Potassium tert -Butoxide Mediated Arylation of 2-Substituted Malononitriles Using Diaryliodonium Salts

Article abstract of DOI:10.1055/s-0036-1589061

Direct arylation of 2-substituted malononitriles using diaryliodonium salts without involving transition-metal catalysts was developed. By using potassium tert -butoxide as a promoter, the desired 2-substituated α-arylmalononitriles derivatives were synthesized in good to excellent yields of 55-96%. This synthetic method provided an efficient way to prepare a variety of 2-substituted arylmalononitriles which were useful in agrochemicals.

Full text of DOI:10.1055/s-0036-1589061

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
J. Han et al.
Letter
Synlett
Potassium tert-Butoxide Mediated Arylation of 2-Substituted
Malononitriles Using Diaryliodonium Salts
CN
Jianwei Han*a,b
Xiaofei Qiana
Bowen Xua
CN
t-BuOK (1.1 equiv)
CN
Ar2I+X–
R
DCM, 0 °C–r. t.
1 h
R
CN
Ar
R = Alk, Ph, ArCH2-
Limin Wang*a
29 examples
up to 96% yield
a Key Laboratory for Advanced Materials, Institute of Fine Chemicals,
School of Chemistry & Molecular Engineering, East China University
of Science and Technology, 130 Meilong Road, Shanghai 200237,
P. R. of China
jianweihan@ecust.edu.cn
wanglimin@ecust.edu.cn
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis,
Shanghai Institute of Organic Chemistry, The Chinese Academy of
Sciences, 345 Ling Ling Road, Shanghai 200237, P. R. of China
Received: 24.04.2017
Accepted after revision: 22.05.2017
Published online: 06.07.2017
lar arylation of dicyanomethylphenyl substrate in the pres-
ence of palladium catalyst and NaH in DMF at high tem-
perature of 130–140 °C.4e The intermolecular variant of ary-
lation of 2-substituted malononitriles is still unknown to
date, one concern is that the sterically hindered reactive
site by substituent and dicyano groups may be problematic.
Of note, many compounds of 2-aryl alkylmalonoitriles
bearing a quaternary carbon center was used to protect
crops from infestation by animal pests.5 Recently, we re-
ported a method of direct arylation of ethyl 2-cyanobuta-
noate derivatives by using diaryliodonium salts under tran-
sition-metal-free conditions.6 It is worth to mention that
construction of C–C bonds by metal-free arylations of ac-
tive methylene substrates using diaryliodonium salts was
attracted much attention in the recent decades.7 As a part
of our ongoing research on the development of metal-free
arylations,8 herein we presented a direct arylation of 2-sub-
stituted malononitriles with diaryliodonium salts mediated
by potassium tert-butoxide.
DOI: 10.1055/s-0036-1589061; Art ID: st-2017-u0285-l
Abstract Direct arylation of 2-substituted malononitriles using dia-
ryliodonium salts without involving transition-metal catalysts was de-
veloped. By using potassium tert-butoxide as a promoter, the desired 2-
substituated α-arylmalononitriles derivatives were synthesized in good
to excellent yields of 55–96%. This synthetic method provided an effi-
cient way to prepare a variety of 2-substituted arylmalononitriles which
were useful in agrochemicals.
