Lewis acid-promoted direct substitution of 2-methoxy-3-cyanopyridines by organo cuprates. Part 3: Facile preparation of nicotinamide and nicotinic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.02.096

2-Methoxy-3-cyano-4,6-diarylpyridines were subjected to Lewis acid-promoted nucleophilic displacement reactions with various organo cuprates to afford the corresponding 2,4,6-trisubstituted nicotinonitriles. Subsequent hydrolysis of compounds 10 and 11 af

Full text of DOI:10.1016/j.tetlet.2007.02.096

Tetrahedron Letters 48 (2007) 2861–2865
Lewis acid-promoted direct substitution of
2-methoxy-3-cyanopyridines by organo cuprates. Part 3:
Facile preparation of nicotinamide and nicotinic acid derivatives
Alaa A.-M. Abdel-Aziz*
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457 Riyadh 11451, Saudi Arabia
Received 30 November 2006; revised 9 February 2007; accepted 22 February 2007
Available online 24 February 2007
Abstract—2-Methoxy-3-cyano-4,6-diarylpyridines were subjected to Lewis acid-promoted nucleophilic displacement reactions with
various organo cuprates to afford the corresponding 2,4,6-trisubstituted nicotinonitriles. Subsequent hydrolysis of compounds 10
and 11 afforded the corresponding 2,4,6-trisubstituted nicotinic acid 22 and nicotinamide 23 derivatives, respectively. The mecha-
nism of the displacement reaction has been studied experimentally and by molecular modeling calculations.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The directed construction of carbon–carbon bonds has
always been a central theme in synthetic organic chem-
istry and the structural diversity and biological impor-
tance of nitrogen-containing heterocycles have made
them attractive targets for synthesis over many years
and justify continuing efforts in the development of
new synthetic strategies.1,2 The pyridine motif is among
the most common heterocyclic compounds found in var-
ious therapeutic agents and is a building block for the
synthesis of nicotinic acid and its amide (nicotinamide)
which are used in pharmaceutical formulations, as
additives in food and animal feed and as brighteners in
electroplating baths and stabilizers for pigmentation in
cured meat.3,4 Thus, extensive efforts have been exerted
on developing methodology for the synthesis of pyridine
derivatives.5 For example, Bryce and co-workers have
reported the synthesis of pyridine derivatives from furan
precursors.6 However, introduction of substituents to
pyridine rings often requires long reaction times and
vigorous conditions to achieve acceptable yields under
conventional heating or photolysis conditions.7 Hence,
a versatile route for the synthesis of 2,4,6-trisubstituted
nicotinonitrile, 2,4,6-trisubstituted nicotinamide and
2,4,6-trisubstituted nicotinic acid derivatives under mild
conditions is highly desirable. In the previous papers,8
we reported the synthesis of 4,6-diaryl-3-cyano-2-alk-
oxypyridines 1 and their reactions with anhydrous
hydrazine or substituted amines in the presence of a
Lewis acid to give the corresponding 1H-pyrazolo-
[3,4-b]pyridines 2 and 2-substituted aminopyridines 3,
respectively (Scheme 1).
