A practical cobalt-catalyzed cross-coupling of benzylic zinc reagents with aryl and heteroaryl bromides or chlorides

Article abstract of DOI:10.1039/c5cc10272c

A catalytic system consisting of 5 mol% CoCl₂ and 10 mol% isoquinoline allows a convenient cross-coupling of benzylic zinc reagents with various aryl and heteroaryl bromides or chlorides leading to polyfunctionalized diaryl- and aryl-heteroaryl-methane derivatives.

Full text of DOI:10.1039/c5cc10272c

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A Practical Cobalt-Catalyzed Cross-Coupling of Benzylic Zinc
Reagents with Aryl and Heteroaryl Bromides or Chlorides
Andreas D. Benischke,a Irina Knoll,a Alice Rérat,b Corinne Gosmini,b and Paul Knochel*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
benzonitrile (3a) in a 2:1 THF:MTBE mixture12 (MTBE = methyl
tert-butyl ether) show that in the absence of transition
catalysts no reaction is observed at 50 °C in 2 h (Table 1,
entries 1 and 2). Also, Fe-catalysts such as Fe(acac)3, Fe(acac)2
or FeCl2 were inefficient (Table 1, entries 3-5).13 However, the
use of 5 mol% CoBr2, Co(acac)2 and CoCl2 show the formation
of the desired cross-coupling product (4a) in 47-76% GC-yield
(Table 1, entries 6-8).14
A catalytic system consisting of 5 mol% CoCl2 and 10 mol%
isoquinoline allows a convenient cross-coupling of benzylic zinc
reagents with various aryl and heteroaryl bromides or
chlorides leading to polyfunctionalized diaryl- and aryl-
heteroaryl-methane derivatives.
Pd-catalyzed cross-couplings between organozinc reagents and
various organic halides constitute a major C-C bond formation
methodology (Negishi cross-coupling).1 Due to the high price
and toxicity of palladium, related transition metal-catalyzed
cross-couplings involving zinc organometallics and Ni-, Fe- or
Co-catalysts have been examined.2-4 Furthermore, the use of
zinc organometallics is of special synthetic interest due to the
high functional group compatibility of zinc reagents.5 Recently,
we have reported several preparation methods of benzylic zinc
halides and demonstrated that these reagents undergo
smooth Negishi cross-couplings.6 Also Bedford reported that
benzylic halides undergo useful Fe-catalyzed cross-couplings
with arylzinc reagents.7 Gosmini has shown in one-pot
procedures that arylzinc reagents generated in situ via a
cobalt-catalyzed zinc insertion undergo cross-couplings with
benzyl chlorides.8 Interestingly, Ingleson has described a
transition metal free cross-coupling between relatively non-
functionalized diarylzincs with benzylic bromides and chlorides
performed in the absence of coordinating ethereal solvents.9
Herein, we report a practical cobalt-catalyzed cross-coupling
promoted by 10 mol% of isoquinoline between various
benzylic zinc reagents with aryl and heteroaryl bromides
or chlorides resulting in the formation of valuable diaryl- and
arylheteroaryl-methane derivatives.10 Preliminary control
experiments performed with benzylzinc chloride (1a; prepared
via the oxidative insertion of magnesium turnings into benzyl
chloride (2a) in the presence of LiCl and ZnCl2)11 and 4-bromo-
Table 1 Screening of Catalysts for the Palladium-free Cross-
Coupling of Benzylzinc Chloride (1a) with 4-Bromobenzonitrile
(
3a).
Catalyst
(mol%)
Additive
(mol%)
Entry
Yielda,b
1
2
none
none
0
none
isoquinoline (10)
none
0
3
Fe(acac)3 (5)
Fe(acac)2 (5)
FeCl2 (5)
0
4
none
traces
5
none
traces
6
CoBr2 (5)
Co(acac)2 (5)
CoCl2 (5)
none
47
7
none
70
8
none
76
9
CoCl2 (5)
4-fluorostyrene (10)
TMEDA (10)
isoquinoline (10)
isoquinoline (5)
isoquinoline (10)
none
66
10
11
12
13
14
CoCl2 (5)
68
CoCl2 (5)
87 (82)c (72)d
CoCl2 (5)
75
69
65
CoCl2·2LiCl (5)
CoCl2·2LiCl (5)
a
b
1.1 equiv of benzylzinc chloride (1a) was used. Determined by
c
GC-analysis with tetradecane as an internal standard. Isolated
yield of pure product. d CoCl2 with a purity of 99.999% was used.
