Practical iron- and cobalt-catalyzed cross-coupling reactions between n-heterocyclic halides and aryl or heteroaryl magnesium reagents

Article abstract of DOI:10.1002/chem.201500747

The reaction scope of iron- and cobalt-catalyzed cross-coupling reactions in the presence of isoquinoline (quinoline) in the solvent mixture tBuOMe/THF has been further investigated. Various 2-halogenated pyridine, pyrimidine, and triazine derivatives were arylated under these mild conditions in excellent yields. The presence of isoquinoline allows us to perform Fe-catalyzed cross-coupling reactions between 6-chloroquinoline and aryl magnesium reagents. Furthermore, it was found that the use of 10% N,N-dimethylquinoline-8-amine increases the yields of some Co-catalyzed cross-coupling reactions with chloropyridines bearing electron-withdrawing substituents. Iron out your coupling! The use of iron and cobalt catalysts in a combination with only 10% isoquinoline represents a practical method for the cross-coupling reactions of various 2-halogenopyridines, -pyrimidines, and -triazines, as well as 6-halogenoquinolines with functionalized aryl or heteroaryl Grignard reagents (see scheme).

Full text of DOI:10.1002/chem.201500747

DOI: 10.1002/chem.201500747
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&
Catalysis
Practical Iron- and Cobalt-Catalyzed Cross-Coupling Reactions
between N-Heterocyclic Halides and Aryl or Heteroaryl
Magnesium Reagents
Olesya M. Kuzmina, Andreas K. Steib, Sarah Fernandez, Willy Boudot, John T. Markiewicz,
and Paul Knochel*[a]
Abstract: The reaction scope of iron- and cobalt-catalyzed
cross-coupling reactions in the presence of isoquinoline
(quinoline) in the solvent mixture tBuOMe/THF has been fur-
ther investigated. Various 2-halogenated pyridine, pyrimi-
dine, and triazine derivatives were arylated under these mild
conditions in excellent yields. The presence of isoquinoline
allows us to perform Fe-catalyzed cross-coupling reactions
between 6-chloroquinoline and aryl magnesium reagents.
Furthermore, it was found that the use of 10% N,N-dime-
thylquinoline-8-amine increases the yields of some Co-cata-
lyzed cross-coupling reactions with chloropyridines bearing
electron-withdrawing substituents.
have also attracted a lot of attention over the last decades.[10]
The high reactivity of several cobalt catalysts for various CÀC
bond-forming reactions was disclosed by Cahiez,[11] Oshima,[12]
Gosmini,[13] and Cossy.[14] In 2009, M. Nakamura showed that
the combination of NHC ligands and cobalt fluorides can also
successfully be applied to biaryl cross-coupling reactions.[15] Al-
ternatively, cobalt-catalyzed cross-coupling reactions of hetero-
cyclic chlorides with aryl and heteroaryl magnesium halides are
possible as well. The desired cross-coupled products were ob-
tained in good yields, using diethyl ether as a solvent.[16]
Cobalt-catalyzed cross-coupling reactions between polyfunc-
tional arylcopper reagents and aryl bromides or chlorides have
also been reported. The addition of 4-fluorostyrene to Bu4NI in
a solvent mixture DME/THF/DMPU (6:3:2) promotes such
cross-coupling reactions.[17] Further extensions of this method
allowed cobalt-catalyzed cross-coupling reactions between
polyfunctional arylcopper reagents and aryl fluorides or tosy-
lates.[18,19]
Introduction
Iron-catalyzed cross-coupling reactions are of high synthetic in-
terest due to the abundance of iron, its low toxicity, and mod-
erate price, especially in comparison with Pd- or Rh-catalyzed
cross-coupling reactions.[1,2] Although, the performance of
Csp2–Csp3 cross-coupling reactions using an iron-catalyst is
well-established,[3] the corresponding cross-couplings between
Csp2-centers is much more challenging due to the formation
of homocoupling side products.[4] The use of copper reagents
instead of magnesium derivatives suppresses most of the ho-
mocoupling side reactions, but the need for stoichiometric
amounts of copper salts is a serious drawback.[5] Alternatively,
the use of heterocyclic carbene (NHC) ligands in combination
with iron fluorides also considerably reduces the amount of
homocoupling as has been demonstrated by M. Nakamura.[6]
This paved the route for a range of new aryl–aryl cross-cou-
pling reactions.[7] Further, polar cosolvents, as shown by
Cahiez[8] and Fꢀrstner,[3b] lead to efficient cross-coupling reac-
tions in some special cases. Recently, we have reported that
a mixture of THF and tBuOMe, an ether of low polarity, im-
proves Csp2–Csp2 cross-coupling reactions with only 3%
FeBr3.[9] Nevertheless, these reaction conditions are not satisfac-
tory in the case of highly functionalized Grignard reagents and
require often several hours of reaction time for reaching an ac-
ceptable conversion. Co-catalyzed cross-coupling reactions
Results and Discussion
During the course of our investigations, we noted that the re-
action of 1-chloroisoquinoline (1a) and PhMgCl (2a) in the
presence of 3% FeBr3 in the solvent mixture tBuOMe/THF
takes only 5 min and provides the cross-coupled product, 1-
phenylisoquinoline (3a) in 90% yield, whereas the cross-cou-
pling of 2-chloropyridine (1b) under the same conditions re-
quires 1.5 h for completion and gives 2-phenylpyridine (3b) in
82% yield (Scheme 1).