This Letter describes the procedures for the smooth
reaction of a wide variety of alkyl and phenyl cuprates
at the 2-position and/or 3-position of 2-methoxy-3-
cyanopyridines 4, 15 and 16, leading to the preparation
of compounds of medicinal interest such as nicotin-
amide and nicotinic acid derivatives. Our approach
depends on the reaction of 2-methoxy-3-cyanopyridines
with organo cuprates promoted by a Lewis acid with or
without reaction of the 3-cyano group9 to afford a new
series of pyridine derivatives. To the best of our
knowledge, no Lewis acid-promoted arylation or alkyl-
ation of 2-methoxy-3-cyanopyridines through regio-
selective C–C bond formation under mild reaction
conditions has been described in the literature. Starting
compound 4 was prepared according to our previous
report in which a,b-unsaturated ketones were condensed
with malononitirile in sodium methoxide/methanol to
yield the corresponding 2-methoxy-3-cyanopyridines
4.8a
Initial experiments10 involved attempted direct substitu-
tion reactions of phenylmagnesium bromide with 2-
methoxy-3-cyano-4,6-diphenylpyridine 4 in the presence
of a variety of Lewis acid-additives such as MgBr2,
*
Tel.: +966 562947305; fax: +966 14676220; e-mail: alaa_moenes@
yahoo.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.096

2862
A. A.-M. Abdel-Aziz / Tetrahedron Letters 48 (2007) 2861–2865
O
N
O
O
N
O
O
O
O
O
O
H N
2
NC
NC
HN
N
Et AlCl (1.0 eq.), THF
EtOH, NH NH
2
2
2
N
MeO
N
H
o
BF , reflux 3 h
3
PhNH , 30 C, 2 h
2
Cl
Cl
Cl
Cl
Cl
Cl
1
3
2
Scheme 1. Lewis acid-promoted reaction of aniline or hydrazine with the 2-methoxypyridine.
FeCl3, ZnCl2, AlCl3 or SnCl4 in THF at ambient tem-
perature. The reactions, however, did not proceed under
any of the conditions and the recovered starting material
was obtained. Next, we examined the same type of reac-
tion employing other Lewis acids. Whereas the reactions
with Et2AlCl and CuI gave the desired substituted prod-
uct 12, but in low yield, the use of BF3ÆEt2O had a dra-
matic effect on the rate and smoothly brought about
formation of target compound 12 in almost quantitative
yield under mild conditions (Table 1, entry 8). Further-
more, the nature of the solvent also affected the reaction
yield. Solvents such as diethyl ether and methylene chlo-
ride afforded low yields, while the result of the reaction
in THF was completely in contrast with that in toluene
and benzene (disfavored nucleophilic attack), that is,
THF gave arylated product, exclusively.
ence of BF3ÆEt2O8,11 was found to give excellent yields
of 2-alkyl or 2-aryl-3-cyanopyridines, while reaction
with a combination of Grignard reagent and BF3ÆEt2O12
resulted in generally lower yields.13 This method is ver-
satile enough to permit the introduction of a range of
alkyl and aryl groups at the 2-position of the pyridine
moiety. Thus, 2-methoxy-3-cyanopyridine was treated
with a mixture of cyclohexylmethylmagnesium bromide
(4.0 equiv), CuCN (4.4 equiv) and LiCl (8.8 equiv) in
the presence of BF3ÆEt2O (2.0 equiv) at 20 ꢁC to give
2-cyclohexylmethyl-3-cyanopyridine 14, regioselectively,
in 98% yield without any substitution at the 3-position
of pyridine (Table 1, entry 10). It is noteworthy that
the observed nucleophilic displacement was highly
dependent on the nature of the Lewis acid, and the
tendency for formation of the target product correlated
approximately with the acidity of the conjugate base
formed.8b
We were delighted to find that comparable results were
obtained in the reaction employing organo cuprates
containing alkyl or aryl moieties. The results from our
survey are summarized in Table 1. Treatment of 2-meth-
oxy-3-cyanopyridine 4 with cuprate reagents in the pres-
The generality of this reaction was examined using
various starting materials containing different electronic
moieties such as nitro and methoxy groups as shown
Table 1. The BF3-promoted direct substitution of 2-methoxy-3-cyanopyridines by alkyl and phenyl cupratesa
CN
R
CN
organo cuprate, BF
3
THF
N
N
OMe
4
5-14
Entry
Compd
Organo cuprate
R
5–14b (%)
1
2
3
4
5
6
7
8
9
5
6
MeCuCNLi, LiClc
Me
Et
i-Pr
n-Bu
i-Bu
t-Bu
1-Adamantyl
Ph
PhCH2
c-C6H11CH2
93
96
89
92
86
77
69
86
92
98
EtCuCNLi, LiCld
7
i-PrCuCNMgBr, LiCl
n-BuCuCNLi, LiCle
i-BuCuCNMgBr, LiCl
t-BuCuCNMgBr, LiCl
1-AdamantylCuCNMgBr, LiCl
PhCuCNMgBr, LiCl
8
9
10
11
12
13
14
PhCH2CuCNMgBr, LiCl
c-C6H11CH2CuCNMgBr, LiCl
10
a The reaction was performed using Grignard reagent (4.0 equiv), CuCN (4.4 equiv) and BF3ÆEt2O (2.0 equiv) in the presence of LiCl (8.8 equiv) at
À78 ꢁC to 20 ꢁC for 3 h, unless otherwise stated.
