Selective Co/Ti cooperatively catalyzed biaryl couplings of aryl halides with aryl metal reagents

Article abstract of DOI:10.1021/ol402599f

Various aryl bromides or chlorides, including those bearing a free COOH, OH, CONHR, and SO₂NHR group, coupled with aryl magnesium or lithium reagents in the presence of 7.5 mol % CoCl₂/15 mol % PBu₃ and substoichiometric Ti(OEt)₄ (40 mol % to ArM) at room temperature in high yields with high chemo- and regioslectivity. This simple reaction represents the first example of Co/Ti cooperative catalysis which plays a key role in suppressing undesired homocouplings.

Full text of DOI:10.1021/ol402599f

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Selective Co/Ti Cooperatively Catalyzed
Biaryl Couplings of Aryl Halides with Aryl
Metal Reagents
Jing Zeng, Kun Ming Liu, and Xin Fang Duan*
College of Chemistry, Beijing Normal University, Beijing, 100875, China
xinfangduan@vip.163.com
Received September 9, 2013
ABSTRACT
Various aryl bromides or chlorides, including those bearing a free COOH, OH, CONHR, and SO2NHR group, coupled with aryl magnesium or
lithium reagents in the presence of 7.5 mol % CoCl2/15 mol % PBu3 and substoichiometric Ti(OEt)4 (40 mol % to ArM) at room temperature in high
yields with high chemo- and regioslectivity. This simple reaction represents the first example of Co/Ti cooperative catalysis which plays a key role
in suppressing undesired homocouplings.
Transition-metal-catalyzed cross-coupling reactions are
one of the most powerful tools for the construction CꢀC
bonds in organic synthesis.1,2 In this field, the catalysts are
largely dominated by palladium and nickel complexes
due to their high catalytic activity for a wide range of
substrates and high functional group tolerance.3 However,
these common catalysts have some disadvantages, such as
the high cost of palladium and the high toxicity of nickel
catalysts, which limit their use in industrial applications. In
this context, relatively low-cost and low-toxic iron and
cobalt complexes are viable alternatives.4,5 Although there
has been muchprogress inCo-catalyzedcouplingreactions
between C(sp2) and C(sp3) centers,6 the corresponding
biaryl cross-couplings have remained a considerable chal-
lenge due to undesired homocoupling reactions.7 To date,
(1) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 2004. (b) Hartwig, J. F. Organo-transi-
tion Metal Chemistry; University Science Books: Sausalito, CA, 2010.
(2) Selected papers on organocatalytic biary couplings: (a) Liu, W.;
Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.;
Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737. (b) Sun,
C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.;
Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem 2010, 2, 1044. (c) De, S.;
Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett. 2012, 14, 4466.
(d) Buden, M. E.; Guastavino, J. F.; Rossi, R. A. Org. Lett. 2013, 15,
1174. (e) De, S.; Mishra, S.; Kakde, B. N.; Dey, D.; Bisai, A. J. Org.
Chem. 2013, 78, 7823.
(3) (a) Handbook of Organopalladium Chemistry for Organic Synth-
esis; Wiley-Interscience: New York, 2002. (b) Miyaura, N. Cross-Coupling
Reactions. A Practical Guide; Springer: Berlin, 2002. (c) Johansson
Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew.
Chem., Int. Ed. 2012, 51, 5062.
(5) For selected reviews on cobalt-catalyzed reactions: (a) Yorimitsu,
H.; Oshima, K. Pure Appl. Chem. 2006, 78, 441. (b) Gosmini, C.;
Begouin, J.-M.; Moncomble, A. Chem. Commun. 2008, 3221. (c) Cahiez,
G.; Moyeux, A. Chem. Rev. 2010, 110, 1435. (d) Gosmini, C.; Moncomble,
A. Isr. J. Chem. 2010, 50, 568.
ꢀ
ꢀ
(6) Selected papers: (a) Avedissian, H.; Berillon, L.; Cahiez, G.;
Knochel, P. Tetrahedron Lett. 1998, 39, 6163. (b) Kamachi, T.; Kuno,
A.; Matsuno, C.; Okamoto, S. Tetrahedron Lett. 2004, 45, 4677. (c) Affo,
W.; Ohmiya, H.; Fujioka, T.; Ikeda, Y.; Nakamura, T.; Yorimitsu, H.;
Oshima, K.; Inamura, Y.; Mizuta, T.; Miyoshi, K. J. Am. Chem. Soc.
