Copper-catalyzed tandem synthesis of pentasubstituted pyridines from sulfonoketenimides and 2-aminoprop-1-ene-1,1,3-tricarbonitrile

Article abstract of DOI:10.1055/s-0034-1378378

Fully substituted pyridines were synthesized in moderate to good yields in a one-pot process by the copper-catalyzed sequential reaction of sulfonyl azides with terminal alkynes and 2-aminoprop-1-ene-1,1,3-tricarbonitrile at room temperature. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378378

2036▌
LETTER
lCettoerpper-Catalyzed Tandem Synthesis of Pentasubstituted Pyridines from
Sulfonoketenimides and 2-Aminoprop-1-ene-1,1,3-tricarbonitrile
Copper-Catalyzed Tandem Synthesis of Pentasubstituted Pyridines
Issa Yavari,* Zohreh Taheri, Manijeh Nematpour, Azam Sheikhi
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, 18716 Tehran, Iran
Fax +98(21)82883455; E-mail: yavarisa@modares.ac.ir
Received: 27.04.2014; Accepted after revision: 30.05.2014
Ethynylbenzene (1a) readily participated in the coupling
Abstract: Fully substituted pyridines were synthesized in moderate
reaction with various sulfonyl azides to give the corre-
to good yields in a one-pot process by the copper-catalyzed sequen-
sponding N-sulfonamides 5a–c in good yields (Table 1,
tial reaction of sulfonyl azides with terminal alkynes and 2-amino-
prop-1-ene-1,1,3-tricarbonitrile at room temperature.
entries 1–3); aromatic and aliphatic sulfonyl azides both
reacted efficiently. Pent-1-yne and hex-1-yne also gave
the corresponding sulfonamides 5d-i, albeit in slightly
lower yields (entries 4–9).
Keywords: pyridines, cyclizations, tandem reactions, copper, ca-
talysis
The structures of compounds 5a–i were assigned by IR,
1
13
Pyridine and its derivatives are an important class of six-
H NMR, and C NMR spectroscopy and by mass spec-
1
membered heterocycles present in a number of biological- trometric analyses. The H NMR spectrum of 5a exhibits
ly active natural products and pharmaceuticals. They also four singlets for methyl (2.54 ppm), methylene (4.33
ppm), NH , and NH (5.78, 8.62 ppm) protons, along with
In particular, they are useful building blocks for the prepa- characteristic multiplets for the phenyl protons. The
1
2
have significant applications in many fields of chemistry.
2
1
3
C
3
ration of chiral ligands or new materials with important NMR spectrum of 5a shows seventeen signals, in agree-
4,5
photo- or electrochemical properties.
ment with the proposed structure. The mass spectrum of
a displayed a molecular ion peak at m/z = 403. The NMR
5
Polynitriles are versatile reagents that have been used ex-
6
spectra of compounds 5b–i were similar to those of 5a,
except for the substituents, which showed characteristic
signals in the appropriate regions of the spectra.
tensively as precursors to heteroaromatics. Interest in de-
veloping the synthetic potential of these compounds has
7
recently been revived. 2-Aminoprop-1-ene-1,1,3-tricar-
bonitrile has proved to be an excellent precursor to con- A plausible mechanism for the formation of compounds 5
densed pyridines.8
is shown in Scheme 1. The copper acetylide 6, formed
from alkyne 1 and copper(I) iodide, undergoes a 1,3-dipo-
lar cycloaddition with azide 2 to give the triazole deriva-
Recently, Zhou and co-workers used 2-(aminomethy-
lene)malononitriles to trap ketenimines generated in situ
to give 4-amino-2-iminopyridines or 6-amino-2-iminopy-
11
tive 7. This intermediate is converted into the
1
2
9
sulfonoketenimide 8, which is attacked by amine 4 (gen-
erated in situ from malononitrile and sodium hydride) to
afford intermediate 9. This intermediate is converted into
product 5 by cyclization and tautomerization.
ridines, depending on the reaction conditions. Their re-
port, prompted us to disclose our results on trapping
sulfonoketenimides by 2-aminoprop-1-ene-1,1,3-tri-
carbonitrile (malononitrile dimer) to give N-[4-amino-5-
cyano-6-(cyanomethyl)-3-(alkyl/aryl)pyridin-2-yl]-4-(al-
kyl/aryl)sulfonamides.10
NC
CN
Initially, we selected ethynylbenzene (1a), 4-toluenesul-
fonyl azide (2a), and malononitrile as model substrates,
and we tested several catalysts, including copper(I) io-
dide, copper(I) bromide, copper(I) chloride, and copper
powder, of which copper(I) iodide gave the best results.
Among several solvents that we screened, dichlorometh-
ane was the best. When the reaction was performed in di-
chloromethane in the presence of one equivalent of
triethylamine at room temperature for eight hours, the de-
sired pyridine 5a was obtained in 85% yield. Thus, the op-
timal conditions are malononitrile (2 mmol), copper(I)
iodide (10 mol%), alkyne (1 mmol), and sulfonyl azide
NH2
R1
SO2R2 CN
Cu
N
C
2
4
1
+ CuI
R1
Cu
N
N
SO2R2
6
N
R1
7
8
NH
N
NC
C
R1
NC
R1
O
cyclization
tautomerism
O
O
O
5
S
S
N
N
R2
N
H
N
R2
H2
CN
CN
9
10
Scheme 1
(
1.2 mmol) in dichloromethane at room temperature.
In conclusion, we have developed a sequential transfor-
mation involving sulfonoketenimide intermediates and
SYNLETT 2014, 25, 2036–2038
Advanced online publication: 04.08.2014
2
-aminoprop-1-ene-1,1,3-tricarbonitrile, which provides
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
a new route to fully substituted pyridines that have im-
DOI: 10.1055/s-0034-1378378; Art ID: st-2014-d0348-l
Georg Thieme Verlag Stuttgart · New York
©

