Synthesis of imidazo[1,2-α]pyridines from unactivated 2-alkyl-4,5-dihydroimidazoles through conjugate N-addition

Article abstract of DOI:10.1039/b001830i

2-Alkyl-4,5-dihydroimidazoles undergo annulation with α,β-unsaturated aldehydes and ketones via conjugate addition of the N-1 nitrogen atom and subsequent enamine-aldol condensation of C(α) to form imidazo[1,2-α]pyridines having reversed regiochemistry of annulation from that observed with a dihydroimidazole carrying an activating group at C(α); annulation with β-ketoesters also affords imidazo[1,2-α]pyridines, but now with the same regiochemistry as found with a C(α)-activated dihydroimidazole and necessitating a revision of earlier reported structures. Dialkyl acetylenedicarboxylates undergo conjugate N-addition but act as 1,2- rather than 1,3-bis-electrophiles to form pyrrolo[1,2-α]imidazoles. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b001830i

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Synthesis of imidazo[1,2-a]pyridines from unactivated 2-alkyl-4,5-
dihydroimidazoles through conjugate N-addition
Raymond C. F. Jones,*a Paschalis Dimopoulos,b Simon C. Coles,c Mark E. Lightc and
Michael B. Hursthousec
1
a Department of Chemistry, Loughborough University, Loughborough, Leics., UK LE11 3TU
b Chemistry Department, The Open University, Walton Hall, Milton Keynes, UK MK7 6AA
c EPSRC National Crystallography Service, Department of Chemistry,
University of Southampton, Highfield, Southampton, UK SO17 1BJ
Received (in Cambridge, UK) 7th March 2000, Accepted 23rd May 2000
Published on the Web 30th June 2000
2-Alkyl-4,5-dihydroimidazoles undergo annulation with α,β-unsaturated aldehydes and ketones via conjugate
addition of the N-1 nitrogen atom and subsequent enamine–aldol condensation of C(α) to form imidazo[1,2-a]-
pyridines having reversed regiochemistry of annulation from that observed with a dihydroimidazole carrying an
activating group at C(α); annulation with β-ketoesters also affords imidazo[1,2-a]pyridines, but now with the same
regiochemistry as found with a C(α)-activated dihydroimidazole and necessitating a revision of earlier reported
structures. Dialkyl acetylenedicarboxylates undergo conjugate N-addition but act as 1,2- rather than 1,3-bis-
electrophiles to form pyrrolo[1,2-a]imidazoles.
and we report now on the facile annulation of 1 (R1 = H) with
Introduction
enals and enones that shows opposite regiochemistry to the
above examples, and is now controlled by conjugate N-addition.
With β-ketoesters as electrophiles, the major products found
from enaminoester 2 are again imidazopyridin-5-ones, now 5,
4,5-Dihydroimidazoles (2-imidazolines) and annulated deriv-
atives display a range of pharmacological properties,1 for
example in interactions with adrenoreceptors.2 We have a pro-
gramme to exploit the potential for nucleophilic reactivity at
C(α)3 and N-14 of 4,5-dihydroimidazoles 1, and have reported
on annulations of the enaminoester 2.5,6 This enaminoester is
and we have proposed that a conjugate addition mechanism via
the enol of the ketoester applies also in these cases.5 We report
now that annulation of 1 (R1 = H) also occurs with β-ketoesters
but to again afford imidazo[1,2-a]pyridin-5-ones, i.e. now with
the same regiochemistry as for enaminoester 2. This is in
contrast with an earlier report, necessitating revision of the
structures therein.10
Results and discussion
In an attempt to prepare dienamine 6, Scheme 1, the 2-(but-3-
enyl)-4,5-dihydroimidazole 7b was heated with but-2-enal in
toluene at reflux, under Dean–Stark conditions for water
removal. No dienamine was observed; instead the tetrahydro-
imidazo[1,2-a]pyridine 8b was isolated (36%). This was
repeated with a range of 2-alkyl-4,5-dihydroimidazoles 7a–e,
namely 2-butyl, 2-(but-3-enyl), 2-(2-phenylethyl), 2-(2-bi-
phenyl-2-ylethyl) and 2-benzyl. The α,β-unsaturated carbonyl
components were the aldehydes but-2-enal, pent-2-enal and
3-phenylpropenal, and the ketones but-3-en-2-one and pent-3-
en-2-one, to produce imidazopyridines 8a–n, Scheme 1 and
Table 1, in some cases in good yields.
tautomeric with, and can be regarded as, a 4,5-dihydroimid-
azole carrying the activating ethoxycarbonyl group at C(α).
With α,β-unsaturated aldehydes and ketones, the reactivity of
enaminoester 2 is dominated by conjugate addition of the
enamine C(α) carbon atom.7 α,β-Enals afford imidazo[1,2-a]-
pyridines 3;5 enones give the Michael adducts but do not pro-
ceed to cyclisation.8 The same regiochemistry is observed in
reactions of enaminoester 2 with α,β-unsaturated acid deriv-
atives, namely esters, acid chlorides and imidazolides, to give
imidazo[1,2-a]pyridin-5-ones 4, although in the latter cases it is
likely that N-acylation precedes the conjugate C-addition.5,9
The annulation potential of simple 2-alkyl-4,5-dihydroimid-
azoles 1 (R1 = H), unactivated at C(α), has been little exploited,
The structures of bicycles 8 are supported by their 1H and 13
C
NMR spectra; for example, 8a shows signals consistent with the
C᎐CH and CH –CH fragments, that would not be present in
᎐
3
DOI: 10.1039/b001830i
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342
This journal is © The Royal Society of Chemistry 2000
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Scheme 1
Table 1 Annulation of 4,5-dihydroimidazoles 7 with α,β-unsaturated aldehydes and ketones (Scheme 1)
Imidazo[1,2-a]-
pyridine 8
(yield %)
Imidazoline
7
R1
R2
R3
7a
7b
7b
7c
7c
7c
7d
7d
7d
7d
7e
7e
7e
7e
CH2CH2Me
Me
Me
Ph
Me
CH2Me
H
Me
CH2Me
H
Me
H
H
H
H
H
Me
H
8a (64)
8b (36)
8c (13)
8d (80)
8e (91)
8f (38)
8g (90)
8h (85)
8i (66)
8j (55)
8k (33)a
8l (15)
8m (98)
8n (86)
CH2CH᎐CH2
᎐
CH2CH᎐CH2
᎐
CH2Ph
CH2Ph
CH2Ph
2-PhC6H4CH2
2-PhC6H4CH2
2-PhC6H4CH2
2-PhC6H4CH2
Ph
Ph
Ph
Ph
H
Me
Me
H
H
Me
Me
Me
CH2Me
H
Me
a Incompletely characterised.