2006, 128, 8068. (d) Tsuji, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem.
Soc. 2006, 128, 1886. (e) Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org.
Lett. 2006, 8, 3093. (f) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.;
Oshima, K. Tetrahedron 2006, 62, 2207. (g) Cahiez, G.; Chaboche, C.;
Duplais, C.; Moyeux, A. Org. Lett. 2009, 11, 277. (h) Chen, Q.; Ilies, L.;
Nakamura, E. J. Am. Chem. Soc. 2011, 133, 428. (i) Nicolas, L.;
Angibaud, P.; Stansfield, I.; Bonnet, P.; Meerpoel, L.; Reymond, S.;
Cossy, J. Angew. Chem., Int. Ed. 2012, 51, 11101.
(7) For Co-catalyzed homocoupling reactions: (a) Gilman, H.;
Lichtenwalter, M. J. Am. Chem. Soc. 1939, 61, 957. (b) Kharasch,
M. S.; Fuchs, C. F. J. Am. Chem. Soc. 1941, 63, 2316. (c) Morizur,
J. P. Bull. Soc. Chim. Fr. 1964, 1331. (d) Moncomble, A.; Le Floch, P.;
Gosmini, C. Chem.;Eur. J. 2009, 15, 4770. (e) Mayer, M.; Czaplik,
W. M.; Jacobi von Wangelin, A. Synlett 2009, 2919.
ꢀ
(4) For selected reviews on iron-catalyzed reactions: (a) Bolm, C.;
Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217. (b) Plietker,
B. Iron Catalysis in Organic Chemistry: Reactions and Applications;
Wiley-VCH: Weinheim, 2008. (c) Enthaler, S.; Junge, K.; Beller, M. Angew.
€
Chem., Int. Ed. 2008, 47, 3317. (d) Sherry, B. D.; Furstner, A. Acc. Chem.
€
Res. 2008, 41, 1500. (e) Furstner, A. Angew. Chem., Int. Ed. 2009, 48,
ꢁ
1364. (f) Czaplik, W. M.; Mayer, M.; Cvengros, J.; Jacobi von Wangelin,
A. ChemSusChem 2009, 2, 396.
r
10.1021/ol402599f
XXXX American Chemical Society

only a few Co-catalyzed biaryl cross-couplings with good
selectivity have been documented.8 However, most of the
reported examples are sensitive to the structure of sub-
strate halides (i.e., heteroaryl halides, halophenones, chlo-
rostyrenes) or require a special catalyst/ligand system
(CoF2/N-heterocyclic carbene).
Table 1. Optimization for Co-Catalyzed Biaryl Cross-Coupling
Reaction of Titanium Ate-Complexa
ligandb
nc
t
yieldd
[%]
entry
X
(solvent)
[mol %]
R
[h]
Herein, we report a novel cobalt/titanium cocatalyzed
biaryl cross-coupling reaction between aryl magnesium or
lithium reagents and aryl chlorides or bromides. This
general coupling reaction proceeds smoothly in the pre-
sence of 40 mol % Ti(OEt)4 (based on the amount of
ArMgX or ArLi) and 7.5 mol % CoCl2/15 mol % PBu3.
Attractive features include the use of a simple and readily
available cobalt catalyst system and substoichiometric
nontoxic titanate, broad generality, mild conditions
(room temperature), and high chemo- and regioslectivity.
Importantly, the present reaction can also take place with
high yields in the presence of free COOH, OH, CONHR,
and SO2NHR. We expect that the reaction presented here
will add to the repertoire of transition-metal-catalyzed
biaryl cross-coupling reactions.
