Versatile and chemoselective transformation of aliphatic and aromatic secondary amides to nitriles

Article abstract of DOI:10.1016/j.tet.2015.03.094

Triflic anhydride in combination with 2-fluoropyridine effectively dehydrates secondary amides to afford nitriles under mild reaction conditions. The reaction is general in scope and compatible with the use of aliphatic, α,β-unsaturated, aromatic, and heteroaromatic amides bearing either secondary, tertiary, or benzylic N-alkyl groups. The reaction also shows good to excellent chemoselectivity for the secondary amide and tolerates several labile functional groups.

Full text of DOI:10.1016/j.tet.2015.03.094

Tetrahedron 71 (2015) 3795e3801
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Versatile and chemoselective transformation of aliphatic and
aromatic secondary amides to nitriles
a
a,b,
*
Hui Geng , Pei-Qiang Huang
a
Department of Chemistry and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, and Collaborative
Innovation Centre of Chemistry for Energy Materials, Xiamen University, Xiamen, Fujian 361005, PR China
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Triflic anhydride in combination with 2-fluoropyridine effectively dehydrates secondary amides to afford
Received 3 February 2015
Received in revised form 19 March 2015
Accepted 23 March 2015
Available online 1 April 2015
nitriles under mild reaction conditions. The reaction is general in scope and compatible with the use of
aliphatic, a,b-unsaturated, aromatic, and heteroaromatic amides bearing either secondary, tertiary, or
benzylic N-alkyl groups. The reaction also shows good to excellent chemoselectivity for the secondary
amide and tolerates several labile functional groups.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Synthetic methods
Secondary amides
Nitriles
One-pot reaction
Chemoselectivity
1
. Introduction
reaction requires N-tert-butylamides as the substrates. Recently,
13s
Prati and co-workers, further optimized the reaction conditions
by using (PhO) P-halogen (Br or Cl ) combination as the de-
Nitriles participate in a wide range of transformations and are
thus versatile and powerful synthetic intermediates for organic
synthesis. For example, the cyano group serves as a good leaving
3
2
2
hydration agents. This method accommodates secondary and ter-
tiary amides with a wide variety of N-substituents including benzyl,
allyl, tertiary and even primary alkyl groups. Although significant
progress has been achieved for the synthesis of nitriles from am-
ides, most of the reported methods still suffer from limited sub-
strate scope and/or harsh reaction conditions. In addition, the
chemoselectivity of the dehydration reactions has rarely been
group to generate reactive species such as iminium ions, carban-
1
ions, and radicals. It stabilizes
a-carbanion and allows the syn-
theses of amines1 and carbonyl compounds via umpolung. In
,2
3
4
addition, nucleophilic or radical addition to nitriles leads to several
important classes of compounds including amines, ketones, and
aldehydes.7
5
6
13t
addressed.
Nitriles are also widely present in natural products, bioactive
With our continued interest in developing synthetic methods
employing readily available amides as the substrates, we report
compounds,8
e10
and materials. For these reasons, many methods
11
16
12,13
have been developed for the synthesis of nitriles,
most of which
herein a convenient method for the dehydration of secondary
1
7
rely on cyanide addition or substitution reactions or dehydration of
amides to give nitriles using triflic anhydride (Tf
fluoropyridine (2-F-Py).
2
O) /2-
oximes1
3bef
and amides.
13deu
Among the methods that have been
18
developed for the dehydration of amides, reactions that employ
secondary amides as substrates are rare.1
3oet
Nonetheless, the
is suitable for the
classical Von Braun amide degradation using PCl
dehydration of secondary and tertiary benzamides. However,
because of the vigorous conditions required, this reaction has rarely
5
2. Results and discussion
14
Our discovery of the nitrile synthesis stemmed from an attempt
to cyclize secondary amide 1-1 using Tf O/2-F-Py (Scheme 1). The
reaction led to the formation of nitrile 2-1 in 55% yield instead of the
desired ketone 3. A survey of the literature showed that only two
been used for the synthesis of nitriles. Gribble and Perni improved
2
as the dehydration agent.1 But the
5
the protocol by using POCl
3
reports have used Tf
Kunz and Pleuss demonstrated in one reaction that Tf
transforms quantitatively N-glycosyl p-methoxybenzamide to p-
2
O to convert secondary amides to nitriles.
2
O
*
Corresponding author. Tel.: þ86 592 2182240; fax: þ86 592 2189959; e-mail
address: pqhuang@xmu.edu.cn (P.-Q. Huang).
http://dx.doi.org/10.1016/j.tet.2015.03.094
0
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

3796
H. Geng, P.-Q. Huang / Tetrahedron 71 (2015) 3795e3801
methoxybenzonitrile.13q However, no experimental procedure was
provided and the protocol suffers from low atom economy. In their
combinatorial synthesis of isoxazoles, Haino and Fukazawa
the same temperature for 30 min, followed by at 30 C until the
disappearance of the substrate.
ꢀ
With the optimized reaction conditions defined, the scope of the
reaction was investigated (Table 2). The dehydration reaction is
compatible with the use of both aliphatic (entries 1e5, 73e85%
yield) and aromatic amides (entries 7, 8, 11e14, 74e93% yield). Note
that even hindered amide 1-5 reacted smoothly to give 1-
adamantanecarbonitrile 2-5 in 73% yield. 2-Phenylacetamide 1-6
failed to afford the corresponding nitrile. The N-substituent has
a dramatic effect on the reaction. Branched alkyl groups including
isopropyl, cyclohexyl, cyclopentyl, tert-butyl or a benzyl group are
well tolerated. In contrast, substrates bearing primary N-alkyl
groups such as Me and n-Bu failed to form the desired nitriles
2
employed a large excess of Tf O/pyridine to cleave a secondary
13r
amide linkage, leading to aryl nitriles. Thus, we decided to develop
a mild and general method for the direct transformation of sec-
2
ondary amides to nitriles using Tf O as the dehydration agent.
(entries 9 and 10). For the naphthamides, both a- and b isomers
reacted smoothly to give 1-naphthonitrile 2-13 and 2-
naphthonitrile 2-14 in 93% and 85% yields, respectively. The chiral
amide 1-15 also reacted without incident to give benzonitrile 2-15
19m
in 74% yield. Finally, vinylogous benzamide derivative 1-16
also a viable substrate and reacted chemoselectively to produce the
-unsaturated nitrile 2-16 in 66% yield.
is
Scheme 1. Unexpected synthesis of nitrile 2-1 from secondary amide 1-1.
a,b
We first examined the effect of base on the reaction of substrate
ꢀ
1
-1 in CH
2
Cl
2
. The substrate was treated with Tf
2
O and a base at 0 C
Table 2
Tf O-Activated transformation of secondary amides to nitriles
ꢀ
for 30 min and then at 30 C until the complete consumption of the
substrate (monitored with TLC). In the absence of a base, the de-
sired nitrile was obtained in only 13% yield (Table 1, entry 1). Tri-
2
3 2
alkyl amines such as Et N and i-Pr NEt were not effective. Various
pyridine-derived bases were tested and 2-chloropyridine (2-Cl-Py,
entry 7) and 2-fluoropyridine (2-F-Py, entry 8) gave the best yields.
