Copper-Catalyzed Cyanation of N-Tosylhydrazones with Thiocyanate Salt as the "cN" Source

Article abstract of DOI:10.1021/acs.joc.7b00836

A novel protocol for the synthesis of α-aryl nitriles has been successfully achieved via a copper-catalyzed cyanation of N-tosylhydrazones employing thiocyanate as the source of cyanide. The features of this method include a convenient operation, readily available substrates, low-toxicity thiocyanate salts, and a broad substrate scope.

Full text of DOI:10.1021/acs.joc.7b00836

Subscriber access provided by EAST TENNESSEE STATE UNIV
Note
Copper-Catalyzed Cyanation of N-Tosylhydrazones
with Thiocyanate Salt as “CN” Source
Yubing Huang, Yue Yu, Zhongzhi Zhu, Chuanle Zhu,
Jinghe Cen, Xianwei Li, Wanqing Wu, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00836 • Publication Date (Web): 28 Jun 2017
Downloaded from http://pubs.acs.org on June 28, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Copper-Catalyzed Cyanation of
N-Tosylhydrazones with Thiocyanate Salt as
“CN” Source
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yubing Huang, Yue Yu, Zhongzhi Zhu, Chuanle Zhu, Jinghe Cen, Xianwei Li,
Wanqing Wu*, Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640,
P. R. China
Fax: (+86) 20ꢀ87112906; Eꢀmail: cewuwq@scut.edu.cn, jianghf@scut.edu.cn
Abstract: A novel protocol for the synthesis of αꢀaryl nitriles has been successfully
achieved, which is via a copperꢀcatalyzed cyanation of Nꢀtosylhydrazones employing
thiocyanate as source of cyanide. The features of this method include convenient
operation, readily available substrates, lowꢀtoxic thiocyanate salts and broad substrate
scope.
αꢀAryl nitriles are important compounds with extensive biological activities,1 and
versatile synthetic intermediates2 for transformations into ketones, esters, αꢀaryl
amides, carboxylic acids, heterocycles compounds etc. As potentially valuable
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
5
6
7
8
9
structural motif and versatile precursors, αꢀaryl nitriles also play an important role in
the construction of drugs, for instance ariflo,3 verapamil, indoprofen,4 anastrozole and
naproxen,5 which has prompted the development of efficient strategies for their
preparation. Commonly known, αꢀaryl nitrile motifs are usually constructed by (i)
nucleophilic substitution reactions involving cyanide and benzyl halides or
alcohols,5ꢀ6 (ii) photolytic reactions,7 (iii) dehydrations,8 etc. Recently, many other
proposals for synthesizing αꢀaryl nitriles have been reported, among them, transition
metalꢀcatalyzed synthetic strategies mainly consist of hydrocyanation of olefins,9
cyanations of alkynes,10 coupling reactions of nitriles with aryl halides or arylboronic
acids11 and acylations of silyl ketene imines.12 Among them, expensive and complex
metal catalysts (Co, Ni, Ru, Pd, etc.), toxic cyanides and harsh reaction conditions are
always thorny problems to be solved. Lately, liu13 has also reported a novel
conversion of benzylic CꢀH bonds into benzylic nitriles via a copperꢀcatalyzed radical
relay pathway with TMSCN as “CN” source.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. The organic transformation of thiocyanate salts
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Thiocyanate salts have been proved to be attractive and versatile reagents in
organic transformations,14 owing to their easy availability, low cost and low toxicity.
As an ambident nucleophilic unit (S or N nucleophilic unit), thiocyanate salts can
introduce “SCN” source, mainly via a nucleophilic substitution or a radical pathway,
to afford thiocyanate products.14, 15 Meanwhile, in recent years, people gradually
recognized that thiocyanate salts can also be used as a sulfur transfer reagent16 or a
stable “CN” source in organic transformations (Scheme 1).17, 18 In general, the
reclamation of “CN” source from thiocyanate is through an oxidation process19 and
peroxidases are sometimes required in these thiocyanate oxidations. Early in 1989,
Saito20c reported the synthesis of diarylacetonitrile from diaryl ketones and
trimethylsilyl cyanide in the presence of base, in which TsNHNH2 promoted diaryl
ketone converting into hydrazone. Based on the previous studies20c, 20d and our interest
in the cyanation of Nꢀtosylhydrazones, herein, we report a copperꢀcatalyzed cyanation
to construct racemic αꢀaryl nitriles from Nꢀtosylhydrazones. Different from N,
Nꢀdialkylhydrazones derived from aldehydes that undergoing oxidative cleavage to
nitrile20a, 20b, this novel cyanation reaction employs KSCN as a “CN” source to access
diverse αꢀaryl nitriles.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In the preliminary experiment, we chose Nꢀtosylhydrazone of benzaldehyde (1aa)
as a model substrate to react with potassium thiocyanate (2) in the presence of CuI (10
mol %), PTSH (1.0 equiv), DBU (2.0 equiv) in 1.0 mL mixed solvent at 80 °C under
1 atm of O2. After investigated different proportions and types of solvent mixtures
(Table 1, entries 1ꢀ7), we found that mixed solvents could promote the reaction more
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
3
4
5
6
7
8
9
than the monoꢀsolvents and the solvent mixture MeCN/NMP (2:1) was effective in
this catalytic system (entry 2). Through the examination of various copper catalysts
(entries 2, 8ꢀ10), we considered that the safer CuI was the optimal choice although
CuI and CuCN were indicated to reach a similar catalytic activity (entries 2 and 8).
The yield was slightly increased to 72% when decreasing the amount of KSCN to 2.5
equiv (entries 2, 11ꢀ12). When MeCN and NMP were used alone as solvent, only 48%
and 31% yields were achieved separately (entries 13ꢀ14). With the addition of 4Å
molecular sieves, the yield was reached 79% (entry 15). When the reaction was
carried out under nitrogen atmosphere, the yield was reduced to 58% (entry 16). In
addition, the 82% yield confirmed that NaSCN could be also used as a “CN” source in
this reaction system (entry 17). In the considerations from economy and similar yield
(entries 15 and 17), KSCN was believed to be more suitable as a “CN” source.
