A simple and versatile route to novel conjugated β-enaminonitriles and their application for the highly regioselective synthesis of nicotinonitriles using a Vilsmeier-type reagent

Article abstract of DOI:10.1021/jo990313g

A straightforward synthesis of conjugated β-enaminonitriles from ketones and β-aminocrotononitrile mediated by TiCl₄ is described. The reaction of these novel dienamines with a Vilsmeier-type reagent provides a mild and highly regioselective route for the preparation of nicotinonitriles.

Full text of DOI:10.1021/jo990313g

6076
J . Org. Chem. 1999, 64, 6076-6079
A Sim p le a n d Ver sa tile Rou te to Novel Con ju ga ted
â-En a m in on itr iles a n d Th eir Ap p lica tion for th e High ly
Regioselective Syn th esis of Nicotin on itr iles Usin g a
Vilsm eier -Typ e Rea gen t
Alan R. Katritzky,* Anna Denisenko, and Michael Arend
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received February 18, 1999
A straightforward synthesis of conjugated â-enaminonitriles from ketones and â-aminocrotononitrile
mediated by TiCl4 is described. The reaction of these novel dienamines with a Vilsmeier-type reagent
provides a mild and highly regioselective route for the preparation of nicotinonitriles.
Sch em e 1
In tr od u ction
Dienamines are versatile building blocks in organic
synthesis.1 They are usually prepared from R,â-unsatur-
ated aldehydes or ketones under conditions analogous to
those used for the preparation of simple enamines.2 We
now report that TiCl4-mediated reactions between ke-
tones and â-aminocrotononitrile provide a series of novel
conjugated â-enaminonitriles 1. â-Enaminonitriles such
as â-aminocrotononitrile are excellent building blocks for
heterocyclic synthesis.3 We demonstrate that this is also
true for conjugated â-enaminonitriles 1 by their trans-
formation into nicotinonitriles 3 using the Vilsmeier-type
reagent 1 (Scheme 1, Table 1).
Pyridine derivatives occur in numerous natural prod-
ucts and are of fundamental importance to living systems
(e.g., nicotinamide adenine dinucleotide (NAD)). They
display interesting physiological activities and have
found attractive applications as pharmaceuticals and
agrochemicals as well as general synthetic building
blocks,4 and many syntheses have been reported.5 Nico-
tinonitrile-like pyridine derivatives are of special syn-
thetic importance,6 and the development of novel routes
remains active.7
effort to extend the scope of this method toward the
synthesis of nicotinonitriles, we attempted to prepare
imines from ketones and â-aminocrotononitrile using a
modification of the TiCl4 procedure.9 However, instead
of the expected imines, we obtained the novel conjugated
â-enaminonitriles 1 (Scheme 1) evidently by a tandem
alkylation-elimination process, in which the â-amino-
crotononitrile reacts as an enamine rather than as a
primary amine (i.e., the enamine R-C atom is attacked
by the carbonyl group10).
Our methodology provides high yields and is of broad
scope: we successfully transformed a variety of repre-
sentative ketones including cyclic and acylic dialkyl or
alkyl, aryl ketones, and sterically hindered ketones (see
Table 1, entries 4, 5, 7, and 9) into the corresponding
dienamines 1a -m . Significantly, if unsymmetrical ke-
tones are used the reaction is highly regioselective (Table
Resu lts a n d Discu ssion
Recently, we disclosed that the Vilsmeier-type reagent
2 reacts with N-arylimines to give quinolines.8 In an
(1) (a) Hickmott, P. W. In The Chemistry of Enamines; Rappoport,
Z., Ed.; Wiley: Chichester, 1994; Part 2, Chapter 26, p 1535. (b)
Hickmott, P. W. Tetrahedron 1984, 40, 2989.
(2) Cervinka, O. In The Chemistry of Enamines; Rappoport, Z., Ed.;
Wiley: New York, 1994; Part 1, Chapter 9, p 467.
(3) Erian, A. W. Chem. Rev. 1993, 93, 1991.
(4) Balasubramanian, M.; Keay, J . G. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 5, Chapter 5.06, p 245.
(5) J ones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 5, Chapter 5.05, p 167.
