Copper-catalyzed cyanation of arylboronic acids using DDQ as cyanide source

Article abstract of DOI:10.1055/s-0031-1290451

In this paper, a copper-catalyzed cyanation of arylboronic acids is achieved with DDQ, providing nitriles with good yields. This new approach represents a safe method for the synthesis of aryl nitriles. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0031-1290451

LETTER
▌2247
lCettoerpper-Catalyzed Cyanation of Arylboronic Acids Using DDQ as Cyanide
Source
Cyanation of Arylboronic Acids
Guangyou Zhang,a Shuyou Chen,a Haiyang Fei,b Jiang Cheng,*b Fan Chen*a
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325000, P. R. of China
E-mail: fanchen@wzu.edu.cn
b
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. of China
Fax +86(577)56998939; E-mail: jiangcheng@cczu.edu.cn
Received: 18.05.2012; Accepted after revision: 23.06.2012
are only five examples on such transformation (Scheme 1).
Abstract: In this paper, a copper-catalyzed cyanation of arylboron-
In 2006, Liebeskind described a palladium-catalyzed cya-
ic acids is achieved with DDQ, providing nitriles with good yields.
nation of boronic acids with thiocyanates.12 Subsequently,
This new approach represents a safe method for the synthesis of aryl
Hartwig reported the copper-mediated cyanation of aryl
boronates and boronic acids with Zn(CN)2.13 In 2011,
Beller demonstrated the rhodium-catalyzed cyanation of
aryl and alkenyl boronic acids using N-cyano-N-phenyl-
p-methylbenzenesulfonamide as a cyanation reagent.14
Recently, we developed a copper-mediated cyanation of
arylboronic acids with CuCN (or TMSCN/CuI).15 Very
recently, Chang developed a copper-mediated cyanation
of boronic acids, boronate esters, and borate salts using
ammonium iodide and DMF as the combined cyanating
source.16 Nevertheless, the development of a cyanation
protocol of arylboronic acids remains a challenging goal
for organic chemists. Herein, we present our new cyana-
tion protocol of arylboronic acids using DDQ as the cya-
nating source.
nitriles.
Key words: copper, cyanation, arylboronic acids, nitriles, DDQ
Aromatic nitriles possess versatile utilities and are found
in many natural products, pharmaceuticals, agrochemi-
cals, dyes, and so on.1 They are also important intermedi-
ates for diverse functional groups.2 Traditional methods
for the preparation of aromatic nitriles are the Sandmeyer
and Rosenmund–von Braun reactions using copper(I) cy-
anide as the cyanating source.3 With the development of
organometallic chemistry, copper- or palladium-catalyzed
cyanation of aryl (pseudo) halides is also well document-
ed (Scheme 1).4 Meanwhile, transition-metal-catalyzed
direct cyanation of C–H bonds has emerged as an attrac-
tive method because it obviates the tedious and multistep
prefunctionality (Scheme 1).5 However, in the aforemen-
tioned cyanation protocols, the ‘CN’ unit usually derived
from toxic metal-bound precursors of MCN (M = Cu, K,
Na, Zn, and TMS). To circumvent this drawback, ap-
proaches by using the combination of ammonium salts
and DMF (or DMSO) as safe cyanide sources were ap-
plied to the Pd-catalyzed cyanation of 2-arylpyridine6 and
indoles7 and cyanation of aryl halides.8 Meanwhile, cer-
tain organic precursors such as acetone cyanohydrin9 and
N-cyano-N-phenyl-p-toluenesulfonamide (NCTS)10 have
been employed in catalytic cyanations to release cyanide
in situ. However, the development of a novel cyanide
source still kept a highly desired goal for organic chem-
ists. The 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ), which is known as a dehydrogenating oxidant,
may serve as the potential cyanide source like acetone cy-
anohydrin and NCTS since it can release the HCN in the
presence of water or some organic solvent.11
We initiated our investigation by examining the reaction
of DDQ with 4-methoxyphenylboronic acid (Table 1). To
our delight, the cyanation took place with the combination
of Cu(OTf)2 (10 mol%) and K2CO3 (1.5 equiv) in dry
DMF in 30% yield (Table 1, entry 1). Using Ag2CO3 as an
additive, the yield sharply increased to 87% (Table 1, en-
try 3). The bases had important effect on the efficiency,
and K2CO3 was the best, while no product was detected
without base (Table 1, entry 19). The copper salts were
crucial for this transformation, and no product was ob-
tained in the absence of copper (Table 1, entry 18).
Among the copper examined, such as Cu(OTf)2, CuI,
CuSO4, and Cu(acac)2, Cu(OTf)2 was the best, providing
3aa in 87% yield (Table 1, entries 1 and 15–17). In the ab-
sence of DDQ, no product was detected (Table 1, entry 3).
Moreover, the procedure was tested in the DMF–H2O
(20:1, v:v), the product was obtained in only 15% yield.
The result showed that water could prohibit the efficiency.
Meanwhile, as far as the aryl donator is concerned, aryl-
borons are readily available and are convenient coupling
reagents. However, their conversions into nitriles have
been rarely studied. To the best of our knowledge, there
"CN"
ArCN
(a)
(b)
ArX
X = N2+, Cl, Br, I, OMs, OTs
"CN"
ArH
ArCN
<20 examples
"CN"
(c) ArB(OH)2
ArCN
SYNLETT 2012, 23, 2247–2250
Advanced online publication: 08.08.2012
only 5 examples
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290451; Art ID: ST-2012-W0428-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1Aryl donators in the cyanation reaction