Table 1. Optimization of Reaction Conditions a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
[Cu]
CuI
CuI
2 (equiv)
3.0
solvent
yield b(%)
39
71
1
2
MeCN/NMP (1:1)
MeCN/NMP (2:1)
MeCN/NMP (3:1)
MeCN/NMP (5:1)
MeCN/ DCE (2:1)
MeCN/DMF (2:1)
MeCN/H2O (2:1)
MeCN/NMP (2:1)
MeCN/NMP (2:1)
MeCN /NMP (2:1)
3.0
CuI
CuI
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
66
47
3
4
CuI
64
5
CuI
32
6
CuI
trace
70
7
CuCN
CuSCN
CuBr
8
61
9
34
10
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2.5
2.0
2.5
2.5
2.5
2.5
ꢀ
MeCN/NMP (2:1)
MeCN/NMP (2:1)
MeCN
72
60
11
12
CuI
CuI
13
48
CuI
CuI
CuI
CuI
CuI
14
NMP
31
15 c
16 d
17 c, e
MeCN/NMP (2:1)
MeCN/NMP (2:1)
MeCN/NMP (2:1)
79 (71) f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
58
82
a Reaction conditions: All reactions were performed with 1aa (0.2 mmol), 2, catalyst (0.02 mmol),
PTSH (0.2 mmol), DBU (0.4 mmol) in 1.0 mL solvent at 80 °C under 1 atm O2 for 7 h unless
otherwise noted. GCꢀMS yield using nꢀdodecane as an internal standard. c 4Å molecular sieves
b
d
e
f
was added. Under N2. 2.5 equivalent of NaSCN was added instead of KSCN. Isolated yield.
PTSH = pꢀtoluenesulfonyl hydrazide.
With the optimal reaction conditions in hand, we subsequently explored the
substrate scopes of Nꢀtosylhydrazones (R2 = H) in this copperꢀcatalyzed cyanation
reaction (Table 2). Hꢀ, methylꢀ, methoxyꢀsubstituted substrates could be tolerated and
converted to the desired phenylacetonitriles in good yields, whereas halogen
substituted products were delivered in lower yields (3ac, 3ad and 3af). Moreover, a
good isolated yield was obtained when heterocyclic (3akꢀ3am) and naphthaldehyde
(3an) derived Nꢀtosylhydrazones were used as substrates respectively. However,
phenylacetaldehyde derived Nꢀtosylhydrazone could only generate the corresponding
nitrile 3am in 51% yield.
Table 2. Substrate Scope of N-Tosylhydrazonesa
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Reaction conditions: All reactions were performed with 1a (0.5 mmol), 2 (1.25 mmol), CuI (0.05
mmol), PTSH (0.5 mmol), DBU (1.0 mmol) in 2 mL MeCN/NMP (2: 1) at 80°C under 1 atm O2
for 7 h unless otherwise noted. Yields refer to the isolated yields.
A series of substrate scopes of Nꢀtosylhydrazones (R2 = alkyl) was then explored
in this copperꢀcatalyzed cyanation reaction (Table 3). When R2 was methyl,
Nꢀtosylhydrazones bearing electronꢀwithdrawing and electronꢀdonating substituents
afforded the products (3baꢀ3bl) in moderate to good yields. Notably,
acylnaphthalenes derived Nꢀtosylhydrazones are good substrates to deliver the
corresponding nitriles in 82% (3bm) and 80% (3bn) yields, respectively. When R2
was ethyl (3bo), isopropyl (3bp) or nꢀpropyl (3br), the desired products were
obtained in good yields, however, only 57% yield could be obtained when R2 was
cyclopropyl. To our delight, the reaction could afford the corresponding benzocyclic
nitriles (3bsꢀ3bu) in excellent yields. Meanwhile, 2ꢀmethylꢀ4ꢀphenylbutanenitrile
(3bv) was also obtained in 76% isolated yield. In addition, when using
4,4ꢀdimethylcyclohexꢀ2ꢀenone derived Nꢀtosylhydrazone as
a
substrate, an
unexpected doubleꢀbond migration product (3bw) was isolated in 62% yield in this
ACS Paragon Plus Environment

Page 7 of 26
The Journal of Organic Chemistry
1
2
3
4
reaction system.
5
6
7
Table 3. Substrate Scope of N-Tosylhydrazones (R2 = alkyl)a
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Reaction conditions: All reactions were performed with 1b (0.5 mmol), 2 (1.25 mmol), CuI (0.05
mmol), PTSH (0.5 mmol), DBU (1.0 mmol) in 2 mL MeCN/NMP (2: 1) at 80 °C under 1 atm O2
for 7 h unless otherwise noted. Yields refer to the isolated yields.
To gain more mechanistic insights into this copperꢀcatalyzed cyanation reaction,
we conducted series of control experiments (Scheme 2). Taking the synthetic
materials of Nꢀtosylhydrazones into account, we suspected that the role of
sulfohydrazide was to regenerate Nꢀtosylhydrazones by reacting with aldehydes or
ketones byproducts. But in fact, no desired nitrile product was detected when
switching benzaldehyde as a substrate to involve in the reaction (Scheme 2, a). When
1.5 equiv of TEMPO was introduced, the desired product was not significantly
inhibited (Scheme 2, b). The results of c and d demonstrated further that KSCN
provides direct nitrile source for the transformation, and PTSH can facilitate this
transformation. Subsequently, we changed PTSH to equivalent BZH, and found that
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
benzoylhydrazine can promote the reaction as well (Scheme 2, e).
5
6
7
Scheme 2. Control Experiments
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
changes
a. Switch benzaldehyde as 1a
b. Add 1.5 equiv of TEMPO;
c. Remove KSCN;
yield (%)a
n.r.
67
n.d
30
d. Remove PTSH;
e. Replace PTSH with 1 equiv BZH.
54
a
GCꢀMS yield using nꢀdodecane as an internal standard. PTSH = pꢀtoluenesulfonyl hydrazide;
BZH = benzoylhydrazine.
A plausible reaction mechanism is proposed as shown in Scheme 3. Initially, the
Cu species A is generated from Cu(I) catalyst and SCNꢀ,21 followed by the reaction
with diazo substrate B, generated in situ from Nꢀtosylhydrazone in the presence of
base, 22 to form the copper(І) carbene species D. Subsequently to the generation of the
thiocarbonyl compound E, which could regenerate the Nꢀtosylhydrazone with
TsNHNH2 and while releasing H2S, the species CuICN (F)23 is formed. On the one
hand, cyanide ion could directly attack Nꢀtosylhydrazone 1 to form nitrile product
3,20c, 20d and on the other hand, the reaction of species CuICN (F) and diazo substrate
B leads to the formation of copper(І) carbene species G, followed by the migratory
insertion21, 24 to generate the intermediate H. The protonation of H releases the nitrile
product 3 and regenerates copper(I) catalyst.
