Cobalt-phenanthroline catalysts for the ortho alkylation of aromatic imines under mild reaction conditions

Article abstract of DOI:10.1002/anie.201101823

Mild mannered: Cobalt catalysts complexed with phenanthroline-type ligands and activated with Grignard reagents serve as inexpensive and effective catalysts for the ortho alkylation of aromatic imines with a variety of olefins (see scheme). The new catalytic systems feature remarkably mild reaction conditions for C-H bond activation and functionalization. Copyright

Full text of DOI:10.1002/anie.201101823

Communications
DOI: 10.1002/anie.201101823
À
C H Bond Functionalization
Cobalt–Phenanthroline Catalysts for the ortho Alkylation of Aromatic
Imines under Mild Reaction Conditions**
Ke Gao and Naohiko Yoshikai*
Table 1: Optimization of ortho alkylation of acetophenone imine 1a with
À
Chelation-assisted C H activation followed by insertion of an
vinyltrimethylsilane 2a[a]
unsaturated molecule offers a straightforward, regioselective,
[1]
À
and atom-economical method for C C bond formation.
While rare-transition-metal catalysts (e.g. Ru, Rh, Pd) have
À
played major roles in this and related types of C H bond
functionalization, the development of cost-effective alterna-
tives has attracted increasing interest.[2] We recently devel-
oped cobalt–phosphine and cobalt–carbene catalysts that
promote ortho alkenylation and ortho alkylation reactions of
aryl pyridine and imine derivatives by insertion of alkynes and
styrenes, respectively.[3] These reactions represent the recent
Entry
Ligand (mol%)
RMgX (mol%)
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
L1 (5)
bpy (5)
bathophen (5)
L2 (5)
L1 (5)
L1 (5)
L1 (5)
PMe2Ph (10)
PCy3 (5)
IMes·HCl (5)
tBuCH2MgBr (40)
tBuCH2MgBr (40)
tBuCH2MgBr (40)
tBuCH2MgBr (40)
MeMgCl (40)
Me3SiCH2MgCl (40)
tBuCH2MgBr (20)
MeMgCl (40)
87 (85)
19
88
50
20
67
7
3
21
À
emergence of cobalt catalysis for C H bond functionaliza-
tion;[4–6] cobalt catalysis is attractive because of the low cost of
the catalysts as well as the unique reactivities or selectivities
often achieved.[7] We report herein a significant expansion of
the scope of this chemistry, achieved with cobalt–phenanthro-
line (L1 or L2) catalysts, which allow the ortho alkylation of
aromatic imines with a variety of olefins under mild reaction
conditions (Scheme 1).[8–10]
Me3SiCH2MgCl (40)
tBuCH2MgBr (40)
20
[a] Reaction was performed on a 0.3 mmol scale at 0.3m concentration.
[b] Determined by GC using n-tridecane as an internal standard. The
yield of the isolated product is shown in parentheses. bathophen=
bathophenanthroline, bpy=2,2’-bipyridine, Cy=cyclohexyl, IMes=1,3-
bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene.
temperature (208C) in the presence of a cobalt catalyst
generated from CoBr2 (5 mol%), L1 (5 mol%), and
tBuCH2MgBr (40 mol%) to afford the alkylation product
3a within 6 hours, in 85% yield upon isolation (Table 1,
entry 1). No dialkylation product was observed. The room-
temperature conditions are in stark contrast to those used for
the related reactions of imines under rhodium or ruthenium
catalysis, which typically require heating at 130–1508C.[8,9]
Among other phenanthroline-type ligands, bathophenanthro-
line performed as efficiently as L1 (Table 1, entries 2–4). The
use of other Grignard reagents such as MeMgCl and
Me3SiCH2MgCl led to lower yields (Table 1, entries 5 and
6). Little conversion was observed when the amount of
tBuCH2MgBr was reduced to 20 mol% (Table 1, entry 7).
The cobalt–phosphine and cobalt–carbene catalysts devel-
oped previously by our group[3] were much less effective
(Table 1, entries 8–10).
The optimized catalytic system was applicable to a wide
variety of aromatic imines (Table 2). Tolerated substituents
on the aromatic ring included methoxy (3b, 3j), chloro (3d,
3 f), fluoro (3i), trifluoromethyl (3g), and cyano (3h) groups
(Table 2, entries 1, 3, and 5–9), although the product yields in
the latter two cases were modest. An imine derived from 4-
bromoacetophenone did not participate in the reaction but
Scheme 1. ortho Alkylation of aromatic imines with a cobalt-phenan-
throline catalyst.