b Total yield after column chromatographic separation.
c MeLi (4.0 equiv) was used.
d EtLi (4.0 equiv) was used.
e n-BuLi (4.0 equiv) was used.

A. A.-M. Abdel-Aziz / Tetrahedron Letters 48 (2007) 2861–2865
2863
Table 2. Effects of electronic and steric factors on the direct substitution of 2-methoxy-3-cyanopyridines by alkyl and phenyl cupratesa
1
R1
R
2
R2
R2
CN
CN
R2
R CuCNMgBr, LiCl, BF
THF, -78 oC - 20 oC, 3 h
3
+
N
OMe
N
N
1
R = H (4), NO (15), MeO (16)
10,12,17–20
21
2
Entry
Compd
R1
R2
10,12,17–20b (%)
21b (%)
1
2
3
4
5
6
12
10
17
18
19
20
H
H
NO2
NO2
MeO
MeO
Ph
t-Bu
Ph
t-Bu
Ph
t-Bu
86c
77c
61
80
97
0
0
30
0
0
0
89
a The reaction was performed using Grignard reagent (4.0 equiv), CuCN (4.4 equiv) and BF3ÆEt2O (2.0 equiv) in the presence or absence of LiCl
(8.8 equiv) at À78 ꢁC to 20 ꢁC, for 3 h, unless otherwise stated.
b Total yield after column chromatographic separation.
c Data were taken from Table 1.
in Table 2. The presence of an electron-withdrawing
group on 4-phenylpyridine such as nitro 15 led to a
decrease in the yield of the target product and the appear-
ance of 3-phenylpyridines when using phenyl cuprate as
a nucleophile, which may be attributable to the increase
of electrophilic character of the pyridine ring (Table 2,
entry 1 vs 3). On the other hand, 4-phenylpyridine 16
containing electron-donating groups such as methoxy
resulted in the formation of only one product in which
the 2-position of pyridine was regioselectively substi-
tuted with phenyl without any effect on the 3-position
(Table 2, entry 3 vs 5). Moreover, due to steric reasons,
the formation of 3-substituted pyridine derivatives was
completely inhibited when highly hindered tert-butyl
cuprate was used as the nucleophile (Table 2, entries 2
and 4 vs 3). Structural variation in the organo cuprates
affected the yields of the product. Increasing the bulki-
ness of the organo cuprate from phenyl to tert-butyl
influences the reaction products (Table 2, entries 3 and
4). It is clear that steric factors can significantly affect
the chelate structures, which might play a crucial role
in the substitution step.
tives of medicinal interest.3g,h,14 The versatility of the
methodology was demonstrated by two representative
routes for nicotinamide and nicotinic acid, as outlined
in Scheme 2. Thus, 2-methoxy-3-cyanopyridine 4 was
converted into its 2-tert-butyl and 2-(1-adamantyl)
derivatives, 10 and 11,15 followed by conventional
transformation into 2-tert-butylnicotinic acid 22 and
2-(1-adamantyl)nicotinamide 23,16 respectively. As shown
in Scheme 2, acid hydrolysis of 3-cyanopyridine 10 with
concd HCl for 5 h gave 2-tert-butylnicotinic acid 22,
while oxidative conversion of 3-cyanopyridine 11 with
MnO2 or hydrolysis with KOH/absolute ethanol in the
presence of H2O2 resulted in exclusive formation of 2-
(1-adamantyl)nicotinamide 23 in a concerted manner.
