Alkylation of 2-(2,4-dichlorophenyl)-3-cyano-6-methyl-4-(1H-1,2,4-triazol-1-yl)methylpyridine at the methylene group

Article abstract of DOI:10.1007/s10593-016-1932-5

[Figure not available: see fulltext.] The reactivity of the 1-triazolyl- and 1-imidazolyl-substituted methylene groups at position 4 of pyridine ring toward alkyl halides is described. Nitrogen heterocycles attached to the methylene group, as well as a 3-cyano group effectively promoted the alkylation, offering a convenient method for constructing structurally diverse molecules that may present pharmaceutical interest.

Full text of DOI:10.1007/s10593-016-1932-5

DOI 10.1007/s10593-016-1932-5
Chemistry of Heterocyclic Compounds 2016, 52(8), 564–569
Alkylation of 2-(2,4-dichlorophenyl)-3-cyano-
6-methyl-4-(1H-1,2,4-triazol-1-yl)methylpyridine
at the methylene group
Yan Zhu1, Zhengyan Cai1, Qun Hao1, Weicheng Zhou1*
1 State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives,
Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry,
285 Gebaini Lu, Shanghai 201203, China; е-mail: zhouweicheng58@163.com
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(8), 564–569
Submitted July 19, 2016
Accepted August 17, 2016
Cl
Cl
CN R1
CN
Me
CN
Cl
R1X, NaH
R
R
DMF, rt, N2
N
N
Cl
Cl
Cl
Me
R = 1-triazolyl, 1-imidazolyl
R1 = Me, Et, CHMe2, CH2C6H11, CH2Ph
The reactivity of the 1-triazolyl- and 1-imidazolyl-substituted methylene groups at position 4 of pyridine ring toward alkyl halides is
described. Nitrogen heterocycles attached to the methylene group, as well as a 3-cyano group effectively promoted the alkylation, offer-
ing a convenient method for constructing structurally diverse molecules that may present pharmaceutical interest.
Keywords: activated methylene compounds, alkyl halides, phenylpyridines, structure–reactivity relationships.
Great advances have been achieved in the field of DPP4
(dipeptidyl peptidase-4) inhibitors as a new class of
antihyperglycemic agents during the last decade. Nine
DPP4 inhibitors have been approved so far for the treat-
ment of type 2 diabetes, including sitagliptin, vildagliptin,
saxagliptin, alogliptin, linagliptin, and related drugs.
Clinical use of these medications has shown the advantages
of decreased risk of hypoglycemia and potential for weight
loss compared to earlier therapies, attracting considerable
interest of many researchers toward DPP4 inhibitors.1
Numerous biaryl scaffolds have recently emerged as a new
class of potent and selective DPP4 inhibitors. These include
derivatives of 6-phenylbenzimidazole,2 1,2-dihydro-4-phenyl-
1-isoquinolone,3 4-phenylquinoline,4 5-phenylpyrido-
pyrimidinedione,5 4-phenyl-7-oxopyrrolopyridine,6 5-phenyl-
imidazo[1,2-a]pyrimidine,7 and phenylpyridine.8–10
In a continuation of search for new DPP4 inhibitors
containing biaryl scaffolds, we designed a series of triazole-
containing phenylpyridine derivatives. Compound 1a was
used as a critical intermediate for the preparation of the
target compounds. While characterizing the structure of
compound 1a by 1H NMR spectroscopy in DMSO-d6 solu-
tion, hydrogen–deuterium exchange was unexpectedly
observed between deuterium oxide and the methylene
group linking the pyridine and triazole rings, which pointed
to the CH acidity of these methylene protons. This sur-
prising observation provoked our interest to further evaluate
the reactivity of this type of 4-substituted phenylpyridine
compounds. Thus, we wish to report here the results of
alkylation of various 4-substituted phenylpyridine deriva-
tives 1 with some alkyl halides under alkaline conditions.
The synthesis of compound 1a is illustrated in Scheme 1.
