The aza-ene reaction of heterocyclic ketene aminals with activated carbonyl compounds: A novel and efficient synthesis of γ-lactam-fused diazaheterocycles

Article abstract of DOI:10.1039/a808328b

Reactions of heterocyclic ketene aminals with activated carbonyl compounds are strongly influenced by the structure of the heterocycle moiety. Six-membered heterocyclic ketene aminals with or without an N-methyl group such as 3 and 4 underwent efficient addition and consecutive cyclocondensation reactions with diethyl oxomalonate 9 to produce γ-lactam-fused pyrimidine derivatives 10 and 11 in moderate to excellent yield. For the five-membered enediamines, however, those compounds without any N-substituent such as 6 underwent the same reaction slowly and no reaction at all was observed with N-methyl and N,N′-dimethyl-substituted analogs 7 and 8. Heterocyclic ketene aminals 3 also reacted with glyoxylic acid esters 17 to afford 8-aroyl-7-hydroxy-6-oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidines 18 in good yield. No asymmetric induction was found, however, when (1R,2S,5R)-(-)-menthyl glyoxylate 17b was employed as a chiral substrate. An aza-ene reaction mechanism involving heterocyclic ketene aminals as the aza-ene component (H-N-C=C) has been proposed. The effects of intramolecular hydrogen bonding and heterocyclic ring size on the reactivity are also discussed.

Full text of DOI:10.1039/a808328b

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The aza-ene reaction of heterocyclic ketene aminals with activated
carbonyl compounds: a novel and efficient synthesis of ã-lactam-
fused diazaheterocycles
Jian-Heng Zhang, Mei-Xiang Wang and Zhi-Tang Huang*
Institute of Chemistry, The Chinese Academy of Sciences, Beijing 100080, China
Received (in Cambridge) 27th October 1998, Accepted 7th December 1998
Reactions of heterocyclic ketene aminals with activated carbonyl compounds are strongly influenced by the structure
of the heterocycle moiety. Six-membered heterocyclic ketene aminals with or without an N-methyl group such as 3
and 4 underwent efficient addition and consecutive cyclocondensation reactions with diethyl oxomalonate 9 to
produce γ-lactam-fused pyrimidine derivatives 10 and 11 in moderate to excellent yield. For the five-membered
enediamines, however, those compounds without any N-substituent such as 6 underwent the same reaction slowly
and no reaction at all was observed with N-methyl and N,NЈ-dimethyl-substituted analogs 7 and 8. Heterocyclic
ketene aminals 3 also reacted with glyoxylic acid esters 17 to afford 8-aroyl-7-hydroxy-6-oxo-1,2,3,4,6,7-hexahydro-
pyrrolo[1,2-a]pyrimidines 18 in good yield. No asymmetric induction was found, however, when (1R,2S,5R)-(Ϫ)-
menthyl glyoxylate 17b was employed as a chiral substrate. An aza-ene reaction mechanism involving heterocyclic
ketene aminals as the aza-ene component (H–N–C᎐C) has been proposed. The effects of intramolecular hydrogen
᎐
bonding and heterocyclic ring size on the reactivity are also discussed.
Type I hetero-ene reactions, little is known of the ene reactions
Introduction
involving hetero-ene components, i.e. Type II and III hetero-ene
reactions. This is particularly true for hetero-ene systems con-
taining a heteroatom at the 2-position (X = Y = C, Z = hetero-
atom) (Scheme 1), with the exception of enols tautomerized
from the corresponding ketones, which have been reported to
undergo thermal intramolecular ene reactions (the Conia reac-
tion).5 This is not surprising, however, since hetero-ene com-
ponents such as secondary enamines exist predominantly in
their more stable tautomeric forms, as imines.6 Therefore they
usually act as the hetero-enophiles rather than the hetero-ene
components. Nevertheless, we believe that secondary enamines
or their imine tautomers would be the hetero-ene components
provided that the enamine–imine tautomerism shifts to the
enamine side. Moreover, the hetero-ene reactions of secondary
enamines would provide novel and valuable synthetic
approaches to imine intermediates, and to ketones, amines and
N-heterocycles, respectively, upon hydrolysis, reduction and
cyclization of the product imines.
Heterocyclic ketene aminals 3–8, also known as cyclic 1,1-
enediamines, are powerful and versatile building blocks for the
synthesis of various types of compounds that are difficult to
access by other synthetic methods.7 One of the notable features
of heterocyclic ketene aminals is the enhanced electron density
on the α-carbon leading to higher nucleophilicity than that
of nitrogen, owing to the conjugative effect of the electron-
donating amino groups and the electron-withdrawing substitu-
ents.8 Considerable effort has been made therefore during the
past decade to study enaminic reactions such as nucleophilic
addition9 and substitution10 with a variety of electrophiles and
even 1,3-dipoles.11 Most noticeably, however, heterocyclic
ketene aminals bearing a secondary amino moiety have been
shown recently to be a unique aza-ene component and to
undergo both Type II and III aza-ene reactions readily when
α,β-unsaturated carboxylic acid esters12 and ketones13 and the
activated azo compounds14 are used as carba- and hetero-
enophiles, respectively. To examine the scope and limitations of
this novel aza-ene component in organic synthesis, we have
explored the aza-ene reactions of heterocyclic ketene aminals
utilizing a wide range of enophiles. Herein we wish to report a
The ene reaction is defined as a σ-bond-forming reaction
between an ene component and an enophile with a concomitant
1,5-hydrogen shift and migration of the double bond1 (Scheme
1). According to the nature of the reactants, the ene reaction
has been divided into two categories. An “all-carbon” ene reac-
tion takes place between an olefin bearing an allylic hydrogen
atom (the carba-ene) and an activated alkene or alkyne (the
carba-enophile), and a hetero-ene reaction describes that taking
place between an ene and enophile, either of which contains at
least one heteroatom.2 The hetero-ene reaction can be further
categorised into three sub-types; Type I reactions describe the
interaction of all-carba-ene components with hetero-enophiles,
Type II reactions involve a hetero-ene component and an all-
carba enophile and Type III reactions include those occurring
between hetero-ene components and hetero-enophiles.