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Scheme 3. Proposed Mechanism
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, a copperꢀcatalyzed cyanation to construct racemic αꢀaryl nitriles
employing KSCN as a “CN” source has been developed. The employ of inexpensive
copper catalyst, ecoꢀfriendly oxygen and readily available starting materials, simple
operation conditions and the regeneration of “CN” sources from lowꢀtoxic thiocyanate
salts have presented a novel and safe protocol for the synthesis of αꢀaryl nitriles.
EXPERIMENTAL SECTION
General Information
Melting points were determined with a Buchi Melting Point Bꢀ545 instrument. 1H and
13C NMR spectra were recorded using a Bruker DRXꢀ400 spectrometer using CDCl3
as solvent. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm,
respectively, and chloroform is solvent with TMS as the internal standard. IR spectra
were obtained either as potassium bromide pellets or as liquid films between two
potassium bromide pellets with a Bruker TENSOR 27 spectrometer. Mass spectra
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
5
6
7
8
9
were recorded on a Thermo Scientific ISQ gas chromatographꢀmass spectrometer. The
data of HRMS was carried out on a highꢀresolution mass spectrometer
(LCMSꢀITꢀTOF). TLC was performed by using commercially prepared 100ꢀ400 mesh
silica gel plates and visualization was effected at 254 nm. Unless otherwise noted, all
reagents and solvents were obtained from commercial suppliers and used without
further purification.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for N-Tosylhydrazones: A mixture of ketone compounds (5.0
mmol) and pꢀtoluenesulfonhydrazide (5.0 mmol) in 7.5 mL MeOH was stirred at 70
oC for 0.5ꢀ3 h to afford the corresponding Nꢀtosylhydrazone 1 as white precipitate.
After that, the precipitate was washed and filtered with petroleum ether twice and
dried under vacuum to provide the pure compounds.
General Procedure for the Synthesis of α-Aryl Nitriles: A mixture of
Nꢀtosylhydrazone (0.5 mmol), KSCN (1.25 mmol), CuI (0.05 mmol), PTSH (0.5
mmol), DBU (1.0 mmol), 4Å MS and 2.0 mL MeCN/NMP (2: 1) was added to a test
tube. The mixture was stirred at 80 °C under 1 atm O2 for 7 h. After that, water was
added and extracted with ethyl acetate twice. The combined organic phase was dried
over Na2SO4 and concentrated. The residue was purified by flash column
chromatography on silica gel with petroleum ether/ethyl acetate (PE/EA = 10: 1–20: 1)
as the eluent to afford the corresponding αꢀaryl nitriles.
1
2-Phenylacetonitrile (3aa): Yield: 41 mg (71%), yellow oil. H NMR (400 MHz,
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CDCl3, ppm): δ = 7.38 (m, 2H), 7.32 (dd, J = 7.3, 3.9 Hz, 3H), 3.75 (s, 2H); 13C NMR
(101 MHz, CDCl3, ppm): δ = 129.9, 129.2, 128.1, 127.9, 117.8, 23.6; IR (KBr, cmꢀ1):
ν = 3039, 2929, 2251, 1681, 1599, 1496, 1415, 670; HRMS (ESI) calc. C8H7NNa
[M+Na]+: 140.0471, found: 140.0469.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(p-Tolyl)acetonitrile (3ab): Yield: 46 mg (70%), yellow oil. H NMR (400 MHz,
CDCl3, ppm): δ = 7.20 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 3.69 (s, 2H), 2.34
(s, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 137.9, 129.8, 127.8, 126.9, 118.1,
23.2, 21.1; IR (KBr, cmꢀ1): ν = 2930, 2928, 2251, 1726, 1526, 1456, 1276, 670;
HRMS (ESI) calc. C9H9NNa [M+Na]+: 154.0627, found: 154.0626.
2-(p-Fluorophenyl)acetonitrile (3ac): Yield: 43 mg (64%), pale yellow oil. 1H NMR
(400 MHz, CDCl3, ppm): δ = 7.30 (t, J = 7.4 Hz, 2H), 7.06 (t, J = 8.3 Hz, 2H), 3.72 (s,
2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 162.4 (d, J = 247.1 H), 129.7 (d, J = 8.3
Hz), 125.7 (d, J = 3.1 Hz), 117.8, 116.1 (d, J = 21.9 Hz), 22.9. IR (KBr, cmꢀ1): ν =
3071, 2349, 2252, 1728, 1511, 1420, 1228, 826; HRMS (ESI) calc. C8H6FNNa
[M+Na]+: 158.0376, found: 158.0375.
2-(p-Chlorophenyl)acetonitrile (3ad): Yield: 52 mg (69%), pale yellow oil. 1H NMR
(400 MHz, CDCl3, ppm): δ = 7.38 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H), 3.75
(s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 134.2, 129.3, 129.3, 128.4, 117.4,
23.1; IR (KBr, cmꢀ1): ν = 3064, 2931, 2253, 1491, 1414, 1095, 805; HRMS (ESI) calc.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
C8H6ClNNa [M+Na]+: 174.0081, found: 174.0080.
5
6
7
8
9
2-(p-Methoxyphenyl)acetonitrile (3ae): Yield: 56 mg (76%), yellowishꢀgreen oil. 1H
NMR (400 MHz, CDCl3, ppm): δ = 7.22 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.3 Hz, 2H),
3.80 (s, 3H), 3.67 (s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 159.4, 129.1, 121.8,
118.3, 114.5, 55.4, 22.8; IR (KBr, cmꢀ1): ν = 2943, 2840, 2250, 1607, 1512, 1447,
1249, 1181, 1028, 823; HRMS (ESI) calc. C9H9NNaO [M+Na]+: 170.0575, found:
170.0576.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(m-Fluorophenyl)acetonitrile (3af): Yield: 44 mg (65%), colorless oil. H NMR
(400 MHz, CDCl3, ppm): δ = 7.35 (dd, J = 14.4, 7.0 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H),
7.04 (t, J = 10.0 Hz, 2H), 3.75 (s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 163.0
(d, J = 247.8 Hz), 132.2 (d, J = 7.9 Hz), 130.8 (d, J = 8.3 Hz), 123.7 (d, J = 3.0 Hz),
117.3, 115.3, 115.1, 23.4; IR (KBr, cmꢀ1): ν = 3088, 2938, 2253, 1600, 1489, 1252,
1078, 784; HRMS (ESI) calc. C8H6FNNa [M+Na]+: 158.0376, found: 158.0381.