2,4-Dichlorobenzonitrile was treated with MeCN in the
presence of t-BuOK to form acrylonitrile 3.11 Cyclization
of compound 3 with ethyl 2,4-dioxovalerate in AcOH gave
pyridine 4.12 After reduction of compound 4 by NaBH4, the
corresponding alcohol 5 was finally converted to com-
pound 1a by a Mitsunobu reaction with 1,2,4-triazole.
1H NMR analysis of compound 1a revealed that the
methylene group singlet at 5.75 ppm was partially deuterated
when D2O was added (Fig. 1). This phenomenon indicated
the existence of an acidic methylene group, which prompted us
to further explore its reactivity through alkylation reactions.
We began our investigations with the reaction of
compound 1a with MeI (Scheme 2, Table 1, entries 1–7).
The reaction was conducted by adding compound 1a into a
suspension of NaH (1.5 equiv) in DMF, followed by the
addition of 2 equiv of MeI. After stirring at room
temperature for 2 h, the reaction mixture was separated by
silica gel column chromatography to give the product in
0009-3122/16/52(8)-0564©2016 Springer Science+Business Media New York
564

Chemistry of Heterocyclic Compounds 2016, 52(8), 564–569
Scheme 1
1
1
Figure 1.1H NMR study of compound 1a. a) H NMR spectrum before adding D2O, b) H NMR
spectrum after maintaining with D2O for 2 days.
565

Chemistry of Heterocyclic Compounds 2016, 52(8), 564–569
Scheme 2
Scheme 3
Table 1. The reactivity of compounds 1a–d toward MeI
Table 2. Reactions of compound 1a with alkyl halides*
Com-
pound
Base
(1.5 equiv)
Product
(Yield, %)
Entry
RX
Product
Yield, %
Entry
R
Solvent
1
2
3
4
5
6
7
8
9
1-Triazolyl
1-Triazolyl
1-Triazolyl
1-Triazolyl
1-Triazolyl
1-Triazolyl
1-Triazolyl
Methoxy
NaH
NaOH
TEA
K2CO3
NaH
NaH
NaH
NaH
NaH
DMF
DMF
DMF
DMF
THF
DMSO
PhMe
DMF
DMF
DMF
7a (75)
7a (59)
No reaction
No reaction
7a (64)
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1
2
3
4
5
EtI
EtBr
69
71
73
68
75
7b
7b
7c
7d
7e
i-PrBr
C6H11CH2Br
PhCH2Br
7a (70)
No reaction
No reaction
No reaction
8 (70)
* Reaction conditions: inert atmosphere (N2), a solution of compound 1a
in DMF was added into a suspension of NaH (1.5 equiv) in DMF at 0°C
and stirred for 20 min, RX (2 equiv) was injected into the reaction mix-
ture, and stirring was continued at room temperature.
1-Pyrrolidinyl
1-Imidazolyl
10
NaH
75% yield (Table 1, entry 1). Other reaction parameters
such as the selection of base and solvent were examined.
Changing the base to NaOH instead of NaH resulted in a
decrease of the yield to 59% (entry 2). No product was
observed with TEA or K2CO3 used as the base (entries 3, 4).
When the solvent DMF was replaced with THF, DMSO, or
toluene the yield deteriorated or the reaction failed
altogether (entries 5–7). The reaction was apparently
promoted by polar solvents such as DMF and DMSO.
The reactivity of compound 1a with other alkyl halides
was explored further (Scheme 3), and the results are shown
in Table 2. Under the optimal conditions, compound 1a
could react efficiently with a variety of alkyl halides in
yields ranging from 68 to 75%. No substantial reactivity
difference toward ethyl iodide and ethyl bromide was
observed (Table 2, entries 1, 2). It seemed that the steric
bulk of these alkylating agents had little effect on the
reaction (entries 3, 4). Similar yields were obtained with
both isopropyl bromide and cyclohexylmethyl bromide,
compared to bromoethane.
In order to further investigate the structure–reactivity
relationships of the active methylene group at position 4 of
pyridine ring, various functionalities including methoxy,
1-pyrrolidinyl, and 1-imidazolyl groups were also intro-
duced instead of the 1-triazolyl group by mesylation and
substitution reactions starting from compound 6 (Scheme 1).
