Synthesis of multi-substituted 2-iminopyridine by conjugate addition of ethyl cyanoacetate derivatives to alkynyl imines

Article abstract of DOI:10.1002/ejoc.200701039

The synthesis of multi-substituted 2-iminopyridines by conjugate addition of ethyl cyanoacetate derivatives to alkynyl imines has been developed. The reaction of ethyl cyanoacetate derivatives with alkynyl imines provided multi-substituted 2-iminopyridine

Full text of DOI:10.1002/ejoc.200701039

FULL PAPER
DOI: 10.1002/ejoc.200701039
Synthesis of Multi-Substituted 2-Iminopyridine by Conjugate Addition of Ethyl
Cyanoacetate Derivatives to Alkynyl Imines
Iwao Hachiya,[a] Yushi Minami,[a] Tetsuya Aramaki,[a] and Makoto Shimizu*[a]
Keywords: Conjugate addition / Imines / Pyridine / Ring-opening / Amines / Alkynes
The synthesis of multi-substituted 2-iminopyridines by con-
jugate addition of ethyl cyanoacetate derivatives to alkynyl
imines has been developed. The reaction of ethyl cyanoace-
tate derivatives with alkynyl imines provided multi-substi-
tuted 2-iminopyridines in good yields. Also described is the
transformation of 2-iminopyridines into 2-aminopyridines by
deprotection of the substituent on the nitrogen under acidic
conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Herein, we report a synthesis of multi-substituted 2-imino-
pyridines by the conjugate addition of ethyl cyanoacetate
derivatives to alkynyl imines (Scheme 2).
Introduction
Biologically active compounds containing a 2-iminopyr-
idine structure are less well known than those containing
the 2-pyridone counterpart.[1] However, due to their strong
biological activities, 2-iminopyridines are highly attractive
compounds compared with members of the large group of
biologically active 2-pyridones.[2,3] Several methods for the
synthesis of 2-iminopyridines by condensation reactions of
cyano derivatives have already been reported.[4] In addition,
the synthesis of 2-iminopyridines by cobalt- or nickel-cata-
lyzed cyclotrimerization of 2 equivalents of alkynes with
carbodiimides has been developed.[5] Takahashi et al. re-
ported a selective preparation of 2-iminopyridines from two
different alkynes via azazirconacycles.[6] However, the for-
mer methods are not satisfactory from the point of view of
synthesizing 2-iminopyridines possessing the desired sub-
stituents. Therefore, the development of alternative methods
for the synthesis of multi-substituted 2-iminopyridines from
readily available starting materials is highly desirable.
Scheme 1. Synthesis of multi-substituted 2-pyridones by the conju-
gate addition of malonic esters or β-keto esters to alkynyl imines.
We previously developed a strategy for the synthesis of
2-pyridones by the conjugate addition of malonic esters or
β-keto esters to alkynyl imines to give 5-alkoxycarbonyl-
or 5-acetyl-2-pyridones, respectively (Scheme 1, R5 = H).[7]
Recently, we found that the reaction of dialkynyl imines
with active methine compounds gave 3,4,5,6-tetrasubsti-
tuted 2-pyridones (Scheme 1, R5 = alkynyl).[8] During these
investigations into the synthesis of heterocycles using alk-
ynyl imines we found that the reaction of ethyl cyanoacetate
derivatives with alkynyl imines gave 2-iminopyridines.
Scheme 2. Synthesis of multi-substituted 2-iminopyridines by the
conjugate addition of ethyl cyanoacetate derivatives to alkynyl
imines.
Results and Discussion
Table 1 shows the effect of base on the model reaction of
ethyl 2-cyanopropanoate (1a) with alkynyl imine 2a, which
was prepared from phenylpropynal and p-methoxyphen-
ylmethylamine, in diethylene glycol dimethyl ether at
160 °C. When NaH was used as a base, the desired 2-imino-
pyridine 3a was obtained in 27% yield (entry 1). Other so-
dium salt bases such as NaOEt and sodium hexamethyl-
disilazide (NaHMDS) gave the adduct 3a in lower yields
[a] Graduate School of Chemistry for Materials, Mie University,
Tsu, Mie 514-8507, Japan
Fax: +81-59-231-9413
E-mail: mshimizu@chem.mie-u.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1411–1417
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1411

I. Hachiya, Y. Minami, T. Aramaki, M. Shimizu
FULL PAPER
(entries 2 and 3). The use of potassium salt bases afforded tion of the cyanoacetate 1c bearing an allyl group, which
the product 3a in better yields because the potassium salt could be transformed into other functional groups such as
of the cyanoacetate derivative 1a is more reactive. Among an aldehyde, carboxylic acid and hydroxy group, was car-
the potassium salt bases tested, potassium hexamethyldisil- ried out. The imines 2d and 2e afforded 2-iminopyridines
azide (KHMDS) was found to be the most effective (en- 3k and 3l both in 66% yields (entries 10 and 11).
try 6). To improve the product yield, the effects of different
Table 2. Synthesis of 2-iminopyridines 3 by conjugate reaction of
ethyl cyanoacetate derivatives 1 to alkynyl imine 2.
reaction conditions, such as solvents, reaction temperature
and the amounts of KHMDS and 1a, were investigated.
When amounts of both KHMDS and 1a were increased, 2-
iminopyridine 3a was obtained in 70% yield (entry 7).
Table 1. Effect of base on the reaction of 2-cyanopropanoate (1a)
with alkynyl imine 2a.
Entry
R1
R2
R3[a][b] Condi-
tions
Time
[h]
Product
%
Yield[c]
Me cHex[d] MPM
A[e]
A[e]
B[f]
C[g]
C[g]
C[g]
B[f]
B[f]
B[f]
B[f]
B[f]
3.5
3.5
3b
3c
3d
3e
3f
3g
3h
3i
57
47
51
81
84
48
84
45
50
66
66
Entry
Base
% Yield[a]
1
2
3
4
5
6
7
8
Me
Ph
Me
nBu MPM
1
2
3
4
5
6
7
NaH
27
2
11
35
33
44
70
Ph
Ph
MPM
PMP
45.0
25.0
19.0
20.0
21.5
20.0
20.0
16.0
16.0
NaOEt
NaHMDS[b]
KOEt
Me cHex PMP
Me
Ph
nBu
Ph
PMP
PMP
KOtBu
KHMDS[c]
KHMDS[d]
Ph
cHex PMP
9
10
11
Ph
Allyl
nBu
Ph
PMP
PMP
3j
3k
3l
[a] Isolated yield. [b] In (CH3OCH2CH2)2O/THF (8:1). [c] In
(CH3OCH2CH2)2O/toluene (8.9:1). [d] KHMDS (4 equiv.) and 1a
(5 equiv.) were used in (CH3OCH2CH2)2O/toluene (3.1:1) at 160 °C
for 3.0 h.