alternative isomers arising from reaction of 7a with but-2-enal
with the opposite regiochemistry. The likely mechanism for
formation of the annulation products 8 is conjugate addition by
N-1 of the 4,5-dihydroimidazole 7, followed by an enamine–
aldol reaction of C(α) as nucleophile, with dehydration, Scheme
1. This is supported by: (i) the isolation of the pre-dehydration
intermediate 9a (R1 = CH CH᎐CH ; R2 = Me; R3 = H) (27%),
᎐
2
2
precursor to 8b, when dihydroimidazole 7b and but-2-enal were
mixed at 20 ЊC (CH2Cl2, MgSO4); (ii) the isolation of the regio-
isomeric alcohols 9b and 10a (R1 = Ph; R2 = H; R3 = Me) as a
1:1 mixture (42%) along with the dehydration product 8m
(21%), from the reaction of 2-benzyl-4,5-dihydroimidazole 7e
and but-3-en-2-one under these same conditions; and (iii) the
isolation of alcohol 10b (R1 = Ph; R2 = Me; R3 = H) (37%) from
the reaction of the same dihydroimidazole 7e with but-2-enal
under the reflux conditions used to form the alkene 8k, but in
more dilute solution. The conjugation in alcohols 10 (R1 = Ph)
presumably favours the enamine form of the aldol product and
inhibits dehydration.
The control of annulation regiochemistry by conjugate
N-addition of the 4,5-dihydroimidazole N-1 to enals or enones,
to afford imidazopyridines 8, is thus in direct contrast to the
situation with α-activated 4,5-dihydroimidazole 2, where conju-
gate C-addition drives the annulation towards the regioisomeric
imidazopyridine series 3.5,6 We determined to examine whether
this reversal of regiochemistry would translate to other
unsymmetrical 1,3-bis-electrophiles.
Scheme 2
hexahydroimidazopyridine 12 (sec-BuLi, THF, Ϫ78 ЊC; 34%).
Although the ester 11 could be reduced to the corresponding
alcohol 13 (LiAlH4, THF, Ϫ78→20 ЊC; 55%), attempts to form
The preference of 4,5-dihydroimidazoles 7 to undergo conju-
gate addition of N-1 to α,β-unsaturated carbonyl compounds
was supported by some further experiments. Methyl propeno-
ate as electrophile was reacted with 2-benzyl-4,5-dihydro-
imidazole 7e (CH2Cl2, reflux) to afford the adduct 11 (81%),
Scheme 2, which could be cyclised in moderate yield to the
a tosylate or mesylate for cyclisation to an octahydroimid-
azopyridine were not successful.
Conjugated alkynes also gave 1,4-adducts. Thus dihydro-
imidazoles 7e–g with methyl propynoate (MeOH, 20 ЊC) gave
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Table 2 Annulation of 2-imidazolines 7 with β-ketoesters (Scheme 4)
Imidazo-pyridinone
16 or -isoquinolinone
17 (yield %)
Imidazoline
7
R1
CH2CH᎐CH2
R2
7b
7b
7c
7e
7e
7c
7d
7e
Me
Ph
Ph
Me
Ph
16a (44)
16b (86)
16c (75)
16d (56)
16e (58)
17a (75)
17b (88)
17c (66)
᎐
CH2CH᎐CH2
᎐
CH2Ph
Ph
Ph
CH2Ph
2-PhC6H4CH2
Ph
the enaminoesters 14a–c, respectively (65, 50, and 60%), whilst
heterocycles 7b and 7e with but-3-yn-2-one led to the enamino-
ketones 15a and 15b, respectively (83 and 72%) (Scheme 3). The
Fig. 1 X-Ray crystal structure of 17c.
the regiochemistry under these reaction conditions. The
assigned regiochemistry is based on NOE studies. For example,
irradiation of the alkenyl-CH3 signal at δ 2.09 in 16a gave
an enhancement of the allyl-CH2 (δ 3.04–3.06) as well as of
the alkenyl-H (δ 5.77) signal; likewise in 16d irradiation of the
alkenyl-CH3 at δ 1.95 gave an enhancement of the aromatic-CH
(δ 7.21–7.41) as well as of the alkenyl-H (δ 5.82) signal. The
reverse NOE enhancements were also observed. The 5-oxo
isomer also exhibits more extended conjugation in the UV
spectrum (λmax 330–340 nm) than would the 7-oxo compounds.
Finally, an X-ray crystal structure determination for 17c
confirmed the regiochemistry, Fig. 1.11
The regiochemistry of formation of imidazopyridin-5-ones
16 and 17 is in contrast to the reported reaction of 2-benzyl-
4,5-dihydroimidazole 7e and β-ketoesters to afford products
assigned as the regioisomeric imidazopyridin-7-ones 18.10 We
Scheme 3
enaminoesters 14 were formed as separable 2:1 Z:E mixtures
at the enamine double bond (in the case of 14b each isolated
component was a 3:1 mixture of 3E:5E and 3Z:5E isomers of
the hepta-3,5-dienyl substituent), whereas the enaminoketones
15 were formed as the (E)-enamines.