(6) For recent applications, see: (a) Palacios, F.; Alonso, C.; Rubiales,
G. 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.; Kashi-
wabara, T.; Nakajima, S.; Munezuka, Y. Chem. Pharm. Bull. 1994,
42, 2475. (f) Moltzen, E. K.; Pedersen, H.; Bøgesø, K. P.; Meier, E.;
Frederiksen, K.; Sa´nchez, 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.
(7) For recent examples, see: (a) Katsuyama, I.; Ogawa, S.; Yamagu-
chi, 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.; Sakai, M.; Uchino, N. Bull. Chem. Soc. J pn. 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.
(8) Katritzky, A. R.; Arend, M. J . Org. Chem. 1998, 63, 9989.
(9) Carlson, R.; Larsson, U.; Hansson, L. Acta Chem. Scand. 1992,
46, 1211.
(10) Takazawa, O.; Kogami, K.; Hayashi, K. Bull. Chem. Soc. J pn.
1985, 58, 2427.
10.1021/jo990313g CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/09/1999

Simple and Versatile Route to Novel Conjugated â-Enaminonitriles
J . Org. Chem., Vol. 64, No. 16, 1999 6077
Ta ble 1. Syn th esis of Con ju ga ted â-En a m in on itr iles 1
fr om Keton es a n d â-Am in ocr oton on itr ile Med ia ted by
TiCl4 a n d Con ver sion of 1 in to Nicotin on itr iles 3 by th e
Rea ction w ith Im in iu m Sa lt 2
Sch em e 2
nonitriles 1a -m were purified by distillation or column
chromatography and characterized by elemental analysis,
GC/MS, and NMR spectroscopy. According to their NMR
spectra, they exist as E/Z- or as E,E/E,Z/Z,E/Z,Z diaster-
eomeric mixtures. They can be stored at 0 °C for several
weeks without any sign of decomposition. Dienamines
corresponding to 1 but derived from aldehydes are
unstable: attempts to prepare them (e.g., from propanal)
by a method analogous to that used for the ketone
derivatives 1a -m led only to the formation of complex
mixtures. To the best of our knowledge, conjugated
â-enaminonitriles 1 have not been described before (e.g.,
no compounds of substructure R1CHdC(R2)C(CN)dC(R3)-
NH2 were found in the Beilstein Crossfire database).
Reactions between the dienamines 1a -m and the
iminium salt 2 provided the nicotinonitriles 3a -m in
good yields (Scheme 1, Table 1). Structures 3a -m were
1
supported by comparison of the H NMR data with those
published for nicotinonitriles 3a -c11 and 3j12 (compare
also ref 7b). Many literature methods are known for the
preparation of specific classes of nicotinonitriles, e.g.:
4-trifluoromethyl,7a 6-aryl,7b 4-aryl,7e 4-benzyl,7f and 4,6-
diaryl (or heteroaryl)7d derivatives. However, literature
methods for the preparation of nicotinonitriles of type
311,12 are of limited scope and generally give regioisomeric
mixtures and poor yields. The reaction between di-
enamines 1 and iminium salt 2 provides for the first time
a straightforward and versatile route to regioisomerically
pure nicotinonitriles 3 (Table 1), including 4-alkyl and
4-phenyl derivatives (3g-i,j), simple 4,5-disubstituted
derivatives (3f,k ), and the corresponding fused bicyclic
(3a -e) or tricyclic ring systems (3l,m ). Our method can
also be applied for the synthesis of nicotinonitriles 3 with
bulky 4- and 5-substituents (3d -e,g,i).
To elucidate the mechanism of the transformation 1
into 3, we monitored the reaction between the conjugated
â-enaminonitrile 1b and the Vilsmeier-type reagent 2 by
1H and 13C NMR spectroscopy. We observed the formation
of a single iminium salt and of benzotriazole in virtually
quantitative yield. A priori, reagent 2 could attack (i) at
the amino group or (ii) at the R- or (iii) γ-C-atom of
dienamine 1b. Such modes of attack would produce
intermediates 4, 5, or 6, respectively (Scheme 2). How-
ever, an APT 13C NMR experiment on the reaction
a
b
Yield of crude enaminonitrile 1. Isolated yield of nicotinoni-
trile 3 after Kugelrohr distillation. c The reaction time was 72 h.
