Highly Regioselective Phosphine-Promoted [2+2+2] Annulations of Cyanoacetylenes and N -Tosylimines to 1,2-Dihydropyridine-3,5-dicarbonitrile Derivatives

Article abstract of DOI:10.1055/s-0037-1610708

A series of fully functionalized dihydropyridine-3,5-dicarbonitrile derivatives were easily prepared through [2+2+2] annulations of cyanoacetylenes and N -tosylimines in the presence of tertiary phosphine. The scope of the cyclization reaction was investi

Full text of DOI:10.1055/s-0037-1610708

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
de
J. Zhang et al.
Letter
Synlett
Highly Regioselective Phosphine-Promoted [2+2+2] Annulations
of Cyanoacetylenes and N-Tosylimines to 1,2-Dihydropyridine-
3,5-dicarbonitrile Derivatives
R2
R2
Jinfeng Zhang
Qi Zhang
R
2 = aryl
R2
NC
R2
CN
R1
NC
R2
CN
R1
high regioselectivity
CN
Ph3P (1.0 equiv.)
Xin Ji
+
N
N
toluene, 110 °C, 36 h
Ling-Guo Meng*
0
0
0
0-0
0
0
2-7
6
8
8-3
4
7
4
Ts
R1
N
Ts
Ts
not found
26 examples
yields up to 82%
R
1 = aryl, heteroaryl
Department of Chemistry, Huaibei Normal University, Huaibei,
Anhui 235000, P. R. of China
milig@126.com
Received: 01.03.2019
Accepted after revision: 04.04.2019
Published online: 25.04.2019
kind of the most important precursor and are widely used
as substrate for the synthesis of various nitrogen-contain-
ing cyclic compounds through different cycloaddition reac-
tions, such as [2+2],8 [2+3],9 [2+4],10 [4+1],11 and [4+2]12 an-
nulations. Apart from the above reactions, sequential
[3+2]/[2+3],13 [2+3]/[2+3],14 and [4+2]/[2+3]15 annulations
were also reported. Nevertheless, there are a few reports
about multicomponent cycloaddition reactions in which N-
tosylimines were used as a precursor in the presence of or-
ganic base.8a,b Recently, the [2+2+2] cycloaddition of active
alkynes with N-tosylimines was developed by Tong’s group
and represented a convenient access to functionalized 1,2-
dihydropyridines (Scheme 1, eq. 1).16 Unfortunately, these
DOI: 10.1055/s-0037-1610708; Art ID: st-2019-w0123-l
Abstract A series of fully functionalized dihydropyridine-3,5-dicarbo-
nitrile derivatives were easily prepared through [2+2+2] annulations of
cyanoacetylenes and N-tosylimines in the presence of tertiary phos-
phine. The scope of the cyclization reaction was investigated, and the
high regioselectivity was explained by a rational reaction mechanism.
Key words phosphine, annulations, cyanoacetylenes, N-tosylimines,
regioselectivity
Dihydropyridines and its derivatives are among the
most prevalent heterocyclic structural units, and these
molecules have attracted much attention from organic
chemists, as they widely exist in pharmaceutical targets,
natural products, bioactive molecules, as well as in func-
tional materials.1 Among them, cyano-substituted dihydro-
pyridines are corrosion inhibitors, show anti-inflammatory
and fluorescence behavior, and are used as antioxidant and
coenzyme inhibitors;2 and their derivatives have also been
used as dyes for synthetic fabrics3 and in security paper.4
However, only a few reports are related to the synthesis of
cyano-substituted dihydropyridines or its derivatives be-
cause of the difficulty to directly introduce a cyano group
into a nitrogen-containing heterocycle.5 Thus, to find a new
and facile method to efficiently construct cyano-substitut-
ed dihydropyridines is a significant research task in organic
synthesis task in organic synthesis.6
Previous [2+2+2] cycloaddition:
COPh
TsN
Ph3P
Ph3P
Ph
Ph
COPh
Ph3P
O
O
O
Ph
Ph
Ts
(1)
+
N
Ph
N
Ph
O
Ts
O
Ph
O
R
R
Ph3P
R
(2)
(3)
Ph
N
Ph
R = Ph
OEt
Ph
Ts
Ph
This work:
