Communication
Recently, we observed the auto-oxidative coupling of glycine
derivatives in acetonitrile (CH3CN) and dichloroethane (DCE) as
mixed reaction solvents. Further investigations revealed that
DCE was crucial for this auto-oxidative progress.[7] This informa-
tion encouraged us to test other halogen-containing reagents.
Initially, glycine ester 1a and styrene 2a were chosen as model
substrates. Interestingly, ethyl 6-methyl-4-phenylquinoline-2-
carboxylate (3aa) was produced in 55% yield when 1.0 equiva-
lent of CBr4 was used under air atmosphere (Table 1, entry 5).
The most surprising finding was that the efficiency of this
transformation was promoted when the reaction was carried
out in an argon-filled Schlenk tube with an air balloon on the
branch pipe (Table 1, entry 6, see the Supporting Information
for experimental device). We believe the reason is that the for-
mation of the side product ethyl 2-oxo-2-(p-tolylamino)ace-
tate[7] from self-oxidation can be avoided under these de-
creased oxygen concentration conditions. Further studies indi-
cated that the yields decreased with lower CBr4 loadings
(Table 1, entries 9 and 10). In addition, both increasing and de-
creasing the temperature resulted in lower yields (Table 1, en-
tries 11–13). The effect of different solvents was also surveyed,
the best choice still being CH3CN. All together it was discov-
ered that 1.0 equivalent of CBr4 in CH3CN at room temperature
were the optimized reaction conditions (81%, Table 1, entry 6).
Under the optimized conditions given above, the scope of
the glycine derivatives 1 was investigated. Various glycine
esters (Table 2,A) and glycine amides (Table 2,B) could be
smoothly transformed into the desired products. In addition,
a short peptide (1k) was also tolerated in this transformation,
generating 3ka in 84% yield (Table 2,F). The scope of this
CBr4-induced anaerobic CDC reaction leading to sub-
Table 1. Dehydrogenative Povarov/aromatization tandem reaction of 1a
with 2a promoted by halogen-containing reagents.
Entry
[Hal]
Atmosphere
Loading
[equiv]
Temp.
Yield
[%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
DCE
DCE
DBE
NBS
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
CBr4
open flask
open flask
open flask
open flask
37.0[c]
1.0
1.0
1.0
1.0
1.0
1.0
1.5
0.5
0.2
1.0
1.0
1.0
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
408C
608C
08C
51
0
0
trace
55
81
0
80
45
22
open flask
Ar+air balloon
vacuum line
Ar+air balloon
Ar+air balloon
Ar+air balloon
Ar+air balloon
Ar+air balloon
Ar+air balloon
74
61
trace
[a] Reaction conditions: 1a (1.0 mmol), 2a (20 equiv), CH3CN (30 mL),
16 h. [b] Yields of the isolated products. [c] DCE as a co-solvent. DCE=di-
chloroethane. DBE=dibromoethane. NBS=N-bromosuccinimide.
(Table 3,C).[12] The combination of N-aryl tetrahydroisoquino-
lines and phosphites could also give the corresponding CÀP
coupling products (Table 3,D).[13]
To probe the mechanism of this transformation, some con-
trol experiments were carried out. Firstly, the reaction of 1a in
the absence of styrene (2) under the standard reaction condi-
tions was investigated. Imine 7a and its dimer 8a were ob-
stituted quinolines was further expanded to a range
of substituted styrenes (Table 2,D, E and F). The re-
Table 2. CBr4-mediated CDC reaction of glycine derivatives with alkenes.[a,b]
sults demonstrate that styrenes with electron-donat-
ing or electron-withdrawing groups on the phenyl
ring are suitable substrates in this transformation. It
is worth noting that when indene was used, complex
polycyclic quinolines were obtained (Table 2,C). To
evaluate the practicability of our method, the reac-
tion of 1a with 2a was performed on a 20 mmol
scale in a single batch; no obvious loss of yield was
observed (78% yield).
To develop a more general and useful method, we
subsequently turned our attention to investigating
the dehydrogenative coupling reaction of tertiary
amines under the CBr4-induced conditions. First, the
sp3–sp2 CÀH coupling between N-aryl tetrahydroiso-
quinolines and indoles was successfully performed.[11]
Different N-aryl tetrahydroisoquinolines (Table 3,A)
and indoles with electron-donating or electron-with-
drawing groups (Table 3,B) all worked well under the
present reaction conditions. The coupling reaction
between two sp3 CÀH bonds is a very attractive but
challenging area. CBr4 was also demonstrated to be
an efficient promoter for the dehydrogenative Man-
nich reaction of N-aryl tetrahydroisoquinolines and
non-activated ketones under mild conditions
[a] Standard reaction conditions: 1 (1.0 mmol), 2 (20 equiv), CBr4 (1.0 equiv), CH3CN
(30 mL), air, RT, 16 h. [b] Yields of the isolated products. [c] 608C.
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Chem. Eur. J. 2015, 21, 1 – 5
2
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!