1, entries 4 and 7) and forms almost exclusively the less
substituted double bond, suggesting that the elimination
step is kinetically controlled. The conjugated â-enami-
(11) J utz, C.; Lo¨bering, H.-G.; Trinkl, K.-H. Synthesis 1977, 326.
(12) Shibata, K.; Urano, K.; Matsui, M. Bull. Chem. Soc. J pn. 1988,
61, 2199.

6078 J . Org. Chem., Vol. 64, No. 16, 1999
Katritzky et al.
3-Am in o-2-(1-cyclopen ten -1-yl)-2-bu ten en itr ile (1a): yel-
low low-melting solid; dr ) 3:1; H NMR δ 5.56 (s, 1H), [5.42
mixture showed that the product possessed two CH3
peaks at 21.7 and 34.6 ppm, four CH2 peaks at 21.0, 21.1,
25.4, and 27.7 ppm, one CH peak at 149.5 ppm, and five
quaternary C peaks at 109.7, 114.6, 131.7, 152.3, and
156.9 ppm. This spectrum is incompatible with structures
4 and 5 (inter alia, both molecules have two CH groups
and four quaternary C atoms); therefore, the formation
of 4 and 5 as intermediates can be excluded. By contrast,
the NMR data for the transient intermediate are in good
accord with structure 6 (only the most likely configura-
tion is depicted). Hence, conjugated â-enaminonitriles
such as 1b react with iminium salt 2 in the manner of
vinylogous enamines. Although a solution of intermediate
6 can be stored at ambient temperature for several days
without decomposition, attempts to isolate 6 failed. The
conversion of hydrochlorides such as 6 into their conju-
gated bases by the addition of aqueous NaOH solution
evidently induces a spontaneous cyclization-elimination
process furnishing the corresponding nicotinonitriles 3.
1
(s, 1H)], 4.99 (br s, 2H), [4.80 (br s, 2H)], 2.60-2.20 (m, 2H,
major and minor diastereomer), 2.11 (s, 3H), [2.01 (s, 3H)],
1.87-1.73 (m, 4H), [1.70-1.59 (m, 4H)]; 13C NMR δ 155.0,
[160.1], 135.9, [135.3], 125.6, [126.0], 121.6, [120.1], 78.5, [82.0],
35.8, [35.9], 33.2, [32.7], 22.5, [23.2], 20.9, [19.3]. Anal. Calcd
for C9H12N2: C, 72.93; H, 8.18; N, 18.91. Found: C, 73.11; H,
8.51; N, 18.46.
3-Am in o-2-(1-cycloh exen -1-yl)-2-bu ten en itr ile (1b): yel-
low solid; mp 76-77 °C; 1H NMR δ 5.73 (br s, 1H), 4.69 (br s,
2H), 2.19-2.02 (m, 7H), 1.75-1.52 (m, 4H); 13C NMR δ 153.7,
130.8, 127.8, 121.7, 83.2, 28.0, 25.4, 22.6, 21.9, 20.5. Anal.
Calcd for C10H14N2: C, 74.03; H, 8.72; N, 17.27. Found: C,
73.96; H, 9.08; N, 17.12.
3-Am in o-2-(1-cycloh epten -1-yl)-2-bu ten en itr ile (1c): yel-
1
low oil; dr ) 8:1; H NMR δ 5.91 (t, J ) 6.6 Hz, 1H), [5.69 (t,
J ) 6.6 Hz, 1H)], 4.87 (br s, 2H), [4.77 (br s, 2H)], 2.34-2.30
(m, 2H), [2.55-2.48 (m, 2H)], 2.25-2.19 (m, 2H, major and
minor diastereomer), 2.12 (s, 3H), [1.98 (s, 3H)], 1.85-1.70 (m,
2H, major and minor diastereomer), 1.61-1.48 (m, 4H, major
and minor diastereomer); 13C NMR δ 153.2, [153.1], 137.1,
[137.0], 132.8, [133.1], 122.0, [120.2], 83.7, [83.6], 32.8, [43.6],
32.0, [33.7], 28.2, [30.1], 26.7, [26.2], 26.5, [24.0], 20.1, [19.1];
HRMS calcd for C11H16N2 176.1313, found 176.1316.