NC
CN
CN
+
Ph3P
Ts
Ph
N
Ph
Ph
N
Ph
Ph
In the past decades, tertiary phosphine, with a compar-
atively strong and readily tunable nucleophilicity, induced
various annulation reactions based on the active alkynes or
allenes and had been certified as efficient synthetic method
to obtain multifunctional cyclic compounds under simple
reaction conditions.7 Among various electrophiles used in
phosphine-promoted cycloadditions, N-tosylimines are one
Ts
TsN
Ph3P
Ph3P
NC
Ar
Ph
CN
possible intermediate compounds
Scheme 1 Phosphine-driven [2+2+2] cycloadditions with different
reaction procedures
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
J. Zhang et al.
Letter
Synlett
synthetic methods were unworkable to construct fully sub-
stituted 1,2-dihydropyridine compounds when -substitut-
ed alkyne ketones or esters participated in the above reac-
tion through our test (Scheme 1, eq. 2). Cyanoacetylene was
often a neglected activated alkyne17 and had a better poten-
tial nucleophilicity in the presence of tertiary phosphine
due to the much stronger electron-withdrawing property of
the cyano group.
Table 1 Optimization of the Reaction Conditionsa
Ph
NC
Ph
CN
phosphine (1.0 equiv.)
Ts
Ph
CN
+
Ph
N
solvent, 110 °C, 36 h
N
Ph
3a
1a
Ts
2a
Entry
Phosphine
Solvent
Yield (%)b
To our delight, cyanoacetylene could be employed to
overcome the above-mentioned problems, and fully substi-
tuted 1,2-dihydropyridine-3,5-dicarbonitrile derivatives
were obtained with high regioselectivity (Scheme 1, eq. 3)
and compared to previous reports. These new protocols
proceeded in different reaction mechanism and had the ad-
vantages of easily controlled reaction conditions, which af-
forded the desired adducts with improved functional group
tolerance, broaden scope of the substrate, and diversity of
1,2-dihydropyridine species. Herein, we report our efforts
in the development of this annulation process, and such
studies would be of benefit in expanding the diversity of
cyano-substituted 1,2-dihydropyridine derivatives in syn-
thetic chemistry.
1
2
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
82
55c
73d
35e
60f
76g
60
3
4
5
6
7
(4-CH3C6H4)3P
(4-CH3OC6H4)3P
(4-FC6H4)3P
(4-ClC6H4)3P
Ph2MeP
DPPEh
8
58
9
46
10
11
12
13
14
15
16
17
18
19
20
42
40
33
In the initial exploration of the [2+2+2] annulation reac-
tion of cyanoacetylenes and N-tosylimines, 3-phenylpropi-
olonitrile (1a) and N-tosyl benzaldimine (2a) were chosen
as model substrates for our investigation, and the results
are summarized in Table 1. The reaction of 1a with 2a in the
presence of Ph3P (1.0 equiv.) at 110 °C in toluene for 36 h
afforded the annulation product 3a as a white solid in 82%
yield (Table 1, entry 1). The amount of Ph3P had an obvious
effect on this annulation reaction. When 0.5 equiv. of Ph3P
were used, the desired product 3a was isolated in 55% yield,
and the yield of 3a was not improved by further increasing
the amount of Ph3P (Table 1, entries 2 and 3). Further, the
yield of 3a was not successfully improved when the reac-
tion was conducted at room temperature, 80 °C, or 130 °C.
