Isocyanatophosphoric acid dichloride: A novel reagent for the introduction of a cyano group into the molecules of electron-rich heterocycles and enamines

Article abstract of DOI:10.1055/s-2002-35238

A new synthetic method is developed which enables a direct one-step introduction of a cyano group into electron-rich heterocyclic systems of the indole, pyrrole, and indolizine series, and also to enamines using isocyanatophosphoryl dichloride.

Full text of DOI:10.1055/s-2002-35238

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PAPER
Isocyanatophosphoric Acid Dichloride: A Novel Reagent for the Introduction
of a Cyano Group into the Molecules of Electron-Rich Heterocycles and
Enamines
I
socyanatophosph
a
oric
A
cid D
d
ichloride omir V. Smaliy,*a Aleksandra A. Chaikovskaya,a Aleksandr M. Pinchuk,a Andrei A. Tolmachevb
a
Institute of Organic Chemistry, National Academy of Sciences of the Ukraine, Murmanska Str. 5, Kyiv-94, 02094, Ukraine
Fax +38(44)5732643; E-mail: iochkiev@ukrpack.net
b
Kyiv National Taras Shevchenko University, Volodymyrska Str. 64, Ukraine
Received 7 June 2002
ides.6 Here we have found that the latter compounds de-
compose in more polar solvents [CH2Cl2, Cl(CH2)2Cl,
CH3CN] at 20 °C to give the desired nitriles and a mixture
of phosphorus-containing inorganic products easily re-
movable with water. As a result, we have elaborated a
one-step method for the introduction of a cyano group into
electron-rich heterocycles and enamines by reacting them
with the Kirsanov isocyanate in polar solvents
(Scheme 1); conditions and results of the synthesis are
listed in Table 1. The nitrile formation rate is limited by
the first reaction step, acylation of the substrate.
Abstract: A new synthetic method is developed which enables a di-
rect one-step introduction of a cyano group into electron-rich het-
erocyclic systems of the indole, pyrrole, and indolizine series, and
also to enamines using isocyanatophosphoryl dichloride.
Key words: nitriles, isocyanatophosphoryl dichloride, indoles,
pyrroles, indolizines, enamines
New chemical agents enabling functional groups to be se-
lectively introduced into organic compounds under mild
conditions attract the active interest of synthetic practitio-
ners. Among such reagents, one can quote triphenylthio-
cyanogen (TPPT)1 and chlorosulfonyl isocyanate (the
Graf isocyanate)2 which made possible a direct one-step
introduction of a cyano group into a number of electron-
rich heterocycles and enamines.1,3 These chemicals, how-
ever, are not free of certain disadvantages: TPPT is rela-
tively difficult to prepare and unstable under storage, and
the reaction mixture resulting on using it contains an
equimolar quantity of hard-to-separate triphenylthiophos-
phine oxide1; as for the Graf isocyanate, it reacts does not
react selectively with more active heterocycles than in-
dole and gives rise to side reactions4.
In most cases, heterocyclic nitriles are formed under mild
conditions over a period of 1-4 h at 20 °C, except for ni-
triles 2a, 5a, 10a, and 12a (Table 1). Thus, in the synthesis
of nitrile 10a, the reaction lasts for 10-12h, which is due
to the electron-acceptor substituent in the substrate.6 The
intermediate N-dichlorophosphorylhetarylcarboxamides
formed in the preparation of 2a and 5a are rather stable
thermally and need heating to release nitriles. To obtain
nitrile 12a, the reaction mixture should be boiled for 1
hour so as to destroy the adduct of the isocyanate and the
heterocycle.
The cyano group is introduced selectively into heterocy-
cles 1b, 3–7b, 10–12b. Highly reactive 2-methylindoliz-
ine reacts with the isocyanate to provide a mixture of
nitriles 8a and 9a readily separable by crystallization. N-
Phenylpyrrole 2b undergoes the nonselective acylation6
resulting in a mixture of - and -isomeric nitriles from
which we have managed to isolate the predominant com-
ponent, the nitrile 2a.
