1,10-Phenanthroline- or Electron-Promoted Cyanation of Aryl Iodides

Article abstract of DOI:10.1055/s-0037-1611793

A 1,10-phenanthroline-promoted cyanation of aryl iodides has been developed. 1,10-Phenanthroline worked as an organocatalyst for the reaction of aryl iodides with tetraalkylammonium cyanide to afford aryl cyanides. A similar reaction occurred through an electroreductive process.

Full text of DOI:10.1055/s-0037-1611793

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© Georg Thieme Verlag Stuttgart · New York
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A
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K. Mitsudo et al.
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1,10-Phenanthroline- or Electron-Promoted Cyanation of Aryl
Iodides
Koichi Mitsudo*a
Kazuki Yoshiokaa
Takayuki Hirataa
Hiroki Mandaia
0
0
0
0-0
0
0
2-
6
7
4
4-7
1
3
6
CN
Ar
I
R4NCN
Ar
1,10-phenanthroline
or
electroreduction
0
0
0
0-0
0
0
1-9
1
2
1-3
8
5
0
Koji Midorikawab
Seiji Suga*a
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0
0
0-
0
0
0
3-0
6
3
5-2
0
7
7
# transition metal free
# strong base free
10 examples ≤ 78% yield
a Division of Applied Chemistry, Graduate School of Natural Sci-
ence and Technology, Okayama University, 3-1-1 Tsushima-
naka, Kita-ku, Okayama 700-8530, Japan
suga@cc.okayama-u.ac.jp
mitsudo@cc.okayama-u.ac.jp
b Nippoh Chemicals Co., Ltd., 8-15, 4-Chome, Nihonbashi-Hon-
chou, Chuo-Ku, Tokyo 103-0023, Japan
Published as part of the Cluster Electrochemical Synthesis and Catalysis
Received: 05.02.2019
Accepted after revision: 24.03.2019
Published online: 11.04.2019
hypervalent iodonium salts.6b Yamaguchi and co-workers
reported a Ni-catalyzed cyanation using aminoacetonitriles
as cyanating agents.6k
DOI: 10.1055/s-0037-1611793; Art ID: st-2019-b0070-c
Abstract A 1,10-phenanthroline-promoted cyanation of aryl iodides
has been developed. 1,10-Phenanthroline worked as an organocatalyst
for the reaction of aryl iodides with tetraalkylammonium cyanide to af-
ford aryl cyanides. A similar reaction occurred through an electroreduc-
tive process.
Conventional methods
Sandmeyer reaction
Rosenmund–von Braun reaction
X
CN
NH
2 1) NaNO2
CN
CuCN
R
R
R
R
2) CuCN
heat
X = I, Br
Key words cyanation, organocatalysis, electrochemistry, aryl iodides,
aryl cyanides
This work
I
CN
R4NCN
R
R
The aryl cyanide group is a significant motif in many
pharmaceuticals, natural products, and organic materials.1
Aryl cyanides are also important as precursors because the
nitrile group can be transformed into a wide variety of oth-
er functional groups, such as amides, carboxylic acids,
imines, ketones, or amines. Conventional methods for syn-
thesizing aryl cyanides include the Sandmeyer reaction2
and the Rosenmund–von Braun reaction3 (Scheme 1). The
Sandmeyer reaction requires diazonium salts, which are
sometimes explosive, whereas the Rosenmund–von Braun
reaction usually requires harsh reaction conditions. Addi-
tionally, a stoichiometric amount of copper(I) cyanide
needs to be used, which is often problematic in large-scale
syntheses. In recent decades, transition-metal-catalyzed
cyanations of aryl halides or arylboronic acids have been
studied intensively.4,5 For instance, Buchwald and co-work-
ers reported a copper-catalyzed Rosenmund–von Braun-
type reaction.5n,5o Recently, cyanation reactions using non-
metallic cyanation agents have also been reported.6 Shen
and co-workers reported a palladium-catalyzed cyanation
reaction that uses ethyl cyanoacetate as a cyanating agent.6a
The Wang group reported iron-catalyzed cyanation using
N
N
1,10-phenanthroline
or
electroreduction
phen
Scheme 1 Syntheses of aryl cyanides
Although there have been many other reports on cyana-
tion reactions, most of them required the use of a stoichio-
metric amount of a metal cyanide or the use of a transition-
metal catalyst. In contrast, there have been only a few re-
ports on cyanation reactions by metal-free approaches.7
Kita and co-workers reported a hypervalent-iodine-mediat-
ed direct cyanation of electron-rich heteroaromatics.7a,7b
A
Lewis acid-catalyzed direct cyanation of indoles and pyr-
roles was reported by the Wang group.7c Nicewicz recently
reported direct cyanation reactions that used photoredox
catalysts.7d In another approach, the Novi group reported
an electroreductive cyanation using diazosulfides as sourc-
es of aryl radicals.8 Although these reactions proceeded
with a catalytic amount of electricity, a large amount (20
equiv) of Bu4NCN was required for the reaction, and its
scope was limited.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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K. Mitsudo et al.