Allyl cHex PMP
[a] MPM = p-methoxyphenylmethyl. [b] PMP = p-methoxyphenyl.
[c] Isolated yield. [d] cHex = 1-cyclohexenyl. [e] Conditions A: in
(CH3OCH2CH2)2O/toluene (3.1:1) at 160 °C. [f] Conditions B: in
1,4-dioxane under reflux. [g] Conditions C: in 1,4-dioxane/toluene
(2.4–3.1:1) under reflux.
Table 2 summarizes the results. The reaction of alkynyl
imine 2b bearing a double bond gave the adduct 3b in 57%
yield (entry 1). The reaction of alkynyl imine 2c possessing
a butyl group gave the corresponding 2-iminopyridine 3c in
We have proposed a plausible mechanism for the conju-
a moderate yield (entry 2). However, the use of ethyl 2-cy- gate addition reaction, as shown in Scheme 3. Metalloena-
ano-2-phenylacetate (1b) in diethylene glycol dimethyl ether mine 4 would be generated by conjugate addition of the
at 160 °C (conditions A) did not give the desired 2-imino- potassium salt of the cyanoacetate derivative 1 to the alk-
pyridine 3d. Although alkynyl imine 2a was not recovered ynyl imine 2 and undergo a chemoselective intramolecular
due to decomposition, the cyanoacetate 1b was recovered cyclization at the ethoxycarbonyl group to give the cyclobu-
in 95% yield. When the reaction of 1b with 2a was carried tene oxide intermediate 5. The cyclobutene oxide 5 would
out in 1,4-dioxane under reflux (conditions B), the desired collapse into metalloenamine 6 by ring-opening to release
2-iminopyridine 3d was obtained in 51% yield (entry 3). ring strain in the cyclobutene and subsequent cyclization
This result indicates that the cyanoacetate 1b is less reactive gives 2-iminopyridine 3 after protonation of the 2-imino-
than 1a because the phenyl group is sterically more de- pyridine potassium salt 7 with water to quench the reaction.
manding and acts as an electron-withdrawing group. We
The use of alkynylthiazole 8 instead of alkynyl imines 2
next examined the use of the alkynyl imines prepared from to synthesize a bicyclic compound containing a 2-iminopyr-
alkynal and p-methoxyphenylamine. The reaction of the im- idine structure was examined. The reaction of 8 with 1a
ines 2d and 2e proceeded in 1,4-dioxane/toluene under re- proceeded to give the corresponding product 9 in 64% yield
flux (conditions C) to give 2-iminopyridines 3e and 3f in 81 (Scheme 4). We also investigated the synthesis of 3,4,5,6-
and 84% yields, respectively (entries 4 and 5). The reaction tetrasubstituted 2-iminopyridine. The reaction of 10 with
of the imine 2f gave 2-iminopyridine 3g in a moderate yield 1a gave 2-iminopyridine 11 in 52% yield (Scheme 5).
(entry 6). Even with the use of the cyanoacetate 1b, the re-
We next examined the transformation of 2-iminopyridine
action of 2d proceeded smoothly to give 2-iminopyridine 3h into 2-aminopyridine by deprotection of the substituent at
in a high yield (entry 7). The reactions of 1b with the imines the nitrogen.[9] 2-Aminopyridines are one of the most im-
2e and 2f also gave 2-iminopyridines 3i and 3j in moderate portant heterocycles due to their biological activity.[4b,10]
yields, respectively (entries 8 and 9). Furthermore, the reac- First, we attempted to deprotect the p-methoxyphenyl
1412
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1411–1417

Synthesis of Multi-Substituted 2-Iminopyridine
out any recovered 3a (entry 2). Because the yield was not
yet satisfactory and 2-iminopyridine 3a was not recovered
by using CAN, other reaction conditions were examined
(entries 3 and 4) but these did not give any 2-aminopyridine
12a. Since the conversion yield of 12a was good in entry 1,
trifluoromethanesulfonic acid (TfOH), which is a stronger
acid than TFA, was added to promote the deprotection of
3a. Under these conditions, the reaction proceeded
smoothly to give 2-aminopyridine 12a in 70% yield (en-
try 5). The deprotection of 2-iminopyridines 3c and 3d was
also carried out under acidic conditions to give the corre-
sponding 2-aminopyridines 12b and 12c in moderate yields
(entries 6–8).
Table 3. Synthesis of 2-aminopyridines 12 by deprotection of 2-
iminopyridines 3.
Scheme 3. Plausible mechanism for the conjugate addition reac-
tion.
Entry
R1 R2
Conditions
Time Prod- % Yield[a]
[h]
uct
1
2
Me Ph
Me Ph
TFA[b], reflux temp.
CAN[d] (4.0)[e] in
24.0
17.0
12a
12a
20 (76)[c]
57
CH3CN/H2O (1:1) at r.t.
3
4
5
6
7
8
Me Ph
Me Ph
DDQ[f] (4.0)[e] in
12.0
20.5
24.0
24.0
24.0
24.0
12a
12a
12a
12b
12b
12c
0 (56)[c]
0 (41)[c]
70
CH3CN/H2O (1:1) at r.t.
AlCl3 (4.0)[e] in anisole/
MeOH (2:1) at 0 °CǞr.t.
Scheme 4. Synthesis of bicyclic 2-iminopyridine 9.
Me Ph TfOH[g] (1.0)[e] in TFA[b]
reflux temp.
Me nBu TfOH[g] (1.3)[e] in TFA[b]
reflux temp.
47 (48)[c]
59
Me nBu TfOH[g] (3.0)[e] in TFA[b]
reflux temp.
Ph Ph TfOH[g] (1.3)[e] in TFA[b]
reflux temp.
62
[a] Isolated yield. [b] TFA = trifluoroacetic acid. [c] Yield of the reco-
vered reagents. [d] CAN = cerium(IV) ammonium nitrate. [e] Equiva-
lent of reagents. [f] DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none. [g] TfOH = trifluoromethanesulfonic acid.
Scheme 5. Synthesis of 3,4,5,6-tetrasubstituted 2-iminopyridine 11.
