The Vinylogous Mannich Reaction: An Efficient Access to Substituted Nicotinonitriles

Article abstract of DOI:10.1055/s-2003-42044

A straightforward method for the preparation of substituted nicotinonitriles has been developed. Starting from conjugated β-enaminonitriles and iminium salts, this methodology establishes a convenient access to 6-aryl- (5), 6-amino- (16) and 6-carboxylic ester-substituted derivatives 14 and as well to acetic acid-substituted pyrroles 12.

Full text of DOI:10.1055/s-2003-42044

LETTER
1959
The Vinylogous Mannich Reaction: An Efficient Access to Substituted
Nicotinonitriles
The
Vinylogous
M
n
annich Reac
d
tion: An Effi
r
c
ient
A
c
e
cess to Sub
a
stituted Nic
s
otinonitriles Winter, Nikolaus Risch*
Fakultät für Naturwissenschaften, Department Chemie, Universität Paderborn, Warburger Str.100, 33098 Paderborn, Germany
Fax +49(5251)603245; E-mail: nr@chemie.upb.de
Received 15 July 2003
Table 1 Synthesis of Conjugated b-Enaminonitriles 3 (R3 = Me)
Abstract: A straightforward method for the preparation of substi-
tuted nicotinonitriles has been developed. Starting from conjugated
b-enaminonitriles and iminium salts, this methodology establishes
a convenient access to 6-aryl- (5), 6-amino- (16) and 6-carboxylic
ester-substituted derivatives 14 and as well to acetic acid-substitut-
ed pyrroles 12.
Com- R1
pound
R2
Yield Entry R1
(%)a
R2
Yield
(%)a
3a
3b
3c
3d
Et
Me
H
68
54
84
48
3g
3h
3i
Ph
Ph
Ph
H
71
68
71
54
i-Pr
t-Bu
CF3
Me
Ph
O
Key words: domino reactions, iminium salts, Mannich bases, b-
enaminonitriles, nicotinonitriles, pyrroles, pyridines
H
H
3j
Pyridine derivatives occur in a variety of natural products
such as alkaloids. Their fundamental importance to living
systems is well known (e. g., nicotinamide adenine dinu-
cleotide). They show interesting physiological activities
and have therefore found numerous applications as phar-
maceuticals or agrochemicals. They display attractive
synthetic building blocks and many syntheses have been
reported.1 Among others, nicotinonitrile-like pyridine de-
rivatives are of special synthetic importance,2 and the in-
vestigation of novel routes still remains active.3
3e
3f
-(CH2)3-
-(CH2)4-
72
60
3k
76
O
a Yield of crude product.
Table 2 Synthesis of Phenyl-Substituted Conjugated b-Enaminoni-
triles 4 (R3 = Ph)
b-Enaminonitriles such as b-aminocrotononitrile have
been widely used to obtain functionalized pyridine deriv-
atives.4 Recently, Katritzky et al. showed that conjugated
b-enaminonitriles 3 also are versatile building blocks for
heterocyclic systems.5 We successfully transformed a
broad number of ketones 1 including cyclic, dialkyl or
alkyl-aryl ketones into the corresponding b-enaminoni-
triles by a modification of Katritzky’s protocol using b-
aminocrotononitrile 2a and TiCl4 as reagent (Scheme 1,
Table 1).6,7
Compound
R1
R2
H
Yield (%)a
4a
4b
4c
4d
t-Bu
-(CH2)4-
Ph
79
81
78
46
H
H
Ph
a Yield of crude product.
Phenyl-substituted b-aminocrotononitrile 2b was ob-
tained according to literature procedures8 and could also
be used to obtain highly substituted b-enaminonitriles 4 in
good yields (Scheme 1, Table 2).
We disclose that not only ketones can react to form conju-
gated b-enaminonitriles. We successfully transferred phe-
nyl-acetaldehyde into the corresponding dienamine (5d).