From the screen of the cobalt catalysts for the addition of
the acetophenone imine 1a (PMP = p-methoxyphenyl) to
vinyltrimethylsilane (2a, 1.2 equiv), we identified 1,10-phe-
nanthroline (L1) as an inexpensive and effective ligand
(Table 1). Thus, the reaction took place smoothly at room
[*] K. Gao, Prof. N. Yoshikai
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax: (+65)6791-1961
E-mail: nyoshikai@ntu.edu.sg
Homepage: http://www3.ntu.edu.sg/home/nyoshikai/yoshi-
kai_group/Home.html
[**] We thank the Singapore National Research Foundation (NRF-
RF2009-05) and Nanyang Technological University for financial
support.
À
afforded a product resulting from the cross-coupling at the C
Br bond with the Grignard reagent (< 5%). Imines derived
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101823.
6888
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6888 –6892

Table 2: Scope of aromatic imines for ortho alkylation with vinylsilanes.
from meta-substituted acetophe-
nones reacted exclusively at the
less-hindered position (3e–3h;
Table 2, entries 4–7) except for the
one bearing
a methoxy group,
which preferentially reacted at the
proximal position (3j and 3j’, regio-
selectivity = 2:1; Table 2, entry 9).
This may be due to the secondary
directing effect of the methoxy
group that has been previously
observed for related reactions with
ruthenium and iridium cata-
lysts.[9c,d,10c,d,f,11,12] The imine derived
from 2-fluorenyl methyl ketone
afforded an approximately 1:1 mix-
ture of two regioisomers (3k and
3k’; Table 2, entry 10) without inter-
ference from the acidic proton of
the fluorenyl group (pKa ꢀ 22).[13] In
contrast to this lack of regioselec-
tivity, the imine derived from 2-
acetonaphthone was alkylated
exclusively at the less-hindered
position in good yield (3l; Table 2,
entry 11). Interestingly, this regio-
selectivity is complementary to the
regioselectivity achieved with the
ruthenium-catalyzed ortho alkyla-
tion of 2-acetonaphthone.[10b,14]
Imines derived from carbonyl
groups other than an acetyl group
also served as excellent directing
groups for the reaction, as exempli-
fied by the products 3m–3q. In
addition to the trimethylsilyl
group, dimethylphenylsilyl and tri-
phenylsilyl groups could be
employed as the silyl groups of the
vinylsilanes (3n and 3o; Table 2,
entries 13 and 14), while no alkyla-
tion took place with vinyltriethoxy-
silane. Note that 2-phenylpyridine
also participated in the reaction
with 2a at 608C, affording the
corresponding alkylation product
3r in 72% yield (Table 2,
entry 17).[15]
Entry
Imine
Product
Yield
[%][a]
1
1b
1c
1d
3b (R=OMe)
3c (R=Ph)
3d (R=Cl)
81
79
70
2
3[b]
4
1e
1 f
1g
1h
3e (R=Me)
3 f (R=Cl)
3g (R=CF3)
3h (R=CN)
74
58
41
24
5[b,c]
6[b,c]
7
8
1i
1j
3i
3j
3j’
60
61
30
9
1k
3k
39
10
3k’
37
80
Prompted by the successful
ortho alkylation with vinylsilanes,
we next explored the scope of
olefinic reaction partners. Although
the reaction of the tetralone-
derived imine and 3,3-dimethyl-1-
butene under cobalt–phenanthro-
line catalysis met with limited suc-
cess (< 30% yield), a relatively
simple modification of the catalytic
system allowed us to achieve
11
1l
3l
12
3m (R3 =Me3)
3n (R3 =Me2Ph)
3o (R3 =Ph3)
92
93
84
13
14[b,d]
1m
Angew. Chem. Int. Ed. 2011, 50, 6888 –6892
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6889

Communications
Table 2: (Continued)
bornene participated in the reaction
to afford the adduct 3y in 76%
yield (Table 3, entry 7). The cata-
lytic system also allowed hydro-
arylation of styrene,[3b] thus afford-
ing the branched product 3z as the
major product (Table 3, entry 8). To
the best of our knowledge, 9-vinyl-
carbazole is a new substrate for
Entry
Imine
Product
Yield
[%][a]
15[b]
1n
1o
1p
3p
3q
3r
89
93
72
À
ortho alkylation through C H bond
16
functionalization (3aa; Table 3,
entry 9).
To probe the reaction mecha-
nism, we examined the degree of H/
D scrambling that occurred during
the reaction of [D5]-1a and vinyl-
dimethylphenylsilane 2b under
cobalt–L1 catalysis (Scheme 2).
