The aza-ene or the Michael addition? Examination of an unusual substituent effect on the reaction of heterocyclic ketene aminals with ethyl propiolate

Article abstract of DOI:10.1016/S0040-4020(02)00002-9

Heterocyclic ketene aminals having at least one secondary amino group underwent the aza-ene reaction with ethyl propiolate under various conditions to yield the corresponding adducts, which were readily transformed into the δ-lactam fused heterocyclic products with or without the aid of sodium ethoxide in refluxing ethanol, while the ester- and cyano-substituted tertiary enediamines acted as the strong Michael donor to add to ethyl propiolate in a polar or a protic solvent. The unusual substituent effect on the reactivity and mechanism was discussed.

Full text of DOI:10.1016/S0040-4020(02)00002-9

TETRAHEDRON
Pergamon
Tetrahedron 58 22002) 1309±1316
The aza±ene or the Michael addition? Examination of an unusual
substituent effect on the reaction of heterocyclic ketene aminals
with ethyl propiolate
Mei-Xin Zhao, Mei-Xiang Wang and Zhi-Tang Huangp
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, People's Republic of China
Received 2 October 2001; revised 26 November 2001; accepted 20 December 2001
AbstractÐHeterocyclic ketene aminals having at least one secondary amino group underwent the aza±ene reaction with ethyl propiolate
under various conditions to yield the corresponding adducts, which were readily transformed into the d-lactamfused heterocyclic products
with or without the aid of sodiumethoxide in re¯uxing ethanol, while the ester- and cyano-substituted tertiary enediamines acted as the strong
Michael donor to add to ethyl propiolate in a polar or a protic solvent. The unusual substituent effect on the reactivity and mechanism was
discussed. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
such as N-alkylation6 and N-acylation7 in the presence of
a strong base. Further interest in heterocyclic ketene aminals
has been generated by their interesting biological activities.8
The chemistry of enamines has been extensively developed
since the pioneering work conducted by Stork and
colleagues,1 and it has become an important aspect of
organic chemistry.2 Heterocyclic ketene aminals or cyclic
1,1-enediamines 1 2Fig. 1), as members of the enamine
family, are versatile synthons for the synthesis of various
types of heterocyclic compounds and they have received
increasing attention recently.3 Owing to the conjugation
effect of the electron-donating amino groups and the
electron-withdrawing substituent, the double bond is highly
polarized and the electron density on the a-carbon is greater
than that of the nitrogen atom. Considerable effort has been
made during the past decades to investigate enaminic
reactions such as nucleophilic additions and substitutions
with a variety of electrophiles,4 even 1,3-diploes.5 As an
ambident nucleophile, however, the secondary amino
group in the molecule can also participate in reactions
Through a systematic study of the reaction of aroyl-substi-
tuted heterocyclic ketene aminals with a,b-unsaturated
compounds, we have proposed that heterocyclic ketene
aminal is an aza±ene component able to undergo an aza±
ene addition reaction with electron de®cient alkenes and
alkynes.9 The aza±ene adduct between 1 2RˆH or RˆMe)
and ethyl propiolate can undergo further isomerization and
cyclocondensation to afford lactam-fused heterocycles.9a
Surprisingly, however, mono-ester substituted heterocyclic
ketene aminal 2 has been reported to exhibit a different
reaction pattern towards electrophiles.10 In contrast to 1,
for example, heterocyclic ketene aminal 2 reacted with
electrophiles to give an exclusive C-alkylation product
even under basic conditions. Furthermore, the C-adducts
between 2 and methyl propiolate could not undergo cyclo-
condensation reaction in re¯uxing ethanol. Interest in the
chemistry of heterocyclic ketene aminals, particularly the
correlation between structure and reactivity, promoted us to
undertake the current study. By utilizing ethyl propiolate as
a reactive probe, we have found a great effect of the
electron-withdrawing group at a-carbon and the substituent
at nitrogen on the reactivity and reaction pathway of hetero-
cyclic ketene aminals. The nature of the solvents, on the
other hand, also plays an important role on the reaction.
Figure 1. Structure of heterocyclic ketene aminals.
2. Results and discussion
Keywords: heterocyclic ketene aminals; ethyl propiolate; substituent effect;
addition reaction.
Corresponding author. Tel.: 186-10-6254-4082; fax: 186-10-6255-
9373; e-mail: huangzt@public.bta.net.cn
p
In order to examine the effect of the structure of heterocyclic
ketene aminals on the reactivity, a number of compounds
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020202)00002-9

1310
M.-X. Zhao et al. / Tetrahedron 58 ,2002) 1309±1316
Scheme 1.
3±6 having a different electron-withdrawing group and
different N-substituents were designed. The aroyl11 and
acetyl-substituted12 heterocyclic ketene aminals were
synthesized fromthe corresponding ketene dithioacetals
and diamines in an open or closed system, while the
cyano- and ester-substituted heterocyclic ketene aminals
were synthesized fromthe reaction of imino esters with
diamines 2Scheme 1). It is worth noting that the reaction
of imino ester hydrochloride13 did not give the desired
product as those reported in the literature. Only when
imino ester, derived from the treatment of imino ester
hydrochloride salt with a base, was used, did the preparative
reaction proceed readily to produce compounds 5 and 6.
strongly dependent upon the structure of the reactant 3±6
and upon the reaction conditions employed 2Scheme 2,
Table 2).
Benzoyl-substituted heterocyclic ketene aminals 3a±c
having at least one secondary amino moiety reacted with
ethyl propiolate 7 in both 1,4-dioxane and ethanol solution
to yield the corresponding adducts 8a±c as the sole or major
product. The con®gurations of both vinylene and enedia-
mine moieties were assigned as E-formon the basis of the
1H NMR spectrum. An AB quartet signal of coupling
constant 15.0±15.9 Hz corresponding to the trans-
con®guration of the vinylene protons was observed, while
a down®eld N±H resonance peak at 8.24±9.70 ppm
indicated intramolecular hydrogen bonding between N±H
and carbonyl groups. Adducts 8a±c were readily trans-
formed into the d-lactam-fused heterocyclic products
12a±c in high yields. Compounds 12a±c can also be
prepared conveniently in one-pot reaction through re¯uxing
3a±c with 7 in ethanol for a prolonged time.
It is interesting to point out that both the chemical shift of
the vinyl proton and the a-carbon of compounds 3±6 were
in¯uenced dramatically by the nature of the substituents on
the a-carbon and on the nitrogen of imidazoline. The
stronger the electron-withdrawing group, the higher the
electron density on the a-carbon. As illustrated in Table 1,
with the electron-withdrawing group being varied from
benzoyl, acetyl, ester to cyano, the chemical shift of the
vinyl proton decreased from5.20±5.42 to 2.93±3.20 ppm.
Similar up®eld shift of the a-carbon in 13C NMR was also
observed with the exception of the acetyl-substituted analog
which gave dC signal in the region of 74.9±76.1 ppm,
higher than that of benzoyl-substituted heterocyclic ketene
aminals. The substitution of methyl or benzyl on the nitro-
gen also led to the down®eld shift of the vinyl proton in the
1H NMR spectra. Since the chemical shifts of both dH and
dC re¯ect the electron density of the a-carbon, therefore,
they can be used a parameter to correlate the nucleophilicity
of the a-carbon under certain circumstances.14
Acetyl-substituted heterocyclic ketene aminals 4a, which
have two secondary amino moieties, underwent similar
reaction with ethyl propiolate 7 in re¯uxing ethanol to afford
a mixture of adduct 9a and the fused heterocyclic product
13a. Prolonged re¯uxing led to the conversion of 9a into
13a. Ester- or cyano-substituted heterocyclic ketene aminals
5a or 6a, however, gave the adduct 10a or 11a as the sole
product. Prolonged re¯uxing led to the conversion of most
10a into 14a, however, no cyclized compound 15a was
found even in a longer reaction period. Only in the presence
of sodiumethoxide, did transformation of 11a into 15a take
place ef®ciently.