2248
G. Zhang et al.
LETTER
With the optimized reaction conditions in hand, we tested example, 87% of 3aa was isolated while 3ab was formed
the scope of this methodology for arylboronic acids, as in 71% yield. Disappointingly, no product was detected
shown in Table 2. A series of functional groups such as by GC–MS when 4,5,5-tetramethyl-2-phenyl-1,3,2-diox-
methoxy, tert-butyl, acetyl, cyano, nitro, alkenyl, formyl, aborolane was subjected to the procedure.
and methoxycarbonyl were tolerated, and the cyanation
Table 2 Copper-Catalyzed Cyanation of Arylboronic Acids with
DDQ
products were isolated in good yields. Particularly, the
formyl group remained untouched (Table 2, entry 11).
O
The electronic properties of the substituents on the phenyl
Cl
Cl
CN
CN
ring had some effect on the reaction. Generally, the aryl-
boronic acids possessing electron-withdrawing groups
gave higher yields than those possessing electron-donat-
ing groups. Steric hindrance on the phenyl ring of arylbo-
ronic acid slightly decreased the reaction efficiency. For
B(OH)2
CN
+
R
R
1a
2a–n
3aa–an
O
Entry Arylboronic acids 2
Product 3
Yield (%)a
Table 1 Selected Results of Screening the Optimal Conditions
MeO
B(OH)2
O
1
3aa
87
Cl
Cl
CN
CN
2a
MeO
B(OH)2
+
MeO
CN
OMe
B(OH)2
2a
3aa
O
2
3
3ab
3ac
71
74
DDQ (1a)
2b
Entry Cu source
Base
Additive
Solvent
Yield
(%)a
MeS
B(OH)2
1
2
3
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
K2CO3
K2CO3
K2CO3
–
DMF
DMF
DMF
30
53
2c
AgOTf
Ag2CO3
87
B(OH)2
(0)b
4
3ad
60
4
5
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KF
AlCl3
DMF
<5
27
47
<5
47
21
2d
ZnF2
DMF
B(OH)2
6
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
–
DMSO
DCE
5
6
3ae
3af
72
72
7
2e
8
MeCN
toluene
Cl
B(OH)2
9
2f
10
11
12
13
14
15
16
17
18
19
20
1,4-dioxane <5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
<5
16
64
67
49
54
47
<5
<5
<5
B(OH)2
B(OH)2
7
8
3ag
3ah
55
83
2g
KHCO3
KOt-Bu
K2CO3
K2CO3
K2CO3
K2CO3
–
2h
2i
CuSO4
B(OH)2
Cu(acac)2
–
9
3ai
3aj
70
79
Cu(OTf)2
Cu(OTf)2
B(OH)2
–
10
O
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), Cu source (10
mol%), base (0.3 mmol), additive (0.2 mmol), dry solvent (2.0 mL),
100 °C, 20 h. Isolated yield.
2j
b No DDQ.
Synlett 2012, 23, 2247–2250
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cyanation of Arylboronic Acids
2249
Table 2 Copper-Catalyzed Cyanation of Arylboronic Acids with
DDQ (continued)
Acknowledgment
We thank the National Natural Science Foundation of China (No.
20972115), the Natural Science Foundation of Zhejiang Province
(Nos. LY12B02010 and R4110294), and the Priority Academic
Program Development of Jiangsu Higher Education Institutions for
financial support.
O
Cl
Cl
CN
CN
B(OH)2
CN
+
R
R
1a
2a–n
3aa–an
O
Supporting Information for this article is available online at
Entry Arylboronic acids 2
Product 3
Yield (%)a
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
H
B(OH)2
References and Notes
11
3ak
91
O
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Pharmaceutical Substances: Syntheses, Patents,
2k
O
Applications, 4th ed.; Thieme: Stuttgart, 2001.
B(OH)2
(b) Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H.
Bioorg. Med. Chem. 1996, 4, 1379. (c) Njar, V. C. O.;
Brodie, A. M. H. Drugs 1999, 58, 233.
12
13
3al
83
95
MeO
2l
(2) (a) Rappoport, Z. The Chemistry of the Cyano Group;
Interscience: New York, 1970. (b) Larock, R. C.
NC
B(OH)2
Comprehensive Organic Transformations; Wiley-VCH:
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3am
2m
B(OH)2
14
15
3an
3ao
88
79
O2N
2n
B(OH)2
2o
a Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), Cu(OTf)2
(10 mol%), K2CO3 (0.3 mmol), Ag2CO3 (0.2 mmol), dry DMF (2.0
mL), 100 °C, 20 h.
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In order to validate the source of the ‘CN’ in this unique
cyanation procedure, a series of experiments were per-
formed. Firstly, we found that CuI or CuSO4 instead of
Cu(OTf)2 as the catalyst also led to the cyanation product
under the same reaction conditions, which eliminated the
possibility of the carbon atom in the cyano group deriving
from Cu(OTf)2. Secondly, the result in the toluene sug-
gested that the ‘CN’ did not come from solvent (Table 1,
entry 9). Thirdly, no product was detected in the absence
of DDQ (Table 1, entry 3). Finally, ‘CN–’ was detected by
indicator paper after DDQ in dry DMF was heated at
100 °C for two hours. The result was consistent with
Thiele and Günther’s observation that DDQ gave HCN in
the presence of solvent.11 Based on these results, the ‘CN’
unit may come from DDQ. However, the mechanism in
detail is still unclear in the current stage.
In conclusion, we have demonstrated a new copper-cata-
lyzed cyanation protocol of arylboronic acids with DDQ
as the cyanide source.17 Using this protocol, a variety of
nitriles can be synthesized in high yields. Further mecha-
nistic investigation is under way.
(8) (a) Zhang, G.; Ren, X.; Chen, J.; Hu, M.; Cheng, J. Org. Lett.
2011, 13, 5004. (b) Ushijima, S.; Togo, H. Synlett 2010,
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2247–2250