The effect of these two bases on the nitrile formation was thus
further investigated using N-isopropylbenzamide (1-7) as the
substrate. The results show that 2-F-Py (yield: 71%, entry 10) is
Entry
1
Substrate
Time (h)
12
Product (% yield)a
superior to 2-Cl-Py (yield: 51%, entry 9) as a base for the Tf
promoted dehydration reaction.
2
O-
A survey of the effect of substrate concentration on the reaction
showed that 0.2 of amide in CH Cl gave the best yield (83%).
Thus, the optimum conditions for the dehydration of secondary
amides to nitriles involve the use of 1.1 equiv of Tf O and 1.2 equiv
in CH Cl . The
M
2
2
2
12
2
of 2-F-Py with a substrate concentration of 0.2
M
2
2
ꢀ
reagents were mixed at 0 C and the reaction mixture was kept at
Table 1
3
4
7
3
Screening of the base additive
Entry
1
Amide
Base
2 (% Yield)a
5
6
7
12
12
12
d
13
2
3
4
5
6
7
8
Et
3
N
Trace
Trace
8
Trace
44
i-Pr
2
NEt
Pyridine
2,6-Lutidine
DTBMP
2-Cl-Py
2-F-Py
58
55
9
2-Cl-Py
2-F-Py
51
71
8
3
1
0
a
Isolated yield.

H. Geng, P.-Q. Huang / Tetrahedron 71 (2015) 3795e3801
3797
Table 2 (continued )
Table 3
2
Tf O-Activated transformation of secondary amides to nitriles
Entry
Substrate
Time (h)
16
Product (% yield)a
9
Entry
1
Substrate
Time (h)
12
Product (% yield)a
1
1
1
1
0
1
2
3
16
12
12
7
2
3
12
12
4
5
1
14
12
12
1
1
5
6
3
6
12
16
a
Isolated yield.
7
8
1
1
We next turned our attention to the chemoselectivity of the re-
action. Benzamides with diverse substituents on the aryl ring were
first examined (Table 3). The dehydration reaction tolerated sub-
stituents having different electronic properties (entries 1e13). In
general, substrates bearing electron-withdrawing groups outperform
those with electron-donating groups. The position of the substituents
does not affect the yields (entries 3, 5 and 6). The reaction proved
tolerant of substrates bearing labile functional groups such as esters
9
6
5
(
entries 9 and 12), a ketone (entry 10), an aldehyde (entry 11), and an
acetal group (entry 13), furnishing the corresponding nitriles in good
to excellent yields. These entries highlight the usefulness of the
current method for the synthesis of functionalized nitriles.
The reaction of heteroaromatic amides N-cyclohexylthiophene-
-carboxamide (entry 14) and N-isopropylbenzothiophenamide
1
1
0
1
2
(
entry 15) produced nitriles 2-30 and 2-31 in 73% and 87% yields,
respectively. N-(tert-Butyl)-4-cyanobenzamide 1-32 reacted simi-
larly as its N-iso-propyl homologous 1-23 to give nitrile 2-23 in 91%
yield (entry 16). As can be seen from entry 17, the reaction can’t
distinguish between primary and secondary amides, both were
converted to cyano groups. The reaction of carboxylic acid group-
containing secondary amide 1-34 produced the desired product
in 50% yield (entry 16).
4
(continued on next page)

3798
H. Geng, P.-Q. Huang / Tetrahedron 71 (2015) 3795e3801
Table 3 (continued )
3. Conclusion
Entry
Substrate
Time (h)
Product (% yield)a
In summary, we have developed a versatile method for the di-
rect transformation of secondary amides to nitriles under mild
ꢀ
reaction conditions (30 C for 1e16 h). The reaction tolerates both
1
1
2
3
3
aliphatic and aromatic amides bearing secondary, tertiary, and
benzylic N-alkyl groups. The reaction is remarkably chemoselective
and a number of sensitive functional groups including esters, a ke-
tone, and even an aldehyde remained intact during the
transformation.
3
4
4
. Experimental section
.1. General methods
1
1
4
5
7
6
1H NMR and C NMR spectra were recorded on a Bruker 400
13
(1
5
H/400 MHz, C/100 MHz) spectrometer and a Bruker 500 ( H/
13
1
13
00 MHz,
expressed in parts per million (
standard of residual chloroform (7.26 ppm for H NMR and
C/125 MHz) spectrometer. Chemical shifts are
d
, ppm) relative to an internal
1
13
1
7
7.0 ppm for C NMR). Data for H NMR are reported as chemical
shift (multiplicity, coupling constant, number of proton). GCeMS
were recorded on a Shimadzu GCMS-QP2010 Plus. Melting points
were determined on a B u€ chi M560 Automatic Melting Point ap-
16
3
paratus. Infrared spectra were recorded with a Nicolet Avatar 330
FT-IR spectrometer using film or KBr pellet technique.
Silica gel (300e400 mesh) was used for flash column chroma-
tography, eluting (unless otherwise stated) with ethyl acetate/pe-
ꢀ
troleum ether (PE) (60e90 C) mixture. Tf
2
O was distilled over
1
1
7
8
6
6
phosphorous pentoxide and used within a week. THF was distilled
over sodium benzophenone ketyl under N . Dichloromethane was
distilled over calcium hydride under N
2
2
.
4.2. General procedure for the transformation of amides into
nitriles
2
-32 (50)b
To an ice bath-cooled solution of a secondary amide (1.0 mmol)
and 2-fluoropyridine (1.2 mmol) in anhydrous CH Cl (5 mL) was
added Tf O (1.1 mmol). After being stirred for 0.5 h, the reaction
mixture was warmed to 30 C and stirred until completion of the
reaction (monitored by TLC analysis). The reaction was quenched
a
2
2
Isolated yield.
Tf O (2.2 equiv) and 2-F-Py (2.4 equiv).
2
b
2
ꢀ
A plausible mechanism for the nitrile formation is provided
1
3oet,14,15
based on results in this work and those reported
). The key intermediate, the nitrilium ion A
upon treating the amide with Tf
loses the N-substituent R to produce nitrile 2 via either an S
path A) or an S
performs well when R is secondary, tertiary or benzyl substituents
but not when R2 equals primary substituents excludes the S
(Scheme
2 2
with 1 M HCl (1.0 mL), and the mixture was extracted with CH Cl
1
6b,c,18
2
is generated
(3ꢁ10 mL). The combined organic layers were washed with satu-
rated sodium carbonate (5 mL) and brine (5 mL), dried over an-
hydrous Na SO , filtered, and concentrated under reduced
2
O and 2-F-Py. This reactive species
2
N
2
2
4
(
N
1 reaction (path B). The fact that the reaction
pressure. The residue was purified by column chromatography on
silica gel eluting with ethyl acetate/petroleum ether to afford the
corresponding nitrile.
2
N
2
mechanism. Primary carbocations are highly unstable and difficult
to form. Thus substrates bearing a Me or an n-Bu group at the
amidyl nitrogen failed to afford the desired nitrile. Hence, the
4.2.1. 4-Phenylbutyronitrile (2-1). Following the general procedure,
the reaction of amide 1-1 (205 mg, 1.0 mmol) gave, after chro-
matographic separation eluting with EtOAc/PE (v/v¼1:10), the
nitrilium ion most likely decomposes through an S
anism (pathway B).