Heterocyclic ketene aminals 3±6a±c reacted with ethyl
propiolate effectively and the outcome, however, was
Having one methyl or benzyl group attached on the nitrogen
of imidazoline, all heterocyclic ketene aminals 4±6b,c were
Table 1. dH and dC values of the a-carbon in heterocyclic ketene aminals
d 2ppm)
3 EWGˆCOPh
4 EWGˆCOCH3
5 EWGˆCO2Et
6 EWGˆCN
a: RˆH
R0ˆH
dH
dC
dH
dC
dH
dC
5.20
73.0
5.30
71.4
5.42
72.9
4.52
76.1
4.62
75.2
4.77
74.9
3.35
60.3
3.36
60.0
4.01
60.1
2.93
33.7
3.01
32.9
3.20
34.6
b: RˆH
R0ˆMe
c: RˆH
R0vCH2Ph

M.-X. Zhao et al. / Tetrahedron 58 ,2002) 1309±1316
1311
Scheme 2.
Table 2. Reaction of heterocyclic ketene aminals 3±6 with ethyl propiolate 7
Entry
Reactant
EWG
R0
Reaction conditions
Product 2%)a
Heterocycle
Adduct
1
2
3
4
5
6
7
8
3ab
3a
COPh
H
1,4-Dioxane, rt 4 d
EtOH, re¯ux, 2 h
EtOH, re¯ux, 2 d
EtOH, re¯ux, 1 h
EtOH, re¯ux, 2 d
EtOH, re¯ux, 1 h
EtOH, re¯ux, 2 d
EtOH, re¯ux, 2 h
EtOH, re¯ux, 2 d
EtOH, re¯ux, 2 h
EtOH, re¯ux, 2 h
EtOH, re¯ux, 2 h
EtOH, re¯ux, 2 d
EtOH, re¯ux, 2 h
EtOH, 208C, 48 h
EtOH, re¯ux, 2 h
EtOH, re¯ux, 2 h
EtOH, 208C, 48 h
8a 292)
8a 254)
8a 20)
8b 259)
8b 20)
8c 256)
8c 20)
9a 249)
9a 20)
9b 263)
9c 265)
10a 269)
10a 217)
10b 280)
10c 268)
11a 269)
11b 275)
11c 280)
12a 20)
12a 233)
12a 280)
12b 20)
12b 278)
12c 20)
12c 279)
13a 223)
13a 262)
13b 20)
13c 20)
14a 20)
14a 265)
14b 20)
14c 20)
15a 20)
15b 20)
15c 20)
13b 270)
13c 295)
14b 249)
14c 262)
15a 2quant.)
15b 2quant.)
15c 280)
3ab
3b
3b
3c
Me
CH2Ph
H
3c
4a
4a
4b
4c
5a
5a
5b
5c
6a
6b
6c
9b
9c
COCH3
CO2Et
CN
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Me
CH2Ph
H
Me
CH2Ph
H
Me
CH2Ph
Me
CH2Ph
Me
CH2Ph
H
Me
COCH3
CO2Et
CN
EtONa/EtOH, re¯ux, 2 h
EtONa/EtOH, re¯ux, 2 h
EtONa/EtOH, re¯ux, 2 h
EtONa/EtOH, re¯ux, 2 h
EtONa/EtOH, re¯ux, 1 h
EtONa/EtOH, re¯ux, 1 h
EtONa/EtOH, re¯ux, 1 h
10b
10c
11a
11b
11c
CH2Ph
a
Isolated yields.
See Ref. 9a.
b
exclusively transformed into the adducts 9±11b,c.
Prolonged reaction only led to a complex reaction mixture
and no cyclized products were observed. Cyclocondensation
of the adducts 9±11b,c was similarly effected as that for 11a
by using sodiumethoxide. The structures of the fused
heterocyclic compounds were established on the basis of
spectroscopic evidence and elemental analyses. The
imidazo[1,2-a]pyridinone structure was con®rmed by the
NMR spectra which showed an AB quartet signal of
To shed further light on the reaction mechanism, hetero-
cyclic ketene aminals bearing two tertiary amino moieties
were subject to the reaction with ethyl propiolate. As
illustrated in Scheme 3, benzoyl-substituted heterocyclic
ketene aminal 3d did not add to ethyl propiolate 7 in both
protic and aprotic solvents such as ethanol and 1,4-dioxane,
respectively.9a By using ester- and cyano-substituted hetero-
cyclic ketene aminal analogs 5d and 6d, we did not observe
the addition reaction in 1,4-dioxane either. This is consistent
with our previous ®nding that the reaction of heterocyclic
ketene aminals with a,b-unsaturated compounds proceeds
via an aza±ene addition mechanism 2Scheme 2).9 In other
words, without a secondary enamine segment 2H±N±CvC)
such as those of N,N-dimethylated heterocyclic ketene
1
coupling constant around 9.3 Hz in H NMR and amide
carbonyl signal around 160 ppmin 13C NMR. The lactam
structure was also supported by the IR spectrumin which an
amide carbonyl vibration band was evident in the region of
1600±1700 cm21
.

1312
M.-X. Zhao et al. / Tetrahedron 58 ,2002) 1309±1316
Scheme 3.
aminals 3±6d, no aza±ene addition reaction takes place.
Surprisingly, however, 5d and 6d were able to react with
7 in re¯uxing ethanol to afford products 10d and 11d in 38
and 81%, respectively. The formation of 10d and 11d most
probably resulted fromthe well-known Michael addition
reaction of 5d and 6d to ethyl propiolate 7, and heterocyclic
ketene aminals 5d and 6d appear as strong Michael donors
2Scheme 3).
aminals to a,b-unsaturated compounds proceeds via the
aza±ene mechanism or the Michael addition pathway
depending on both the nature of the substituents at the
a-carbon and at amino group and the reaction conditions
used. Heterocyclic ketene aminals with a secondary
enamine moiety 2HN±CvC) undergo aza±ene reaction
with ethyl propiolate to give the corresponding adduct
which is readily transformed into d-lactamfused hetero-
cyclic products with or without the aid of sodiumethoxide
in re¯uxing ethanol. Only ester and cyano-substituted
tertiary enediamines act as the strong Michael donor to
add to ethyl propiolate in a polar and protic solvent. This
investigation has provided not only a convenient synthetic
route to imidazo[1,2-a]pyridinone heterocycles but also the
better understanding of the reaction mechanism which are
important in guiding further study.