Due to its synthetic potential and its intriguing reaction
pathways in organic chemistry, the ene reaction has received
much attention since the first report in 1943.3 Great develop-
ments have been achieved in the past three decades. Both “all-
carbon” ene reactions and Type I hetero-ene reactions employ-
ing hetero-enophiles such as carbonyl and thiocarbonyl
compounds, imines, nitroso and azo compounds are well
documented and have often been utilized in the synthesis of
natural products. Most “all-carbon” ene reactions have been
shown to proceed by a concerted mechanism through a six-
membered cyclic transition state under thermal and catalytic
conditions. Hetero-ene and some Lewis-acid catalyzed ene reac-
tions can occur stepwise by way of a zwitterionic intermediate.4
In contrast to these extensively studied “all-carbon” ene and
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321

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Table 1 The reactions of heterocyclic ketene aminals 3, 4 and 6 with
diethyl oxomalonate 9
Type III aza-ene reaction of benzoyl-substituted heterocyclic
ketene aminals with activated carbonyl compounds.
Starting
materials
t/ha
Products
Yields (%)b
Results and discussion
In order to study the effect of the structure of the enediamine
on its addition to carbonyl compounds, heterocyclic ketene
aminals 3–8 were synthesized by the cyclocondensation of
ketene dithioacetals 1a–e and diamines 2 by a literature
method15 (Scheme 2). Among the products prepared, 1,3-
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
6a
6b
6c
6d
6e
2
2
2
2
2
5
5
5
5
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
91
92
92
81
82
31
58
62
47
41
41
42
53
30
51
5
48
48
48
48
48
a In 1,4-dioxane or acetonitrile. b Isolated yields.
strongly dependent upon the structure of the heterocycle
moiety of 3–8 (Scheme 2). As illustrated in Table 1, the six-
membered heterocyclic ketene aminals 3 underwent a rapid and
efficient reaction with 9 in both non-polar and polar solvents
such as 1,4-dioxane and acetonitrile at ambient temperature
to afford γ-lactam-fused pyrimidines 10. Reaction of mono-N-
methylated analogues 4 was also effective yielding the corre-
sponding products 11 in fairly good yield. However, when a
tertiary cyclic enediamine 5 was applied, reaction gave a com-
plicated mixture of inseparable products. Attempts were made
to optimize the reaction but no characterizable products were
yielded. In contrast to 3, heterocyclic ketene aminals 6 with an
imidazolidine ring were found to be much less reactive towards
9, the reaction being sluggish and taking two days to give a low
to moderate yield of pyrrolo[1,2-a]imidazole derivatives 12.
More significantly, N-methyl- and N,NЈ-dimethyl heterocyclic
ketene aminals 7 and 8 did not react at all with 9 and most
of the starting material was recovered even after a prolonged
reaction period.
The structures of all products 10–12 were established on the
basis of spectroscopic evidence and elemental analyses. Obser-
vation of an amide carbonyl signal around 170 ppm in the 13C-
NMR spectrum (Table 2) excludes the possible structure of
products such as 13 which might result from addition of the
secondary amino group of the heterocyclic ketene aminals to
the carbonyl of 9 followed by annulation of the enaminic
carbon to an ester group. If the product had the structure of 13,
the carbonyl of the pyrrolidin-3-one moiety would give a
carbon signal around 187 ppm.17 The lactam structure was also
supported by the infra-red spectrum in which an amide
carbonyl vibration band was evident around 1615–1645 cmϪ1
.
It should be noted that the methylene protons of the ester group
1
in 10–12 appeared as multiple signals in the H–NMR spec-
trum. This is because the ester group is attached to a chiral
center.18 Thus the methylene protons, being non-equivalent,
exhibit an AB-quartet which is further split by the adjacent
methyl hydrogens.
These results suggest that an unusual substituent effect oper-
ates during the reaction. Thus, with differently substituted
heterocyclic ketene aminals, reaction differed considerably. It
appears essential that the secondary amino group in the hetero-
cyclic ketene aminals add to the carbonyl compound, since the
N,NЈ-dimethylated cyclic enediamines did not react with 9.
However, the secondary amino group does not attack the
carbonyl group initially, only a C-adduct being produced as
evidenced by structural analyses. This indicates that the ‘effect-
Scheme 2
dimethyl-2-para-substituted benzoylmethylene hexahydropyri-
midines 5 are notable as they have not been reported before.