2-(m-Tolyl)acetonitrile (3ag): Yield: 46 mg (71%), colorless oil. 1H NMR (400 MHz,
CDCl3, ppm): δ = 7.25 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 8.6 Hz, 3H), 3.69 (s, 2H), 2.35
(s, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 139.0, 129.8, 129.0, 128.8, 128.6,
125.0, 118.0, 23.5, 21.3; IR (KBr, cmꢀ1): ν = 3031, 2927, 2251, 1606, 1485, 777, 694;
HRMS (ESI) calc. C9H9NNa [M+Na]+: 154.0627, found: 154.0625.
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
2-(m-Methoxyphenyl)acetonitrile (3ah): Yield: 56 mg (77%), pale yellow oil. H
NMR (400 MHz, CDCl3, ppm): δ = 7.27 (t, J = 8.1 Hz, 1H), 6.87 (m, 3H), 3.80 (s,
3H), 3.70 (s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 160.1, 131.4, 130.2, 120.2,
117.9, 113.7, 113.6, 55.3, 23.6; IR (KBr, cmꢀ1): ν = 2949, 2840, 2251, 1600, 1479,
1263, 1158, 1044, 779; HRMS (ESI) calc. C9H10NO [M+H]+: 148.0762, found:
148.0761.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(o-Tolyl)acetonitrile (3ai): Yield: 49 mg (75%), pale yellow oil. H NMR (400
MHz, CDCl3, ppm): δ = 7.34 (d, J = 6.9 Hz, 1H), 7.22 (q, J = 6.9 Hz, 3H), 3.64 (s,
2H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 136.1, 130.7, 128.6, 128.5,
128.4, 126.75, 117.6, 21.9, 19.3; IR (KBr, cmꢀ1): ν = 2934, 2250, 1604, 1469, 750;
HRMS (ESI) calc. C9H9NNa [M+Na]+: 154.0627, found: 154.0628.
1
2-(o-Methoxyphenyl)acetonitrile (3aj): Yield: 59 mg (80%), pale yellow oil. H
NMR (400 MHz, CDCl3, ppm): δ = 7.32 (m, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.88 (d, J =
8.2 Hz, 1H), 3.86 (s, 3H), 3.67 (s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 156.8,
129.6, 129.2, 120.8, 118.6, 118.1, 110.5, 55.5, 18.7; IR (KBr, cmꢀ1): ν = 2946, 2841,
2251, 1597, 1492, 1252, 1110, 1029, 751; HRMS (ESI) calc. C9H10NO [M+H]+:
148.0764, found: 148.0762.
1
2-(Thiophen-2-yl)acetonitrile (3ak): Yield: 49 mg (80%), tan oil. H NMR (400
MHz, CDCl3, ppm): δ = 7.26 (d, J = 5.3 Hz, 1H), 7.05 (s, 1H), 6.98 (d, J = 3.0 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
7
8
9
1H), 3.91 (s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 131.0, 127.4, 127.2, 126.0,
117.0, 18.6; IR (KBr, cmꢀ1): ν = 2926, 2253, 1418, 1246, 840, 707; HRMS (ESI) calc.
C6H5NNaS [M+Na]+: 146.0035, found: 146.0037.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(Benzo[b]thiophen-3-yl)acetonitrile (3al): Yield: 74 mg (85%), white solid, M.p.:
65ꢀ67 ºC. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.92 (d, J = 7.7 Hz, 1H), 7.72 (d, J =
7.6 Hz, 1H), 7.51 (s, 1H), 7.46 (dd, J = 14.6, 7.3 Hz, 2H), 3.92 (s, 2H); 13C NMR (101
MHz, CDCl3, ppm): δ = 140.5, 137.0, 125.1, 125.0, 124.7, 123.9, 123.2, 120.8, 117.0,
17.8; IR (KBr, cmꢀ1): ν = 3076, 2922, 2247, 1643, 1426, 1263, 75; HRMS (ESI) calc.
C10H7NNaS [M+Na]+: 196.0191, found: 196.0194.
2-(Benzo[d][1,3]dioxol-5-yl)acetonitrile (3am): Yield: 78 mg (81%), white solid,
1
M.p.: 43ꢀ45 ºC. H NMR (400 MHz, CDCl3, ppm): δ = 6.78 (m, 3H), 5.97 (s, 2H),
3.65 (s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 148.3, 147.5, 123.4, 121.3,
118.0, 108.7, 108.4, 101.4, 23.3; IR (KBr, cmꢀ1): ν = 2904, 2249, 1500, 1439, 1248,
1112, 1038, 92; HRMS (ESI) calc. C9H7NNaO2 [M+Na]+: 184.0369, found:
184.0372.
2-(Naphthalen-2-yl)acetonitrile (3an): Yield: 69 mg (83%), white solid, M.p.: 84ꢀ85
1
ºC. H NMR (400 MHz, CDCl3, ppm): δ = 7.84 (m, 4H), 7.52 (m, 2H), 7.38 (d, J =
8.4 Hz, 1H), 3.90 (s, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 133.4, 132.7, 129.1,
127.8, 127.7, 127.2, 126.9, 126.8, 126.5, 125.5, 117.9, 23.8; IR (KBr, cmꢀ1): ν = 3056,
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
2947, 2251, 1603, 1363, 1265, 954, 827, 753; HRMS (ESI) calc. C12H10N [M+H]+:
168.0813, found: 168.0817.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3-Phenylpropanenitrile (3ao): Yield: 33 mg (51%), pale yellow oil. H NMR (400
MHz, CDCl3, ppm): δ = 7.33 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 6.6 Hz, 1H), 7.22 (d, J =
13
7.4 Hz, 2H), 2.93 (t, J = 7.4 Hz, 2H), 2.59 (t, J = 7.4 Hz, 2H); C NMR (101 MHz,
CDCl3, ppm): δ = 138.1, 128.9, 128.3, 127.3, 119.2, 31.6, 19.3; IR (KBr, cmꢀ1): ν =
3034, 2937, 2247, 1600, 1339, 749; HRMS (ESI) calc. C9H10N [M+H]+: 132.0813,
found: 132.0811.