N
1 type mech-
19a
known nitrile 2-1 (115 mg, yield: 79%) as a colorless oil; IR (film)
ꢂ1
1
nmax: 3027, 2913, 2850, 2246 cm
;
H NMR (CDCl
3
, 400 MHz):
d
1.92e2.03 (m, 2H), 2.30 (t, J¼7.1 Hz, 2H), 2.77 (t, J¼7.5 Hz, 2H),
13
7
.15e7.21 (m, 2H), 7.21e7.27 (m, 1H), 7.27e7.36 (m, 2H) ppm;
C
NMR (CDCl
3
, 100 MHz):
d
16.3, 26.8, 34.3, 119.4, 126.4, 128.4, 128.6,
þ
139.6 ppm; MS (EI, m/z): 145 (40, M ), 104 (28), 91(100), 65 (19); t
R
(GC)¼8.670 min.
4.2.2. 3-Phenylpropanenitrile (2-2). Following the general pro-
cedure, the reaction of amide 1-2 (191 mg, 1.0 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
19b
known nitrile 2-2 (100 mg, yield: 76%) as a colorless oil; IR (film)
ꢂ1
1
nmax: 3029, 2916, 2849, 2246 cm
;
3
H NMR (CDCl , 400 MHz):
2
Scheme 2. Plausible mechanism for the Tf O mediated transformation of secondary
amides to nitriles.
d
2.59 (t, J¼7.6 Hz, 2H), 2.94 (t, J¼7.6 Hz, 2H), 7.15e7.42 (m,

H. Geng, P.-Q. Huang / Tetrahedron 71 (2015) 3795e3801
3799
5
H) ppm; 13C NMR (CDCl
3
, 100 MHz):
d
19.2, 31.4, 119.1, 127.1, 128.2,
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
13m
þ
128.8, 138.0 ppm; MS (EI, m/z): 131 (28, M ), 91 (100), 65 (15); t
R
known nitrile
(film) max: 3034, 2926, 2872, 2231 cm
00 MHz): 7.43e7.53 (m, 2H), 7.57e7.71 (m, 3H) ppm; C NMR
2-7 (84 mg, yield: 82%) as a pale yellow oil; IR
ꢂ1
1
(
GC)¼7.948 min.
n
;
3
H NMR (CDCl ,
13
4
d
4
.2.3. Undecanenitrile (2-3). Following the general procedure, the
(CDCl
3
, 100 MHz):
d
112.3, 118.7, 129.0, 132.1, 132.7 ppm; MS (EI, m/
(GC)¼6.353 min.
þ
reaction of amide 1-3 (138 mg, 0.5 mmol) gave, after chromato-
z): 103 (100, M ), 76 (55), 50 (28), 28 (62); t
R
graphic separation eluting with EtOAc/PE (v/v¼1:10), the known
nitrile1 2-3 (71 mg, yield: 85%) as a colorless oil; IR (film)
9c
n
:
4.2.10. 1-Naphthonitrile (2-13). Following the general procedure,
the reaction of amide 1-13 (213 mg, 1.0 mmol) gave, after chro-
max
ꢂ1
1
2
963, 2922, 2855, 2246 cm ; H NMR (CDCl
3
, 500 MHz): d 0.88 (t,
J¼7.0 Hz, 3H), 1.24e1.34 (m, 12H), 1.40e1.48 (m, 2H), 1.61e1.69 (m,
matographic separation eluting with EtOAc/PE (v/v¼1:10), the
13
19d
2
H), 2.33 (t, J¼7.3 Hz, 2H) ppm; C NMR (CDCl
3
, 125 MHz):
d
14.0,
known nitrile
2-13 (142 mg, yield: 93%) as a white solid. Mp
ꢀ
19d
ꢀ
1
7.0, 22.6, 25.3, 28.6, 28.7, 29.2 (2C), 29.4, 31.8, 119.7 ppm; MS (EI,
35e36 C (lit.
35e36 C); IR (film)
n
max: 3067, 2916, 2849,
, 500 MHz): 7.46e7.53 (m, 1H),
7.57e7.63 (m, 1H), 7.65e7.70 (m, 1H), 7.85e7.93 (m, 2H), 8.05 (d,
þ
ꢂ1
1
m/z): 152 (4, M -CH3), 138 (22), 124 (54), 110 (73), 96 (97), 82 (95),
7 (60), 43 (70), 41(100); t
(GC)¼10.404 min.
2221 cm
;
H NMR (CDCl
3
d
5
R
13
J¼8.5 Hz, 1H), 8.21 (d, J¼8.5 Hz, 1H) ppm; C NMR (CDCl
125 MHz): 110.1, 117.7, 124.8,125.0,127.5,128.5,128.6,132.3,132.5,
132.8, 133.2 ppm; MS (EI, m/z): 154 (12), 153 (100, M ), 126 (24),
125 (9), 76 (10), 63 (13), 28 (20); t
(GC)¼11.517 min.
3
,
4.2.4. Cyclohexanecarbonitrile (2-4). Following the general pro-
d
þ
cedure, the reaction of amide 1-4 (217 mg, 1.0 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10),
the known nitrile1 2-4 (85 mg, yield: 78%) as a colorless oil; IR
R
3m
ꢂ1
1
(
film)
n
max: 2959, 2917, 2849, 2246 cm
00 MHz): 1.36e1.56 (m, 4H), 1.64e1.79 (m, 4H), 1.79e1.89 (m,
H), 2.55e2,71 (m, 1H) ppm; C NMR (CDCl
;
H NMR (CDCl
3
,
4.2.11. 2-Naphthonitrile (2-14). Following the general procedure,
the reaction of amide 1-14 (213 mg, 1.0 mmol) gave, after chro-
5
2
2
9
6
d
13
3
, 125 MHz):
d
23.9,
matographic separation eluting with EtOAc/PE (v/v¼1:10), the
þ
19e
5.1, 27.9, 29.4, 122.5 ppm; MS (EI, m/z): 109 (18, M ), 108 (30),
4 (40), 81 (30), 56 (100), 54 (83), 41 (91), 27 (22); t
known nitrile
2-14 (130 mg, yield: 85%) as a white solid. Mp
ꢀ
19f
ꢀ
R
(GC)¼
65e67 C (lit.
65e66 C); IR (film)
n
max: 3059, 2917, 2852,
, 500 MHz): 7.56e7.66 (m, 3H),
.86e7.96 (m, 3H), 8.17e8.25 (m, 1H) ppm; C NMR (CDCl
125 MHz): 109.4, 119.2, 126.3, 127.6, 128.0, 128.4, 129.0, 129.2,
132.2, 134.1, 134.6 ppm; MS (EI, m/z): 154 (12), 153 (100, M ), 126
(28), 125 (9), 76 (9), 63 (10); t
(GC)¼9.703 min.
ꢂ1
1
.515 min.
2225 cm
;
H NMR (CDCl
3
d
13
7
3
,
4.2.5. 1-Adamantanecarbonitrile (2-5). Following the general pro-
d
þ
cedure, the reaction of amide 1-5 (221 mg, 1.0 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
R
19b
known nitrile 2-5 (118 mg, yield: 73%) as a pale yellow solid. Mp
ꢀ
19b
ꢀ
1
89e191 C (lit.