However, attempts to prepare analogous dienamines de-
rived from aliphatic aldehydes only led to the formation of
complex mixtures. All products obtained can be used for
further transformations without prior purification. Further
work in this field will focus on the introduction of other
electron-withdrawing groups different from the nitrile-
functionality and on the employment of functionalized
ketones and aldehydes.
R3
O
R3
NC
R1
NC
TiCl4, NEt3
NH2
+
R1
CH2Cl2, rt, 24 h
NH2
R2
R2
1
2a (R3 = Me)
2b (R3 = Ph)
3 (R3 = Me)
4 (R3 = Ph)
Scheme 1 Synthesis of conjugated b-enaminonitriles 3 and 4
Vilsmeier-type iminium9 salts react with b-enaminoni-
triles 3 and 4 in a Mannich-type reaction to give nicotino-
nitriles 5 in good yields.5 In this reaction either
benzotriazole or chloride acts as a leaving group. Due to
SYNLETT 2003, No. 13, pp 1959–1964
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42044; Art ID: G17203ST
© Georg Thieme Verlag Stuttgart · New York

1960
A. Winter, N. Risch
LETTER
Table 3 Synthesis of Substituted Nicotinonitriles 5
Com- Nicotinonitrile 5
the nature of the reagents, this method is limited to the
synthesis of 6-unsubstituted derivatives 5 (R4 = H).
However, the reaction of b-enaminonitriles with ternary
iminium salts 6 has not yet been investigated. b-Enamino-
nitriles can be considered as vinylogous enamines. In all
cases, we observed that they are attacked by electrophiles
in g-positions selectively. Reactions of 3 or 4 with imini-
um salt 6a (R4 = H) or aryl-substituted iminium salts
6b,c (R4 = phenyl, pyridine-2-yl) were carried out in re-
fluxing CHCl3 yielding dienimines 7 as intermediates
(Scheme 2). The in situ conversion of these hydro-
chlorides into their conjugated bases by the addition of aq
NaOH solution induces a spontaneous cyclization-elimi-
nation process. After oxidation under the reaction condi-
tions the corresponding nicotinonitriles 5 are formed in
good overall yields (34–53%, Table 3).10
Enami- Iminium salt
Yield
(%)a
pound
nonitrile
5a
3a
6a (R4 = H)
41
NC
NC
N
N
5b
3a
6b (R4 = Ph)
38
5c
3b
3b
6a (R4 = H)
6b (R4 = Ph)
48
45
NC
NC
N
N
R3
R3
N
Cl
NC
R1
NC
R1
5d
N
NH2
R4
3 (R3 = Me)
4 (R3 = Ph)
5
6
R4
R2
R2
6
- HNMe2
oxidation
5e
5f
3c
3c
6a (R4 = H)
6b (R4 = Ph)
47
51
NC
NC
N
N
R3
R3
R3
NC
R1
NC
R1
NC
R1
NH
NH2 Cl
R4
NH
NaOH
- HCl
R4
R4
R2
R2
R2
7
Scheme 2 Synthesis of substituted nicotinonitriles 5 from conjuga-
ted b-enaminonitriles 3/4
5g
5h
5i
3d
3e
3e
6b (R4 = Ph)
6b (R4 = H)
6b (R4 = Ph)
34b
39
NC
N
Our methodology of transforming conjugated b-enamino-
nitriles 3 or 4 into nicotinonitriles 5 can be considered as
major extension to Katritzky’s protocol.5 However, un-
substituted iminium salt 6a gives lower yields of nicotino-
nitriles with R4 = H compared to the literature.5,11 Aryl-
substituted ternary iminium salts 6b,c provide highly sub-
stituted nicotinonitriles 5 in good yields. Although many
literature methods are known for the preparation of 6-aryl
derivatives,3 especially the synthesis of fused bicyclic or
tricyclic ring systems is still of limited scope. Our method
can be applied for the synthesis of novel fused ring sys-
tems (Table 3, entries 5h–5m, 5t–5v, 5x–5y) and is a ver-
satile route to derivatives with new substitution patterns.