The reactions of these derivatives with MeI were carried
out under the same conditions (Scheme 2), with the results
described in Table 1. As shown in Table 1, the reactivity of
the tested compounds was significantly affected by the
functional groups connected to the methylene linker. For
example, the derivative bearing 1-imidazolyl group could
be efficiently methylated with MeI in 70% yield while the
substrates containing methoxy or pyrrolidinyl groups failed
to undergo this reaction (Table 1, entries 8–9).
The results suggested that the reactivity of carbanions
generated from the methylene linker could be effectively
enhanced by aromatic nitrogen heterocycles (imidazole and
triazole) linked by the methylene group to position 4 of
pyridine ring. This might be mainly due to the p-π
conjugation between carbanion and two adjacent aromatic
conjugated systems, namely, pyridine ring and imidazole or
triazole. At the same time, methoxy and pyrrolidinyl
groups showed only weak electron-withdrawing effects that
were not sufficient to stabilize the carbanion. On the other
hand, when the cyano group in compound 1a was reduced
to an aminomethyl group, no hydrogen–deuterium exchange
between deuterium oxide and the methylene group adjacent
to the aminomethyl group was observed in 1H NMR
spectra acquired in DMSO-d6 solution. This indicated that
the strong electron-withdrawing effects of cyano group
might also contribute to delocalization of the negative
charge of the carbanion, which would provide an additional
stabilizing effect to enhance the reactivity of methylene
group toward alkylation reactions.
Thus, we have demonstrated the reactivity of the active
methylene group at position 4 of pyridine ring through
the reaction of 4-[(triazol-1-yl)methyl]pyridine and
4-[(imidazol-1-yl)methyl]pyridine derivatives with some
alkyl halides. The presence of nitrogen heterocycles
including imidazole and triazole at the methylene group,
as well as the cyano group in the pyridine ring were
important for enabling these alkylation reactions, and this
method could conveniently provide a series of structurally
diverse compounds that may be of interest for medicinal
chemists.
566

Chemistry of Heterocyclic Compounds 2016, 52(8), 564–569
Experimental
mixture was stirred at ambient temperature for 2 h. Then
H2O (5 ml) was added and the aqueous phase was extracted
with EtOAc (2×5 ml). The combined organic layers were
dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography using CH2Cl2 as eluent to give 0.521 g
1H and 13C NMR spectra were acquired on a Bruker
AV-400 instrument (400 and 100 MHz, respectively) in
CDCl3 solution, TMS was used as internal standard. HRMS
data were acquired on an Agilent 6210TOF instrument
equipped with an electrospray ionization (ESI) source.
Melting points were determined on a Buchi Melting Point
M-565 apparatus and are uncorrected.
The starting materials were purchased from commercial
suppliers and used without further purification. The
synthesis of compounds 3 and 4 was performed according
to the reported methods.11,12
1
(83%) of compound 6. Mp 86–87°C. H NMR spectrum,
δ, ppm (J, Hz): 2.75 (3H, s, 6-CH3); 3.21 (3H, s, SO2CH3);
5.45 (2H, s, CH2); 7.41 (2H, m, H-5,6 Ar); 7.50 (1H, s, H-3
Ar); 7.58 (1H, s, H-5 Py). 13C NMR spectrum, δ, ppm:
25.2; 38.0; 66.8; 105.8; 114.4; 121.2; 127.6; 130.0;
131.6; 133.6; 135.0; 136.6; 146.7; 159.5; 163.6. Found,
m/z: 369.9953 [M]+. C15H12Cl2N2O3S. Calculated, m/z:
369.9946.