The deuterium content at the ortho
position of the acetophenone that
was recovered after a 1 hour reac-
tion had decreased to 85%. The
17[b,e]
[a] Yields of the isolated products. [b] Catalyst loading was doubled. [c] Reaction time was 36 h.
[d] Reaction time was 48 h. [e] Performed at 608C.
ortho alkylation with a variety of
olefins (Table 3). Thus, a modified
catalytic system consisting of CoBr2
Table 3: Addition of aromatic imine to various olefins.
(10 mol%),
neocuproine
(L2;
10 mol%), and Me3SiCH2MgCl
(60 mol%) promoted the reaction
to afford the product 3s in 73%
yield and a small amount of an
ortho-trimethylsilylmethylation
Entry
1
Imine
Olefin
Product
Yield
[%][a]
product (10%; Table 3, entry 1).[5d]
The use of an aryl Grignard reagent
73
1m
3s (R=tBu)
(78)[b]
62
2
3
1m
1m
1m
1m
3t (R=n-C6H13)
3u (R=c-C6H13)
3v (R=PhCH2)
3w (R=Me3SiCH2)
4-MeOC6H4MgBr
Me3SiCH2MgCl afforded 3s in
78% yield with only small
instead
of
68
54
57
4[c]
5[d]
a
amount (1%) of an ortho-arylation
product.
6
1m
3x
18
76
Terminal olefins bearing allylic
hydrogen atoms also participated in
the reaction to afford the alkylation
products 3t–3w in moderate to
good yield (Table 3, entries 2–5),
even though such olefins have
been reported to undergo isomer-
ization to the corresponding inter-
nal olefins in the presence of a
7
8
1a
1a
3y
3z
76
(86:14)[e]
cobalt catalyst and
a Grignard
reagent.[16] The addition reaction
to the exocyclic double bond of
methylenecyclohexane also took
place, albeit in low yield (3x;
Table 3, entry 6). An internal
olefin such as trans-oct-2-ene
9
1a
3aa
52
afforded only
a small amount
(5%) of the n-octylation product,
while its cis isomer was entirely
[a] Yields of the isolated products. [b] Yield in parentheses was obtained using 4-MeOC6H4MgBr instead
of Me3SiCH2MgCl. [c] Catalyst loading was doubled. [d] Reaction was performed with the cobalt–L1
unreactive. Not unexpectedly, nor- catalyst at RT for 48 h. [e] Branched/linear ratio is shown in parentheses.
6890 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6888 –6892

À
Keywords: alkenes · alkylation · C H activation · cobalt · imines
.
[1] For recent reviews, see: a) D. A. Colby, R. G. Bergman, J. A.
Ellman, Chem. Rev. 2010, 110, 624 – 655; b) F. Kakiuchi, T.
Kochi, Synthesis 2008, 3013 – 3039; c) F. Kakiuchi, N. Chatani,
Adv. Synth. Catal. 2003, 345, 1077 – 1101; d) Y. Kuninobu, K.
Takai, Chem. Rev. 2011, 111, 1938 – 1953; e) T. W. Lyons, M. S.
Sanford, Chem. Rev. 2010, 110, 1147 – 1169; f) C. L. Sun, B. J. Li,
Z. J. Shi, Chem. Commun. 2010, 46, 677 – 685; g) X. Chen, K. M.
Engle, D. H. Wang, J. Q. Yu, Angew. Chem. 2009, 121, 5196 –
5217; Angew. Chem. Int. Ed. 2009, 48, 5094 – 5115; h) L.
Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. 2009,
121, 9976 – 10011; Angew. Chem. Int. Ed. 2009, 48, 9792 – 9826.
[2] a) A. A. Kulkarni, O. Daugulis, Synthesis 2009, 4087 – 4109; b) E.
Nakamura, N. Yoshikai, J. Org. Chem. 2010, 75, 6061 – 6067;
c) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Rev. 2011, 111, 1293 – 1314;
d) E. Nakamura, K. Sato, Nat. Mater. 2011, 10, 158 – 161.
[3] a) K. Gao, P. S. Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc.
2010, 132, 12249 – 12251; b) K. Gao, N. Yoshikai, J. Am. Chem.
Soc. 2011, 133, 400 – 402.
[4] For earlier studies, see: a) S. Murahashi, J. Am. Chem. Soc. 1955,
77, 6403 – 6404; b) S. Murahashi, S. Horiie, J. Am. Chem. Soc.
1956, 78, 4816 – 4817; c) C. P. Lenges, M. Brookhart, J. Am.