Key words arylation, diaryliodonium salts, metal-free, arylmalononi-
triles, agrochemicals
α-Arylmalononitriles were demonstrated to be import-
ant compounds in organic functional materials as well as
chemical intermediates for the preparation of useful bioac-
tive agents.1–3 For examples, dicyanomethylphenyl scaffold
was well-studied in organic radicals because of their sim-
plicity in formation of radicals via a dimerization equilibri-
um (A, Figure 1).1 In light of their utilization in organic syn-
thesis, pinoxaden, the active ingredient of the herbicide for
the postemergence control of grass weeds in cereals, was
prepared with 2,4,6-trialkylaryl malononitrile as starting
material (B, Figure 1).2 Aminopyrazolopyrimidine deriva-
tives as promising drug leads for treatment of myeloprolif-
erative disorders was also synthesized from arylmalononi-
triles (C, Figure 1).3 Therefore, an efficient access to the
family of α-arylmalononitriles is still highly desirable. A
survey of the literature showed that several catalytic sys-
tems involving transition-metal complexes (copper, palla-
dium, or nickel) afforded α-arylmalonates in good yields
with cross-coupling of aryl halides with malononitrile.4
However, the construction of quaternary carbon center by
direct arylation of 2-substituted malononitriles is very rare,
one reported example by Ciufolini et al. is the intramolecu-
CN
R
Ar
CN
R
O
N
O
N
N
CN
CN
N
N
N
O
O
H2N
R
N
N
A
B
C
Aryldicyanomethyl radical
Aminopyrazolopyrimidines
Pinoxaden
Figure 1 Selective examples of useful compounds from α-aryl-
malonates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
J. Han et al.
Letter
Synlett
Inspired by our previous work,6 we initiated this study
using diphenyliodonium triflate (2a) with 2-ethylmalono-
nitrile (1a) to optimize the conditions (Table 1, entries 1–
10). It was pleased to find that the reaction gave the arylat-
ed product of ethyl 2-phenyl-2-ethylmalononitrile (3a) in
an excellent yield of 96% by using 1.1 equivalents potassium
tert-butoxide as the base in dichloromethane at 0 °C. As
shown in Table 1, we examined the impact of bases on the
reaction, it was shown that potassium hydroxide resulted in
an identical yield of 89% (Table 1, entry 3) while organic
bases of Et3N and DMAP gave no product or low yield, re-
spectively. After examining several solvents, it is found that
the solvents showed significant effect on this reaction. The
reaction also worked well in toluene, which gave 3a in high
yield of 84% (Table 1, entry 7), while the solvents MeCN,
THF, and DMF gave only a trace amount of the desired prod-
ucts (Table 1, entries 6, 9, and 10). When DCE was used as
the solvent, it gave 3a in 30% yield. Next, we evaluated dif-
ferent anions of diphenyliodonium salts. A negligible influ-
ence was observed on the yield of 3a (Table 1, entries 11–
14). In the optimization process, it revealed that the previ-
ous reported conditions of strong base of potassium tert-
butoxide in DCM was still the most efficient in delivering
the desired product of 3a.6
With the optimized reaction condition in hand, we then
investigated the substrate scope of various diaryliodonium
salts as arylation partners. The results are shown in Table 2,
the reaction system was suitable for most functional groups
on the diphenyliodonium salts, and the reactions were fin-
ished in one hour at 0 °C as determined by thin-layer chro-
matography. It was found that the results were significantly
affected by the electronic nature of the aromatic rings (Ta-
ble 2, entries 1–12). The electron-donating substituents on
the benzene ring, such as methoxy and alkyl, gave the rela-
tive higher yields. While the electron-withdrawing nitro
groups led to decomposition of the diaryliodonium salts, no
desired product was observed in this procedure (Table 2,
entry 12). Moreover, the steric factor also affected the reac-
tivity of this reaction, for example, double substituted dia-
ryliodonium salts only gave moderate yields of the desired
product 3 in comparison with their corresponding mono-
substituted diaryliodonium salts (Table 2, entries 5, 6, and
11 vs. entries 1 and 8, respectively).
Table 2 Scope of Iodonium Salts in Arylation of 2-Ethylmalononitrilea
CN
t-BuOK (1.1 equiv)
CN
+
[Ar2I]+X–
CN
DCM, 0 °C–r.t.
1 h
CN
Ar
1a
2
3
Table 1 Screening of Reaction Conditions for Arylation of Ethyl 2-
Methylcyanoacetatea
Entry
Ar
(4-MeC6H4)2
Xb
Product
Yield (%)c
CN
1
2
OTf
OTf
OTf
OTf
OTf
PF6
3b
3c
3d
3e
3f
86
88
90
85
55
65
61
65
72
62
62
0
CN
Base (1.1 equiv)
Solvent, 0 °C, 1 h
CN
+
[Ph2I]+X–
2
(4-t-BuC6H4)2
(4-MeOC6H4)2
(3-MeC6H4)2
(2,4-Me2C6H3)2
(2,5-Me2C6H3)2
(4-FC6H4)2
CN
Ph
3
1a
3a
4
Entry
Xb
Base
Solvent
Yield (%)c
5
1
2
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTs
Br
t-BuOK
DCM
DCM
DCM
DCM
DCM
MeCN
toluene
DCE
96
6
3g
3h
3i
K2CO3
KOH
82
7
OTf
OTf
OTf
OTf
BF4
PF6
3
89
8
(4-ClC6H4)2
4
Et3N
trace
23
9
(4-BrC6H4)2
3j
5
DMAP
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
10
11
12
(4-CF3C6H4)2
(3,4-Cl2C6H3)2
(3-O2NC6H4)2
3k
3l
6
trace
84
7
3m
a Reaction conditions (unless otherwise specified): 1a (0.5 mmol), iodoni-
um salt (0.55 mmol, 1.1 equiv), t-BuOK (0.55 mmol, 1.1 equiv), and DCM
(2 mL); 0 °C to r.t.; 1 h; under nitrogen.