192e195 C); IR (film)
H NMR (CDCl , 500 MHz):
3
.91e1.96 (m, 1H), 1.98e2.10 (m, 8H) ppm; C NMR (CDCl ,
n
max: 2914, 2850,
4.2.12. Benzonitrile (2-7). Following the general procedure, the
reaction of amide 1-15 (225 mg, 1.0 mmol) gave, after chromato-
graphic separation eluting with EtOAc/PE (v/v¼1:10), the known
ꢂ1
1
2
235 cm
;
3
d 1.70e1.78 (m, 6H),
1
3
1
1
3m
1
25 MHz):
d
27.1 (2C), 27.6, 30.1, 35.7 (2C), 36.3, 38.2, 39.9 (2C),
nitrile
3034, 2926, 2872, 2231 cm
7.43e7.53 (m, 2H), 7.57e7.71 (m, 3H) ppm; C NMR (CDCl
00 MHz): 112.3, 118.7, 129.0, 132.1, 132.7 ppm; MS (EI, m/z): 103
(100, M ), 76 (55), 50 (28), 28 (62); t
(GC)¼6.353 min.
max
2-7 (76 mg, yield: 74%) as a pale yellow oil; IR (film) n :
þ
ꢂ1
1
125.2 ppm; MS (EI, m/z): 161 (48, M ), 146 (23), 134 (100), 119 (12),
;
3
H NMR (CDCl , 400 MHz):
13
1
04 (15), 93 (55), 69 (20); t
R
(GC)¼9.197 min.
d
3
,
1
d
þ
4.2.6. Benzonitrile (2-7). Following the general procedure, the re-
R
action of amide 1-7 (163 mg,1.0 mmol) gave, after chromatographic
1
3m
separation eluting with EtOAc/PE (v/v¼1:10), the known nitrile
4.2.13. Cinnamonitrile (2-16). Following the general procedure, the
reaction of amide 1-16 (189 mg, 1.0 mmol) gave, after chromato-
2
2
2
-7 (85 mg, yield: 83%) as a pale yellow oil; IR (film)
n
max: 3034,
7.43e7.53 (m,
ꢂ1
1
926, 2872, 2231 cm ; H NMR (CDCl
3
, 400 MHz):
d
graphic separation eluting with EtOAc/PE (v/v¼1:10), the known
13
19g
H), 7.57e7.71 (m, 3H) ppm; C NMR (CDCl
3
, 100 MHz):
d
112.3,
nitrile
n
2-17 (85 mg, yield: 66%) as a pale yellow wax; IR (film)
þ
ꢂ1
1
1
18.7, 129.0, 132.1, 132.7 ppm; MS (EI, m/z): 103 (100, M ), 76 (55),
max: 3053, 2917, 2849, 2217 cm
;
H NMR (CDCl
3
, 500 MHz):
5.87 (d, J¼16.7 Hz, 1H), 7.37e7.46 (m, 6H) ppm; C NMR (CDCl
25 MHz): 96.3, 118.1, 127.3, 129.0, 131.1, 133.5, 150.5 ppm; MS (EI,
m/z): 130 (10), 129 (100, M ), 128 (26), 102 (46), 76 (15), 63 (8), 51
(20); t
(GC)¼9.584 min.
13
5
0 (28), 28 (62); t
R
(GC)¼6.353 min.
d
3
,
1
d
þ
4.2.7. Benzonitrile (2-7). Following the general procedure, the re-
action of amide 1-8 (177 mg,1.0 mmol) gave, after chromatographic
R
1
3m
separation eluting with EtOAc/PE (v/v¼1:10), the known nitrile
2
2
2
-7 (76 mg, yield: 74%) as a pale yellow oil; IR (film)
n
max: 3034,
4.2.14. p-Toluonitrile (2-17). Following the general procedure, the
reaction of amide 1-17 (177 mg, 1.0 mmol) gave, after chromato-
graphic separation eluting with EtOAc/PE (v/v¼1:10), the known
ꢂ1
1
926, 2872, 2231 cm ; H NMR (CDCl , 400 MHz): d 7.43e7.53 (m,
3
13
H), 7.57e7.71 (m, 3H) ppm; C NMR (CDCl
3
, 100 MHz):
d
112.3,
þ
19h
ꢀ
2-17 (78 mg, yield: 67%) as a white solid. Mp 27e28 C; IR
1
18.7, 129.0, 132.1, 132.7 ppm; MS (EI, m/z): 103 (100, M ), 76 (55),
nitrile
(film)
ꢂ1
1
5
0 (28), 28 (62); t
R
(GC)¼6.353 min.
nmax: 3019, 2959, 2911, 2850, 2226 cm ; H NMR (CDCl
3
,
4
00 MHz): d 2.42 (s, 3H), 7.22e7.30 (m, 2H), 7.46e7.60 (m,
13
4.2.8. Benzonitrile (2-7). Following the general procedure, the re-
2H) ppm; C NMR (CDCl
132.0, 143.6 ppm; MS (EI, m/z): 118 (9), 117(100, M ), 116 (61), 90
3
, 100 MHz):
d
21.8, 109.3, 119.1, 129.8,
þ
action of amide 1-11 (203 mg, 1.0 mmol) gave, after chromato-
graphic separation eluting with EtOAc/PE (v/v¼1:10), the known
(47), 89 (27), 63 (13), 51 (6), 39 (10); t
R
(GC)¼7.599 min.
nitrile1 2-7 (86 mg, yield: 83%) as a pale yellow oil; IR (film)
3m
max
n :
ꢂ1
1
3
d
034, 2926, 2872, 2231 cm
7.43e7.53 (m, 2H), 7.57e7.71 (m, 3H) ppm; C NMR (CDCl
00 MHz): 112.3, 118.7, 129.0, 132.1, 132.7 ppm; MS (EI, m/z): 103
100, M ), 76 (55), 50 (28), 28 (62); t
(GC)¼6.353 min.
;
H NMR (CDCl
3
, 400 MHz):
4.2.15. Anisonitrile (2-18). Following the general procedure, the
reaction of amide 1-18 (193 mg, 1.0 mmol) gave, after chromato-
graphic separation eluting with EtOAc/PE (v/v¼1:10), the known
13
3
,
1
(
d
þ
13m
ꢀ
2-18 (86 mg, yield: 65%) as a white solid. Mp 56e58 C
R
nitrile
(
1
9g
ꢀ
ꢂ1 1
lit. 55e57 C); IR (film)
NMR (CDCl , 500 MHz): 3.86 (s, 3H), 6.91e7.00 (m, 2H), 7.54e7.64
(m, 2H) ppm; C NMR (CDCl , 125 MHz): 55.5, 104.0, 114.7, 119.2,
nmax: 3005, 2916, 2849, 2224 cm ; H
4.2.9. Benzonitrile (2-7). Following the general procedure, the re-
3
d
13
action of amide 1-12 (189 mg, 1.0 mmol) gave, after
3
d

3800
H. Geng, P.-Q. Huang / Tetrahedron 71 (2015) 3795e3801
þ
19f
1
33.9, 162.8 ppm; MS (EI, m/z): 134 (9), 133 (100, M ), 118 (10), 103
v¼1:10), the known nitrile 2-25 (65 mg, yield: 80%) as a white
ꢀ
ꢀ
(
47), 90 (50), 76 (12), 63 (18); t
R
(GC)¼8.148 min.
solid. Mp 66e68 C (lit.19f 65e66 C); IR (film)
n
max: 3079, 2957,
H NMR (CDCl , 500 MHz):
3.94e3.99 (m, 3H), 7.70e7.88 (m, 2H), 8.01e8.24 (m, 2H) ppm;
ꢂ1
1
2
922, 2851, 2229, 1719 cm
;
3
13
4
.2.16. 4-Bromobenzonitrile (2-19). Following the general pro-
d
C
cedure, the reaction of amide 1-19 (121 mg, 0.5 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
NMR (CDCl
3
, 125 MHz):
d
52.6, 116.3, 117.8, 130.0, 132.1, 133.8,
þ
165.3 ppm; MS (EI, m/z): 161 (28, M ), 130 (100), 102 (50), 75 (16),
19i
known nitrile
2-19 (73 mg, yield: 80%) as a white solid. Mp
51 (9); t
R
(GC)¼10.209 min.