Chem. Soc. 1997, 119, 3165 – 3166; d) C. P. Lenges, P. S. White,
M. Brookhart, J. Am. Chem. Soc. 1998, 120, 6965 – 6979; e) J. K.
Funk, H. Yennawar, A. Sen, Helv. Chim. Acta 2006, 89, 1687 –
1695; f) A. D. Bolig, M. Brookhart, J. Am. Chem. Soc. 2007, 129,
14544 – 14545.
Scheme 2. Deuterium-labeling experiment.
recovered vinylsilane contained 28% deuterium at the
a position, while the degree of deuteration at the b position
was much lower (8%). The deuterium distribution in the
alkylation product was consistent with these observations.
The present result is in stark contrast to the H/D scrambling in
the cobalt-catalyzed styrene hydroarylation, where significant
deuterium incorporation was observed at both the a and
b positions of styrene.[3b]
It is worthwhile to compare the above result with the
previous studies on H/D scrambling in the Murai reaction, i.e.
ruthenium-catalyzed ortho alkylation of aromatic ketones
with vinylsilanes.[10b,g,17] While the Murai reaction at high
temperature (1358C) led to nearly complete (i.e. statistical)
scrambling of the ortho D atoms of [D5]acetophenone and the
vinylic protons of vinylsilane,[10b] only partial H/D scrambling
took place under mild reaction conditions (258C) when using
a highly active catalyst, as reported recently.[10g] Our result is
closer to the latter case, and suggests that the present reaction
[5] a) Z. Ding, N. Yoshikai, Org. Lett. 2010, 12, 4180 – 4183; b) Q.
Chen, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2011, 133, 428 –
429; c) L. Ilies, Q. Chen, X. Zeng, E. Nakamura, J. Am. Chem.
Soc. 2011, 133, 5221 – 5223; d) B. Li, Z.-H. Wu, Y.-F. Gu, C.-L.
Sun, B.-Q. Wang, Z.-J. Shi, Angew. Chem. 2011, 123, 1141 – 1145;
Angew. Chem. Int. Ed. 2011, 50, 1109 – 1113; e) J. Y. Kim, S. H.
Cho, J. Joseph, S. Chang, Angew. Chem. 2010, 122, 10095 – 10099;
Angew. Chem. Int. Ed. 2010, 49, 9899 – 9903; f) T. Truong, J.
Alvarado, L. D. Tran, O. Daugulis, Org. Lett. 2010, 12, 1200 –
1203.
[18]
À
involves reversible C H oxidative-addition
and olefin-
[6] N. Yoshikai, Synlett 2011, 1047 – 1051.
insertion[19] steps, while such an equilibrium process may not
be significantly faster than the product-forming step (i.e.
reductive elimination). The small amount of deuterium
incorporation into the b position of vinylsilane suggests that
the olefin-insertion step predominantly leads to a linear
aryl(alkyl)cobalt intermediate.
À
[7] Reviews on cobalt-catalyzed C C bond formations: a) H.
Yorimitsu, K. Oshima, Pure Appl. Chem. 2006, 78, 441 – 449;
b) W. Hess, J. Treutwein, G. Hilt, Synthesis 2008, 3537 – 3562;
c) G. Cahiez, A. Moyeux, Chem. Rev. 2010, 110, 1435 – 1462.
[8] For rhodium catalysis, see: a) C. H. Jun, J. B. Hong, Y. H. Kim,
K. Y. Chung, Angew. Chem. 2000, 112, 3582 – 3584; Angew.
Chem. Int. Ed. 2000, 39, 3440 – 3442; b) Y. G. Lim, J. S. Han, S. S.
Yang, J. H. Chun, Tetrahedron Lett. 2001, 42, 4853 – 4856;
c) C. H. Jun, C. W. Moon, J. B. Hong, S. G. Lim, K. Y. Chung,
Y. H. Kim, Chem. Eur. J. 2002, 8, 485 – 492; d) Y. G. Lim, J. S.
Han, B. T. Koo, J. B. Kang, J. Mol. Catal. A 2004, 209, 41 – 49;
e) S. G. Lim, J. A. Ahn, C. H. Jun, Org. Lett. 2004, 6, 4687 – 4690;
f) G. Vo-Thanh, H. Lahrache, A. Loupy, I. J. Kim, D. H. Chang,
C. H. Jun, Tetrahedron 2004, 60, 5539 – 5543; g) J. H. Yoon, Y. J.
Park, J. H. Lee, J. Yoo, C. H. Jun, Org. Lett. 2005, 7, 2889 – 2892;
h) Y. G. Lim, B. T. Koo, Tetrahedron Lett. 2005, 46, 7997 – 8001.