(Table 1, entries 4–6). Then in toluene solvent and 110 °C,
several tertiary phosphines were screened as promoter. It
was found that various aromatic phosphines, such as (4-
CH3C6H4)3P, (4-CH3OC6H4)3P, (4- FC6H4)3P, and (4-ClC6H4)3P
(Table 1, entries 7–10), could all promote the reaction, but
no one gave a better yield than that of using Ph3P. Mean-
while, alternative promoters such as Ph2MeP, 1,2-bis(di-
PhMe2P
Bn3P
25
18
nBu3P
<10
<10
41
DPPPyi
Ph3P
Ph3P
CH3CN
DMF
<10
NDj
NDj
Ph3P
Ph3P
DMSO
a Reaction conditions: 1a (0.40 mmol), 2a (0.20 mmol), phosphine (0.2
mmol), solvent (2.0 mL), 110 °C, in sealed tube, 36 h.
b Isolated yield.
c 0.5 equiv. of Ph3P was used.
d 2.0 equiv. of Ph3P was used.
e At room temperature.
f At 80 °C.
g At 130 °C.
h 1,2-Bis(diphenylphosphino)ethane.
i 2-(Diphenylphosphino)pyridine.
j ND: No product was detected.
h), the substrate scope and limitations for the annulations
of 3-phenylpropiolonitrile (1a) and N-tosylimines 2 were
studied (Scheme 2). For a wide range of aromatic N-to-
sylimines with either relatively electron-poor or electron-
rich aryl groups, their corresponding [2+2+2] annulations
with 1a readily proceeded, giving fully substituted 1,2-di-
hydropyridine 3 with high regioselectivity, and the repre-
sentative results are shown in Scheme 2. But the efficiency
of this reaction was relatively sensitive to changes in the
aryl substituents when different aromatic imines 2 were
tested. The substrate with an electron-donating group on
the aromatic ring gave a better yield than that with an elec-
tron-withdrawing group on the aromatic ring. The sub-
strate containing an electron-donating group, such as me-
n
phenylphosphino)ethane (DPPE), PhMe2P, Bn3P, Bu3P, and
2-(diphenylphosphino)pyridine (DPPPy) resulted in rela-
tively lower yields (Table 1, entries 11–16). Choosing Ph3P
as the optimized promoter and after testing various com-
mon solvents, toluene was found to be the best one. THF
was inferior and afforded only 41% yield of 3a. When the
solvent was switched to CH3CN, only a trace amount of 3a
was detected. No desired product was detected when DMF
and DMSO were used as solvent (Table 1, entries 17–20).
Under the preferred conditions (1.0 equiv. of Ph3P was
used as the promoter in refluxing toluene at 110 °C for 36
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
J. Zhang et al.
Letter
Synlett
thoxy and methyl, on its phenyl ring, the corresponding
products were isolated in 70% and 78% yields, respectively.
Substrate 2 containing multiple electron-donating groups
could also give the desired annulation products 3d–f) in
56–71% yields. The reaction was difficult to manipulate
when electron-withdrawing group are introduced in the
substrate.
when the substituents were phenyl bearing a chloro or bro-
mo group, nBu3P and (4-ClC6H4)3P are needed to trigger the
annulation, respectively. Treatment of N-tosylimines 2, con-
taining 3-bromo- or 3-nitrophenyl groups, with 1a also af-
forded the desired products 3j and 3k in 51% and 62%
yields, respectively. However, when a nitro group was locat-
ed at the ortho-position of its benzene ring, the correspond-
ing product 3l was obtained in only 27% yield, which might
be ascribed to steric hindrance. Furthermore, multiple elec-
tron-withdrawing groups introduced in the imine 2 also
could be converted to corresponding product, albeit the
yield was so low. In addition, N-tosylimines 2 containing 2-
naphthyl or heteroaryl groups (such as furyl, thienyl) could
also be used in the reaction. On the other hand, no desired
product was detected when aliphatic N-tosylimine was
submitted to this reaction. It should be noted that the prod-
ucts 1,2-dihydropyridine 3 were isolated as single diaste-
reomers in all tested cases, which were analyzed through
1H NMR and 13C NMR spectroscopy. Its analogues 3′ could
not be formed.18
To evaluate the scope of this reaction further, various
cyanoacetylenes were also tested under the standard condi-
tions, and the results are summarized in Scheme 3. Various
aromatic cyanoacetylenes bearing different substituents af-
forded the corresponding products 3 in moderate to good
yields. Moreover, the substrate with an electron-donating
group on the aromatic ring gave a better yield than that
with an electron-withdrawing group. For example, cyano-
acetylenes with electron-donating functionalities, such as
methyl, propyl, tert-butyl groups, reacted with different N-
tosylimines to afford the corresponding products 3q–w in
48–70% yields. While electron-withdrawing functionalities,
such as fluoro and chloro groups, introduced in substrate 1,
the yields of products 3x–z were decreased to 45–47%. No-
tably, the bulk of the substituents in 1 had slight effect on
the yield of this annulation (3r vs 3s vs 3u; 3t vs 3w). Fur-
thermore, aliphatic cyanoacetylene was in place of aromat-
ic cyanoacetylene, the reaction was disordered, and the de-
sired product cannot be detected. The structures of com-
pound 3 were identified by 1H NMR and 13C NMR
spectroscopy and HRMS analysis.