Their structure was confirmed by spectral data and micro-
analysis. It is worth noting that all these compounds show a
characteristic absorption band of a carbonyl group at νmax 1600
cmϪ1 in the infra-red spectrum. Such a large bathochromic shift
of the carbonyl group has been rationalized as the effect of a
strong conjugation system involving the nitrogen atoms, the
double bond and the electron-withdrawing benzoyl group.8
The first carbonyl reactant we chose in this study was diethyl
oxomalonate 9 as it is one of the most reactive and frequently
used hetero-enophiles.16 We found that heterocyclic ketene
aminals can react with it, the outcome of the reaction being
ive reaction unit’ is the secondary enamine moiety (H–N–C᎐C),
᎐
rather than the tertiary enamine. In other words, if the reaction
proceeded by way of the tertiary enamine, then N,NЈ-dimethyl-
322
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Table 2 13C NMR Data of compounds 10, 11, 12 and 18
Compound
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10 C-11 C-12 C-13 C-14 C-15 C-16 C-17
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
18a
18b
18c
18d
38.7 37.4 20.0
38.5 37.2 19.5
38.7 37.3 19.7
38.8 37.3 19.6
38.8 37.3 19.6
159.8 90.8 77.2 172.0 187.9 140.6 127.8 126.9 130.0
158.9 92.0 77.2 172.4 184.2 138.1 127.9 127.2 139.0 20.9
159.1 92.0 77.4 172.6 184.2 133.5 129.3 112.8 160.6 51.3
159.2 92.3 77.1 172.4 183.4 134.4 129.2 127.6 139.7
159.2 92.4 77.1 172.5 183.5 140.1 129.4 130.5 123.2
169.7 62.9
168.9 60.9
169.1 61.1
168.9 61.1
168.9 61.2
169.8 62.8
169.9 62.8
169.2 62.1
169.7 62.9
169.7 62.9
168.9 61.0
169.0 61.0
169.1 61.0
168.9 61.1
168.9 61.1
13.6
13.4
13.6
13.6
13.6
13.7
13.8
13.1
13.7
13.7
13.6
13.7
13.7
13.7
13.7
43.7 37.4 20.3 49.5 158.7 91.0 78.8 171.4 186.6 141.4 128.1 127.6 130.6
43.7 37.4 20.3 49.4 158.5 90.9 78.9 171.5 186.7 138.7 128.3 128.2 140.9 21.4
42.9 36.8 19.6 48.7 157.8 90.0 78.3 170.9 185.4 133.4 129.5 112.2 160.9 54.5
43.7 37.4 20.2 49.5 159.2 90.5 78.6 171.4 185.0 136.5 129.7 127.8 139.7
43.8 37.5 20.2 49.6 159.3 90.6 78.6 171.5 185.1 140.1 129.9 130.8 125.1
49.3 38.3
49.2 38.2
49.2 38.2
49.3 38.3
49.3 38.3
38.3 36.6 19.4
38.5 36.8 19.7
38.4 36.7 19.6
38.4 36.8 19.5
163.0 90.9 83.7 169.2 184.6 140.3 127.8 127.4 130.1
162.8 90.8 83.7 169.2 184.4 137.5 128.3 127.6 139.8 21.1
162.8 90.6 83.8 169.2 183.7 132.6 129.6 113.0 161.1 55.3
163.1 90.8 83.5 169.1 183.2 134.9 129.4 127.9 139.0
163.2 90.8 83.5 169.1 183.3 139.4 129.9 130.8 123.8
158.7 90.2 68.0 175.3 183.2 141.0 127.7 127.3 129.4
158.8 90.2 68.3 175.5 183.3 138.4 128.5 127.6 139.3 21.1
158.7 89.8 68.2 175.3 182.5 133.4 129.4 113.0 160.5 55.2
158.8 90.3 67.9 175.3 181.7 134.3 129.3 127.9 139.8
ated heterocyclic ketene aminals would give the desired add-
ition products. It is concluded therefore that the addition most
probably proceeds via an aza-ene reaction between the hetero-
cyclic ketene aminals 3, 4, 6 and diethyl oxomalonate 9.
The mechanism depicted in Scheme 3 can best interpret the
experimental facts. The aza-ene reaction between heterocyclic
ketene aminals 3, 4 and 6, and 9 forms an intermediate 15 which
undergoes a rapid imine–enamine tautomerization to give 16.
Intramolecular cyclocondensation of 16 leads to the formation
of final products 10–12. Without a secondary enamine moiety
(H–N–C᎐C) in the molecule, as in compounds 5 and 8, no
᎐
aza-addition was effected. The cyclocondensation step is much
faster than the first two steps since no intermediate 15 or 16 was
isolated. The great difference in reaction rate between 3 and
4 and between 6 and 7 may be attributed to the effect of intra-
molecular hydrogen bonds between carbonyl and secondary
amine moieties in 3, 4, 6 and 7. Intramolecular hydrogen bond
Scheme 3
should be stressed that although the six-membered heterocyclic
ketene aminals always show higher nucleophilic reactivity than
the five-membered analogs,9–14,17 the remarkable difference in
reaction velocity in this case is unexpected. A precise explan-
ation of the effect of the size of heterocycle on the reactivity is
formation decreases the aza-ene addition rate. A similar corre-
lation between hydrogen bonding and the rate of the aza-ene
reaction has been noted previously by us when heterocyclic
ketene aminals were allowed to react with ethyl propiolate.12 It
J. Chem. Soc., Perkin Trans. 1, 1999, 321–326
323

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Scheme 4
still open to debate, although we may ascribe this to the differ-
ence in conjugation systems between 3 and 6. In other words,
six-membered heterocyclic ketene aminals 3 may form a better
conjugation system involving amino nitrogens, double bond
and aroyl moieties because of their smaller ring strain. This
would lead to more extensive delocalization of the electrons
and a more concentrated electron density on the α-carbon than
its five-membered analogs, as evidenced by the fact that the
vinyl proton of 3 resonates at higher field than that of 6 in the
1H–NMR spectrum.8
analyses were carried out at the Analytical Laboratory of the
Institute.
Preparation of 1,3-dimethyl-2-[(4-substituted benzoyl)methyl-
ene]perhydropyrimidines 5
Mixtures of benzoyl-substituted ketene dithioacetals 1a,c,d and
N,NЈ-dimethylpropane-1,3-diamine 2 were refluxed in toluene
for 5–8 h to give 5a,c,d.15
2-Benzoylmethylene-1,3-dimethylperhydropyrimidine
5a.
The reaction of heterocyclic ketene aminals 3–8 with n-butyl
glyoxylate 17 was also investigated. Being a weaker hetero-
enophile compared to diethyl oxomalonate 9, compound 17
was only attacked by the most reactive heterocyclic ketene
aminal 3. Thus, under the identical conditions as for the reac-
tion of 3–8 with 9, compound 3 underwent an aza-ene addition
to 17a and a consecutive cyclocondensation reaction to produce
8-aroyl-7-hydroxy-6-oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]-
pyrimidine 18 (Scheme 4). As a chiral center was created during
the aza-ene addition, a chiral substrate (1R,2S,5R)-(Ϫ)-
menthyl glyoxylate 17b was then tested in order to prepare
optically active compounds 18. The reaction was equally effi-
cient, but unfortunately, no asymmetric induction was
observed. Glyoxylate 17b is probably not a good chiral reagent
in this case, since its chiral centers are remote from the aza-ene
reaction site. The structure of 18 has been proven by spectro-
Yield, 78%; mp 153–155 ЊC (Found: C, 73.32; H, 7.52; N, 12.11.