[a] Dr. O. M. Kuzmina, Dr. A. K. Steib, M. Sc. S. Fernandez, W. Boudot,
Dr. J. T. Markiewicz, Prof. Dr. P. Knochel
Department of Chemistry
The reactivity difference of these substrates led us to postu-
late that the catalytically active iron species, generated in situ,
may contain an isoquinoline fragment as a ligand.[20] To check
this, we have performed the reaction between 2-chloropyridine
(1b) and PhMgCl (2a) in the presence of 7% isoquinoline and
Ludwig-Maximilians-Universitꢀt
Butenandtstr. 5-13, 81377 Munich (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500747.
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but had no effect, when it was attached to the 8-position
(entry 10).
An electron-withdrawing group such as a chloride in posi-
tion 6 decreases the catalytical activity of the quinoline ligand
(Table 1, entry 11). Interestingly, 6-bromoquinoline undergoes
a Br/Mg-exchange reaction with PhMgCl (2a), providing the
debrominated quinoline, which gave similar results to quino-
line (compare entries 3 and 12). Based on this small snapshot
of all tested ligands, the following trend could be found. Elec-
tron-donating substituents give better results than electron-
withdrawing ones. The 2-position of quinoline should not be
substituted. Electron-donating groups placed in position 6 of
quinoline are beneficial. Finally, chelating ligands such as bis-
pyridine deactivate the iron catalyst, probably due to chela-
tion. We have found that 10 mol% was the optimum amount
of isoquinoline and that most reactions were complete within
15 min at 258C. Screening of various metal salts showed that
isoquinoline was also a good ligand for Co-catalyzed cross-cou-
pling reactions.
Scheme 1. Iron-catalyzed cross-couplings of 1-chloroisoquinoline (1a) or 2-
chloropyridine (1b) with PhMgCl (2a).
have found that the arylated pyridine 3b was obtained at
a much faster rate (within 15 min) and with an increased isolat-
ed yield of 89% under these new reaction conditions
(Scheme 1). Herein, we report our full investigations on the
iron- and cobalt-catalyzed cross-coupling reactions promoted
by N-heterocyclic ligands. We describe the reaction scope as
well as some extensions allowing a direct aryl–aryl cross-cou-
pling with some special substrates.
Both FeBr3 and CoCl2 had similar activity in combination
with isoquinoline and both metal salts catalyze under these
conditions the cross-couplings between N-heterocyclic halides
and aryl- or heteroaryl-magnesium reagents.[21] Thus, 2-bromo-
pyridine (4a) reacted with the heterocyclic Grignard reagent
(2b), providing the desired pyridine (5a) in 61% isolated yield
(Table 2, entry 1). TMS-substituted 2-bromopyridine (4b) under-
goes Fe- and Co-catalyzed coupling reactions with various
electron-rich (2c) and sulfur-containing Grignard reagents (2d–
f) to furnish the respective 2,3-disubstituted bis(hetero)aromat-
ics (5b–e) in 49–91% yields (entries 2–5). Also, 2-halogenated
6-methoxypyridines (4c–d) couple well with 4-fluorophenyl-
magnesium bromide (2g) as well as the indolylmagnesium re-
agent (2b) to furnish the coupling products (5 f–g) in 65–75%
yields (entries 6–7). Bis-halogenated pyridine (4e) undergoes
cross-coupling reactions with the ester substituted phenylmag-
nesium bromide (2h) and the electron-rich nucleophile (2i) ex-
clusively at position 2 (entries 8–9). We subsequently screened
various substituted 3-arylated 2-halogenated pyridines (4 f–g)
in Fe- and Co-catalyzed Csp2–Csp2 cross-coupling reactions.
