Tetrahedron Letters
Pd-catalyzed amidation of aryl(Het) halides with tert-butyl carbamate
b
a
Lijin Qin a,b, Hongmeng Cui a,b, Dapeng Zou a,b, , Jingya Li , Yangjie Wu , Zhiwu Zhu a,b, Yusheng Wu b,c,
*
*
a Department of Chemistry, Key laboratory of Chemical Biology and Organic Chemistry of Henan Province, Zhengzhou University, Zhengzhou, Henan 450052, PR China
b Tetranov Biopharm, LLC. 75 Daxue Road, Zhengzhou, Henan 450052, PR China
c Tetranov International Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd-catalyzed cross-coupling reaction of tert-butyl carbamate with various aryl(Het) halides with Cs2CO3
as base in 1,4-dioxane as solvent was investigated, which resulted in the formation of the desired com-
pounds in moderate to excellent yields.
Received 24 April 2010
Revised 15 June 2010
Accepted 16 June 2010
Available online 20 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
chosen as model reaction in 1,4-dioxane at 100 °C in the presence
of Cs2CO3 as base (as shown in Table 1). The combination of
Aryl amines are traditionally valuable in organic synthesis,
pharmaceuticals, and materials science.1–5 The synthesis of aryl-
amines has always been a topic of interest in organic chemistry.6
In the past years, palladium-catalyzed C–N coupling has received
an increased attention.7 A variety of excellent work has been car-
ried out for this reaction.8 Lithium bis(trimethylsilyl)amide,8d lith-
ium amide,8e zinc bis(hexamethyl-disilazide),8f and benzophenone
imine8g have been successfully utilized in this conversion. Hartwig
and Buchwald have demonstrated that ammonia can be used as a
coupling partner in the Pd-catalyzed conversion of aryl halides to
anilines.8a,c However, the published ammonia equivalents are not
in a conveniently protected form except for tert-butyl carbamate.
Pd(OAc)2 and SPhos, DavePhos, RuPhos, or CyJohnPhos (as shown
in Fig. 1) give moderate to good yields (Table 1, entries 1–4). When
XPhos was used, 94% yield was offered (Table 1, entry 5). It is re-
ported that the increasing ligand bulk leads to more effective reac-
tions, presumably due to an increase in the rate of reductive
elimination.7a In the used ligands, XPhos appears to offer the opti-
mal bulk to most efficiently promote the reaction rate (Table 1, en-
tries 1–4 vs 5). Switching the Pd source to Pd2(dba)3ÁCHCl3 gives
lower yield (Table 1, entry 6). Then the combination of Pd(OAc)2/
XPhos was fixed.
To study the effect of solvents and bases on the cross-coupling
reaction, tert-butyl carbamate 1 and 3-bromoanisole 2 were cho-
sen as the model reaction by fixing 3 mol % Pd(OAc)2 and 9 mol %
XPhos (as shown in Table 2). Several bases such as t-BuONa,
Cs2CO3, K3PO4, K2CO3, and KOAc were examined in the reaction,
The tert-butyloxycarbonyl (Boc) group is
a very convenient
amine-protecting group because it is easy to be removed. There
are only limited examples of tert-butyl carbamate reported to be
used in the palladium-catalyzed C–N coupling.6b,9,10 It is reported
first time that the Pd-catalyzed amidation of aryl bromides using
tert-butyl carbamate as substrate by Hartwig in 1999.9 In 2009,
Keith R. Hornberger studied the Pd-catalyzed coupling of aryl
bromides with tert-butyl carbamate, which gave the desired
cross-coupling products in good to excellent yield.10 However, aryl
chlorides were not studied for this type of reaction in the report.10
We were interested in exploring a broad scope of this type of reac-
tion with a new catalytic system and specially the reaction using
aryl chlorides and heteroaryl halides.
Table 1
Screen of catalysts and ligands for the cross-coupling of tert-butyl carbamate with 3-
bromoanisolea
NHBoc
Br
O
Catalyst, ligand, Cs CO
2
3
+
O
O
o
O
NH
2
dioxane, 100
C
1
2
3
Entry
Catalyst
Ligand
Yieldb (%)
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
SPhos
DavePhos
RuPhos
CyJohnPhos
XPhos
XPhos
57
66
77
50
94
80
2. Optimization of the Pd-catalyzed amidation reactions of aryl
bromides
To evaluate the activity of the combination of different catalysts
and ligands, tert-butyl carbamate 1 and 3-bromoanisole 2 were
Pd2(dba)ÁCHCl3
a
All reactions based on 0.25 mmol 3-bromoanisole, 0.3 mmol tert-butyl carba-
mate, 3 mol % catalyst, 9 mol % ligand, 0.35 mmol Cs2CO3, 2.0 ml dioxane, 100 °C,
* Corresponding authors. Tel.: +1 732 253 7326; fax: +1 732 253 7327 (Y.W.).
4 h.
b
The reactions averaged on two runs, isolated yields.
.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.