Herein we report isocyanatophosphoryl dichloride (the
Kirsanov isocyanate)5 as an easily accessible and conve-
nient reagent for the introduction of a cyano group into
electron-rich heterocycles and enamines. As was reported
by us previously, the Kirsanov isocyanate dissolved in oc-
tane readily acylates electron-rich heterocycles to furnish,
in good yields, N-dichlorophosphorylheterylcarboxam-
Scheme 1
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2416,2420,ftx,en;P02802SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Isocyanatophosphoric Acid Dichloride
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Table 1 Introduction of a Cyano Group with Isocyanatophosphoryl Dichloride
Compound
No.
Nitrile aa
Substrate b
Solvent
Reaction Time (h);
Temperature (°C)
Yields (%)b
1
Cl(CH2)2Cl
1; 20
64
2
3
CH2Cl2
2; reflux
4; 20
45
92
Cl(CH2)2Cl
4
Cl(CH2)2Cl
4; 20
95
5
6
CH2Cl2–CH3CN (1:1)
Cl(CH2)2Cl
1; reflux
2; 20
89
93
7
Cl(CH2)2Cl
2; 20
95
8
9
Cl(CH2)2Cl
Cl(CH2)2Cl
2; 20
2; 20
50
20
10
Cl(CH2)2Cl
12; 20
90
11
12
13
Cl(CH2)2Cl
CH2Cl2
4; 20
80
67
46
1; reflux
4; 20
CH2Cl2
14
Cl(CH2)2Cl
2; 20
95
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R. V. Smaliy et al.
PAPER
Table 1 Introduction of a Cyano Group with Isocyanatophosphoryl Dichloride (continued)
Compound
No.
Nitrile aa
Substrate b
Solvent
CH2Cl2
Reaction Time (h);
Temperature (°C)
Yields (%)b
15
12; 20
57
16
Cl(CH2)2Cl
1; reflux
15
17
18
Cl(CH2)2Cl
Cl(CH2)2Cl
2; 20
2; 20
30
70
a Compounds 1a, 2a, 5a–7a, 12a, 13a, 15a–18a were previously described in the literature.
b Isolated yields.
c Reaction is run in the presence of Et3N.
1H NMR (DMSO-d6): = 3.90 (s, 3 H, N-CH3), 6.20 (t, J = 3 Hz, 1
H, H-4), 7.0 (d, J = 2.5 Hz, 1 H, H-3), 7.20 (br s, 1 H, H-5).
The Kirsanov isocyanate makes it also possible to intro-
duce, in one step, a cyano group into enamine molecules.
Nitriles 13a, 14a, 17a, and 18a are synthesized under mild Anal. Calcd for C6H6N2: C, 67.91; H, 5.70; N, 26.40. Found: C,
67.85; H, 5.74; N, 26.37.
conditions like heterocyclic nitriles. To obtain 15a and
16a, the reaction should be run in the presence of excess
triethylamine in order to avoid the hydrolytic cleavage of
the enamines into the ketonitriles. The low yield of nitrile
17a is attributed to the nonselective reaction of the Kir-
sanov isocyanate with aminocrotonic acid, an ambident
nucleophile.
1-Phenyl-1H-pyrrole-2-carbonitrile (2a)
The general procedure was followed starting from 2b (1.43 g). To
the residue was added H2O (20 mL) and the precipitate was filtered.
The product was extracted from residue with heptane (3 10 mL)
and the solvent was removed in vacuo. The product was purified by
recrystallization from heptane; yield: 0.76 g (45%); colorless solid;
mp 58–59 °C.
1H NMR (DMSO-d6): = 6.40 (t, J = 7.5 Hz, 1 H, H-4), 7.12 (d,
J = 7.5 Hz, 1 H, H-5), 7.50 (m, 6 H, C6H5, H-3).
In summary, good yields, the simple work-up and the
comparatively easy accessibility of the Kirsanov isocyan-
ate enable us to regard this compound as a convenient and
promising reagent for the direct one-step introduction of a
cyano group in the molecules of electron-rich heterocy-
cles and enamines.