C14H18N2O requires C, 73.01; H, 7.88; N, 12.17%); νmax(KBr)/
cmϪ1 1590; δH(CDCl3) 7.86 (2H, m, ArH), 7.34 (3H, m, ArH),
4.82 (1H, s, ᎐CH–), 3.32 (4H, t, J 5.1, 2 × CH ), 3.14 (6H, s,
᎐
2
2 × NCH3) and 2.04 (2H, quintet, J 5.1, CH2); m/z (EI) 230
(Mϩ, 68%), 213 (100), 202 (23), 153 (50), 125 (69) and 105 (48).
1,3-Dimethyl-2-[(4-methoxybenzoyl)methylene]perhydropyri-
midine 5c. Yield, 73%; mp 114–116 ЊC (Found: C, 68.83; H,
7.33; N, 10.53. C15H20N2O2 requires C, 69.20; H, 7.75; N,
10.76%); νmax(KBr)/cmϪ1 1590; δH(CDCl3) 7.84 (2H, d, J 8.9,
ArH), 6.88 (2H, d, J 8.9, ArH), 4.80 (1H, s, ᎐CH–), 3.82 (3H, s,
᎐
OCH3), 3.30 (4H, t, J 5.2, 2 × CH2), 3.12 (6H, s, 2 × NCH3) and
2.02 (2H, quintet, J 5.2, CH2); m/z (EI) 260 (Mϩ, 69%), 243
(100), 232 (19), 153 (28), 135 (48) and 125 (78).
1
scopic data and microanalyses. Interestingly in the H NMR
2-[(4-Chlorobenzoyl)methylene]-1,3-dimethylperhydropyrimid-
ine 5d. Yield, 68%; mp 44–46 ЊC (Found: Mϩ ϩ 1 (FAB)
265.1108. C14H18ClN2O requires 265.1102); νmax(KBr)/cmϪ1
1590; δH(CDCl3) 7.80 (2H, d, J 6.6, ArH), 7.32 (2H, d, J 6.9,
spectrum, the signal of the proton at the 7-position appears as
a pseudo-triplet while its adjacent hydroxy proton appears as
a doublet (J ~ 8 Hz). After treating the sample with D2O,
the former signal becomes a singlet and the hydroxy signal
disappears. Also to disappear is the secondary amino proton
which had been observed as a broad peak around 10 ppm.
Apparently, the proton at the 7-position couples with the
hydroxy proton, and furthermore is also probably correlated
with the amino proton through a long range ‘zig zag’ coupling.
In conclusion, heterocyclic ketene aminals are good aza-ene
components and undergo Type III hetero-ene reactions readily
and efficiently with activated carbonyl compounds. By the reac-
tion of 3, 4 and 6 with diethyl oxomalonate 9 and glyoxalic acid
esters 17, we have provided a novel and efficient synthetic route
to γ-lactam-fused diazaheterocycles.
ArH), 4.76 (1H, s, ᎐CH–), 3.32 (4H, t, J 5.3, 2 × CH ), 3.14
᎐
2
(6H, s, 2 × NCH3) and 2.04 (2H, quintet, J 5.3, CH2); m/z (EI)
264 (Mϩ, 53%), 247 (91), 236 (24), 153 (45), 139 (45) and 125
(100).
General procedure for the preparation of pyrrolo[1,2-a]pyrimid-
ine derivatives 10a–e, 11a–e and pyrrolo[1,2-a]imidazole
derivatives 12a–e
To a solution of heterocyclic ketene aminals 3a–e, 4a–e, 6a–e (3
mmol) in 1,4-dioxane or acetonitrile (20 cm3) was added drop-
wise diethyl 2-oxomalonate 919 (3.5 mmol). The mixture was
stirred at room temperature under argon and the reaction was
monitored by TLC. Product 10a–e precipitated directly from
the mixture while 11a–e and 12a–e were obtained after removal
of solvent under vacuum. Recrystallization from the appropri-
ate solvent gave pure 10, 11 and 12.
Experimental
Melting points, which are uncorrected, were determined using a
Reichert Kofler hot-stage apparatus. Infrared spectra were
obtained on a Perkin-Elmer 782 instrument as KBr discs or
liquid films. NMR spectra were recorded in CDCl3 or [2H6]-
DMSO solution with SiMe4 as internal standard on a Varian
Unity 200 spectrometer. Chemical shifts are reported in ppm
while the coupling constant J values are in Hz. Mass spectra
were measured on a AEI MS-50 mass spectrometer and micro-
8-Benzoyl-7-ethoxycarbonyl-7-hydroxy-6-oxo-1,2,3,4,6,7-
hexahydropyrrolo[1,2-a]pyrimidine 10a. Mp 190–192 ЊC (abso-
lute ethanol) (Found: C, 61.84; H, 5.61; N, 8.55. C17H18N2O5
requires C, 61.81; H, 5.49; N, 8.48%); νmax(KBr)/cmϪ1 3340,
3200 (OH, NH), 1760, 1735 and 1640 (C᎐O); δ (CDCl ) 10.30
᎐
H
3
324
J. Chem. Soc., Perkin Trans. 1, 1999, 321–326

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(1H, s, NH), 7.30–7.73 (5H, m, ArH), 4.36 (1H, s, OH), 3.80–
3.96 (2H, m, CH2), 3.68 (2H, t, J 5.9, CH2), 3.56 (2H, t, J 5.9,
CH2), 2.14 (2H, quintet, J 5.9, CH2) and 0.88 (3H, t, J 10.7,
CH3); m/z (EI) 330 (Mϩ, 8%), 312 (50), 283 (10), 266 (23) and
257 (100).
δH(CDCl3) 7.62 (2H, d, J 8.0, ArH), 7.15 (2H, d, J 8.0, ArH),
4.38 (1H, s, OH), 3.80–4.00 (3H, m, CH2, CHH), 3.30–3.65
(3H, m, CHH, CH2), 3.15 (1H, s, NCH3), 2.35 (3H, s, CH3),
2.15 (2H, quintet, J 5.1, CH2) and 1.10 (3H, t, J 7.4, CH3);
m/z (EI) 358 (Mϩ, 2%), 342 (3), 285 (38), 269 (25), 193 (26), 151
(16), 136 (64), 119 (87) and 91 (100).