Ph
Ph
Ph
CN
NC
Ph
CN
R1
NC
Ph
CN
R1
Ph3P (1.0 equiv.)
1a
+
toluene, 110 °C, 36 h
N
N
Ts
R1
N
Ts
Ts
3a
3' not formed
2
Ph
Ph
Ph
NC
Ph
CN
NC
Ph
CN
NC
Ph
CN
N
N
N
Ts
Ts
Ts
OMe
Me
3b, 70%
3c, 78%
3a, 82%
Ph
Ph
Ph
NC
CN
NC
Ph
CN
NC
CN
OMe
OMe
OMe
OMe
O
O
Ph
N
N
Ph
N
Ts
Ts
Ts
3f, 56%
3d, 71%
3e, 67%
OMe
CN
Ph
Ph
Ph
NC
Ph
CN
NC
Ph
CN
NC
N
N
Ph
N
Ts
Ts
Ts
Cl
F
Br
3h, < 5% (32%)b
3i, < 5% (47%)c
3g, 45%
Ph
Ph
Ph
NC
CN
NC
CN
NC
Ph
CN
CN
NO2
NO2
Br
Ph
N
Ts
Ph
N
Ts
N
Ts
3k, 62%
3l, 27%
3j, 51%
Ph
Ph
Ph
NC
Ph
NC
Ph
CN
NC
CN
NO2
Cl
O
N
N
Ts
Ph
N
Ts
Ts
3m, 14%
3n, 71%
3o, 62%
Ph
NC
Ph
CN
X-ray crystallographic analysis for representative com-
pound 3q provided unequivocal evidence for the position of
double bond in the structure of the annulation product, and
the corresponding CIF data were presented in the Support-
ing Information. Furthermore, with the obtained fully func-
tionalized 1,2-dihydropyridine-3,5-dicarbonitrile deriva-
tives in hand, their further transformation into pyridine-
3,5-dicarbonitrile derivatives is desirable. When typical
1,2-dihydropyridine-3,5-dicarbonitrile derivative 3a or 3j
was solved into DMF, and the mixture was performed at
140 °C for 12 h, the corresponding pyridine-3,5-dicarboni-
trile products 4a and 4b were obtained in 96% and 92%
yields, respectively.
S
N
Ts
3p, 55%
Scheme 2 Ph3P-mediated formal [2+2+2] cycloadditions of 3-phenyl-
propiolonitrile (1a) with N-tosylimines. Reaction conditions: 1a (0.4 mmol),
2 (0.2 mmol), Ph3P (0.20 mmol), toluene (2.0 mL), 110 °C, in sealed
tube, 36 h.a Isolated yields. b 1.0 equiv. of nBu3P was used.c1.0 equiv. of
(4-ClC6H4)3P was used.
