adducts are prepared by the reaction of activated alkenes such
as ethyl acrylate, acrylonitrile, and methyl vinyl ketone with
aldehydes or imines in the presence of nucleophilic catalysts
such as 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine,
4-(N,N-dimethylamino)pyridine (DMAP), and phosphine.9 In
addition to the intrinsic usefulness of the Baylis-Hillman
adducts, they and their acetates are valuable precursors for the
preparation of a variety of trisubstituted alkenes with various
functional groups such as esters, ketones, and nitriles by reaction
with a variety of nucleophiles.10,11
We have been investigating alternative protocols for the
synthesis of nitrogen-containing heterocycles, based on transi-
tion-metal-mediated carbonylation reactions.12 In this paper, we
report an interesting method for the synthesis of seven-
membered unsaturated ring lactams as well as substituted
benzazepine derivatives, by the palladium-catalyzed one-pot
amination and intramolecular cyclocarbonylation reactions of
amines and Baylis-Hillman acetates (Scheme 1).
Scheme 2. Synthesis of Baylis-Hillman Acetates
perform the amination and intramolecular cyclocarbonylation
reaction under different reaction conditions. The results are
shown in Table 1.
Table 1. Optimization of the Palladium-Catalyzed Amination
and Carbonylation Reaction of Baylis-Hillman Acetate and
Benzylaminea
Scheme 1
.
Strategic Approach to the Synthesis of Substituted
Benzazepine Derivatives
isolated
yield
entry catalyst
ligand
A/B
base
CO
time
1
2
3
4
5
6
Pd(OAc)2 dppb
Pd(OAc)2 dppb
Pd(OAc)2 PPh3
Pd(OAc)2 BIPHEP
Pd(OAc)2 dppb
Pd(OAc)2 dppb
1:1.2 DBU 400 psi 20 h
K2CO3 400 psi 20 h
K2CO3 400 psi 20 h
K2CO3 400 psi 20 h
K2CO3 1 atm 20 h
16%
62%
35%
52%
55%
75%
1:3
K2CO3 100 psi 30 h
First, various Baylis-Hillman acetates were prepared from
different 2-halobenzaldehydes according to the literature8
(Scheme 2).
a Reaction conditions: A (1 mmol), B (1.2 or 3 mmol), Pd(OAc)2 (0.05
mmol), PPh2 (0.20 mmol), dppb or BIPHEP (0.10 mmol), base (2 mmol),
toluene (5 mL), 110 °C.
Then the ethyl 2-(acetoxy(2- bromophenyl)methyl)acrylate
and benzyl amine were chosen as the model substrates to
In our first trial, with Pd(OAc)2/dppb as the catalyst
system, DBU as base, toluene as the solvent, at 400 psi of
CO for 20 h, the reaction gave a 16% yield of the desired
product. To find the best conditions for this new hydroami-
nation and intramolecular cyclocarbonylation reaction of
Baylis-Hillman acetate and amines, we tried different
ligands and bases and varied the ratio between the two
substrates. The results showed that dppb was more efficient
than other bidentate ligands and PPh3 (Table 1, entries 2-4).
The inorganic base K2CO3 is better than DBU (Table 1,
entries 1, 2). The reaction could be carried out under 1 atm
of CO affording the product in 55% yield (Table 1, entry
5). We were pleased to observe that, with 3 equiv of
benzylamine and 100 psi of CO, the reaction provided the
highest yield (75%) of the seven-membered ring lactam after
30 h (Table 1, entry 6).
Having determined the optimized conditions, we carried
out the palladium-catalyzed amination and intramolecular
cyclocarbonylation reaction with a series of amines. The
results are listed in Figure 1. Most of the amines employed
for the reaction showed good reactivities and provided the
target seven-membered ring lactams in good to excellent
yields. Both aromatic and aliphatic amines were active for
the reactions. Aliphatic amines usually afforded lower yields
than aromatic amines with 4-MePhCH2NH2 giving the
highest product yield (98%).
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Org. Lett., Vol. 13, No. 1, 2011