2-Phenylpropanenitrile (3ba): Yield: 44 mg (67%), yellow oil. 1H NMR (400 MHz,
CDCl3, ppm): δ = 7.36 (m, 5H), 3.90 (q, J = 7.3 Hz, 1H), 1.65 (d, J = 7.3 Hz, 3H); 13C
NMR (101 MHz, CDCl3, ppm): δ = 137.1, 129.2, 128.1, 126.7, 121.6, 31.3, 21.5; IR
(KBr, cmꢀ1): ν = 2924, 2242, 1725, 1454, 1288, 990, 896, 752; HRMS (ESI) calc.
C9H9NNa [M+Na]+: 154.0627, found: 154.0625.
1
2-(p-Tolyl)propanenitrile (3bb): Yield: 48 mg (67%), yellow oil. H NMR (400
MHz, CDCl3, ppm): δ = 7.24 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 3.86 (q, J
= 7.3 Hz, 1H), 2.35 (s, 3H), 1.62 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3,
ppm): δ = 137.9, 134.1, 129.8, 126.6, 121.8, 30.9, 21.5, 21.1; IR (KBr, cmꢀ1): ν =
2926, 2859, 2242, 1728, 1512, 1453, 1298, 994, 819, 734; HRMS (ESI) calc.
C10H11NNa [M+Na]+: 168.0784, found: 168.0778.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
7
8
2-(p-Ethylphenyl)propanenitrile (3bc): Yield: 56 mg (70%), yellowishꢀgreen oil. 1H
NMR (400 MHz, CDCl3, ppm): δ = 7.27 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H),
3.87 (q, J = 7.2 Hz, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.63 (d, J = 7.3 Hz, 3H), 1.23 (t, J =
7.7 Hz, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 144.2, 134.3, 128.6, 126.7, 121.8,
30.9, 28.4, 21.5, 15.5; IR (KBr, cmꢀ1): ν = 2924, 2848, 1727, 1458, 1282, 986, 834,
743; HRMS (ESI) calc. C11H13NNa [M+Na]+: 182.0940, found: 182.0938.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2-(p-Methoxyphenyl)propanenitrile (3bd): Yield: 60 mg (75%), yellow oil. H
NMR (400 MHz, CDCl3, ppm): δ = 7.26 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H),
3.85 (d, J = 7.5 Hz, 1H), 3.81 (s, 3H), 1.61 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3, ppm): δ = 159.3, 129.11, 127.8, 121.9, 114.5, 55.4, 30.5, 21.5; IR (KBr, cmꢀ1):
ν = 2927, 2848, 2240, 1608, 1512, 1455, 1251, 1027, 827, 734; HRMS (ESI) calc.
C10H11NNaO [M+Na]+: 184.0733, found: 184.0732.
2-(p-(Methylthio)phenyl)propanenitrile (3be): Yield: 69 mg (78%), yellow solid.
1
M.p.: 65ꢀ67 ºC. H NMR (400 MHz, CDCl3, ppm): δ = 7.28 (s, 4H), 3.88 (q, J = 7.3
Hz, 1H), 2.50 (s, 3H), 1.64 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ
= 138.7, 133.8, 127.2, 127.1, 121.5, 30.8, 21.38, 15.7; IR (KBr, cmꢀ1): ν = 2986, 2927,
2240, 1600, 1491, 1432, 1314, 1097, 963, 819; HRMS (ESI) calc. C10H11NNaS
[M+Na]+: 200.0504, found: 200.0509.
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-(p-Fluorophenyl)propanenitrile (3bf): Yield: 51 mg (68%), tan oil. 1H NMR (400
MHz, CDCl3, ppm): δ = 7.33 (m, 2H), 7.08 (m, 2H), 3.89 (q, J = 7.3 Hz, 1H), 1.63 (d,
J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 162.4 (d, J = 247.3 Hz),
132.9 (d, J = 3.3 Hz), 128.4 (d, J = 8.3 Hz), 121.4, 116.1 (d, J = 21.8 Hz), 30.6, 21.5;
IR (KBr, cmꢀ1): ν = 2921, 2853, 1648, 1462, 1305, 1231, 960; HRMS (ESI) calc.
C9H9FN [M+H]+: 150.0714, found: 150.0712.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(p-Chlorophenyl)propanenitrile (3bg): Yield: 59 mg (72%), tan oil. 1H NMR (400
MHz, CDCl3, ppm): δ = 7.36 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 3.88 (q, J
= 7.2 Hz, 1H), 1.63 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 135.6,
134.1, 129.3, 128.1, 121.1, 30.7, 21.4; IR (KBr, cmꢀ1): ν = 2930, 2243, 1658, 1489,
1290, 1094, 1010, 827, 736; HRMS (ESI) calc. C9H8ClNNa [M+Na]+: 188.0237,
found: 188.0234.
1
2-(m-Tolyl)propanenitrile (3bh): Yield: 48 mg (67%), tan oil. H NMR (400 MHz,
CDCl3, ppm): δ = 7.30 (t, J = 6.7 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 7.6 Hz, 2H), 3.88
(q, J = 7.2 Hz, 1H), 2.40 (s, 3H), 1.66 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3, ppm): δ = 139.0, 137.0, 129.0, 128.8, 127.4, 123.7, 121.7, 31.2, 21.5, 21.4; IR
(KBr, cmꢀ1): ν = 2923, 2855, 1646, 1451, 1291, 990, 781, 701; HRMS (ESI) calc.
C10H11NNa [M+Na]+: 168.0784, found: 168.0783.
1
2-(m-Chlorophenyl)propanenitrile (3bi): Yield: 60 mg (73%), tan oil. H NMR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
7
8
9
(400 MHz, CDCl3, ppm): δ = 7.35 (s, 1H), 7.32 (d, J = 5.4 Hz, 2H), 7.25 (d, J = 6.1
Hz, 1H), 3.88 (q, J = 7.2 Hz, 1H), 1.64 (d, J = 7.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3, ppm): δ = 138.9, 135.0, 130.5, 128.4, 127.0, 125.0, 120.9, 31.0, 21.3; IR (KBr,
cmꢀ1): ν = 2927, 2856, 2243, 1583, 1469, 1245, 1082, 992, 881, 786; HRMS (ESI)
calc. C9H8ClNNa [M+Na]+: 188.0237, found: 188.0234.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(o-Tolyl)propanenitrile (3bj): Yield: 51 mg (70%), yellow oil. 1H NMR (400 MHz,
CDCl3, ppm): δ = 7.48 (d, J = 7.0 Hz, 1H), 7.28 (dd, J = 12.3, 7.1 Hz, 2H), 7.22 (t, J =
5.9 Hz, 1H), 4.07 (q, J = 7.2 Hz, 1H), 2.39 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3, ppm): δ = 135.3, 134.8, 131.0, 128.1, 127.0, 126.7, 121.8, 28.2,
20.0, 19.0; IR (KBr, cmꢀ1): ν = 2984, 2932, 2883, 2241, 1457, 1297, 1230, 985, 752;
HRMS (ESI) calc. C10H11NNa [M+Na]+: 168.0784, found: 168.0781.