Conclusions
group of 2-iminopyridine 3e by using ceric(IV) ammonium
nitrate (CAN) as oxidant. However, the desired 2-amino-
We have found an efficient method for the synthesis of
pyridine was not obtained and instead 2-iminnopyridine 3e multi-substituted 2-iminopyridines by conjugate addition of
was recovered in 79% yield. We next investigated the use of ethyl cyanoacetate derivatives to alkynyl imines and also the
different conditions for the deprotection of the p-methoxy- transformation of 2-iminopyridines into 2-aminopyridines
phenylmethyl group of 2-iminnopyridine 3a. The results are by deprotection of the substituent on the nitrogen under
summarized in Table 3. The deprotection of 3a was carried acidic conditions. These methodologies are attractive be-
out in trifluoroacetic acid (TFA) under reflux to give the cause alkynyl imines and substituted ethyl cyanoacetate de-
desired 2-aminopyridine 12a in 20% yield along with reco- rivatives are readily available from alkynals, cyanoacetic es-
vered 3a in 76% yield (entry 1). The reaction of 3a with ters and nitriles, respectively. Studies exploring the applica-
CAN (4 equiv.) in CH3CN/H2O (1:1) at room temperature tion of 2-imino- and 2-aminopyridines to the synthesis of
proceeded to give 2-aminopyridine 12a in 57% yield with- biologically active compounds are now in progress.
Eur. J. Org. Chem. 2008, 1411–1417
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1413

I. Hachiya, Y. Minami, T. Aramaki, M. Shimizu
FULL PAPER
1248, 1174, 1108, 1035, 962, 823, 757 cm–1. 1H NMR (270 MHz,
CDCl3): δ = 53–7.54 (m, 1 H), 7.23–7.26 (m, 1 H), 7.15–7.18 (m,
1 H), 6.82–6.87 (m, 2 H), 4.75 (d, J = 1.7 Hz, 1 H), 4.58 (s, 1 H),
3.75 (s, 1.5 H), 3.74 (s, 1.5 H), 2.30–2.43 (m, 2 H), 1.37–1.59 (m, 4
H), 0.87–0.96 (m, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
158.7, 158.5, 145.6, 143.5, 131.4, 130.3, 129.3, 129.1, 113.8, 113.8,
100.5, 94.0, 78.7, 74.7, 64.7, 64.3, 59.0, 55.1, 30.1, 30.0, 21.8, 18.9,
18.8, 13.4 ppm. HRMS (EI): calcd. for C15H19NO 229.1467 [M]+;
found 229.1547.
Experimental Section
General: Infrared spectra were recorded with a JASCO FT/IR-460
Plus spectrometer. 1H NMR spectra were recorded with a JEOL
EX-270 (270 MHz) or JNM α-500 spectrometer (500 MHz) with
tetramethylsilane as the internal standard. 13C NMR spectra were
recorded with a JEOL EX-270 (67.8 MHz) or JNM α-500 spec-
trometer (126 MHz). Chemical sifts are reported in δ units, parts
per million from the central peak of CDCl3 (δ = 77.0 ppm) as the
internal reference. High-resolution mass spectra (EI) were recorded
with a JEOL JMS-700D mass spectrometer. 1,4-Dioxane and di-
ethylene glycol dimethyl ether were distilled from calcium hydride
and stored over sodium. Products was purified by column
chromatography on silica gel [Kanto Chemical Co. Inc., Silica Gel
60  (spherical, neutral)] and/or preparative TLC on silica gel
(Merck Kiesel Gel GF254). Potassium hexamethyldisilazide
(KHMDS) toluene solution was purchased from Tokyo Chemical
Industry Co., Ltd. (TCI) and used after titration. 95% Potassium
hexamethyldisilazide (KHMDS) was purchased from Aldrich and
used without further purification. Ethyl 2-cyanopropanoate (1a) is
commercially available from TCI and was used after distillation.
Ethyl cyanoacetate derivatives 1b[11] and 1c,[12] alkynyl imines 2d,[7a]
2e[7a] and 2f[7a] and alkynylthiazole 8 were prepared according to
the literature.[13] A solution of ammonia in dichloromethane was
prepared by extracting ammonia from aqueous ammonia with
dichloromethane and drying with sodium sulfate. All reactions
were carried out under argon.
Synthesis of Dialkynyl Imine 10 (Scheme 6): nBuLi (3.3 mL, 1.58 
in hexane, 5.21 mmol) was added to a solution of 1-ethynlcyclohex-
ene (13) (541 mg, 5.10 mmol) in THF (20 mL) at –78 °C. After stir-
ring for 30 min, BF3·OEt2 (0.65 mL, 5.27 mmol) was added to the
solution and the mixture was stirred for 10 min. Alkynyl imine 14
(610 mg, 2.55 mmol) was then added and the reaction mixture was
warmed to room temperature and stirred for 1 h. Saturated aque-
ous NaHCO3 (20 mL) was added to quench the reaction. The mix-
ture was extracted with diethyl ether (3ϫ20 mL). The combined
organic layers were washed with water (20 mL), brine (20 mL) and
then dried with sodium sulfate. The solvents were evaporated in
vacuo and then the residue was purified by chromatography on
silica gel (hexane/ethyl acetate, 7:1) to give the (dialkynylmethyl)-
amine 15 as a brown oil (821 mg, 93% yield).
Synthesis of Alkynyl Imines 2a–2c: A solution of phenylpropynal
(1.92 g, 15.3 mmol) in CH2Cl2 (4.9 mL) was added to a solution of
p-methoxyphenylmethylamine (1.85 g, 15.0 mmol) in CH2Cl2
(7.7 mL) in the presence of 4-Å molecular sieves (6 g) at 0 °C. The
reaction mixture was warmed to room temperature and stirred for
1 h. The reaction mixture was filtered through a Celite pad to re-
move the molecular sieves. The solvents were evaporated in vacuo
and then the residue was purified by chromatography on silica gel
(hexane/ethyl acetate, 7:1) to give imine 2a as a black oil (3.55 g,
93% yield).
Scheme 6.
2a: The ratio of geometrical mixtures of the C=N bond was 58:42.