Mechanistically, it is reasonable to assume that the first
step in the reaction may involve coordination of BF3
with the pyridine through various models including
two open models M-1 and M-2 and two cyclic models
M-3 and M-4 (Fig. 1). It is clear from the relative energy
calculations that M-1 is more favored than M-2, M-3
and M-4 by 16, 28, and 25 kcal/mol,17 respectively.
The above coordination facilitates substitution of the
methoxy group by the organo cuprate reagent. A
preliminary investigation of the reaction mechanism to
The products thus obtained are useful precursors for the
preparation of nicotinamide and nicotinic acid deriva-
NC
H NOC
2
HOOC
EtOH, KOH (3 eq.)
Conc. HCl
N
N
N
R
H2O2, 70 oC, 2 h
86%
reflux 5 h, 88%
R= t-Bu (10), 1-adamantyl (11)
22
23
Scheme 2. Preparation of nicotinamide and nicotinic acid derivatives.

2864
A. A.-M. Abdel-Aziz / Tetrahedron Letters 48 (2007) 2861–2865
Figure 1. Plausible coordination models of BF3 with 2-methoxy-3-cyanopyridines as calculated by PM3 semi-empirical molecular orbital calculations
in THF.
References and notes
1. (a) Abdel-Aziz, A. A.-M.; Okuno, J.; Tanaka, S.; Ish-
izuka, T.; Matsunaga, H.; Kunieda, T. Tetrahedron Lett.
PhCuCNMgBr/ LiCl, BF (2.0 eq.)
3
N
N
2000, 41, 8533–8537; (b) Seo, R.; Ishizuka, T.; Abdel-Aziz,
A. A.-M.; Kunieda, T. Tetrahedron Lett. 2001, 42, 6353–
6355; (c) Abdel-Aziz, A. A.-M.; Matsunaga, H.; Kunieda,
T. Tetrahedron Lett. 2000, 42, 6565–6567; (d) Abdel-Aziz,
A. A.-M.; Serry, A. A. E.; Goda, F. E.; Kunieda, T.
Tetrahedron Lett. 2004, 45, 8073–8077.
MeO
o
o
THF, -78 C - 20 C, 3 h (10%)
24
25
Scheme 3. Lewis acid-promoted arylation of the 2-methoxypyridine.
´
´
2. (a) Trecourt, F.; Gervais, B.; Mallet, M.; Queguiner, G. J.
Org. Chem. 1996, 61, 1673–1676; (b) Pasquinet, E.; Rocca,
determine the behavior of the Lewis acid (coordination
model) in this process and the role of the nitrile moiety
at the 3-position of pyridine, an experiment (Scheme 3)
was carried out ranging the temperature from À78 ꢁC to
20 ꢁC over 3 h. Thus, arylation of 2-methoxy-4,6-diphen-
ylpyridine 24 lacking a cyano group using the phenyl
cuprate reagent afforded 2,4,6-triphenylpyridine 25 in
10% isolated yield along with 85% recovered starting
material.18 It is evident that the electrophilicity of the
reacting pyridines is crucial in such cases, and therefore,
the reaction proceeds smoothly with 2-methoxy-3-
cyanopyridine 4, leading to the formation of 12. In
contrast, substitution of the methoxy group of 2-meth-
oxypyridine 24 was incomplete, perhaps due to the
increased p-electron density compared with 2-methoxy-
3-cyanopyridine 4. This result proves the importance
of the nitrile moiety, which accelerates the reaction rate
via an electronic effect through increasing the electro-
philicity of the pyridine ring and may be involved in
coordination with the Lewis acid. On the basis of
these observations, a possible reaction mechanism may
depend on the electrophilic behavior of the pyridine core
and the coordination model M-1 which facilitates
substitution of the methoxy group.
´
P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron
1998, 54, 8771–8782; (c) Verbeek, J.; Brandsma, L. J. Org.