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Meanwhile, t-BuOK- and t-BuONa-mediated cross-cou-
pling reactions between aryl halides and arenes have re-
ceived considerable attention as novel transition-metal-
free cross-coupling reactions.9 These reactions are believed
to proceed by an SRN1 mechanism. A key step is single-elec-
tron transfer (SET) from t-BuOM/diamine (M = K or Na) to
the aryl halide to generate an aryl radical species that reacts
with an arene. We surmised that aryl radical species gener-
ated in this manner might participate in other reactions,
such as cyanation. Aryl cyanides are obtained when aryl ha-
lides react with an appropriate cyanating agent. On the ba-
sis of this hypothesis, we began to study of t-BuOM-mediat-
ed cyanation reactions of aryl halides. Although the desired
reactions proceeded, we unexpectedly found that t-BuOM
was unnecessary and that a catalytic amount of 1,10-
phenanthroline (phen) promoted the cyanation reactions.
Similar reactions were realized by electroreduction. Here,
we report the first phen- or electron-promoted cyanation
reactions of aryl halides in a metal-free fashion.
Table 1 Cyanation of 1a under Various Conditions
–CN source (5.0 equiv)
base (2.0 equiv)
CN
I
phen (10 mol%)
+
DMSO (0.1 M)
150 °C , 6 h
1a
2a
3a
Entry CN− source
Base
Yielda (%) Yielda (%) of Recovered 1aa
of 2a
3a
(%)
1
2
3
4
5
NaCN
t-BuONa
1
8
N.D.b
KCN
t-BuONa
t-BuONa
t-BuONa
t-BuONa
N.D.
14
20
11
N.D.
12
Me3SiCN
Bu4NCN
Et4NCN
39
69
N.D.
29 (6)c
(19)d
66 (94)c
(31)d
N.D. (43)c
(N.D)d
6
Et4NCN
Et4NCN
Et4NCN
Et4NCN
t-BuOK
29 (40)e
32
60 (55)e
49
N.D.
7
–
–
–
N.D.
8f
9h
45 (48)g
47
46 (47)g
50
N.D. (N.D.)g
N.D.
On the basis of our preliminary hypothesis, we first car-
ried out t-BuOM-mediated cyanation of 1-iodonaphthalene
(1a) as a model compound (Table 1). In the presence of t-
BuONa (2.0 equiv) and 1,10-phenanthroline (phen, 10
mol%), iodide 1a was treated with several cyanide sources
at 150 °C (Table 1, entries 1–5). NaCN and KCN were ineffec-
tive (entries 1 and 2). With Me3SiCN, the desired cyanated
product 2a was obtained in 14% yield together with a 39%
yield of the dehalogenated product 3a (entry 3). The use of
tetraalkylammonium cyanides gave better results (entries 4
and 5). With tetrabutylammonium cyanide (Bu4NCN) or
tetraethylammonium cyanide (Et4NCN), 2a was obtained in
yields of 20 and 29%, respectively. The effect of the solvent
was examined next. Among several solvents studied, di-
methyl sulfoxide (DMSO) gave the best results. For instance,
the yield of 2a decreased markedly to 6% in N,N-dimethyl-
formamide (DMF) and to 19% in acetonitrile (MeCN). When
we used t-BuOK instead of t-BuONa, we obtained 2a and 3a
in similar yields (entry 6). Decreasing the amount of t-BuOK
to 1.0 equivalents increased the yield of 2a to 40%. Surpris-
ingly, the cyanation proceeded in the absence of a base, and
2a was obtained in 32% yield (entry 7).10 This result sug-
gested that phen itself can be used as an organocatalyst for
the cyanation. Increasing the amount of phen increased the
yield of 2a, and with 50 mol% of phen, 2a was obtained in
45% yield (entry 8); this reaction was complete within three
hours. The use of 80 mol% of phen gave a similar result to
that with 50 mol% of phen (entry 9). These results are quite
different from the results of previously reported t-BuOM-
mediated cross-coupling reactions, which did not proceed
in the absence of t-BuOM. Although the reason is not clear
at present time, the reduction potentials of the iodoarene
and phen were rather close to one another [see the cyclic
voltammetry results in the Supplementary Information
(SI)], which would lead to SET from phen to the iodoarene.