8
30
9
THF
trace
trace
78
b OTf = trifluoromethansulfonate; OTs = 4-toluenesulfonate.
c Isolated yield.
10
11
12
13
14
DMF
DCM
DCM
DCM
DCM
70
To further investigate the scope of this reaction, a wide
variety of 2-substituted malononitrile derivatives were
phenylated into the corresponding dicyanomethylphenyl
products 4 in the presence of potassium tert-butoxide in di-
chloromethane. This reaction procedure was proved to be
efficient in the phenylation as shown in Scheme 1. 2-Alkyl
2-phenylmalononitriles 4 were obtained in good to excel-
BF4
PF6
85
88
aReaction conditions (unless otherwise specified): 1a (0.5 mmol), 2 (0.55
mmol, 1.1 equiv), base (0.55 mmol, 1.1 equiv), and solvent (2 mL); 0 °C; 1
h under nitrogen.
b OTf = trifluoromethansulfonate; OTs = 4-toluenesulfonate.
c Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
J. Han et al.
Letter
Synlett
sodium tert-butoxide under reflux in ethanol,9 the other
cyano group of 4d was cleaved off under these conditions as
determined by NMR and MS spectra. The triazines are
promising hetercyclic compounds for the development of
bioactive agents in pharmaceutical industry.3,9
CN
CN
t-BuOK (1.1 equiv)
CN
+
[Ph2I]+OTf–
R
DCM, 0 °C–r.t.
1 h
R
CN
Ph
2a
1
4
CN
CN
CN
CN
CN
CN
CN
CN
Ph
4a, 89%
Ph
Ph
Ph
NH
Ph
CN
t-BuONa (1.1 equiv)
CN
4b, 59%
4c, 88%
4d, 86%
+
H2N
N
N
NH2
EtOH, reflux
8 h
H
F
Ph
CN
N
N
Cl
CN
CN
CN
CN
NH2
6, 56% yield
CN
4d
5
CN
Ph
Ph
Ph
4e, 85%
Scheme 2 Related transformation with 4d
4f, 89%
4g, 77%
Cl
Regarding the mechanism of this reaction, the previous
reports on metal-free arylation by diaryliodonium salts
were believed to proceeded though ligand exchange with
nucleophiles by associative or dissociative mechanism.10
The ligand-coupling pathway by reductive elimination af-
fords the product along with releasing loss of ArI. Nucleo-
philic aromatic substitution (SNAr) or single-electron-trans-
fer reaction (SET) were discussed with special cases and
conditions.10b At this stage it is premature to draw a conclu-
sive mechanism of this reaction, however, based on the
mechanistic insights on the arylation involving hypervalent
iodine, a plausible mechanism of this reaction was pro-
posed as shown in Scheme 3.
CN
CN
CN
CN
CN
CN
Br
O2N
Ph
Ph
Ph
4i, 96%
4j, 77%
4h, 83%
MeO
NC
CN
CN
CN
CN
CN
Ph
4m, 90%
CN
Ph
Ph
4l, 88%
4k, 60%
CN
CN
CN
CN
CN
CN
Ph
CN
CN
Ph
Ph
Ph
Ar
I
O
OTf
I
4p, 62%
4q, 75%
4o, 85%
4n, 85%
Ar
O
Scheme 1 Arylation of 2-substituted malononitriles 1.a,b a Reaction
Ar
Ar
NC
ArI
conditions (unless otherwise specified): 1a (0.5 mmol), iodonium salt
(0.55 mmol, 1.1 equiv), t-BuOK (0.55 mmol, 1.1 equiv), and DCM (2
mL); 0 °C to r.t.; 1 h; under nitrogen.b Isolated yield.
7
NC • – CN
Ar
NC
CN
t-BuOK
NC CN
3a
or
N–
lent yields of 80–92% (Scheme 1, 4a–e). Among them (R =
chloroalkyl) 4e was furnished in good yield of 85% without
hydrolysis of the alkyl halide under the standard condi-
tions. Moreover, the desired products were obtained in
good yields of 60–96% when R of 1 is benzyl or substituted
benzyl groups. 4-Fluoro, 4-chloro, 2-bromo, 2-nitro, 4-cya-
no, 4-methyl, 4-methoxyl, and 2,4,6-trimethyl groups sub-
stituted on the 2-benzyl group regardless of their electronic
nature or steric effect were well accommodated in this re-
action (Scheme 1, 4f–n). Dicyanomethyl substrates 1 bear-
ing a phenyl group were employed, 2,2-diphenylmalononi-
trile 4o were readily prepared in 85% yield. In addition,
when R of 1 is cyclohexyl or 1-tetralin, the phenylation
products 4p and 4q were provided in a yield of 62% and
75%, respectively.