[9] For ruthenium catalysis, see: a) F. Kakiuchi, M. Yamauchi, N.
Chatani, S. Murai, Chem. Lett. 1996, 111 – 112; b) F. Kakiuchi, T.
Sato, T. Tsujimoto, M. Yamauchi, N. Chatani, S. Murai, Chem.
Lett. 1998, 1053 – 1054; c) R. Martinez, R. Chevalier, S. Darses,
J. P. Genet, Angew. Chem. 2006, 118, 8412 – 8415; Angew. Chem.
Int. Ed. 2006, 45, 8232 – 8235; d) R. Martinez, M. O. Simon, R.
Chevalier, C. Pautigny, J. P. Genet, S. Darses, J. Am. Chem. Soc.
2009, 131, 7887 – 7895.
In summary, we have developed cobalt–phenanthroline
catalysts for the ortho alkylation of aromatic imines with a
variety of olefins under mild reaction conditions. The present
cobalt catalysis may serve as an inexpensive and mild
alternative to rhodium and ruthenium catalysis, which tradi-
tionally require high reaction temperatures.[8–10,15] Because
monoalkylation products are formed exclusively, the present
reaction may be complementary to the ruthenium-catalyzed
ortho alkylation of aromatic ketones,[9c,d,10] a reaction which
often affords dialkylation products in the absence of any steric
bias on the aromatic substrates. The regioselectivity observed
for the product 3l also highlights the complementary nature
of the cobalt and ruthenium catalysis. Further synthetic and
À
mechanistic exploration of the cobalt-catalyzed C H bond
functionalization is currently under way.
[10] For ortho alkylation of aromatic ketones, see Ref. [9c,d], and the
following: a) S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A.
Kamatani, M. Sonoda, N. Chatani, Nature 1993, 366, 529 – 531;
Received: March 15, 2011
Published online: June 10, 2011
Angew. Chem. Int. Ed. 2011, 50, 6888 –6892
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6891

Communications
b) F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda,
[14] To the best of our knowledge, no related case with a rhodium
catalyst has been reported.
N. Chatani, S. Murai, Bull. Chem. Soc. Jpn. 1995, 68, 62 – 83;
c) M. Sonoda, F. Kakiuchi, N. Chatani, S. Murai, J. Organomet.
Chem. 1995, 504, 151 – 152; d) M. Sonoda, F. Kakiuchi, N.
Chatani, S. Murai, Bull. Chem. Soc. Jpn. 1997, 70, 3117 – 3128;
e) C. P. Lenges, M. Brookhart, J. Am. Chem. Soc. 1999, 121,
6616 – 6623; f) R. Martinez, J. P. Genet, S. Darses, Chem.
Commun. 2008, 3855 – 3857; g) F. Kakiuchi, T. Kochi, E.
Mizushima, S. Murai, J. Am. Chem. Soc. 2010, 132, 17741 – 17750.
[11] K. Tsuchikama, M. Kasagawa, K. Endo, T. Shibata, Synlett 2010,
97 – 100.
[12] A meta-methoxy group did not cause such a directing effect in
the rhodium-catalyzed ortho alkylation of aromatic aldimines
(see Ref. [8b]).
[13] W. S. Matthews, J. E. Bares, J. E. Bartmess, F. G. Bordwell, F. J.
Cornforth, G. E. Drucker, Z. Margolin, R. J. McCallum, G. J.
McCollum, N. R. Vanier, J. Am. Chem. Soc. 1975, 97, 7006 –
7014.
[15] a) Y. G. Lim, Y. H. Kim, J. B. Kang, J. Chem. Soc. Chem.
Commun. 1994, 2267 – 2268; b) Y. G. Lim, J. B. Kang, Y. H. Kim,
J. Chem. Soc. Perkin Trans. 1 1996, 2201 – 2206.
[16] T. Kobayashi, H. Yorimitsu, K. Oshima, Chem. Asian J. 2009, 4,
1078 – 1083.
[17] Note that Brookhart and co-workers also studied H/D scram-
bling in the ortho alkylation of aromatic ketones with vinylsilane
under rhodium catalysis (see Ref. [10e]). In contrast to the
Murai-type and our systems, their system caused H/D scram-
bling not only at the ortho positions, but also at the meta and
para positions.
[18] H. F. Klein, S. Camadanli, R. Beck, D. Leukel, U. Florke, Angew.
Chem. 2005, 117, 997 – 999; Angew. Chem. Int. Ed. 2005, 44, 975 –
977.
[19] C. P. Lenges, M. Brookhart, B. E. Grant, J. Organomet. Chem.
1997, 528, 199 – 203.
6892 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6888 –6892