15: IR (neat): ν = 3363, 3027, 2930, 2859, 2833, 2220, 2046, 1617,
˜
IR (neat): ν = 3058, 3033, 3000, 2933, 2905, 2834, 2206, 1607, 1511,
˜
1512, 1441, 1407, 1343, 1238, 1179, 1118, 1073, 1040, 977, 918,
821 cm–1. 1H NMR (500 MHz, CDCl3): δ = 6.74–6.81 (m, 4 H),
6.09–6.10 (m, 2 H), 5.10 (s, 1 H), 3.71–3.81 [m, 4 H, including a
singlet of OCH3 at δ = 3.75 (3 H)], 2.04–2.10 (m, 4 H), 1.53–
1.62 (m, 4 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 153.4,
139.5, 135.5, 119.9, 116.9, 114.4, 84.4, 83.3, 55.5, 39.8, 28.9, 25.5,
22.1, 21.4 ppm. HRMS (EI): calcd. for C24H27NO 345.2093 [M]+;
found 345.2032.
1444, 1364, 1335, 1300, 1247, 1175, 1109, 1034, 976, 920, 821, 758,
692, 589 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.81 (t, J =
1.4 Hz, 0.42 H), 7.79 (t, J = 1.2 Hz, 0.58 H), 7.51–7.54 (m, 2 H),
7.21–7.45 (m, 5 H), 6.87–6.90 (m, 2 H), 4.88 (d, J = 1.4 Hz, 0.84
H), 4.71 (d, J = 1.2 Hz, 1.16 H), 3.80 (s, 3 H) ppm. 13C NMR
(67.8 MHz, CDCl3): δ = 158.8, 158.6, 145.3, 143.0, 132.1, 132.1,
131.2, 130.0, 129.7, 129.7, 129.4, 129.2, 128.5, 128.3, 121.4, 121.2,
113.9, 113.8, 97.6, 91.5, 86.6, 82.0, 65.1, 59.5, 55.1 ppm. HRMS
(EI): calcd. for C17H15NO: 249.1154 [M]+; found 249.1168.
To
a solution of the (dialkynylmethyl)amine 15 (821 mg,
2.38 mmol) in dichloromethane (25 mL) was added MnO2 (6 g,
69 mmol) at room temperature. The reaction mixture was stirred
for 13 h at room temperature. The reaction mixture was filtered
through a Celite pad. The solvents were evaporated in vacuo and
then the residue was purified by chromatography on silica gel (hex-
ane/ethyl acetate, 7:1) to give the dialkynyl imine 10 as a brown
solid (721 mg, 88% yield).
2b: The ratio of geometrical mixtures of the C=N bond was 50:50.
Brown oil. IR (neat): ν = 3027, 2999, 2932, 2859, 2835, 2190, 1656,
˜
1604, 1511, 1441, 1341, 1299, 1247, 1176, 1137, 1109, 1076, 1037,
1
959, 920, 819 cm–1. H NMR (500 MHz, CDCl3): δ = 7.68 (t, J =
2.1 Hz, 1 H), 7.25–7.29 (m, 1 H), 7.17–7.20 (m, 1 H), 6.85–6.89 (m,
2 H), 6.28–6.34 (m, 1 H), 4.76 (d, J = 2.1 Hz, 1 H), 4.64 (s 1 H),
3.79 (s, 1.5 H), 3.79 (s, 1.5 H), 2.10–2.21 (m, 4 H), 1.56–1.70 (m, 4
H) ppm. 13CNMR (126 MHz, CDCl3): δ = 158.7, 158.5, 145.6,
143.4, 139.2, 138.6, 131.5, 130.3, 129.3, 129.1, 119.7, 119.6, 113.9,
113.8, 99.9, 93.8, 84.5, 80.1, 65.0, 59.2, 55.1, 28.6, 28.5, 25.8, 25.8,
22.0, 22.0, 21.2, 21.1 ppm. HRMS (EI): calcd. for C17H19NO:
253.1467 [M]+; found 253.1470.
10: M.p. 126–127 °C. IR (KBr): ν = 3052, 2997, 2965, 2932, 2837,
˜
2190, 1596, 1570, 1519, 1493, 1456, 1330, 1294, 1248, 1200, 1161,
1120, 1072, 1023, 955, 921, 837, 754, 690 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.26–7.31 (m, 2 H), 6.85–6.90 (m, 2 H),
6.37–6.39 (m, 1 H), 6.21–6.23 (m, 1 H), 3.81 (s, 3 H), 2.20–2.25 (m,
2 H), 2.05–2.18 (m 6 H), 1.54–1.69 (m 8 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 157.9, 143.0, 140.0, 139.0, 132.2, 123.6,
119.8, 113.5, 96.5, 91.3, 86.9, 82.9, 55.4, 28.5, 28.1, 25.9, 22.1, 21.9,
2c: The ratio of geometrical mixtures of the C=N bond was 50:50.
Brown oil. IR (neat): ν = 2955, 2867, 2216, 1608, 1512, 1459, 1300,
˜
1414
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1411–1417

Synthesis of Multi-Substituted 2-Iminopyridine
21.3, 21.1 ppm. HRMS (EI): calcd. for C24H25NO 343.1936 [M]+; methane/methanol, 20:1) to give 2-iminopyridine (3d) as a light
found 343.1931.
brown solid (44.4 mg, 51%).
3d: M.p. 142–143 °C. IR (KBr): ν = 3316, 2947, 2832, 1718, 1624,
˜
Synthesis of 2-Iminopyridines 3a–c (Conditions A): A solution of
ethyl 2-cyanopropanoate (1a) (131 mg, 1.0 mmol) in diethylene
glycol dimethyl ether (2.0 mL) was added to KHMDS (1.3 mL,
0.62  in toluene, 0.80 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 10 min and then to it
was added a solution of alkynyl imine 2a (49.9 mg, 0.20 mmol) in
diethylene glycol dimethyl ether (2.0 mL). The resulting reaction
mixture was stirred at 160 °C for 3.0 h and then cooled to room
temperature. Saturated aqueous NaHCO3 (10 mL) was added to
quench the reaction. The mixture was extracted with dichlorometh-
ane (3ϫ15 mL). The combined organic layers were dried with so-
dium sulfate. The solvents were evaporated in vacuo and then the
residue was purified by preparative TLC on silica gel (ammonia
solution in dichloromethane/methanol, 20:1) to give 2-iminopyr-
idine 3a as a brown oil (50.8 mg, 70%).
1553, 1511, 1438, 1388, 1360, 1302, 1244, 1208, 1173, 1120, 1077,
1
1031, 961, 874, 799, 762, 701 cm–1. H NMR (500 MHz, CDCl3):
δ = 8.01 (s, 1 H), 7.38–7.42 (m, 2 H), 6.89–7.20 (m, 12 H), 5.19 (s,
2 H), 3.89 (q, J = 7.0 Hz, 2 H), 3.82 (s, 3 H), 0.85 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 165.3, 159.7, 159.4,
143.4, 142.9, 138.6, 135.4, 130.5, 130.2, 129.8, 128.4, 128.4, 127.7,
127.4, 127.0, 126.5, 114.3 107.7, 60.1, 55.2, 53.8, 13.6 ppm. HRMS
(EI): calcd. for C28H26N2O3 438.1943 [M]+; found 438.1997.