All the results obtained suggested that the reaction of
heterocyclic ketene aminals with ethyl propiolate could
proceed in a different manner depending not only on the
structure of the reactant but also on the reaction conditions
employed with the former being the dominant factor. In
most cases, heterocyclic ketene aminals having at least
one secondary amino group undergo the aza±ene addition
reaction when treated with ethyl propiolate under various
conditions. No addition reaction was found in general when
N,N0-disubstituted heterocyclic ketene aminals were used
because of the lack of secondary enamine moiety. Only in
the case of ester- and cyano-substituted tertiary enediamines
using a polar and protic solvent, did the reaction proceed in
a Michael addition fashion. The higher Michael addition
reactivity of the ester- and cyano-substituted tertiary
enediamines 5d and 6d than that of the benzoyl-substituted
analog 3d is not surprising, since the nucleophilicity of
a-carbon of 5d and 6d is greater than that of 3d, which
has been revealed by the comparison of the chemical shifts
of both vinyl proton and a-carbon among compounds 3±6
2vide supra). It is also important to note that the higher
nucleophilicity of a-carbon concomitantly lead to the
lower nucleophilicity of the enamine nitrogen because of
the ambident conjugation effect within the enediamine
segment. This accounts not only for the easy aza±ene
addition of ester-, and particularly cyano-substituted hetero-
cyclic ketene aminals 6a±c to ethyl propiolate but also for
the dif®culty of the consecutive d-lactamforamtion
reaction. The presence of sodiumethoxide increased the
nucleophilicity of the secondary amino group and therefore
facilitated the cyclocondensation reaction.
4. Experimental
4.1. General
Melting points are uncorrected. IR spectra were obtained on
1
a Perkin±Elmer 782 instrument as KBr discs. H and 13C
NMR spectra were recorded in CDCl3 or d6-DMSO solution
with SiMe4 as internal standard on Bruker DMX-300 spec-
trometers. Chemical shifts are reported in ppm and coupling
constants are in Hz. Mass spectra were measured on an AEI
MS-50 spectrometer. HR mass spectra were measured on a
Bruker APEXR spectrometer. Elemental analyses were
carried out at the Analytical Laboratory of the Institute.
All solvents and chemicals were commercially available
and, unless otherwise indicated, were used as received.
The heterocyclic ketene aminals 311 and 412 were prepared
according to literature methods.
4.1.1. 2-0Acetylmethylene)-1-benzyl-imidazolidine 04c).
A mixture of ketene dithioacetals11 derived fromacetyl
acetone 210 mmol) and N-benzyl-1,2-ethylenediamine
212 mmol) in 30 mL of toluene was heated at 1108C for
9 h in a closed system. The solvent was removed under
vacuumand the residue was chromatographed over a silica
gel column using ethyl acetate/petroleum ether as an eluant
to give 4c. White crystals; yield: 32%; mp 115±1168C;
2Found: C, 72.29; H, 7.48; N, 13.05. C13H16N2O requires
C, 72.19; H, 7.46; N, 12.96%); nmax 2KBr) cm21: 3288
2NH), 1603, 1544; dH 2d6-DMSO): 9.07 21H, s, NH),
3. Conclusion
Heterocyclic ketene aminals or heterocyclic enediamines
are a unique enamine analog exhibiting intriguing reaction
properties. The addition reaction of heterocyclic ketene

M.-X. Zhao et al. / Tetrahedron 58 ,2002) 1309±1316
1313
C9H17N2O2 required 185.1284; nmax 2KBr) cm21: 1737,
1644; dH 2CDCl3): 3.85 22H, q, Jˆ6.9 Hz, OCH2CH3),
3.70 21H, s, vCH), 3.22 24H, s, 2£NCH2), 2.74 26H, s,
3£NCH2), 1.05 23H, t, Jˆ6.9 Hz, OCH2CH3); dC 2CDCl3):
165.4, 164.1, 59.9, 55.9, 48.3, 34.4, 12.7; m/z 2EI): 184 2M1,
36%), 139 2100), 112 272).
1
7.38±7.24 25H, m, ArH), 4.77 21H, s, vCH), 4.34 22H, s,
benzyl of CH2), 3.48 22H, t, Jˆ7.8 Hz, NCH2), 3.30 22H, t,
Jˆ7.8 Hz, NCH2), 1.78 23H, s, COCH3); dC 2d6-DMSO):
189.1, 163.0, 137.1, 128.9, 127.9, 127.7, 74.9, 48.4, 47.1,
42.0, 29.0; m/z 2EI): 216 2M1, 57%), 201 245), 173 251), 91
2100).
4.3.5. 2-0Cyanomethylene)imidazolidine 06a). White
crystals; yield: 42%; mp 104±1068C 2lit.16 1068C); dH
2d6-DMSO): 6.84 21H, s, NH), 6.74 21H, s, NH), 3.50±
3.46 24H, m, 2£NCH2), 2.93 21H, s, vCH); dC 2d6-
DMSO): 166.6, 124.6, 43.9, 43.4, 33.7; m/z 2EI): 109
2M1, 60%), 80 2100).
4.2. General procedure for the synthesis of imino ester
Imino ester hydrochloride13 250 mmol) was added to a
mixture of 70 mL 40% K2CO3 solution and 50 mL cold
diethyl ether. The organic layer was separated quickly and
the water layer was extracted by diethyl ether twice.
Combined the organic layer and poured it into anhydrous
K2CO3 and then the organic layer was dried by anhydrous
Na2SO4 for 4 h again. After removal of solvent under
vacuum, the crude product was recrystallized from ethyl
ether to give the imino ester as white crystals which can
be used in the next step reaction directly.
4.3.6. 0E)-2-0Cyanomethylene)-1-methylimidazolidine
06b). White crystals; yield: 76%; mp 120±1218C; 2Found:
C, 58.38; H, 7.23; N, 34.28. C6H9N3 requires C, 58.51; H,
7.37; N, 34.12%); nmax 2KBr) cm21: 3268 2NH), 2165 2CN),
1601, 1520; dH 2d6-DMSO): 6.71 21H, s, NH), 3.32±3.24
24H, m, 2£NCH2), 3.01 21H, s, vCH), 2.63 23H, s, NCH3);
dC 2d6-DMSO): 165.8, 124.0, 51.1, 41.8, 34.4, 32.9; m/z
2EI): 123 2M1, 100%), 95 227), 80 251).
4.3. General procedure for the synthesis of 5 and 6
A solution of imino ester 23 mmol) and diamine 23.3 mmol)
in dry CH2Cl2 was re¯uxed for 10 h under nitrogen. After
removal of the solvent under vacuum, the residue was
recrystallized fromethyl acetate or fractionated by chroma-
tography on a silica gel column using ethyl acetate or ethyl
acetate/petroleumether as an eluant to give products 5 and
6.
4.3.7.
0E)-2-0Cyanomethylene)-1-benzylimidazolidine
06c). White crystals; yield; 78%; mp 141±1438C; 2Found:
C, 72.08; H, 6.59; N, 21.32. C12H13N3 requires C, 72.33; H,
6.57; N, 21.09%); nmax 2KBr) cm21: 3294 2NH), 2170 2CN),
1588, 1506; dH 2d6-DMSO): 7.33 25H, m, ArH), 6.73 21H, s,
NH), 4.20 22H, s, benzylic CH2), 3.32±3.23 24H, m,
2£NCH2), 3.20 21H, s, vCH); dC 2d6-DMSO): 165.0,
137.0, 128.9, 128.0, 127.7, 124.0, 49.2, 48.7, 41.9, 34.6;
m/z 2EI): 199 2M1, 33%), 91 2100).
4.3.1. 2-0Ethoxycarbonylmethylene)imidazolidine 05a).
