the scope of the chemoselective chromium-
catalyzed cross-coupling reaction led to the arylation of
a
range of dichloro-N-heterocycles at room temperature
(Table 1). Both 2,3-dichloropyridine (1b) and 2,5-dichloropyri-
dine (1c) reacted with Grignard reagent 2a within minutes to
selectively form the 2-arylated products 3b (76% yield,
entry 1) and 3c (87% yield, entry 2) respectively. Methyl substi-
tution on the pyridine ring also led to high levels of selectivity,
Table 1. Chemoselective Csp2ÀCsp2 cross-coupling reactions between
dichlorinated pyridines (1b–g) and PhMgCl (2a).[a]
Entry[a] Substrate
Product
Reaction
time
Yield
[%]
[min]
1
2
1b
1c
3b
3c
15
15
76
87
3
4
5
1d
1e
1 f
3d
3e
3 f
15
15
30
85
88
67
Scheme 2. Cr(II)-catalyzed cross-coupling reactions of isoquinoline 1h and
quinoline 1i with PhMgCl (2a) by using cyclopentyl methyl ether as solvent
and mechanistic aspects.
To further evaluate the utility of the chemoselective chro-
mium(II)-catalyzed cross-coupling reaction, various aromatic
Grignard reagents 2b–i were employed (Table 2).[12] Electron-
rich Grignard reagents, such as 3-(methoxyphenyl) magnesium
bromide (2b), methylenedioxyarylmagnesium bromide 2c, and
4-(dimethylamino)phenylmagnesium bromide (2d), reacted
with dihalogenated pyridines 1a and c and with quinolines 1j
and k resulting in the formation of the coupled products 3j–n
in 71–82% yield (entries 1–5). Notably, complete control in site
6
1g
3g
30
76
[a] Reaction conditions: PhMgCl (2a; 1.2 equiv), dichlorinated pyridine
(1 equiv), CrCl2 (3 mol%) in THF at 258C.
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selectivity was obtained in these cross-coupling reactions.
Heteroaromatic nucleophile 5-magnesiated indole 2e reacts
with 2,3-dichloro-5-(trifluoromethyl)pyridine (1l) within one
hour to give the 2-arylated coupling product 3o in 56%
yield (entry 6). Silyl-protected 3-hydroxyphenyl magnesium
bromide 2 f and acetal-substituted arylmagnesium deriva-
tive 2g participated in the CrCl2-catalyzed cross-coupling re-
action with dichlorinated pyridines 1b, g, and l selectively
on C2, affording the desired products in 66–82% isolated
yields (entries 7–9).
Table 2. Chemoselective Csp2ÀCsp2 cross-coupling reactions between
dichlorinated heterocycles and various aromatic Grignard reagents.[a]
Entry Substrate
Grignard reagent
Product
1
1c
1j
2b
2b
3j: 71%; 30 min
3k: 72%; 2 h
Electron-poor Grignard reagent 4-(trifluoromethyl)phenyl
magnesium bromide (2h) was particularly effective in the
Cr-catalyzed cross-coupling reaction. When this substrate
was treated with pyridine 1a in the presence of 3 mol%
CrCl2, the formation of heterocycle 3s in 92% yield
(entry 10) occurred.
2[b]
Chloro-substituted Grignard reagent 2i, when coupled
with quinoline 1k and trifluoromethylated 2,3-dichloropyri-
dine 1l, gave the desired products 3t and u in 87 and 66%
yield, respectively (entries 11 and 12).
3
1a
1k
2c
2c
3l: 77%; 15 min
3m: 82%; 1 h
The ability to conduct these experiments at room tem-
perature poses a significant advantage. Thermally sensitive
Grignard reagents, such as those containing an ester (2j) or
4-fluorophenylmagnesium bromide 2k, undergo rapid
cross-coupling reactions leading to trisubstituted pyridines
3v–w in 70–79% yield (Scheme 3).[13] Ester 2j has previously
been used in Pd-catalyzed cross-coupling reactions on
monohalogenated systems,[14] therefore, this method
provides more practical means to access heterobiaryls that
are commonly found in bioactive pharmaceuticals.