3h: White solid; m.p. 118–119 °C. IR (CHCl ): ν = 3444, 3061,
˜
3
2970, 2842, 1694, 1619, 1562, 1510, 1447, 1372, 1303, 1229, 1143,
1081, 1021, 923, 836, 797, 702 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 8.02 (s, 1 H), 7.39–7.42 (m, 2 H), 7.17–7.20 (m, 2 H), 7.08–7.14
(m, 4 H), 7.00–7.05 (m, 4 H), 6.95–6.98 (m, 2 H), 3.94 (q, J =
7.2 Hz, 2 H), 3.85 (s, 3 H), 0.92 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 165.2, 159.5, 143.7, 138.5, 130.5, 128.4,
128.1, 127.4, 127.1, 126.6, 114.9, 108.0, 60.2, 55.5, 13.7 ppm.
HRMS (EI): calcd. for C27H24N2O3 424.1787 [M]+; found
424.1797.
3a: IR (neat): ν = 3348, 3058, 2983, 2837, 1695, 1624, 1566, 1513,
˜
1445, 1369, 1294, 1250, 1177, 1109, 1032, 958, 916, 845, 772,
704 cm–1. 1H NMR (270 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.29–
7.39 (m, 5 H), 7.05–7.07 (m, 2 H), 6.89–6.92 (m, 2 H), 5.19 (s, 2
H), 3.88 (q, J = 7.0 Hz, 2 H), 3.79 (s, 3 H), 1.74 (s, 3 H), 0.87 (t,
J = 7.0 Hz, 3 H) ppm. 13C NMR (67.8 MHz, CDCl3): δ = 165.3,
159.7, 159.3, 142.9, 141.4, 139.7, 129.5, 127.9, 127.8, 127.8, 127.0,
123.6, 114.2, 107.5, 60.0, 55.2, 53.8, 15.3, 13.6 ppm. HRMS (EI):
calcd. for C23H24N2O3 376.1787 [M]+; found 376.1786.
3i: Brown solid; m.p. 110–111 °C. IR (CHCl ): ν = 3431, 2930,
˜
3
2838, 1719, 1622, 1559, 1511, 1442, 1368, 1308, 1256, 1201, 1080,
1128, 1074, 1024, 900, 837, 799, 766, 737, 704, 603 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.20–7.30 (m, 5 H), 7.06–
7.10 (m, 2 H), 6.90–6.95 (m, 2 H), 5.18–5.22 (m, 1 H), 4.14 (q, J
= 7.2 Hz, 2 H), 3.76 (s, 3 H), 1.05–2.15 [m, 11 H, including a triplet
at δ = 1.20 (J = 7.2 Hz, 3 H)] ppm. 13C NMR (126 MHz, CDCl3):
δ = 164.8, 160.6, 159.4, 146.5, 143.7, 135.7, 135.5, 134.8, 129.5,
128.3, 128.0, 127.5, 126.0, 114.8, 107.8, 60.3, 55.5, 29.3, 24.8, 22.3,
21.5, 14.3 ppm. HRMS (EI): calcd. for C27H28N2O3 428.2100
[M]+; found 428.2127.
3b: Yellow oil. IR (neat): ν = 3352, 3020, 2936, 2858, 2838, 1710,
˜
1626, 1560, 1513, 1442, 1371, 1293, 1249, 1218, 1181, 1107, 1034,
979, 919, 780, 765, 748, 735, 669 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 7.90 (s, 1 H), 7.26–7.28 (m, 2 H), 6.88–7.05 (m, 2 H),
5.32–5.37 (m, 1 H), 5.16 (d, J = 14.5 Hz, 1 H), 5.11 (d, J = 14.5 Hz,
1 H), 4.14–4.21 (m, 2 H), 3.78 (s, 3 H), 2.19–2.26 (m, 1 H), 2.11–
2.16 (m, 2 H), 1.97 (s, 3 H), 1.86–1.93 (m, 1 H), 1.72–1.78 (m, 3
H), 1.58–1.67 (m, 1 H), 1.26 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR
(67.8 MHz, CDCl3): δ = 165.0, 159.9, 159.2, 145.2, 141.6, 136.7,
129.4, 127.9, 123.7, 122.1, 114.2, 107.1, 60.1, 55.2, 53.7, 29.1, 25.0,
22.7, 21.9, 14.6, 14.4 ppm. HRMS (EI): calcd. for C23H28N2O3
380.2100 [M]+; found 380.2101.
3j: Brown oil. IR (neat): ν = 3314, 2928, 1710, 1619, 1559, 1507,
˜
1459, 1416, 1367, 1296, 1223, 1173, 1071, 1035, 833, 797, 736,
710 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.44–
7.47 (m, 2 H), 7.31–7.39 (m, 3 H), 7.18–7.22 (m, 2 H), 6.99–7.02
(m, 2 H), 4.25 (q, J = 7.2 Hz, 2 H), 3.83 (s, 3 H), 2.50–2.57 (m, 2
H), 1.33–1.40 (m, 2 H), 1.31 (t, J = 7.2 Hz, 3 H), 1.14–1.21 (m, 2
H), 0.73 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 165.2, 160.5, 159.4, 145.5, 144.3, 135.9, 134.8, 130.1, 129.9,
129.1, 128.1, 128.0, 114.8, 107.0, 60.3, 55.5, 32.4 30.9, 22.8, 14.3,
13.6 ppm. HRMS (EI): calcd. for C25H28N2O3 404.2100 [M]+;
found 404.2104.
3c: Brown oil. IR (neat): ν = 3352, 2956, 1705, 1627, 1560, 1512,
˜
1444, 1378, 1287, 1251, 1211, 1165, 1076, 1031, 959, 918, 815,
773 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.23–
7.26 (m, 2 H), 6.87–6.90 (m, 2 H), 5.13 (s, 2 H), 4.21 (q, J = 7.0 Hz,
2 H), 3.79 (s, 3 H), 2.83 (t, J = 7.6 Hz, 2 H), 2.01 (s, 3 H), 1.39–
1.46 (m 4 H), 1.29 (t, J = 7.0 Hz, 3 H), 0.94 (t, J = 6.9 Hz, 3
H) ppm. 13CNMR (126 MHz, CDCl3): δ = 165.3, 159.4, 159.1,
143.6, 141.8, 129.1, 127.9, 122.3, 114.0, 106.7, 60.0, 55.1, 53.6, 31.7,
29.8, 22.9, 14.1, 13.8, 13.4 ppm. HRMS (EI): calcd. for
C21H28N2O3 356.2100 [M]+; found 356.2063.
