Simple, efficient protocols for the Pd-catalyzed cross-coupling reaction of aryl chlorides and dimethylamine

Article abstract of DOI:10.1016/j.tetlet.2009.03.137

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 of these precatalysts in reactions that benefit from an easily activated source of L₁Pd(0).

Full text of DOI:10.1016/j.tetlet.2009.03.137

Tetrahedron Letters 50 (2009) 3672–3674
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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
*
Corresponding author. Tel.: +1 617 253 1885; fax: +1 617 253 3297.
E-mail address: sbuchwal@mit.edu (S.L. Buchwald).
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

B. K. Lee et al. / Tetrahedron Letters 50 (2009) 3672–3674
3673
Table 1
Table 3
Ligand screen in the cross-coupling of dimethylamine and 4-chloroanisole at room
temperature
Cross-coupling reactions of dimethylamine and aryl chlorides using K
3
PO
4
ÁH
2
O at
110 °C
HNMe2
(2M in THF)
2.0 equiv
2 mol% 7
K PO • H O (1.2 equiv)
Cl
NMe2
ArCl
equiv
ArNMe2
LHMDS
1
3
4
2
(
1M in THF)
HNMe2
2M in THF)
NH2
Cl
110 ºC, 16 h
Pd
(
rt, 20 min
L
Yielda (%)
Entry
Product
OMe
1 mol %
OMe
NMe2
Entry
Precatalyst
Conversiona (%)
1
2
83
1
2
3
4
5
t-BuXPhos; 6
XPhos; 7
BrettPhos; 8
SPhos; 9
100
20
1
16
25
MeO
MeO
NMe2
NMe2
90
RuPhos; 10
OMe
a
Determined by GC.
3
4
95
n-Bu
times in excess of 5 h are required to achieve complete conversion
to product.
NMe2
82b
MeO C
2
Based upon our success in using precatalyst 6 to effect the
cross-coupling of dimethylamine and 4-chloroanisole, we em-
ployed it in cross-coupling reactions of dimethylamine and a vari-
ety of aryl and heteroaryl chlorides (Table 2). Using 1 mol % Pd, we
found that the cross-coupling reactions proceed efficiently with
deactivated aryl chlorides (entry 1), ortho-substituted aryl chlo-
NMe2
N
70c
94
5
6
NC
NMe2
a
b
c
Average isolated yields of 2 runs.
h reaction time.
Volatile product.
6
Table 2
Cross-coupling reactions of dimethylamine and aryl chlorides with LHMDS at room
temperature
rides (entry 4), as well as a variety of heteroaryl chlorides (entries
3, 5–7). All of these reactions were complete in less than 2 h at
room temperature. The solutions of dimethylamine and LHMDS
used in these reactions are commercially available and were used
as received (see Supplementary data).
Because LHMDS is not compatible with substrates bearing base-
sensitive functional groups, we also investigated conditions for the
arylation of dimethylamine that would permit the use of a weak
base. Although the t-BuXPhos precatalyst (6) created the most effi-
cient catalytic system at room temperature, we found that the
XPhos precatalyst (7) afforded the optimal catalytic system with
weak bases at elevated temperatures. Using 2 mol % 7 with
HNMe2
2M in THF)
1 mol% 6
ArCl
equiv
ArNMe2
(
1
.5 equiv LHMDS
1
(
1M in THF)
rt, 2h
1
.5 equiv
Entry
Product
Yielda (%)
NMe2
1
2
3
4
99
MeO
MeO
NMe2
97
OMe
K
3
PO
4
ÁH
2
O, cross-coupling reactions of aryl chlorides and dimeth-
N
NMe2
ylamine were performed efficiently at 110 °C (Table 3). We found
88
that the use of rigorously anhydrous conditions led to drastically
N
diminished yields. Employing K
3
PO
4
2
ÁH O is required to obtain con-
NMe2
sistent yields. Under these conditions, potentially base-sensitive
functional groups can be tolerated (entries 4 and 6). Additionally,
dimethylamine can be successfully cross coupled to deactivated
aryl and heteroaryl chlorides (entries 1 and 5, respectively) using
the combination of a weak base and an elevated temperature.
Although no problems were observed during the course of these
reactions, a blast shield should be employed as an additional pre-
caution when conducting these sealed, high temperature reactions.
In summary, we have developed simple procedures for the effi-
cient cross-coupling reaction of dimethylamine and aryl and het-
eroaryl chlorides. Separate methods have been developed which
use a strong base at room temperature and a weak base at an ele-
vated temperature. These procedures constitute the first general
methods to form dimethylanilines via the cross-coupling reaction
of aryl halides and dimethylamine. Commercially available
reagents were exclusively used in these reactions. Additionally,
palladacyclic precatalysts were employed as sources of highly
Me
81b
Me
N
5
97
NMe2
6
7
99
96
MeO
N
N
NMe2
O
Me N
2
S
8
96
Me N
NMe2
2
3
active, mono-ligated Pd(0). Such palladacycles are easily activated
a
Average isolated yields from 2 runs.
Volatile product.
and permit the formation of Pd(0) complexes in the absence of
potentially inhibitory ligands such as dba and PPh .
3
b

3
674
B. K. Lee et al. / Tetrahedron Letters 50 (2009) 3672–3674
2
3
.
.
Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686.
Precatalysts 7 and 9 are currently commercially available from Strem. We
expect 6 to be available in the near future.
Acknowledgments
We thank the National Institutes of Health (NIH) for support
4. Amatore, C.; Broeker, G.; Jutand, A.; Khalil, F. J. Am. Chem. Soc. 1997, 119, 5176.
5. Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008,
(
(
GM-058160). M.R.B. thanks the NIH for a postdoctoral fellowship
GM-F32-75685). We also thank Amgen, Merck, and Boehringer
1
30, 13552.
6
7
.
.
Martin, R.; Buchwald, S. L. Org. Lett. 2008, 10, 4561.
A Scifinder search generated approximately 40,000 hits for molecules containing
the Ar–NMe subunit, whose biological activities have been studied.
2
Ingelheim for additional unrestricted funds. B.K.L. was a recipient
of a 2008 MIT UROP Summer fellowship.
8
.
To the best of our knowledge, there are only four examples of dimethylaniline
formation via the direct Pd-catalyzed C–N cross-coupling reaction of
dimethylamine and an aryl halide: (a) Hosokawa, S.; Ogura, T.; Togashi, H.;
Tatsuta, K. Tetrahedron Lett. 2005, 46, 333; (b) Thanh, N. C.; Ikai, M.; Kajioka, T.;
Fujikawa, H.; Taga, Y.; Zhang, Y.; Ogawa, S.; Shimada, H.; Miyahara, Y.; Kuroda,
S.; Oda, M. Tetrahedron 2006, 62, 11227; (c) Joubert, N.; Pohl, R.; Klepetarova, B.;
Hocek, M. J. Org. Chem. 2007, 72, 6797; (d) Li, J. J.; Wang, Z.; Mitchell, L. H. J. Org.
Chem. 2007, 72, 3606.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.03.137.
References and notes
1
.
(a) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions; de
Meijere, A., Diederich, F., Eds., 2nd ed.; Wiley-VCH: Weinheim, 2004; (b) Surry,
D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.