4[b]
5
1k
2d
3n: 71%; 3 h
To rationalize the site selectivity in the Cr-catalyzed cross-
coupling reactions we postulate a mechanism, in which the
pyridine-ring nitrogen directs the attack of the low-valent
phenyl–chromium organometallic onto the dihaloaromat-
ic.[15,16] To support the notion of a directed delivery of the
aryl nucleophile, treatment of 3,4-dichloropyridine 1m (in
which a ring nitrogen is not proximal to the CÀCl bond)
with Grignard reagent 2a in the presence of 3 mol%
chromium chloride led to the exclusive formation of
biphenyl, and none of the cross-coupled product was
observed (Scheme 4). Furthermore, high selectivity for aryl
incorporation proximal to the nitrogen with various 2,4-
and 2,5-dichloropyridines supports the hypothesis of an
N-directed addition.
6[c]
1l
2e
2 f
3o: 56%; 1 h
7
1b
3p: 82%; 15 min
8
1l
2g
3q: 71%; 15 min
Having demonstrated a wide substrate scope, we turned
our attention to the removal of chromium. Despite the high
permitted daily oral exposure for chromium(III) picolinate,[8]
we sought to lower the overall chromium content from our
reaction mixture prior to chromatography. Employing 2,4-di-
chloropyridine 1a as a prototype, treatment with PhMgCl
(2a) in the presence of 3 mol% CrCl2, quenching unreacted
Grignard reagent with an aqueous solution of ammonium
chloride, separation and treatment of the organic layer
using various solid supports was evaluated. As illustrated in
Figure 1, several scavengers resulted in high recovery
of arylated pyridine 3a with remarkably low levels
of chromium,[17] thereby enhancing the utility of this
9
1g
2g
3r: 66%; 30 min
10
1a
2h
2i
3s: 92%; 30 min
11[b] 1k
3t: 87%; 1 h
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methodology for pharmaceutical applications, in which
low levels of concerning metals are critical.
Table 2. (Continued)
Entry Substrate
Grignard reagent
Product
Conclusion
We have reported a highly efficient regioselective Cr-cata-
lyzed cross-coupling reaction of various dichloropyridines
or -quinolines with a range of functionalized arylmagnesi-
um reagents. Furthermore, we have demonstrated that
chromium salts formed during the course of this reaction
may be effectively removed prior to subsequent transfor-
mations.
12
1l
2i
3u: 66%; 30 min
[a] Reaction conditions: Grignard reagent (1.2 equiv), dichlorinated heterocycle
of type 1 (1 equiv), CrCl2 (3 mol%) in THF at room temperature. [b] CPME was
used as solvent. [c] The reaction was performed at 508C.
Experimental Section
Typical procedure for the Cr-catalyzed cross-coupling
reactions
A solution of the appropriate Grignard reagent (concentration in
THF varying depending on the nature of the Grignard reagent,
1.2 mmol, 1.2 equiv) was added dropwise to a suspension of anhy-
drous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and the
aryl halide (1 mmol, 1.0 equiv) in, accordingly, THF or CPME (5 mL)
at 258C. The suspension was stirred at 258C for the indicated time
before being quenched with brine and extracted with EtOAc. The
organic layer was dried with MgSO4, filtered, and concentrated in
vacuo to give the crude compound, which was purified by column
chromatography to give the final compound as an analytically
pure substance.
Scheme 3. Regioselective Cr(II)-catalyzed cross-coupling reactions of pyri-
dines 1 f and l with thermally sensitive Grignard reagents 2j–k.
Acknowledgements
The authors thank Desheng Wang for helping determine trace
levels of chromium present after scavenging. The research
leading to these results has received funding from the
European Research Council under the European Community’s
Seventh Framework Programme (FP7/2007-2013; ERC grant
agreement no. 227763).
Scheme 4. Evidence for N-directed site selectivity.
Keywords: chromium
· cross-
coupling · magnesium · nitrogen
heterocycles
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Received: September 15, 2014
Published online on December 2, 2014
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1965
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