Con clu sion
3-Am in o-2-(6-m et h yl-1-cycloh exen -1-yl)-2-b u t en en i-
tr ile (1d ): light yellow low-melting solid (consists of a major
diastereomer, traces of the minor diastereomer and a regio-
isomer); major diastereomer, 1H NMR δ 5.69 (t, J ) 3.8 Hz,
1H), 4.73 (br s, 2H), 2.42-1.40 (m, 7H), 2.14 (s, 3H), 1.00 (d,
J ) 7.1 Hz, 3H); 13C NMR δ 154.8, 135.5, 128.7, 121.8, 81.5,
31.2, 30.3, 25.7, 19.9, 19.5, 18.7. Anal. Calcd for C11H16N2: C,
74.95; H, 9.17; N, 15.90. Found: C, 74.81; H, 9.24; N, 15.82.
3-Am in o-2-(3,3,5,5-t et r a m et h yl-1-cyclop en t en -1-yl)-2-
In summary, we have developed a straightforward
method for the preparation of previously unknown con-
jugated â-enaminonitriles 1 from ketones and â-amino-
crotononitrile. We have demonstrated the great potential
of dienamines 1 as synthetic building blocks. Their
reaction with the Vilsmeier-type reagent 2 provides for
the first time a broadly applicable and highly regiose-
lective synthesis of nicotinonitriles of type 3. Further-
more, our mild procedure should be suitable for sensitive
substrates.
1
bu ten en itr ile (1e): white solid; mp 41-43 °C; dr ) 4:1; H
NMR δ 5.33 (s, 1H), [5.12 (s, 1H)], 4.75 (br s, 2H, major and
minor diastereomer), 2.10 (s, 3H), [1.88 (s, 3H)], 1.62 (s, 2H,
major and minor diastereomer), 1.13 (s, 6H), [1.08 (s, 6H)],
1.05 (s, 6H), [1.03 (s, 6H)]; 13C NMR δ 157.1, [158.2], 140.5,
[140.0], 140.4, [141.0], 122.1, [120.5], 74.7, [73.5], 54.9, [54.9],
48.4, [48.0], 42.9, [42.4], 30.4, [30.2], 29.4, [29.4], 20.1, [18.5].
Anal. Calcd for C13H20N2: C, 76.41; H, 9.89; N, 13.71. Found:
C, 76.54; H, 10.24; N, 14.05.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
Koefler hot-stage apparatus and are not corrected. 1H and 13C
NMR spectra were recorded at 300 and 75 MHz, respectively,
in CDCl3 referenced to TMS for the proton spectra and to the
solvent for the carbon spectra. The benzotriazole iminium salt
2 was prepared by refluxing a THF solution of equimolar
amounts of N-trimethylsilylbenzotriazole, DMF, and SOCl2.13
CH2Cl2 used for the reaction between dienamine 1 and
iminium salt 2 was distilled under argon from CaH2 prior to
use. Column chromatography was conducted with silica gel
(230-400 mesh).
Gen er a l P r oced u r e for th e Syn th esis of Con ju ga ted
â-En a m in on itr iles 1. To a solution of â-aminocrotononitrile
(4.9 g, 60 mmol) and NEt3 (15.3 mL, 110 mmol) in CH2Cl2 (60
mL) cooled with an ice bath was added slowly with stirring a
solution of TiCl4 (3.3 mL, 30 mmol) in CH2Cl2 (40 mL).
Subsequently, the ketone (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 â-enaminonitriles 1, which were
used for the preparation of the nicotinonitriles 3 without prior
purification. Analytical samples were purified by Kugelrohr
distillation or flash column chromatography. In many cases,
E/Z (the NMR data of the minor diasteromer are bracketed)
or E,E/Z,Z/E,Z/Z,E mixtures were obtained. The diastereo-
meric ratios (dr) were determined by 1H NMR spectroscopy
after purification.
2-(1-Am in oeth yliden e)-3-eth yl-3-pen ten en itr ile (1f): yel-
low oil (mixture of four diastereomers); major diastereomer,
1H NMR δ 5.57-5.44 (m, 1H), 4.74 (br s, 2H), 2.24-2.12 (m,
6H, together with minor diastereomers), 1.74-1.66 (m, 2H),
1.02-0.92 (m, 3H, together with minor diastereomers); 13C
NMR δ 154.9, 134.9, 125.4, 122.0, 82.0, 22.9, 20.0, 13.2, 12.6.