The bromopyridines (4 f–g) undergo high-yielding coupling re-
actions with Grignard reagents 2c, 2g, and 2i that result in
the 2,3-bisarylated pyridines (5j–l) in 68–82% yields (en-
tries 10–12). 4-Thienyl-2-bromopyridine (4h) is well tolerated in
these coupling reactions, resulting in various 2,4-bisarylated
pyridines (5m–o) in 65–79% yields (entries 13–15). Polyhalo-
genated 4-arylated pyridines (4i–k) undergo Fe- and Co-cata-
lyzed coupling reactions exclusively in position 2, using steri-
cally demanding aromatic Grignard reagents like mesitylmag-
nesium bromide (2m) or the Grignard reagent 2h leading to
the products (5p–r) in 65–82% yields (entries 16–18). Sensitive
functional groups, such as an alkyne, which may undergo car-
bometallation with Fe catalysis,[22] gave poor yields of cross-
coupling products. However, it was found that the use of 3%
CoCl2 and 10% isoquinoline improved this yield and allowed
the isolation of pyridine 5s in 62% yield (entry 19). Oligomeri-
sation reactions of the pyridyl halides may explain the low
yields.
The accelerating effect of isoquinoline for performing cross-
coupling reactions (see Scheme 1) led us to screen other li-
gands. We systematically examined various substituted quino-
lines and isoquinolines (Table 1). 1-Methylisoquinoline had
Table 1. Screening of various additives for the Fe-catalyzed cross-cou-
pling reaction of 2-chloropyridine (1b) with PhMgCl (2a).
Entry]
Additive
Yield of 3b [%][a]
1
2
3
without additive
isoquinoline
quinoline
40
92 (89)[b]
75
4
5
6
7
8
9
10
11
12
1-methylisoquinoline
2-methylquinoline
8-methylquinoline
6-methylquinoline
4-methoxyquinoline
6-methoxyquinoline
8-methoxyquinoline
6-chloroquinoline
6-bromoquinoline
91
67
48
82
73
82
40
58
73
[a] Yield determined after 15 min by integration of a GC chromatogram
and comparison against undecane as a calibrated internal standard.
[b] Isolated yield after purification by flash column chromatograpy.
a similar catalytic activity as isoquinoline (Table 1, entry 4). An
erosion of the rate enhancement occurs when a methyl group
is attached either to the 2- or 8-position (entries 5 and 6), and
only a slight improvement was observed when the methyl
group is attached to position 6 of the quinoline ring (entry 7).
An electron-donating methoxy group had a positive effect,
when it was placed at the 4- or 6-positions (entries 8 and 9)
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Table 2. Fe- and Co-catalyzed cross-coupling reactions between pyridine derivatives and aromatic Grignard reagents, utilizing isoquinoline as a ligand.
Entry Starting material Grignard reagent
Product[a]
Entry Starting material Grignard reagent
Product[a]
1
10
2
11
12
13
3
4[b]
5[c]
14
15
6
7[d]
16
8
17[e]
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Table 2. (Continued)
Entry Starting material Grignard reagent
Product[a]
Entry Starting material Grignard reagent
Product[a]
9
18
19[f]
[a] Isolated yield after purification by flash column chromatography. [b] The reaction was performed at 258C for 24 h. [c] The reaction was performed at
508C for 12 h, when 3% FeBr3 was used and at 258C for 12 h, when 3% CoCl2 was used. [d] The reaction was performed at 258C for 1 h. [e] The reaction
was performed at 258C for 5 h. [f] The reaction was performed at 258C for 30 min.