F
F
F
NC
N
49
NC
NC
N
N
5j
3e
6c (R4 = 2-Py) 53
Recently, we have disclosed that ternary iminium salts de-
rived from alkyl glyoxylate 8 are efficient building blocks
in the synthesis of g-oxo- and a-aryl-a-amino acids.12,13
The iminium salt 10 is generated in situ by an electrophilic
attack of acetyl chloride on the aminal 9 and can be used
in Mannich reactions (Scheme 3).
N
Synlett 2003, No. 13, 1959–1964 © Thieme Stuttgart · New York

LETTER
The Vinylogous Mannich Reaction: An Efficient Access to Substituted Nicotinonitriles
1961
Table 3 Synthesis of Substituted Nicotinonitriles 5 (continued) Table 3 Synthesis of Substituted Nicotinonitriles 5 (continued)
Com- Nicotinonitrile 5
pound
Enami- Iminium salt
nonitrile
Yield
(%)a
Com- Nicotinonitrile 5
pound
Enami- Iminium salt
nonitrile
Yield
(%)a
5k
3f
6a (R4 = H)
45
5u
3k
3k
4a
6a (R4 = H)
6b (R4 = Ph)
6a (R4 = H)
41
47
53
NC
N
NC
N
5l
3f
6b (R4 = Ph)
41
5v
NC
N
NC
N
5m
3f
6c (R4 = 2-Py) 44
5w
NC
N
N
NC
N
5n
3g
3g
3g
3h
3h
3i
6a (R4 = H)
43
37
NC
N
5x
4b
4b
4c
6a (R4 = H)
6b (R4 = Ph)
6a (R4 = H)
37
NC
N
5o
6b (R4 = Ph)
NC
N
5y
43b
5p
6c (R4 = 2-Py) 47
NC
N
NC
N
N
5q
6a (R4 = H)
6a (R4 = H)
6b (R4 = Ph)
47
5z
42
NC
N
NC
N
5r
28
NC
N
5aa
4d
6b (R4 = Ph)
47 b
5s
38b
NC
N
NC
N
5t
3j
6b (R4 = Ph)
45
a Isolated yield after flash column chromatography.
b Yield of crude product as determined by GC.
NC
N
Synlett 2003, No. 13, 1959–1964 © Thieme Stuttgart · New York

1962
A. Winter, N. Risch
LETTER
However, reaction of 3c (R1 = tert-butyl, R2 = H) with imi-
nium salt 10 led to the formation of carboxylic ester sub-
stituted nicotinonitrile 14a in good overall yield
(Scheme 4, pathway b). Due to the steric hindrance of the
bulky tert-butyl group a conformation of 11 supporting
the reaction pathway a is less favored. This steric effect
suppresses the formation of the 5-membered ring and sup-
ports the formation of the dihydropyridine 13. Depending
on the steric demand of R2 either a pyrrole or a pyridine
derivative is formed. The general influence of diverse
groups on the nature of the product will therefore be part
of further investigations.15
O
CH3COCl
HNMe2
Me2N
NMe2
CO2Et
NMe2 Cl
- CH3CONR'2
EtO2C
CO2Et
10
8
9
Scheme 3 Preparation of carboxylic ester-substituted iminium salt
10
Reactions between dienamines 3 or 4 and the ternary imi-
nium salt 10 provides pyrrole derivatives 12 or substituted
nicotinonitriles 14 depending on the nature of the substit-
uents R1 and R2 (Scheme 4).14 Conjugated b-enaminoni-
triles react with the iminium salt 10 in the manner of
vinylogous enamines to form intermediates 11.