7-Ethoxycarbonyl-7-hydroxy-8-(4-methylbenzoyl)-6-oxo-1,2,
3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 10b. Mp 203–205 ЊC
(absolute ethanol and acetonitrile) (Found: C, 62.74; H, 6.00;
N, 8.25. C18H20N2O5 requires C, 62.78; H, 5.85; N, 8.14%);
νmax(KBr)/cmϪ1 3340, 3200 (OH, NH), 1760, 1735 and 1640
7-Ethoxycarbonyl-7-hydroxy-1-methyl-8-(4-methoxybenzoyl)-
6-oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 11c. Mp
135–137 ЊC (ethyl acetate and ethanol) (Found: C, 60.92; H,
5.87; N, 7.45. C19H22N2O6 requires C, 60.95; H, 5.92; N, 7.48%);
(C᎐O); δ ([2H ]DMSO) 10.20 (1H, s, NH), 7.66 (2H, d, J 10.7,
νmax(KBr)/cmϪ1 3370 (OH), 1735, 1710 and 1625 (C᎐O);
᎐
᎐
H
6
ArH), 7.12 (2H, d, J 10.7, ArH), 6.68 (1H, s, OH), 3.60–3.90
(2H, m, CH2), 3.58 (2H, t, J 6.8, CH2), 3.46 (2H, t, J 6.8, CH2),
2.28 (3H, s, CH3), 1.96 (2H, quintet, J 6.8, CH2) and 0.70 (3H, t,
J 8.5, CH3); m/z (EI) 344 (Mϩ, 9%), 326 (42), 297 (8), 280 (33),
271 (74), 255 (38), 243 (17) and 179 (100).
δH(CDCl3) 7.72 (2H, d, J 8.4, ArH), 6.84 (2H, d, J 8.4, ArH),
4.40 (1H, s, OH), 3.80–4.00 (3H, m, CH2, CHH), 3.82 (3H, s,
OCH3), 3.30–3.65 (3H, m, CHH, CH2), 3.15 (1H, s, NCH3),
2.15 (2H, quintet, J 4.5, CH2) and 1.08 (3H, t, J 6.6, CH3);
m/z (EI) 374 (Mϩ, 3%), 358 (4), 301 (13), 285 (23), 193 (43), 152
(76) and 135 (100).
7-Ethoxycarbonyl-7-hydroxy-8-(4-methoxybenzoyl)-6-oxo-
1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 10c. Mp 196–
198 ЊC (absolute ethanol and acetonitrile) (Found: C, 60.07; H,
5.57; N, 7.72. C18H20N2O6 requires C, 59.96; H, 5.59; N, 7.78%);
νmax(KBr)/cmϪ1 3330, 3200 (OH, NH), 1760, 1735 and 1645
8-(4-Chlorobenzoyl)-7-ethoxycarbonyl-7-hydroxy-1-methyl-6-
oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 11d. Mp
136–138 ЊC (ethyl acetate and ethanol) (Found: C, 56.98; H,
4.97; N, 7.40. C18H19ClN2O5 requires C, 57.07; H, 5.06; N,
7.40%); νmax(KBr)/cmϪ1 3400 (OH), 1760, 1740 and 1615
(C᎐O); δ ([2H ]DMSO) 10.24 (1H, s, NH), 7.82 (2H, d, J 9.0,
᎐
H
6
ArH), 6.84 (2H, d, J 9.0, ArH), 6.74 (1H, s, OH), 3.60–3.90
(2H, m, CH2), 3.76 (3H, s, OCH3), 3.58 (2H, t, J 4.8, CH2), 3.48
(2H, t, J 4.8, CH2), 1.96 (2H, quintet, J 4.8, CH2) and 0.70 (3H,
t, J 8.5, CH3); m/z (EI) 360 (Mϩ, 8%), 342 (42), 296 (29), 287
(37), 271 (35), 179 (91) and 135 (100).
(C᎐O); δ (CDCl ) 7.68 (2H, d, J 8.4, ArH), 7.30 (2H, d, J 8.4,
᎐
H 3
ArH), 4.34 (1H, s, OH), 3.80–4.00 (3H, m, CH2, CHH), 3.30–
3.65 (3H, m, CHH, CH2), 3.20 (1H, s, NCH3), 2.15 (2H, quin-
tet, J 4.9, CH2) and 1.08 (3H, t, J 7.1, CH3); m/z (EI) 378 (Mϩ,
1%), 362 (2), 205 (19), 289 (16), 193 (13), 156 (60) and 139 (100).
8-(4-Chlorobenzoyl)-7-ethoxycarbonyl-7-hydroxy-6-oxo-1,2,3,
4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 10d. Mp 202–204 ЊC
(absolute ethanol and acetonitrile) (Found: C, 56.01; H, 4.87;
N, 7.92. C17H17ClN2O5 requires C, 55.97; H, 4.70; N, 7.68%);
νmax(KBr)/cmϪ1 3350, 3320 (OH, NH), 1760, 1735 and 1640
8-(4-Bromobenzoyl)-7-ethoxycarbonyl-7-hydroxy-1-methyl-6-
oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 11e. Mp
133–135 ЊC (ethyl acetate) (Found: C, 51.38; H, 4.45; N, 6.60.
C18H19BrN2O5 requires C, 51.08; H, 4.52; N, 6.62%); νmax(KBr)/
cmϪ1 3400 (OH), 1760, 1740 and 1615 (C᎐O); δ (CDCl ) 7.60
᎐
H
3
(C᎐O); δ ([2H ]DMSO) 10.16 (1H, s, NH), 7.76 (2H, d, J 9.0,
(2H, d, J 8.4, ArH), 7.46 (2H, d, J 8.4, ArH), 4.35 (1H, s, OH),
3.80–4.00 (3H, m, CH2, CHH), 3.30–3.65 (3H, m, CHH, CH2),
3.22 (1H, s, NCH3), 2.15 (2H, quintet, J 5.0, CH2) and 1.08 (3H,
t, J 5.3, CH3); m/z (EI) 424 (2%), 422 (Mϩ, 2), 406 (2), 349 (19),
333 (15), 200 (78), 193 (17) and 183 (100).