2250
G. Zhang et al.
LETTER
Lett. 2011, 52, 2404. (d) Ushijima, S.; Moriyama, K.; Togo,
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(17) General Procedure of Cyanation Protocol of Arylboronic
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Under air, a reaction tube was charged with arylboronic
acids (0.2 mmol), DDQ (45.2 mg, 0.2 mmol), Cu(OTf)2
(7.2 mg, 10 mol%), K2CO3 (41.4 mg, 0.3 mmol), Ag2CO3
(55 mg, 0.2 mmol), and dry DMF (2 mL). The mixture was
stirred at 100 °C for 20 h. After the completion of the
reaction, monitored by TLC, the solvent was evaporated
under reduced pressure, and the residue was purified by flash
column chromatography on silica gel to give the product.
4-(Methylthio)benzonitrile (3ac)
Yellowlish solid; mp 61–62 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.53 (d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz,
2 H), 2.51 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 146.1,
132.2, 125.6, 119.0, 107.7, 14.7. IR (neat): ν = 2223, 1699,
1593, 1483, 1434, 1361, 1218, 1089, 816 cm–1. HRMS (EI):
m/z calcd for C8H7NS [M+]: 149.0299; found: 149.0291.
Methyl 4-Cyanobenzoate (3al)
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Ed. 2011, 50, 519.
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2012, 134, 2528.
Yellowlish solid; mp 67–68 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.12 (d, J = 8.1 Hz, 2 H), 7.73 (d, J = 8.1 Hz,
2 H), 3.95 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 165.4,
133.9, 132.2, 130.0, 117.9, 116.4, 52.6. IR (neat): ν = 2221,
1699, 1582, 1424, 1358, 1210, 1089 cm–1. HRMS (EI): m/z
calcd for C9H7NO2 [M+]: 161.0477; found: 161.0486.
Synlett 2012, 23, 2247–2250
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