The reactivity of phosgene iminium salt 15 was studied by
Viehe et al.16 In general, the chemical behavior of this
quaternary iminium salt is similar to the properties of ter-
nary iminium salts such as 6 or 10. It is well known, that
Mannich bases formed from ketones and 15 easily elimi-
nate HCl. The elimination of amine has not been de-
scribed in the literature. We successfully prepared 6-
amino functionalized nicotinonitriles 16 from b-enamino-
nitriles 3 in very good yields using the procedure men-
tioned above (Scheme 5, Table 5).5,10
Due to the carboxylic ester group, the electronic proper-
ties are different compared to the intermediate 7
(Scheme 2). In a sequence of intramolecular Michael ad-
dition and isomerization of the double bonds the pyrrole
derivative 12 is formed. Evidently, the reaction will fol-
low pathway a for b-enaminonitriles bearing terminal
double bonds (R2 = H). Pyrroles 13 (R1 = Ph) were ob-
tained in good yields and have not been described in the
literature before.
In any case, we could not observe the formation of the
analogous Cl-substituted derivatives. As chloride is the
much better leaving group, the elimination of HCl is fa-
vored. To the best of our knowledge, 6-amino-functional-
ized nicotinonitriles 16 have not been described before.
Table 4 Reaction of b-Enaminonitriles 3 or 4 with Iminium Salt 10
Compound R1
R2
H
H
H
R3
Yield (%)a
12a
12b
14a
14b
14c
Ph
Me
Ph
34
We also communicate that the phosphonic acid dialkylest-
er-substituted iminium salt 1717,18 reacts with b-enamino-
nitriles 3 in the manner of a Vilsmeier-type reagent. It was
our target to synthesize the phosphorous analogues 19 of
carboxylic ester-derivatives 14 (Scheme 6, Table 6).
Ph
38
tert.-Bu
-(CH2)3-
-(CH3)4-
Me
Me
Me
42
17b
23b
On addition of iminium salt 17 to the vinylogous enamine
3, intermediate 18 is formed after elimination and cycliza-
tion. Aromatization of this dihydropyridine 19 may occur
in two different ways. Phosphonic acid dialkylester is
eliminated to form unsubstituted nicotinonitrile 6 (path-
a Isolated yield after flash column chromatography.
b Yield of crude product as determined by GC.
R3
NMe2 Cl
R3
R3
H
10
COOEt
NC
N
NC
CO2Et
NH2
N
or
R1
NC
R1
14
COOEt
R1
R2
3 or 4
R2
12 (R1 = Ph, R2 = H)
- HNMe2
- HCl
10
a
oxidation
R3
R3
NC
R1
NC
NH
b
NH
R1
COOEt
COOEt
R2
R2
11
13
Scheme 4 Reaction of b-enaminonitriles 3 or 4 with iminium salt 10
Synlett 2003, No. 13, 1959–1964 © Thieme Stuttgart · New York

LETTER
The Vinylogous Mannich Reaction: An Efficient Access to Substituted Nicotinonitriles
1963
Table 6 Synthesis of Nicotinonitriles 5 from b-Enaminonitriles 3
and Iminium Salt 17
NC
NC
R1
NH2
N
N
Cl
+
Compound
R1
R2
Yield (%)a
R1
Cl
Cl
NMe2
16
R2
R2
5e
5f
-(CH2)3-
-(CH2)4-
Ph
17
15
22
3
15
- 2 HCl
- HCl
5g
H
a Isolated yield after flash column chromatography.
NC
R1
NC
R1
NH
NH
Cl
NMe2
Cl
NMe2
In conclusion, we have demonstrated that ternary iminium
salts are versatile building blocks for the efficient synthe-
sis of substituted nicotinonitriles. This method is of broad
scope as functionalized iminium salts such as 10 and 17
can be used for the preparation of previously unknown
nicotinonitriles 14 and 16 and pyrroles 12.
R2
R2
Scheme 5 Synthesis of 6-amino-functionalized nicotinonitriles 16
Table 5 Synthesis of 6-Amino-Functionalized Nicotinonitriles 16
Compound
16a
R1
R2
H
Yield (%)a
Acknowledgment
-(CH2)4-
Ph
61
53
We would like to thank the Fonds der Chemischen Industrie, the
Deutsche Forschungsgemeinschaft and the Grünenthal GmbH for
supporting this research.
