An addition of benzylic sp3 C-H to electron-deficient olefins

Article abstract of DOI:10.1016/j.tetlet.2012.11.100

An addition of benzylic sp3 C-H to electron-deficient olefins has been developed. This reaction provides a new method for the benzylic C-H bond functionalization of azaarenes without using any catalyst and additives.

Full text of DOI:10.1016/j.tetlet.2012.11.100

Tetrahedron Letters 54 (2013) 858–860
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Tetrahedron Letters
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An addition of benzylic sp3 C–H to electron-deficient olefins
⇑
⇑
Hong-Ying Li, Li-Juan Xing, Tong Xu, Peng Wang, Rui-Hua Liu , Bin Wang
State Key Laboratory of Elemento-Organic Chemistry, College of Pharmacy, Nankai University, 94 Weijin Road, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An addition of benzylic sp3 C–H to electron-deficient olefins has been developed. This reaction provides a
new method for the benzylic C–H bond functionalization of azaarenes without using any catalyst and
additives.
Received 29 September 2012
Revised 15 November 2012
Accepted 23 November 2012
Available online 5 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzylic sp3 C–H activation
Electron-deficient olefins
Catalyst free
Aza-ene reaction
In recent years, metal-catalyzed direct transformation of sp3 C–
H bonds has received considerable attention.1–10 Of these pro-
cesses, the benzylic sp3 C–H functionalization of 2-alkylazaarenes
has been extensively studied. Palladium species and Lewis acids
are frequently used in these transformations.11–19 Due to the
importance of 2-alkylazaarenes in medicinal chemistry20,21 and or-
ganic catalysis,22–25 as well as in materials,26–29 the catalyst-free
strategies for the benzylic C–H functionalization of these heterocy-
cles would find significant applications in organic synthesis. It has
been established that 2-alkylpyridine 1 can be transformed to its
enamine counterpart 2, giving a benzylic carbon-nucleophile,
which subsequently reacts with an electrophile to form C–C bonds
(Scheme 1).14,30 In light of these findings, we envisioned that the
nucleophilic carbon of 2 might react with electron-deficient olefins
via an aza-ene reaction31–34 to form C–C bonds. Herein, we present
a facile addition of benzylic sp3 C–H bonds to electron-deficient
olefins under catalyst- and additive-free conditions (Scheme 1).
Our initial investigation focused on the PdCl2-catalyzed addi-
tion of 2-methylquinoline 1a with N-phenylmaleimide 2a at
80 °C in o-xylene (Table 1, entry 1), and only traces of adduct
3aa was observed. When the reaction was carried out in DMSO,
3aa was obtained in 46% yield (Table 1, entry 2). To our surprise,
the addition proceeded well at 100 °C in the absence of the cata-
lyst, providing 3aa in 70% yield (Table 1, entry 3).35 We further
found that the higher yield could be achieved by increasing the
amount of 1a to 1.5 equiv (Table 1, entry 4). It is well known that
bases or Brønsted acids play crucial roles in the traditional Michael
addition and ene reaction. We next investigated whether these
additives could promote the present transformation. The results
indicated that the addition was completely inhibited by either
NaOMe or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and starting
materials were recovered (Table 1, entries 5, 6). In sharp contrast,
good yield was obtained by the use of 0.1 equiv of trifluorometh-
anesulfonic acid (TfOH) (Table 1, entry 7). With these optimized
conditions in hand (Table 1, entry 4), the reaction scope was sub-
sequently explored. As summarized in Table 2, the addition of 2-
methylazaarenes with olefins could be extended to a variety of
substrates. 2-Methylquinolines with functional groups, such as
fluoro, chloro, bromo, methoxy, and nitro group were compatible
with the reaction conditions, and gave the corresponding products
in moderate to good yields (Table 2, 3aa–3ia). We also evaluated
the applicability of these conditions to other methyl-N-heterocy-
cles. Under the standard conditions, 2-methylquinoxaline 1k and
1-methylisoquinoline 1l both reacted to give 56% and 80% isolated
yields, respectively. With 2,6-dimethylpyridine, higher reaction
temperature and longer reaction time were required, allowing
the isolation of the product in 14% yield. In addition to N-phenyl-
maleimide (Table 2, 3aa–3ma), N-methylmaleimide, N-benzylma-
leimide, trans-b-nitrostyrene, and benzylidenemalononitrile are
compatible olefin components (Table 2, 3ab–3ae). The structure
of compound 3da was further confirmed by single crystal X-ray
crystallographic analysis (Fig. 1).36 As shown in Scheme 2, a
possible mechanism has been proposed. First, 2-methylquinoline
transforms to its enamine counterpart 4, which provides an ene
component. Subsequently, the reaction of ene 4 with enophile 2a
affords the product 3aa via aza-ene reaction.34
In summary, we have developed an addition of 2-methylazaa-
renes to electron-deficient olefins without using any catalyst or
additives. This atom-economic method provides a new pathway
⇑
Corresponding authors. Tel.: +86 222 350 6290; fax: +86 222 350 7760.
E-mail addresses: yangyangliu@nankai.edu.cn (R.-H. Liu), wangbin@nankai.e-
du.cn (B. Wang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.100