White crystals; yield: 94%; mp 112±1138C; 2Found: C,
53.62; H, 7.89; N, 18.11. C7H12N2O2 requires C, 53.83; H,
7.75; N, 17.94%); nmax 2KBr) cm21: 3379 2NH), 3310 2NH),
1628, 1574; dH 2d6-DMSO): 7.39 21H, s, NH), 6.84 21H, s,
NH), 3.87 22H, q, Jˆ6.9 Hz, OCH2CH3), 3.35 21H, s,
vCH), 3.46±3.28 24H, m, 2£NCH2), 1.09 23H, t,
Jˆ6.9 Hz, OCH2CH3); dC 2d6-DMSO): 169.8, 165.0, 60.3,
57.0, 43.7, 42.4, 15.4; m/z 2EI): 156 2M1, 66%), 127 255),
111 2100).
4.3.8. 2-0Cyanomethylene)-1,3-dimethylimidazolidine
06d). Yellow oil; yield: 67%; MS 2high resolution, positive
FAB) m/z: 138.1027 [2M1H)1]; C7H12N3 required
1
138.1026; nmax 2KBr) cm21: 2180, 1591, 1503; dH
2CDCl3): 3.07±3.01 24H, m, 2£NCH2), 2.83 23H, s,
NCH3), 2.68 21H, s, vCH), 2.39 23H, s, NCH3); dC
2CDCl3): 164.2, 123.3, 50.5, 49.0, 35.4, 35.1, 34.0; m/z
2EI): 137 2M1, 50%), 97 239), 81 248), 56 2100).
4.3.2. 0E)-2-0Ethoxycarbonylmethylene)-1-methylimi-
dazolidine 05b). White crystals; yield: 75%; mp 98±
1008C 2lit.15 98±101.58C); nmax 2KBr) cm21: 3368 2NH),
1639, 1584; dH 2d6-DMSO): 7.40 21H, s, NH), 3.91 22H,
q, Jˆ7.2 Hz, OCH2CH3), 3.36 21H, s, vCH), 3.41±3.28
24H, m, 2£NCH2), 2.67 23H, s, NCH3), 1.11 23H, t,
Jˆ7.2 Hz, OCH2CH3); dC 2d6-DMSO): 169.7, 164.1, 60.0,
57.2, 50.3, 42.1, 32.6, 15.2.
4.4. General procedure for the reaction of heterocyclic
ketene aminals with ethyl propiolate
A mixture of heterocyclic ketene aminals 3±6 21 mmol) and
ethyl propiolate 7 21 mmol) was re¯uxed 2or was stirred at
208C) in ethanol or 1,4-dioxane for some period. After
removal of the solvent under vacuum, the residue was
chromatographed on a silica gel column using ethyl acetate/
petroleumether or ethyl acetate/methanol as an eluant to
give the corresponding adducts. Prolonged reaction time,
some adducts can be converted to the fused d-lactam
heterocycles.
4.3.3.
0E)-2-0Ethoxycarbonylmethylene)-1-benzylimi-
dazolidine 05c). White crystals; yield: 70%; mp 106±
1088C 2lit.17 105±1078C); nmax 2KBr) cm21: 3365 2NH),
1645, 1591; dH 2d6-DMSO): 7.52 21H, s, NH), 7.37±7.23
25H, m, ArH), 4.30 22H, s, benzyl of CH2), 4.01 21H, s,
vCH), 3.90 22H, q, Jˆ6.9 Hz, OCH2CH3), 3.46±3.29
24H, m, 2£NCH2), 1.10 23H, t, Jˆ6.9 Hz, OCH2CH3); dC
2d6-DMSO): 169.9, 163.4, 137.4, 128.8, 127.7, 127.5, 60.1,
57.2, 48.8, 48.0, 42.1, 15.2.
4.4.1. 2-01-Benzoyl-3-ethoxycarbonylprop-2-enylidene)-
2,3,4,5-tetrahydroimidazole 08a). Yellow crystals; yield:
54%; mp 122±1248C 2lit.9a 123±1248C); dH 2CDCl3): 8.18
22H, s, NH), 7.68 21H, d, Jˆ15.9 Hz, vCH), 7.39±7.38
25H, m, ArH), 5.43 21H, d, Jˆ15.9 Hz, vCH), 4.09 22H,
q, Jˆ7.2 Hz, OCH2CH3), 3.74 24H, s, 2£NCH2), 1.20 23H, t,
Jˆ7.2 Hz, OCH2CH3).
4.3.4. 2-0Ethoxycarbonylmethylene)-1,3-dimethylimi-
dazolidine 05d). Yellow viscous liquid; yield: 61%; MS
2high resolution, positive FAB) m/z: 185.1284 [2M1H)1];

1314
M.-X. Zhao et al. / Tetrahedron 58 ,2002) 1309±1316
4.4.2. 1-Methyl-2-01-benzoyl-3-ethoxycarbonylprop-2-
enylidene)-2,3,4,5-tetrahydroimidazole 08b). Yellow
crystals; yield: 59%; mp 142±1448C 2Found: C, 67.91; H,
6.64; N, 9.38. C17H20N2O3 requires C, 67.98; H, 6.71; N,
9.33%); nmax 2KBr) cm21: 3239 2NH), 1656, 1561; dH
2CDCl3): 8.88 21H, s, NH), 7.59 21H, d, Jˆ15.0 Hz,
vCH), 7.37±7.36 25H, m, ArH), 5.05 21H, d, Jˆ15.3 Hz,
vCH), 3.95 22H, q, Jˆ6.9 Hz, OCH2CH3), 3.79±3.67 24H,
m , 2£NCH2), 2.74 23H, s, NCH3), 1.11 23H, t, Jˆ6.9 Hz,
OCH2CH3); dC 2CDCl3): 186.2, 168.8, 168.1, 145.6, 143.0,
129.4, 128.2, 128.1, 97.4, 90.3, 58.4, 50.9, 42.0, 35.1, 15.0;
m/z 2EI): 300 2M1, 8%), 271 29), 254 2100).
Jˆ9.3 Hz, NCH2), 3.50 22H, t, Jˆ9.3 Hz, NCH2), 2.33
23H, s, COCH3), 2.05 23H, s, COCH3), 1.13 23H, t,
Jˆ7.2 Hz, OCH2CH3); dC 2CDCl3): 192.1, 168.7, 167.2,
142.7, 135.5, 128.6, 127.9, 127.6, 104.5, 91.2, 59.2, 53.0,
47.2, 42.3, 27.0, 14.3; m/z 2EI): 314 2M1, 3%), 268 213), 216
214), 91 2100).
4.4.7. 2-01-Ethoxycarbonyl-3-ethoxycarbonylprop-2-enyl-
idene)-2,3,4,5-tetrahydroimidazole 010a). White crystals;
yield: 69%; mp 166±1678C; 2Found: C, 56.59; H, 7.24; N,
11.17. C12H18N2O4 requires C, 56.68; H, 7.13; N, 11.02%);
nmax 2KBr) cm21: 3350 2NH), 1669, 1634, 1551; dH
2d6-DMSO): 8.14 21H, s, NH), 7.55 21H, s, NH), 7.55
21H, d, Jˆ15.3 Hz, vCH), 5.80 21H, d, Jˆ15.3 Hz,
vCH), 4.08 22H, q, Jˆ6.9 Hz, OCH2CH3), 4.03 22H, q,
Jˆ6.9 Hz, OCH2CH3), 3.54 24H, s, 2£NCH2), 1.21 23H, t,
Jˆ6.9 Hz, OCH2CH3), 1.17 23H, t, Jˆ6.9 Hz, OCH2CH3);
dC 2d6-DMSO): 169.2, 168.4, 165.4, 141.3, 101.3, 78.3,
58.8, 58.7, 43.5, 43.4, 15.1, 15.0; m/z 2EI): 254 2M1,
100%), 209 288), 181 245), 163 292).