Chem. 1984, 49, 3857–3859; (d) Pal, M.; Batchu, V. R.;
Dager, I.; Swamy, N. K.; Padakanti, S. J. Org. Chem.
2005, 70, 2376–2379.
`
´
´
3. (a) Fernandez, J.-C.; Sole-Feu, L.; Fernandez-Forner, D.;
de la Figuera, N.; Forns, P.; Albericio, F. Tetrahedron
Lett. 2005, 46, 581–585; (b) Kim, D. S. H. L.; Ashendel, C.
L.; Zhou, Q.; Chang, C.-t.; Lee, E.-S.; Chang, C.-j. Bioorg.
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Zhou, Q.; Ashendel, C. L.; Chang, C.-t.; Chang, C.-j.
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L.-X.; Kim, T. S.; Ahn, S.-H.; Kim, T.-H.; Kim, E.-k.;
Cho, W.-J.; Choi, H.; Lee, C.-S.; Kim, J. A.; Jeong, T. C.;
Chang, C.-j.; Lee, E.-S. Bioorg. Med. Chem. Lett. 2001, 11,
2659–2662; (e) Hankel, T.; Brunne, R. M.; Muller, H.;
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Reichel, F. Angew. Chem., Int. Ed. 1999, 38, 643–647; (f)
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515–516; (g) Sharma, N. N.; Sharma, M.; Kumar, H.;
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Almatawah, Q. A.; Cowan, D. A. Enzyme Microb.
Technol. 1999, 25, 718–724.
4. (a) Mukkala, V. M.; Helenius, M.; Hemmila, I.; Kankare,
J.; Takalo, H. Helv. Chim. Acta 1993, 76, 1361–1378; (b)
Mukkala, V. M.; Kwiatkowski, M.; Kankare, J.; Takalo,
H. Helv. Chim. Acta 1993, 76, 893–899; (c) Lowe, G.;
Droz, A. S.; Park, J. J.; Weaver, G. W. Bioorg. Chem.
1999, 27, 477–486.
5. For a recent review of de novo methods for pyridine
synthesis see: Henry, G. D. Tetrahedron 2004, 60, 6043–
6061.
In conclusion, we have successfully explored an efficient
new methodology for the synthesis of 2,4,6-trisubsti-
tuted nicotinonitriles from the parent 2-methoxy-3-
cyanopyridines by their reaction with organo cuprates
under mild conditions in the presence of BF3 as a Lewis
acid. Using this method, we have successfully synthe-
sized pure nicotinonitrile, nicotinamide and nicotinic
acid derivatives, which can serve as potential precursors
of medicinal interest. The mechanism of the direct sub-
stitution of 2-methoxy-3-cyanopyridines has been stud-
ied in which model M-1 was the active complex in this
reaction which was augmented by the presence of a
cyano group at the 3-position of pyridine.
6. Chubb, R. W. J.; Bryce, M. R.; Tarbit, B. J. Chem. Soc.,
Perkin Trans. 1 2001, 1853–1854.
7. (a) Kro¨hnke, F.; Zecher, W.; Drechsler, D.; Pfleghar, K.;
Schnalke, K.-E.; Weis, W. Angew. Chem. 1962, 74, 811–
817; (b) Katritzky, A. R.; Thind, S. S. J. Chem. Soc.,
Perkin Trans. 1 1980, 1895–1900; (c) Tewari, R. S.;
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A. R.; Chermprapai, A.; Patel, R. C.; Terraga-Tomas, A.
J. Org. Chem. 1982, 47, 492–497; (e) Wenkert, E.; Hanna,
J. M., Jr.; Leftin, M. H.; Michelotti, E. L.; Potts, K. T.;

A. A.-M. Abdel-Aziz / Tetrahedron Letters 48 (2007) 2861–2865
2865
Usifer, D. J. Org. Chem. 1985, 50, 1125–1126; (f)
Houghton, P. G.; David, F. P.; Rees, C. W. J. Chem.