Anal. Calcd for C11H8N2: C, 78.55; H, 4.79; N, 16.65. Found: C,
78.49; H, 4.81; N, 16.61.
2,5-Dimethyl-1-(4-methylphenyl)-1H-pyrrole-3-carbonitrile
(3a)
1H NMR spectra were recorded on Varian Gemini – 300 spectro-
meter at 300 MHz using TMS as an internal standard. IR spectra
were recorded on a UR–20 spectrophotometer using KBr discs for
solid samples and films on NaCl plates for oils. IR spectra of the
compounds obtained exhibit the characteristic signal for the C N
bond (2200 cm–1). Solvents were dried and purified prior to use.
The general procedure was followed starting from 3b (1.85 g). To
the residue was added H2O (20 mL) and the precipitate was filtered
and dried in vacuo. The product was purified by recrystallization
from Et2O; yield: 1.93 g (92%); yellow solid; mp 110–111 °C.
1H NMR (CDCl3): = 2.0 (s 3 H, 5-CH3), 2.19 (s, 3 H, 2-CH3), 2.44
(s, 3 H, Ar-CH3), 6.12 (s, 1 H, H-4), 7.16 (d, J = 7.5 Hz, 2 H, m-Ar),
7.31 (d, J = 7.5 Hz, 2 H, o-Ar).
Nitriles 1a–18a; General Procedure
Anal. Calcd for C14H14N2: C, 79.97; H, 6.71; N, 13.32. Found: C,
79.90; H, 6.76; N, 13.29.
To a stirred solution of the substrate (10 mmol) in the respective sol-
vent (20 mL) was added isocyanatophosphoryl dichloride (1.6 g, 10
mmol). The mixture was left at r.t. or refluxed for the time given in
Table 1. The solvent was removed in vacuo and the residue was pu-
rified.
1-(4-Bromophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile
(4a)
Prepared according to the method described for 3a starting from 4b
(2.5 g). The product was purified by recrystallization from 70% aq
MeOH; yield: 2.6 g (95%); colorless solid; mp 140–141 °C.
1H NMR (CDCl3): = 1.98 (s, 3 H; 2-CH3), 2.14 (s, 3 H, 5-CH3),
6.15 (s, 1 H, H-4), 7.26 (d, J = 8.3 Hz, 2 H, m-ArH), 7.70 (d, J = 8.3
Hz, 2 H, o-ArH).
1-Methyl-1H-pyrrole-2-carbonitrile (1a)
The general procedure was followed starting from 1b (0.81 g). The
residue was distilled in vacuo; yield: 0.68 g (64%); yellow oil;
bp 60–62 °C/20 mmHg.
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Isocyanatophosphoric Acid Dichloride
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Anal. Calcd for C13H11BrN2: C, 56.75; H, 4.03; N, 10.18. Found: C,
56.70; H, 4.10; N, 10.12.
2-Methyl-3-(3-nitrobenzoyl)indolizine-1-carbonitrile (10a)
Compound 10a was prepared according to the method described for
3a starting from 10b (2.8 g), by leaving the reaction mixture at r.t.
for 12 h. The product was purified by recrystallization from MeOH;
yield: 2.75 g (90%); yellow solid; mp 229–230 °C.
1H NMR (CDCl3): = 2.15 (s, 3 H, CH3), 7.20 (t, J = 8.1 Hz, 1 H,
H-5), 7.40 (t, J = 8.7 Hz, 1 H, H-6), 7.69 (t, J = 8.1 Hz, 1 H, m-
ArH), 8.0 (d, J = 6.6 Hz, 1 H, H-7), 8.10 (d, J = 8.7 Hz, 1 H, o-ArH),
8.41 (d, J = 7.5 Hz, 1 H, p-ArH), 8.50 (s, 1 H, o-ArH), 9.56 (d,
J = 6.9 Hz, 1 H, H-4).
1H-Indole-3-carbonitrile (5a)
The general procedure was followed starting from 5b (1.17 g). To
the residue was added H2O (20 mL) and the mixture was stirred for
2 h. The precipitate was filtered, dried in vacuo and purified by re-
crystallization from 70% aq MeOH, yield: 1.26 g (88.7%); pink sol-
id; mp 178–180 °C.