2-(2,4-Dichlorophenyl)-4-hydroxymethyl-6-methyl-
nicotinonitrile (5). A suspension of compound 4 (12.00 g,
35.82 mmol) and NaBH4 (3.40 g, 89.55 mmol) in t-BuOH
(125 ml) was stirred at 35°C for 6 h. Then the reaction
mixture was poured into ice water (200 ml). After cooling
the mixture below 5°C, 50% AcOH solution was added to
adjust pH to 7. The yellow precipitate was filtered off and
purified by recrystallization from EtOAc–petroleum ether
mixture to afford 6.83 g (65%) of compound 5 as a light-
2-(2,4-Dichlorophenyl)-4-(methoxymethyl)-6-methyl-
nicotinonitrile (1b). A mixture of compound 6 (0.260 g,
0.70 mmol) and MeONa (0.076 g, 1.41 mmol) in MeOH
(5 ml) was stirred at room temperature for 18 h. Then H2O
(5 ml) was added and the solution was adjusted to pH 7
with 2 N HCl solution. The aqueous phase was extracted
with EtOAc (3×5 ml). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography using CH2Cl2 as eluent to give
1
yellow powder. Yield 65.0%. Mp 148–150°C. H NMR
spectrum, δ, ppm (J, Hz): 2.56 (1H, t, J = 5.2, OH); 2.72
(3H, s, 6-CH3); 4.95 (2H, d, J = 5.2, CH2); 7.38 (1H, d,
J = 8.4, H-6 Ar); 7.41 (1H, dd, J = 8.4, J = 2.0, H-5 Ar);
7.55 (1H, d, J = 2.0, H-3 Ar); 7.57 (1H, s, H-5 Py). 13C
NMR spectrum, δ, ppm: 25.1; 61.7; 105.0; 114.7; 120.1;
127.5; 130.0; 131.5; 133.6; 135.3; 136.3; 154.3; 159.0;
162.9. Found, m/z: 292.0177 [M]+. C14H10Cl2N2O.
Calculated, m/z: 292.0170.
1
0.179 g (83%) of product 1b. Mp 95–96°C. H NMR
spectrum, δ, ppm (J, Hz): 2.71 (3H, s, 6-CH3); 3.57 (3H, s,
CH3); 4.71 (2H, s, CH2); 7.38 (1H, d, J = 8.0, H-6 Ar); 7.41
(1H, d, J = 8.0, J = 1.6, H-5 Ar); 7.50 (1H, s, H-5 Py); 7.56
(1H, d, J = 1.6, H-3 Ar). 13C NMR spectrum, δ, ppm: 25.2;
59.3; 71.1; 105.4; 114.8; 120.4; 127.5; 129.9; 131.6; 133.7;
135.5; 136.2; 151.9; 159.0; 162.8. Found, m/z: 306.0327
[M]+. C15H12Cl2N2O. Calculated, m/z: 306.0327.
2-(2,4-Dichlorophenyl)-6-methyl-4-[(1H-1,2,4-triazol-
1-yl)methyl]nicotinonitrile (1a). DEAD (1.67 g, 9.57 mmol)
was added to a solution of compound 5 (2.00 g, 6.83 mmol),
1,2,4-triazole (0.66 g, 9.57 mmol), and Ph3P (2.51 g,
9.57 mmol) in THF (20 ml) at 0–5°C. The mixture was
stirred at ambient temperature for 2 h and the solvent was
evaporated under vacuum. The residue was dissolved in
CH2Cl2 (35 ml) and 3 N HCl/MeOH solution (4 ml) was
added to form the hydrochloride salt which was separated
by filtration. Then the filtrate was added to a mixture of
H2O (10 ml) and CH2Cl2 (10 ml), and 2 N NaOH solution
was added to basify the aqueous layer, followed by
extraction with CH2Cl2 (5×10 ml). The organic layers were
combined, dried over Na2SO4, and evaporated under
reduced pressure to give 2.1 g (83%) of compound 1a as a
Synthesis of nicotinonitriles 1c,d (General method).
A mixture of compound 6 (1.50 g, 4.05 mmol), pyrrolidine
or imidazole (8.11 mmol), and K2CO3 (0.67 g, 4.86 mmol)
in MeCN (15 ml) was stirred at room temperature for 5 h.
After the reaction was complete, the solvent was
evaporated under vacuum. The residue was purified by
silica gel column chromatography using 60:1 CH2Cl2–
MeOH as eluent, giving the pure products 1c,d.