Our research started with an investigation into the Co-
catalyzed cross-coupling reaction of 4-bromobenzophe-
none with titanium ate-complexes [ArTi(OR)4M], which
areoften usedasa simplemeans toadjustthe reactivityand
selectivity of organomagnesium and lithium reagents.9,10
As illustrated in Table 1, various representative ligands or
additives were examined using the model reaction between
1a and the phenyl titanium ate-complex. To our delight, a
high yield cross-coupling could be achieved by using a
simple trialkylphosphine ligand with a low excess of
Grignard reagent (0.15 equiv of 1.4 equiv of PhMgBr was
needed to reduce CoCl2) in a short reaction time (Table 1,
entries 7ꢀ9). Tributylphosphine, being the cheapest and
most easily handled among the three tested trialkylpho-
sphines, was chosen for further investigation. Under the
same conditions, Co(acac)2 could also promote the cross-
coupling equally well, yet with a prolonged reaction time
1
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
F
ꢀ (THF)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
i-Pr
Ri
12
12
12
12
12
12
4
19
29
23
27
42
63
86
84
85
84
81
41
49
44
79
34
85
85
84
46
81
--
2
ꢀ (NMP/THF)
TMEDA (THF)
PPh3 (THF)
dmadppe(THF)
dpppf(THF)
PCy3(THF)
PMe3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(ether)
PBu3(DME)
PBu3(toluene)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
PBu3(THF)
3
4
5
6
7
8
4
9
4
10g
11h
12
13
14
15
16
17
18
19
20
21h
22
23
24
25
26
12
4
8
8
8
4
8
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4
60
4
40
4
20
8
40
4
40
12
8
Cl
40
21
55j
21
45
I
40
2
OTs
OTf
40
4
40
4
a PhMgBr (1.4 equiv) was used unless otherwise noted. b TMEDA
was used at 40 mol % and 100 mol %, and other ligands, at 15 mol %.
c Based on the amount of PhMgBr or PhLi. d Isolated yield. e Me2N-
(CH2)3PPh2. f Ph2P(CH2)3PPh2. g Co(acac)2 was used instead of CoCl2.
h PhLi (1.4 equiv) was used instead of PhMgBr. i Me2CHCHMe2.
j Benzophenone was isolated in 34% yield.
(entry 10). Also, phenyllithium showed a comparable yield
(Table 1, entries 11 and 21). THF proved to be an ideal
solvent, for the reactions carried out in ether, DME, or
toluenegaveremarkablyloweryieldsthaninTHF(Table1,
entries 12ꢀ14). Titanates with high-steric-hindrance li-
gands gave relatively lower yields (Table 1, entries 15 and
16). Very importantly, when a substoichiometric amount
of Ti(OEt)4 was applied (as low as 40 mol % to Grignard
or lithium reagents), the reaction occurred equally well
(Table 1, entries 17ꢀ21). To the best of our knowledge, the
reaction described herein represents the first example
where only 40 mol % titanate was used in the reactions
involving titanium ate-complexes formed from Grignard
or lithium reagents.10h Therefore, this procedure can be
regarded as a cobalt/titanium cooperatively catalyzed
cross-coupling reaction between aryl magnesium or
lithium reagents and aryl halides.
(8) Selected recent papers: (a) Korn, T. J.; Knochel, P. Angew. Chem.,
Int. Ed. 2005, 44, 2947. (b) Korn, T.; Schade, M.; Schade, S.; Knochel, P.
Org. Lett. 2006, 8, 725. (c) Amatore, M.; Gosmini, C. Angew. Chem., Int.
Ed. 2008, 47, 2089. (d) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.;
ꢀ
Nakamura, M. J. Am. Chem. Soc. 2009, 131, 11949. (e) Begouin, J.-M.;
Rivard, M.; Gosmini, C. Chem. Commun. 2010, 46, 5972. (f) Kuzmina,
O. M.; Steib, A. K.; Markiewicz, J. T.; Flubacher, D.; Knochel, P.
€
Angew. Chem., Int. Ed. 2013, 52, 4945. (g) Gulak, S.; Stepanek, O.;
Malberg, J.; Rad, B. R.; Kotora, M.; Wolf, R.; Jacobi von Wangelin, A.
Chem. Sci. 2013, 4, 776.
(9) For selected reviews on organotitanium reagents: (a) Weidmann,
B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1983, 12, 31. (b) Reetz,
M. T. Organotitanium Reagents in Organic Synthesis; Springer: Verlag,
1986. (c) Duthaler, R. O.; Hafner, A. Chem. Rev. 1992, 92, 807. (d) Marek,
I. Titanium and Zirconium in Organic Synthesis; Wiley-VCH: Weinheim,
2002.