When dihydroimidazoles 7b–e were heated (toluene, reflux)
with the β-ketoesters ethyl acetoacetate, ethyl benzoylacetate
and ethyl 2-oxocyclohexanecarboxylate, the corresponding
imidazopyridin-5-ones 16a–e and imidazoisoquinolin-5-ones
17a–c were formed, Scheme 4 and Table 2. Although initial
must conclude that the structures formerly assigned as
7-oxo isomers 18 should be revised to the 5-oxo isomers 16
and 17; indeed, our data for compounds 16d, 16e and 17c
agree with those reported for the appropriate misassigned
products.10
Whilst examining the reactions of dihydroimidazoles 7 with
alkyne diesters, we have uncovered a further annulation that is
based on N-1 conjugate addition but followed in this case by
C(α)-acylation. Thus reaction of 4,5-dihydroimidazoles 7b, 7d
and 7e with diethyl acetylenedicarboxylate (CH2Cl2, 20 ЊC, 8 h)
afforded the (E)-conjugate adducts 19a–c (17%, 54% and 34%,
respectively) and the (Z)-tetrahydropyrrolo[1,2-a]imidazol-6-
ones 20a and 20c (6% and 42%, respectively), Scheme 5; none
of the cyclised material 20b was found from the reaction of
dihydroimidazole 7d but the (Z)-isomer of adduct 19b was also
isolated (15%). Reaction of dihydroimidazole 7e with dimethyl
acetylenedicarboxylate over an extended reaction time of 72 h
afforded only (Z)-pyrroloimidazole 20d (24%) along with its
(E)-isomer (33%). Base treatment of adducts 19b and 19c (tert-
BuOK, THF) led to the corresponding pyrroloimidazoles 20b
(54%), and 20c along with its (E)-isomer (Z:E 5:1, 67%),
rather than to the possible imidazopyridines. The alkyne diester
is thus acting as a 1,2-bis-electrophile rather than as a 1,3-bis-
electrophile.12
Scheme 4
reaction of the 4,5-dihydroimidazole N-1 at the keto-carbon
(via direct 1,2-addition or through conjugate addition to the
enol form) leading to the enamine may be the kinetic pathway,
formation of the more stable amide linkage appears to control
The (Z)-geometry of 20c was confirmed by an X-ray crystal
structure determination, Fig. 2, and correlation with the other
(Z)-pyrroloimidazoles 20 was based on the downfield shifts
1
of the alkene–CH protons in the H NMR spectra (approx.
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342
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Fig. 2 X-Ray crystal structure of 20c.
Fig. 3 X-Ray crystal structure of 19b.
N-addition to alkyne diesters leads to pyrrolo[1,2-a]imidazoles
rather than to imidazopyridines.6
Experimental
Melting points were measured on a Kofler hot-stage and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 1710
FTIR spectrometer in chloroform unless otherwise stated. UV
spectra were recorded in ethanol using a Kontron Uvicon 860
spectrometer. NMR spectra were recorded in deuteriochloro-
form unless otherwise stated (internal standard TMS) on JEOL
1
LAMBDA300 or JEOL EX400 spectrometers; H spectra at
300 or 400 MHz and 13C spectra at 75 MHz or 100 MHz,
respectively. Low resolution mass spectra were obtained using
an AEI MS902 spectrometer in EI-positive mode. Solvents were
dried and distilled before use: chloroform and dichloromethane
from CaH2; tetrahydrofuran (THF) from K immediately before
use. Column chromatography was performed under medium
pressure using silica gel (Kieselgel 60; 220–440 mesh). Organic
extracts were dried over anhydrous MgSO4 for 20 min.
Scheme 5
δ 5.5–5.8) when compared with the (E)-isomers (approx. δ 5.0).
An X-ray crystal structure determination of conjugate adduct
intermediate 19b, Fig. 3, established its (E)-stereochemistry;
again 1H NMR spectral correlations supported the same geom-
etry for the other adducts 19, in particular the alkene–CH at
approx. δ 5.0 in each case (in contrast to δ 6.3 for the (Z)-isomer
of 19b). Interestingly, the solid-state structure of adduct 19b
shows the α-ester group ideally positioned for cyclisation with
C(α), leading to the pyrroloimidazole, whereas the β-ester
forms part of a planar enaminoester system and is hence
deactivated. This is in agreement with the observed 1,2-electro-
philic reactivity of the alkyne diesters.
General method for the synthesis of 2,3,5,6,-tetrahydroimidazo-
[1,2-a]pyridines 8
The α,β-unsaturated aldehyde or ketone (1.5–2 equiv.) was
added to a solution of 2-substituted-4,5-dihydroimidazole 7 in
toluene (20 cm3) at 20 ЊC. The mixture was heated at reflux
using a Dean–Stark trap for 12 h. The toluene was removed
under reduced pressure and the residue was purified by column
chromatography on silica gel (100:0→98:2 v/v ethyl acetate–
isopropylamine) to give the 2,3,5,6-tetrahydroimidazo[1,2-a]-
pyridine 8.
We have demonstrated herein that simple 2-alkyl-4,5-dihydro-
imidazoles 7, with no additional activation at C(α), undergo
annulation with conjugated aldehydes and ketones to give
imidazo[1,2-a]pyridines via an annulation controlled by initial
conjugate addition of N-1; other observations support this
preference for N-1 conjugate addition. The annulation regio-
chemistry is thus reversed from that observed with enamino-
esters such as 2, where conjugate addition of C(α) dominates.5,6
Reaction of 7 with β-ketoesters affords imidazopyridin-5-ones
through reaction of N-1 at the ester carbonyl, necessitating a
revision of earlier assigned structures.10 Finally, conjugate
5-Methyl-8-propyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine
8a. Prepared by the general method, using 2-butyl-4,5-
dihydroimidazole 7a (0.10 g, 0.79 mmol) and but-2-enal (0.10 g,
1.19 mmol), as a yellow oil (0.09 g, 64%) (Found: Mϩ 178.1470.