a Determined by GC with dodecane as an internal standard.
b Not detected.
c Performed in DMF.
d Performed in MeCN.
e Performed with 1.0 equivalent of base.
f Performed with 50 mol% of phen.
g Performed for 3 h.
h Performed with 80 mol% of phen.
We focused on the unexpected phen-promoted cyana-
tion and we optimized the conditions for this reaction.
First, we screened several diamines as catalysts for the cya-
nation (Table 2). Without a catalyst, the reaction did not
proceed at all, and the starting material 1a was recovered
quantitatively (Table 2, entry 1). 4,7-Dichloro-1,10-phenan-
throline (dcphen) could also be used for the cyanation, but
its efficiency was lower than that of phen (entry 2). In con-
trast, 3,4,7,8-tetramethylphenanthroline (tmphen), 4,7-di-
chlorophenanthroline (Ph-phen), 4,4′-dimethyl-2,2′-bipyr-
idyl (dmbpy), 4,4′-di-tert-butyl-2,2′-bipyridyl (dtbpy), and
N,N′-dimethylethylenediamine (DMEDA) were ineffective
(entries 3–8).
Table 2 Diamine Promoted Cyanation of 1a
CN
I
Et4NCN (5.0 equiv)
diamine (50 mol%)
+
DMSO (0.1 M)
150 °C , 3 h
1a
2a
3a
Entry
Diamine
Yielda (%) of 2a
Yielda (%) of 3a
Recovered
1aa (%)
1
2
3
4
–
N.D.b
23
N.D.
20
4
>99
N.D.
89
dcphen
tmphen
Ph-phen
2
N.D.
2
94
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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Table 2 (continued)
With the optimized conditions, we conducted phen-
promoted cyanations of several aryl halides (Scheme 2).
With 1-bromonaphthalene, nitrile 2a was obtained in 19%
yield. The reaction using 1-chloronaphthalene did not give
2a at all. With iodobenzene, we obtained benzonitrile (2b)
in 48% yield. p-Iodoanisole and p-iodotoluene, which bear
electron-donating substituents, gave the corresponding ni-
triles 2c and 2d in yields of 45 and 42%, respectively. p-Io-
doacetophenone and ethyl 4-iodobenzoate, which bear
electron-withdrawing groups, gave the corresponding ni-
triles 2e and 2f in yields of 25 and 20%, respectively. In con-
trast, 4-iodobiphenyl, a -extended precursor, gave nitrile
2g in 62% yield. The dicyanated product 2h was readily ob-
tained from 4,4′-diiodobiphenyl.
Entry
Diamine
Yielda (%) of 2a
Yielda (%) of 3a
Recovered
1aa (%)
5
6
7
8
bpy
N.D.
N.D.
N.D.
N.D.
2
3
2
3
96
96
92
92
dmbpy
dtbpy
DMEDA
a Determined by GC with dodecane as an internal standard.
b Not detected.
A problem of the reaction was that dehalogenation of
the substrate competed with the desired cyanation, proba-
bly because the naphthyl radical generated from 1a partial-
ly reacted with DMSO before it reacted with Et4NCN.11 We
therefore surmised that a higher concentration would be
better for the reaction. The effect of the concentration on
the cyanation is summarized in Table 3. As expected, in-
creasing the concentration of 1a from 0.1 M to 0.3 M drasti-
cally suppressed the generation of the dehalogenated by-
product 3a, and increased the yield of 2a to 55% (Table 3,
entry 2). With 0.5 M of 1a, the yield of 2a increased to 60%
(entry 3). At a much higher concentration or under neat
conditions, the dehalogenation was efficiently suppressed,
but the yield of 2a decreased (entries 4 and 5). During the
course of further optimizations, we found that the reaction
was also markedly affected by the reaction temperature
(entries 6 and 7). When the reaction was performed at 130
°C, the yield of 2a increased considerably (entry 6). In this
case, the amount of phen could be reduced to 20 mol% and
2a was obtained in 78% isolated yield within one hour. In
contrast, 2a was not obtained at 100 °C, demonstrating that
precise control of the reaction temperature is important for
the reaction.