1H NMR (CDCl3): = 7.22 (m, 2 H, H-5,6), 7.51 (d, J = 7.5 Hz, 1
H, H-4), 7.61 (d, J = 7.5 Hz, 1 H, H-7), 8.12 (d, J = 3 Hz, 1 H, H-2),
12.0 (s, 1 H, N).
Anal. Calcd for C17H11N3O3: C, 66.88; H, 3.63; N, 13.76. Found: C,
66.90; H, 3.65; N, 13.72.
Anal. Calcd for C9H6N2: C, 76.04; H, 4.25; N, 19.71. Found: C,
76.00; H, 4.27; N, 19.70.
2-Phenylindolizine-3-carbonitrile (11a)
Compound 11a was prepared according to the method described for
3a starting from 11b (1.93 g). The product was purified by recrys-
tallization from EtOH; yield: 1.74 g (80%); green solid; mp 90–93
°C.
1H NMR (CDCl3): = 6.69 (s, 1 H, H-1), 6.83 (t, J = 6.9 Hz, 1 H,
H-5), 7.03 (t, J = 7.8 Hz, 1 H, H-6), 7.43 (m, 1 H, H-7), 7.60 (m, 5
H, C6H5), 8,30 (d, J = 6.3 Hz, 1 H, H-4).
1-Methyl-1H-indole-3-carbonitrile (6a)
The general procedure was followed starting from 6b (1.31 g). To
the residue was added H2O (20 mL) and the mixture was stirred for
20 min. The product was extracted from the crude residue with oc-
tane (3 10 mL) and the solvent was removed in vacuo; yield:
1.45 g (93%); yellow oil; bp 135 °C/20 mmHg.
1H NMR (CDCl3): = 3.89 (s, 3 H, N-CH3), 7.30 (m, 2 H, H-5,6),
7.52 (m, 2 H, H-4,7), 8.15 (s, 1 H, H-2).
Anal. Calcd for C15H10N2: C, 82.55; H, 4.62; N, 12.83. Found: C,
82.51; H, 4.64; N, 12.77.
Anal. Calcd for C10H8N2: C, 76.90; H, 5.16; N, 17.94. Found: C,
76.87; H, 5.17; N, 18.00.
6-Methylimidazo[2,1-b][1,3]thiazole-5-carbonitrile (12a)
The general procedure was followed starting from 12b (1.38 g). To
the stirred residue were added first H2O (15 mL) and then the ad-
justed to 7.5 with 15% aq NaOH. The mixture was stirred for 30
min, the precipitate was filtered and dried in vacuo. The product
was purified by recrystallization from MeOH; yield: 1.1 g (66.5%);
colorless or pink solid; mp 135–136 °C.
1,2-Dimethyl-1H-indole-3-carbonitrile (7a)
This compound was prepared according to the method described for
6a starting from 7b (1.45 g); yield: 1.62 g (95%); yellow solid;
mp 104–106 °C.
1H NMR (CDCl3): = 2.57 (s, 3 H, 2-CH3), 3.73 (s, 3 H, N-CH3),
7.31 (m, 2 H, H-5,6), 7.50 (m, 2 H, H-4), 7.56 (m, 4 H, H-7).
1H NMR (CDCl3): = 2.39 (s, 3 H, CH3), 7,50 (d, J = 4.2 Hz, 1 H,
H-1), 8,1 (d, J = 4.2 Hz, 1H, H-6).
Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C,
77.60; H, 5.95; N, 16.45.
Anal. Calcd for C7H5N3S: C, 51.52; H, 3.09; N, 25.75. Found: C,
51.48; H, 3.10; N, 25.70.