C11H18N2 requires: M 178.1470); νmax (film)/cmϪ1 2965, 2932,
1655, 1589, 1467, 1451, 1425, 1258, 1198, 1154; δH (400 MHz)
0.90 (3H, t, J 7.2, CH3CH2), 1.15 (3H, d, J 6.4, CH3CH), 1.45–
1.60 (2H, m, CH3CH2), 2.11–2.40 (4H, m, CH3CH2CH2,
CH3CHCH2), 2.76–2.82 and 2.96–3.05 (each 1H, m, NCH2-
CH2N), 3.51–3.66 (2H, m, NCH2CH2N), 3.85–3.90 (1H, m,
CH CH), 6.05 (1H, dd, J 3.4 and 1.9, CH᎐C); δ (100 MHz)
᎐
3
C
2334
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14.0 and 20.6 (CH3), 21.5, 33.0 and 33.6 (CH2), 49.9 (NCH2),
2.14 and 2.19–2.26 (each 1H, m, CH CH᎐C), 2.73–2.83 and
᎐
2
51.8 (CH CH), 52.6 (NCH ), 130.1 (CH᎐C), 131.0 (CH᎐C),
3.46–3.57 (each 2H, m, NCH2CH2N), 3.60 (2H, s, PhCH2),
3.82–3.86 (1H, m, CH3CH2CH), 5.68 (1H, dd, J 1.9 and 5.4,
᎐
᎐
3
2
164.0 (N–C᎐N); m/z 178 (Mϩ, 57%), 163 (100), 149 (100), 135
᎐
(74), 121 (32), 108 (6), 106 (5), 94 (12), 79 (8), 70 (19), 65 (11), 53
(11), 42 (24).
CH᎐C), 7.11–7.23 (5H, m, Ar-H); δ (100 MHz) 8.7 (CH ), 26.9
᎐
C 3
and 29.9 (CH2), 36.5 (PhCH2), 50.1 and 52.9 (NCH2), 57.0
(CH CH CH), 126.0 (CH᎐C), 128.5, 129.5 and 130.7 (Ar-CH),
᎐
3
2
5-Methyl-8-(prop-2-enyl)-2,3,5,6-tetrahydroimidazo[1,2-a]-
pyridine 8b. Prepared by the general method, using 2-(but-3-
enyl)-4,5-dihydroimidazole 7b (0.10 g, 0.80 mmol) and but-2-
enal (0.085 g, 1.2 mmol), as a yellow oil (0.05 g, 36%) (Found:
Mϩ 176.1300. C11H16N2 requires: M 176.1313); νmax (film)/cmϪ1
2967, 2929, 2853, 2824, 1654, 1592, 1496, 1454, 1423, 1258,
1199, 1157; δH (400 MHz) 1.18 (3H, d, J 6.4, CH3CH), 2.16–
2.23 and 2.30–2.37 (each 1H, m, CH3CHCH2), 2.76–2.83 and
132.6 (CH᎐C), 139.2 (Ar-C), 164.2 (NCN); m/z 240 (Mϩ, 35%),
᎐
239 (100), 225 (10), 211 (52), 197 (3), 155 (3), 140 (3), 119 (21),
105 (15), 91 (28).
8-Benzyl-7-methyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine
8f. Prepared by the general method, using 2-(2-phenylethyl)-
4,5-dihydroimidazole 7c (0.11 g, 0.63 mmol) and but-3-en-2-
one (0.10 cm3, 1.26 mmol), as a yellow oil (55 mg, 38%) (Found:
(M Ϫ H)ϩ 225.1389. C15H18N2 requires: M Ϫ H 225.1392);
νmax(film)/cmϪ1 2921, 2852, 2823, 1650, 1586, 1494, 1454, 1419,
1279, 1238, 1210, 1057, 1031, 1015, 754, 737, 700; δH (400 MHz)
1.77 (3H, s, CH3), 2.39–2.43 and 2.99–3.02 (each 2H, t, J 6.6,
CCH2CH2N), 3.12–3.17 and 3.65–3.70 (2H, t, J 8.8, NCH2-
CH2N), 3.76 (2H, s, PhCH2), 7.13–7.19 (5H, m, Ar-H); δC (100
MHz) 20.1 (CH3), 31.8 (CCH2CH2N), 32.2 (PhCH2), 45.5 and
2.96–3.08 (each 1H, m, CH CH᎐CH ), 3.09–3.11 and 3.51–3.64
᎐
2
2
(each 2H, m, NCH2CH2N), 3.83–3.89 (1H, m, CH3CH), 5.03–
5.10 (2H, m, CH᎐CH ), 5.85–5.95 (1H, m, CH᎐CH ), 6.05 (1H,
᎐
᎐
2
2
dd J 3.4 and 1.9, CH᎐C); δ (100 MHz) 20.7 (CH3), 33.7 and
᎐
C
34.8 (CH2), 50.1 (NCH2), 51.8 (CH3CH), 52.8 (NCH2), 116.2
(CH᎐CH ), 129.4 (CH᎐C), 131.9 (CH᎐C), 135.8 (CH᎐CH ),
᎐
᎐
᎐
᎐
2
2
163.8 (NCN); m/z 176 (Mϩ, 31%), 175 (100), 161 (34), 147 (18),
133 (17), 119 (19), 106 (9), 92 (7), 79 (11), 77 (9), 65 (11), 53 (15).
53.0 (NCH ), 53.2 (CCH CH N), 123.9 (CH C᎐C), 125.5,
᎐
2 2 2 3
128.1 and 128.2 (Ar-CH), 140.4 (C᎐CCH Ph), 142.6 (Ar-C),
᎐
2
5-Phenyl-8-(prop-2-enyl)-2,3,5,6-tetrahydroimidazo[1,2-a]-
pyridine 8c. Prepared by the general method, using 2-(but-
3-enyl)-4,5-dihydroimidazole 7b (0.20 g, 1.60 mmol) and 3-
phenylpropenal (0.30 cm3, 2.41 mmol), as a yellow gum (0.05 g,
13%) (Found: Mϩ 238.1470. C16H18N2 requires: M 238.1470);
νmax (KBr)/cmϪ1 2968, 2932, 2855, 2824, 1657, 1592, 1454, 1423,
1257, 1223, 1199, 1157; δH (400 MHz) 2.54–2.60 (2H, m,
164.6 (NCN); m/z 226 (Mϩ, 28%), 225 (100), 199 (5), 171 (3),
149 (9), 128 (4), 115 (4), 105 (3), 91 (9), 56 (4).