(10) For selected papers on the reactions of the titanium ate complex:
(a) Arai, M.; Nakamura, E. J. Org. Chem. 1991, 56, 5489. (b) Bernardi,
A.; Cavicchioli, M.; Marchionni, C.; Potenza, D.; Scolastico, C. J. Org.
Chem. 1994, 59, 3690. (c) Mahrwald, R. Tetrahedron 1995, 51, 9015. (d)
Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305. (e) Itoh,
Y.; Houk, K. N.; Mikami, K. J. Org. Chem. 2006, 71, 8918. (f) Mikami,
K.; Murase, T.; Itoh, Y. J. Am. Chem. Soc. 2007, 129, 11686. (g)
Manolikakes, G.; Dastbaravardeh, N.; Knochel, P. Synlett 2007,
2077. For the titanium ate-complex mediated enantioselective alkylation
and arylation of aldehydes: (h) Muramatsu, Y.; Kanehira, S.; Tanigawa,
M.; Miyawaki, Y.; Harada, T. Bull. Chem. Soc. Jpn. 2010, 83, 19 and
references cited therein.
The above cross-coupling reaction was found to be
sensitive to the nature of the leaving group of the electro-
phile (Table 1, entries 22ꢀ26). The corresponding chloride,
tosylate, and triflate showed relatively poor conversions,
while fluoride did not react in this case. 4-Iodobenzophe-
none could be consumed within a short period to give an
B
Org. Lett., Vol. XX, No. XX, XXXX

55ꢀ98% within 4 h, while aryl chlorides with an electron-
withdrawing group reacted to afford the biaryl products in
54ꢀ92% yield within 11 h (3bbꢀ3kb). In addition to ester,
phenyl ketone, amide, sulfonate, and sulfonamide groups
(3acꢀ3kb), an ethyl or isopropyl ketone group could be
well tolerated without competive deprotonation (3ed and
3fa). It was noticed that an ortho-ketone group could
facilitate the cross-coupling where aryl bromide, chloride,
and fluoride could undergo the reaction equally well
(3geꢀ3ga).8a,b Remarkably, functionalized aryl and het-
eroaryl Grignard reagents could also react well to furnish
the biaryl products (3gf, 3gg, 3jj, and 3jf), and the use of
aryl lithium reagents gave comparable yields to those with
Grignard reagents (3da, 3ga, 3kb, 3la, 3pa). Particularly
important is that this cross-coupling proceeded very well in
the presence of free COOH, OH, CONHR, and SO2NHR
(3laꢀ3rb).11 By comparing the results of 3da and 3ha with
those of 3laꢀ3rb, it can be seen that the presence of such
functional groups could promote the cross-couplings even
more effectively. For example, the cross-coupling of
4-MeOC6H4Cl could not occur and that of 4-MeOC6H4Br
only gave 56% yield; conversely, 4-HOC6H4Cl and
4-HOC6H4Br could couple in 46% and 86% yield respec-
tively. Notewothy is that this reaction can thus allow
the simple and efficient arylation of highly functionalized
aryl halides (i.e., 3ma) without a protection/deprotection
sequence.
Scheme 1. Cobalt/Titanium Catalyzed Cross-Couplings
between Aryl Halides and Aryl Grignard or Lithium Reagentsa
Scheme 2. Cobalt/Titanium Catalyzed Cross-Couplings between
N-Heteroaryl Halides and Aryl Grignard or Lithium Reagentsaꢀc
a The reaction temperature was rt, X = Br unless otherwise indicated,
and all yields are isolated yields. b The yield in parentheses was obtained
using PhLi. c The reaction was carried outat 60 °C. d This Grignard reagent
was prepared via bromine/magnesium exchange using i-PrMgCl LiCl.
3
e
ꢀ
2.4 equiv of ArM and 0.96 equiv of Ti(OEt)4 were used.
acceptable yield of cross-coupling product. However a
remarkable amount of benzophenone resulting from the
reduction of the starting iodide was observed (Table 1,
entry 24).
b
a Conditions were the same as those in Scheme 2. The yield in
parentheses was obtained using PhLi. c 2.4 equiv of ArM and 0.96 equiv
of Ti(OEt)4 were used.