᎐
H
6
ArH), 7.38 (2H, d, J 8.7, ArH), 6.78 (1H, s, OH), 3.60–3.90
(2H, m, CH2), 3.58 (2H, t, J 8.3, CH2), 3.48 (2H, t, J 8.3, CH2),
1.98 (2H, quintet, J 8.3, CH2) and 0.75 (3H, t, J 5.1, CH3);
m/z (EI) 366 ([M ϩ 2]ϩ, 3%), 364 (Mϩ, 9), 346 (37), 291 (80),
275 (47) and 179 (100).
7-Benzoyl-6-ethoxycarbonyl-6-hydroxy-5-oxo-2,3,5,6-tetra-
hydro-1H-pyrrolo[1,2-a]imidazole 12a. Mp 201-203 ЊC (abso-
lute ethanol and acetonitrile) (Found: C, 60.72; H, 5.00; N,
8.78. C16H16N2O5 requires C, 60.75; H, 5.10; N, 8.86%);
νmax(KBr)/cmϪ1 3340, 3280 (OH, NH), 1760, 1735 and 1660
8-(4-Bromobenzoyl)-7-ethoxycarbonyl-7-hydroxy-6-oxo-1,2,3,
4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 10e. Mp 203-205 ЊC
(absolute ethanol and acetonitrile) (Found: C, 49.80; H, 4.40;
N, 6.88. C17H17BrN2O5 requires C, 49.89; H, 4.19; N, 6.85%);
νmax(KBr)/cmϪ1 3340, 3200 (OH, NH), 1760, 1735 and 1640
(C᎐O); δ ([2H ]DMSO) 9.10 (1H, br. s, NH), 7.25–7.75 (5H, m,
᎐
H
6
(C᎐O); δ ([2H ]DMSO) 10.16 (1H, s, NH), 7.68 (2H, d, J 8.9,
ArH), 6.70 (1H, s, OH), 4.00 (2H, t, J 5.9, CH2), 3.60–3.90 (4H,
m, 2 × CH2) and 0.70 (3H, t, J 5.9, CH3); m/z (EI) 316 (Mϩ,
3%), 298 (18), 243 (66), 225 (8), 215 (27), 165 (14) and 105 (100).
᎐
H
6
ArH), 7.50 (2H, d, J 8.3, ArH), 6.78 (1H, s, OH), 3.60–3.90
(2H, m, CH2), 3.58 (2H, t, J 6.9, CH2), 3.46 (2H, t, J 6.9, CH2),
1.96 (2H, quintet, J 6.9, CH2) and 0.72 (3H, t, J 5.1, CH3);
m/z (EI) 410 ([M ϩ 2]ϩ, 6%), 408 (Mϩ, 6), 390 (29), 346 (16),
335 (66), 319 (44), 183 (51) and 179 (100).
6-Ethoxycarbonyl-6-hydroxy-7-(4-methylbenzoyl)-5-oxo-2,3,
5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazole 12b. Mp 203–205 ЊC
(absolute ethanol and acetonitrile) (Found: C, 61.71; H, 5.64;
N, 8.68. C17H18N2O5 requires C, 61.81; H, 5.49; N, 8.48%);
νmax(KBr)/cmϪ1 3350, 3290 (OH, NH), 1755, 1730 and 1655
8-Benzoyl-7-ethoxycarbonyl-7-hydroxy-1-methyl-6-oxo-1,2,3,
4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 11a. Mp 133–135 ЊC
(ethyl acetate) (Found: C, 62.49; H, 5.76; N, 8.09. C18H20N2O5
requires C, 62.78; H, 5.85; N, 8.14%); νmax(KBr)/cmϪ1 3320
(C᎐O); δ ([2H ]DMSO) 9.10 (1H, br s, NH), 7.68 (2H, d, J 8.0,
᎐
H
6
ArH), 7.14 (2H, d, J 8.0, ArH), 6.70 (1H, s, OH), 4.02 (2H, t,
J 7.6, CH2), 3.70–3.95 (4H, m, 2 × CH2), 2.32 (3H, s, CH3) and
0.78 (3H, t, J 5.1, CH3); m/z (EI) 330 (Mϩ, 3%), 312 (20), 257
(45), 229 (16), 165 (38) and 119 (100).
(OH), 1745, 1710 and 1625 (C᎐O); δ (CDCl ) 7.30–7.75 (5H,
᎐
H
3
m, ArH), 4.36 (1H, s, OH), 3.80–4.00 (3H, m, CH2, CHH),
3.30–3.65 (3H, m, CHH, CH2), 3.18 (1H, s, NCH3), 2.16 (2H,
quintet, J 4.8, CH2) and 1.10 (3H, t, J 7.6, CH3); m/z (EI) 344
(Mϩ, 2%), 271 (16), 255 (22), 193 (11), 151 (10), 122 (65) and
105 (100).
6-Ethoxycarbonyl-6-hydroxy-7-(4-methoxybenzoyl)-5-oxo-2,3,
5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazole 12c. Mp 192–194 ЊC
(absolute ethanol and acetonitrile) (Found: C, 58.82; H, 5.36;
N, 7.99. C17H18N2O6 requires C, 58.95; H, 5.24; N, 8.09%);
νmax(KBr)/cmϪ1 3340, 3280 (OH, NH), 1750, 1720 and 1650
7-Ethoxycarbonyl-7-hydroxy-1-methyl-8-(4-methylbenzoyl)-6-
oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidine 11b. Mp
146–148 ЊC (ethyl acetate and ethanol) (Found: C, 63.65; H,
6.13; N, 7.84. C19H22N2O5 requires C, 63.67; H, 6.19; N, 7.82%);
(C᎐O); δ ([2H ]DMSO) 9.10 (1H, br s, NH), 7.84 (2H, d, J 8.4,
᎐
H
6
ArH), 6.90 (2H, d, J 8.4, ArH), 6.76 (1H, s, OH), 4.04 (2H, t,
J 7.6, CH2), 3.70–3.95 (4H, m, 2 × CH2), 3.80 (3H, s, OCH3)
νmax(KBr)/cmϪ1 3380 (OH), 1755, 1740 and 1615 (C᎐O);
᎐
J. Chem. Soc., Perkin Trans. 1, 1999, 321–326
325

View Article Online
and 0.80 (3H, t, J 6.3, CH3); m/z (EI) 346 (Mϩ, 2%), 328 (22),
273 (17), 255 (11), 165 (37) and 135 (100).