4.4.3. 1-Benzyl-2-01-benzoyl-3-ethoxycarbonylprop-2-
enylidene)-2,3,4,5-tetrahydroimidazole 08c). Yellow
crystals; yield: 56%; mp 62±648C; MS 2high resolution,
positive FAB) m/z: 377.1860 [2M1H)1]; C23H25N2O3
1
required 377.1860; nmax 2KBr) cm21: 3400 2NH), 1687,
1551; dH 2CDCl3): 9.70 21H, br, NH), 7.74 21H, d,
Jˆ15.6 Hz, vCH), 7.49±7.22 25H, m, ArH), 5.18 21H, d,
Jˆ15.6 Hz, vCH), 4.64 22H, s, CH2), 4.04 22H, q,
Jˆ7.2 Hz, OCH2CH3), 3.74±3.55 24H, m, 2£NCH2), 1.15
23H, t, Jˆ7.2 Hz, OCH2CH3); dC 2CDCl3): 190.8, 168.7,
167.7, 144.7, 141.2, 135.3, 129.4, 128.9, 128.1, 128.0,
127.9, 127.8, 102.6, 90.8, 59.1, 52.6, 47.2, 42.2, 14.3; m/z
2EI): 376 2M1, 4%), 330 228), 105 217), 91 2100).
4.4.8. 1-Methyl-2-01-ethoxycarbonyl-3-ethoxycarbonyl-
prop-2-enylidene)-2,3,4,5-tetrahydroimidazole
010b).
Pale yellow crystals; yield: 80%; mp 77±798C; 2Found: C,
58.11; H, 7.61; N, 10.22; C13H20N2O4 requires C, 58.19; H,
7.51; N, 10.44%); nmax 2KBr) cm21: 3318 2NH), 1687, 1632,
1583, 1556; dH 2d6-DMSO): 8.28 21H, s, NH), 7.63 21H, d,
Jˆ15.3 Hz, vCH), 5.33 21H, d, Jˆ15.3 Hz, vCH), 4.03
22H, q, Jˆ6.9 Hz, OCH2CH3), 3.99 22H, q, Jˆ6.9 Hz,
OCH2CH3), 3.76±3.71 22H, m, NCH2), 3.69±3.57 22H, m,
NCH2), 2.84 23H, s, NCH3), 1.19 23H, t, Jˆ6.9 Hz,
OCH2CH3), 1.16 23H, t, Jˆ6.9 Hz, OCH2CH3); dC
2d6-DMSO): 169.1, 167.6, 166.5, 144.0, 98.6, 76.7, 58.4,
51.8, 41.7, 37.2, 15.2, 15.1; m/z 2EI): 268 2M1, 25%), 222
243), 177 243), 170 247), 125 2100).
4.4.4. 2-01-Acetyl-3-ethoxycarbonylprop-2-enylidene)-
2,3,4,5-tetrahydroimidazole 09a). Pale yellow solid;
yield: 49%; mp 141±1438C; 2Found: C, 58.88; H, 7.11; N,
12.52. C11H16N2O3, requires C, 58.91; H, 7.19; N, 12.49%);
nmax 2KBr) cm21: 3250 2NH), 1691, 1562; dH 2d6-DMSO):
8.75 21H, s, NH), 8.70 21H, s, NH), 7.70 21H, d, Jˆ15.6 Hz,
vCH), 5.45 21H, d, Jˆ15.6 Hz, vCH), 4.05 22H, q,
Jˆ6.9 Hz, OCH2CH3), 3.55 24H, s, 2£NCH2), 2.13 23H, s,
COCH3), 1.18 23H, t, Jˆ6.9 Hz, OCH2CH3); dC
2d6-DMSO): 191.9, 168.7, 164.6, 143.2, 119.2, 102.9,
91.5, 59.1, 43.2, 28.3, 14.9; m/z 2EI): 224 2M1, 27%), 178
226), 163 236), 151 2100), 44 240).
4.4.9. 1-Benzyl-2-01-ethoxycarbonyl-3-ethoxycarbonyl-
prop-2-enylidene)-2,3,4,5-tetrahydroimidazole 010c).
Yellow viscous liquid; yield: 68%; MS 2high resolution,
positive FAB) m/z: 345.1810 [2M1H)1]; C19H25N2O4
1
4.4.5. 1-Methyl-2-01-acetyl-3-ethoxycarbonylprop-2-enyl-
idene)-2,3,4,5-tetrahydroimidazole 09b). Yellow viscous
liquid; yield: 63%; mp 101±1038C; MS 2high resolution,
required 345.1809; nmax 2KBr) cm21: 3344 2NH), 1642,
1590, 1546, 1148; dH 2d6-DMSO): 8.61 21H, s, NH), 7.65
21H, d, Jˆ11.4 Hz, ArH), 7.47±7.30 25H, m, ArH1vCH),
5.46 21H, d, Jˆ15.0 Hz, vCH), 4.42 22H, s, NCH2), 4.13±
3.93 24H, m, 2£OCH2CH3), 3.58±3.56 24H, m, 2£NCH2),
1.18±1.09 26H, m, 2£OCH2CH3); dC 2d6-DMSO): 169.0,
168.3, 166.7, 143.7, 136.6, 129.0, 128.0, 127.9, 99.2, 76.9,
58.5, 58.4, 53.0, 48.7, 42.1, 15.2, 15.0; m/z 2EI): 344 2M1,
9%), 271 214), 257 240), 246 2100), 211 222), 201 227), 173
245), 132 216), 104 217), 91 227), 65 220).
1
positive FAB) m/z: 239.1390 [2M1H)1]; C12H19N2O3
required 239.1390; nmax 2KBr) cm21: 3178 2NH), 1682,
1617, 1576; dH 2CDCl3): 8.88 21H, s, NH), 7.75 21H, d,
Jˆ15.0 Hz, vCH), 4.88 21H, d, Jˆ15.0 Hz, vCH), 4.03
22H, q, Jˆ6.9 Hz, OCH2CH3), 3.86±3.69 24H, m,
2£NCH2), 2.83 23H, s, NCH3), 2.05 23H, s, COCH3), 1.19
23H, t, Jˆ6.9 Hz, OCH2CH3); dC 2CDCl3): 186.2, 168.7,
167.8, 143.9, 96.0, 90.9, 58.2, 50.7, 41.8, 35.3, 26.3, 14.9;
m/z 2EI): 238 2M1, 16%), 192 231), 177 256), 165 2100), 58
242).
4.4.10. 1,3-Dimethyl-2-01-ethoxycarbonyl-3-ethoxycar-
bonylprop-2-enylidene)-2,3,4,5-tetrahydroimidazole 010d).
Yellow viscous liquid; yield: 38%; MS 2high resolution,
positive FAB) m/z: 283.1650 [2M1H)1]; C14H23N2O4
required 283.1652; nmax 2KBr) cm21: 1637, 1571, 1530;
dH 2d6-DMSO): 8.00 21H, d, Jˆ15.0 Hz, vCH), 4.67 21H,
d, Jˆ15.0 Hz, vCH), 4.19±4.08 24H, m, 2£OCH2CH3),
3.74 24H, s, 2£NCH2), 2.91 26H, s, 2£NCH3), 1.28±1.17
26H, m, 2£OCH2CH3); dC 2d6-DMSO): 168.8, 167.6, 165.3,
144.4, 93.3, 73.1, 58.0, 58.0, 48.9, 35.2, 15.1, 14.9; m/z 2EI):
282 2M1, 60%), 237 248), 209 252), 178 254), 150 286), 123
2100).