2-(2,4-Dichlorophenyl)-6-methyl-4-(pyrrolidin-1-yl-
methyl)nicotinonitrile (1c). Yield 73%. White solid. Mp
1
103–104°C. H NMR spectrum, δ, ppm (J, Hz): 1.86–1.89
(4H, m, H pyrrolidine); 2.65–2.67 (4H, m, H pyrrolidine);
2.70 (3H, s, 6-CH3); 3.91 (2H, s, CH2); 7.40 (2H, s, H-5,6 Ar);
7.51 (1H, s, H-5 Py); 7.56 (1H, s, H-3 Ar). 13C NMR
spectrum, δ, ppm: 23.7 (2C); 25.0 (2C); 54.3; 57.5; 107.2;
115.3; 122.4; 127.4; 129.9; 131.6; 133.7; 135.7; 136.1;
153.3; 159.1; 162.3. Found, m/z: 345.0793 [M]+. C18H17Cl2N3.
Calculated, m/z: 345.0800.
1
light-yellow solid. Mp 125–127°C. H NMR spectrum,
δ, ppm (J, Hz): 2.65 (3H, s, 6-CH3); 5.60 (2H, s, CH2); 7.00
(1H, s, H-5 Py); 7.36 (1H, d, J = 8.4, H-6 Ar); 7.40 (1H, dd,
J = 8.4, J = 1.6, H-5 Ar); 7.55 (1H, d, J = 1.6, H-3 Ar);
8.06 (1H, s, H triazole); 8.31 (1H, s, H triazole). 13C NMR
spectrum, δ, ppm: 25.2; 50.5; 106.2; 114.6; 121.3; 127.6;
130.1; 131.6; 133.5; 134.9; 136.6; 144.3; 147.7; 153.2;
159.7; 163.7. Found, m/z: 343.0394 [M]+. C16H11Cl2N5.
Calculated, m/z: 343.0392.
2-(2,4-Dichlorophenyl)-4-[(1H-imidazol-1-yl)methyl]-
6-methylnicotinonitrile (1d). Yield 81%. Light-yellow
1
solid. Mp 110–112°C. H NMR spectrum, δ, ppm (J, Hz):
2.64 (3H, s, 6-CH3); 5.42 (2H, s, CH2); 6.72 (1H, s, H-5 Py);
7.04 (1H, s, H imidazole); 7.24 (1H, s, H imidazole); 7.39
(1H, d, J = 8.0, H-6 Ar); 7.44 (1H, dd, J = 8.0, J = 1.6, H-5 Ar);
7.59 (1H, d, J = 1.6, H-3 Ar); 7.67 (1H, s, H imidazole).
13C NMR spectrum, δ, ppm: 25.2; 48.0; 105.7; 114.6;
119.5; 120.0; 127.6; 130.0; 130.9; 131.5; 133.5; 135.0;
[3-Cyano-2-(2,4-dichlorophenyl)-6-methylpyridin-4-yl]-
methyl methanesulfonate (6). MsCl (0.234 g, 2.05 mmol)
was added to a solution of compound 5 (0.500 g, 1.71 mmol)
and TEA (0.380 g, 3.42 mmol) in THF (5 ml) at 0–5°C. The
567

Chemistry of Heterocyclic Compounds 2016, 52(8), 564–569
136.6; 137.8; 149.7; 159.6; 163.9. Found, m/z: 342.0435
H-5 Ar); 7.57 (1H, d, J = 2.0, H-3 Ar); 8.10 (1H, s,
H triazole); 8.30 (1H, s, H triazole). 13C NMR spectrum,
δ, ppm: 25.3; 25.8; 26.0; 26.1; 32.1; 33.4; 34.2; 42.3; 58.6;
106.0; 114.8; 120.1; 127.6; 130.0; 131.6; 133.6; 135.2;
136.5; 143.8; 152.5; 152.8; 159.5; 163.5. Found, m/z:
439.1333 [M]+. C23H23Cl2N5. Calculated, m/z: 439.1331.
2-(2,4-Dichlorophenyl)-6-methyl-4-[2-phenyl-1-(1H-
1,2,4-triazol-1-yl)ethyl]nicotinonitrile (7e). Yield 75%.
[M]+. C17H12Cl2N4. Calculated, m/z: 342.0439.