Et4NCN (5.0 equiv)
phen (20 mol %)
X
CN
Ar
1
Ar
2
DMSO (0.5 M)
130 °C, 1 h
CN
CN
CN
CN
MeO
Me
2a
2b
X = I, 48%
2c
2d
X = I, 78%
X = Br, 19%
X = Cl, N.D.a
X = I, 45%
X = I, 42%b
CN
CN
CN
CN
EtO2C
O
NC
2e
2f
2g
X = I, 62%
2h
X = I, 25%
X = I, 20%
X = I, 48%c
Scheme 2 Cyanation of several aryl halides under the optimized condi-
tions. Isolated yields are reported. a Not detected. b Performed at a 1.0
M concentration of 1. c Performed with Et4NCN (10 equiv).
To obtain further insights into the reaction mechanism,
we conducted two control experiments (Scheme 3). When
the cyanation was carried out in DMSO-d6, nitrile 2a was
obtained in 63% yield together with deuterated naphtha-
lene 3a-d (58% D) [Scheme 3(a)]. This result suggests that
the major hydrogen donor of the reaction is DMSO, al-
though there are other hydrogen sources.11 When the reac-
tion was carried out in the presence of 20 mol% of TEMPO,
the cyanation did not proceed at all [Scheme 3(b)]. Even
with 5 mol % of TEMPO, only a trace of 2a was obtained and
a quantitative amount of 1a was recovered. These results
suggest that the reaction proceeds via radical intermedi-
ates.12
A plausible mechanism for the phen-promoted cyana-
tion reaction is shown in Scheme 4. First, SET occurs to the
aryl iodide 1 from phen, which has a more-positive reduc-
tion potential than that of 1 (see SI); this generates a radical
anion of the aryl iodide A. Subsequent elimination of iodide
(I−) gives aryl radical B, which reacts with DMSO to give the
Table 3 Effect of the Concentration and Reaction Temperature
CN
I
Et4NCN (5.0 equiv)
phen (50 mol%)
+
DMSO
Temperature, 3 h
1a
2a
3a
Entry [1a]
(M)
Temp.
(°C)
Yielda (%) of 2a
Yielda (%) of Recovereda
3a
1a (%)
1
2
3
4
5
6
7
0.1
150
48
47
N.D.b
N.D.
0.3
0.5
1.0
neat
0.5
0.5
150
150
150
150
130
100
55
13
60
12
N.D.
58
9
N.D.
48
6
N.D.
71 (77)c (78)c,d
N.D.
10 (10)c
N.D.
N.D. (N.D.)c
95%
a Determined by GC with dodecane as an internal standard.
b Not detected.
c Performed with 20 mol% of phen.
d Performed for 1 h; isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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K. Mitsudo et al.
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cal reaction is mainly required because of the low solubility
of Et4NCN in DMSO. Indeed, the electrochemical cyanation
with Bu4NCN, which is more soluble than Et4NCN in DMSO,
could be conducted at room temperature, and the desired
product 2a was obtained in 60% yield. The high temperature
necessary for the phen-promoted reaction might be due to
the higher energy requirement for the SET from phen to the
aryl iodide. In electrochemical reaction, electron-deficient
aryl iodides gave better results than did electron-rich aryl
iodides, probably because electron-deficient aryl iodides
are more readily reduced to generate the corresponding
aryl radical species. For instance, the electrochemical reac-
tion of 4-iodoanisole did not give the desired compound 2c,
whereas that of 3-iodoanisole gave the desired compound
2i in 24% yield. In contrast, the reaction of the electron-de-
ficient aryl iodides p-iodoacetophenone, ethyl 4-iodoben-
zoate, and 4-iodobenzonitrile gave the desired products 2e,
2f, and 2j in yields of 68, 70, and 57%, respectively.
(a) Cyanation in DMSO-d6
CN
D
I
Et4NCN (5.0 equiv)
phen (50 mol %)
+
DMSO-d6 (0.1 M)
150 °C , 3 h
1a
2a
3a-d
21%
58% D
63%
(b) Effect of TEMPO
Et4NCN (5.0 equiv)
CN
I
phen (20 mol %)
TEMPO (20 mol %)
+
+
1a
DMSO (0.5 M)
130 °C, 1 h
1a
2a
3
94%
N.D.
N.D.
Scheme 3 Control experiments
–
dehalogenated product ArH. When B reacts with CN, an
aryl cyanide radical anion C is generated. Subsequent SET
from C to 1 affords the aryl cyanide 2 with regeneration of A.