(ethanol) (Found: C, 57.70; H, 4.63; N, 9.54. C14H13ClN2O3
requires C, 57.44; H, 4.48; N, 9.57%); νmax(KBr)/ cmϪ1 3360,
3210 (OH, NH), 1765 and 1640 (C᎐O); δ ([2H ]DMSO) 10.04
᎐
H
6
7-(4-Chlorobenzoyl)-6-ethoxycarbonyl-6-hydroxy-5-oxo-2,3,5,
6-tetrahydro-1H-pyrrolo[1,2-a]imidazole 12d. Mp 205–207 ЊC
(absolute ethanol and acetonitrile) (Found: C, 54.99; H, 4.66;
N, 7.95. C16H15ClN2O5 requires C, 54.78; H, 4.31; N, 7.99%);
νmax(KBr)/cmϪ1 3340, 3285 (OH, NH), 1750, 1725 and 1650
(1H, br s, NH), 7.88 (2H, d, J 9.6, ArH), 7.44 (2H, d, J 8.9,
ArH), 5.82 (1H, d, J 8.3, OH), 4.80 (1H, s, CH), 3.38–3.57
(4H, m, 2 × CH2) and 1.94 (2H, quintet, J 6.2, CH2); δH([2H6]-
DMSO ϩ D2O) 7.76 (2H, d, J 8.0, ArH), 7.47 (2H, d, J 8.0,
ArH), 4.88 (1H, s, CH), 3.34–3.60 (4H, m, 2 × CH2) and 1.97
(2H, quintet, J 6.2, CH2); m/z (EI) 294 ([Mϩ ϩ 2], 2%), 292
(Mϩ, 5), 274 (100), 245 (25), 218 (56) and 211 (59).
(C᎐O); δ ([2H ]DMSO) 9.10 (1H, br s, NH), 7.68 (2H, d, J 9.1,
᎐
H
6
ArH), 7.40 (2H, d, J 9.1, ArH), 6.84 (1H, s, OH), 4.05 (2H, t,
J 6.3, CH2), 3.70–3.95 (4H, m, 2 × CH2) and 0.80 (3H, t, J 6.5,
CH3); m/z (EI) 350 (Mϩ, 3%), 332 (22), 277 (64), 259 (12), 249
(21), 165 (34) and 139 (100).
Acknowledgements
We thank the National Natural Science Foundation of China
for the financial support.
7-(4-Bromobenzoyl)-6-ethoxycarbonyl-6-hydroxy-5-oxo-2,3,5,
6-tetrahydro-1H-pyrrolo[1,2-a]imidazole 12e. Mp 203–205 ЊC
(absolute ethanol and acetonitrile) (Found: C, 48.79; H, 4.25;
N, 7.03. C16H15BrN2O5 requires C, 48.62; H, 3.83; N, 7.09%);
νmax(KBr)/cmϪ1 3300, 3290 (OH, NH), 1750, 1720 and 1650
References
1 For reviews see, H. M. R. Hoffmman, Angew. Chem., Int. Ed. Engl.,
1969, 8, 556; G. V. Boyd, in The Chemistry of Double-Bonded
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part 1, p. 477; B. B. Snider, in Comprehensive Organic Synthesis,
ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 5, p. 1.
2 J. E. Baldwin, R. M. Adlington, A. U. Jain, J. N. Kolhe and M. W. D.
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Chem., Int. Ed. Engl., 1964, 3, 693; R. M. Borzilleri and S. M.
Weinreb, Synthesis, 1995, 347; J. Cossy, A. Bouzide and M. Pfau,
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3 K. Alder, F. Pascher and A. Schmitz, Chem. Ber., 1943, 76, 27.
4 B. B. Snider, Acc. Chem. Res., 1980, 13, 426.
5 J. M. Conia and P. Le Perchec, Synthesis, 1975, 1.
6 Z.-T. Huang and M.-X. Wang, in The Chemistry of Enamines, ed,
Z. Rappoport, Wiley, New York, 1994, p. 889.
7 For a review see, Z.-T. Huang and M.-X. Wang, Heterocycles, 1994,
37, 1233.
8 M.-X. Wang, J.-M. Liang and Z.-T. Huang, J. Chem. Res. (S), 1994,
166; J. Chem. Res. (M), 1994, 1001.
9 For recent examples see, R. C. F. Jones, P. Patel, S. C. Hirst and
M. J. Smallridge, Tetrahedron, 1998, 54, 6191; R. C. F. Jones and
M. J. Smallridge, Tetrahedron Lett., 1988, 29, 5005; Z.-T. Huang and
Z.-R. Liu, Heterocycles, 1986, 24, 2247; Z.-T. Huang and L.-H. Tzai,
Chem. Ber., 1986, 119, 2208; A. K. Gupta, H. Ila and H. Junjapa,
Synthesis, 1988, 285; Z.-T. Huang and H. Wamhoff, Chem. Ber.,
1984, 117, 1856; Z.-T. Huang and X.-J. Wang, Tetrahedron Lett.,
1987, 28, 1527.
10 R. C. F. Jones, P. Patel, S. C. Hirst and I. Turner, Tetrahedron, 1997,
53, 11781; M.-X. Wang and Z.-T. Huang, J. Org. Chem., 1995, 60,
2807; Z.-T. Huang and Z.-R. Liu, Chem. Ber., 1989, 122, 95.
