Photoinduced direct cyanation of C(sp3)-H bonds

Article abstract of DOI:10.1055/s-0032-1318325

A general and practical synthetic protocol for the direct transformation of unreactive C(sp³)-H bonds to C(sp³)-CN bonds has been developed. The homolytic cleavage of the C-H bond is initiated by photo-excited benzophenone, and the resulting carbon radical subsequently reacts with tosyl cyanide to afford the corresponding nitrile in a highly efficient manner. The present methodology is widely applicable to various starting materials including ethers, alcohols, amine derivatives, alkanes, and alkylbenzenes. This newly developed C-H cyanation protocol provides a powerful tool for selective one-carbon elongation for the construction of architecturally complex molecules. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318325

874▌
FEATURE ARTICLE
3
feature article
Photoinduced Direct Cyanation of C(sp )–H Bonds
Direct Cyanation of C(sp3)–H Bonds
Tamaki Hoshikawa, Shun Yoshioka, Shin Kamijo,1 Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58410568; E-mail: inoue@mol.f.u-tokyo.ac.jp
Received: 19.12.2012; Accepted after revision: 08.02.2013
for the introduction of cyano groups have been developed
to date, methods for the direct conversion of an unreactive
C(sp3)–H bond into a C(sp3)–CN bond are still limited.9
Abstract: A general and practical synthetic protocol for the direct
transformation of unreactive C(sp3)–H bonds to C(sp3)–CN bonds
has been developed. The homolytic cleavage of the C–H bond is ini-
tiated by photo-excited benzophenone, and the resulting carbon rad-
ical subsequently reacts with tosyl cyanide to afford the
corresponding nitrile in a highly efficient manner. The present
methodology is widely applicable to various starting materials in-
cluding ethers, alcohols, amine derivatives, alkanes, and alkylben-
zenes. This newly developed C–H cyanation protocol provides a
powerful tool for selective one-carbon elongation for the construc-
tion of architecturally complex molecules.
We recently found that a combination of benzophenone
and tosyl cyanide can effectively convert C(sp3)–H bonds
in a variety of compounds into C(sp3)–CN bonds under
photoirradiation conditions (Scheme 1).10 The present cy-
anation is applicable to a broad range of substrates 1; al-
kanes, alkylbenzenes, ethers, alcohols, and amine
derivatives are all converted in a highly chemoselective
manner into the corresponding nitriles 2 in good to excel-
lent yields. In this article, we report the full details of our
simple, yet powerful, protocol for the direct cyanation of
C(sp3)–H bonds.11
Key words: radical reaction, nitriles, photochemistry, cyanation,
C–H functionalizations
Introduction
H
CN
hν, TsCN, Ph2C=O
R1
XR2
R1
XR2
The carbon–carbon (C–C) bond forming reaction is one of
the most important transformations in synthetic organic
chemistry. The direct transformation of C–H bonds to C–
C bonds has attracted particularly intense interest in recent
years, because it avoids prior functional group manipula-
tions for the activation of the substrate and thus greatly
simplifies synthetic schemes. Among such reactions, the
functionalization of unreactive C(sp3)–H bonds is espe-
cially advantageous for the construction of highly com-
plex natural products, which generally contain a high
proportion of sp3-hybridized carbon centers.2 Develop-
ment of this extremely useful reaction has, however, re-
mained challenging largely due to the lack of general
strategies for functionalizing inert C(sp3)–H bonds in
comparison to the methods available for functionalization
of the C(sp2)–H bonds of aromatic compounds.3,4 For this
reason, we undertook a research program to develop a
new strategy for the direct transformation of C(sp3)–H
bonds to C(sp3)–C bonds.
C–H cyanation
1
2
X = O, NH, CH2
Scheme 1 Direct photochemical transformation of a C(sp3)–H bond
to a C(sp3)–CN bond
Direct C–H Cyanation of Ethers and Alcohols
We began our investigations into direct C–H cyanation
using saturated ethers as the starting materials, since the
electron-rich ethereal C–H bonds showed relatively high
reactivities toward direct functionalization in our previous
studies.5 From among the saturated ethers, we selected
1,4-dioxane (1a) for the purpose of an initial screening to
establish the optimal photochemical conditions. Although
the C–H bonds of 1a are not as reactive as those of other
cyclic ethers such as tetrahydrofuran and tetrahydropy-
ran,12 the presence of four equivalent methylene units in
1a was expected to simplify the analysis of the experi-
mental results.
We have been particularly interested in the introduction of
highly oxidized carbon units, since such groups can be
universally utilized as a versatile handle for further carbon
elongations or for various standard functional group ma-
nipulations.5 Accordingly, the cyano group was selected
as a versatile one-carbon unit.6 Aside from its utility in or-
ganic synthesis, the cyano group is a component function-
al group of numerous natural products7 and
pharmaceutical agents.8 Although many efficient methods
First, 1a together with various cyanide sources was mixed
with benzophenone in benzene and irradiated with a me-
dium pressure mercury lamp. While cyanogen bro-
mide,9a,b trichloroacetonitrile, methyl cyanoformate,9f,13
or diethyl cyanophosphonate14 did not function as cyanide
donors, the use of tosyl cyanide did result in efficient cy-
anation of the C–H bond of 1a.15 Namely, a reagent com-
bination of tosyl cyanide (1 equiv) and benzophenone (1
equiv) was found to promote the conversion of 1a (8
equiv) into nitrile 2a in benzene after six hours (74%
yield, Table 1, entry 1). Under these conditions, recovery
of benzophenone (59%) and formation of benzopinacol
SYNTHESIS 2013, 45, 0874–0887
Advanced online publication: 21.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318325; Art ID: SS-2012-Z0984-FA
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Direct Cyanation of C(sp3)–H Bonds
875
(1,1,2,2-tetraphenylethane-1,2-diol) were observed in ad- amount of tosyl cyanide was recovered (entry 4), indicat-
dition to formation of 2a. While the transformation of 1a ing that the photo-excited benzophenone functions as the
to 2a was not accelerated by employing increased hydrogen abstraction agent. A notable retardation of the
amounts of benzophenone (2 equiv, entry 2), the use of a reaction and a decrease in the yield were observed upon
reduced amount of benzophenone (0.5 equiv, entry 3) reducing the amount of 1a (2 equiv, entry 5). On the other
slightly lowered the yield of 2a. In the absence of benzo- hand, when 1a was employed as the solvent, the cyanation
phenone, no product was formed, and a significant reaction was complete within one hour and gave 2a in
Biographical Sketches█
Tamaki Hoshikawa was kyo in 2008. He is currently development of direct trans-
born in 1985 in Shenyang, carrying out his Ph.D. stud- formations of unreactive
China, and raised in ies under the guidance of chemical bonds and their
Kanagawa, Japan. He re- Prof. M. Inoue at the same applications to organic syn-
ceived his bachelor degree university. At present, his theses.
from the University of To- research is focused on the
Shun Yoshioka was born in rently studying for a mas- focused on the development
1990 in Kyoto, Japan. He ter’s degree under the of new reactions for synthe-
received his bachelor’s de- guidance of Professor M. ses of highly functionalized
gree from the University of Inoue at the same universi- organic molecules.