2-Methyl-3-indolizinecarbonitrile and 2-methyl-1,3-indoliz-
inedicarbonitrile (9a)
2-(1,3,3-Trimethyl-1,3-dihydro-2H-indol-2-ylidene)acetoni-
trile (13a)
To a stirred solution of 2-methylindolizine (1.31 g, 10 mmol) in 1,2-
dichloroethane (20 mL) at 0 °C was added isocyanatophosphoryl
dichloride (1.6 g, 10 mmol). The mixture was left at r.t. for 2 h. The
solvent was removed in vacuo. To the residue was added H2O (20
mL) and the precipitate was filtered and dried in vacuo. The precip-
itate was dissolved in MeOH and cooled to 3 °C and the precipitated
9a, was filtered. The mother liquor was concentrated in vacuo and
the residue of compound 8a was recrystallized from Et2O.
To a stirred solution of 13b (1.73 g, 10 mmol) in CH2Cl2 (20 mL) at
–50 °C was added isocyanatophosphoryl dichloride (1.6 g, 10
mmol). The mixture was left at r.t. for 4 h. The reaction mixture pH
was adjusted to 7 with 10% aq NaOH. The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2 (30 mL).
The organic layers were combined and the solvent was removed in
vacuo. The product was purified by silica gel column chromatogra-
phy using CCl4–benzene, 1:1 as eluent; yield: 0.91 g (46%); pink
solid; mp 115–116 °C.
8a
Yield: 0.78 g (50%); yellow solid; mp 93–94 °C.
1H NMR (CDCl3): = 1.576 (s, 6 H, 2 CH3), 3.4 (s, 3 H, N-CH3),
4.39 (s, 1 H C-H) 6.92 (m, 2 H, ArH) 7.22 (m, 2 H, ArH).
1H NMR (CDCl3): = 3.03 (s, 3 H, CH3), 6.27 (s, 1 H, H-1), 6.72
(t, J = 6.8 Hz, 1 H, H-6), 6.95 (t, J = 8.6 Hz, 1 H, H-5), 7,30 (d,
J = 8.9 Hz, 1 H, H-7), 8.13 (d, J = 6.9 Hz, 1 H, H-4).
Anal. Calcd for C13H14N2: C, 78.75; H, 7.12; N, 14.13. Found: C,
78.71; H, 7.17; N, 14.11.
Anal. Calcd for C10H8N2: C, 76.90; H, 5.16; N, 17.94. Found: C,
76.98; H, 5.17; N, 18.02.
Ethyl 2-Cyano-2-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-
ylidene)acetate (14a)
9a
Compound 14a was prepared according to the method described for
3a starting from 14b (2.45 g), by leaving the reaction mixture to stir
at r.t. for 2 h. The product was purified by recrystallization from oc-
tane; yield: 2.57 g (95%); yellow solid; mp 105–106 °C.
1H NMR (CDCl3): = 1.25 (t, J = 9 Hz, 3 H, CH3), 1.62 (s, 6 H, 2
CH3), 3.52(s, 3 H, N-CH3), 4.18 (q, J = 9 Hz, 2 H, CH2), 7.23 (m,
4 H, ArH).
Yield: 0.36 g (20%); yellow solid; mp 222–223 °C.
1H NMR (CDCl3): = 3.10 (s, 3 H, CH3), 7.06 (t, J = 6.9 Hz, 1 H,
H-6), 7.36 (t, J = 7.8 Hz, 1 H, H-5), 7.70 (d, J = 9.2 Hz, 1 H, H-7),
8.29 (d, J = 6.9 Hz, 1 H, H-4).
Anal. Calcd for C11H7N3: C, 72.92; H, 3.89; N, 23.19. Found: C,
72.90; H, 3.95; N, 23.16.
Anal. Calcd for C16H18N2O2: C, 74.97; H, 6.71; N, 11.66. Found: C,
74.95; H, 6.74; N, 11.71.
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R. V. Smaliy et al.
PAPER
2-(4-Morpholinyl)-3-(phenylmethylidene)cyclopent-1-ene-1-
carbonitrile (15a)
1H NMR (CDCl3): = 2.15 (s, 3 H, CH3), 3.63 (s, 3 H, OCH3), 8.9
(br s, 2 H, NH2).