16b
a Isolated yield after crystallization from EtOH.
References
way a). Spontaneous oxidation under the reaction condi-
tions (pathway b) yielding the desired product 19 was not
observed. Though phosphonic esters are rather poor leav-
ing groups, here the elimination is favored compared to
the oxidation of the dihydropyridine.
(1) Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996.
(2) (a) Palacios, F.; Alonso, C.; Rubiales, G. J. J. Org. Chem.
1997, 62, 1146. (b) Reich, S. H.; Melnick, M.; Pino, M. J.;
Fuhry, M. A. N.; Trippe, A. J.; Appelt, K.; Davies, J. F. II;
Wu, B. W.; Musick, L. J. Med. Chem. 1996, 39, 2781.
(c) Lavilla, R.; Gotsens, T.; Guerrero, M.; Bosch, J.
Synthesis 1995, 382. (d) Vohra, R.; MacLean, D. B.
Heterocycles 1994, 39, 445. (e) Nakajima, T.; Izawa, T.;
Kashiwabara, T.; Nakajima, S.; Munezuka, Y. Chem.
Pharm. Bull. 1994, 42, 2475. (f) Moltzen, E. K.; Pedersen,
H.; Bøgesø, K. P.; Meier, E.; Frederiksen, K.; Sánchez, C.;
Lembøl, H. L. J. Med. Chem. 1994, 37, 4085. (g) Boquel,
P.; Taillefumier, C.; Chapleur, Y.; Renaut, P.; Samreth, S.;
Bellamy, F. D. Tetrahedron 1993, 49, 83.
NMe2 Cl
NC
R1
NC
R1
(EtO)2OP
NH2
17
N
5
R2
R2
3
- HNMe2
- 2 HCl
17
- HP(O)(OEt)2
a
(3) (a) Katsyama, I.; Ogawa, S.; Yamaguchi, Y.; Funabiki, K.;
Matsui, M.; Muramatsu, H.; Shibata, K. Synthesis 1997,
1321. (b) Petrich, S. A.; Hicks, F. A.; Wilkinson, D. R.;
Tarrant, J. G.; Bruno, S. M.; Vargas, M.; Hosein, K. N.;
Gupton, J. T.; Sikorski, J. A. Tetrahedron 1995, 51, 1575.
(c) Sakakibara, Y.; Ido, Y.; Sasaki, K.; Sasaki, M.; Uchino,
M. Bull. Chem. Soc. Jpn. 1993, 66, 2776. (d) Matsui, M.;
Oji, A.; Hiramatsu, K.; Shibata, K.; Muramatsu, H. J. Chem.
Soc., Perkin Trans. 2 1992, 201. (e) Gundersen, L.-L.; Rise,
F.; Undheim, K. Tetrahedron 1992, 48, 5647. (f) Shing, T.
L.; Chia, W.-L.; Shiao, M.-J.; Chau, T.-Y. Synthesis 1991,
849.
NC
R1
NC
R1
NH
NH
18
P(O)(OEt)2
P(O)(OEt)2
R2
R2
b
oxidation
(4) Erian, C. A. Chem. Rev. 1993, 93, 1991.
(5) Katritzky, A. R.; Denisenko, A.; Arend, M. J. Org. Chem.
1999, 64, 6076.
(6) Carlson, R.; Larsson, U.; Hansson, L. Acta Chem. Scand.
1992, 46, 1211.