ꢀ
19b
ꢀ
1
2
7
1
09e111 C (lit.
114e115 C); IR (film)
H NMR (CDCl , 500 MHz):
, 125 MHz):
n
max: 3089, 2917, 2849,
ꢂ1
1
224 cm
;
3
d
7.49e7.56 (m, 2H),
4.2.23. 4-Acetylbenzonitrile (2-26). Following the general pro-
cedure, the reaction of amide 1-26 (205 mg, 1.0 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
13
.58e7.67 (m, 2H) ppm; C NMR (CDCl
27.9, 132.5, 133.3 ppm; MS (EI, m/z): 183 (50), 181 (53, M ), 102
3
d
111.2, 117.9,
þ
1
9g
(
100), 75 (40), 50 (20); t
R
(GC)¼7.139 min.
known nitrile
2-26 (115 mg, yield: 79%) as a white solid. Mp
ꢀ
19g
ꢀ
5
4e56 C (lit. 56e58 C); IR (film)
nmax: 3096, 2918, 2849, 2229,
ꢂ1
1
4.2.17. 4-Trifluormethylbenzonitrile (2-20). Following the general
1694 cm
;
H NMR (CDCl
3
, 500 MHz): 2.66 (s, 3H), 7.29 (d,
d
13
procedure, the reaction of amide 1-20 (231 mg, 1.0 mmol) gave,
after chromatographic separation eluting with EtOAc/PE (v/
J¼8.4 Hz, 2H), 8.05 (d, J¼8.4 Hz, 2H) ppm; C NMR (CDCl
3
,
125 MHz): 26.6, 116.3, 117.8, 128.6, 132.4, 139.8, 196.4 ppm; MS (EI,
d
1
9h
þ
v¼1:10), the known nitrile
2-20 (127 mg, yield: 75%) as a white
max: 3067, 2955, 2918, 2849,
, 500 MHz):
7.76 (d, J¼8.2 Hz, 2H), 7.81
, 125 MHz): 116.1, 117.4,
23.0 (d, J¼272.8 Hz), 126.2 (q, J¼3.7 Hz), 132.7, 134.5 (d,
m/z): 145 (22, M ), 130 (100), 102 (55), 75 (17), 43 (12); t
8.703 min.
R
(GC)¼
ꢀ
solid. Mp 36e38 C; IR (film)
n
ꢂ1
1
2
(
237 cm ; H NMR (CDCl
3
d
13
d, J¼8.2 Hz, 2H) ppm; C NMR (CDCl
3
d
4.2.24. 4-Formylbenzonitrile (2-27). Following the general pro-
cedure, the reaction of amide 1-27 (191 mg, 1.0 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
1
þ
J¼34.0 Hz) ppm; MS (EI, m/z): 172 (8), 171 (100, M ), 170 (25), 152
56), 121 (78), 102 (13), 75 (21), 69 (7), 50 (11); t
(GC)¼5.923 min.
1
9j
(
R
known nitrile
2-27 (61 mg, yield: 46%) as a white solid. Mp
ꢀ
19j
ꢀ
1
03e105 C (lit. 97e100 C); IR (film)
n
max: 3094, 2917, 2849,
, 500 MHz): 7.83e7.87 (m, 2H),
7.98e8.02 (m, 2H), 10.1 (s, 1H) ppm; C NMR (CDCl , 125 MHz):
117.6, 129.8, 132.8, 132.9, 138.8, 190.5 ppm; MS (EI, m/z): 131 (72,
ꢂ1
1
4.2.18. 2-Bromobenzonitrile (2-21). Following the general pro-
2229, 1706 cm ; H NMR (CDCl
3
d
13
cedure, the reaction of amide 1-21 (121 mg, 0.5 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
3
d
1
9a
þ
known nitrile
5
2-21 (70 mg, yield: 77%) as a white solid. Mp
M ), 130 (100), 102 (60), 75 (33), 50 (27); t
R
(GC)¼9.073 min.
ꢀ
ꢂ1 1
3e55 C; IR (film)
n
max: 3092, 2917, 2830, 2225 cm ; H NMR
13
(
CDCl
NMR (CDCl
34.2 ppm; MS (EI, m/z): 183 (67), 181 (70, M ), 102 (100), 75 (30),
3
, 500 MHz):
d
7.36e7.52 (m, 2H), 7.59e7.73 (m, 2H) ppm;
C
4.2.25. 2-Acetoxybenzonitrile (2-28). Following the general pro-
cedure, the reaction of amide 1-28 (221 mg, 1.0 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
3
, 125 MHz): d 115.8, 117.0, 125.2, 127.6, 133.1, 133.8,
þ
1
19h
5
0 (19); t
R
(GC)¼9.353 min.
known nitrile
film)
500 MHz):
7.59e7.64 (m, 1H), 7.64e7.70 (m, 1H) ppm; C NMR (CDCl
125 MHz): 20.6, 107.0, 115.0, 123.1, 126.2, 133.1, 133.9, 152.2,
2-28 (145 mg, yield: 90%) as a colorless oil; IR
ꢂ1
1
(
n
max: 3083, 2917, 2849, 2233, 1769 cm
3
; H NMR (CDCl ,
4.2.19. 3-Bromobenzonitrile (2-22). Following the general pro-
d
2.38 (s, 3H), 7.25e7.29 (m, 1H), 7.30e7.35 (m, 1H),
13
cedure, the reaction of amide 1-22 (121 mg, 0.5 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
3
,
d
1
9h
þ
known nitrile
3
2-22 (74 mg, yield: 81%) as a pale yellow solid. Mp
168.1 ppm; MS (EI, m/z): 161 (19, M ), 119 (44), 91 (23), 43 (100); t
(GC)¼8.306 min.
R
ꢀ
ꢂ1 1
5e36 C; IR (film)
n
max: 3071, 2917, 2849, 2232 cm ; H NMR
(
(
1
CDCl
3
, 500 MHz):
d
7.33e7.40 (m,1H), 7.55e7.65 (m,1H), 7.65e7.85
13
m, 2H) ppm; C NMR (CDCl
30.6, 134.6, 136.0 ppm; MS (EI, m/z): 183 (57), 181 (60, M ), 102
3
, 125 MHz):
d
114.1, 117.1, 122.8, 130.5,
4.2.26. Piperonylonitrile (2-29). Following the general procedure,
the reaction of amide 1-29 (128 mg, 0.5 mmol) gave, after chro-
matographic separation eluting with EtOAc/PE(v/v¼1:10), theknown
þ
(
100), 75 (30), 50 (19); t
R
(GC)¼7.768 min.