1
2-(o-Chlorophenyl)propanenitrile (3bk): Yield: 64 mg (77%), yellow oil. H NMR
(400 MHz, CDCl3, ppm): δ = 7.61 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.33
(dd, J = 15.4, 7.5 Hz, 2H), 4.38 (q, J = 6.7 Hz, 1H), 1.65 (d, J = 7.0 Hz, 3H); 13C
NMR (101 MHz, CDCl3, ppm): δ = 134.8, 132.5, 130.0, 129.5, 128.2, 127.8, 121.0,
28.9, 19.9; IR (KBr, cmꢀ1): ν = 2925, 2855, 2244, 1675, 1454, 1305, 1034, 752;
HRMS (ESI) calc. C9H8ClNNa [M+Na]+: 188.0237, found: 188.0233.
1
2-(3,4-Dimethoxyphenyl)propanenitrile (3bl): Yield: 74 mg (78%), yellow oil. H
NMR (400 MHz, CDCl3, ppm): δ = 6.89 (m, 3H), 3.89 (m, 7H), 1.65 (d, J = 7.3 Hz,
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 149.4, 148.9, 129.5, 121.8, 121.8, 118.9,
118.9, 111.5, 109.9, 56.0, 30.8, 21.5; IR (KBr, cmꢀ1): ν = 2932, 2846, 2241, 1709,
1515, 1258, 1150, 1024, 750; HRMS (ESI) calc. C11H13NNaO2 [M+Na]+: 214.0838,
found: 214.0843.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(Naphthalen-2-yl)propanenitrile (3bm): Yield: 74 mg (82%), white solid, M.p.:
69ꢀ70 ºC. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.89 (m, 4H), 7.55 (m, 2H), 7.46 (d,
J = 8.5 Hz, 1H), 4.09 (q, J = 7.2 Hz, 1H), 1.75 (d, J = 7.3 Hz, 3H); 13C NMR (101
MHz, CDCl3, ppm): δ = 134.4, 133.4, 132.8, 129.2, 127.9, 127.7, 126.8, 126.5, 125.6,
124.4, 121.6, 31.4, 21.4; IR (KBr, cmꢀ1): ν = 3055, 2988, 2932, 2241, 1601, 1509,
1453, 1372, 1148, 821, 750; HRMS (ESI) calc. C13H12N [M+H]+: 182.0970, found:
182.0972.
2-(Naphthalen-1-yl)propanenitrile (3bn): Yield: 72 mg (80%), yellow oil. 1H NMR
(400 MHz, CDCl3, ppm): δ = 7.91 (m, 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 6.8
Hz, 1H), 7.54 (m, 3H), 4.61 (q, J = 7.2 Hz, 1H), 1.78 (d, J = 7.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3, ppm): δ = 134.1, 132.7, 129.8, 129.3, 129.0, 127.0, 126.2, 125.6,
124.7, 122.1, 121.8, 28.3, 20.6; IR (KBr, cmꢀ1): ν = 3057, 2987, 2928, 2240, 1762,
1595, 1452, 1249, 769; HRMS (ESI) calc. C13H12N [M+H]+: 182.0970, found:
182.0967.
2-Phenylbutanenitrile (3bo): Yield: 57 mg (79%), colorless oil. 1H NMR (400 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
5
6
7
8
9
CDCl3, ppm): δ = 7.38 (t, J = 6.6 Hz, 2H), 7.32 (m, 3H), 3.74 (t, J = 7.1 Hz, 1H), 1.94
(p, J = 7.1 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ =
135.8, 129.0, 128.0, 127.3, 120.8, 38.9, 29.2, 11.5; IR (KBr, cmꢀ1): ν = 3045, 2963,
2241, 1600, 1458, 1327, 753, 700; HRMS (ESI) calc. C10H11NNa [M+Na]+: 168.0784,
found: 168.0785.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Ethyl-2-phenylbutanenitrile (3bp): Yield: 62 mg (78%), yellow oil. 1H NMR (400
MHz, CDCl3, ppm): δ = 7.37 (d, J = 6.6 Hz, 2H), 7.30 (d, J = 6.9 Hz, 3H), 3.66 (d, J
= 6.1 Hz, 1H), 2.14 (m, 1H), 1.05 (t, J = 7.9 Hz, 6H); 13C NMR (101 MHz, CDCl3,
ppm): δ = 135.0, 128.8, 128.0, 127.9, 119.8, 45.1, 33.8, 20.8, 18.8; IR (KBr, cmꢀ1): ν =
2926, 2865, 2240, 1723, 1457, 1266, 976, 749, 700; HRMS (ESI) calc. C11H13NNa
[M+Na]+: 182.0940, found: 182.0936.
2-Cyclopropyl-2-phenylacetonitrile (3bq): Yield: 45 mg (57%), yellow oil. 1H NMR
(400 MHz, CDCl3, ppm): δ = 7.39 (d, J = 4.1 Hz, 5H), 3.50 (d, J = 7.5 Hz, 1H), 1.28
(m, 1H), 0.70 (m, 2H), 0.52 (m, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ = 135.6,
129.0, 128.2, 127.4, 119.8, 41.0, 15.5, 4.8, 3.9; IR (KBr, cmꢀ1): ν = 3017, 2923, 2241,
1725, 1454, 1280, 1021, 743, 698; HRMS (ESI) calc. C11H11NNa [M+Na]+: 180.0784,
found: 180.0782.