Tokyo in 2012. He is cur- ty. His current research is
Shin Kamijo was born in with Prof. G. B. Dudley at uate School of Science and
1973 in Yamaguchi, Japan. Florida State University Engineering,
Yamaguchi
He received his B.Sc. (2004–2006) and one year University as an Associate
(1997) and Ph.D. (2002) de- as a Postdoctoral Associate Professor. His research in-
grees from Tohoku Univer- with Prof. M. Shibasaki at terests focus on methodolo-
sity under the supervision of The University of Tokyo gy developments involving
Prof. Y. Yamamoto. He was (2006–2007), he joined the activation and functional-
then appointed as a Re- research group of Prof. M. ization of unreactive bonds
search Associate in the same Inoue at The University of and their utilizations in or-
group (2002–2004). After Tokyo as an Assistant Pro- ganic synthesis.
spending two years as a fessor (2007–2012). In
JSPS Postdoctoral Fellow 2012, he moved to the Grad-
Masayuki Inoue was born hoku University as an assis- Banyu Lectureship Award
in 1971 in Tokyo, Japan. He tant professor in the (2004), The Chemical Soci-
received a B.Sc. degree in research group of Prof. M. ety of Japan Award for
chemistry from the Univer- Hirama. At Tohoku Univer- Young Chemists (2004), the
sity of Tokyo in 1993. In sity, he was promoted to as- Thieme Journal Award
1998, he obtained his Ph.D. sociate professor in 2004. 2005, the Novartis Lecture-
from the same university, He concurrently served as a ship 2008/2009, and the 5th
working under the supervi- PRESTO researcher of the JSPS Prize (2009). His re-
sion of Profs. K. Tachibana Japan Science and Technol- search interests include the
and M. Sasaki. After spend- ogy Agency (2005–2008). synthesis, design, and study
ing two years with Prof. S. J. In 2007, he moved to the of biologically important
Danishefsky at the Sloan- Graduate School of Pharma- molecules, with particular
Kettering Institute for Can- ceutical Sciences, Universi- emphasis on the total syn-
cer Research (1998–2000), ty of Tokyo as a full thesis of structurally com-
he joined the Graduate professor. He has been hon- plex natural products.
School of Science at To- ored with the First Merck-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 874–887

876
T. Hoshikawa et al.
FEATURE ARTICLE
Table 1 Optimization of Cyanation Conditionsa
hν, Ph2C=O
TsCN (1 equiv)
O
O
solvent (0.04 M)
r.t.
O
O
CN
1a (8 equiv)
2a
Entry
Solvent
Equiv of benzophenone Time (h)
Yieldb (%) of 2a
Recovery (%) of benzophenone
1
benzene
benzene
benzene
benzene
benzene
dioxane
MeCN
1
6
6
74c
80
59
66
<4
–
2
2
3
0.5
0
12
12
24
1
64c
0d
4
5e
6f
7
1
46
48
90
87
<5
88
1
85
1
6
72 (63)c,g
63
8
t-BuOH
MeCN
1
18
6
9
0.5
74
a Reaction conditions: 1a/TsCN (8:1), solvent (0.04 M), r.t., hν.
b Yield was determined by NMR analysis of the crude mixture; the isolated yield is shown in parentheses.
c TsCN was recovered in ca. 10% yield.
d TsCN was recovered in 83% yield.
e The reaction was performed using 1a (2 equiv). Recovery of TsCN (21%) was observed after the reaction.
f Dioxane 1a was employed as a solvent; 1a/TsCN (~300:1).
g Due to its volatile nature, the isolated yield of 2a was lower than that indicated by NMR analysis.
85% yield (entry 6). The reaction also proceeded in both C–H bonds adjacent to oxygen-based functionalities (Ta-
aprotic and protic polar solvents, such as acetonitrile (en- ble 2). The cyanation of tetrahydrofuran (1b) proceeded
try 7) and tert-butyl alcohol (entry 8). Judging from the readily and nitrile 2b18 was formed in three hours (entry
high yield of 2a and the high recovery of benzophenone 2). When the ester-attached cyclic ether 1c was subjected
even upon using a catalytic amount of benzophenone (en- to the same conditions, the O-substituted methylene car-
try 9), acetonitrile appeared to be the most favorable sol- bon was selectively cyanated to give nitrile 2c (entry 3).
vent for the transformation.
O
The present photoinduced C–H cyanation of 1,4-dioxane
(1a) to the nitrile product 2a is considered to consist of a
Ph
Ph
sequence of radical reactions (Scheme 2). Electrophilic
oxyl radical A, photochemically generated from benzo-
phenone, abstracts hydrogen from the electron-rich ethe-
real C(sp3)–H bond of 1a to furnish carbon radicals B and
C.16 Subsequently, although there are several potentially
reactive species present, the nucleophilic α-alkoxy radical
C selectively reacts with tosyl cyanide, which is both elec-
tron-deficient and the radical acceptor with the least steric
hindrance. This reaction leads to nitrile 2a with concur-
rent expulsion of sulfonyl radical D.17 If D then abstracts
the hydrogen from ketyl radical B, it regenerates benzo-
phenone to provide sulfinic acid F. It is also possible,
however, for the ketyl radical B to dimerize to afford ben-
zopinacol E. Noteworthily, high yielding transformation
from 1a to 2a (Table 1, entry 7) indicates that all the reac-
tive radical species A, B, C, and D properly follow the se-
ries of these reactions.
hν
O
O
S
Tol
C
N
O
Ph
Ph
O
A
O
O
O
O
O
CN
H
O
2a
1a
C
OH
O
S
Tol
Ph
Ph
D
B
HO
Ph
OH
O
O
S
Ph
Ph
Ph
Ph Tol
OH
Ph
E
F
Having successfully determined the optimal reaction con-
ditions for C–H cyanation, we next investigated the che-
moselective transformation of a variety of electron-rich
Scheme 2 Proposed mechanism for transformation of C(sp3)–H
bonds to C(sp3)–CN bonds
Synthesis 2013, 45, 874–887
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Direct Cyanation of C(sp3)–H Bonds
877
In contrast to the results typically observed with base- 1c was functionalized in this case, demonstrating the
induced C–C bond formation, the less acidic position of unique chemoselectivity of the present reaction.
Table 2 C–H Cyanation Adjacent to Oxygen-Based Functionalitiesa
Entry
Starting material
Time (h)
Product
Yieldb (%)
63 (72)
O
O
1
6
O
O
CN
CN
2a
1a
O
O
2
3
3
(92)
80c
1b
2b
MeO2C
CN
MeO2C
O
O
10
1c
2c
CN
O
O
4d
10
91
84
1d
2d
CN
O
O
O
O
O
O
O
5
3
O
O
O
1e
2e
CN
O
H
O
H
6
2
24
89e
71e
7f
H
H
1f
2f
O
O
O
O
8g
1
84
CN
1g
1h
1i
2g
OH
OH
4
2
9
3
72
97
3
1
CN
2h
OH
O
CN
10
10
2i
a Reaction conditions: 1/TsCN/benzophenone (8:1:1), MeCN (0.04 M), r.t., hν.
b Isolated yield; NMR yield is shown in parentheses.
c Mixture of diastereomers (dr 9:2).
d Benzene was employed as a solvent instead of MeCN.
e Mixture of diastereomers (dr 4:3).
f Reaction conditions: 1f/TsCN/benzophenone (1:4:1).
g The reaction was conducted using 2,6-di-tert-butylpyridine (2 equiv).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 874–887

878
T. Hoshikawa et al.
FEATURE ARTICLE
Phthalan (1d) gave the corresponding benzyl cyanide 2d the most useful methods for the preparation of α-amino ni-
in 91% yield (entry 4), and monocyanation occurred ex- trile derivatives from the corresponding imines.22 After
clusively in the case of 15-crown-5 ether (1e), despite the having established a direct method for the synthesis of α-
presence of many potentially reactive ethereal C–H bonds oxy nitriles, we envisaged that the same radical-based C–
(entry 5). Cyanation of structurally complex (–)-ambrox- H cyanation process would allow the direct synthesis of α-
ide (1f) exhibited high chemoselectivity at the ethereal C– amino nitriles from readily available amine derivatives.
H bond, giving the corresponding nitrile 2f in 89% yield
without affecting the other aliphatic methylene and me-
thine C–H bonds (entry 6). As shown in entry 7, only a
The reaction conditions for the C–H cyanation of amine
derivatives were first re-optimized using Boc-protected
azepane 3a (Table 3). The reaction between 3a and tosyl
slight decrease in yield (71%) was observed even upon
cyanide (8:1) under the same conditions used for the
treating a limited amount of 1f (1 equiv) with excess tosyl
ethers proceeded via the chemoselective hydrogen ab-
straction of the electron-rich N-substituted methylene,
leading to the corresponding nitrile 4a in 85% yield (entry
cyanide (4 equiv). When the acetal-protected cis-1,2-diol
1g was subjected to the reaction in the presence of two
equivalents of 2,6-di-tert-butylpyridine (acting as an acid
1). The high efficiency of this transformation from 3a to
scavenger of sulfinic acid), cis-fused nitrile 2g was ob-
4a prompted us to reduce the ratio of the starting material
3a to tosyl cyanide. However, modifying this ratio from
8:1 to 1:2 without altering any other factors resulted in a
tained in 84% yield as the sole isomer (entry 8).19 This re-
action, therefore, allowed the stereoselective formation of
the hindered tetrasubstituted carbon center of 2g in a sin-
low yield of the desired product 4a (17%, entry 2). As this
gle step.
disappointing result was attributed to removal of the Boc
group by sulfinic acid generated in situ, we examined the
addition of 2,6-di-tert-butylpyridine as an acid scavenger
OH
hν, Ph2C=O, TsCN
O
(entries 3–5). Through varying the amounts of the base,
the addition of four equivalents was found to be optimal
in terms of the product yield (78%, entry 4). It also should
CN
1i
2i
Table 3 Optimization of Cyanation Conditions for C–H Bonds Ad-
OH
jacent to Nitrogen-Based Functionalitiesa
OH
hν, Ph2C=O
TsCN (2 equiv)
2,6-di(tert-butyl)pyridine
H
G
N
N
CN
MeCN (0.04 M)
r.t., time
Scheme 3 Ring-opening reaction from 1i to 2i
Boc
Boc
3a (1 equiv)
4a
Unprotected alcohols were also directly functionalized
under the same conditions. While the C–H bond adjacent
to the primary hydroxy group of 1h was chemoselectively
cyanated to afford cyanohydrin 2h (entry 9), treatment of
1-cyclopropylethanol (1i) under the same conditions
quantitatively furnished 5-oxohexanenitrile (2i) (entry
10). As shown in Scheme 3, this transformation proceeded
via ring opening of the cyclopropane of secondary radical
G and subsequent CN trapping by the primary carbon rad-
ical H.20 The formation of 2i therefore provides evidence
of the involvement of the α-oxy radical intermediate dur-
ing this reaction.
Entry Equiv
Time (h) Yieldb (%)
Benzophenone 2,6-Di-tert-butylpyridine
1c
2
1
–
–
2
4
8
4
4
4
4
6
95 (85)
17
1
4.5
3
1
15
58
4
1
10
9
83 (78)
84 (83)
80
5d
6
1
0.5
0.2
0.5e
0.5f
5
Here direct C–H cyanation of various ethers and alcohols
was achieved. The cyanation occurred chemoselectively
at the C(sp3)–H bonds adjacent to oxygen atoms with no
reactions at the aliphatic methylene and methine C–H
bonds in the same molecule.
7
8
85 (79)
77
8
24
24
9
74
a Reaction conditions: 3a/TsCN/benzophenone (1:2:1), MeCN (0.04
M), r.t., hν.
b Yield was determined by NMR analysis of the crude mixture; the iso-
lated yield is shown in parentheses.
Direct C–H Cyanation of Amine Derivatives
c 3a/TsCN/benzophenone (8:1:1).
α-Amino nitriles play an important role in organic chem-
istry, especially as the synthetic equivalents of α-amino
acids.21 In addition, several pharmaceutical agents con-
taining α-amino nitrile moieties have recently been de-
signed and manufactured.8 The Strecker reaction is one of
d The reaction was conducted using TsCN (4 equiv).
e The reaction was conducted using 4,4′-dimethoxybenzophenone in-
stead of benzophenone.
f The reaction was conducted using xanthone instead of benzophe-
none.
Synthesis 2013, 45, 874–887
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Direct Cyanation of C(sp3)–H Bonds
879
be noted that a second cyanation of 4a did not take place Direct cyanation of the methylene carbons of acyclic car-
upon use of two equivalents of tosyl cyanide, reflecting bamate derivatives 3o–q was also achieved even when ap-
the relatively low reactivity of the N-substituted methy- plying conditions B (entries 20–23). The α-amino positions
lene of the cyanated product 4a. Even when the amount of in each of these linear and branched carbon chains were
benzophenone was reduced from one equivalent (entry 4) chemoselectively functionalized to generate the amino
to 0.5 or 0.2 equivalents (entries 6 and 7), the cyanation of acid derivatives 4o–q. When the starting materials pos-
3a in the presence of the base proceeded efficiently with sessed asymmetric carbons (entries 24–27), acyclic carba-
high yields, demonstrating the robustness of the present mates 4r and 4s were obtained as approximately 1:1
procedure. Interestingly, other oxyl radical precursors, diastereomeric mixtures.
4,4′-dimethoxybenzophenone (entry 8) and xanthone (en-
try 9) required longer reaction times and gave the product
in somewhat lower yields.
The results presented thus far confirm that the present pro-
tocol is capable of direct cyanation of the N-substituted
methylene and methine carbons within both cyclic and
To explore the applicability, we next examined the cyana- acyclic structures in a highly efficient fashion, even when
tion of a variety of nitrogen-containing substrates (Table the starting materials are present as the limiting reagent.
4); this was done by applying the two optimized condi- Since the generated N-protected α-amino nitriles serve as
tions in Table 3: conditions A (entry 1, 3/TsCN/benzophe- the synthetic equivalents of α-amino acids, this methodol-
none, 8:1:1) and conditions B (entry 4, 3/TsCN/benzo- ogy provides an expeditious way to access natural and ar-
phenone/2,6-di-tert-butylpyridine, 1:2:1:4). Under both tificial α-amino acids starting from readily available
of these conditions, Boc-protected pyrrolidine 3b and pi- amine derivatives.
peridine 3c were cyanated to give the corresponding ni-
triles 4b and 4c in high yields (entries 3–6). In the case of
Table 4 C–H Cyanation Adjacent to Nitrogen-Based Functionalitiesa
N-Boc-morpholine 3d, C–H cyanation chemoselectively
occurred at the methylene proximal to the nitrogen atom,
and nitrile 4d was produced in 70% yield (entry 7). This
result indicates that the C–H bond adjacent to the nitrogen
atom is more reactive than that next to oxygen. Cyclic car-
bamates 3e and 3f were stereoselectively converted into
trans-substituted nitriles 4e and 4f, respectively (entries
8–10). Similarly, cyanation of Boc-protected L-proline
derivative 3g afforded trans-substituted nitrile 4g in a
completely stereoselective fashion (entries 11 and 12).
The stereochemistry of the ester-attached carbon center in
4g was retained, showing that the C–H bond adjacent to
the electron-withdrawing group was resistant to hydrogen
abstraction.23
Entry Starting
materials
Conditions, Product
time
Yieldb
(%)
1
2
A, 6 h
B, 10 h
85
78
N
N
CN
CN
Boc
Boc
3a
4a
N
N
3
A, 2 h
94
86
4c
B, 8 h
Boc
Boc
3b
4b
The effect of varying the substituent on the nitrogen atom
was examined using several N-protected azepane deriva-
tives. Similarly to Boc-protected 3a (entry 2), Troc-pro-
tected 3h, and Ac-protected 3i were successfully
transformed to their corresponding nitriles 4h (entry 13)
and 4i (entry 14), respectively. Whereas the Ts-protected
amine 3j gave the cyanated product 4j (entry 15), the 4-
nitrophenylsulfonyl (Ns) group of 3k inhibited the reac-
tion, and a significant amount of the starting material 3k
was recovered (entry 16).
5
A, 5 h
B, 10 h
74
69
N
N
CN
CN
6c
Boc
Boc
3c
4c
O
O
N
N
7c
B, 44 h
70
Boc
Boc
3d
3e
4d
Despite the substantial steric hindrance, the cyanation of
several cyclohexane derivatives proceeded smoothly to
introduce the N-substituted tetrasubstituted carbons (en-
tries 17–19). The methine C–H bond of Boc-protected cy-
clohexylamine 3l was chemoselectively functionalized to
provide 4l (entry 17). Monocyanation of cis- and trans-di-
aminocyclohexane derivatives 3m and 3n took place ste-
reoselectively, resulting in the formation of the same cis-
fused bicyclic compound 4m as the sole product (entries
18 and 19). The stereochemical interconversion from the
trans-fused 3n to the cis-fused 4m again supported the in-
volvement of a radical intermediate during the course of
the reaction.
O
O
O
O
83
23
(30)
NH
8
A, 10 h
B, 48 h
NH
9c
CN
4e
O
O
O
O
NH
42
(43)
10c
B, 24 h
NH
t-Bu
t-Bu
CN
3f
4f
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 874–887

880
T. Hoshikawa et al.
FEATURE ARTICLE
Table 4 C–H Cyanation Adjacent to Nitrogen-Based Functionalitiesa
Table 4 C–H Cyanation Adjacent to Nitrogen-Based Functionalitiesa
(continued)
(continued)
Entry Starting
materials
Conditions, Product
time
Yieldb
(%)
Entry Starting
materials
Conditions, Product
time
Yieldb
(%)
NHBoc
73
41
(33)
CO2Me
NC
CO2Me
22
23
A, 12 h
B, 48 h
11
12
N
A, 24 h
B, 48 h
N
91
67
NHBoc
CN
Boc
Boc
3q
3r
4q
3g
4g
H
N
H
N
76
35
(44)
Ph
Boc
24
25
A, 10 h
B, 48 h
Boc
N
N
CN
CN
13
14
15
B, 8 h
75
75
Troc
Troc
4rd
3h
3i
4h
H
N
H
69
44
(31)
Ph
Boc
N
26
27
A, 12 h
B, 48 h
Ph
Boc
CN
N
N
CN
CN
B, 10 h
3s
Ac
4se
Ac
a Conditions A: 3/TsCN/benzophenone (8:1:1), MeCN (0.04 M), r.t.,
hν; Conditions B: 3/TsCN/benzophenone (1:2:1), 2,6-di-tert-butyl-
pyridine (4 equiv), MeCN (0.04 M), r.t., hν.
4i
b Isolated yield; the recovery of starting material 3 is shown in paren-
theses.
30
(24)
N
N
B, 22 h
c The reaction was conducted using benzophenone (0.2 equiv).
d Mixture of diastereomers (dr 1:1).
Ts
Ts
3j
4j
e Mixture of diastereomers (dr 6:5).
0
(61)
N
16
17
18
B, 22 h
B, 48 h
B, 30 h
–
Direct C–H Cyanation of Alkanes and Alkylbenzenes
Ns
Compared with the C–H bonds adjacent to heteroatoms
such as oxygen and nitrogen, the C–H bonds of unfunc-
tionalized alkanes are generally less reactive toward hy-
drogen abstraction by the oxyl radical. In fact, the highly
chemoselective cyanation results presented in Tables 2–4
clearly show the relative inertness of the non-heteroatom
substituted methylene and methine groups. In an attempt
to expand the scope of our newly developed cyanation
protocol, we investigated the functionalization of a num-
ber of unactivated aliphatic and benzylic C–H bonds (Ta-
ble 5).
3k
3l
NHBoc
CN
27
(38)
NHBoc
4l
H
H
N
H
H
N
O
O
O
N
H
43
51
N
H
H
H
NC
H
3m
3n
4m
4m
H
N
As shown in Table 5, treatment of cyclooctane (5a) under
our standard conditions (5/TsCN/benzophenone, 8:1:1)
provided cyclooctanecarbonitrile 6a in 87% yield (entry
1). This result indicated that the present cyanation proto-
col was applicable even to the functionalization of unacti-
vated aliphatic methylene groups, in which the carbon is
not next to oxygen or nitrogen. The cyanations of both ad-
amantane (5b) (entry 2) and its hydroxylated derivative 5c
(entry 3) occurred exclusively at the tertiary C–H bond,
installing the quaternary carbons of 6b and 6c, respective-
ly. The reaction of benzoate 5d also produced nitrile 6d
with the quaternary carbon (entry 4). The evidently great-
er reactivities of the methine C–H bonds in these mole-
cules (entries 2–4), as compared to the methylene C–H
bonds, should originate from their more electron-rich na-
ture. Accordingly, the more substituted tertiary C–H bond
was selectively converted into the C–CN bond in the pres-
H
N
O
19
B, 21 h
N
H
N
H
H
NC
NHBoc
NHBoc
NC
NHBoc
NHBoc
20
21
B, 24 h
B, 48 h
57
55
4
4
3o
4o
N
Boc
N
Boc
CN
3p
4p
Synthesis 2013, 45, 874–887
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Direct Cyanation of C(sp3)–H Bonds
881
ence of primary and secondary C–H bonds, resulting in
selective formation of the sterically encumbered quater-
nary carbon.16
hν, Ph2CO
TsCN, MeCN
r.t., 24 h
OBz
BzCl, pyridine
CH2Cl2
r.t., 3.5 h
CN
OBz
5d
6d
35%
(entry 4, Table 5)
90%
Table 5 C–H Cyanation of Alkanes and Alkylbenzenesa
Entry Starting materials
Time Product
(h)
Yieldb
(%)
OH
1h
4
2
3
1
CN
BzCl, Et3N
DMAP, CH2Cl2
r.t., 1 h
hν, Ph2CO
TsCN, MeCN
r.t., 3 h
1
10
87
82
OH
CN
OBz
2h
7
CN
86%
72%
(entry 9, Table 2)
5a
6a
Scheme 4 Divergent synthesis of functionalized nitriles
CN
CN
2
16
6b
5b
Intriguingly, the cyanated positions of alcohol 2h (Table
2, entry 9) and its benzoylated derivative 6d (Table 5, en-
try 4) were different, demonstrating that the reaction can
be predictably directed to either the α-alkoxy carbon at C1
or the tertiary carbon at C4 simply by detaching or attach-
ing the electron-withdrawing benzoyl group. By applying
these results, the two structural isomers 6d and 7 were
both synthesized from the same starting material 1h by
switching the reaction order of the cyanation and benzo-
ylation (Scheme 4).
OH
OH
3
24
87
5c
6c
CN
OBz
4
2
OBz
3
1
4
24
35c
6d
5d
CN
The reactivity of the benzylic C–H bonds was found to be
higher than that of their aliphatic counterparts (Table 5).
The reaction of butylbenzene (5e) provided benzyl cya-
nide 6e in 41% yield as the sole product (entry 5). Instal-
lation of an electron-donating methoxy group on the
phenyl ring 5f increased the yield (entry 6), and presence
of an electron-withdrawing acetoxy group 5g decreased
the yield (entry 7). The cyanation of ibuprofen methyl es-
ter (5h) occurred on the isobutyl substituent to give benzyl
nitrile 6h as the major product along with its regioisomer
6i (entry 8). This result proved the greater reactivity of the
benzylic C–H bond in comparison to both the aliphatic
tertiary C–H bond and the ester-attached benzylic C–H
bond.
R
R
41
(37)
5d
6d
7d
5e R = H
18
15
18
6e
6f
72
(14)
5f R = OMe
5g R = OAc
27
(55)
6g
CN
45
8d
18
These studies have demonstrated that the direct C–H cya-
nation of both alkanes and alkylbenzenes is possible, thus
enabling the preparation of branched carboskeletons,
whether starting from cyclic or acyclic compounds. The
obtained products would be useful for construction of
more complex structures by taking advantage of the in-
stalled nitrile as a starting point for further functionaliza-
tion.
(27)
CO2Me
CO2Me
5h
6he
CN
10
CO2Me
6i
a Reaction conditions: 5/TsCN/benzophenone (8:1:1), MeCN (0.04
M), r.t., hν.
Conclusion
b Isolated yield; the recovery of TsCN is shown in parentheses.
c Trace amount of product cyanated at the methylene C–H bond was
observed.