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Previously reported additives like 4-fluorostyrene15, TMEDA16
or isoquinoline17 indicate a very positive effect of 10 mol%
isoquinoline18 leading to an isolated yield of 82% for 4a (Table
1, entry 11; compared with entries 9 and 10). Decreasing the
amount of isoquinoline to 5 mol% reduces somewhat the yield
of 4a (Table 1, entry 12). Also, we found that the use of
CoCl2·2LiCl19 was not advantageous (Table 1, entries 13 and
14). Additionally, we have examined the influence of the
commercial origin of CoCl2 as well as its purity. Thus, CoCl2
2
1b
3a
4b: 77%, 4 h
3
4
1c
3a
3a
4c: 74%, 18 h
4d: 79%, 1 h
having
a purity of 99.999% provides under the same
conditions (50 °C, 2 h) the diarylmethane 4a in 72% yield
(compared to 82%; see Table 1, entry 11).20,21 The addition
of MTBE as a cosolvent usually decreases the amount of
homo-coupling and therefore enhances the product yield.
However, large amounts of MTBE reduce the reaction rate.
We found the solvent mixture THF : MTBE 2:1 to be optimal.22
Concerning the need of isoquinoline as ligand, an extensive
screening showed that N-heterocycles behave best, whereas
various phosphines did not promote the cross-coupling.23
With these optimized conditions in hand, we studied the
reaction scope of the cross-coupling between various benzylic
zinc chlorides (1a-i) with a broad range of aryl and heteroaryl
bromides or chlorides. First, the treatment of benzylic zinc
1d
5
1e
3a
4e: 70%, 2 h
6
7
8
1f
1g
1h
3a
3a
3a
4f: 62%, 18 h
4g: 82%, 2 h
reagents (1a
isoquinoline with 4-bromobenzonitrile (3a) at 50 °C within 2 to
4 h is leading to the diarylmethane derivatives 4a in 77-82%
,b) in the presence of 5 mol% CoCl2 and 10 mol%
,
b
(Table 2, entries 1 and 2). Furthermore, the cross-coupling of
an ortho-substituted benzylzinc chloride (1c) with 3a afforded
the desired arene (4c) in 74% yield (Table 2, entry 3). Similarly,
the two functionalized benzylic zinc reagents (1d
coupled with 3a giving the products 4d in 70-79% (Table 2,
entries 4 and 5). The ester-substituted benzylzinc chloride (1f
,e) cross-
,
e
)
4h: 65%, 18 h
underwent a smooth cross-coupling with 3a leading to the
functionalized diaryl-methane 4f in 62% yield (Table 2, entry
6). Additionally, the cross-couplings of the more electron-
a
b
1.3-1.5 equiv of benzylic zinc reagent were used. Isolated
yield of pure product. c Less than 15% of homo-coupling of the
zinc reagent was observed.
donating benzylic zinc reagents
(
1g
,
h
)
with 4-bromo-
benzonitrile (3a) furnished the arenes 4g,h in 65-82% yield
(Table 2, entries 7 and 8).
The reaction scope of this cross-coupling proved to be quite
broad. Thus, 2-bromo-benzophenone (3b) underwent the
cobalt-catalyzed cross-coupling with the benzylzinc chloride
Table 2 Isoquinoline-promoted Co-Catalyzed Cross-Coupling of
Benzylic Zinc Reagents (1a-h) with 4-Bromobenzonitrile (3a).
(
1b) yielding to the corresponding ketone 5a in 64% yield
(Table 3, entry 1). Similarly, the coupling of ethyl 4-bromo-
benzoate (3c) with the two benzylic zinc reagents (1e ) led to
the functionalized diarylmethane derivatives (5b ) in 54-70%
,
g
,
c
yield (Table 3, entries 2 and 3). Remarkably, 2-chloropyridines
react well with various benzylic zinc reagents (Table 3, entries
4-9). The cross-couplings of the benzylzinc chlorides (1b,e)
with ethyl 2-chloronicotinate (3d) proceeded smoothly under
these conditions affording the 2,3-disubstituted pyridines
Benzylic Zinc
Reagenta
Entry
Electrophile
Product, Yieldb,c
(
5d
,e
) in 60-95% yield (Table 3, entries 4 and 5). Also,
1f underwent the
3-(ethoxycarbonyl)benzyl-zinc chloride
(
)
coupling with the 2,3-di-substituted pyridine (3d) giving the
functionalized aryl-hetero-arylmethane 5f in 68% yield (Table
3, entry 6). Furthermore, the cross-couplings of the benzylic
zinc reagents (1d,g,i) with 2-chloro-nicotinonitrile (3e) led to
1
1a
3a
4a: 82%, 2 h
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the desired benzylated pyridines (5g-i) in 67-77% yield (Table
3, entries 7-9). Finally, the reaction of 3-fluorobenzylzinc
chloride
(1d) with ethyl 5-bromofuran-2-carboxylate (3f)
afforded within 3 h the 2,5-disubstituted furan (5j) in 60% yield
(Table 3, entry 10). The use of aryl bromides bearing electron-
donating substituents led to low yields.24
8
9
1g
1i
3e
3e
5h: 77%, 2 h
5i: 68%, 18 h
Table 3 Co-Catalyzed Cross-Coupling Reactions of Benzylic Zinc
Reagents with Aryl and Heteroaryl Halides.