NC
ArI
Ar
I
Ar
NC
N
OTf
I
Ar
Ar
Scheme 3 Proposed mechanism for the formation of α-arylmalonates
In summary, we have succeeded in the development of
an approach for direct arylation of 2-substituted malononi-
triles using diaryliodonium salts without the use of transi-
tion-metal catalysts.11 Various 2-substituted 2-arylmalono-
nitrile were prepared in good yields, which are valuable
chemical intermediates in agrochemical or medical re-
search. Current studies are focused on further transforma-
tion of these dicyanomethylaryl products into useful het-
erocycles and synthetic utility of this arylation method in
our laboratories.
Moreover, 2-isopentyl-2-phenylmalononitrile (4d) was
employed for one further transformation. As shown in
Scheme 2, one cyano group of 4d underwent cyclization
with dicyandiamide to produce triazine 6 in 56% yield with
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
J. Han et al.
Letter
Synlett
(6) Qian, X.; Han, J.; Wang, L. Adv. Synth. Catal. 2016, 358, 940.
Funding Information
(7) (a) Chai, Z.; Wang, B.; Chen, J.-N.; Yang, G. Adv. Synth. Catal.
2014, 356, 2714. (b) Monastyrskyi, A.; Namelikonda, N. K.;
Manetsch, R. J. Org. Chem. 2015, 80, 2513. (c) Dey, C.; Lindstedt,
E.; Oloffson, B. Org. Lett. 2015, 17, 4554.
(8) (a) Guo, F.; Wang, L.; Wang, P.; Yu, J.; Han, J. Asian J. Org. Chem.
2012, 1, 218. (b) Mao, S.; Geng, X.; Yang, Y.; Qian, X.; Wu, S.;
Han, J.; Wang, L. RSC Adv. 2015, 5, 36390. (c) Zhang, Y.; Han, J.;
Liu, Z. -J. Synlett 2015, 26, 2593. (d) Qian, X.; Han, J.; Wang, L.
RSC Adv. 2016, 6, 89234. (e) Yang, Y.; Wu, X.; Han, J.; Mao, S.;
Qian, X.; Wang, L. Eur. J. Org. Chem. 2014, 6854.
The work was supported by the National Nature Science Foundation
of China (NSFC 21472213, 21272069), National Key Program
(2016YFA0200302, Study on application and preparation of aroma
nanocomposites), and the Fundamental Research Funds for the Cen-
tral Universities.
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Supporting Information
Supporting information for this article is available online at
https://doi.org /10.1055/s-0036-1589061.
(9) Li, M.-B.; Li, H.; Wang, J.; Liu, C.-R.; Tian, S.-K. Chem. Commun.
2013, 49, 8190.
S
u
p
p
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References and Notes
(11) General Procedure for the Synthesis of 3 and 4
An oven-dried Schlenk tube was charged with 2-substituted
malononitriles (0.5 mmol, 1 equiv), the tube was evacuated and
charged with nitrogen, then 2 mL anhydrous DCM and t-BuOK
(61.7 mg, 0.55 mmol, 1.1 equiv) were added, and the mixture
was stirred at 0 °C for 5 min. The solution of diaryliodonium
salts (0.55 mmol, 1.1 equiv) in 2 mL anhydrous DCM was added
through a syringe subsequently for 5 min. The reaction was
stirred for another 1 h, and the reaction temperature was ele-
vated to r.t. The reaction mixture was quenched with 20 mL
water, then the mixture was extracted with EtOAc (3 × 10 mL).
The combined extracts were washed with brine, dried over
Na2SO4, and filtered. After the solvent was removed under
vacuum, and the residue was purified by flash chromatography
to give the desired product. Analytical data for representative
sample 3a is provided below.
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2-Ethyl-2-phenylmalononitrile (3a)
81.7 mg (96% yield), colorless oil. 1H NMR (400 MHz, CDCl3): δ =
7.58–7.53 (m, 2 H), 7.52–7.45 (m, 3 H), 2.29 (q, J = 7.4 Hz, 2 H),
1.23 (t, J = 7.4 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 132.0,
129.9, 129.7, 125.8, 115.0, 43.2, 36.6, 10.0. HRMS (EI): m/z calcd
for C11H10N2 [M]+: 170.0844; found: 170.0843.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D