Tetrahedron Letters 50 (2009) 3672–3674
Tetrahedron Letters
Simple, efficient protocols for the Pd-catalyzed cross-coupling reaction
of aryl chlorides and dimethylamine
Brian K. Lee, Mark R. Biscoe, Stephen L. Buchwald *
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and efficient procedures for the Pd-catalyzed cross-coupling reaction of aryl chlorides and
dimethylamine are described. At room temperature with a strong base, t-BuXPhos is employed as the
supporting ligand; at 110 °C with a weak base, XPhos is employed as the supporting ligand. In each of
these cases, commercially available solutions constitute the source of the dimethylamine, and recently
disclosed precatalysts constitute the source of the ligand and Pd. This work further expands the utility
Received 10 January 2009
Revised 16 March 2009
Accepted 18 March 2009
Available online 25 March 2009
1
of these precatalysts in reactions that benefit from an easily activated source of L Pd(0).
Ó 2009 Elsevier Ltd. All rights reserved.
Biarylmonophosphine ligands are components of some of the
most active catalytic systems for the formation of C(aryl)–N bonds
(
t-BuXPhos precatalyst (6) was most active, with complete conver-
sion of 4-chloroanisole observed in less than 20 min. The XPhos
and RuPhos precatalysts (7 and 10, respectively) can also be suc-
cessfully employed under these conditions, although reaction
Fig. 1).1 We recently disclosed a new class of palladium precata-
lysts based upon biarylmonophosphines that are easily activated
and ensures the formation of the active mono-ligated Pd(0) com-
2
,3
plex. Activation of these precatalysts is achieved by deprotona-
tion of the amine complex, followed by the reductive elimination
of a molecule of indoline (Scheme 1). These precatalysts are partic-
ularly useful in situations where reactions must be conducted un-
der mild conditions that normally preclude the efficient generation
of Pd(0), or where it is necessary to generate the active Pd(0) spe-
OMe
Pt-Bu2
i-Pr
PCy2
i-Pr
MeO
i-Pr
PCy2
i-Pr
i-Pr
i-Pr
4
cies in the absence of potentially inhibitory ligands such as dba or
2
,5,6
i-Pr
t-BuXPhos (1)
i-Pr
XPhos (2)
i-Pr
3
PPh .
BrettPhos (3)
Dimethylaniline is a common subunit of biologically active or-
7
2
ganic compounds. In light of the ubiquity of Ar–NMe groups in
the substructure of biologically interesting molecules, we were
surprised to note that there was no general process available for
the Pd-catalyzed C–N bond-forming cross-coupling reaction be-
tween dimethylamine and an aryl halide.8 Herein, we report effi-
cient, general, and experimentally simple procedures to effect the
cross-coupling of aryl chlorides and dimethylamine using the re-
cently reported precatalysts. The first procedure employs the t-
BuXPhos-derived precatalyst (6) and a strong base at room tem-
perature. The second procedure employs the XPhos version of the
precatalyst (7) and a weak base at 110 °C.
NH2
Pd
PCy2
OMe
PCy2
Oi-Pr
MeO
i-PrO
L
Cl
; L = 1
7; L = 2
6
8
; L = 3
SPhos (4)
RuPhos (5)
9; L = 4
10; L = 5
Figure 1.
Using precatalysts derived from biarylphosphines 1–5, we at-
tempted the direct cross-coupling reaction of dimethylamine and
4
-chloroanisole. In these reactions, a 2 M solution of dimethyl-
amine in THF was employed in combination with a 1 M solution
of LHMDS in THF at room temperature. As shown in Table 1, the
Base
indoline
NH2
LPd(0)
Pd
–
L
Cl
monoligated, active
catalytic species
*
Scheme 1. Base-Mediated Activation of Precatalysts 6–10.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.137