3k: Brown solid; m.p. 113–114 °C. IR (KBr): ν = 3433, 3058, 2959,
˜
1705, 1633, 1562, 1505, 1414, 1365, 1312, 1284, 1248, 1218, 1175,
1132, 1029, 903, 852, 767, 701 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.92 (s, 1 H), 7.32–7.40 (m, 5 H), 7.15–7.20 (m, 2 H), 7.03–7.08
(m, 2 H), 5.74–5.88 (m, 1 H), 4.92–5.06 (m, 2 H), 3.91 (q, J =
7.0 Hz, 2 H), 3.86 (s, 3 H), 3.03 (d, J = 4.9 Hz, 2 H), 0.91 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 165.1, 159.7,
144.2, 142.3, 139.0, 134.7, 128.3, 127.7, 127.6, 127.1, 116.0, 115.1,
107.8, 60.1, 55.5, 33.5, 13.7 ppm. HRMS (EI): calcd. for
C24H24N2O3 388.1787 [M]+; found 388.1789.
Synthesis of 2-Iminopyridines 3d, 3h–l, 9 and 11 (Conditions B): A
solution of ethyl 2-cyano-2-phenylacetate (1b) (189 mg, 1.0 mmol)
in 1,4-dioxane (2.0 mL) was added to solid 95% KHMDS (168 mg,
0.80 mmol) at room temperature. The reaction mixture was stirred
at room temperature for 10 min and then a solution of the alkynyl
imine 2a (49.9 mg, 0.20 mmol) in 1,4-dioxane (2.0 mL) was added.
The resulting reaction mixture was stirred under reflux for 45.0 h
and then cooled to room temperature. A saturated aqueous
NaHCO3 solution (10 mL) was added to quench the reaction. The
mixture was extracted with dichloromethane (3ϫ15 mL). The
combined organic layers were dried with sodium sulfate. The sol-
vents were evaporated in vacuo and then the residue was purified
by preparative TLC on silica gel (ammonia solution in dichloro-
3l: Brown solid; m.p. 109–111 °C. IR (KBr): ν = 3304, 3074, 2930,
˜
2837, 1715, 1629, 1564, 1510, 1414, 1366, 1286, 1247, 1170, 1122,
1030, 913, 838, 783, 734 cm–1. 1H NMR (500 MHz, CDCl3): δ =
7.86 (s, 1 H), 7.26–7.29 (m, 2 H), 7.00–7.03 (m, 2 H), 5.83–5.93 (m,
1 H), 5.43–5.47 (m, 1 H), 5.10 (d, J = 17.1 Hz, 1 H), 5.05 (d, J =
10.1 Hz, 1 H), 4.15–4.24 (m, 2 H), 3.85 (s, 3 H), 3.34 (dd, J = 15.0,
5.6 Hz, 1 H), 3.24 (dd, J = 15.0, 5.8 Hz, 1 H), 2.25–2.32 (m, 1 H),
2.13–2.18 (m, 2 H), 1.94–2.01 (m, 1 H), 1.73–1.81 (m, 3 H), 1.60–
Eur. J. Org. Chem. 2008, 1411–1417
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1415

I. Hachiya, Y. Minami, T. Aramaki, M. Shimizu
FULL PAPER
1.68 (m, 1 H), 1.27 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 164.8, 159.6, 158.7, 146.5, 142.6, 136.1, 135.7, 134.1,
128.3, 125.3, 123.9, 115.9, 115.1, 107.2, 60.1, 55.5, 33.3, 29.4, 25.0,
22.7, 21.9, 14.4 ppm. HRMS (EI): calcd. for C24H28N2O3 392.2100
[M]+; found 392.2142.
775 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.83 (s, 1 H), 7.24–
7.27 (m, 2 H), 7.02–7.05 (m, 2 H), 4.22 (q, J = 7.0 Hz, 2 H), 3.86
(s, 3 H), 2.88 (t, J = 7.8 Hz, 2 H), 2.12 (t, 3 H), 1.43–1.52 (m, 4
H), 1.29 (t, J = 7.2 Hz, 3 H), 0.97 (t, J = 7.0 Hz, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 165.5, 159.8, 159.0, 144.1, 141.9,
133.8, 128.5, 124.5, 115.3, 107.6, 60.3, 55.6, 31.7, 29.9, 23.1, 14.3,
13.9.13.7 ppm. HRMS (EI): calcd. for C20H26N2O3 342.1943 [M]+;
found 342.2008.
9: Brown solid; m.p. 110–111 °C. IR (KBr): ν = 3451, 3048, 2977,
˜
2925, 1650, 1587, 1490, 1442, 1397, 1372, 1305, 1265, 1214, 1148,
1
1036, 980, 908, 829, 768, 700 cm–1. H NMR (500 MHz, CDCl3):
δ = 8.54 (d, J = 4.6 Hz, 1 H), 7.32–7.39 (m, 3 H), 7.07–7.10 (m, 3
H), 3.86–3.91 (m, 2 H), 1.81 (s, 3 H), 0.69–0.73 (m, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 166.2, 157.8, 152.9, 143.6, 140.8,
127.8, 127.7, 126.7, 124.8, 115.1, 113.9, 99.6, 60.0, 14.9, 13.3 ppm.
HRMS (EI): calcd. for C17H16N2O2S 312.0933 [M]+; found
312.0932.
Synthesis of 2-Aminopyridines 12a–c: A solution of trifluorome-
thansulfonic acid (3.2 mL, 0.02  in trifluoroacetic acid,
0.064 mmol) was added to iminopyridine 3a (24.0 mg, 0.064 mmol)
at room temperature. The reaction mixture was stirred under reflux
for 24 h and then cooled to room temperature. A saturated aqueous
NaHCO3 solution (15 mL) was added to quench the reaction. The
mixture was extracted with dichloromethane (3ϫ15 mL). The
combined organic layers were dried with sodium sulfate. The sol-
vents were evaporated in vacuo and then the residue was purified
by preparative TLC on silica gel (ammonia solution in dichloro-
methane/methanol, 50:1) to give 2-aminopyridine 12a as a white
oil (11.3 mg, 70%).