19k
ꢀ
19k
nitrile 2-29(66 mg, yield: 89%)as awhite solid. Mp92e94 C (lit.
ꢀ
ꢂ1 1
4.2.20. Terephthalonitrile (2-23). Following the general procedure,
90e92 C); IR (film)
(CDCl , 500 MHz):
(d, J¼8.0 Hz,1H) ppm; C NMR (CDCl
nmax: 3079, 2930, 2851, 2223 cm ; H NMR
the reaction of amide 1-23 (188 mg, 1.0 mmol) gave, after chro-
matographic separation eluting with EtOAc/PE (v/v¼1:10), the
3
d
6.07(s, 2H), 6.86(d, J¼8.0Hz,1H), 7.02(s,1H), 7.21
13
3
,125MHz):
d
102.1,104.9,109.0,
1
9g
þ
known nitrile
2-23 (119 mg, yield: 93%) as a white solid. Mp
111.3, 118.8, 128.1, 148.0, 151.5 ppm; MS (EI, m/z): 147 (68, M ), 146
ꢀ
19g
ꢀ
2
2
4
26e228 C (lit.
851, 2231, 1503, 1277 cm ; H NMR (CDCl
H) ppm; 13C NMR (CDCl
, 125 MHz): 116.7, 116.9, 132.8 ppm; MS
(GC)¼8.056 min.
226e228 C); IR (film)
n
max: 3098, 3054, 2917,
(100), 62 (20), 38 (9); t
R
(GC)¼8.740 min.
ꢂ1
1
3
, 500 MHz): 7.80 (s,
d
3
d
4.2.27. 2-Thiophenecarbonitrile (2-30). Following the general pro-
cedure, the reaction of amide 1-30 (209 mg, 0.5 mmol) gave, after
chromatographic separation eluting with EtOAc/PE (v/v¼1:10), the
þ
(
EI, m/z): 128 (100, M ),101 (30), 75 (14), 50 (16); t
R
13m
4.2.21. 4-Nitrobenzonitrile (2-24). Following the general procedure,
known nitrile
2-30 (80 mg, yield: 73%) as a colorless oil; IR (film)
ꢂ1
1
the reaction of amide 1-24 (208 mg, 1.0 mmol) gave, after chro-
matographic separation eluting with EtOAc/PE (v/v¼1:10), the
n
max: 3098, 2918, 2850, 2222 cm
;
H NMR (CDCl
3
, 500 MHz):
7.11e7.21 (m, 1H), 7.54e7.76 (m, 2H) ppm; C NMR (CDCl
109.8, 114.1, 127.6, 132.5, 137.3 ppm; MS (EI, m/z): 110
13
d
3
,
1
3m
known nitrile
1
2
2
2-24 (141 mg, yield: 95%) as a pale yellow solid. Mp
125 MHz):
d
ꢀ
13m
ꢀ
þ
47e149 C (lit.
854, 2233 cm ; H NMR (CDCl
148e149 C); IR (film)
n
max: 3100, 3054, 2913,
, 500 MHz):
7.90 (d, J¼8.4 Hz,
, 125 MHz): 116.7,
(7), 109 (100, M ), 58 (39), 45 (29), 39 (8); t
R
(GC)¼6.306 min.
ꢂ1
1
3
d
13
H), 8.37 (d, J¼8.4 Hz, 2H) ppm; C NMR (CDCl
3
d
4.2.28. Benzothiophene-2-carbonitrile (2-31). Following the gen-
eral procedure, the reaction of amide 1-31 (219 mg, 1.0 mmol) gave,
after chromatographic separation eluting with EtOAc/PE (v/
þ
1
18.3, 124.2, 133.4, 150.2 ppm; MS (EI, m/z): 148 (53, M ), 118 (12),
1
02 (100), 90 (32), 75 (51), 51 (31), 30 (50); t
R
(GC)¼10.106 min.
1
9i
v¼1:10), the known nitrile 2-31 (139 mg, yield: 87%) as a pale
ꢂ1
1
4.2.22. Methyl 4-cyanobenzoate (2-25). Following the general
yellow wax; IR (film)
n
max: 3090, 3058, 2962, 2850, 2216 cm ; H
7.44e7.57 (m, 2H), 7.80e7.95 (m,
, 100 MHz): 109.7, 114.4, 122.4, 125.3,
procedure, the reaction of amide 1-25 (111 mg, 0.5 mmol) gave,
after chromatographic separation eluting with EtOAc/PE (v/
NMR (CDCl , 400 MHz): d
3
13
3H) ppm; C NMR (CDCl
3
d

H. Geng, P.-Q. Huang / Tetrahedron 71 (2015) 3795e3801
3801
þ
1
25.7,127.8, 134.9,137.4,141.3 ppm; MS (EI, m/z): 159 (100, M ), 132
Pharm. Bull. 1998, 46, 199e206; (d) Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.;
Jacobsen, E. N. Nature 2009, 461, 968e970; (e) Wang, J.; Liu, X.; Feng, X. Chem.
Rev. 2011, 111, 6947e6983; (f) Kuethe, J. T.; Gauthier, D. R.; Beutner, G. L., Jr.;
Yasuda, N. J. Org. Chem. 2007, 72, 7469e7472; (g) Masumoto, S.; Usuda, H.;
Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634e5635; (h)
Senecal, T. D.; Shu, W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52,
(
8), 115 (7), 69 (8); t
R
(GC)¼9.539 min.
4
.2.29. Terephthalonitrile (2-23). Following the general procedure,
the reaction of amide 1-32 (202 mg, 1.0 mmol) gave, after chro-
matographic separation eluting with EtOAc/PE (v/v¼1:10), the
10035e10039; (i) Cohen, D. T.; Buchwald, S. L. Org. Lett. 2015, 17, 202e205.
1
3. For a review on the synthesis of aromatic nitriles using non-metallic cyano-
19g
known nitrile
2-23 (116 mg, yield: 91%) as a white solid. Mp
group sources see: (a) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem., Int. Ed. 2012,
51, 11948e11959; For selected examples on the conversion of oximers into
nitriles, see: (b) Hendrickson, J. B.; Bair, K. W.; Keehn, P. M. Tetrahedron Lett.
ꢀ
19g
ꢀ
1
2
2
4
26e228 C (lit.
226e228 C); IR (film)
n
max: 3098, 3054, 2917,
, 500 MHz): 7.80 (s,
116.7, 116.9, 132.8 ppm; MS
(GC)¼8.056 min.
ꢂ1
851, 2231, 1503, 1277 cm ; H NMR (CDCl
3
d
1976, 17, 603e604; (c) Campagna, F.; Carotti, A.; Casini, G. Tetrahedron Lett. 1977,
H) ppm; 13C NMR (CDCl
d
3
, 125 MHz):
18, 1813e1816; (d) Ishihara, K.; Furuya, Y.; Yamamoto, H. Angew. Chem., Int. Ed.