5-Methyl-8-(biphenyl-2-ylmethyl)-2,3,5,6-tetrahydroimidazo-
[1,2-a]pyridine 8g. Prepared by the general method, using
2-(2-biphenyl-2-ylethyl)-4,5-dihydroimidazole 7d (0.16 g, 0.62
mmol) and but-2-enal (0.1 cm3, 1.25 mmol), as a colourless oil
(0.17 g, 90%) (Found: C, 81.47; H, 7.24; N, 9.05%; (M Ϫ H)ϩ
301.1701. C21H22N2ؒ0.4H2O requires: C, 81.50; H, 7.37; N,
9.05%; M Ϫ H 301.1701); νmax(film)/cmϪ1 2968, 2930, 2855,
2825, 1655, 1592, 1479, 1425, 1258, 1200, 1157; δH (400 MHz)
1.06 (3H, d, J 6.4, CH3), 1.99–2.07 and 2.12–2.20 (each 1H, m,
CH CH᎐CH ), 2.68–2.76 (1H, m, PhCHCHH), 3.15–3.20 (2H,
᎐
2
2
m, NCH2CH2N), 3.21–3.25 (1H, m, PhCHCHH), 3.58–3.67
and 3.80–3.90 (each 1H, m, NCH2CH2N), 3.99 (1H, t, J 7.8,
PhCHCH ), 5.10–5.20 (2H, m, CH᎐CH ), 5.90–6.00 (1H, m,
᎐
2
2
CH᎐CH ), 6.12 (1H, dd J 3.4 and 1.9, CH᎐C), 7.30–7.42 (5H,
᎐
᎐
2
m, Ar-H); δC (100 MHz) 34.9 and 35.4 (CH2), 51.3 and 52.7
(NCH ), 61.9 (PhCH), 116.5 (CH᎐CH ), 127.2, 128.3 and 128.9
CH CH᎐C), 2.67–2.74 and 2.83–2.83 (each 1H, m, NCH -
᎐
2 2
CH2N), 3.41–3.55 (2H, m, NCH2CH2N), 3.60 (2H, s, ArCH2),
3.72–3.78 (1H, m, CH3CH), 5.47 (1H, dd, J 1.9 and 3.4,
CH᎐C), 7.16–7.28 (9H, m, Ar-H); δ (100 MHz) 20.5 (CH3),
᎐
2
2
(Ar-CH), 129.0 (CH᎐C), 131.5 (CH᎐C), 135.8 (CH᎐CH ),
᎐
᎐
᎐
2
142.1 (Ar-C), 163.7 (NCN); m/z 238 (Mϩ, 46%), 237 (100), 2.09
(10), 173 (8), 161 (17), 147 (6), 145 (8), 133 (8), 119 (11), 115
(12), 105 (22), 91 (28), 84 (15), 78 (14), 63 (7), 51 (19).
᎐
C
33.7 (CH CH᎐C), 33.8 (ArCH ), 50.1 (NCH ), 51.7 (CH CH-
᎐
2
2
2
3
CH CH᎐C), 52.8 (NCH ), 126.2 (CH᎐C), 126.7, 127.2, 128.0,
᎐
᎐
2
2
128.8, 130.1, 130.9 and 131.0 (Ar-CH), 132.6 (CH᎐C), 136.3,
᎐
8-Benzyl-5-methyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine
8d. Prepared by the general method, using 2-(2-phenylethyl)-
4,5-dihydroimidazole 7c (0.23 g, 1.32 mmol) and but-2-enal
(0.15 cm3, 1.84 mmol), as a yellow oil (0.24 g, 80%) (Found: C,
78.57; H, 8.02; N, 12.11%; (M Ϫ H)ϩ 225.1390; C15H18N2ؒ
0.2H2O requires: C, 78.39; H, 7.83; N, 12.19%; M Ϫ H
225.1392); νmax (film)/cmϪ1 2967, 2929, 2853, 2824, 1654, 1592,
1496, 1454, 1423, 1258, 1199, 1157; δH (400 MHz) 1.11 (3H, d,
J 6.4, CH3CH), 2.08–2.16 and 2.19–2.26 (each 1H, m,
CH3CHCH2), 2.70–2.81 and 2.90–3.00 (each 1H, m, NCH2-
CH2N), 3.48–3.58 (2H, m, NCH2CH2N), 3.60 (2H, s, PhCH2),
3.80–3.87 (1H, m, CH3CH), 5.67 (1H, dd, J 1.9 and 3.4,
141.5 and 142.6 (Ar-C), 163.9 (NCN); m/z 302 (Mϩ, 43%), 301
(75), 287 (16), 273 (3), 260 (3), 231 (2), 225 (100), 209 (4), 165
(15), 143 (10), 127 (3), 83 (3).
5-Ethyl-8-(biphenyl-2-ylmethyl)-2,3,5,6-tetrahydroimidazo-
[1,2-a]pyridine 8h. Prepared by the general method, using
2-(2-biphenyl-2-ylethyl)-4,5-dihydroimidazole 7d (0.13 g, 0.52
mmol) and pent-2-enal (0.10 cm3, 1.04 mmol), as a pale yellow
oil (0.14 g, 85%) (Found: (M Ϫ H)ϩ 315.1861. C22H24N2
requires: M Ϫ H 315.1865); λmax/nm 223; νmax (film)/cmϪ1 2965,
2933, 2862, 1656, 1594, 1479, 1451, 1435, 1247, 1194, 1158 703;
δH (400 MHz) 0.80 (3H, t, J 7.3, CH3CH2), 1.31–1.37 and
1.52–1.60 (each 1H, m, CH3CH2), 2.02–2.07 and 2.13–2.20
CH᎐C), 7.10–7.18 (3H, m, Ar-H), 7.20–7.25 (2H, m, Ar-H); δ
᎐
C
(100 MHz) 20.6 (CH3), 33.7 and 36.5 (CH2), 50.1 (NCH2), 51.8
(CH CH), 52.9 (NCH ), 126.0 (CH᎐C), 128.2, 129.4 (Ar-CH),
(each 1H, m, CHCH CH᎐C), 2.67–2.74 and 3.40–3.53 (each
2H, m, NCH2CH2N), 3.60 (2H, s, ArCH2), 3.72–3.75 (1H, m,
᎐
2
᎐
3
2
130.7 (CH᎐C), 132.7 (Ar-CH), 139.2 (Ar-C), 164.0 (NCN); m/z
CHCH CH᎐C), 5.49 (1H, dd, J 1.9 and 5.4, CH᎐C), 7.19–7.26
᎐ ᎐
2
(9H, m, Ar-H); δC (100 MHz) 8.7 (CH3), 26.7 and 29.9 (CH2),
36.7 (ArCH2), 50.1 and 52.8 (NCH2), 56.9 (CH2CHCH2),
᎐
225 [(M Ϫ H)ϩ, 100%], 211 (15), 184 (3), 149 (4), 133 (3), 128
(5), 119 (7), 105 (13), 91 (16), 70 (6), 65 (6), 56 (3).