To a stirred solution of 15b (2.41 g, 10 mmol) and Et3N (5.05g, 50
mmol) in CH2Cl2 (20 mL) was added isocyanatophosphoryl
dichloride (1.6 g, 10 mmol). The mixture was left at r.t. for 12 h. The
solvent was removed in vacuo. The product was extracted from the
crude residue with heptane–Et2O (1:1, 10 6 mL) afford the prod-
uct 16a in 24 h; yield: 1.52 g (57%); brown solid; mp 105–106 °C.
1H NMR (CDCl3): = 2.5 (m, 2 H, CH2,), 2.82 (m, 2 H, CH2), 3.36
(m, 4 H, CH2N-CH2), 3.74 (m, 4 , OCH2-CH2), 6.65 (s, 1 H, CH),
7,33 (m, 5 H, C6H5).
Anal. Calcd for C6H8N2O2: C, 51.42; H, 5.75; N, 19.99. Found: C,
51.39; H, 5.78; N, 20.01.
Ethyl 2-Cyano-3-(1-pyrrolidinyl) but-2-enoate (18a)
Compouind 18a was prepared according to the method described
for 3a starting from 18b (1.83 g). The product was extracted from
the residue with octane (3 10 mL) and the solvent was removed in
vacuo; yield: 1.36 g (70%); yellow oil.
1H NMR (CDCl3): = 1.20 (t, J = 9 Hz, 3 H, CH3), 1.89 (s, 3 H,
CH3), 2.42 (s, 4 H, pyrrolidinyl), 3.63 (s, 4 H, pyrrolidinyl), 4.04 (q,
J = 9 Hz, 2 H, CH2).
Anal. Calcd for C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C,
76.61; H, 6.85; N, 10.50.
Anal. Calcd for C10H16N2O2: C, 61.84; H, 7.27; N, 14.42. Found: C,
61.81; H, 7.30; N, 14.40.
2-(4-Morpholinyl)cyclopent-1-ene-1-carbonitrile (16a)
To a stirred solution of 16b (1.53 g, 10 mmol) and Et3N (5.05g, 50
mmol) in dichloroethane (20 mL) was added isocyanatophosphoryl
dichloride (1.6 g, 10 mmol). The mixture was refluxed for 1 h and
the solvent was removed in vacuo. The product was extracted from
the residue with benzene (3 20 mL) and the solvent was removed
in vacuo; yield: 0.267 g (15%); yellow oil.
References
(1) Tamura, Y.; Kawasaki, T.; Adachi, M.; Tanio, M.; Kita, Y.
Tetrahedron Lett. 1977, 50, 4417.
(2) Graf, R. Chem. Ber. 1956, 89, 1071.
(3) (a) Tamura, Y.; Adachi, M.; Kawasaki, T.; Yasuda, H.; Kita,
Y. J. Chem. Soc., Perkin Trans. 1 1980, 1132. (b) Lohaus,
G. Cem. Ber. 1967, 100, 2719. (c) Mehta, G.; Dhar, D.;
Suri, S. Synthesis 1978, 374.
1H NMR (CDCl3): = 2.45 (m, 2 H, CH2,), 2.74 (m, 2 H, CH2),3.19
(br s, 4 H, CH2N-CH2), 3.45 (m 6 H, CH2, OCH2-CH2).
Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92; N, 15.72. Found: C,
67.35; H, 7.90; N, 15.75.
(4) Barnet, G.; Anderson, H.; Loader, C. Can. J. Chem. 1980,
58, 409.
(5) Kirsanov, A. V. Zh. Obshch. Chem. 1954, 24, 1033; Chem.
Abstr. 1955, 49, 8787.
(6) Chaykovskaya, A. A.; Smaliy, R. V.; Tolmachev, A. A.;
Kudrya, T. N.; Pinchuk, A. M. Heteroatom Chem. 1999, 10,
343.
Methyl 3-Amino-2-cyanobut-2-enoate (17a)
Compound 17a was prepared according to the method described for
3a starting from 17b (1.15 g), by leaving the reaction mixture at r.t.
for 2 h. The product was purified by recrystallization from octane;
yield: 0.42 g (30%); yellow solid; mp 182–183 °C.
Synthesis 2002, No. 16, 2416–2420 ISSN 0039-7881 © Thieme Stuttgart · New York