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Nitta, M. Chem. Lett. 1986, 9, 1549–1552; (h) Katritzky,
A. R.; Aurrecoechea, J. M. Synthesis 1987, 4, 342–345; (i)
Kobayashi, T.; Kawate, H.; Kakiuchi, H.; Kato, H. Bull.
Chem. Soc. Jpn. 1990, 63, 1937–1942; (j) Kiselyov, A. S.
Tetrahedron Lett. 1995, 36, 9297–9300; (k) Promod, S.;
Dipak, P.; Jagir, S. S. Tetrahedron Lett. 2003, 44, 8725–
8727, and references cited therein.
H, 6.39; N, 9.01. Calcd for C22H20N2: C, 84.58; H, 6.45;
N, 8.97. Spectroscopic data for 2-(1-adamantyl)-3-cyano-
4,6-diphenylpyridine (11). Yield 69%; white crystals, mp
198–199 ꢁC (MeCN). IR (KBr): m 2983 (aromatic CH),
2216 (CN), 1608, 1587 (C@N, C@C) cmÀ1 1H NMR
;
(500 MHz, DMSO-d6, d ppm): 1.47 (s, 6H, adamantane-
H), 1.51 (d, 3H, J = 12.0 Hz, adamantane-H), 1.67 (d, 3H,
J = 12.1 Hz, adamantane-H), 2.06 (s, 3H, adamantane-
H), 7.19–7.50 (m, 10H, Ph-H), 7.69 (s, 1H, Pyr-H).
Analysis found: C, 85.98; H, 6.70; N, 7.14. Calcd for
C28H26N2: C, 86.12; H, 6.71; N, 7.17.
8. (a) Fatma, E. G.; Abdel-Aziz, A. A.-M.; Omar, A. Bioorg.
Med. Chem. 2004, 12, 1845–1852; (b) Abdel-Aziz, A. A.-
M.; El-Subbagh, H. I.; Kunieda, T. Bioorg. Med. Chem.
2005, 13, 4929–4935.
9. (a) Penney, J. M.; Miller, J. A. Tetrahedron Lett. 2004, 45,
4989–4992; (b) Miller, J. A.; Dankwardt, J. W.; Penney, J.
M. Synthesis 2003, 1643–1648.
16. Spectroscopic data for 2-tert-butyl-4,6-diphenylnicotinic
acid (22). Yield 88%; white crystals, mp 183–184 ꢁC
(methanol). IR (KBr): m 3321 (carboxyl OH), 2960
(aromatic CH), 1721 (carboxyl C@O), 1606, 1571 (C@N,
C@C) cmÀ1; 1H NMR (500 MHz, DMSO-d6, d ppm): 1.11
(s, 9H, t-Bu), 7.30–7.66 (m, 10H, Ph-H), 8.11 (s, 1H, Pyr-
H), 12.15 (s, 1H, OH). Analysis found: C, 79.68; H, 6.46;
N, 4.15. Calcd for C22H21NO2: C, 79.73; H, 6.39; N, 4.23.
Spectroscopic data for 2-(1-adamantyl)-4,6-diphenylnico-
tinamide (23). Yield 86%; white crystals, mp 211–212 ꢁC
(ethanol). IR (KBr): m 3431, 3254, 3145 (NH2), 2991
(aromatic CH), 1685 (C@O), 1610, 1584 (C@N, C@C)
10. Typical procedure is as follows:
a solution of 4
(0.47 mmol) in THF (2.2 mL) and BF3ÆEt2O (134 mg,
0.94 mmol) was added to a suspension of LiC1 (175 mg,
4.13 mmol; dried at 150 ꢁC for 1 h under reduced
pressure), CuCN (185 mg, 2.07 mmol) and organo metal
reagent (1.88 mmol) in THF (9.9 mL) which had been
stirred at À78 ꢁC under nitrogen for 30 min. The mixture
was then stirred at 20 ꢁC for an additional 3 h. The
reaction was quenched by the addition of saturated NH4Cl
aq (1.4 mL) and EtOAc (100 mL) was added. The whole
was washed with (i) satd NH4Cl aq (20 mL · 3), (ii) brine
(45 mL · 3), dried (Na2SO4) and evaporated in vacuo
followed by chromatography on silica gel (hexane–EtOAc
(9:1 to 6:4)) to afford compounds 5–14 (Table 1).