2002, 41, 2983e2986; (e) Rai, A.; Yadav, L. D. S. Eur. J. Org. Chem. 2013,
þ
(
EI, m/z): 128 (100, M ),101 (30), 75 (14), 50 (16); t
R
1889e1893; (f) Whiting, E.; Lanning, M. E.; Scheenstra, J. A.; Fletcher, S. J. Org.
Chem. 2015, 80, 1229e1234; For selected examples on the conversion of pri-
mary amides into nitriles, see: (g) Davis, B.; Brandstetter, T. W.; Smith, C.;
Hackett, L.; Winches, B. G.; Fleer, G. W. J. Tetrahedron Lett. 1995, 36, 7507e7510;
4
.2.30. Terephthalonitrile (2-23). The reaction of amide 1-33
(
67 mg, 0.3 mmol) also gave 2-23 (33 mg, yield: 86%).
(h) Charette, A. B.; Chua, P. Synlett 1998, 163e165; (i) Bose, D. S.; Jayalakshmi, B.
Synthesis 1999, 64e65; (j) Rychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter, A. J.
Org. Lett. 2001, 3, 807e810; (k) Altmann, E.; Aichholz, R.; Betschart, C.; Buhl, T.;
Green, J.; Lattmann, R.; Missbach, M. Bioorg. Med. Chem. Lett. 2006, 16,
4
.2.31. 4-Cyanobenzoic acid (2-32) (CAS: 619-65-8). Following the
general procedure, the reaction of amide 1-34 (124 mg, 0.5 mmol)
gave, after chromatographic separation eluting with EtOAc/PE (v/
2549e2554; (l) Kuo, C.-W.; Zhu, J.-L.; Wu, J.-D.; Chu, C.-M.; Yao, C.-F.; Shia, K.-S.
Chem. Commun. 2007, 301e303; (m) Bhalerao, D. S.; Mahajan, U. S.; Chaudhari,
K. H.; Akamanchi, K. G. J. Org. Chem. 2007, 72, 662e665; (n) Sueoka, S.; Mit-
sudome, T.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem. Commun. 2010,
8243e8245; For selected examples on the conversion of second amides into
nitriles, see: (o) Ketcha, D. M.; Gribble, G. W. J. Org. Chem. 1985, 50, 5451e5460;
19l
v¼2:1), the commercially available nitrile 2-32 (24 mg, yield:
ꢀ
19g
ꢀ
3
2%) as a white solid. Mp 219e221 C (lit. 219e221 C); IR (film)
ꢂ1
1
n
max: 3150, 3058, 2954, 2855, 2231, 1703 cm ; H NMR (DMSO-d ,
6
4
1
00 MHz):
d 7.94e8.01 (m, 2H), 8.05e8.11 (m, 2H), 13.54 (br s,
(p) Huang, Y.; Luedtke, R. R.; Freeman, R. A.; Wua, L.; Mach, R. H. Bioorg. Med.
H) ppm; 13C NMR (DMSO-d
, 100 MHz):
d
þ
115.5, 118.6, 130.4, 133.1,
6
Chem. 2001, 9, 3113e3122; (q) Pleuss, N.; Kunz, H. Synthesis 2005, 122e130; (r)
Tanaka, M.; Haino, T.; Ideta, K.; Kubo, K.; Moriba, A.; Fukazawaa, Y. Tetrahedron
135.3, 166.5 ppm; MS (EI, m/z): 147 (63, M ), 131 (10), 130 (100), 119
2
1
2
007, 63, 652e665; (s) Vaccari, D.; Davoli, P.; Spaggiari, A.; Prati, F. Synlett 2008,
317e1320; (t) Shabashov, D.; Maldonado, J. R. M.; Daugulis, O. J. Org. Chem.
008, 73, 7818e7821; For an example on the conversion of tertiary amides into
(
5), 102 (49), 76 (25), 75 (23); t
R
(GC)¼11.773 min.
nitriles, see: (u) Phillips, B. A.; Fodor, G.; Gal, J.; Letourneau, F.; Ryan, J. J. Tet-
rahedron 1973, 29, 3309e3327.
Acknowledgements
1
4. (a) von Pechmann, H. Ber. Dtsch. Chem. Ges. 1900, 33, 611e612; (b) von Braun, J.
Ber. Dtsch. Chem. Ges. 1904, 37, 3210e3213; (c) Leonard, N. J.; Nommensen, E. W.
J. Am. Chem. Soc. 1949, 71, 2808e2813; (d) Vaughan, W. R.; Carlson, R. D. J. Am.
Chem. Soc. 1962, 84, 769e774.
The authors are grateful to the Natural Science Foundation of
China (NSFC, Grant No. 21332007), and the Program for Changjiang
Scholars and Innovative Research Team in University of the Min-
istry of Education of China for financial support.
15. (a) Perni, R. B.; Gribble, G. W. Org. Prep. Proced. Int. 1983, 15, 297e302; (b)
Markevitch, D. Y.; Rapta, M.; Hecker, S. J.; Renau, T. E. Synth. Commun. 2003, 33,
3285e3289; (c) Kelly, J.; Puar, M. S.; Afonso, A.; McPhail, A. T. J. Org. Chem. 1998,
6
3, 6039e6042.
References and notes
1
6. (a) Xiao, K.-J.; Luo, J.-M.; Ye, K.-Y.; Wang, Y.; Huang, P.-Q. Angew. Chem., Int. Ed.
2
010, 49, 3037e3040; (b) Xiao, K.-J.; Wang, A.-E; Huang, P.-Q. Angew. Chem., Int.
1
. Husson, H. P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383e394.
. For general reviews, see: (a) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React.
984, 32, 1e92; (b) Fleming, F. F.; Zhang, Z. Tetrahedron 2005, 61, 747e789.
Ed. 2012, 51, 8314e8317; (c) Xiao, K.-J.; Huang, Y.-H.; Huang, P.-Q. Acta Chim.
Sin. 2012, 70, 1917e1922; (d) Huo, H.-H.; Xia, X.-E.; Zhang, H.-K.; Huang, P.-Q. J.
Org. Chem. 2013, 78, 455e465; (e) Huang, S.-Y.; Chang, Z.; Tuo, S.-C.; Gao, L.-H.;
Wang, A.-E; Huang, P.-Q. Chem. Commun. 2013, 7088e7090; (f) Deng, H.-Q.;
Qian, X.-Y.; Li, Y.-X.; Zheng, J.-F.; Xie, L.-F.; Huang, P.-Q. Org. Chem. Front. 2014, 1,
2
3
1
. For a review, see: (a) Albright, J. D. Tetrahedron 1983, 39, 3207e3233; For an
example, see: (b) Wang, M.-X.; Deng, G.; Wang, D.-X.; Zheng, Q.-Y. J. Org. Chem.
2005, 70, 2439e2444.
2
8
58e266; (g) Huang, P.-Q.; Ou, W.; Xiao, K.-J.; Wang, A.-E Chem. Commun. 2014,
761e8763; (h) Huang, P.-Q.; Lang, Q.-W.; Wang, A.-E; Zheng, J.-F. Chem.
4
5
. (a) Schnermann, M. J.; Untiedt, N. L.; Jim eꢀ nez-Os eꢀ s, G.; Houk, K. N.; Overman, L.
E. Angew. Chem., Int. Ed. 2012, 51, 9581e9586; (b) Bahde, R. J.; Rychnovsky, S. D.
Org. Lett. 2008, 10, 4017e4020.