4.4.6. 1-Benzyl-2-01-acetyl-3-ethoxycarbonylprop-2-enyl-
idene)-2,3,4,5-tetrahydroimidazole 09c). Yellow viscous
liquid; yield: 65%; mp 101±1038C; MS 2high resolution,
1
positive FAB) m/z: 315.1707 [2M1H)1]; C18H23N2O3
required 315.1703; nmax 2KBr) cm21: 3200 2NH), 1679,
1561, 1502; dH 2CDCl3): 9.82 21H, br, NH), 7.88 21H, d,
Jˆ15.6 Hz, vCH), 7.34±7.25 23H, m, ArH), 7.18 22H, t,
Jˆ6.9 Hz, ArH), 5.31 21H, d, Jˆ15.6 Hz, vCH), 4.49 22H,
s, CH2), 4.13 22H, q, Jˆ7.2 Hz, OCH2CH3), 3.66 22H, t,

M.-X. Zhao et al. / Tetrahedron 58 ,2002) 1309±1316
1315
4.4.11. 2-01-Cyano-3-ethoxycarbonylprop-2-enylidene)-
2,3,4,5-tetrahydroimidazole 011a). White solid; yield:
69%; mp 218±2208C; 2Found: C, 57.90; H, 6.45; N,
20.02. C10H13N3O2 requires C, 57.96; H, 6.32; N,
20.28%); nmax 2KBr) cm21: 3250 2NH), 2181 2CN), 1663,
1573; dH 2d6-DMSO): 8.25 21H, s, NH), 7.51 21H, s, NH),
7.52 21H, d, Jˆ14.4 Hz, vCH), 5.11 21H, d, Jˆ14.4 Hz,
vCH), 4.00 22H, q, Jˆ7.2 Hz, OCH2CH3), 3.51 24H, s,
2£NCH2), 1.15 23H, t, Jˆ7.2 Hz, OCH2CH3); dC
2d6-DMSO): 167.8, 164.3, 142.5, 120.1, 100.2, 58.9, 57.9,
43.8, 43.7, 14.9; m/z 2EI): 207 2M1, 44%), 162 2100).
vCH), 4.20 22H, t, Jˆ9.3 Hz, NCH2), 3.86 22H, t,
Jˆ9.3 Hz, NCH2), 2.94 23H, s, NCH3).
4.4.17. 1-Benzyl-8-benzoyl-1,2,3,5-tetrahydroimidazo-
[1,2-a]pyridin-5-one 012c). Pale yellow crystals; yield:
79%; mp 138±1408C; 2Found: C, 76.15; H, 5.50; N, 8.41.
C21H18N2O2 requires C, 76.34; H, 5.49; N, 8.48%); nmax
2KBr) cm21: 1672, 1624, 1556; dH 2CDCl3): 7.55±7.16
210H, m, ArH), 7.35 21H, d, Jˆ9.3 Hz, vCH), 5.79 21H,
d, Jˆ9.3, vCH), 4.66 22H, s, CH2), 4.26 22H, t, Jˆ9.6 Hz,
NCH2), 3.91 22H, t, Jˆ9.6 Hz, NCH2); dC 2CDCl3): 191.8,
161.3, 153.9, 144.3, 138.5, 134.7, 131.9, 129.3, 128.7,
128.2, 127.8, 105.2, 99.6, 77.4, 52.6, 49.5, 42.4; m/z 2EI):
330 2M1, 39%), 91 2100).
4.4.12. 1-Methyl-2-01-cyano-3-ethoxycarbonylprop-2-
enylidene)-2,3,4,5-tetrahydroimidazole 011b). White
crystals; yield: 75%; mp 131±1338C; 2Found: C, 59.33; H,
6.81; N, 19.00. C11H15N3O2 requires C, 59.71; H, 6.83; N,
18.99%); nmax 2KBr) cm21: 3312 2NH), 2174 2CN), 1680,
1572; dH 2d6-DMSO): 7.98 21H, s, NH), 7.50 21H, d,
Jˆ14.4 Hz, vCH), 5.18 21H, d, Jˆ14.4 Hz, vCH), 3.99
22H, q, Jˆ6.9 Hz, OCH2CH3), 3.59 22H, m, NCH2), 3.41
22H, m, NCH2), 3.08 23H, s, NCH3), 1.13 23H, t, Jˆ6.9 Hz,
OCH2CH3); dC 2d6-DMSO): 165.9, 161.3, 141.8, 118.3,
99.2, 57.1, 55.4, 51.0, 39.3, 33.0, 13.0; m/z 2EI): 221 2M1,
80%), 175 2100).
4.4.18. 8-Acetyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyri-
din-5-one 013a). White crystals; yield: 62%; mp 206±
2088C; 2Found: C, 60.25; H, 5.56; N, 15.85; C9H10N2O2
requires C, 60.66; H, 5.66; N, 15.72%); nmax 2KBr) cm21
:
3321 2NH), 1668, 1607, 1581; dH 2CDCl3): 8.77 21H, s,
NH), 7.69 21H, d, Jˆ9.3 Hz, vCH), 5.51 21H, d,
Jˆ9.3 Hz, vCH), 3.97 22H, t, Jˆ9.3 Hz, NCH2), 3.72
22H, t, NCH2), 2.24 23H, s, COCH3); dC 2CDCl3): 192.9,
161.1, 155.6, 142.3, 104.7, 97.5, 43.2, 43.0, 26.4; m/z 2EI):
178 2M1, 93%), 163 2100).
4.4.13.
enylidene)-2,3,4,5-tetrahydroimidazole
1-Benzyl-2-01-cyano-3-ethoxycarbonylprop-2-
011c). Pale
4.4.19.
8-Ethoxycarbonyl-1,2,3,5-tetrahydroimidazo-
[1,2-a]pyridin-5-one 014a). White crystals; yield: 65%;
mp 153±1558C; 2Found: C, 57.69; H, 5.80; N, 13.52;
C10H12N2O3 requires C, 57.68; H, 5.81; N, 12.46%); nmax
2KBr) cm21: 3359 2NH), 1683, 1614, 1570; dH 2d6-DMSO):
7.99 21H, s, NH), 7.53 21H, d, Jˆ9.3 Hz, vCH), 5.50 21H,
d, Jˆ9.3 Hz, vCH), 4.14 22H, q, Jˆ10.8 Hz, OCH2CH3),
3.97 22H, t, Jˆ9.0 Hz, NCH2), 3.69 22H, t, Jˆ9.0 Hz,
NCH2), 1.21 23H, t, Jˆ10.8 Hz, OCH2CH3); dC
2d6-DMSO): 164.9, 161.2, 155.8, 140.8, 105.0, 86.4, 59.6,
43.6, 42.8, 14.7; m/z 2EI): 208 2M1, 100%), 161 280).
yellow crystals; yield: 80%; mp 134±1368C; 2Found: C,
68.44; H, 6.44; N, 14.24. C17H19N3O2 requires C, 68.67;
H, 6.44; N, 14.13%); nmax 2KBr) cm21: 3330 2NH), 2179
2CN), 1668, 1549, 1526; dH 2d6-DMSO): 8.17 21H, s, NH),
7.56 21H, d, Jˆ14.4 Hz, vCH), 7.37±7.24 25H, m, ArH),
5.21 21H, d, Jˆ14.4 Hz, vCH), 4.80 22H, s, CH2), 3.99 22H,
q, Jˆ6.9 Hz, OCH2CH3), 3.57±3.31 24H, m, 2£NCH2), 1.13
23H, t, Jˆ6.9 Hz, OCH2CH3); dC 2d6-DMSO): 167.5, 162.5,
143.4, 136.3, 129.0, 127.8, 127.5, 119.8, 101.4, 58.8, 57.0,
50.2, 50.1, 41.0, 14.7; m/z 2EI): 297 2M1, 2%), 251 218), 91
2100).