2-Phenylpentanenitrile (3br): Yield: 64 mg (81%), yellow oil. 1H NMR (400 MHz,
CDCl3, ppm): δ = 7.36 (d, J = 6.7 Hz, 2H), 7.31 (t, J = 7.2 Hz, 3H), 3.78 (t, J = 7.4 Hz,
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H), 1.87 (m, 2H), 1.51 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3,
ppm): δ =136.1, 129.0, 128.0, 127.2, 120.9, 37.9, 37.2, 20.3, 13.4; IR (KBr, cmꢀ1): ν =
3035, 2955, 2871, 2240, 1682, 1456, 1380, 753, 699; HRMS (ESI) calc. C11H13NNa
[M+Na]+: 182.0940, found: 182.0939.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2,3-Dihydro-1H-indene-1-carbonitrile (3bs): Yield: 51 mg (72%), yellow oil. H
NMR (400 MHz, CDCl3, ppm): δ = 7.42 (d, J = 5.3 Hz, 1H), 7.26 (s, 3H), 4.09 (t, J =
8.1 Hz, 1H), 3.08 (m, 1H), 2.96 (m, 1H), 2.57 (ddd, J = 11.8, 8.2, 3.7 Hz, 1H), 2.36
(m, 1H); 13C NMR (101 MHz, CDCl3, ppm): δ = 142.9, 137.6, 128.6, 127.3, 125.0,
124.3, 121.1, 34.5, 31.4, 31.2; IR (KBr, cmꢀ1): ν = 3035, 2940, 2858, 2240, 1609,
1466, 1317, 1147, 753; HRMS (ESI) calc. C10H9NNa [M+Na]+: 166.0627, found:
166.0623.
1,2,3,4-Tetrahydronaphthalene-1-carbonitrile (3bt): Yield: 63 mg (80%), yellow
oil. 1H NMR (400 MHz, CDCl3, ppm): δ = 7.35 (d, J = 6.7 Hz, 1H), 7.20 (dd, J = 5.4,
3.1 Hz, 2H), 7.11 (d, J = 6.5 Hz, 1H), 3.96 (t, J = 6.2 Hz, 1H), 2.82 (dt, J = 14.1, 8.4
Hz, 2H), 2.13 (m, 2H), 2.03 (m, 1H), 1.84 (d, J = 5.9 Hz, 1H); 13C NMR (101 MHz,
CDCl3, ppm): δ = 136.4, 129.9, 129.8, 128.8, 128.0, 126.6, 121.8, 30.8, 28.4, 27.4,
20.8; IR (KBr, cmꢀ1): ν = 3024, 2938, 2238, 1688, 1448, 1283, 739; HRMS (ESI) calc.
C11H12N [M+H]+: 158.0970, found: 158.0962.
1
Chroman-4-carbonitrile (3bu): Yield: 67 mg (85%), yellowishꢀgreen oil. H NMR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
5
6
7
8
9
(400 MHz, CDCl3, ppm): δ = 7.29 (d, J = 7.7 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.95 (t,
J = 7.5 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.34 (m, 1H), 4.23 (m, 1H), 4.03 (t, J = 6.0
Hz, 1H), 2.34 (dd, J = 10.3, 5.8 Hz, 2H); 13C NMR (101 MHz, CDCl3, ppm): δ =
154.0, 129.9, 129.4, 121.2, 120.5, 117.8, 115.2, 63.6, 26.9, 26.1; IR (KBr, cmꢀ1): ν =
3889, 3746, 3557, 3208, 2922, 2856, 1646, 1477, 1227, 754; HRMS (ESI) calc.
C10H10NO [M+H]+: 160.0762, found: 160.0766.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Methyl-4-phenylbutanenitrile (3bv): Yield: 60 mg (76%), yellow oil. 1H NMR
(400 MHz, CDCl3, ppm): δ = 7.31 (m, 2H), 7.22 (m, 3H), 2.87 (ddd, J = 14.2, 9.0, 5.5
Hz, 1H), 2.75 (m, 1H), 2.58 (m, 1H), 1.95 (ddd, J = 14.5, 8.6, 4.5 Hz, 1H), 1.84 (m,
1H), 1.33 (d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3, ppm): δ = 140.2, 128.6,
128.4, 126.4, 122.8, 35.8, 33.2, 24.8, 18.0; IR (KBr, cmꢀ1): ν = 3337, 3190, 2922,
2856, 1730, 1464, 1272, 743; HRMS (ESI) calc. C11H13NNa [M+Na]+: 182.0940,
found: 182.0936.
4,4-Dimethylcyclohex-2-enecarbonitrile (3bw): Yield: 42 mg (62%), yellow oil. 1H
NMR (400 MHz, CDCl3, ppm): δ = 6.56 (dq, J = 5.8, 1.8 Hz, 1H), 2.24 (ddd, J = 8.9,
3.8, 2.4 Hz, 2H), 1.96 (dd, J = 6.5, 2.8 Hz, 2H), 1.43 (t, J = 6.4 Hz, 2H), 0.93 (s, 6H);
13C NMR (101 MHz, CDCl3, ppm): δ = 144.3, 119.7, 111.3, 39.4, 34.1, 29.7, 28.0,
28.0, 24.5; IR (KBr, cmꢀ1): ν = 2930, 2661, 2222, 1762, 1454, 1249, 1035, 753;
HRMS (ESI) calc. C9H13NNa [M+Na]+: 158.0940, found: 158.0952.
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Acknowledgements
7
8
9
The authors are grateful to the National Key Research and Development Program of
China (2016YFA0602900), the National Natural Science Foundation of China
(21672072 and 21420102003), and the Fundamental Research Funds for the Central
Universities (2015ZY001 and 2017ZD0063) for financial support.
Supporting Information
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Characterization data of the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
Reference
(1) (a) Li, D.; Zhan, P.; Clercq, E. D.; Liu, X. J. Med. Chem. 2012, 55, 3595. (b)
Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J. Med. Chem. 2010,
53, 7902. (c). MacFaul, P. A.; Morley, A. D.; Crawford, J. J. Bioorg. Med. Chem. Lett.
2009, 19, 1136.
(2) (a) Kukushkin, V. Y.; Pombeiro, A. J. L. Inorganica Chimica Acta. 2005, 358, 1.
(b) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002, 102, 1771.
(3) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824.
(4) Allegretti, M.; Bertini, R.; Cesta, M. C.; Bizzarri, C.; Bitondo, R. D.; Cioccio, V.
D.; Galliera, E.; Berdini, V.; Topai, A.; Zampella, G.; Russo, V.; Bello, N. D.; Nano, G.;
Nicolini, L.; Locati, M.; Fantucci, P.; Florio, S.; Colotta, F. J. Med. Chem. 2005, 48,
4312.
(5) Chen, G.; Wang, Z.; Wu, J.; Ding, K. Org. Lett. 2008, 10, 4573.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
5
6
7
8
9
(6) (a) Zhang, A.; Neumeyer, J. L. Org. Lett. 2003, 5, 201. (b) Iranpoor, N.;
Firouzabadi, H.; Akhlaghinia, B.; Nowrouzi, N. J. Org. Chem. 2004, 69, 2562. (c)
Soli, E. D.; Manoso, A. S.; Patterson, M. C.; DeShong, P. J. Org. Chem. 1999, 64,
3171.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) (a) Yoshida, H.; Fujimura, Y.; Yuzawa, H.; Kumagai, J.; Yoshida, T. Chem.