126.2 (CH᎐C), 126.7, 127.2, 127.9, 128.1, 128.8, 130.0 and
᎐
8-Benzyl-5-ethyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine 8e.
Prepared by the general method, using 2-(2-phenylethyl)-4,5-
dihydroimidazole 7c (0.15 g, 0.86 mmol) and pent-2-enal (0.17
cm3, 1.72 mmol), as a pale yellow oil (0.19 g, 91%) (Found: C,
78.54; H, 8.34; N, 11.43%; (M Ϫ H)ϩ 239.1542. C16H20N2ؒ
0.2H2O requires: C, 78.81; N, 8.37; N, 11.49%; M Ϫ H
239.1548); νmax(film)/cmϪ1 2966, 2933, 2858, 1656, 1593, 1495,
1454, 1426, 1249, 1192, 1158; δH (400 MHz) 0.83 (3H, t, J 7.3,
CH3), 1.35–1.44 and 1.57–1.64 (each 1H, m CH3CH2), 2.07–
130.9 (Ar-CH), 132.5 (CH᎐C), 136.4, 141.5 and 142.6 (Ar-C),
᎐
164.0 (NCN); m/z 316 (Mϩ, 56%), 315 (75), 287 (60), 239 (100),
225 (11), 165 (31), 142 (22), 127 (7), 84 (5), 44 (10).
7-Methyl-8-(biphenyl-2-ylmethyl)-2,3,5,6-tetrahydroimidazo-
[1,2-a]pyridine 8i. Prepared by the general method, using
2-(2-biphenyl-2-ylethyl)-4,5-dihydroimidazole 7d ( 0.11 g, 0.44
mmol) and but-3-en-2-one (0.077 cm3, 0.88 mmol), as a white
solid (0.09 g, 66%), mp 111–113 ЊC (Found: (M Ϫ H)ϩ
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342
2335

View Article Online
301.1705. C21H22N2 requires: M Ϫ H 301.1705); νmax(film)/cmϪ1
2956, 2917, 2859, 2820, 1651, 1588, 1476, 1431, 1279, 754; δH
(400 MHz) 1.42 (3H, s, CH3), 2.31–2.35 and 2.95–2.98 (each
2H, t, J 6.3, CCH2CH2N), 3.12–3.17 and 3.66–3.69 (each 2H, t,
J 8.8, NCH2CH2N), 3.70 (2H, s, ArCH2), 7.06–7.32 (9H, m, Ar-
H); δC (100 MHz) 20.0 (CH3), 30.2 and 31.7 (CH2), 45.5, 53.0
1636, 1587, 1494, 1466, 1442, 1418, 1285, 1229, 1190, 1168, 978;
δH (400 MHz) 1.65 (3H, s, CH3), 2.48–2.51 and 3.06–3.10 (each
2H, t, J 6.6, CCH2CH2N), 3.11–3.16 and 3.62–3.67 (each 2H, t,
J 8.8, NCH2CH2N), 7.10–7.28 (5H, m, Ar-H); δC (100 MHz)
20.9 (CH3), 31.5 (CH2), 45.4, 52.8 and 53.6 (NCH2), 126.8
(CH C᎐C), 127.7, 127.8 and 129.8 (Ar-CH), 136.6 (C᎐CPh),
᎐
᎐
3
and 53.3 (CH N), 124.3 (CH C᎐C), 125.4, 126.7, 127.5, 127.6,
142.5 (Ar-C), 164.3 (NCN); m/z 212 (Mϩ, 56%), 211 (100), 195
᎐
2
3
128.0, 129.3, 129.3 and 137.8 (Ar-CH), 141.5 (C᎐CCH Ar),
(5), 183 (2), 154 (2), 128 (6), 115 (7), 105 (5), 69 (3), 56 (4).
᎐
2
141.8 and 142.0 (Ar-C), 165.1 (NCN); m/z 302 (Mϩ, 25%), 301
(53), 287 (19), 225 (100), 165 (9), 149 (11), 115 (3), 105 (2), 91
(5), 56 (5).