For example, the substituent was a phenyl group bear-
ing a fluoro group that could be converted into the desired
product in 45% yield under optimized conditions. However,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
J. Zhang et al.
Letter
Synlett
The reaction is believed to be initiated by the nucleophilic
addition of Ph3P to the 3-phenylpropiolonitrile (1a), thus
giving the zwitterionic intermediate A, followed by two
consecutive nucleophilic attacks of another molecular 1a
and N-tosylimines 2 to afford intermediate B to generate C
through two consecutive proton-transfer steps. Then elimi-
nation of Ph3P yields intermediate D. Our attempts to iso-
late D were not successful which might be ascribed to its
unstable structure property, and D is rapidly reacted with
Ph3P to give E. Then electron-transfer-generated intermedi-
ate F, which undergoes an intramolecular nucleophilic at-
tack of the nitrogen anion (TsN–) to the double bond (Mi-
chael-type) to give intermediate G, followed by elimination
of Ph3P to afford the desired product 3. On the other hand,
intermediate D also might be converted into 3 through 6-
annulation mode. Meanwhile, it is worth noting that 3′
could not be formed because of the failed transformation of
B into H due to the steric hindrance.
R2
R2
CN
1
NC
CN
R1
Ph3P (1.0 equiv.)
R2
N
+
toluene, 110 °C, 36 h
Ts
Ts
R1
N
2
3a
Me
Me
NC
CN
NC
CN
OMe
OMe
N
N
Ts
Ts
Me
OMe
Me
3q, 64%
3r, 70%
nPr
nPr
NC
NC
NC
CN
NC
NC
NC
CN
CN
CN
Ph
Ph
OMe
OMe
O
O
NC
Ph
CN
Ar
NC
CN
Ar
N
N
Ts
Ts
Ph
nPr
tBu
F
nPr
tBu
tBu
N
N
Ph3P
3t, 61%
Ts
3s, 63%
Ts
Ph3P
3'
H
tBu
tBu
CN
Ph
Ph
CN
CN
Ts
Ph
Ph
Ar
N
Ph
CN
CN
Ph3P
2
1a
Ph3P
TsN
Ph3P
Ph
CN
Ph3P
OMe
OMe
OMe
OMe
N
N
CN
Ar
Ts
Ts
B
A
1a
[1,2]-H
3u, 55%
transfer
3v, 48%
OMe
tBu
F
CN
Ar
CN
CN
CN
Ph
Ph
Ph
Ph
[1,6]-H
transfer
Ph
Ph
Ph
Ph
Ph3P
Ph3P
Ph3P
TsHN
TsN
TsHN
TsN
CN
CN
CN
CN
Ph3P
CN
Ar
Ar
Ar
D
C
6π-annulation
O
O
OMe
OMe
N
N
Ph3P
Ts
Ts
CN
CN
Ph
PPh3
3x, 46%
3w, 50%
Ph
Ph
Ph
Ph
Ph
NC
Ph
CN
NC
Ph
CN
Ar
Cl
Cl
PPh3
CN
PPh3
CN
TsN
TsN
N
Ar
Ph P
3
N
Ts
Ts
Ar
E
Ar
F
G
3
NC
CN
NC
CN
Scheme 4 Proposed reaction mechanism
OMe
OMe
N
N
Ts
Ts
Cl
Cl
OMe
In conclusion, an easy and facile protocol for the synthe-
sis of fully functionalized 1,2-dihydropyridine-3,5-dicarbo-
nitrile derivatives has been developed by [2+2+2] annula-
tion of cyanoacetylene and N-tosylimine.19 These nitrogen
heterocyclic compounds prepared from the reactions are
important compounds which exhibit interesting biological
and pharmacological properties. A plausible mechanism
has been proposed to explain this annulation with high re-
gioselectivity. Further investigations using new phosphine-
3y, 47%
OMe
3z, 45%
Scheme 3 Ph3P-mediated formal [2+2+2] cycloaddition reactions of
cyanoacetylenes 1 and N-tosylimines 2. Reaction conditions: 1 (0.40
mmol), 2 (0.20 mmol), Ph3P (0.20 mmol), toluene (2.0 mL), 110 °C, in
sealed tube, 36 h. a Isolated yields.