LETTER
Copper-Catalyzed Tandem Synthesis of Pentasubstituted Pyridines
2037
Table 1 Formation of N-[4-Amino-5-cyano-6-(cyanomethyl)-3-(alkyl/aryl)pyridin-2-yl]-4-(alkyl/aryl)sulfonamides 5
NC
CN
CN
+
NC
NaH, CH2Cl2, r.t.
H2N
CN
CN
R1
O
O
NH2
CuI (10 mol%)
Et3N, CH2Cl2
S
NC
R1
O
1
+
N
R2
NC
4
O
C
NC
S
r.t., 30 min
3 h
R2
O
O
N
N
H
S
R1
R2
N3
5
3
2
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Pr
4-Tol
Ph
5a
5b
5c
5d
5e
5f
85
81
78
70
68
64
69
63
60
Me
4-Tol
Ph
Pr
Pr
Me
Bu
Bu
Bu
4-Tol
Ph
5g
5h
5i
Me
portant applications in syntheses of biologically active
and drug-like molecules.
(8) (a) Freeman, F. Chem. Rev. 1969, 69, 591. (b) Fatiadi, A. J.
Synthesis 1978, 165.
(9) Zhou, F.; Liu, X.; Zhang, N.; Liang, Y.; Zhang, R.; Xin, X.;
Dong, D. Org. Lett. 2013, 15, 5786.
Supporting Information for this article is available online
(10) N-[4-Amino-5-cyano-6-(cyanomethyl)-3-
(alkyl/aryl)pyridin-2-yl]-4-(alkyl/aryl)sulfonamides;
General Procedure
at
http://www.thieme-connect.com/products/ejournals/journal/
1
0.1055/s-00000083.SunpfgIpi
o
nr
i
o
The tetracyano compound 4 was prepared by self-
condensation of malononitrile (2 mmol) in CH Cl
2
2
References and Notes
containing NaH (1 equiv) at r.t. for 30 min. A mixture of
sulfonyl azide 2 (1.2 mmol), alkyne 1 (1 mmol), CuI (10
mmol%), and Et N (1 mmol) in CH Cl (3 mL) was slowly
(
1) (a) Pozharskii, A. F.; Soldatenkov, A.; Katritzky, A. R.
Heterocycles in Life and Society: An Introduction to
Heterocyclic Chemistry, Biochemistry and Applications;
Wiley: Hoboken, 2011, 2nd ed. (b) Fu, P.; Wang, S.; Hong,
K.; Li, X.; Liu, P.; Wang, Y.; Zhu, W. J. Nat. Prod. 2011, 74,
3
2
2
added. The mixture was stirred at r.t. under N for about 3 h
2
until the reaction was complete [TLC; EtOAc–hexane (1:5)].
The mixture was then diluted with CH Cl (2 mL) and aq
2
2
NH Cl (3 mL), and stirred for 10 min. The layers separated
4
1
751. (c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
and the aqueous layer was extracted with CH Cl (3 × 3 mL).
2
2
(d) Basnet, A.; Thapa, P.; Karki, R.; Na, Y.; Jahng, Y.;
The organic fractions were combined, dried (Na SO ),