Synthesis of nicotinonitriles 7a–e (General method).
A solution of compound 1a (1.00 g, 2.91 mmol) in DMF
(2 ml) was added under N2 atmosphere to a cooled (0°C)
suspension of NaH (0.17 g, 4.36 mmol) in anhydrous DMF
(8 ml). After 20 min of stirring, the appropriate alkyl halide
(5.82 mmol) was injected. The mixture was stirred at room
temperature for 2 h. After the reaction was complete,
saturated NH4Cl solution (50 ml) was added and the water
phase was extracted with EtOAc (3×15 ml). The organic
phase was collected, dried over Na2SO4, and evaporated
under vacuum. The residue was purified by silica gel
column chromatography using CH2Cl2–MeOH, 50:1 as
eluent, giving the pure products 7a–e.
1
Light-yellow oil. H NMR spectrum, δ, ppm (J, Hz): 2.73
(3H, s, 6-CH3); 3.45–3.50 (1H, m) and 3.77–3.83 (1H, m,
CHCH2); 5.89–5.93 (1H, m, CHCH2); 7.08–7.10 (2H, m,
H Ph); 7.25–7.26 (3H, m, H Ph); 7.37 (1H, d, J = 8.0, H-6
Ar); 7.42 (1H, dd, J = 8.0, J = 1.6, H-5 Ar); 7.57 (1H, d,
J = 1.6, H-3 Ar); 7.71 (1H, s, H-5); 8.03 (1H, s, H triazole);
8.11 (1H, s, H triazole). 13C NMR spectrum, δ, ppm: 25.4;
41.3; 62.9; 106.3; 114.9; 120.5; 127.6; 127.7; 128.9; 129.0;
130.0; 131.6; 133.6; 135.1 (2C); 136.6; 144.3; 151.2;
152.8; 159.5; 163.6. Found, m/z: 433.0858 [M]+.
C23H17Cl2N5. Calculated, m/z: 433.0861.
2-(2,4-Dichlorophenyl)-4-[1-(1H-imidazol-1-yl)ethyl]-
6-methylnicotinonitrile (8). A solution of compound 1d
(1.00 g, 2.91 mmol) in DMF (2 ml) was added under N2
atmosphere to a cooled (0°C) suspension of NaH (0.17 g,
4.36 mmol) in anhydrous DMF (8 ml). After stirring for
20 min, MeI (0.83g, 5.82 mmol) was injected. The mixture
was stirred at room temperature for additional 2 h. After
the reaction was complete, saturated NH4Cl solution (50 ml)
was added and the water phase was extracted with EtOAc
(3×15 ml). The organic phase was collected, dried over
Na2SO4, and evaporated under vacuum. The residue was
purified by silica gel column chromatography using
CH2Cl2–MeOH, 40:1, as eluent, giving 0.73 g (70%) of
product 8. Yellow solid. Mp 102–104°C. 1H NMR
spectrum, δ, ppm (J, Hz): 2.01 (3H, d, J = 6.8, CHCH3);
2.63 (3H, s, 6-CH3); 5.75–5.80 (1H, m, CHCH3); 6.76 (1H,
s, H-5 Py); 7.07 (1H, s, H imidazole); 7.22 (1H, s,
H imidazole); 7.40 (1H, d, J = 8.4, H-6 Ar); 7.44 (1H, dd,
J = 8.4, J = 2.0, H-5 Ar); 7.59 (1H, d, J = 2.0, H-3 Ar); 7.74
(1H, s, H imidazole). 13C NMR spectrum, δ, ppm: 20.8;
25.3; 54.4; 105.5; 114.7; 118.2; 118.5; 127.6; 130.0; 130.3;
131.5; 133.6; 135.1; 136.1; 136.6; 155.0; 159.8; 163.9.
Found, m/z: 356.0600 [M]+. C18H14Cl2N4. Calculated, m/z:
356.0596.
