Efficient assembly of α-aryl and α-vinyl nitriles via iron-catalyzed ether bond activation

Article abstract of DOI:10.1016/j.tetlet.2013.12.083

A novel and practical method for the synthesis of diverse α-aryl and α-vinyl nitriles was developed via an iron-catalyzed sp³ C-O ether bond cleavage with C-C bond formation in the reaction of π-activated ethers with TMSCN.

Full text of DOI:10.1016/j.tetlet.2013.12.083

Tetrahedron Letters 55 (2014) 1068–1071
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Tetrahedron Letters
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Efficient assembly of a-aryl and a-vinyl nitriles via iron-catalyzed
ether bond activation
a
a
a
a
a
a
Xiaohui Fan a,b, , Kun Guo , Yong-Hong Guan , Lin-An Fu , Xiao-Meng Cui , Hao Lv , Hong-Bo Zhu
⇑
a School of Chemical and Biological Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China
b Beijing National Laboratory for Molecular Sciences (BNLMS), Beijing 100190, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and practical method for the synthesis of diverse
a
-aryl and
a
-vinyl nitriles was developed via an
iron-catalyzed sp3 C–O ether bond cleavage with C–C bond formation in the reaction of
p-activated ethers
Received 8 October 2013
Revised 14 December 2013
Accepted 24 December 2013
Available online 3 January 2014
with TMSCN.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
a-Aryl and a-vinyl nitriles
Trimethylsilyl cyanide
Cyanation reaction
C–O bond activation
Catalysis by iron
a
-Aryl nitriles are an attractive family of organic compounds,
MeO
MeN
Ph
which are found as core structures in a number of naturally occur-
ring molecules and pharmaceutically useful compounds (Fig. 1).1
They also serve as useful synthetic intermediates for heterocycles,
aldehydes, ketones, amides, carboxylic acids, and amines,2 as well
as biologically active compounds such as indoprofen, cicloprofen,
Ph
CN
CN
Ph
Ph
N
1
2
N
and naproxen.3 Usually,
tion of
a
-aryl nitriles are synthesized by dehydra-
MeO
MeO
OMe
OMe
CN
a
-substituted amides,4 cyanation of benzyl halides or tri-
Verapamil
flates,5 and hydrocyanation of olefins.6 In addition, several other
useful strategies also can be applied for the synthesis of these com-
1:
2-[(3S)-1-(4-methoxyphenyl)pyrrolidin-3-yl]-2,2-diphenyl-ethanenitrile
2: 3-(8-methyl-8-azabicyclo-[3.2.1]octan-3-yl)-2,2-diphenylpropanenitrile
pounds.7 Recently, two facile accesses to
a-aryl nitriles, i.e. transi-
tion metal-catalyzed
a
-arylation of nitriles with aryl halides8 and
Figure 1. Selected examples of biologically active a-aryl nitriles.
Lewis acid-mediated direct cyanation of benzylic alcohols by
TMSCN have drawn much attention.9,10 In 2008, Ding and co-work-
ers reported an attractive method for the synthesis of
a-aryl ni-
triles by direct cyanation of alcohols with TMSCN under the
catalysis of InBr3.9 After that, other Lewis acids such as B(C6F5)3
and Zn(OTf)2, have also been developed to this transformation by
Kim and Lalitha groups, respectively.9b,c Despite these methodolo-
In continuation of our previous work in the synthesis of N-alkyl-
ation compounds via an iron-catalyzed sp3 C–O ether bond cleav-
age protocol,11 we were attracted to extend this strategy for
preparing
a-aryl nitriles. To our knowledge, approach to nitriles
gies providing fascinating routes to a-aryl nitriles, however, there
that combination of ecologically benign Lewis acid FeCl3 with read-
ily available ethers has not been reported previously. Ethers are
environmentally friendly compounds that have been extensively
explored over the past decade as novel electrophiles in transition
metal-catalyzed cross-coupling reactions,12 such as using aryl or
benzyl ethers instead of halides in Suzuki and Kumada cou-
plings.12c,e,h,i In contrast with transition metal-catalyzed reactions,
relatively few examples exist on the Lewis acids catalytic activa-
tion of C–O ether bonds for construction of C–C bonds.13 As part
remain some drawbacks to these reported protocols, such as using
air-sensitive and expensive Lewis acids as catalysts, performing the
reaction at high temperature and complicated workup procedures.
Therefore, further exploration of mild, economical, and environ-
mentally friendly synthetic methods for nitriles would be valuable.
⇑
Corresponding author. Tel./fax: +86 0931 4938 755.
E-mail address: fanxh@mail.lzjtu.cn (X. Fan).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.083