ꢀ
With optimized reaction conditions in hand, we then
investigated the scope of this biaryl coss-coupling reaction
between various aryl halides with aryl Grignard reagents
or aryl lithium reagents. The results are summarized in
Scheme 1. This cross-coupling reaction showed a broad
scope with remarkable functional-group tolerance. Var-
ious aryl bromides underwent smooth cross-couplings in
To further demonstrate the broad generality of this
cross-coupling reaction, we subsequently investigated the
cross-couplings between N-heteroaryl halides and aryl
(11) For papers on the cross-coupling reactions of halides bearing
acidic protons: Manolikakes, G.; Dong, Z., M.Sc.; Mayr, H.; Li, J.;
Knochel, P. Chem.;Eur. J. 2009, 15, 1324 and references cited therein.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Regioselective Arylation and One-Pot Iterative
Diarylationa
Scheme 4. Competition and Control Experiments
a See Supporting Information for experimental details.
Grignard or lithium reagents. The results are summarized
in Scheme 2. Notably, this Co-catalyzed cross-coupling
reaction was also applicable to various N-heteroaryl ha-
lides. In sharp contrast to the fact that 3-pyridyl bromides
could hardly couple with aryl Grignard reagents using
the reported cobalt catalys system,8d in this case 3-pyridyl
bromides as well as 3-quinolinyl bromide underwent
smooth cross-couplings based on the present procedure
(5aaꢀ5ed). Besides, 2-bromo or chloro pyridines or qui-
nolines could also couple well with aryl Grignard reagents
as expected (5faꢀ5kb). Once again, the cross-coupling
occurred smoothly in the presence of a free carboxyl and
phenolic hydroxyl group (5cc, 5da, 5gf, and 5ge).
This Co-catalyzed biaryl cross-coupling reaction also
exhibited high regioselectivity. As illustrated in Scheme 3,
2,5-dibromopyridine (6) could be arylated at C2 with high
regioselectivity. Taking advantage of this high regioselec-
tivity, dibromopyridine 6 could be iteratively diarylated in
a one-pot manner .
To probe the selectivity between this biaryl cross-
coupling and those of C(sp2) and C(sp3) centers,6 compe-
tition and control experiments were performed (Scheme 4).
The results clearly indicated that the present biaryl cross-
coupling had remarkable selectivity over the couplings
between C(sp2) and C(sp3) centers. Moreover, the homo-
coupling occurred as a main reaction in the absence of
titanate, clearly demonstrating that the synergetic effect of
titanium played a key role in suppressing the undesired
homocouplings. We assume that the cobaltꢀtitanium
bimetallic cooperativity suppresses the formation of the
symmetrical diaryl cobalt complex [Co(Ar)2 or Co(Ar0)2]
and the consequent undesired homocouplings. It should be
noted that this bimetallic cooperativity may be signifi-
cantly enhanced when the groups such as OH, COOH,
etc., are presented, for the salts of these groups have a
strong tendency to complex with titanium and thus facil-
itate the formation of the bimetallic complex.
In summary, we have developed general and high che-
mo- and regioslective biaryl cobalt/titanium cocatalyzed
cross-coupling reactions. With a simple catalyst system
and substoichiometric nontoxic titanate, a broad range of
reactants, particularly those bearing a free COOH, OH,
CONHR, or SO2NHR group, can be efficiently cross-
coupled in a single solvent at room temperature. Since the
present easy-handling reaction takes full advantage of the
ready availabilityof organolithium and organomagnesium
reagents and at the same time overcomes many of the
limitations of previously reported cross-couplings (such
as low functional group tolerance, undesired homo-
coupling, etc.), we believe that our discovery would enrich
the repertoire of transition-metal-catalyzed biaryl cross-
coupling reactions. Furthermore, the cobalt/titanium co-
operativity provides a practical and eco-friendly protocol
for developing efficient transition-metal-catalyzed cross-
couplings using classic reagents. Further cooperative
cross-couplings using titanium are being investigated in
our laboratories.
Acknowledgment. We gratefully acknowledge the Na-
tional Nature Science Foundation of China (21242006,
21372031). The authors thank Prof. B. Gong at NYSU,
Buffalo, for his helpful discussions.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX