Carbocyanation of trisubstituted olefins via Cu-catalyzed atom transfer radical addition

Article abstract of DOI:10.1016/j.tetlet.2012.06.004

A regioselective Cu(I)-catalyzed carbocyanation of non-polarized trisubstituted olefins 1 has been achieved by employing chlorinated cyanides 2 as starting materials. The present reaction gives the carbocyanated product 3 through radical-based 1,3-transfer of CN. Consequently, two different carbon units, cyano and chlorocyanomethyl groups, are introduced into the highly substituted olefins, generating consecutive quaternary and tertiary carbons. Since both of the attached carbon units can be used as handles for further synthetic elaborations, the present transformation offers a new synthetic methodology for rapid construction of architecturally complex carboskeletons.

Full text of DOI:10.1016/j.tetlet.2012.06.004

Tetrahedron Letters 53 (2012) 4324–4327
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carbocyanation of trisubstituted olefins via Cu-catalyzed atom transfer
radical addition
⇑
Shin Kamijo , Shinya Yokosaka, Masayuki Inoue
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A regioselective Cu(I)-catalyzed carbocyanation of non-polarized trisubstituted olefins 1 has been
achieved by employing chlorinated cyanides 2 as starting materials. The present reaction gives the carb-
ocyanated product 3 through radical-based 1,3-transfer of CN. Consequently, two different carbon units,
cyano and chlorocyanomethyl groups, are introduced into the highly substituted olefins, generating con-
secutive quaternary and tertiary carbons. Since both of the attached carbon units can be used as handles
for further synthetic elaborations, the present transformation offers a new synthetic methodology for
rapid construction of architecturally complex carboskeletons.
Received 14 May 2012
Revised 30 May 2012
Accepted 1 June 2012
Available online 13 June 2012
Keywords:
Copper catalyst
Radical reaction
Regioselective addition
C–CN bond cleavage
Trisubstituted olefin
Ó 2012 Elsevier Ltd. All rights reserved.
Bis-functionalization of C–C double bonds via addition reaction
enables installation of two functional groups of contiguous sp3-
carbon centers in a single step, and thus is synthetically useful
for construction of various sp3-rich molecular frameworks.1
Among such bond transformations, carbocyanation of olefins is
especially appealing, because the two different carbon units intro-
duced can be utilized as handles for syntheses of more complex
carboskeletons. However, while many examples of the transition-
metal catalyzed alkyne carbocyanation were reported to date,2,3
its olefin counterpart has been relatively unexplored. Pd- or
Ni-catalyzed carbocyanation of the double bonds was demon-
strated only as an intramolecular reaction4,5 or an intermolecular
reaction with reactive norbornene derivatives.6
Cl
atom transfer radical reaction
X
H
CN
Cl
-
via C Cl cleavage
R
1 = R2 = H, R3 = alkyl
H
R3
R2
3
Cl CN
Cl
R1
+
cat CuI
R3
X
Cl
X
Cl
1
2
R1 = R2 = R3 = alkyl
olefin carbocyanation
CN
R2
R1
R3
-
via C CN cleavage
4
Scheme 1. Cu-catalyzed atom transfer radical addition (ATRA) and olefin
carbocyanation.
Recently, we reported Cu(I)-catalyzed atom transfer radical
reactions (ATRA)7 of chlorinated cyanides 2 for functionalization
of electronically non-polarized olefins (Scheme 1).8,9 The inher-
ently unreactive terminal olefin of 1 (R1 = R2 = H, R3 = alkyl) was
derivatized into the corresponding 1,3-dichrolinated product 3
via homolytic C–Cl cleavage without affecting a wide array of polar
functionalities such as carbonyl and alcohol moieties.1,10 During
investigation of the scope and limitation of the substrates,8 we
found that Cu(I)-catalyzed reaction of trisubstituted olefins 1
(R1 = R2 = R3 = alkyl) with 2 led to the carbocyanation product 4
through C–CN cleavage. Here we report the application of Cu(I)-
catalyzed carbocyanation to various trisubstituted olefins and its
proposed radical-based mechanism. The present new methodology
realized simultaneous formation of the cyanated quaternary car-
bon and chlorocyanomethylated tertiary carbon in a regioselective
fashion.
As shown in entry 1 (Table 1), the reaction with trisubstituted
olefin 1a with dichloromalononitrile 2a using 1 mol % CuCl/dppf
at 100 °C in dioxane regioselectively yielded the C–CN cleaved ad-
duct 4aa as a major product in 33% yield. The expected ATRA prod-
uct 3aa or its elimination product 5aa was not obtained under
these conditions. Removal of the phosphine ligand and alternation
of the counterion on Cu species significantly affected the yield of
the carbocyanated adduct 4aa (entries 2–4). Among the Cu species
screened, Cu(MeCN)4PF6 exhibited the highest activity toward this
transformation (entry 5). Changing the solvent from dioxane to
less-polar toluene and trifluoromethylbenzene decreased the yield
⇑
Corresponding author. Tel.: +81 3 5841 1354; fax: +81 3 5841 0568.
E-mail address: inoue@mol.f.u-tokyo.ac.jp (M. Inoue).
Present address: Graduate School of Science and Engineering, Yamaguchi
University, Yoshida, Yamaguchi 753-8511, Japan
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.004

S. Kamijo et al. / Tetrahedron Letters 53 (2012) 4324–4327
4325
Table 1
Having established the optimized conditions for regioselective
carbocyanation, we demonstrated the applicability of the present
carbocyanation using a variety of trisubstituted olefins 1 (Table
2). The substrates with oxygen functionalities such as benzoyloxy
(1a), mesyloxy (1b), and siloxy groups (1c) were converted into
the corresponding adducts 4aa–4ca in a yield range of 75–46% (en-
tries 1–3). The adduct 4da with nosyl-protected amide (1d) was
also formed in 62% yield (entry 4). The reaction was applicable to
olefin 1e containing the highly acidic malonate moiety, affording
the carbocyanated product 4ea in 63% yield (entry 5). Compatibil-
ity of the various acid- and base-sensitive functional groups dem-
onstrated mildness of the present olefin carbocyanation.
Furthermore, more hindered 1,1-diethyl substituted olefin 1f (en-
try 6) and olefin having the cyclohexane ring 1g (entry 7) were suc-
cessfully transformed into the corresponding carbocyanated
adducts 4fa (78% yield) and 4ga (74% yield) in a completely regio-
selective manner. Therefore, as far as using trisubstituted olefins as
starting materials is concerned, the cyano group is attached to the
more hindered side of the olefin to generate the quaternary carbon
and the chlorocyanomethyl group is introduced to the less hin-
dered side to form the tertiary carbon.
Optimization of carbocyanation conditionsa
Cl
NC
BzO
Cl
Cl
Cl
CN
CN
catalyst
BzO
+
4
CN
solvent (1 M)
100 °C
4
1a
2a
4aa
Entry
Catalyst (mol %)
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
CuCl/dppfc (1)
CuCl (1)
Dioxane
Dioxane
18
18
18
18
18
18
18
1
33
57d,e
63d,e
67d
CuCN (1)
Dioxane
CuOAc (1)
Dioxane
Cu(MeCN)4PF6 (1)
Cu(MeCN)4PF6 (1)
Cu(MeCN)4PF6 (1)
Cu(MeCN)4PF6 (1)
Cu(MeCN)4PF6 (1)
Dioxane
Toluene
PhCF3
MeNO2
Dioxane/MeNO2
Dioxane/MeNO2
70d
48d,e
49d,e
35d,e
71d
f
f
8
16
Cu(MeCN)4PF6 (0.1)
75d
a
Reaction conditions: olefin 1a (0.5 mmol), dichloromalononitrile 2a (1.0 mmol),
Cu catalyst (0.1–1 mol %), solvent (1 M), at 100 °C under Ar atmosphere unless
otherwise noted.
b
Isolated yield.
c
1,10-Bis(diphenylphosphino)ferrocene.
d
Side products 3aa and 5aa were observed in less than 20% combined yield.
Next, we investigated the reactivity of various cyanides 2 by
modifying their substituent under the optimized conditions (Table
Cl
Cl
NC
BzO
3aa
CN
Cl
NC
BzO
5aa
CN
4
4
Table 3
e
f
Carbocyanation of olefin 1a with various cyanides 2a
Yield was determined by NMR analysis of the crude mixture.
Dioxane/MeNO2 (3:1) was employed as a solvent.
Entry Cyanide
Temperature
(°C)
Product
Yieldb (%)
Time (h)
of 4aa, probably due to low solubility of the Cu catalyst (entries 6
and 7). Although more-polar MeNO2 increased the catalyst solubil-
ity and shortened the time of olefin consumption, the product yield
was diminished (entry 8). Accordingly, we attained both reaction
acceleration and yield improvement by applying a mixed solvent
system of dioxane/MeNO2 (3:1) (entry 9). Furthermore, the cata-
lyst amount was successfully reduced as low as 0.1 mol % without
loss of the product yield under this mixed solvent system (75%
yield, entry 10).
Cl CN
Cl
Cl
NC
Cl
Cl CN
100
16
BzO
CN
1
75
4
2a
4aa
Cl CN
Cl
Cl
Cl
Cl Cl
130
48
BzO
CN
CN
2
54
4
2b
4ab
Cl CN
Cl
MeO2C
BzO
Cl CO2Me
Table 2
130
24
3
24c
Carbocyanation of various olefins 1 with dichloromalononitrile 2aa
4
2c
Entry
Olefin
Product
Yieldb (%)
4ac
Cl
CN
Cl
X
4
Cl
NC
CH2Ph
CN
NC
Cl
PhH2C CN
130
24
BzO
X
4
CN
4
34c (1:1)d
4
2d
4ad
1
2
3
4
5
1a:X = OBz
1b:X = OMs
1c:X = OTBS
1d:X = NHNs
1e:X = CH(CO2Et)2
4aa
4ba
4ca
4da
4ea
75
59
46
62
63
Me CN
Me CN
Me
NC
Me
130
24
5e
0f
BzO
CN
4
2e
BzO
Et
Cl
4ae
NC
BzO
Cl
Et
4
Et
F
F
CN
F
6
78
74
1f
CN
Et
CF3(CF2)5
F
4
(CF2)5CF3
130
24
4fa
BzO
CN
6
0f
BzO
Cl
4
2f
NC
BzO
Cl
4
4af
1g
7c
CN
a
Reaction conditions: olefin 1a (0.5 mmol), cyanide 2 (1.0 mmol), Cu(MeCN)4PF6
(0.1 mol %), dioxane/MeNO2 (3:1, 1 M), under Ar atmosphere unless otherwise
noted.
4
4ga
a
b
Reaction conditions: olefin 1 (0.5 mmol), dichloromalononitrile 2a (1.0 mmol),
Cu(MeCN)4PF6 (0.1 mol %), dioxane/MeNO2 (3:1, 1 M), at 100 °C for 16 h under Ar
atmosphere unless otherwise noted.
Isolated yield.
c
Formation of unidentified side products was observed.
d
Ratio of diastereomers.
Cu(MeCN)4PF6 (1 mol %) was employed.
Olefin 1a was recovered in 99% yield.
b
e
Isolated yield.
The reaction was completed in 2 h.
c
f

4326
S. Kamijo et al. / Tetrahedron Letters 53 (2012) 4324–4327
Cl
3). Similarly to the case of dichloromalononitrile 2a (entry 1), the
reaction of trichloroacetonitrile 2b with trisubstituted olefin 1a
took place to give the carbocyanated adduct 4ab in 54% yield via
C–CN cleavage (entry 2). The cyanoester 2c and benzylchloromal-
ononitrile 2d also afforded the corresponding adducts 4ac in 24%
yield (entry 3) and 4ad in 34% yield (entry 4), respectively. Among
the four chlorocyanides (2a–2d), 2a was found to have the highest
reactivity, because higher reaction temperature (130 °C) and long-
er reaction time (24–48 h) were required for 2b, 2c, and 2d. Impor-
tantly, as shown in entries 5 and 6, the carbocyanation did not
proceed even at elevated temperatures when the reagents pos-
sessed no chloride. The corresponding adduct 4ae (entry 5) or
4af (entry 6) was not obtained from dimethylmalononitrile 2e or
perfluorooctanonitrile 2f, and quantitative recovery of olefin 1a
was observed. Accordingly, these results clarified that starting cya-
X
Cl
Cl
Cl
CN
X
CN
R2
R1
CuI
R3
4
2
Cl
X
CuIICl
Cl CN
CN
R2
R1
X
R3
D
A
R2
Cl
R1
Cl
X
CN
X
R3
1
N
R1
R1
R2
R2
R3
slow
fast
R3
C
B
nides 2 are required to have at least one chloride atom at the a-po-
Cl
X
CN
Cl
R2
sition to the cyano group for productive Cu-catalyzed
carbocyanation.
CuIICl
R1
CuI
To gain further mechanistic information, the two experiments
were performed using two different substituted olefins (Scheme
2). In sharp contrast to the results of the trisubstituted olefins,
the reaction of monosubstituted olefin 1h with dichloromalononit-
rile 2a only gave the 1,3-dichloro compound 3ha via the ATRA pro-
cess. When cyclopropane was attached to the trisubstituted olefin,
2a added to 1i to generate the 1,6-dichlorinated adduct 3ia as the
sole product. Clean formation of 3ha and 3ia indicated that the ini-
tial stage of the reaction involved Cu-catalyzed homolytic cleavage
of the C–Cl bond of 2a to generate the corresponding radical
[ꢀCCl(CN)2], which then added to the olefin. In the case of 1i, the
resultant radical species B0 underwent facile ring opening of the
strained cyclopropane to form the methyl radical, which was
trapped by chloride to afford 3ia. The results in Table 2 and Scheme
2 also revealed the structural requirement of the starting olefin for
the present carbocyanation: the substrate olefins need to have
three alkyl substituents.
R3
3
Scheme 3. Proposed radical mechanism for carbocyanation of trisubstituted olefins
1 with chlorinated cyanides 2.
alkyl groups (R1, R2, and R3) is used as a starting material, forma-
tion of 3 becomes slower than cyclization of B to iminyl radical
C, presumably due to steric hindrance induced by the three alkyl
substituents. Then, ring opening of the strained cyclobutane of
thus generated C furnishes the more stabilized tertiary carbon
radical D through 1,3-cyanide transfer.13,14 Finally, delivery of the
chloride from Cu(II)Cl to D gives rise to the cyanocarbonated
adduct 4 as the final product with regeneration of the Cu(I)
catalyst. Most importantly, the C–CN bond is not directly cleaved
by the action of the catalyst unlike the Ni- or Pd-catalyzed carbo-
cyanation, but is shifted via the radical-based ring-closing/ring-
opening process.
On the basis of the above data, a radical-based reaction pathway
for the Cu(I)-catalyzed carbocyanation was proposed (Scheme 3).
Requirement of the chloride substituent in the starting cyanides
2 was noted in Table 3, and the radical-based C–Cl cleavage path-
ways are demonstrated in Scheme 2. Therefore, the first process of
the carbocyanation should be Cu(I) catalyzed cleavage of the C–Cl
bond of chlorinated cyanide 2 to generate the carbon radical A
along with Cu(II)Cl.8,11,12 The highly electron-deficient carbon rad-
ical A reacts with the electron-rich C–C double bond of trisubsti-
tuted olefin 1 selectively from the less hindered side, yielding
carbon radical B. Reaction between B and Cu(II)Cl would produce
the ATRA product 3. However, only when the olefin with three
In conclusion, we developed a mild radical carbocyanation of
non-polarized trialkylated olefins 1 using the Cu(I)-catalyst and
chlorinated cyanides 2. The present transformation regioselec-
tively functionalizes trisubstituted C–C double bonds in the pres-
ence of polar functionalities such as benzoyloxy, mesyloxy,
siloxy, nosylamide, and malonate groups. Moreover, this method
allows introduction of two different carbon units, cyano and chlor-
ocyanomethyl groups, into highly substituted olefins to generate
consecutive quaternary and tertiary carbon centers. Since both of
the attached carbon units can be used as handles for further syn-
thetic elaborations, the present transformation offers a new syn-
thetic methodology for rapid construction of architecturally
complex carboskeletons.
Cl
Cl
CN
CN
Acknowledgments
2a
(2 equiv)
Cl Cl
BzO
CN
CN
This research was financially supported by the Funding Pro-
gram for Next Generation World-Leading Researchers (JSPS) to M.I.
Cu(MeCN)4PF6 (0.1 mol %)
BzO
Ph
4
4
dioxane/MeNO2 (3:1, 1 M)
100 °C, 10 h
1h
3ha (88%)
Supplementary data
Cl
2a (2 equiv)
NC
CN
Cl
Cu(MeCN)4PF6 (0.1 mol %)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.004.
Ph
1i
dioxane/MeNO2 (3:1, 1 M)
100 °C, 1 h
3ia
(E:Z = 1:1)
(88%)
Cl
References and notes
NC
Ph
CN
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