In summary, we have developed a new synthetic method-
ology for the direct transformation of C(sp3)–H bonds to
C(sp3)–CN bonds by using a combination of tosyl cyanide
and benzophenone under photoirradiation conditions. The
C–H cyanation proceeds at ambient temperature and is ap-
plicable to various starting materials including ethers, al-
d Benzene was employed as a solvent instead of MeCN.
e Mixtures of diastereomers (dr = 1:1).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 874–887

882
T. Hoshikawa et al.
FEATURE ARTICLE
IR (neat): 2241, 1127, 1103 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.70–3.83 (m, 3 H), 3.87 (d,
J = 3.2 Hz, 2 H), 4.05 (m, 1 H), 4.54 (t, J = 3.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 63.8, 64.5, 66.5, 67.6, 116.1.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C5H7NO2Na: 136.0369;
cohols, amine derivatives, alkanes, and alkylbenzenes. In
general, the cyano group is selectively attached to the car-
bon possessing the most electron-rich C–H bond on the
starting molecular framework. The obtained compounds
possess branched carboskeletons, which are difficult to
make by other reactions. The particularly important fea-
tures of the present methodology include simplicity of the
synthetic technique, predictability in terms of the stereo-
and chemoselectivity, and efficiency in the single-step
construction of hindered tetrasubstituted carbons. Since
the introduced nitrile moiety can be universally utilized as
a versatile handle for further carbon elongations or func-
tional group manipulations, the present C–H cyanation
should serve as a powerful tool for the synthesis of various
natural and artificial amino acids, complex natural prod-
ucts, and molecules of pharmaceutical interest.
found: 136.0344.
Tetrahydrofuran-2-carbonitrile (2b)18
[CAS Reg. No.: 14631-43-7]
Colorless oil; yield: 92% (based on the analysis of crude 1H NMR
spectrum).
1H NMR (400 MHz, CDCl3): δ = 1.95–2.15 (m, 2 H), 2.20–2.30 (m,
2 H), 3.90–4.00 (m, 2 H), 4.68 (dd, J = 5.0, 6.8 Hz, 1 H).
Methyl 5-Cyanotetrahydrofuran-2-carboxylate (2c)
Major Isomer
Yellow oil; yield: 23.6 mg (66%).
IR (neat): 2248, 1743, 1213, 1077 cm–1.
All reactions sensitive to air or moisture were carried out under an
argon atmosphere and in anhydrous conditions unless otherwise
noted. Reagents were used as supplied unless otherwise stated. An-
alytical TLC was performed using E. Merck Silica gel 60 F254 pre-
coated plates. Flash column chromatography was generally per-
formed using 40–50 μm Silicagel 60N (Kanto) or 75 μm Activated
Alumina (Wako). 1H and 13C NMR spectra were recorded on a Jeol
JNM-ECX-500 (500 MHz), JNM-ECA-500 (500 MHz), or a JNM-
ECS-400 (400 MHz) spectrometer with reference to residual sol-
vent signals [1H NMR: CDCl3 (δ = 7.26); 13C NMR: CDCl3 (δ =
77.0)]. IR spectra were recorded on a Jasco FT/IR-4100 spectropho-
tometer. ESI-TOF mass spectra were recorded on a Bruker Dalton-
ics micrOTOF II (HRMS). UV irradiation was carried out by using
a Riko 100 W medium-pressure Hg lamp.
1H NMR (400 MHz, CDCl3): δ = 2.19 (m, 1 H), 2.25–2.50 (m, 3 H),
3.74 (s, 3 H), 4.69 (dd, J = 4.5, 8.3 Hz, 1 H), 4.93 (dd, J = 4.1, 7.8
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.1, 30.6, 52.4, 67.3, 77.5, 118.4,
171.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C7H9NO3Na: 178.0475;
found: 178.0475.
Minor Isomer
Yellow oil; yield: 4.8 mg (14%).
IR (neat): 2242, 1740, 1213, 1081 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.20–2.50 (m, 4 H), 3.80 (s, 3 H),
4.60 (m, 1 H), 4.81 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.5, 31.2, 52.5, 67.3, 78.3, 118.3,
171.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C7H9NO3Na: 178.0475;
found: 178.0478.
Cyclooctanecarbonitrile (6a); Typical Procedure Conditions A
for Direct C–H Cyanation of Ethers, Alcohols, Amine Deriva-
tives, Alkanes, and Alkylbenzenes
To a MeCN (5.5 mL) soln of TsCN (40.4 mg, 223 μmol) in a Pyrex
test tube were added benzophenone (40.6 mg, 223 μmol) and cy-
clooctane (5a, 240 μL, 1.78 mmol) at r.t. The mixture was degassed
by three successive freeze-thaw cycles and purged with argon. The
test tube was placed at 5-cm distance from a UV lamp and it was ir-
radiated (Riko 100-W medium-pressure Hg lamp) at r.t. for 10 h.
The mixture was then treated with sat. aq NaHCO3 and extracted
with Et2O (3 × 20 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated. The residue was pu-
rified with flash column chromatography (hexane–EtOAc, 50:1) to
give 6a; yield: 26.7 mg (87%).
1,3-Dihydroisobenzofuran-1-carbonitrile (2d)24
[CAS Reg. No.: 1246678-37-4]
Colorless oil; yield: 28.7 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 5.17 (d, J = 12.4 Hz, 1 H), 5.30
(dd, J = 2.7, 12.4 Hz, 1 H), 5.92 (d, J = 2.7 Hz, 1 H), 7.31 (d, J = 6.4
Hz, 1 H), 7.35–7.50 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 71.3, 74.2, 117.5, 121.5, 121.8,
128.5, 129.7, 134.0, 138.5.
tert-Butyl 2-Cyanoazepane-1-carboxylate (4a); Typical Proce-
dure Conditions B for Direct C–H Cyanation of Amine Deriva-
tives
1-Cyano-15-crown-5 (2e)
[CAS Reg. No.: 1338695-80-9]
To a MeCN (5.0 mL) soln of tert-butyl azepane-1-carboxylate (3a,
39.9 mg, 200 μmol) in a Pyrex test tube were added benzophenone
(36.4 mg, 200 μmol), 2,6-di(tert-butyl)pyridine (175 μL, 800
μmol), and TsCN (72.5 mg, 400 μmol). The mixture was degassed
by three successive freeze-thaw cycles and purged with argon. The
test tube was placed at 5-cm distance from a UV lamp and it was ir-
radiated (Riko 100-W medium-pressure Hg lamp) at r.t. for 10 h.
The mixture was treated with sat. aq NaHCO3. The mixture was ex-
tracted with EtOAc (3 × 20 mL), washed with brine, dried
(Na2SO4), and concentrated. The residue was purified with flash
column chromatography (hexane–EtOAc 20:1) to give 4a; yield:
35.0 mg (78%).
Colorless oil; yield: 47.3 mg (84%).
IR (neat): 2239, 1126 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.60–3.75 (m, 13 H), 3.78–3.90
(m, 5 H), 4.87 (t, J = 6.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 69.1, 69.3, 70.1, 70.4 (2 ×), 70.5,
70.9, 71.1, 71.6, 71.8, 117.8.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H19NO5Na:
268.1155; found: 268.1152.
Ambroxide-12-carbonitrile (2f)
[CAS Reg. No.: 1338695-82-1]
1,4-Dioxane-2-carbonitrile (2a)
Colorless solid; yield: 51.0 mg (89%); mixture of 2 diastereomers:
ratio 4:5 (1H NMR).
[CAS Reg. No.: 14717-00-1]
Colorless oil; yield: 16.4 mg (63%).
Synthesis 2013, 45, 874–887
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Direct Cyanation of C(sp3)–H Bonds
883
1H NMR (400 MHz, CDCl3): δ = 0.826 (s, 3 H), 0.832 (s, 3 H), 0.86
and 0.89 (s, 3 H), 1.00 and 1.03 (d, J = 2.8 Hz, 1 H), 1.09 (s, 3 H),
1.13–1.30 (m, 3 H), 1.40–1.85 (m, 7 H), 1.98 (dt, J = 3.2, 11.9 Hz,
1 H), 2.05–2.30 (m, 2 H), 4.58 (t, J = 8.2 Hz, 4/9 H) and 4.68 (dd,
J = 2.3, 11.4 Hz, 5/9 H).
13C NMR (100 MHz, CDCl3): δ (major diastereomer): 15.2, 18.2,
20.6, 21.0, 21.5, 29.7, 33.0, 33.5, 36.3, 39.4, 39.7, 42.3, 56.8, 59.1,
63.3, 83.8, 120.2; δ (minor diastereomer): 15.1, 18.2, 20.4, 21.0,
21.9, 29.6, 33.0, 33.5, 36.4, 39.3, 39.8, 42.2, 57.0, 60.0, 63.1, 83.8,
120.9.
1H NMR (400 MHz, CDCl3): δ = 1.48 (s, 18/5 H), 1.51 (s, 27/5 H)
(9 H), 1.98–2.30 (m, 4 H), 3.25–3.40 (m, 1 H), 3.40–3.60 (m, 1 H),
4.44 (m, 3/5 H), 4.56 (m, 2/5 H).
13C NMR (100 MHz, CDCl3): δ = 23.8, 24.6, 28.1, 28.3, 30.8, 31.6,
45.7, 46.0, 47.1, 80.9, 81.4, 119.1, 153.0.
tert-Butyl 2-Cyanopiperidine-1-carboxylate (4c)26
[CAS Reg. No.: 153749-89-4]
Colorless solid; yield: 33.3 mg (74%, conditions A), 21.9 mg (69%,
conditions B).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H27NONa:
284.1985; found: 284.1979.
1H NMR (400 MHz, CDCl3): δ = 1.48 (s, 9 H), 1.56–1.57 (m, 2 H),
1.68–1.76 (m, 4 H), 2.94 (br m, 1 H), 4.05 (br m, 1 H), 5.23 (br m,
1 H).
13C NMR (100 MHz, CDCl3): δ = 20.3, 24.5, 28.4, 28.8, 41.4, 43.9,
81.4, 117.7, 154.0.
cis-Hexahydrospiro[benzo[d][1,3]dioxole-2,1′-cyclohexane]-3a-
carbonitrile (2g)
[CAS Reg. No.: 1338695-86-5]
tert-Butyl 3-Cyanomorpholine-4-carboxylate (4d)27
[CAS Reg. No.: 518047-40-0]
Colorless oil; yield: 43.8 mg (84%).
IR (neat): 2241, 1121, 1073 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.35–1.90 (m, 16 H), 2.00–2.10
(m, 2 H), 4.41 (t, J = 4.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 18.6, 20.0, 23.5, 23.8, 24.9, 25.7,
33.6, 34.8, 37.5, 72.8, 76.2, 111.7, 120.2.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H19NO2Na:
Colorless solid; yield: 29.6 mg (70%).
1H NMR (400 MHz, CDCl3): δ = 1.49 (s, 9 H), 3.25 (br m, 1 H), 3.49
(dt, J = 2.7, 11.9 Hz, 1 H), 3.62 (dd, J = 3.2, 11.9 Hz, 1 H), 3.81 (m,
1 H), 3.99 (br d, J = 11.4 Hz, 1 H), 4.06 (d, J = 12.4 Hz, 1 H), 4.91
(br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.1, 66.5, 67.5, 82.3, 116.5,
153.5.
244.1308; found: 244.1301.
2-Hydroxy-5-methylhexan-1-ol (2h)
trans-5-Methyl-2-oxooxazolidine-4-carbonitrile (4e)28
[CAS Reg. No.: 73683-33-7]
[CAS Reg. No.: 144688-70-0]
Colorless oil; yield: 20.5 mg (72%).
IR (neat): 3439, 2249, 1071 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.92 (d, J = 6.4 Hz, 6 H), 1.39 (m,
2 H), 1.61 (septet, J = 6.4 Hz, 1 H), 1.85 (m, 2 H), 2.45 (br d, J = 6.4
Hz, 1 H, OH), 4.46 (br dt, J = 6.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.31, 22.35, 27.6, 33.2, 33.3,
61.7, 119.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C7H13NONa: 150.0889;
found: 150.0896.
Colorless solid; yield: 22.8 mg (83%, conditions A), 5.7 mg (23%,
conditions B); mp 83–85 °C.
IR (neat): 3290, 2251, 1759, 1222, 1105, 1066 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.57 (d, J = 6.4 Hz, 3 H), 4.24 (dd,
J = 1.4, 5.0 Hz, 1 H), 4.92 (dq, J = 5.0, 6.4 Hz, 1 H), 6.28 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.0, 48.6, 76.2, 116.2, 156.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C5H6N2O3Na:
149.0321; found: 149.0318.
5-Oxohexanenitrile (2i)25
trans-5-tert-Butyl-2-oxooxazolidine-4-carbonitrile (4f)
Colorless solid; yield: 9.4 mg (42%); mp 135–138 °C.
[CAS Reg. No.: 10412-98-3]
IR (neat): 3412, 2254, 1771, 1389, 1227, 1044, 1027 cm–1.
Yellow oil; yield: 24.8 mg (97%).
1H NMR (400 MHz, CDCl3): δ = 1.03 (s, 9 H), 4.39 (d, J = 6.4 Hz,
1 H), 4.50 (d, J = 6.4 Hz, 1 H), 6.39 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.1, 34.4, 43.3, 87.0, 116.9,
1H NMR (400 MHz, CDCl3): δ = 1.90 (tt, J = 7.3, 7.3 Hz, 2 H), 2.17
(s, 3 H), 2.42 (t, J = 7.3 Hz, 2 H), 2.63 (t, J = 7.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.3, 19.2, 30.0, 41.1, 119.2,
157.3.
206.8.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C8H12N2O2Na:
191.0798; found: 191.0792.
tert-Butyl 2-Cyanoazepane-1-carboxylate (4a)26
[CAS Reg. No.: 153749-93-0]
1-tert-Butyl 2-Methyl (2S,5S)-5-Cyanopyrrolidine-1,2-dicar-
boxylate (4g)29
Colorless oil; yield: 44.9 mg (85%, conditions A), 35.0 mg (78%,
conditions B).
[CAS Reg. No.: 649728-62-1]
1H NMR (400 MHz, CDCl3): δ = 1.36–1.43 (m, 2 H), 1.48 and 1.50
(m, 9 H), 1.55–1.60 (m, 1 H), 1.70–1.80 (m, 2 H), 1.80–1.90 (m, 2
H), 2.20–2.32 (m, 1 H), 2.96–3.06 (m, 1 H), 3.79 (br d, J = 15.1 Hz,
3/5 H), 3.89 (br d, J = 15.1 Hz, 2/5 H), 4.76 (dd, J = 6.0, 11.0 Hz,
2/5 H), 5.11 (dd, J = 6.9, 10.5 Hz, 3/5 H).
13C NMR (100 MHz, CDCl3): δ = 24.3, 25.1, 28.3, 28.6, 28.7, 32.6,
32.9, 43.2, 43.8, 45.9, 47.3, 81.0, 81.5, 119.3, 119.4, 155.0.
Colorless oil; yield: 51.0 mg (91%, conditions A), 23.8 mg (67%,
conditions B); [α]D25 –100.0 (c 2.14, CHCl3).23
1H NMR (400 MHz, CDCl3): δ = 1.41 (s, 9/2 H), 1.50 (s, 9/2 H),
2.10–2.60 (m, 4 H), 3.72 (s, 3/2 H), 3.73 (s, 3/2 H), 4.33 (d, J = 8.2
Hz, 1/2 H), 4.43 (d, J = 8.7 Hz, 1/2 H), 4.65 (d, J = 8.2 Hz, 1/2 H),
4.75 (d, J = 7.8 Hz, 1/2 H).
13C NMR (100 MHz, CDCl3): δ = 28.1, 28.2, 28.5, 28.8, 29.6, 29.7,
47.6, 47.7, 52.3, 52.5, 58.5, 58.8, 81.9, 82.4, 118.7, 118.8, 152.56,
152.60, 172.2, 172.4.
tert-Butyl 2-Cyanopyrrolidine-1-carboxylate (4b)26
[CAS Reg. No.: 144688-70-0]
Colorless solid; yield: 42.9 mg (94%, conditions A), 23.4 mg (86%,
conditions B).
1-(3,3,3-Trichloropropanoyl)azepane-2-carbonitrile (4h)
Colorless oil; yield: 31.4 mg (75%).
IR (neat): 2936, 2243, 1718, 1415, 716 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 874–887

884
T. Hoshikawa et al.
FEATURE ARTICLE
1H NMR (400 MHz, CDCl3): δ = 1.31–1.50 (m, 2 H), 1.60–1.98 (m,
5 H), 2.29–2.40 (m, 1 H), 3.14 (ddt, J = 1.8, 5.0, 14.7 Hz, 1 H), 3.98
(dd, J = 4.1, 15.1 Hz, 1 H), 4.68 (d, J = 12.4 Hz, 7/10 H), 4.69 (d,
J = 11.9 Hz, 3/10 H), 4.91 (d, J = 11.9 Hz, 7/10 H), 4.94 (d, J = 11.9
Hz, 3/10 H), 4.98 (dd, J = 6.4, 11.0 Hz, 3/10 H), 5.10 (dd, J = 6.8,
10.5 Hz, 7/10 H).
1H NMR (400 MHz, CDCl3): δ = 1.22–1.52 (m, 6 H), 1.43 (s, 9 H),
1.45 (s, 9 H), 1.75–1.83 (m, 2 H), 3.04–3.18 (m, 2 H), 4.55 (m, 1 H),
4.55 (br s, 1 H), 4.97 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.9, 25.8, 28.2, 28.4, 29.8, 33.3,
40.1, 42.1, 79.2, 81.1, 118.9, 156.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H31N3O4Na:
364.2198; found: 364.2231.
13C NMR (125 MHz, CDCl3): δ = 24.3, 24.8, 28.2, 28.3, 28.4, 32.6,
32.7, 44.0, 44.3, 47.0, 75.3, 75.4, 95.1, 118.4, 118.5, 153.0, 154.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H13N2O2Cl3Na:
320.9898; found: 320.9932.
tert-Butyl Butyl(1-cyanobutyl)carbamate (4p)
Colorless oil; yield: 19.7 mg (55%).
IR (neat): 2963, 2240, 1700, 1368, 1154 cm–1.
1-Acetylazepane-2-carbonitrile (4i)
Yellow oil; yield: 17.8 mg (75%).
IR (neat): 3490, 2935, 2859, 2239, 1652, 1413, 1207 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.94 (t, J = 7.3 Hz, 3 H), 0.97 (t,
J = 7.3 Hz, 3 H), 1.32 (q, J = 7.3 Hz, 2 H), 1.47 (s, 9 H), 1.36–1.79
(m, 5 H), 1.80–1.91 (m, 1 H), 3.14–3.29 (m, 2 H), 4.98 (br s, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.32–1.43 (m, 1 H), 1.44–1.65 (m,
2 H), 1.71–1.80 (m, 1 H), 1.81–1.97 (m, 3 H), 2.18 (s, 27/10 H),
2.21 (s, 3/10 H), 2.23–2.31 (m, 1 H), 2.88 (ddd, J = 1.8, 11.9, 12.8
Hz, 1/10 H), 3.34 (ddd, J = 2.3, 11.0, 15.6 Hz, 9/10 H), 3.72 (dt,
J = 3.9, 15.6 Hz, 9/10 H), 4.25 (m, 1/10 H), 4.57 (dd, J = 6.4, 10.5
Hz, 1/10 H), 5.48 (dd, J = 6.4, 10.0 Hz, 9/10 H).
13C NMR (100 MHz, CDCl3): δ = 21.2, 21.8, 24.3, 24.5, 27.9, 28.0,
28.7, 28.9, 32.0, 33.3, 42.2, 44.1, 45.1, 48.8, 53.4, 118.8, 170.8.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H14N2ONa:
189.1004; found: 189.0993.
13C NMR (100 MHz, CDCl3): δ = 13.3, 13.7, 18.9, 20.1, 28.3, 31.2,
34.3, 45.4, 47.3, 81.2, 118.6, 154.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H26N2O2Na:
227.1898; found: 277.1893.
tert-Butyl 1-Cyano-2-methylpropylcarbamate (4q)30
[CAS Reg. No.: 130457-35-1]
Colorless solid; yield: 32.7 mg (73%, conditions A), 11.3 mg (41%,
conditions B).
1H NMR (400 MHz, CDCl3): δ = 1.07 (t, J = 7.3 Hz, 6 H), 1.45 (s,
9 H), 2.01 (octet, J = 6.9 Hz, 1 H), 4.45 (br m, 1 H), 4.93 (br d,
J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 17.9, 18.5, 28.2, 31.8, 48.4, 81.1,
118.0, 154.4.
1-Tosylazepane-2-carbonitrile (4j)
Colorless oil; yield: 16.7 mg (30%).
IR (neat): 2238, 1597, 1338, 1159 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.44–1.56 (m, 1 H), 1.62–1.72 (m,
1 H), 1.74–1.83 (m, 3 H), 1.85–1.96 (m, 2 H), 2.22–2.32 (m, 1 H),
2.43 (s, 3 H), 2.96 (ddd, J = 2.9, 10.9, 14.9 Hz, 1 H), 3.71 (dt,
J = 4.6, 14.9 Hz, 1 H), 5.01 (t, J = 6.9 Hz, 1 H), 7.34 (d, J = 8.0 Hz,
2 H), 7.74 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.6, 23.9, 27.7, 28.8, 34.1, 45.3,
47.7, 117.3, 127.3, 129.9, 135.3, 144.2.
tert-Butyl 1-Cyano-2-methylbutylcarbamate (4r)
White solid; yield: 37.1 mg (76%, conditions A), 10.2 mg (35%,
conditions B); mixture of 2 diastereomers, ratio 1:1 (1H NMR).
1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3 H), 1.05 (t,
J = 7.3 Hz, 3 H), 1.20–1.60 (m, 11 H), 1.77 (m, 1 H), 4.55 (br m, 1
H), 4.93 (br s, 1 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H18N2O2SNa:
301.0998; found: 301.0983.
13C NMR (100 MHz, CDCl3): δ = 11.10, 11.13, 14.9, 15.0, 25.0,
25.6, 28.2, 28.3, 38.0, 38.1, 46.9, 47.2, 81.0, 81.1, 117.9, 118.4,
154.4, 154.5.
tert-Butyl (1-Cyanocyclohexyl)carbamate (4l)
Colorless solid; 12.3 mg (27%); mp 96–97 °C.
IR (neat): 3336, 2937, 2239, 1704, 1367, 1166 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.47 (s, 9 H), 1.54–1.77 (m, 8 H),
2.25–2.37 (m, 2 H), 4.67 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 22.0, 24.7, 28.3, 35.8, 51.9, 81.1,
120.1, 153.6.
tert-Butyl 1-Cyano-2-phenylpropylcarbamate (4s)
Colorless solid; yield: 41.5 mg (69%, conditions A), 23.0 mg (44%,
conditions B); mixture of 2 diastereomers, ratio 6:5 (1H NMR).
1H NMR (400 MHz, CDCl3): δ = 1.39 (s, 45/11 H), 1.44 (s, 54/11
H), 1.48 (d, J = 7.3 Hz, 3 H), 3.11 (dq, J = 7.3, 7.3 Hz, 6/11 H), 3.20
(br dq, J = 6.4, 6.9 Hz, 5/11 H), 4.60–4.90 (br m, 2 H), 7.27–7.40
(m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 16.9, 17.6, 28.08, 28.14, 42.3,
42.6, 48.2, 81.2, 117.6, 118.0, 127.6, 127.9, 127.8, 128.1, 128.8,
129.0, 139.1, 139.3, 154.2.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H20N2O2Na:
247.1398; found: 247.1422.
cis-2-Oxooctahydro-1H-benzimidazole-3a-carbonitrile (4m)
Yellow solid; yield: 9.9 mg (43%); mp 109–111 °C.
IR (neat): 3202, 2939, 2231, 1713 cm–1.
Cyclooctanecarbonitrile (6a)
[CAS Reg. No.: 40636-30-4]
1H NMR (400 MHz, CDCl3): δ = 1.37–1.45 (m, 1 H), 1.49–1.73 (m,
4 H), 1.84–1.95 (m, 1 H), 1.98–2.13 (m, 2 H), 3.93 (t, J = 5.5 Hz, 1
H), 5.43 (br s, 1 H), 5.73 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 19.4, 19.5, 27.5, 32.8, 54.6, 55.7,
120.3, 162.1.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C8H11N3ONa:
188.0798; found: 188.0797.
Colorless oil; yield: 26.7 mg (87%).