11: Yellow oil. IR (neat): ν = 3442, 2931, 2856, 2198, 1716, 1621,
˜
1553, 1509, 1446, 1378, 1300, 1253, 1227, 1174, 1140, 1079, 1022,
919, 835, 783 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.18–7.22
(m, 2 H), 7.02–7.06 (m, 2 H), 5.76–5.80 (m, 1 H), 5.56–5.60 (m, 1
H), 4.24–4.34 (m, 1 H), 4.12–4.22 (m, 1 H), 3.87 (s, 3 H), 2.61 (m,
1 H), 2.11 (s, 3 H), 2.09–2.01 (m, 3 H), 1.75–1.51 (m, 8 H), 1.49–
1.47 (m, 4 H), 1.33 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 166.9, 159.8, 159.0, 143.9, 137.8, 136.0, 132.2, 130.1,
128.0, 126.2, 125.6, 119.6, 117.4, 115.1, 103.3, 79.5, 74.7, 61.1, 55.6,
28.9, 27.9, 25.7, 25.0, 22.6, 21.8, 21.1, 15.3, 14.2 ppm. HRMS (EI):
calcd. for C30H34N2O3 470.2569 [M]+; found 470.2510.
12a: M.p. 83–84 °C. IR (KBr): ν = 3415, 2987, 2935, 2873, 1702,
˜
1606, 1583, 1547, 1472, 1428, 1371, 1328, 1294, 1270, 1211, 1180,
1153, 1094, 1028, 963, 861 cm–1. 1H NMR (500 MHz, CDCl3): δ =
7.89 (s, 1 H), 7.34–7.42 (m, 3 H), 7.09–7.12 (m, 2 H), 4.98 (br. s, 2
H), 3.98 (q, J = 7.3 Hz, 2 H), 1.83 (s, 3 H), 0.96 (t, J = 7.3 Hz, 3
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 166.6, 159.5, 150.7,
148.8, 139.1, 127.9, 127.2, 117.5, 114.2 60.2, 13.8, 13.7 ppm.
HRMS (EI): calcd. for C15H16N2O2 256.1212 [M]+; found
256.1132.
Synthesis of 2-Iminopyridines 3e–g (Conditions C): A solution of
ethyl 2-cyanopropanoate (1a) (131 mg, 1.0 mmol) in 1,4-dioxane
(2.0 mL) was added to KHMDS (1.3 mL, 0.45  in toluene,
0.77 mmol) at room temperature. The reaction mixture was stirred
at room temperature for 10 min, and then a solution of the alkynyl
imine 2d (47.1 mg, 0.20 mmol) in 1,4-dioxane (2.0 mL) was added.
The resulting reaction mixture was stirred at 160 °C for 25.0 h and
then cooled to room temperature. A saturated aqueous NaHCO3
solution (10 mL) was added to quench the reaction. The mixture
was extracted with dichloromethane (3ϫ15 mL). The combined
organic layers were dried with sodium sulfate. The solvents were
evaporated in vacuo and then the residue was purified by prepara-
tive TLC on silica gel (ammonia solution in dichloromethane/meth-
anol, 20:1) to give 2-iminopyridine 3e as a yellow solid (58.6 mg,
81%).
12b: Yellow oil. IR (neat): ν = 3300, 3135, 2927, 2860, 1711, 1638,
˜
1
1589, 1550, 1429, 1385, 1269, 1167, 1092, 1025, 969, 793 cm–1. H
NMR (500 MHz, CDCl3): δ = 8.54 (s, 1 H), 4.73 (br. s, 2 H), 4.31
(q, J = 7.0 Hz, 2 H), 2.96–2.99 (m, 2 H), 2.09 (s, 3 H), 1.41–1.52
(m, 4 H), 1.36 (t, J = 7.2 Hz, 3 H), 0.96 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (126 MHz, CDCl3): δ = 166.9, 159.3, 152.0, 149.4, 117.0,
113.8, 60.3, 32.1, 29.4, 23.1, 14.3, 13.9, 12.2 ppm. HRMS (EI):
calcd. for C13H20N2O2 236.1525 [M]+; found 236.1498.
12c: Brown solid; m.p. 130–131 °C. IR (KBr): ν = 3417, 3360, 3304,
˜
3053, 2982, 1696, 1640, 1605, 1576, 1469, 1437, 1393, 1368, 1305,
1273, 1213, 1151, 1117, 1073, 1044, 1022, 910, 811, 759, 735,
700 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.72 (s, 1 H), 7.16–
7.27 (m, 3 H), 7.09–7.14 (m, 3 H), 7.02–7.05 (m, 2 H), 6.92–6.95
(m, 2 H), 4.84 (br. s, 2 H), 4.01 (q, J = 7.0 Hz, 2 H), 0.95 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 166.7, 158.7,
150.7, 150.5, 138.2, 135.2, 130.3, 128.7, 128.6, 127.5, 127.2, 126.8,
120.6, 117.5, 60.3, 13.7 ppm. HRMS (EI): calcd. for C20H18N2O2
318.1368 [M]+; found 318.1368.
3e: M.p. 123–124 °C. IR (CHCl ): ν = 3302, 3019, 2963, 2841, 1711,
˜
3
1632, 1562, 1510, 1463, 1444, 1418, 1373, 1356, 1293, 1221, 1167,
1132, 1070, 1029, 960, 909, 882, 855, 835, 782, 764, 739, 704,
668 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.89 (s, 1 H), 7.38–
7.42 (m, 2 H), 7.32–7.37 (m, 3 H), 7.13–7.17 (m, 2 H), 7.05–7.08
(m, 2 H), 3.92 (q, J = 7.0 Hz, 2 H), 3.88 (s, 3 H), 1.85 (s, 3 H),
0.92 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
165.2, 159.8, 143.2, 141.4, 139.5, 128.4, 127.9, 127.8, 127.0, 115.3,
108.1, 60.1, 55.5, 15.7, 13.7 ppm. HRMS (EI): calcd. for
C22H22N2O3 362.1630 [M]+; found 362.1621.