Anal. Calcd for C9H14N2: N, 18.65. Found: N, 18.66.
2-Am in om e t h ylid e n e -3-isop r op yl-3-p e n t e n e n it r ile
(1g): yellow low-melting solid (consists of a major diastere-
omer, traces of the minor diastereomer and the regioisomer);
major diastereomer, 1H NMR δ 4.72 (s, 2H), 4.20 (s, 2H), 2.50-
2.35 (m, 1H), 2.04 (s, 3H), 1.67 (s, 3H), 1.00 (t, J ) 6.3 Hz,
3H); 13C NMR δ 152.8, 132.9, 121.9, 120.2, 82.2, 32.2, 21.2,
20.0, 17.4. Anal. Calcd for C9H14N2: C, 71.95; H, 9.41; N, 18.65.
Found: C, 72.21; H, 9.48; N, 19.17.
3-Am in o-2-(1-cyclopr opylvin yl)-2-bu ten en itr ile (1h ): yel-
low oil; 1H NMR δ 5.12 (s, 1H), 5.10-5.00 (m, 2H), 4.96 (s,
1H), 2.18 (s, 3H), 1.57-1.45 (m, 1H), 0.76 (d, J ) 6.6 Hz, 2H),
0.61 (d, J ) 5.2 Hz, 2H); 13C NMR δ 155.6, 143.1, 121.8, 111.7,
80.5, 20.5, 16.2, 6.7. Anal. Calcd for C9H12N2: C, 72.93; H, 8.18;
N, 18.91. Found: C, 72.86; H, 8.31; N, 19.11.
3-Am in o-2-[1-(ter t-bu tyl)vin yl]-2-bu ten en itr ile (1i): white
solid; mp 77-79 °C; 1H NMR δ 5.30 (s, 1H), 4.96 (s, 1H), 4.54
(br s, 2H), 2.10 (s, 3H), 1.10 (s, 9H); 13C NMR δ 155.8, 150.6,
122.5, 116.5, 80.0, 37.9, 29.4, 19.7. Anal. Calcd for C10H16N2:
C, 73.12; H, 9.84. Found: C, 72.91; H, 10.00.
3-Am in o-2-(1-p h en ylvin yl)-2-bu ten en itr ile (1j): yellow
1
oil; dr ) 4:1; H NMR δ 7.43-7.30 (m, 5H, major and minor
diastereomer), 5.57 (s, 1H), [5.55 (s, 1H)], 5.38 (s, 1H), [5.21
(s, 1H)], 4.52 (br s, 2H), [4.88 (br s, 2H)], 2.19 (s, 3H), [1.78 (s,
3H)]; 13C NMR δ 156.0, [157.2], 141.4, [141.8], 138.3, [140.0],
128.6, [128.6], 128.4, [128.3], 126.8, [126.2], 122.0, [120.5],
(13) Katritzky, A. R.; Cheng, D.; Leeming, P.; Ghiviriga, I.; Hart-
shorn, C. M.; Steel, P. J . J . Heterocycl. Chem. 1996, 33, 1935.

Simple and Versatile Route to Novel Conjugated â-Enaminonitriles
116.9, [117.0], 79.9, [79.2], 20.9, [18.9]. Anal. Calcd for
J . Org. Chem., Vol. 64, No. 16, 1999 6079
57.0, 44.1, 41.0, 31.1, 28.7, 23.2. Anal. Calcd for C14H18N2: C,
78.46; H, 8.48; N, 13.07. Found: C, 78.80; H, 8.87; N, 13.29.
4-Eth yl-2,5-d im eth yln icotin on itr ile (3f): yellow oil; 1H
NMR δ 8.30 (s, 1H), 2.83-2.73 (q, J ) 7.4 Hz, J ) 7.7 Hz,
2H), 2.64 (s, 3H), 2.25 (s, 3H), 1.16 (t, J ) 7.6 Hz, 3H); 13C
NMR δ 159.6, 155.1, 152.6, 128.7, 116.3, 109.0, 25.0, 23.4, 15.5,
13.3. Anal. Calcd for C10H12N2: C, 74.96; H, 7.56; N, 17.49.
Found: C, 74.64; H, 8.12; N, 17.56.