IR (neat): 2235 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.40–1.65 (m, 8 H), 1.70–1.90 (m,
4 H), 1.96 (dddd, J = 2.8, 4.1, 9.6, 13.3 Hz, 2 H), 2.75 (tt, J = 4.1,
8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 24.3, 25.1, 26.8, 28.7, 29.4, 123.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C9H15NNa: 160.1097;
found: 160.1092.
Di-tert-butyl (1-Cyanohexane-1,6-diyl)dicarbamate (4o)
Colorless oil; yield: 27.4 mg (57%).
Adamantane-1-carbonitrile (6b)31
[CAS Reg. No.: 23074-42-2]
IR (neat): 3334, 2979, 2934, 2247, 1691, 1519, 1168 cm–1.
Synthesis 2013, 45, 874–887
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Direct Cyanation of C(sp3)–H Bonds
885
Colorless solid; yield: 29.6 mg (82%).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H15NO2Na:
240.0995; found: 240.0991.
1H NMR (400 MHz, CDCl3): δ = 1.73 (br s, 6 H), 2.04 (br s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 27.0, 30.1, 35.7, 39.9, 125.3.
Methyl 2-[4-(1-Cyano-2-methylpropyl)phenyl]propanoate (6h)
[CAS Reg. No.: 1338695-84-3]
3-Hydroxyadamantane-1-carbonitrile (6c)32
[CAS Reg. No.: 59223-70-0]
Colorless oil; yield: 24.7 mg (45%); mixture of 2 diastereomers.
IR (neat): 2238, 1737, 1210, 1165, 843 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.03 (d, J = 6.9 Hz, 3 H), 1.05 (d,
J = 6.9 Hz, 3 H), 1.50 (d, J = 7.3 Hz, 3 H), 2.11 (dq, J = 6.4, 6.9 Hz,
1 H), 3.63 (d, J = 6.4 Hz, 1 H), 3.67 (s, 3 H), 3.73 (m, 1 H), 7.25 (d,
J = 8.7 Hz, 2 H), 7.30 (d, J = 8.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 18.5, 18.8, 20.8, 33.7, 44.8, 45.0,
52.1, 119.8, 127.9, 128.1, 133.8, 140.31, 140.33, 174.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H19NO2Na:
268.1308; found: 268.1308.
Colorless solid; yield: 35.2 (87%).
IR (neat): 3261, 2226, 1141, 1034 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.61 (d, J = 3.2 Hz, 2 H), 1.72 (d,
J = 3.2 Hz, 4 H), 1.94 (br d, J = 2.3 Hz, 4 H), 2.04 (s, 2 H), 2.28 (br
dd, J = 2.8, 3.2 Hz, 2 H), 1.49 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 29.6, 32.8, 34.3, 38.7, 43.7, 46.9,
67.0, 123.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H15NONa:
200.1046; found: 200.1046.
Methyl 2-[4-(2-Cyano-2-methylpropyl)phenyl]propanoate (6i)
5-(Benzoyloxy)-2,2-dimethylpentanenitrile (6d)
[CAS Reg. No.: 1338695-85-4]
[CAS Reg. No.: 1338695-82-1]
Colorless oil; yield: 5.3 mg (10%).
IR (neat): 2233, 1735, 1206, 1163, 847 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.35 (s, 6 H), 1.50 (d, J = 7.5 Hz,
3 H), 2.79 (s, 2 H), 3.67 (s, 3 H), 3.72 (q, J = 7.5 Hz, 1 H), 7.23 (d,
J = 8.6 Hz, 2 H), 7.27 (d, J = 8.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 18.5, 26.5, 33.5, 45.1, 46.3, 52.0,
124.7, 127.5, 130.5, 134.5, 139.6, 174.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H19NO2Na:
268.1308; found: 268.1301.
Colorless oil; yield: 18.6 mg (35%).
IR (neat): 2234, 1719, 1277, 714 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.38 (s, 6 H), 1.69 (m, 2 H), 1.98
(m, 2 H), 4.37 (t, J = 6.4 Hz, 2 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.57 (t,
J = 7.5 Hz, 1 H), 8.04 (dd, J = 1.4, 7.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 24.8, 26.6, 32.1, 37.6, 64.3, 124.7,
128.4, 129.5, 130.1, 133.0, 166.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H17NO2Na:
254.1151; found: 254.1161.
2-(Benzoyloxy)-5-methylhexanenitrile (7)
2-Phenylpentanenitrile (6e)33
To a CH2Cl2 (2.5 mL) soln of 2-hydroxy-5-methylhexanenitrile
(2h, 6.4 mg, 50.3 μmol) were added BzCl (8.5 μL, 75 μmol), Et3N
(14 μL, 100 μmol), and DMAP (0.2 mg) at r.t. The mixture was
stirred for 1 h, and then the reaction was quenched with H2O. The
mixture was extracted with CH2Cl2 (3 × 10 mL), and the combined
organic layers were washed with sat. aq NaHCO3 and brine, dried
(Na2SO4), and concentrated. The residue was purified with flash
column chromatography (hexane–EtOAc, 50:1) to give 7 as a col-
orless oil; yield: 10.0 mg (86%).
[CAS Reg. No.: 5558-78-1]
Colorless oil; yield: 15.4 mg (41%).
1H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 7.3 Hz, 3 H), 1.50 (m,
2 H), 1.90 (m, 2 H), 3.78 (dd, J = 6.4, 8.7 Hz, 1 H), 7.30–7.40 (m, 5
H).
13C NMR (100 MHz, CDCl3): δ = 13.4, 20.3, 37.2, 37.9, 120.9,
127.2, 128.0, 129.0, 136.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H13NNa: 182.0940;
IR (neat): 1732, 1602, 1585, 1266, 1093, 711 cm–1.
found: 182.0945.
1H NMR (400 MHz, CDCl3): δ = 0.95 (d, J = 6.4 Hz, 6 H), 1.40–
1.50 (m, 2 H), 1.66 (septet, J = 6.4 Hz, 1 H), 2.00–2.10 (m, 2 H),
5.57 (t, J = 6.4 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.63 (t, J = 7.8
Hz, 1 H), 8.06 (dd, J = 1.6, 7.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 22.28, 22.32, 27.6, 30.5, 33.4,
61.8, 117.0, 128.3, 128.6, 129.9, 134.0, 164.8.
2-(4-Methoxyphenyl)pentanenitrile (6f)34
[CAS Reg. No.: 648409-06-7]
Colorless oil; yield: 29.0 mg (72%).
IR (neat): 2238, 1512, 1253, 1034, 831 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.95 (t, J = 7.3 Hz, 3 H), 1.50 (m,
2 H), 1.85 (m, 2 H), 3.73 (dd, J = 6.4, 8.8 Hz, 1 H), 3.81 (s, 3 H),
6.89 (d, J = 8.8 Hz, 2 H), 7.23 (d, J = 8.8 Hz, 2 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H17NO2Na:
254.1151; found: 254.1154.
13C NMR (100 MHz, CDCl3): δ = 13.4, 20.2, 36.3, 37.9, 55.3, 114.3,
121.2, 128.0, 128.3, 159.2.
Acknowledgment
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H15NONa:
212.1046; found: 212.1039.
This research was financially supported by the Funding Program for
Next Generation World-Leading Researchers (JSPS) to M.I.
2-(4-Acetoxyphenyl)pentanenitrile (6g)
[CAS Reg. No.: 1338695-83-2]
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Colorless oil; yield: 13.2 mg (27%).
IR (neat): 2239, 1760, 1512, 1201, 1015, 846 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 7.3 Hz, 3 H), 1.51 (m,
2 H), 1.85 (m, 2 H), 2.30 (s, 3 H), 3.79 (dd, J = 6.4, 8.7 Hz, 1 H),
7.10 (d, J = 8.7 Hz, 2 H), 7.33 (d, J = 8.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 13.4, 20.3, 21.1, 36.6, 37.8, 120.6,
122.2, 128.3, 133.5, 150.2, 169.3.
References
(1) Present address: Graduate School of Science and
Engineering, Yamaguchi University, Yoshida, Yamaguchi
753-8511, Japan.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 874–887

886
T. Hoshikawa et al.
FEATURE ARTICLE
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