2
4
Jeong, B. S.; Jeong, T. C.; Lee, C. S.; Lee, E.-S. Bioorg.
Med. Chem. 2007, 15, 4351.
filtered, and concentrated under reduced pressure to give a
residue that was purified by flash column chromatography
(
(
(
(
2) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Wiley-
Blackwell: Chichester, 2010, 5th ed..
3) Durola, F.; Sauvage, J. P.; Wenger, O. S. Chem. Commun.
[
silica gel (230–400 mesh; Merck), hexane–EtOAc (5:1)].
N-[4-Amino-5-cyano-6-(cyanomethyl)-3-phenylpyridin-
-yl]-4-methylbenzenesulfonamide (5a)
Cream powder; yield: 0.34 g (85%); mp 147–149 °C. IR
2
2
006, 171.
4) Tang, B.; Yu, F.; Li, P.; Tong, L.; Duan, X.; Xie, T.; Wang,
X. J. Am. Chem. Soc. 2009, 131, 3016.
5) Havas, C. F.; Leygue, N.; Danel, M.; Mestre, B.; Galaup, C.;
Picard, C. Tetrahedron 2009, 65, 7673.
–1 1
(KBr): 3345, 3106, 2127, 1534, 1399, 1192, 1036 cm ; H
NMR (500 MHz, CDCl ): δ = 2.54 (s, 3 H, Me), 4.33 (s, 2 H,
3
s, CH ), 5.78 (s, 2 H, NH ) 7.30–7.35 (m, 3 H, Ph), 7.67 (d,
2
2
3
3
3
J = 7.4 Hz, 2 H, Ar), 7.70 (d, J = 7.8 Hz, 2 H, Ar), 8.24 (d,
J = 7.8 Hz, 2 H, Ar), 8.62 (s, 1 H, NH). C NMR (125.7
(6) Erian, A. W. Chem. Rev. 1993, 93, 1991.
13
(
7) (a) Al-Matar, H. M.; Khalil, K. D.; Meier, H.; Kolshorn, H.;
Elnagdi, M. H. ARKIVOC 2008, (xvi), 288. (b) Al-Awadi, N.
A.; Abdelkhalik, M. M.; Abdelhamid, I. A.; Elnagdi, M. H.
Synlett 2007, 2979.
MHz, CDCl ): δ = 24.4 (CH ), 29.3 (Me), 116.9 (CN), 117.8
3
2
(
(
CN), 119.0 (C), 122.5 (C), 124.9 (C), 127.0 (2 CH), 128.9
2 CH), 130.0 (C), 131.8 (2 CH), 132.4 (2 CH), 135.6 (CH),
145.8 (C), 148.1 (C), 153.1 (C), 159.0 (C). EI-MS:
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2036–2038

2038
I. Yavari et al.
LETTER
+
m/z (%) = 403 [M ] (4), 337 (18), 233 (28), 170 (71), 156
(11) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(12) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127,
2038.
(
100), 91 (57), 77 (30). Anal. Calcd for C H N O S
403.46): C, 62.52; H, 4.25; N, 17.36. Found: C, 63.03; H,
.22; N, 17.52.
21 17 5 2
(
4
Synlett 2014, 25, 2036–2038
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.