C
12H12N2: C, 78.22; H, 6.58. Found: C, 78.09; H, 6.88.
2-(1-Am in oeth ylid en e)-3-p h en yl-3-h exen en itr ile (1k ):
yellow low-melting solid (mixture of two diastereomers); dr )
1
6:1; H NMR δ 7.34-7.17 (m, 5H, major and minor diastere-
omer), 6.00 (t, J ) 7.4 Hz, 1H), [5.79 (t, J ) 7.4 Hz, 1H)], 4.30
(br s, 2H), [4.73 (br s, 2H)], 2.17-2.10 (m, 5H), [2.08-2.00 (m,
5H)], 1.02 (t, J ) 7.4 Hz, 3H), [0.93 (t, J ) 7.4 Hz, 3H)]; 13C
NMR δ 155.8, [158.8], 139.0, [138.1], 136.2, [135.7], 131.1,
[132.9], 128.5, [128.8], 127.5, [128.3], 126.2, [127.1], 121.7,
[122.3], 82.9, [82.9], 23.3, [23.4], 19.8, [21.2], 13.5, [14.2]. Anal.
Calcd for C14H16N2: C, 79.20; H, 7.61; N, 13.20. Found: C,
78.83; H, 7.92; N, 13.21.
4-Isop r op yl-2-m eth yln icotin on itr ile (3g): yellow oil; 1H
NMR δ 8.51 (d, J ) 5.2 Hz, 1H), 7.10 (d, J ) 5.3 Hz; 1H),
3.33-3.20 (m, 1H), 2.71 (s, 3H), 1.26 (d, J ) 6.8 Hz, 6H); 13C
NMR δ 161.8, 161.5, 151.8, 117.8, 116.0, 108.8, 32.4, 23.9, 22.4.
Anal. Calcd for C10H12N2: N, 17.49. Found: N, 17.58.
4-Cyclop r op yl-2-m eth yln icotin on itr ile (3h ): tan crys-
3-Am in o-2-(3,4-d ih yd r o-1-n a p h t h a len yl)-2-b u t en en i-
1
1
tr ile (1l): yellow solid; mp 57-60 °C; H NMR δ 7.21-7.13
tals; mp 62-64 °C; H NMR δ 8.37 (d, J ) 5.5 Hz, 1H), 6.53
(m, 4H), 6.20 (t, J ) 4.5 Hz, 1H), 4.33 (br s, 2H), 2.79 (t, J )
7.9 Hz, 2H), 2.41-2.33 (m, 2H), 2.25 (s, 3H); 13C NMR δ 156.1,
136.2, 131.9, 131.6, 130.3, 127.7, 127.5, 126.5, 124.0, 122.3,
77.3, 27.4, 23.1, 19.9. Anal. Calcd for C14H14N2: C, 79.96; H,
6.72. Found: C, 80.20; H, 6.77.
(d, J ) 5.4 Hz, 1H), 2.68 (s, 3H), 2.26-2.15 (m, 1H), 1.22-
1.18 (m, 2H), 0.84-0.81 (m, 2H); 13C NMR δ 161.4, 158.0,
151.4, 116.3, 114.9, 109.7, 23.8, 14.0, 11.3. Anal. Calcd for
C
10H10N2: C, 75.92; H, 6.38; N, 17.71. Found: C, 75.96; H,
6.55; N, 17.58.
3-Am in o-2-(2H-ch r om en -4-yl)-2-bu ten en itr ile (1m ): tan
4-(ter t-Bu tyl)-2-m eth yln icotin on itr ile (3i): yellow crys-
1
1
solid; mp 110-113 °C; H NMR δ 7.13-7.11 (m, 2H), 6.87 (t,
tals; mp 57-59 °C; H NMR δ 8.47 (d, J ) 5.5 Hz, 1H), 7.18
(d, J ) 5.5 Hz, 1H), 2.73 (s, 3H), 1.44 (s, 9H); 13C NMR δ 163.3,
162.9, 151.7, 118.1, 117.9, 107.5, 35.7, 29.2, 24.1. Anal. Calcd
for C11H14N2: C, 75.82; H, 8.11; N, 16.08. Found: C, 75.89; H,
8.44; N, 16.24.