The pyrimidine scaffold is often found in pharmaceutical
compounds[23] and therefore is an important structure for
cross-coupling reactions. Various pyrimidines were prepared
using 3% of FeBr3 and 3% of CoCl2 in a combination with 10%
of isoquinoline (Table 3).
sium derivative (2k) performed in the presence of isoquinoline
(10%) led to the desired product (7h) within 30 min at 258C in
63–78% yield. In the absence of isoquinoline only low yields of
11–26% were obtained. Longer reaction times (over 2 h) im-
prove somewhat these low yields. Similarly, the 1,3,5-triazine
(8d) reacts with p-anisylmagnesium halides (2c) in the pres-
ence of 3% CoCl2 or FeBr3 and isoquinoline (10%) leading to
the triazine (9d) in 79–81% yields within 15 min at 258C. In
the absence of isoquinoline, the triazine (9d) was only isolated
in 54–55% yield (Scheme 2).
Thus, 2-chloro-4,6-dimethylpyrimidine (6a) undergoes an
iron-catalyzed cross-coupling reaction with electron-poor aro-
matic Grignard reagent (2g) in 71% yield (Table 3, entry 1). The
more electron-rich pyrimidine (6b) is also a good substrate for
this transformation (entry 2). An iron-catalyzed double-aryla-
tion of 4,6-dichloropyrimidine (6c) was performed with an
excess of Grignard reagent (2l), furnishing the bis-arylated pyr-
imidine (7c) in 95% yield (entry 3). Arylated 2-bromopyrimi-
dines (6d–e) participate in such reactions, leading to Fe- or
Co-catalyzed cross-coupling reactions with the polyhalogenat-
ed and acetal-substituted aromatic Grignard reagents (2o and
2q), as well as with phenylmagnesium bromide (2n) and 1-
naphthylmagnesium bromide (2p) (entries 4–7).
Also quinolines, like the polysubstituted 2-chloroquinoline
10a can be coupled efficiently with 4-fluorophenylmagnesium
bromide (2g) in 67% yield using 3% CoCl2 and in 82% yield
using 3% FeBr3 (Table 5, entry 1). The aryl-substituted 2-bromo-
quinoline 10b was arylated with 4-anisylmagnesium bromide
(2c), resulting in bis-arylated quinoline (11 b) in 78% yield
(entry 2). 2,6-Dichloroquinoline (10c) undergoes regioselective
coupling reactions in position 2 with electron-poor Grignard
reagents 2g and 2r leading to the quinolines (11 c–d) in 63–
65% yields (entries 3–4).
The functionalization of triazines is of great importance,
since these compounds are often used as building blocks in
material chemistry[24] and as agrochemicals.[25]
During the course of our investigations, we found that not
only the 2-position of halogenated quinolines, but also the 6-
position can be functionalized using iron or cobalt catalysts in
combination with isoquinoline as a ligand. 6-Chloro-2-phenyl-
quinoline (12) undergoes an iron-catalyzed cross-coupling re-
action with 4-fluorophenylmagnesium bromide (2g) in a mod-
erate yield of 42%. The addition of 10 mol% isoquinoline ac-
celerates this reaction considerably and also increases the yield
of 13 to 88%. Compared to CoCl2, FeBr3 is the superior catalyst
in this reaction. We were also able to couple the electron-rich
Various heteroatomic substituted 2-chlorinated triazines, like
pyrrolidyl-substituted triazine (8a), ethoxy-substituted triazine
(8b), and ethylthiotriazine 8c were coupled with various (het-
ero)aromatic Grignard reagents, like 2-thienylmagnesium chlo-
ride (2d) or the acetal-substituted Grignard reagent (2q), re-
sulting in arylated triazines (9a–c) in 61–84% yields (Table 4).
To demonstrate the effect of the isoquinoline ligand, several
control experiments have been performed.[20] Thus, in the case
of the chloropyrimidine (6a) the reactions with the arylmagne-
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Table 3. Fe- and Co-catalyzed cross-coupling reactions between pyrimi-
dine derivatives and aromatic Grignard reagents, utilizing isoquinoline as
a ligand.
Table 4. Fe- and Co-catalyzed cross-coupling reactions between triazine
derivatives and aromatic Grignard reagents, utilizing isoquinoline as
a ligand.
Product[a]
Entry Starting material Grignard reagent
Product[a]
Entry Starting material Grignard reagent
1
1[b]
2
2[c]
3[b]
3
[a] Isolated yield after purification by flash column chromatography.
[b] The reaction was performed at 508C for 12 h. [c] The reaction was per-
formed at 258C for 12 h.
4
5
6
Table 5. Fe- and Co-catalyzed cross-coupling reactions between quinoline deriv-
atives and aromatic Grignard reagents, utilizing isoquinoline as a ligand.