Acknowledgments
3f: Brown oil. IR (neat): ν = 3301 3021, 1708, 1630, 1513, 1425,
˜
1371, 1293, 1218, 1136, 1034, 927, 746, 673 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.26–7.29 (m, 2 H), 7.01–
7.04 (m, 2 H), 5.40–5.42 (m, 1 H), 4.17–4.22 (m, 2 H), 3.86 (s, 3
H), 2.26–2.32 (m, 1 H), 2.14–2.18 (m, 2 H), 2.05 (s, 3 H), 1.95–2.01
(m, 1 H), 1.75–1.82 (m, 3 H), 1.63–1.70 (m, 1 H), 1.27 (t, J =
7.2 Hz, 3 H) ppm. 13CNMR (126 MHz, CDCl3): δ = 165.1, 159.7,
145.5, 141.7, 136.7, 128.4, 123.8, 115.2, 107.6, 60.2, 55.6, 29.1 25.1,
22.7, 22.0, 14.9, 14.4 ppm. HRMS (EI): calcd. for C22H26N2O3
366.1943 [M]+; found 366.1918.
This work was supported in part by a Grant-in-Aid for Young Sci-
entists (B) from the Japan Society for the Promotion Science.
[1] a) C. Hamdouchi, J. de Blas, M. de Prado, J. Gruber, B. A.
Heinz, L. Vance, J. Med. Chem. 1999, 42, 50–59; b) M. A. Is-
mail, R. Brun, T. Wenzler, F. A. Tanious, W. D. Wilson, D. W.
Boykin, J. Med. Chem. 2004, 47, 3658–3664.
[2] A. H. Abadi, H. A. Al-Khamees, Arch. Pharmacol. Med.
Chem. 1998, 331, 319–324.
[3] a) A. Z. Schultz, Chem. Rev. 1973, 73, 385–405; b) D. P. Cur-
ran, H. Liu, J. Am. Chem. Soc. 1992, 114, 5863–5864; c) A. P.
Kozikowski, G. Campiani, L.-Q. Sun, S. Wang, A. Saxena,
3g: Brown oil. IR (neat): ν = 3453, 2959, 2929, 1709, 1635, 1560,
˜
1511, 1463, 1369, 1290, 1252, 1218, 1152, 1087, 1015, 962, 836,
1416
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1411–1417

Synthesis of Multi-Substituted 2-Iminopyridine
B. P. Doctor, J. Am. Chem. Soc. 1996, 118, 11357–11362; d)
D. R. Williams, P. D. Lowder, Y.-G. Gu, Tetrahedron Lett.
1997, 38, 327–330; e) M.-L. Bennasar, E. Zulaica, C. Juan, Y.
Alonso, J. Bosch, J. Org. Chem. 2002, 67, 7465–7474; f) G.
Semple, B.-M. Andersson, V. Chhajlani, J. Georgsson, M. J.
Johannsson, A. Rosenquist, L. Swanson, Bioorg. Med. Chem.
Lett. 2003, 13, 1141–1145; g) J. J. Parlow, M. S. South, Tetrahe-
dron 2003, 59, 7695–7701; h) J. J. Palow, R. G. Kurumbail,
R. A. Stegeman, A. M. Stevens, W. C. Stallings, M. S. South,
J. Med. Chem. 2003, 46, 4696–4701; i) P. Fossa, G. Menozzi,
P. Dorigo, M. Floreani, L. Mosti, Bioorg. Med. Chem. 2003,
11, 4749–4759.
a) G. Ege, H. O. Frey, E. Schuck, Synthesis 1979, 376–378; b)
A. H. H. Elghandour, M. M. M. Ramiz, M. H. Elnagdi, Syn-
thesis 1989, 775–777; c) Y. M. Elkholy, A. W. Erian, Heteroat.
Chem. 2003, 14, 503–508; d) A.-Z. A.-A. Elassar, Heteroat.
Chem. 2004, 15, 293–299.
[8] a) I. Hachiya, S. Fukushima, M. Shimizu, Heterocycles 2006,
69, 43–48; for the synthesis of bicyclic compounds containing
a 2-pyridone structure by addition reactions of malonic esters
to alkynylpyridines, pyrimidine, and thiazoles, see: b) I.
Hachiya, M. Atarashi, M. Shimizu, Heterocycles 2006, 67,
523–528.
[9] For examples of the transformation of 2-iminopyridines into
2-aminopyridines, see: a) R. Adams, I. J. Pachter, J. Am. Chem.
Soc. 1952, 74, 4906–4909; b) K. Hartke, M. Sauebier, W. F.
Richter, Arch. Pharm. 1992, 325, 279–284.
[10] For recent examples, see: a) S. A. S. Ghozlan, A. Z. A. Hassan-
ien, Tetrahedron 2002, 58, 9423–9429; b) O. S. Moustafa, R. A.
Ahmad, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178,
475–484; c) J. L. Marco, C. del los Ríos, A. G. García, M. Vil-
larroya, M. C. Carreiras, C. Martins, A. Eleutério, A. Morre-
ale, M. Orozco, F. J. Luque, Bioorg. Med. Chem. 2004, 12,
2199–2218; d) R. León, J. Marco-Contelles, A. G. García, M.
Villarroya, Bioorg. Med. Chem. 2005, 13, 1167–1175; e) A.-
G. E. Amr, A. M. Mohamed, S. F. Mohamed, N. A. Abel-
Hafez, A. E.-F. G. Hammam, Bioorg. Med. Chem. 2006, 14,
5481–5488.
[4]
[5]
a) P. Hong, H. Yamazaki, Tetrahedron Lett. 1977, 18, 1333–
1336; b) H. Hoberg, G. Burkhart, Synthesis 1979, 525–526; c)
P. Diversi, G. Ingrosso, A. Lucherini, S. Malquori, J. Mol. Ca-
tal. 1987, 40, 267–280; d) D. D. Young, A. Deiters, Angew.
Chem. Int. Ed. 2007, 46, 5187–5190.
[11] K. Okuro, M. Furuune, M. Miura, M. Nomura, J. Org. Chem.
1993, 58, 7606–7607.
[12] K. Terao, A. Toshimitsu, S. Uemura, J. Chem. Soc. Perkin
Trans. 1 1986, 1837–1843.
[13] B. G. Van den Hoven, H. Alper, J. Am. Chem. Soc. 2001, 123,
[6] T. Takahashi, F.-U. Tsai, Y. Li, H. Wang, Y. Kondo, M. Yam-
anaka, K. Nakajima, M. Korota, J. Am. Chem. Soc. 2002, 124,
5059–5067.
[7] a) I. Hachiya, K. Ogura, M. Shimizu, Org. Lett. 2002, 4, 2755–
2757; b) I. Hachiya, K. Ogura, M. Shimizu, Synthesis 2004,
1349–1352.
1017–1022.
Received: November 5, 2007
Published Online: January 10, 2008
Eur. J. Org. Chem. 2008, 1411–1417
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1417