J ) 7.2 Hz, 1H), 6.79 (d, J ) 8.1 Hz, 1H), 5.84 (s, 1H), 5.02 (br
s, 2H), 4.76 (d, J ) 2.9 Hz, 2H), 2.18 (s, 3H); 13C NMR δ 157.5,
154.3, 129.4, 127.8, 124.5, 123.7, 121.7, 121.1, 120.7, 115.8,
73.5, 64.8, 19.7. Anal. Calcd for C13H12N2O: N, 13.20. Found:
N, 13.22.
2-Meth yl-4-p h en yln icotin on itr ile (3j): tan crystals; mp
1
Gen er a l P r oced u r e for th e Syn th esis of Nicotin on i-
tr iles 3. The reactions were conducted in a water-free ap-
paratus under argon. To a solution of the conjugated â-enam-
inonitriles 1 (4 mmol) in CH2Cl2 (20 mL) was added the
iminium salt 2 (5 mmol) in one portion. The mixture was
stirred for 24 h at ambient temperature. Subsequently, dilute
NaOH (2 N, 40 mL) was added, and the resulting mixture was
stirred vigorously for ca. 5 min. The organic phase was
decanted off, and the aqueous phase was extracted with Et2O
(3 × 50 mL). The combined organic phases were dried over
Na2SO4, and the solvent was removed in vacuo. Kugelrohr
distillation of the residue provided the nicotinonitriles 3.
3-Meth yl-6,7-d ih yd r o-5H-cyclop en ta [c]p yr id in e-4-ca r -
103-104 °C; H NMR δ 8.66 (d, J ) 5.2 Hz, 1H), 7.59-7.49
(m, 5H), 7.27 (d, J ) 5.2 Hz, 1H), 2.86 (s, 3H); 13C NMR δ
162.6, 153.1, 151.5, 135.9, 129.8, 128.9, 128.3, 121.2, 116.6,
107.7, 24.0. Anal. Calcd for C13H10N2: C, 80.38; H, 5.20; N,
14.43. Found: C, 80.24; H, 5.15; N, 14.23.
5-Eth yl-2-m eth yl-4-p h en yln icotin on itr ile (3k ): yellow
oil; 1H NMR δ 8.48 (s, 1H), 7.40-7.36 (m, 3H), 7.20-7.15 (m,
2H), 2.68 (s, 3H), 2.42 (q, J ) 7.7 Hz, 2H), 0.94 (t, J ) 7.7 Hz,
3H); 13C NMR δ 159.0, 152.4, 152.1, 135.1, 134.7, 128.9, 128.5,
128.0, 116.2, 109.3, 23.4, 23.2, 15.0. Anal. Calcd for C15H14N2:
C, 81.04; H, 6.36; N, 12.61. Found: C, 80.79; H, 6.36; N, 12.94.
2-Met h yl-5,6-d ih yd r oben zo[f]isoq u in olin e-1-ca r b on i-
1
tr ile (3l): tan crystals; mp 165-167 °C; H NMR δ 8.51 (s,
1
bon itr ile (3a ): tan solid; mp 74-75 °C; H NMR δ 8.41 (s,
1H), 8.43-8.39 (m, 1H), 7.44-7.38 (m, 2H), 7.35-7.31 (m, 1H),
2.83 (s, 3H), 2.85-2.79 (m, 4H); 13C NMR δ 161.8, 150.4, 144.9,
139.6, 130.8, 130.6, 129.7, 128.3, 127.2, 126.9, 118.0, 103.8,
28.6, 25.4, 24.0. Anal. Calcd for C15H12N2: N, 12.72. Found:
N, 12.59.
1H), 3.03 (t, J ) 7.5 Hz, 2H), 2.93 (t, J ) 7.4 Hz, 2H), 2.66 (s,
3H), 2.10-2.03 (m, 2H); 13C NMR δ 158.6, 158.4, 147.5, 137.7,
116.1, 105.8, 32.5, 30.1, 24.5, 23.1. Anal. Calcd for C10H10N2:
C, 75.92; H, 6.38; N, 17.71. Found: C, 75.61; H, 6.56; N, 17.68.