As mentioned above, the cyanation reaction proceeded
in the presence of a catalytic amount of phen, meaning that
phen operates as a SET initiator in the first stage of the reac-
tion to generate the radical anion A. We therefore examined
the use of electroreduction instead of phen to generate the
initial radical anion species (Scheme 5). Electricity was sim-
ply passed through a mixed solution of the aryl iodide 1a
and Et4NCN (5.0 equiv) in DMSO at 70 °C. With 0.3 F of elec-
tricity per mole of iodide 1a, the iodide 1a was consumed
and nitrile 2a was obtained in 68% yield. Notably, the reac-
tion proceeded with a catalytic amount of electricity. This
result suggests that electricity is required for the generation
of the aryl radical species and that the subsequent catalytic
cycle proceeds without electricity in the same manner as
the phen-promoted reaction. This protocol without any
chemical initiator is operationally simple. In addition, it is
advantageous that the reactions using electricity can be
carried out at lower temperatures than those required for
the phen-promoted reactions. Heating of the electrochemi-
I
CN
Et4NCN (5.0 equiv)
Ar
1
Ar
2
undivided cell, (CF)–(Pt)
DMSO (0.5 M), 70 °C
10 mA, 0.3 F/mol (24 min)
CN
CN
CN
MeO
CN
MeO
CN
2a, 68% (60%)a
2b, 10%b
2c, N.D.
2i, 24%b
CN
CN
CN
EtO2C
NC
O
2e, 68%c
2f, 70%
2g, 36%b
2j, 57%
Scheme 5 Electroreductive cyanation of several aryl iodides. Isolated
yields are reported. a Performed with Bu4NCN (7 equiv) at r.t. using (Pt)-
–(Pt) electrodes. b Performed with Et4NCN (7 equiv) at 90 °C; 0.5 F/mol
of electricity was used. c 0.1 F/mol of electricity was used.
I–
Ar
Ar
H
N
N
N
N
DMSO
B
CN
Ar-I
[Ar-I]
A
Single-electron
transfer
[Ar-CN]
Ar-CN
C
2
Ar-I
1
Scheme 4 A plausible mechanism for the phen-promoted cyanation of aryl iodides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

E
K. Mitsudo et al.
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In conclusion, we have developed a phen-promoted cya-
nation reaction of aryl iodides with Et4NCN. Several aryl cy-
anides were synthesized by this method.13 An electrochem-
ical approach was also successful, and the cyanated prod-
ucts were obtained with a catalytic amount of electricity.
Further investigations on the phen-promoted and electro-
chemical reactions are ongoing in our laboratory.
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Funding Information
This work was supported in part by JSPS KAKENHI Grant Numbers
JP16K05695, JP16K05777, JP16H01155, and JP18H04415 in Middle
Molecular Strategy.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611793.
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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(12) It is known that the addition of TEMPO suppresses SRN1-type
reactions; see refs 9(a), 9(d), and 9(e).
(13) 1-Naphthonitrile (2a); Typical Procedure
A solution of 1-iodonaphthalene (127 mg, 0.50 mmol), Et4NCN
(391 mg, 2.50 mmol), and 1,10-phenanthroline (18.2 mg, 0.1
mmol) in DMSO (1 mL) was stirred at 130 °C for 1 h. H2O (15
mL) was added and the resulting mixture was extracted with
EtOAc (3 × 5 mL). The combined organic phase was dried
(MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography [silica gel,
hexane–EtOAc (30:1)] to give a yellow oil; yield: 59.5 mg (0.39
mmol, 78%).IR (neat): 3061, 2222, 1591, 1512, 1375 cm–1 1H
.
NMR (400 MHz, CDCl3):  = 7.53 (t, J = 7.8 Hz, 1 H), 7.63 (t, J =
7.6 Hz, 1 H), 7.70 (t, J = 7.9 Hz, 1 H), 7.87–7.96 (m, 2 H), 8.08 (d,
J = 7.9 Hz, 1 H), 8.24 (d, J = 7.9 Hz, 1 H). 13C NMR (100 MHz,
CDCl3):  = 110.0, 117.7, 124.8, 125.0, 127.4, 128.5, 128.6, 132.2,
132.5, 132.8, 133.2.
(10) Shirakawa and Hayashi reported that their cross-coupling reac-
tion did not proceed without t-BuOM [see Ref. 9(c)].
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F