Although the detailed reaction mechanism is not clear
at the current stage, a rational reaction pathway is pro-
posed and is different from Tong’s mechanism (Scheme 4).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
J. Zhang et al.
Letter
Synlett
mediated multicomponent cycloaddition reactions to the
synthesis of other heterocycles are currently underway in
our laboratory.
(8) (a) Zhao, G.-L.; Huang, J.-W.; Shi, M. Org. Lett. 2003, 5, 4737.
(b) Zhao, G.-L.; Shi, M. J. Org. Chem. 2005, 70, 9975. (c) Meng, L.-
G.; Cai, P.; Guo, Q.; Xue, S. J. Org. Chem. 2008, 73, 8491.
(9) For selected examples about [2+3] cycloadditions, see: (a) Xu,
Z.; Lu, X. J. Org. Chem. 1998, 63, 5031. (b) Zhu, X.-F.; Henry, C. E.;
Kwon, O. Tetrahedron Lett. 2005, 61, 6276. (c) Fang, Y.-Q.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660. (d) Zhang, B.;
He, Z.; Xu, S.; Wu, G.; He, Z. Tetrahedron 2008, 64, 9471.
(e) Zheng, S.; Lu, X. Org. Lett. 2008, 10, 4481. (f) Wang, Y.-Q.;
Zhang, Y.; Dong, H.; Zhang, J.; Zhao, J. Eur. J. Org. Chem. 2013,
3764. (g) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031.
Funding Information
We gratefully acknowledge the Project of Science and Technology of
the Department of Education, Anhui Province (No.KJ2017B005), and
the Natural Science Foundation of Anhui (No.1708085MB45) for fi-
nancial support of this work.
N
aturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
A
n
h
u
iPro
v
i
n
c
e
(1
7
0
8
0
8
5
M
B
4
5)
(10) For selected examples about [2+4] cycloadditions, see: (a) Zhu,
X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716.
(b) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.
(11) Tian, J.; Zhou, R.; Sun, H.; Song, H.; He, Z. J. Org. Chem. 2011, 76,
2374.
(12) Shi, Z.; Loh, T.-P. Angew. Chem. Int. Ed. 2013, 52, 8584.
(13) Li, E.; Jia, P.; Liang, L.; Huang, Y. ACS Catal. 2014, 4, 600.
(14) Yang, L.-J.; Wang, S.; Nie, J.; Li, S.; Ma, J.-A. Org. Lett. 2013, 15,
5214.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610708.
S
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p
p
orti
n
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o
n
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(19) Typical Procedure for the Highly Regioselective Annulations
of Cyanoacetylenes and N-Tosylimines
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To a solution of cyanoacetylenes (0.4 mmol) with N-tosylimines
(0.2 mmol) in toluene (2 mL) was added Ph3P (0.2 mmol). The
mixture was then stirred at 110 °C for 36 h in a reaction flask.
Then the solvent was removed in vacuo, and residue was puri-
fied by column chromatography on silica gel to give the desired
product 3a. Yield 82%; yellow solid; mp 230–231 °C. 1H NMR
(400 MHz, CDCl3):  = 7.63 (d, J = 8.0 Hz, 2 H), 7.54–7.38 (m, 13
H), 7.35 (d, J = 8.0 Hz, 2 H), 7.24–7.19 (m, 2 H), 6.46 (s, 1 H), 2.39
(s, 3 H). 13C NMR (100 MHz, CDCl3):  = 153.5, 148.0, 145.8,
135.3, 134.1, 132.9, 132.4, 132.3, 130.8, 130.1, 130.0, 129.6,
129.3, 128.7, 128.5, 128.3, 127.1, 127.0, 116.0, 115.5, 102.1,
100.4, 58.7, 21.4. HRMS (ESI): m/z calcd for C32H24N3O2S [M +
H]+: 514.1584; found: 514.1584.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E