Commun. 2015, 1096e1099.
7. For reviews on the chemistry of triflic acid and its derivatives, see: (a) Stang,
P. J.; White, M. R. Aldrichimica Acta 1983, 16, 15e22; (b) Baraznenok, I. L.;
Nenajdenko, V. G.; Balenkova, E. S. Tetrahedron 2000, 56, 3077e3119; For
1
. For a review on the Blaise reaction, see: (a) Rao, H. S. P.; Rafi, S.; Padmavathy, K.
Tetrahedron 2008, 8037e8043; (b) Hertzberg, R.; Moberg, C. J. Org. Chem. 2013,
7
8, 9174e9180; (c) Ramachandran, P. V.; Mitsuhashi, W.; Nicponski, D. R. Tet-
2
selected examples on the use of Tf O as a powerful amide activator for
rahedron Lett. 2013, 54, 5001e5003; (d) Li, W.; Gao, J. J.; Lorenz, J. C.; Xu, J.;
Johnson, J.; Ma, S.; Lee, H.; Grinberg, N.; Busacca, C. A.; Lu, B.; Senanayake, C. H.
Org. Process Res. Dev. 2012, 16, 836e839; (e) Kim, J. H.; Shin, H.; Lee, S. J. Org.
Chem. 2012, 77, 1560e1565; (f) Gauvreau, D.; Dolman, S. J.; Hughes, G.; O’Shea,
P. D.; Davies, I. W. J. Org. Chem. 2010, 75, 4078e4085; (g) Behr, J.-B.; Kalla, A.;
Harakat, D.; Plantier-Royon, R. J. Org. Chem. 2008, 73, 3612e3615; (h) Bertus, P.;
Szymoniak, J. J. Org. Chem. 2003, 68, 7133e7136.
. (a) Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551e3558; (b) Zhou, L.; Zhang,
Y. Tetrahedron 2000, 56, 2953e2960; (c) Molander, G. A.; Wolfe, C. N. J. Org.
Chem. 1998, 63, 9031e9036; (d) Hamann, B.; Namy, J.-L.; Kagan, H. B. Tetrahe-
dron 1996, 52, 14225e14234.
. Laval, S.; Dayoub, W.; Pehlivan, L.; M eꢀ tay, E.; Delbrayelle, D.; Mignani, G.;
Lemaire, M. Tetrahedron Lett. 2014, 55, 23e26.
. (a) Larraufie, M.-H.; Malacria, M.; Courillon, C.; Ollivier, C.; Fensterbank, L.;
Lac o^ te, E. Tetrahedron 2013, 69, 7699e7705; (b) Fern ꢀa ndez-Mateos, A.;
Madrazo, S. E.; Teij oꢀ n, P. H.; Clemente, R. R.; Gonz ꢀa lez, R. R.; Gonz aꢀ lez, F. S. J.
a variety of transformations, see: (c) Cui, S.-L.; Wang, J.; Wang, Y.-G. J. Am.
Chem. Soc. 2008, 130, 13526e13527; (d) Wang, J.; He, Z.; Chen, X. P.; Song,
W.; Lu, P.; Wang, Y. Tetrahedron 2010, 66, 1208e1214; (e) B eꢀ langer, G.;
Boudreault, J.; Levesque, F. Org. Lett. 2011, 13, 6204e6207; (f) Belanger, G.;
Dupuis, M.; Larouche-Gauthier, R. J. Org. Chem. 2012, 77, 3215e3221; (g)
Medley, J. W.; Movassaghi, M. Angew. Chem., Int. Ed. 2012, 51, 4572e4576; (h)
Valerio, V.; Petkova, D.; Madelaine, C.; Maulide, N. Chem.dEur. J. 2013, 19,
ꢀ
ꢀ
6
2
(
1
606e2610; (i) Medley, J. W.; Movassaghi, M. Org. Lett. 2013, 15, 3614e3617;
j) Peng, B.; Geerdink, D.; Maulide, N. J. Am. Chem. Soc. 2013, 135,
4968e14971; (k) Peng, B.; Geerdink, D.; Far eꢁ s, C.; Maulide, N. Angew. Chem.,
Int. Ed. 2014, 53, 5462e5466; (l) Mewald, M.; Medley, J. W.; Movassaghi, M.
Angew. Chem., Int. Ed. 2014, 53, 11634e11639.
7
1
1
8. Medley, J. W.; Movassaghi, M. J. Org. Chem. 2009, 74, 1341e1344.
9. (a) Chiba, S.; Zhang, L.; Ang, G. Y.; Hui, B. W.-Q. Org. Lett. 2010, 12, 2052e2055;
b) Suzuki, Y.; Yoshino, T.; Moriyama, K.; Togo, H. Tetrahedron 2011, 67,
809e3814; (c) Ryu, I.; Uehara, S.; Hirao, H.; Fukuyama, T. Org. Lett. 2008, 10,
005e1008; (d) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
25, 2890e2891; (e) Zhou, W.; Xu, J.; Zhang, L.; Jiao, N. Org. Lett. 2010, 12,
888e2891; (f) Zhang, Z.; Liebeskind, L. S. Org. Lett. 2006, 8, 4331e4333; (g)
8
(
3
1
1
Org. Chem. 2013, 78, 9571e9578.
. Fleming, F. F. Nat. Prod. Rep. 1999, 16, 597e606.
9
1
0. (a) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem.
010, 53, 7902e7917; (b) Fatiadi, A. J. Preparation and Synthetic Applications of
Cyano Compounds; Wiley: New York, NY, 1983.
1. (a) Goujon, L. J.; Khaldi, A.; Maziz, A.; Plesse, C.; Nguyen, G. T. M.; Aubert, P.-H.;
2
2
Lamani, M.; Prabhu, K. R. Angew. Chem., Int. Ed. 2010, 49, 6622e6625; (h) En-
thaler, S. Chem.dEur. J. 2011, 17, 9316e9319; (i) Zhou, S.; Junge, K.; Addis, D.;
Das, S.; Beller, M. Org. Lett. 2009, 11, 2461e2464; (j) Kornblum, N.; Fifolt, M. J.
Tetrahedron 1989, 45, 1311e1322; (k) Suzuki, Y.; Moriyama, K.; Togo, H. Tetra-
hedron 2011, 67, 7956e7962; (l) Littke, A.; Soumeillant, M.; Kaltenbach, R. F., III;
Cherney, R. J.; Tarby, C. M.; Kiau, S. Org. Lett. 2007, 9, 1711e1714; (m) Sarkar, S.
D.; Studer, A. Org. Lett. 2010, 12, 1992e1995.
1
Vidal, F.; Chevrot, C.; Teyssi eꢀ , D. Macromolecules 2011, 44, 9683e9691; (b)
Miller, J. S.; Manson, J. L. Acc. Chem. Res. 2001, 34, 563e570.
2. (a) Adams, R.; Marvel, C. S. Org. Synth. 1921, 1, 33e34; (b) Miyashita, A.; Suzuki,
1
Y.; Okumura, Y.; Iwamoto, K.-I.; Higashino, T. Chem. Pharm. Bull. 1998, 46, 6e11;
(
c) Suzuki, Y.; Takemura, Y.; Iwamoto, K.-I.; Higashino, T.; Miyashita, A. Chem.