4.5. General procedure for the cyclization of adducts in
the presence of sodium ethoxide
4.4.14. 1,3-Dimethyl-2-01-cyano-3-ethoxycarbonylprop-
2-enylidene)-2,3,4,5-tetrahydroimidazole 011d). Yellow
crystals; yield: 81%; mp 102±1048C; 2Found: C, 60.95; H,
7.24; N, 17.79. C12H17N3O2 requires C, 61.25; H, 7.28; N,
17.86%); nmax 2KBr) cm21: 2172 2CN), 1688, 1587, 1538;
dH 2d6-DMSO): 7.41 21H, d, Jˆ14.7 Hz, vCH), 5.59 21H,
d, Jˆ14.7 Hz, vCH), 4.16 22H, q, Jˆ7.2 Hz, OCH2CH3),
3.63 24H, s, 2£NCH2), 3.12 26H, s, 2£NCH3), 1.28 23H, t,
Jˆ7.2 Hz, OCH2CH3); dC 2d6-DMSO): 168.8, 166.5, 142.7,
120.4, 102.5, 59.3, 55.6, 50.5, 37.9, 14.5; m/z 2EI): 235 2M1,
60%), 190 275), 162 229), 148 2100).
To a solution of the adduct 21 mmol) in ethanol 215 mL) was
added sodium ethoxide 21 mmol) and the reaction mixture
was re¯uxed for 1±2 h. Removal of solvent under vacuum
gave a residue that was fractionated by chromatography on a
silica gel column using petroleum ether/ethyl acetate or
ethyl acetate/methanol as an eluant to give the fused
imidazo[1,2-a]pyridinone products.
4.5.1. 1-Methyl-8-acetyl-1,2,3,5-tetrahydroimidazo[1,2-
a]pyridin-5-one 013b). White crystals; yield: 70%; mp
106±1088C; 2Found: C, 62.06; H, 6.32; N, 14.53;
C10H12N2O2 requires C, 62.48; H, 6.29; N, 14.58%); nmax
2KBr) cm21: 1671, 1616, 1555; dH 2CDCl3): 7.65 21H, d,
Jˆ9.3 Hz, vCH), 5.83 21H, d, Jˆ9.3 Hz, vCH), 4.16 22H,
t, Jˆ9.3 Hz, NCH2), 3.83 22H, t, Jˆ9.3 Hz, NCH2), 3.05
23H, s, NCH3), 2.41 23H, s, COCH3); dC 2CDCl3): 192.3,
161.0, 154.7, 142.5, 105.7, 99.9, 51.8, 42.1, 38.8, 27.6; m/z
2EI): 192 2M1, 62%), 177 2100).
4.4.15. 8-Benzoyl-1,2,3,5-tetrahydroimidazo-[1,2-a]pyri-
din-5-one 012a). Pale yellow crystals; yield: 80%; mp 179±
1818C 2lit.9a 179±180.58C); dH 2CDCl3): 8.67 21H, s, NH),
7.56±7.44 26H, m, ArH1vCH), 5.77 21H, d, Jˆ9.6 Hz,
vCH), 4.29 22H, t, Jˆ9.0 Hz, NCH2), 4.02 22H, t,
Jˆ9.0 Hz, NCH2).
4.4.16. 1-Methyl-8-benzoyl-1,2,3,5-tetrahydroimidazo-
[1,2-a]pyridin-5-one 012b). Yellow green crystals; yield:
78%; mp 130±1328C 2lit.9a 130±132.58C); dH 2CDCl3):
7.74 22H, d, Jˆ7.5 Hz, ArH), 7.53±7.42 23H, m, ArH),
7.38 21H, d, Jˆ9.3 Hz, vCH), 5.74 21H, d, Jˆ9.3 Hz,
4.5.2. 1-Benzyl-8-acetyl-1,2,3,5-tetrahydroimidazo[1,2-
a]pyridin-5-one 013c). White crystals; yield: 95%; mp
121±1238C; 2Found: C, 71.68; H, 6.02; N, 10.44;

1316
M.-X. Zhao et al. / Tetrahedron 58 ,2002) 1309±1316
C16H16N2O2 requires C, 71.62; H, 6.01; N, 10.44%); nmax
2KBr) cm21: 1672, 1624, 1527, 1541; dH 2d6-DMSO): 7.72
21H, d, Jˆ9.3 Hz, vCH), 7.34±7.23 25H, m, ArH), 5.63
21H, d, Jˆ9.3 Hz, vCH), 4.66 22H, s, CH2), 4.00 22H, t,
Jˆ9.3 Hz, NCH2), 3.72 22H, t, Jˆ9.3 Hz, NCH2), 2.19 23H,
s, COCH3); dC 2d6-DMSO): 191.8, 159.7, 153.1, 142.4,
135.7, 127.8, 127.1, 126.7, 104.2, 99.4, 52.2, 48.8, 41.7,
27.3; m/z 2EI): 268 2M1, 29%), 91 2100).
Acknowledgements
The ®nancial support fromthe Major Basic Research
Development Program 2No. G2000077502), the National
Natural Science Foundation of China and the Chinese
Academy of Sciences is gratefully acknowledged.
References
4.5.3. 1-Methyl-8-ethoxycarbonyl-1,2,3,5-tetrahydro-
imidazo[1,2-a]pyridin-5-one 014b). White crystals; yield:
49%; mp 92±948C 2lit.15 88±928C); dH 2d6-DMSO): 7.77
21H, d, Jˆ9.6 Hz, vCH), 5.83 21H, d, Jˆ9.6 Hz, vCH),
4.25 22H, q, Jˆ7.2 Hz, OCH2CH3), 4.15 22H, t, Jˆ9.3 Hz,
NCH2), 3.78 22H, t, Jˆ9.3 Hz, NCH2), 1.34 23H, t,
Jˆ7.2 Hz, OCH2CH3).
1. 2a) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc.
1954, 76, 2029. 2b) Stork, G.; Landesman, H. J. Am. Chem.
Soc. 1956, 78, 5182. 2c) Stork, G.; Brizzolara, A.;
Szmuszkovicz, J. J. Am. Chem. Soc. 1963, 85, 207.
2. 2a) Cook, A. G. Enamines: Synthesis, Structure, and
Reactions; 2nd ed.; Marcel Dekker: New York, 1988.
2b) Hickmott, P. W. Tetrahedron 1982, 38, 1976.
2c) Hickmott, P. W. Tetrahedron 1982, 38, 3363.
2d) Hickmott, P. W. Tetrahedron 1984, 40, 2989.
3. 2a) Rajappa, S. Tetrahedron 1981, 37, 1453. 2b) Huang, Z.-T.;
Wang, M.-X. Heterocycles 1994, 37, 1233.
4.5.4.