2-(2,4-Dichlorophenyl)-6-methyl-4-[1-(1H-1,2,4-triazol-
1-yl)ethyl]nicotinonitrile (7a). Yield 75%. White solid. Mp
110–111°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.06 (3H, d,
J = 6.8, CHCH3); 2.66 (3H, s, 6-CH3); 5.98 (1H, q, J = 6.8,
CHCH3); 7.13 (1H, s, H-5 Py); 7.39 (1H, d, J = 8.4, H-6
Ar); 7.43 (1H, d, J = 8.4, H-5 Ar); 7.58 (1H, s, H-3 Ar);
8.08 (1H, s, H triazole); 8.34 (1H, s, H triazole). 13C NMR
spectrum, δ, ppm: 20.5; 25.3; 56.7; 106.7; 114.7; 119.5;
127.6; 130.0; 131.6; 133.6; 135.1; 136.6; 143.0; 152.8;
153.1; 159.7; 163.7. Found, m/z: 357.0552 [M]+.
C17H13Cl2N5. Calculated, m/z: 357.0548.
2-(2,4-Dichlorophenyl)-6-methyl-4-[1-(1H-1,2,4-triazol-
1-yl)propyl]nicotinonitrile (7b). Yield 71%. White solid.
1
Mp 105–106°C. H NMR spectrum, δ, ppm (J, Hz): 1.01
(3H, t, J = 7.2, CHCH2CH3); 2.26–2.33 (1H, m) and 2.55–
2.59 (1H, m, CHCH2CH3); 2.68 (3H, s, 6-CH3); 5.64–5.68
(1H, m, CHCH2CH3); 7.39 (1H, d, J = 8.4, H-6 Ar); 7.42 (1H,
dd, J = 8.4, J = 1.6, H-5 Ar); 7.44 (1H, s, H-5 Py); 7.58
(1H, d, J = 1.6, H-3 Ar); 8.10 (1H, s, H triazole); 8.35 (1H,
s, H triazole). 13C NMR spectrum, δ, ppm: 10.9; 25.3; 28.3;
62.6; 106.3; 114.9; 120.2; 127.6; 130.0; 131.6; 133.6;
135.2; 136.5; 143.9; 151.9; 152.9; 159.5; 163.6. Found, m/z:
371.0701 [M]+. C18H15Cl2N5. Calculated, m/z: 371.0705.
2-(2,4-Dichlorophenyl)-6-methyl-4-[2-methyl-1-(1H-
1,2,4-triazol-1-yl)propyl]nicotinonitrile (7c). Yield 73%.
1
White solid. Mp 136–138°C. H NMR spectrum, δ, ppm
(J, Hz): 0.93 (3H, d, J = 6.8) and 1.00 (3H, d, J = 6.8,
CHCH(CH3)2); 2.72 (3H, s, 6-CH3); 2.83–2.92 (1H, m,
CHCH(CH3)2); 5.32 (1H, d, J = 10.4, CHCH(CH3)2); 7.39
(1H, d, J = 8.4, H-6 Ar); 7.43 (1H, dd, J = 8.4, J = 2.0, H-5
Ar); 7.58 (1H, d, J = 2.0, H-3 Ar); 7.84 (1H, s, H-5 Py);
8.07 (1H, s, H triazole); 8.26 (1H, s, H triazole). 13C NMR
spectrum, δ, ppm: 19.0; 19.6; 25.4; 33.5; 67.1; 107.4;
115.3; 121.1; 127.6; 130.0; 131.5; 133.6; 135.3; 136.5;
144.1; 150.7; 153.0; 159.3; 163.4. Found, m/z: 385.0859
[M]+. C19H17Cl2N5. Calculated, m/z: 385.0861.
A Supplementary information file containing the pro-
cedures for synthesis of compounds 3 and 4, 1H and
13C NMR spectra of the synthesized compounds is
available at http://link.springer.com/journal/10593.
This work was supported by the Shanghai Committee of
Science & Technology (Project No. 13ZR1461600 and
13431900202).
2-(2,4-Dichlorophenyl)-4-[2-cyclohexyl-1-(1H-1,2,4-
triazol-1-yl)ethyl]-6-methylnicotinonitrile (7d). Yield 68%.
References
1
White solid. Mp 75–76°C. H NMR spectrum, δ, ppm
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