X. Fan et al. / Tetrahedron Letters 55 (2014) 1068–1071
1069
Table 1
of our ongoing program examining the utility of ethers in organic
synthesis, we report herein a practical and efficient method
Optimization of reaction conditionsa
OMe
CN
for the synthesis of
-activated ethers with TMSCN under the catalysis of FeCl3.
At the outset of our studies, we focused our attention on the
a-aryl and a-vinyl nitriles in the reaction of
Catalyst
p
+
TMSCN
Solvent, rt, 1.5 h
MeO
MeO
reaction of 1-(4-methoxyphenyl)-1-methoxypropane 1a with
TMSCN under the catalysis of FeCl3 in a range of solvents to estab-
lish the reaction conditions (Table 1). To our delight, the reaction
proceeded very well with 10 mol % catalytic amount of FeCl3 in
dichloromethane (DCM) at room temperature within 1.5 h (Table 1,
entry 2). Further investigation of the solvent effect indicates that
the nature of the reaction media significantly affects the reaction
(Table 1, entries 4–7), DCM was found to be the most suitable sol-
vent. With respect to the substrate loading, 1:1.5 ratio of 1a with
TMSCN gave the best result (Table 1, entries 2 and 3). Under this
optimized reaction conditions, the desired cyanation product 2a
could be isolated in 97% yield (Table 1, entry 2). Replacing FeCl3
with FeCl3Á6H2O, the reaction proceeded in a slightly lower yield
(91%, Table 1, entry 8). Other Lewis acids such as FeBr3, BF3ÁEt2O,
TiCl4, ZnCl2, AlCl3, and FeCl2 were proved to be less effective or
ineffective to promote this transformation (Table 1, entries
9–14). Control experiment indicated that FeCl3 is essential for this
reaction (Table 1, entry 15). Furthermore, among the examined
Brønsted acids (e.g., TfOH and HCl), only triflic acid exhibited
catalytic activity and a relatively lower yield of 2a was obtained
1a
2a
Entry
TMSCN (equiv)
Catalyst (mol %)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
1.5
1.5
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
FeCI3 (5)
DCM
DCM
DCM
DCE
Dioxane
CH3NO2
Toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
86
97
90
80
0
Trace
Trace
91
78
49
71
0
FeCI3 (10)
FeCI3 (10)
FeCI3 (10)
FeCI3 (10)
FeCI3 (10)
FeCI3 (10)
FeCl3 6H2O (10)
FeBr3 (10)
BF3 Et2O (10)
TiCI4 (10)
ZnCI2 (10)
AICI3 (10)
FeCI2 (10)
None
9
10
11
12
13
14
15
16
85
0
0
TfOH (10)
76
a
Reaction conditions: benzylic ether (0.35 mmol), TMSCN (0.525 or 0.42 mmol),
solvent (3 mL), room temperature, in air.
b
Isolated yield.
Table 2
FeCl3-catalyzed direct cyanation of ethers with TMSCNa
Entry
1
Ether
Product
t (h)
Yieldb (%)
97
OMe
OMe
OMe
CN
CN
CN
1.5
1a
1b
2a
2b
MeO
MeO
MeO
MeO
MeO
MeO
2
1.5
90
3
4
5
1.5
1.5
1.0
99
99
85
1c
2c
OMe
CN
O
O
O
O
1d
2d
OMe
CN
O
O
1e
2e
O
O
MeO
NC
6
0.5
91
1f
2f
OMe
OMe
OMe
CN
CN
CN
7
8
9
0.5
1.5
0.5
87
89
1g
2g
1h
1i
2h
89
2i
(continued on next page)