5,7-Dimethyl-8-phenyl-2,3,5,6-tetrahydroimidazo[1,2-a]-
pyridine 8n. Prepared by the general method, using 2-benzyl-
4,5-dihydroimidazole 7e (1.00 g, 6.25 mmol) and pent-3-en-2-
one (1.20 cm3, 12.5 mmol) in toluene (62 cm3), as a yellow oil
(1.22 g, 86%) (Found (M Ϫ H)ϩ, 225.1393. C15H18N2 requires:
M Ϫ H 225.1392); λmax/nm 219; νmax(film)/cmϪ1 2967, 2930,
2851, 1642, 1590, 1495, 1443, 1411, 1378, 1282, 1252, 1229,
1177, 990, 700; δH (400 MHz) 1.23 (3H, d, J 6.2, CH3CH), 1.72
5,7-Dimethyl-8-(biphenyl-2-ylmethyl)-2,3,5,6-tetrahydroimid-
azo[1,2-a]pyridine 8j. Prepared by the general method, using
2-(2-biphenyl-2-ylethyl)-4,5-dihydroimidazole 7d ( 0.11 g, 0.43
mmol) and pent-3-en-2-one (0.084 cm3, 0.86 mmol), as a
colourless oil (75 mg, 55%) (Found: MHϩ 317.2005. C22H24N2
requires: MH 317.2017); νmax(film)/cmϪ1 2968, 2852, 1651, 1588,
1478, 1416, 1329, 1281, 1209, 750, 704; λmax/nm 209, 238;
δH (300 MHz) 1.17 (3H, d, J 6.2, CH3CH), 1.47 (3H, s,
(3H, s, CH C᎐C), 2.39–2.43 (2H, m, CHCH ), 2.78–2.87 and
᎐
3
2
3.11–3.20 (each 1H, m, NCH2CH2N), 3.53–3.66 (2H, m,
NCH2CH2N), 3.80–3.90 (1H, m, CH3CH), 7.16–7.37 (5H, m,
Ar-H); δC (100 MHz) 20.8 and 21.0 (CH3), 40.2 (CH2), 50.4
CH C᎐C), 2.13–2.32 (2H, m, CHCH ), 2.79–2.86 and 2.95–3.02
᎐
3
2
(each 1H, m, NCH2CH2N), 3.53–3.59 (2H, m, NCH2CH2N),
3.75 (2H, s, CH2Ar), 3.80–3.91 (1H, m, CH3CH), 7.12–7.41
(9H, m, Ar-H); δC (75 MHz) 19.7 and 20.6 (CH3), 30.4 and 40.3
(CH2), 50.8 and 51.4 (CH2N), 53.2 (CH), 124.1, 125.3, 126.7
and 51.4 (NCH ), 53.8 (CH), 127.7 (Ar-CH), 128.1 (CH C᎐C),
᎐
2 3
128.4 and 129.9 (Ar-CH), 136.9 (C᎐CPh), 142.4 (Ar-C), 164.8
᎐
(NCN); m/z 226 (Mϩ, 75%), 225 (100), 211 (21), 195 (10), 183
(4), 166 (5), 154 (4), 128 (9), 115 (10), 91 (4), 70 (9), 42 (10).
and 127.6 (Ar-CH), 128.0 (CH C᎐C), 129.3 (Ar-CH), 137.9
᎐
3
(C᎐CCH Ar), 141.4, 141.8 and 142.5 (Ar-C), 165.5 (NCN); m/z
7-Hydroxy-5-methyl-8-(prop-2-enyl)-2,3,5,6,7,8-hexahydroimid-
azo[1,2-a]pyridine 9a
᎐
2
316 (Mϩ, 34%), 315 (55), 301 (28), 239 (100), 165 (33), 152 (17),
135 (12), 115 (8), 77 (20).
To 2-(but-3-enyl)-4,5-dihydroimidazole 7b (70 mg, 0.56 mmol)
in anhydrous dichloromethane (6 cm3) was added but-2-enal
(47 mg, 0.67 mmol). A small amount of MgSO4 was added to
the reaction mixture which was stirred at 20 ЊC for 12 h. The
mixture was filtered and the dichloromethane was removed
under reduced pressure. The crude reaction mixture was puri-
fied by column chromatography on silica gel (0:100→3:97 v/v
isopropylamine–chloroform) to give the title compound as a
white solid (30 mg, 27%) (Found: Mϩ 194.1419. C11H18N2O
requires: M 194.1491); νmax(film)/cmϪ1 3100, 2972, 2936, 1612,
1424, 1346, 1277, 1139; δH (400 MHz) 1.18 (3H, d, J 6.4,
CH3CH), 1.60–1.69 (1H, q, J 11.2, NCHCHH), 2.06–2.11 (2H,
dt, J 3.6 and 11.2, NCHCHH), 2.34–2.37 and 2.56–2.62 (each
5-Methyl-8-phenyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine
8k. Prepared by the general method, using 2-benzyl-4,5-
dihydroimidazole 7e (0.50 g, 3.12 mmol) and but-2-enal (0.28 g,
3.43 mmol), as a yellow oil (0.22 g, 33%) that was not com-
pletely characterised; νmax(film)/cmϪ1 2967, 2936, 1619, 1586,
1495, 1448, 1282, 1246, 1180, 996; δH (400 MHz) 1.23 (3H, d,
J 6.4, CH3), 2.30–2.41 and 2.50–2.57 (each 1H, m, CHCH2-
CH᎐C), 2.82–2.91 and 3.09–3.19 (each 1H, m, NCH CH N),
᎐
2
2
3.55–3.70 (2H, m, NCH2CH2N), 3.87–3.96 (1H, m, CHCH2-
CH᎐C), 6.32 (1H, dd, J 3.4 and 1.9, CH᎐C), 7.24–7.38 (3H, m,
᎐
᎐
Ar-H) and 7.45–7.48 (2H, m, Ar-H); δC (100 MHz) 20.7 (CH3),
34.1 (CH2), 49.8, 51.5 (CH), 53.2 (NCH2), 127.8, 128.1 and
1H, m CH CH᎐CH ), 2.79–2.86 (3H, m, NCH CH N and
᎐
2
2
2
2
128.7 (Ar-CH), 132.4 (CH᎐C), 134.5 (CH᎐C), 137.6 (Ar-C),
᎐
᎐
CHCH2CH᎐CH2), 3.55–3.60 (2H, m, NCH2CH2N), 3.69–3.75
᎐
162.8 (NCN); m/z 212 (Mϩ, 8%), 197 (12), 183 (8), 171 (2), 159
(1H, m, NCH), 3.85 (1H, t, J 11.2, CHOH), 5.05 and 5.17–5.21
(13), 128 (2), 91 (17).
(each 1H, m, CH᎐CH ), 6.00–6.07 (1H, m, CH᎐CH ), OH not
᎐
᎐
2
2
observed; δC (100 MHz) 22.7 (CH3), 33.0 (CHCH2), 40.8
(CH CH᎐CH ), 44.5 (CHCH CH᎐CH ) 50.3 and 51.6 (NCH ),
5-Ethyl-8-phenyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine 8l.