Commun. 2013, 49, 3793. (b) Kurz, M. E.; Lapin, S. C.; Mariam, K.; Hagen, T. J.;
Qian, X. Q. J. Org. Chem. 1984, 49, 2728.
(8) (a) Stazi, F.; Maton, W.; Castoldi, D.; Westerduin, P.; Curcuruto, O.; Bacchi, S.
Synthesis 2010, 3332. (b) Kuo, C.ꢀW.; Zhu, J.ꢀL.; Wu, J.ꢀD.; Chu, C.ꢀM.; Yao, C.ꢀF.;
Shia, K.ꢀS. Chem. Commun. 2007, 301.
(9) (a) Fang, X.; Yu, P.; Morandi, B. Science 2016, 351, 832. (b) Falk, A.; Göderz,
A.ꢀL.; Schmalz, H.ꢀG. Angew. Chem. Int. Ed. 2013, 52, 1576. (c) Greef, M.; Breit, B.;
Angew. Chem. Int. Ed. 2009, 48, 551. (d) Gaspar, B.; Carreira, E. M. Angew. Chem.
Int. Ed. 2007, 46, 4519.
(10) (a) Hamachi, Y.; Katano, M.; Ogiwara, Y.; Sakai, N. Org. Lett. 2016, 18, 1634.
(b) Fukumoto, Y.; Dohi, T.; Masaoka, H.; Chatani, N.; Murai, S. Organometallics
2002, 21, 3846.
(11) (a) LindsayꢀScott, P. J.; Clarke, A.; Richardson, J. Org. Lett. 2015, 17, 476. (b)
Dunn, J. M. M. C.; Kuethe, J. T.; Orr, R. K.; Tudge, M.; Campeau, L.ꢀC. Org. Lett.
2014, 16, 6314. (c) Shang, R.; Ji, D.ꢀS.; Chu, L.; Fu, Y.; Liu, L. Angew. Chem. Int. Ed.
2011, 50, 4470. (d) Yeung, P. Y.; Chung, K. H.; Kwong, F. Y. Org. Lett. 2011, 13,
2912. (e) You, J.; Verkade, J. G. Angew. Chem. Int. Ed. 2003, 42, 5051. (f) You, J.;
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Verkade, J. G. J. Org. Chem. 2003, 68, 8003. (g) Culkin, D. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 9330.
7
8
9
(12) Mermerian, A. H.; Fu, G. C. Angew. Chem. Int. Ed. 2005, 44, 949.
(13) Zhang, W.; Wang, F.; MeCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G.
Science 2016, 353, 1014.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) Castanheiro, T.; Suffert, J.; Donnard, M.; Gulea, M. Chem. Soc. Rev. 2016, 45,
494.
(15) (a) Chen, B.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Org. Lett. 2015, 17, 4698. (b)
Yang, H.; Duan, X.ꢀH. Zhao, J.ꢀF. Guo, L.ꢀN. Org. Lett. 2015, 17, 1998.
(16) (a) Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen, L. J. Angew. Chem. Int.
Ed. 2015, 54, 5753. (b) Wang, F.; Chen, C.; Deng, G.; Xi, C. J. Org. Chem. 2012, 77,
4148. (c) Ke, F.; Qu, Y.; Jiang, Z.; Li, Z.; Wu, D.; Zhou, X. Org. Lett. 2011, 13, 454.
(17) Zhang, G.ꢀY.; Yu, J.ꢀT.; Hu, M.ꢀL.; Cheng, J. J. Org. Chem. 2013, 78, 2710.
(18) Wagner, A.; Ofial, A. R. J. Org. Chem. 2015, 80, 2848.
(19) (a) Chung, J.; Wood, J. L. J. Biol. Chem. 1971, 246, 555. (b) Adak, S.;
Mazumdar, A.; Banerjee, R. K. J. Biol. Chem. 1997, 272, 11049. (c) Pintus, F.; Spano,
̀
D.; Belleli, A.; Angelucci, F.; Scorciapino, A. M.; Anedda, R.; Medda, R.; Floris, G.
Biochemistry 2010, 49, 8739.
(20) (a) Stanković, S.; and Espenson, J. H. Chem. Commun. 1998, 1579. (b)
Fernández, R.; Gasch, C.; Lassaletta, J.ꢀM.; Liera, J.ꢀM.; Vázquez, J. Tetrahedron Lett.
1993, 34, 141. (c) Saito, K.; Kagabu, S.; Horie, Y.; Takahashi, K.OPPI BRIEFS. 1989,
21, 354. (d) Jiricny, J.; M. Orere, D.; B. Reese, C. J. C. S. Perkin I, 1980, 1487.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
5
6
7
8
9
(21) (a) Hu, M.; Rong, J.; Miao, W.; Ni, C.; Han, Y.; Hu, J. Org. Lett. 2014, 16,
2030. (b) Lefebvre, Q.; Fava, E.; Nikolaienko, P.; Rueping, M.; Chem. Commun. 2014,
50, 6617. (c) Wang, X.; Zhou, Y.; Ji, G.; Wu, G.; Li, M.; Zhang, Y.; Wang, J. Eur. J.
Org. Chem. 2014, 3093. (d) Hu, M.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2012, 134,
15257.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(22) (a) Huang, Y.; Li, X.; Yu, Y.; Zhu, C.; Wu, W.; Jiang, H. J. Org. Chem. 2016, 81,
5014. (b) Li, X.; Liu, X.; Chen, H.; Wu, W.; Qi, C.; Jiang, H. Angew. Chem. Int. Ed.
2014, 53, 14485.
(23) (a) Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen, L. J. Angew. Chem. Int.
Ed. 2015, 54, 5753. (b) Billard, T.; Large, S.; Langlois, B. R. Tetrahedron Lett. l997,
38, 65.
(24) (a) Xiao, Q.; Ling, L.; Ye, F.; Tan, R.; Tian, L.; Zhang, Y.; Li, Y.; Wang, J. J.
Org. Chem. 2013, 78, 3879. (b) Ye, F.; Ma, X.; Xiao, Q.; Li, H.; Zhang, Y.; Wang, J. J.
Am. Chem. Soc. 2012, 134, 5742.
ACS Paragon Plus Environment