A significantly larger number of structurally diverse halides
are commercially available at present, usually at a sub-
stantially lower price. Hence, our goal was to develop an
alternative method that would allow the application of aryl
halides as aryl donors. Herein, we report the Ru(II)-catalyzed
direct arylation of benzylic amines with aryl bromides, again
taking advantage of 3-substituted pyridines as crucial direct-
ing groups to facilitate selectivity (Scheme 1).
Table 1. Optimization Studies for the Direct Arylation of
Benylic Amine 1aa
In our previously disclosed protocol, we had already
established that pyridines bearing a bulky and inert sub-
stituent in the 3-position could effectively direct a metal
catalyst toward the CÀH bond to be arylated. Preliminary
computational studies indicated that a certain steric bulk
at this position of the directing group is necessary to
stabilize the required conformation in which the CÀH
bond in question is in close proximity to the pyridine
ligated metal catalyst (unpublished results). Furthermore,
we could develop a method for the cleavage of the
3-substituted pyridine group, enabling access to the Boc
protected or the free amine. On the basis of this rationale, we
decided to maintain these advantageous properties of the
directing group and set out to identify a suitable catalytic
system for our purpose. Initially, different Pd-, Rh-, and
Ru-catalysts were tested. Among the investigated com-
plexes, only [RuCl2(p-cymene)]2 showed promising results.
entry
cocatalyst
X
T [°C]
3a:4b
yield of 3ac (%)
1
Br
Br
Br
Br
Br
Br
Br
Cl
I
120
120
120
120
120
120
120
120
120
130
140
140
140
150
6:1
2:1
2:1
4:1
6:1
2:1
6:1
21
34
32
34
43
42
46
2
2
AcOH
3
KOAc
4
AdCO2H
AdCO2K
PivOH
KOPiv
KOPiv
KOPiv
KOPiv
KOPiv
5
6
7
8
9
15:1
6:1
53
66
75
42
57
74
10
11
12
13
14
Br
Br
Br
I
6:1
6:1
KOPiv
KOPiv
30:1
6:1
Scheme 1. Ru-Catalyzed Direct Arylation of Benzylic Amines
Br
a Reaction conditions: 1a (0.5 mmol), PhX (0.75 mmol), [RuCl2-
(p-cymene)]2 (2.5 mol %), cocatalyst (30 mol %), K2CO3 (1.5 mmol),
and PhMe (2 mL). b Ratio based on GC analysis. c Yield determined by
GC analysis with respect to 1a (dodecane as internal standard).
of sp2 CÀH bonds during recent years.8,9 However, to the
best of our knowledge, there is no report about sp3 CÀH
bond arylation using this system. In our initial experiment,
substrate 1a was reacted with bromobenzene using
[RuCl2(p-cymene)]2 as catalyst in toluene at 120 °C, which
yielded a moderate 21% of the desired product 3a together
with its imine derivative 4 in a 6:1 ratio (Table 1, entry 1).
The [RuCl2(p-cymene)]2/carboxylate system is a promi-
nent method for the direct arylation of sp2 CÀH bonds,
and a variety of catalytic reactions were developed during
the last years.6a These carboxylate assisted CÀH bond
transformations are proposed to proceed via a concerted
deprotonation metalation (CMD) mechanism. To increase
the yield of our reaction, different carboxylates were
screened as cocatalyst (Table 1), indicating a substantially
beneficial effect of KOPiv (Table 1, entry 7; 46% yield).
While the ratio of 3a:4 was not affected when using
bromobenzene (6:1), a further increase in the formation
of 3a was observed when employing iodobenzene (entry 9;
53% yield, 15:1 ratio 3a:4). Chlorobenzene was not suita-
ble for this transformation (Table 1, entry 8). Finally, by
increasing the temperatureto140°C (Table1, entry11), we
could achieve a reasonable GC yield of 75% using bromo-
benzene as phenyl source. This Ru(II) mediated protocol
offers the additional benefit of a lower catalyst loading of
The [RuCl2(p-cymene)]2 catalyst has attracted much
attention for the direct chelation-assisted functionalization
(8) For recent papers on [RuCl2(p-cymene)]2 catalyzed CÀH bond
functionalization, see (a) Ackermann, L.; Pospech, J.; Graczyk, K.;
Rauch, K. Org. Lett. 2012, 14, 930–933. (b) Chinnagolla, R. K.;
Jeganmohan, M. Chem. Commun. 2012, 48, 2030–2032. (c) Saidi, O.;
Marafie, J.; Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.; Kociok-Kohn,
G.; Whittlesey, M. K.; Frost, C. G. J. Am. Chem. Soc. 2011, 133, 19298–
19301. (d) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2011, 13, 706–708. (e) Arockiam, P. B.;
Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green Chem. 2011, 13,
3075–3078.
(9) For recent papers on [RuCl2(p-cymene)]2 catalyzed CÀH bond
arylation with aryl halides, see (a) Ackermann, L.; Diers, E.; Manvar, A.
Org. Lett. 2012, 14, 1154–1157. (b) Lakshman, M. K.; Deb, A. C.;
Chamala, R. R.; Pradhan, P.; Pratap, R. Angew. Chem., Int. Ed. 2011,
50, 11400–11404. (c) Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13,
3332–3335. (d) Li, B.; Bheeter, C. B.; Darcel, C.; Dixneuf, P. H. ACS Catal.
2011, 1, 1221–1224. (e) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.;
Dixneuf, P. H. Angew. Chem., Int. Ed. 2010, 49, 6629–6632. (f) Ackermann,
L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K. Synthesis 2010,
2245–2253.
Org. Lett., Vol. 14, No. 14, 2012
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