10
1d
3f
5j: 60%, 3 h
a
b
1.3-1.5 equiv of benzylic zinc reagent were used. Isolated
yield of pure product. c Less than 15% of homo-coupling of the
zinc reagent was observed.
Benzylic Zinc
Reagenta
Entry
Electrophile
Product, Yieldb,c
Moreover, such benzylic zinc reagents undergo high yield
cross-couplings with various chloro- or bromo-N-heterocycles.
Thus, the reaction of 4-methoxybenzylzinc chloride (1g) with 2-
bromopyrimidine (3g) and the two substituted pyridines, 2-
chloro-5-(trifluoromethyl)pyridine (3h) and 2-chloro-6-fluoro-
pyridine (3i), led rapidly (within 2 h) to the functionalized aryl-
heteroarylmethanes (6a-c) in 52-83% yield (Scheme 1).
1
1b
3b
5a: 64%, 4 h
E+
E
ZnCl
CoCl2 (5 mol%)
isoquinoline (10 mol%)
THF : MTBE = 2:1
50°C, 2 h
2
3
4
1e
1g
1b
3c
3c
3d
5b: 54%, 18 h
5c: 70%, 1 h
5d: 95%, 4 h
MeO
MeO
1g
6a-c
N
N
N
MeO
CF3
MeO
6a: 71%; X = Br
6b: 83%; X = Cl
N
MeO
F
6c: 52%; X = Cl
Scheme 1 Isoquinoline-promoted Cross-Coupling of the Benzylic
Zinc Reagent 1g with selected N-Heterocycles (3g-i).
5
1e
3d
3d
5e: 60%, 2 h
In summary, we have reported a new practical Co-catalyzed,
isoquinoline-promoted cross-coupling of various benzylic zinc
chlorides with a range of aryl and heteroaryl bromides and
chlorides, producing polyfunctionalized diaryl- or aryhetero-
aryl-methane derivatives. This method tolerates a variety of
functional groups, such as esters, nitriles or ketones, and
proceeds smoothly at 50 °C within 1-18 h. Remarkably, the
combination of MTBE (MTBE = methyl tert-butyl ether) as co-
solvent and isoquinoline as additive led only to small amounts
of homo-coupling. In most cases, shorter reaction times and
improved yields could be obtained. Further investigations
towards the synthesis and applications of benzylic organo-
metallics are underway in our laboratories.
6
7
1f
5f: 68%, 18 h
5g: 67%, 3 h
CN
Cl
N
1d
3e
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21, 1961; (c) O. M. Kuzmina, A. K. Steib, A. Moyeux, G. Cahiez
and P. Knochel, Synthesis, 2015, 47, 1696.
13 For recent iron-catalyzed cross-coupling reactions and
Acknowledgements
We would like to thank the DFG for financial support. We also
thank BASF SE (Ludwigshafen, Germany) and Rockwood
Lithium GmbH for the generous gift of chemicals.
related reactions, see: (a) C. Bolm, Nature Chem., 2009, 1,
420; (b) A. Fürstner, Angew. Chem. Int. Ed., 2009, 48, 1364;
(c) W. M. Czaplik, M. Mayer, J. Cvengros and A. Jacobi von
Wangelin, ChemSusChem., 2009, 2, 396; (d) E. Nakamura and
N. Yoshikai, J. Org. Chem., 2010, 75, 6061; (e) C. J. Adams, R.
B. Bedford, E. Carter, N. J. Gower, M. F. Haddow, J. N.
Harvey, M. Huwe, M. Ángeles Cartes, S. M. Mansell, C.
Mendoza, D. M. Murphy, E. Neeve and J. Nunn, J. Am. Chem.
Soc., 2012, 134, 10333; (f) R. B. Bedford, E. Carter, P. M.