11 Z.-T. Huang and M.-X. Wang, J. Org. Chem., 1992, 57, 184 and
references therein.
12 Z.-T. Huang and M.-X. Wang, J. Chem. Soc., Perkin Trans. 1, 1993,
1085.
13 J.-H. Zhang, M.-X. Wang and Z.-T. Huang, Tetrahedron Lett., 1998,
39, 9237.
14 J.-H. Zhang, M.-X. Wang and Z.-T. Huang, J. Chem. Res. (S), 1998,
486.
(C᎐O); δ ([2H ]DMSO) 9.10 (1H, br s, NH), 7.72 (2H, d, J 6.4,
᎐
H
6
ArH), 7.56 (2H, d, J 6.4, ArH), 6.84 (1H, s, OH), 4.06 (2H, t,
J 6.7, CH2), 3.70–3.95 (4H, m, 2 × CH2) and 0.80 (3H, t, J 6.4,
CH3); m/z (EI) 396 (4%), 394 (Mϩ, 3), 376 (33), 348 (9), 321 (88),
305 (22), 393 (16) and 183 (100).
General procedure for the preparation of pyrrolo[1,2-a]-
pyrimidines 18a–d. A mixture of heterocyclic ketene aminals
3a–d (3 mmol) and n-butyl glyoxylate 17a20 (3.5 mmol) or
(1R,2S,5R)-(Ϫ)-menthyl glyoxylate 17b21 (3.5 mmol) in 1,4-
dioxane (20 cm3) was stirred at room temperature for 24 h. The
crude products precipitated after partial removal of the solvent
under reduced pressure. Recrystallization from the appropriate
solvent gave pure 18a–d.
8-Benzoyl-7-hydroxy-6-oxo-1,2,3,4,6,7-hexahydropyrrolo-
[1,2-a]pyrimidine 18a. Yield, 91%; mp 155–157 ЊC (ethanol and
acetonitrile) (Found: C, 65.10; H, 5.65; N, 10.78. C14H14N2O3
requires C, 65.10; H, 5.46; N, 10.85%); νmax(KBr)/ cmϪ1 3400,
3200 (OH, NH), 1755 and 1645 (C᎐O); δ ([2H ]DMSO) 10.06
᎐
H
6
(1H, br s, NH), 7.30–7.88 (5H, m, ArH), 5.78 (1H, d, J 7.9,
OH), 4.75 (1H, t, J 5.1, CH), 3.39–3.57 (4H, m, 2 × CH2) and
1.94 (2H, quintet, J 5.6, CH2); m/z (EI) 258 (Mϩ, 2%), 240
(100), 211 (42) and 183 (47).
7-Hydroxy-8-(4-methylbenzoyl)-6-oxo-1,2,3,4,6,7-hexahydro-
pyrrolo[1,2-a]pyrimidine 18b. Yield, 55%; mp 167–169 ЊC (ethyl
acetate and ethanol) (Found: C, 65.86; H, 6.04; N, 10.11.
C15H16N2O3 requires C, 66.16; H, 5.92; N, 10.29%); νmax(KBr)/
cmϪ1 3400, 3200 (OH, NH), 1750 and 1635 (C᎐O); δ ([2H ]-
᎐
H
6
DMSO) 10.06 (1H, br s, NH), 7.78 (2H, d, J 6.8, ArH), 7.18
(2H, d, J 6.8, ArH), 5.78 (1H, d, J 7.6, OH), 4.79 (1H, t, J 4.6,
CH), 3.38–3.52 (4H, m, 2 × CH2), 2.32 (3H, s, CH3) and 1.92
(2H, quintet, J 6.7, CH2); m/z (EI) 272 (Mϩ, 2%), 254 (100), 225
(24), 211 (22) and 197 (21).
15 Z.-T. Huang and Z.-R. Liu, Synth. Commun., 1989, 19, 943.
16 For a review see, B. B. Snider, in Comprehensive Organic Synthesis,
ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 2,
p. 527.
17 L.-B. Wang, C.-Y. Yu and Z.-T. Huang, Synthesis, 1994, 1441.
18 D. Nasipuri, Stereochemistry of Organic Compounds, Principles and
Applications, Wiley, New York, 1991, pp. 123–134.
7-Hydroxy-8-(4-methoxybenzoyl)-6-oxo-1,2,3,4,6,7-hexa-
hydropyrrolo[1,2-a]pyrimidine 18c. Yield, 78%; mp 153–155 ЊC
(ethanol and acetonitrile) (Found: C, 62.58; H, 5.58; N, 9.75.
C15H16N2O4 requires C, 62.49; H, 5.59; N, 9.72%); νmax(KBr)/
cmϪ1 3340, 3190 (OH, NH), 1760 and 1635 (C᎐O); δ ([2H ]-
᎐
H
6
DMSO) 10.10 (1H, br s, NH), 7.90 (2H, d, J 6.4, ArH), 6.90
(2H, d, J 6.7, ArH), 5.80 (1H, d, J 8.0, OH), 4.79 (1H, t, J 4.0,
CH), 3.80 (3H, s, OCH3), 3.36–3.55 (4H, m, 2 × CH2) and 1.94
(2H, quintet, J 5.1, CH2); m/z (EI) 288 (Mϩ, 1%), 271 (64), 244
(42), 137 (87) and 135 (100).
19 S. N. Pardo and R. G. Salomon, J. Org. Chem., 1981, 46, 2598;
J. Faust and R. Mayer, Synthesis, 1976, 411.
20 F. J. Wolf and J. Weijlard, Org. Synth., 1963, Coll. Vol. 4, 124.
21 J. Jurczak and A. Zamojski, Rocz. Chem., 1970, 44, 2257 (Chem.
Abstr., 1971, 74, 140858p).
8-(4-Chlorobenzoyl)-7-hydroxy-6-oxo-1,2,3,4,6,7-hexahydro-
pyrrolo[1,2-a]pyrimidine 18d. Yield, 49%; mp 156–158 ЊC
Paper 8/08328B
326
J. Chem. Soc., Perkin Trans. 1, 1999, 321–326