NC
R1
N
19
P(O)(OEt)2
R2
(7) General Procedure for the Synthesis of Conjugated b-
Enaminonitriles 3 and 4: To a solution of b-aminocroto-
nonitrile 2 (60 mmol) and Et3N (15.3 mL, 110 mmol) in
anhyd CH2Cl2 (60 mL) cooled with an ice bath was added
Scheme 6 Synthesis of nicotinonitriles 5 from b-enaminonitriles 3
and iminium salt 17
Synlett 2003, No. 13, 1959–1964 © Thieme Stuttgart · New York

1964
A. Winter, N. Risch
LETTER
slowly with stirring a solution of TiCl4 (3.3 ml, 30 mmol) in
anhyd toluene (40 mL). Subsequently, the ketone 1 (50
mmol) was added in one portion. After the mixture was
stirred for 24 h at ambient temperature, the solvent was
removed in vacuo and the residue was crushed with a
spatula. Then Et2O (200 mL) was added, and the resulting
mixture was stirred vigorously until the residue was ground
to a fine powder. Subsequently, the powder was sucked off
and washed with Et2O (200 mL). Evaporation of the solvent
provided the crude conjugated b-enaminonitriles 3 or 4,
which were used for preparation of nicotinonitriles without
further purification.
(11) Jutz, C.; Löbering, H.-G.; Trinkl, K.-H. Synthesis 1977, 326.
(12) Merla, B.; Grumbach, H.-J.; Risch, N. Synthesis 1998, 1609.
(13) Grumbach, H.-J.; Merla, B.; Risch, N. Synthesis 1999, 1027.
(14) General Procedure for the Synthesis of Pyrroles 12 and
Nicotinonitriles 14: The reactions were conducted under
Ar. A solution of ethyl glyoxylate aminal 9 (5 mmol) in
anhyd CH2Cl2 (20 mLl) was cooled to 0 °C. Acetyl chloride
(0.35 mL, 5 mmol) was added in one portion under stirring
to generate the iminium salt 10. After stirring the mixture for
1 h at 0 °C the b-enaminonitrile 3 or 4 (4 mmol) was added
and the solution heated under reflux for 15 h. After cooling
to r.t., dilute NaHCO3 (4 M, 40 mL) was added, and the
resulting mixture was stirred vigorously for 15 min. The
organic phase was decanted, and the aq phase was extracted
with Et2O (3 × 50 mL). The combined organic phases were
dried over MgSO4, and the solvent was removed in vacuo.
The crude products were purified by flash column
(8) Yamaguchi, Y.; Katsuyama, I.; Funabiki, K.; Matsui, M.;
Shibata, K. J. Heterocycl. Chem. 1998, 35, 805.
(9) Katritzky, A. R.; Arend, M. J. Org. Chem. 1998, 63, 9989.
(10) General Procedure for the Synthesis of Nicotinonitriles 5
and 16: The reactions were conducted in a water-free
apparatus under Ar. To a solution of the conjugated b-
enaminonitrile 3 or 4 (4 mmol) in anhyd CHCl3 (20 mL) was
added the iminium salt 6 or 15 (5 mmol) in one portion. The
mixture was stirred and kept at reflux for 15 h. After cooling
to r.t., dilute NaOH (2 N, 40 mL) was added, and the
resulting mixture was stirred vigorously for 15 min. The
organic phase was decanted, and the aq phase was extracted
with Et2O (3 × 50 mL). The combined organic phases were
dried over MgSO4, and the solvent was removed in vacuo.
The crude products were purified either by Kugelrohr
distillation or flash column chromatography (SiO2, EtOAc–
hexanes 3:1).
chromatography (SiO2, EtOAc–hexanes 3:1).
(15) Carboxylic ester substituted nicotinonitriles 14 derived from
b-enaminonitriles such as 3e or 3f (R2 H) could not be
isolated. Reaction of 3e and 3f with 10 led to the formation
of complex mixtures. However, we were able to identify the
desired products 14b,c by GC-MS analysis (Table 4).
(16) Viehe, H. G. Angew. Chem. 1971, 83, 616.
(17) Gross, H.; Costisella, B. J. Prakt. Chem. 1969, 311, 925.
(18) Gross, H.; Costisella, B. Justus Liebigs Ann. Chem. 1971,
750, 44.
Synlett 2003, No. 13, 1959–1964 © Thieme Stuttgart · New York