Cogswell, N. J. Gower, M. F. Haddow, J. N. Harvey, D. M.
Murphy, E. C. Neeve and J. Nunn, Angew. Chem. Int. Ed.,
2013, 52, 1285.
Notes and references
1
(a) E.-i. Negishi, L. F. Valente and M. Kobayashi, J. Am. Chem.
Soc., 1980, 102, 3298; (b) E.-i. Negishi, Acc. Chem. Res., 1982,
15, 340; (c) F. Diederich and P. Stang, Metal-Catalyzed Cross-
Coupling Reactions, Wiley-VCH, Weinheim, 1998; (d) A. de
Meijere and F. Diederich, Metal-Catalyzed Cross-Coupling
Reactions, Wiley-VCH, Weinheim, 2004.
14 For recent cobalt-catalyzed cross-coupling reactions and
related reactions, see: (a) M. Amatore and C. Gosmini, Chem.
Eur. J., 2010, 16, 5848; (b) X. Qian, A. Auffrant and C.
Gosmini, Angew. Chem. Int. Ed., 2011, 50, 10402; (c) T.
Sawano, K. Ou, T. Nishimura and T. Hayashi, J. Org. Chem.,
2013, 78, 8986; (d) C. E. I. Knappke, S. Grupe, D. Gärtner, M.
Corpet, C. Gosmini and A. Jacobi von Wangelin, Chem. Eur. J.,
2014, 20, 6828; (e) B. Barré, L. Gonnard, R. Campagne, S.
Reymond, J. Marin, P. Ciapetti, M. Brellier, A. Guérinot and J.
Cossy, Org. Lett., 2014, 16, 6160; (f) L. Gonnard, A. Guérinot
and J. Cossy, Chem. Eur. J., 2015, 21, 12797; (g) A. Moyeux,
G. Cahiez and J. Cossy, Adv. Synth. Catal., 2015, 357, 1983;
(h) N. Sauermann, M. J. Gonzalez and L. Ackermann, Org.
Lett., 2015, 17, 5316; (i) J. Li and L. Ackermann, Angew.
Chem. Int. Ed., 2015, 54, 8551; (j) M. Moselage, N.
Sauermann, S. C. Richter and L. Ackermann, Angew. Chem.
Int. Ed., 2015, 54, 6352; (k) Y. Cai, X. Qian, A. Rérat, A.
Auffrant and C. Gosmini, Adv. Synth. Catal., 2015, 357, 3419.
15 (a) A. E. Jensen and P. Knochel, J. Org. Chem., 2002, 67, 79;
2
For selected Ni-catalyzed Negishi cross-couplings, see: (a) J.
Zhou and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 14726; (b)
C. Fischer and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 4594;
(c) Y. Tamaru, Modern Organonickel Chemistry, Wiley-VCH,
Weinheim, 2005; (d) A. Gavryushin, C. Kofink, G.
Manolikakes and P. Knochel, Org. Lett., 2005, 7, 4871; (e) G.
Manolikakes, C. Munoz Hernandez, M. A. Schade, A. Metzger
and P. Knochel, J. Org. Chem., 2008, 73, 8422; (f) M. A.
Schade, A. Metzger, S. Hug and P. Knochel, Chem. Commun.,
2008, 3046; (g) L. Melzig, A. Metzger and P. Knochel, J. Org.
Chem., 2010, 75, 2131.
For selected Fe-catalyzed Negishi cross-couplings, see: (a) A.
Fürstner, A. Leitner, M. Méndez and H. Krause, J. Am. Chem.
Soc., 2002, 124, 13856; (b) C. Bolm, J. Legros, J. Paih and L.
Zani, Chem. Rev., 2004, 104, 6217; (c) B. Plietker, Iron-
Catalysis in Organic Chemistry: Reactions and Applications,
Wiley-VCH, Weinheim, 2008; (d) B. D. Sherry and A. Fürstner,
Acc. Chem. Res., 2008, 41, 1500.
For selected Co-catalyzed Negishi cross-couplings, see: (a) J.-
M. Bégouin and C. Gosmini, J. Org. Chem., 2009, 74, 3221;
(b) A. Moyeux and G. Cahiez, Chem. Rev., 2010, 110, 1435;
(c) J.-M. Bégouin, M. Rivard and C. Gosmini, Chem.
Commun., 2010, 46, 5972; (d) M. Corpet, X.-Z. Bai and C.
Gosmini, Adv. Synth. Catal., 2014, 356, 2937.
(a) G. Dagousset, C. Francois, T. León, R. Blanc, E. Sansiaume-
Dagousset and P. Knochel, Synthesis, 2014, 46, 3133; (b) T.