H.-Y. Li et al. / Tetrahedron Letters 54 (2013) 858–860
859
E
R1
R2
metal or Lewis acid
N
E
Previous work
R1
R1
R2
N
R2
N
H
EWG
EWG
1
2
EWG
EWG
R1
N
aza-ene reaction
R2
This work
catalyst-, additive-free
Scheme 1. Benzylic C–H bond functionalization.
Table 1
Optimization of the reaction conditionsa
O
O
O
conditions
+
N
Ph
N
Ph
N
N
O
2a
1a
3aa
Entry
1a (mmol)
2a (mmol)
Solvent (2 ml)
Catalyst (20%)
Additive (1.0 equiv)
T (°C)
Yield (%)
1
2
3
4
5
6
7
0.5
0.5
0.5
0.75
0.75
0.75
0.75
0.5
0.5
0.5
0.5
0.5
0.5
0.5
o-Xylene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
PdCl2
PdCl2
—
—
—
—
—
—
—
80
80
Trace
46
100
100
100
100
100
70
83(82)b
NaOMe
DBU
TfOHc
0
0
81
—
—
a
b
c
Reaction conditions: 5 h, NMR yield using benzyl phenyl ether as an internal standard.
Isolated yield.
0.1 equiv.
Table 2
Addition of benzylic C–H to electron-deficient olefinsa
O
O
O
Br
N
Ph
N
Ph
N
Ph
N
N
N
O
O
O
O
Cl
3aa
3ba
, 70%
, 82%
3ca
, 29%
O
O
F
N
Ph
N Ph
N
Ph
O
N
N
N
O
O
O
NO2
3da, 60%
3ea, 73%
3fa, 54%
O
Cl
N
O
MeO
N
Ph
N Ph
N
Ph
Ph
N
Cl
N
O
O
O
O
3ga, 40%
3ia, 66%
3ha, 68%
O
N
N
N
N
N
Ph
N
O
O
O
N
Ph
O
3ka, 56%
3ja
, 35%
3la, 80%
(continued on next page)

860
H.-Y. Li et al. / Tetrahedron Letters 54 (2013) 858–860
O
O
O
N
Phb
N
N Bnc
c
N
N
N
O
O
O
3ma, 14%b
3ab, 28%c
3ac, 40%c
NO2
NC
CN
c
Ph
3ad, 54%c
Ph
N
N
3ae, 78%
a
b
c
Reaction conditions: 1 (0.75 mmol, 1.5 equiv), 2 (0.5 mmol, 1.0 equiv), DMSO (2.0 mL) 100 °C, 5 h, isolated yield.
120 °C, 11 h.
10 h.
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heat
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36. The information of crystal structure of 3da (CCDC 880756) can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
We thank the National Natural Science Foundation of China for
the financial support (No. 21172120, 20902050). We also thank
Professor Yue-Ming Li for his useful suggestions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.100.