1-Benzyl-8-ethoxycarbonyl-1,2,3,5-tetrahydro-
imidazo[1,2-a]pyridin-5-one 014c). White crystals; yield:
62%; mp 66±688C; MS 2high resolution, positive FAB) m/z:
299.1391 [2M1H)1]; C17H19N2O31 required 299.1390; nmax
2KBr) cm21: 1699, 1650, 1546; dH 2d6-DMSO): 7.85 21H, d,
Jˆ9.6 Hz, vCH), 7.37±7.29 25H, m, ArH), 5.90 21H, d,
Jˆ9.6 Hz, vCH), 4.84 22H, s, CH2), 4.21 22H, q,
Jˆ7.2 Hz, OCH2CH3), 4.13 22H, t, Jˆ9.0 Hz, NCH2),
3.67 22H, t, Jˆ9.0 Hz, NCH2), 1.28 23H, t, Jˆ7.2 Hz,
OCH2CH3); dC 2d6-DMSO): 163.5, 161.0, 153.3, 142.3,
134.7, 127.5, 126.6, 126.5, 105.6, 89.5, 59.1, 52.9, 47.4,
41.3, 13.0; m/z 2EI): 298 2M1, 29%), 91 2100).
4. 2a) Chafer, H.; Gewald, K. J. Prakt. Chem. 1977, 87.
2b) Huang, Z.-T.; Liu, Z.-R. Synthesis 1987, 357.
5. 2a) Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 1992, 57, 184.
2b) Huang, Z.-T.; Wang, M.-X. Synth. Commun. 1991, 21,
1167. 2c) Huang, Z.-T.; Wang, M.-X. Synth. Commun. 1991,
21, 1909.
6. 2a) Wang, M.-X.; Wu, X.-D.; Wang, L.-B.; Huang, Z.-T.
Synth. Commun. 1995, 25, 343. 2b) Wang, L.-B.; Yu, C.-Y.;
Huang, Z.-T. Synthesis 1994, 1441. 2c) Wang, M.-X.; Huang,
Z.-T. J. Org. Chem. 1995, 60, 2087.
4.5.5. 8-Cyano-1,2,3,5-tetrahydroimidazo[1,2-a]pyridin-
5-one 015a). White crystals; yield: quant.; mp 220±2228C;
2Found: C, 59.59; H, 4.41; N, 26.04; C8H7N3O requires C,
59.62; H, 4.38; N, 26.07%); nmax 2KBr) cm21: 3277 2NH),
2213 2CN), 1668, 1561; dH 2d6-DMSO): 8.64 21H, s, NH),
7.34 21H, d, Jˆ9.3 Hz, vCH), 5.54 21H, d, Jˆ9.3 Hz,
vCH), 4.02 22H, t, Jˆ9.3 Hz, NCH2), 3.67 22H, t,
Jˆ9.3 Hz, NCH2); dC 2d6-DMSO): 159.2, 156.4, 140.8,
116.7, 104.9, 64.4, 43.3, 41.1; m/z 2EI): 161 2M1, 100%),
133 252).
7. 2a) Yu, C.-Y.; Huang, Z.-T.; Wang, L.-B. J. Chem. Res. ,S)
1996, 410. 2b) Yu, C.-Y.; Huang, Z.-T.; Wang, L.-B. J. Chem.
Res. ,M) 1996, 2375. 2c) Yu, C.-Y.; Wang, L.-B.; Huang, Z.-T.
Synthesis 1996, 959.
8. 2a) Stetter, J.; Lieb, F. Angew. Chem., Int. Ed. Engl. 2000, 39,
1724. 2b) Tieman, C. H.; Kollmeyer, W. D.; Roman, S. A. US
Patent 3,971,774, 1976; Chem. Abstr. 1977, 5460k. 2c) Porter,
P. E.; Kollmeyer, W. D. US Patent 4,053,623, 1977; Chem.
Abstr. 1977, 37796g.
9. 2a) Huang, Z.-T.; Wang, M.-X. J. Chem. Soc., Perkin Trans. 1
1993, 1085. 2b) Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T.
Tetrahedron Lett. 1998, 39, 9237. 2c) Zhang, J.-H.; Wang,
M.-X.; Huang, Z.-T. J. Chem. Res. ,S) 1998, 486. 2d) Zhang,
J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc., Perkin
Trans. 1 1999, 321.
4.5.6. 1-Methyl-8-cyano-1,2,3,5-tetrahydroimidazo[1,2-
a]pyridin-5-one 015b). Pale yellow crystals; yield: quant.;
mp 181±1838C; 2Found: C, 61.41; H, 5.08; N, 24.12;
C9H9N3O requires C, 61.70; H, 5.18; N, 23.99%); nmax
2KBr) cm21
: 2200 2CN), 1661, 1595, 1571; dH
10. 2a) Jones, R. C. F.; Patel, P.; Hirst, S. C.; Turner, I.
Tetrahedron 1997, 53, 11781. 2b) Jones, R. C. F.; Patel, P.;
Hirst, S. C.; Smallridge, M. J. Tetrahedron 1998, 54, 6191.
11. Huang, Z.-T.; Liu, Z.-R. Synth. Commun. 1989, 19, 943.
12. Wang, H.-T.; Wang, X.-J.; Huang, Z. T. Chem. Ber. 1990,
122, 2141.
2d6-DMSO): 7.35 21H, d, Jˆ9.3 Hz, vCH), 5.60 21H, d,
Jˆ9.3 Hz, vCH), 3.93 22H, t, Jˆ9.3 Hz, NCH2), 3.70
22H, t, Jˆ9.3 Hz, NCH2), 3.17 23H, s, NCH3); dC
2d6-DMSO): 160.2, 155.2, 143.2, 118.6, 106.6, 65.4, 50.3,
42.5, 33.6; m/z 2EI): 175 2M1, 100%), 147 236).
13. 2a) Wamhoff, H.; Materne, C. Liebigs Ann. Chem. 1973, 573.
2b) Mcelvain, S. M.; Schroeder, J. P. J. Am. Chem. Soc. 1949,
71, 40.
4.5.7. 1-Benzyl-8-cyano-1,2,3,5-tetrahydroimidazo[1,2-
a]pyridin-5-one 015c). White needle crystals; yield: 80%;
mp 104±1068C; 2Found: C, 71.94; H, 5.28; N, 16.69.
C15H13N3O requires C, 71.70; H, 5.21; N, 16.72%); nmax
2KBr) cm21: 2215 2CN), 1658, 1587, 1562; dH 2CDCl3):
7.42±7.31 26H, m, ArH1vCH), 5.88 21H, d, Jˆ9.6 Hz,
vCH), 4.94 22H, s, CH2), 4.12 22H, t, Jˆ9.0 Hz, NCH2),
3.66 22H, t, Jˆ9.0 Hz, NCH2); dC 2CDCl3): 160.7, 153.9,
143.0, 134.1, 129.1, 128.4, 128.0, 117.7, 108.0, 66.7, 50.2,
47.2, 42.2; m/z 2EI): 251 2M1, 17%), 91 2100).
14. Huang, Z.-T.; Wang, M.-X. In The Chemistry of Enamines;
Rappoport, Z., Ed.; Wiley: New York, 1994; p 1303.
15. Huang, Z.-T.; Tsai, L.-H. Chem. Ber. 1986, 119, 2208.
16. Meyer, H.; Kurtz, J. Liebigs Ann. Chem. 1978, 1491.
17. Anderson, M. W.; Begley, M. J.; Jones, R. C. F. J. Chem. Soc.,
Perkin Trans. 1 1984, 2599.