11. Shono, T.; Terauchi, J.; Ohkr, Y.; Matsumura, Y.
Tetrahedron Lett. 1990, 31, 6385–6386.
cmÀ1 1H NMR (500 MHz, DMSO-d6, d ppm): 1.51 (s,
;
6H, adamantane-H), 1.64 (d, 3H, J = 12.0 Hz, adaman-
tane-H), 1.72 (d, 3H, J = 12.1 Hz, adamantane-H), 2.12 (s,
3H, adamantane-H), 6.10 (s, 2H, NH2), 7.26–7.43 (m,
10H, Ph-H), 7.98 (s, 1H, Pyr-H). Analysis found: C, 82.24;
H, 6.78; N, 6.66. Calcd for C28H28N2O: C, 82.32; H, 6.91;
N, 6.86.
17. Initial structures for complexes M-1, M-2, M-3 and M-4
were constructed using the HyperChem program version
5.1.19 The MM+20 (calculations in vacuo, bond dipole
option for electrostatics, Polak-Ribiere algorithm, RMS
12. Normant, J. F.; Alexakis, A.; Ghnbi, A.; Mangeney, P.
Tetrahedron 1989, 45, 507–516.
˚
gradient of 0.01 kcal/A mol) conformational searching in
13. For comparison, 2-methoxy-3-cyano-4,6-diphenylpyridine
was treated with n-BuMgBr and PhCH2MgBr (4.0 equiv)
and BF3ÆEt2O (1.5 equiv) in THF at À78 ꢁC to 20 ꢁC
(10 h) to give the 2-substituted products in 55% and 38%
yields, respectively.
14. (a) Kuramochi, T.; Kakefuda, A.; Sato, I.; Tsukamoto, I.;
Taguchi, T.; Sakamoto, S. Bioorg. Med. Chem. 2005, 13,
717–724; (b) Girgis, A. S.; Kalmouch, A.; Ellithey, M.
Bioorg. Med. Chem. 2006, 14, 8488–8494; (c) Girgis, A. S.;
Hosni, H. M.; Barsoum, F. F. Bioorg. Med. Chem. 2006,
14, 4466–4476.
torsional space was performed. Energy minima were
determined by a semi-empirical method PM321 and
AM122 (as implemented in HyperChem 5.1). The PM3
semi-empirical calculations were performed in the pres-
ence of one molecule of THF which gave good results
compared with AM1 semi-empirical calculations.
18. A study of the detailed substitution reactions and mech-
anism with 2-methoxy-4,6-diphenylpyridine 24 on experi-
mental and theoretical levels will be the subject of a
separate paper.
19. HyperChem version 5.1; Hypercube.
15. Spectroscopic data for 2-tert-butyl-3-cyano-4,6-diphenyl-
pyridine (10). Yield 77%; pale yellow crystals, mp 175–
176 ꢁC (ethanol). IR (KBr): m 2971 (aromatic CH), 2219
20. (a) Profeta, S.; Allinger, N. L. J. Am. Chem. Soc. 1985,
107, 1907–1918; (b) Allinger, N. L. J. Am. Chem. Soc.
1977, 99, 8127–8134.
21. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209–220.
22. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J.
J. P. J. Am. Chem. Soc. 1985, 107, 3902–3909.
(CN), 1608, 1587 (C@N, C@C) cmÀ1
;
1H NMR (500
MHz, DMSO-d6, d ppm): 1.05 (s, 9H, t-Bu), 7.12–7.45 (m,
10H, Ph-H), 7.71 (s, 1H, Pyr-H). Analysis found: C, 84.50;