Klatt, J. T. Markiewicz, C. Saemann and P. Knochel, J. Org.
Chem., 2014, 79, 4253.
(a) A. Metzger, M. A. Schade and P. Knochel, Org. Lett., 2008,
10, 1107; (b) A. Metzger, M. A. Schade, G. Manolikakes and
P. Knochel, Chem. Asian J., 2008, 3, 1678; (c) A. Metzger, F.
M. Piller and P. Knochel, Chem. Commun., 2008, 5824.
M. Huwe, M. C. Wilkinson and R. B. Bedford, Chem.
Commun., 2009, 600.
(a) M. Amatore and C. Gosmini, Chem. Commun., 2008,
5019; (b) J.-M. Bégouin, S. Claudel and C. Gosmini, Synlett,
2009, 3192.
J. J. Dunsford, E. R. Clark and M. J. Ingleson, Angew. Chem.
Int. Ed., 2015, 54, 5688.
3
4
(b) T. J. Korn and P. Knochel, Angew. Chem. Int. Ed., 2005, 44
,
2947; (c) S. H. Wunderlich and P. Knochel, Angew. Chem. Int.
Ed., 2009, 48, 9717.
16 (a) M. Nakamura, K. Matsuo, S. Ito and E. Nakamura, J. Am.
Chem. Soc., 2004, 126, 3686.; (b) M. Nakamura, S. Ito, K.
Matsuo and E. Nakamura, Synlett, 2005, 1794; (c) R. B.
Bedford, P. B. Brenner, E. Carter, P. M. Cogswell, M. F.
Haddow, J. N. Harvey, D. M. Murphy, J. Nunn and C. H.
Woodall, Angew. Chem. Int. Ed., 2014, 53, 1804.
17 (a) O. M. Kuzmina, A. K. Steib, J. T. Markiewicz, D. Flubacher
and P. Knochel, Angew. Chem. Int. Ed., 2013, 52, 4945; (b) O.
M. Kuzmina, A. K. Steib, S. Fernandez, W. Boudot, J. T.
Markiewicz and P. Knochel, Chem. Eur. J., 2015, 21, 8242.
18 We observed that 2,2‘-bipyridine is also a satisfactory ligand
for such cross-couplings.
5
6
7
8
19 (a) J. M. Hammann, A. K. Steib and P. Knochel, Org. Lett.,
2014, 16, 6500; (b) J. M. Hammann, D. Haas and P. Knochel,
Angew. Chem. Int. Ed., 2015, 54, 4478.
20 (a) S. L. Buchwald and C. Bolm, Angew. Chem. Int. Ed., 2009,
48, 5586; (b) P.-F. Larsson, A. Correa, M. Carril, P.-O. Norrby
and C. Bolm, Angew. Chem. Int. Ed., 2009, 48, 5691.
21 The obtained yield difference using the high purity CoCl2
(99.999%) instead of the commercial CoCl2 (≥ 97%, Sigma
Aldrich) is attributed to the difference of solubility of these
two salts. The CoCl2 with the highest purity is significantly
less soluble than the 97% pure CoCl2. In fact, this control
reaction was performed in only THF.
22 For a corresponding solvent screening, see: Supporting
information, Table 1.
23 For an extensive ligand screening, see: Supporting
information, Table 2.
9
10 (a) W. Hassan, R. Edrada, R. Ebel, V. Wray, A. Berg, R. van
Soest, S. Wiryowidagdo and P. Proksch, J. Nat. Prod., 2004,
67, 817; (b) Z. Jin, Nat. Prod. Rep., 2005, 22, 196; (c) M. D.
Elia and G. A. Molander, J. Org. Chem., 2006, 71, 9198; (d) N.
Kaila, K. Janz, A. Huang, A. Moretto, S. DeBernardo, P. W.
Bedard, S. Tam, J. Clerin, J. C. Keith, D. H. H. Tsao, N.
Sushkova, G. D. Shaw, R. T. Camphausen, R. G. Schaub and Q.
Wang, J. Med. Chem., 2007, 50, 40.
11 A. Metzger, F. M. Piller and P. Knochel, Chem. Commun.,
2008, 5824.
12 (a) O. M. Kuzmina, A. K. Steib, D. Flubacher and P. Knochel,
Org. Lett., 2012, 14, 4818; (b) A. K. Steib, O. M. Kuzmina, S.
Fernandez, S. Malhotra and P. Knochel, Chem. Eur. J., 2015,
24 Mechanistic studies are underway to explain these
phenomena.
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