1070
X. Fan et al. / Tetrahedron Letters 55 (2014) 1068–1071
Table 2 (continued)
Entry
Ether
Product
t (h)
Yieldb (%)
81
OMe
CN
10
11
12
3.5
1j
2j
C6H13
OMe
C6H13
CN
2k
CN
2l
1.5
1.5
99
67
1k
OMe
1l
OMe
CN
13
14
15
1.5
3.5
1.5
65
82
86
1m
2h
Ph
Ph
1n
2n
2o
Ph
OMe
Ph
CN
Ph
Ph
OMe
CN
1o
OMe
CN
16
17
1.5
36
1p
2p
F
F
OMe
CN
1q
2q
n.r.
n.r.
1.5
1.5
OMe
CN
1r
2r
18
a
Reaction conditions: benzylic ether (0.35 mmol), TMSCN (0.525 mmol), DCM (3 mL), FeCl3 (10 mol %), room temperature, in air.
Isolated yield.
b
(Table 1, entry 16), which suggests that the present reaction is cat-
that the allylic secondary ether 1m ((E)-1-methoxy-1-phenylbut-
2-ene) led cleanly to the thermodynamically favored regioisomeric
cyanation product 2h ((E)-2-methyl-4-phenyl-3-butenenitrile,
Table 2, entry 13), suggesting that the reaction most likely proceeds
via a carbocation pathway. In order to verify this proposal, enantio-
enriched (R)-1a (63% ee) was subjected to this reaction. After 1.5 h,
the racemic cyanation product 2a was obtained in 95% yield. This
result is consistent with our previously mechanistic study in
iron-catalyzed N-alkylation.11 Moreover, benzylic ethyl ether such
as 1-(1-ethoxypropyl)-4-methoxybenzene was also tested to this
reaction. However, only trace amount of cyanation product 2a
was obtained,15 which might be attributed to the difficulty in the
formation of a carbocation intermediate from benzylic ethyl ether.
Based on the above experimental results and previously re-
ported studies by us and Ding group,9a,11 a tentative reaction path-
way was proposed in Scheme 1. We speculate that the reaction
might involve activation of the C–O bond through coordination
of FeCl3 with the methoxy group in ethers. This delivers the
Fe(III)-coordinated species A, which then undergoes an iron-cata-
lyzed sp3 C–O ether bond cleavage to give the benzylic cation
alyzed by Fe(III) species. It is worth noting that FeCl3 has been
demonstrated to be an incompetent catalyst for direct cyanation
of benzylic alcohols,9a,c however, it showed excellent catalytic abil-
ity in our reaction.
With the optimized reaction conditions in hand (Table 1, entry
2), the substrate scope and limitations of this reaction were then
investigated on a series of primary, secondary, and tertiary ben-
zylic and allylic methyl ethers (Table 2). It was found that the pres-
ent reaction conditions showed good substrate compatibility with
a wide variety of secondary and tertiary ethers, providing the cor-
responding nitriles in good to excellent yields within a short period
of reaction time at room temperature (Table 2, entries 1–15). Pri-
mary benzylic and allylic methyl ethers, such as 1q and 1r, could
not undergo this transformation even under harsh reaction condi-
tions (Table 2, entries 17–18),14 presumably because of the lower
stability of the primary carbocation intermediates derived from
1q and 1r. Functional groups, e.g., aromatic fluoro, or methoxy
groups, C@C double bond, cyclopropyl, and acetal, tolerate the
reaction conditions very well (Table 2, entries 2, 4, 5, 7, and 16).
Overall, the reaction is facilitated with electron-rich benzylic
methyl ethers and gives the corresponding cyanation products in
high yield (Table 2, entries 1, 4, and 6). In contrast, the use of elec-
tron-poor benzylic ether 1p, which bear a fluorine atom at the
para-position of the phenyl ring, resulted in a quite lower yield
of product 2p (36%, Table 2, entry 16). With respect to the steric
properties of the ethers, no obvious influence on the reaction
was observed, tertiary benzylic ethers also served as efficient elec-
trophiles in this transformation (Table 2, entries 14–15). For exam-
ple, the higher sterically hindered triphenylmethyl methyl ether
1n reacted smoothly with TMSCN at room temperature to give
the desired tertiary nitrile 2n in high yield (Table 2, entry 14). Note
O
FeCl3
R2
O
Ar
R2
Ar
CN
A
FeCl3
Ar
R2
Ar
R2
CH3OFeCl3
TMSCN
CN
CH3OTMS
FeCl3
B
Scheme 1. Proposed mechanism.

X. Fan et al. / Tetrahedron Letters 55 (2014) 1068–1071
1071
intermediate B and FeÀCl3(OCH3). Subsequently, disassociation of
TMSCN by FeÀCl3(OCH3) followed by a simultaneous addition of
the in situ formed cyanide ion to benzylic cation intermediate
B would give rise to the cyanation product and regenerate the
catalyst FeCl3.
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In summary, a practical and efficient route to a-aryl and a-vinyl
nitriles that combination of the readily available ethers and TMSCN
with a catalytic amount of environmentally benign Lewis acid
FeCl3 has been achieved. This method can be used for a structurally
diverse set of secondary and tertiary benzylic and allylic methyl
ethers and gives the corresponding nitriles in good to excellent
yields at room temperature. Further exploration of ethers as elec-
trophiles in organic synthesis via Lewis acid-catalyzed C–O bond
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We thank the Natural Science Foundation of China (21162013)
and Beijing National Laboratory for Molecular Sciences (BNLMS)
for financial support, Prof. Zhi-Xiang Yu for helpful discussions.
Supplementary data
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the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
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