3-Me t h yl-5,6,7,8-t e t r a h yd r o-4-isoq u in olin e ca r b on i-
tr ile (3b): tan solid; mp 100-101 °C; 1H NMR δ 8.34 (s, 1H),
2.96-2.88 (m, 2H), 2.80-2.73 (m, 2H), 2.70 (s, 3H), 1.92-1.81
(m, 4H); 13C NMR δ 158.8, 152.2, 150.0, 130.5, 116.0, 109.1,
27.7, 25.7, 23.2, 21.8, 21.7. Anal. Calcd for C11H12N2: C, 76.71;
H, 7.04; N, 16.27. Found: C, 76.65; H, 7.44; N, 16.30.
3-Meth yl-6,7,8,9-tetr a h yd r o-5H-cycloh ep ta [c]p yr id in e-
4-ca r bon itr ile (3c): light yellow solid; mp 35-37 °C; 1H NMR
δ 8.25 (s, 1H), 3.10-2.94 (m, 2H), 2.76-2.70 (m, 2H), 2.64 (s,
3H), 1.87-1.77 (m, 2H), 1.66-1.52 (m, 4H); 13C NMR δ 159.4,
155.7, 150.8, 136.1, 116.5, 108.7, 33.6, 32.5, 32.0, 27.3, 26.4,
23.5; HRMS calcd for C12H14N2 187.1232, found 187.1235.
3,5-Dim et h yl-5,6,7,8-t et r a h yd r o-4-isoqu in olin eca r bo-
n itr ile (3d ): yellow oil; 1H NMR δ 8.35 (s, 1H), 3.30-3.20
(m, 1H), 2.83-2.78 (m, 1H), 2.74-2.60 (m, 1H), 2.71 (s, 3H),
1.90-1.78 (m, 4H), 1.36 (d, J ) 7.1 Hz, 3H); 13C NMR δ 158.8,
154.6, 152.4, 129.5, 116.1, 108.5, 30.7, 28.5, 25.5, 23.1, 21.3,
16.7. Anal. Calcd for C12H14N2: C, 77.38; H, 7.59; N, 15.04.
Found: C, 76.93; H, 7.87; N, 15.13.
2-Met h yl-5H -ch r om en o[3,4-c]p yr id in e-1-ca r b on it r ile
(3m ): tan crystals; mp 163-165 °C; H NMR δ 8.51 (d, J )
8.0 Hz, 1H), 8.45 (s, 1H), 7.44 (t, J ) 8.0 Hz, 1H), 7.18 (t, J )
8.0 Hz, 1H), 7.07 (d, J ) 8.0 Hz, 1H), 5.04 (s, 2H), 2.84 (s,
3H); 13C NMR δ 163.3, 156.6, 147.3, 140.1, 133.2, 126.3, 124.7,
122.6, 119.0, 117.9, 117.4, 102.3, 65.4, 24.1. Anal. Calcd for
1
C
14H10N2O: C, 75.65; H, 4.54; N, 12.61. Found: C, 75.31; H,
4.69; N, 12.39.
Ack n ow led gm en t. Financial support from the Al-
exander von Humboldt Foundation (Feodor Lynen Fel-
lowship to M.A.) and the US Civilian Research and
Development Foundation (Grant No. 166607612) are
gratefully acknowledged. We thank Professor Gevorg
Danagulyan (Institute of National Economy, Yerevan,
Armenia) for helpful discussions.
Su p p or t in g In for m a t ion Ava ila b le: 1H and C13 NMR
and HRMS spectra for compounds 1c and 3c. This material
is available free of charge via the Internet at http://pubs.acs.org.
3,5,5,7,7-P en ta m eth yl-6,7-d ih yd r o-5H-cyclop en ta [c]p y-
1
r id in e-4-ca r bon itr ile (3e): yellow solid; mp 63-65 °C; H
NMR δ 8.33 (s, 1H), 2.69 (s, 3H), 1.93 (s, 2H), 1.45 (s, 6H),
1.29 (s, 6H); 13C NMR δ 163.0, 160.5, 147.2, 145.0, 116.1, 104.1,
J O990313G