Entry Starting material
Grignard reagent
Product[a]
1
2
7
3
4
[a] Isolated yield after purification by flash column chromatography.
[b] An excess of Grignard reagent 2l (4 equiv) was used.
[a] Isolated yield after purification by flash column chromatography.
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(Scheme 4). The cross-coupling
reaction of the CF3-substituted
pyridine (16) afforded the ex-
pected cross-coupled product
17 after 15 min in 79% yield.
Whereas in the presence of iso-
quinoline, a yield of only 18%
was reached after 15 min at
258C.[27]
Conclusion
The scope of the iron-catalyzed
cross-coupling reactions be-
tween electron-deficient 2-halo-
geno-N-heterocycles can be
greatly improved by the pres-
Scheme 2. Co- and Fe-catalyzed cross-coupling reactions with and without isoquinoline.
ence of 10% isoquinoline or 10% quinoline. We have shown
that 2-halogenopyridines, -pyrimidines, and -triazines are excel-
lent substrates for such cross-coupling reactions. Furthermore,
the presence of isoquinoline also improves aryl–aryl ring cross-
coupling reactions if 6-halogenoquinolines are used. In some
cases, Co-catalyzed cross-coupling reactions with electron-poor
chloropyridines can be greatly improved by using 10% of N,N-
dimethylquinolin-8-amine (15) as a new ligand. Further exten-
sion of this catalysis is underway in our laboratories.
Experimental Section
Representative procedure: Preparation of arylated quinoline
13 (Scheme 3)
A solution of the Grignard reagent 2g (1 mL, 2 equiv, 1.0m in THF
containing 1 equiv LiCl) was added dropwise to a suspension of
FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg,
0.05 mmol, 0.10 equiv), and 6-chloro-2-phenylquinoline 12
(120 mg, 0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 258C. The sus-
pension was stirred at 508C for the 15 min before being quenched
with NaHCO3 sat. aq. The mixture was diluted with CH2Cl2 and an
ethylenediaminetetraacetic acid (EDTA) (1.0m, H2O) solution was
added. The mixture was stirred at 258C for 15 min, before being fil-
tered through a pad of Celite. After washing the pad of Celite with
CH2Cl2, NaCl sat. aq. was added, and the mixture was extracted
with CH2Cl2. The organic layer was dried with MgSO4, filtered, and
concentrated in vacuo to yield the crude compound, which was
purified by column chromatography to yield 13 (120 mg, 88%) as
a white solid.
Scheme 3. Co- and Fe-catalyzed cross-coupling reactions between 6-chloro-
quinoline 12 and Grignard reagents 2g and 2s.
3-anisylmagnesium bromide (2s) with 6-chloro-2-phenylquino-
line (12) and could isolate the 2,6-bisarylated quinoline 14 in
71% yield (Scheme 3).[26]
We have also observed that Co-catalyzed cross-coupling re-
actions with pyridines, bearing an electron-withdrawing group
such as the CF3 group, could be improved by using 10 mol%
of N,N-dimethylquinoline-8-amine (15) instead of isoquinoline
Acknowledgements
We would like to thank the DFG
(Deutsche
Forschungsgemein-
schaft) for financial support. We
also thank BASF SE and Rock-
wood Lithium GmbH for the
generous gift of chemicals.
Scheme 4. Co-catalyzed cross-coupling reaction between pyridine 16 and PhMgCl (2a) utilizing N,N-dimethylqui-
nolin-8-amine (15) as a ligand.
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Keywords: cobalt · cross-coupling · Grignard reagents · N-
heterocycles · iron
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Received: February 24, 2015
Published online on && &&, 0000
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FULL PAPER
&
Catalysis
O. M. Kuzmina, A. K. Steib, S. Fernandez,
W. Boudot, J. T. Markiewicz, P. Knochel*
&& – &&
Practical Iron- and Cobalt-Catalyzed
Cross-Coupling Reactions between N-
Heterocyclic Halides and Aryl or
Heteroaryl Magnesium Reagents
Iron out your coupling! The use of
iron- and cobalt-catalysts in a combina-
tion with only 10% isoquinoline repre-
sents a practical method for the cross-
coupling reactions of various 2-halogen-
opyridines, -pyrimidines, and -triazines
as well as 6-halogenoquinolines with
functionalized aryl or heteroaryl
Grignard reagents (see scheme).
Chem. Eur. J. 2015, 21, 1 – 9
www.chemeurj.org
9
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