Prepared by the general method, using 2-benzyl-4,5-dihydro-
imidazole 7e (0.55 g, 3.44 mmol) and pent-2-enal (0.67 cm3,
6.88 mmol), as a dark yellow oil (0.12 g, 15%) (Found: MHϩ
227.1540. C15H18N2 requires: MH 227.1548); νmax(film)/cmϪ1
2966, 2936, 1619, 1586, 1495, 1448, 1423, 1282, 1246, 1180, 996,
753; δH (400 MHz) 0.97 (3H, t, J 7.8, CH3), 1.46–1.59 and 1.71–
1.80 (each 1H, m, CH3CH2), 2.37–2.44 and 2.50–2.57 (each 1H,
᎐
᎐
2
2
2
2
2
53.0 (NCH), 69.9 (CHOH), 116.7 (CH᎐CH2), 137.5
᎐
(CH᎐CH2), 166.9 (NCN); m/z 194 (Mϩ, 24%), 176 (80), 161
᎐
(32), 150 (28), 137 (21), 132 (17), 121 (34), 109 (15), 106 (11), 94
(100), 81 (16), 67 (17).
7-Hydroxy-7-methyl-8-phenyl-2,3,5,6,7,8-hexahydroimidazo-
[1,2-a]pyridine 9b and 7-hydroxy-7-methyl-8-phenyl-1,2,3,5,6,7-
hexahydroimidazo[1,2-a]pyridine 10a
m, CHCH CH᎐C), 2.85–2.95 and 2.98–3.05 (each 1H, m,
᎐
2
NCH2CH2N), 3.57–3.68 (2H, m, NCH2CH2N), 3.91–3.95 (1H,
m, CHCH CH᎐C), 6.38 (1H, dd, J 2.7 and 6.1, CH᎐C), 7.26–
7.50 (5H, m, Ar-H); δC (100 MHz) 8.8 (CH3), 27.1 and 30.5
To 2-benzyl-4,5-dihydroimidazole 7e (3.17 g, 19.81 mmol) in
dichloromethane (100 cm3) was added but-3-en-2-one (1.97
cm3, 23.77 mmol) and the resulting solution was stirred at 20 ЊC
for 12 h. The title compounds precipitated out of solution as a
white solid (1:1 mixture of regioisomers) which was filtered
(1.93 g, 42%), mp 141–143 ЊC (Found: C, 72.57; H, 7.84; N,
12.03%; Mϩ 230.1419. C14H18N2O requires: C, 73.01; H, 7.88;
N, 12.16%; M 230.1417); νmax(film)/cmϪ1 3435, 3083, 3063,
2970, 1616, 1495, 1424, 1344, 1276, 1139, 704; δH (400 MHz;
CD3OD) 1.01 and 1.14 (each 3H, s, CH3), 1.63–1.72, 1.88–1.93,
1.98–2.03 and 2.05–2.09 (each 1H, m, CH2CH2COH), 3.09–
3.21, 3.28–3.42 and 3.53–3.69 (each 4H, m, 2 × NCH2), 3.69–
3.72 (1H, m, PhCH), 7.22–7.36 (10H, m, Ar-H); δC (100 MHz,
CD3OD) 27.7 and 28.0 (CH3), 32.2 and 32.4 (CH2COH), 44.8,
᎐
᎐
2
(CH ), 49.9 and 53.3 (NCH ), 56.8 (CH), 127.4 (CH᎐C), 127.9,
᎐
2
2
128.2 and 128.7 (Ar-CH), 134.7 (CH᎐C), 137.8 (Ar-C), 163.1
᎐
(NCN); m/z 227 (MHϩ, 100%), 197 (6), 171 (3), 159 (6), 91 (2),
71 (2).
7-Methyl-8-phenyl-2,3,5,6-tetrahydroimidazo[1,2-a]pyridine
8m. Prepared by the general method, using 2-benzyl-4,5-
dihydroimidazole 7e (0.50 g, 3.12 mmol) and but-3-en-2-one
(0.50 cm3, 6.24 mmol) in toluene (30 cm3), as a yellow oil (0.65
g, 98%) (Found: C, 77.14; H, 7.69; N, 13.16%; (M Ϫ H)ϩ
211.1234. C14H16N2ؒ0.3H2O requires: C, 77.27; H, 7.63; N,
12.88%; M Ϫ H 211.1235); νmax(film)/cmϪ1 2918, 2851, 2821,
2336
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342

View Article Online
48.1, 49.5 and 49.8 (NCH2), 48.4 (PhCH), 52.5 and 52.8
(NCH ), 55.9 (NC᎐CPh), 71.2 and 71.8 (COH), 128.2, 128.6,
mp 139–141 ЊC (Found: Mϩ 214.1103. C13H14N2O requires: M
214.1106); νmax(KBr)/cmϪ1 3111 (NH), 2975, 2868, 1563, 1548,
1532, 1505, 1479, 1441, 1319, 1301, 1279, 1101; δH (300 MHz)
2.56 (2H, t, J 7.1, CH2CO), 3.28 (2H, t, J 7.1, NCH2CH2N),
3.40 (2H, m, CH2CH2CO), 3.48 (2H, m, NCH2CH2N), 4.85
(1H, br s, NH), 7.00–7.28 (5H, m, Ar-H); δC (75 MHz) 35.4
(CH2CO), 43.1, 45.2 and 50.6 (NCH2), 94.5 (PhC), 125.8,
128.4, 130.6 (Ar-CH), 135.0 (Ar-C), 164.6 (NCN), 185.7 (CO);
m/z 214 (Mϩ, 100%), 185 (92), 171 (6), 157 (18), 129 (35), 115
(15), 103 (24), 89 (16), 77 (19), 63 (9).
᎐
2
129.2, 130.1 and 132.0 (Ar-CH), 138.4 and 140.5 (Ar-C), 169.0
(NCN); m/z 230 (Mϩ, 6%), 211 (100), 196 (4), 183 (3), 171 (9),
159 (7), 128 (9), 115 (11), 102 (3), 91 (12), 77 (7), 56 (5); the
tetrahydroimidazo[1,2-a]pyridine 8m was isolated from the
filtrate by chromatography as a yellow oil (0.91 g, 21%),
identical with a sample prepared as described above.
7-Hydroxy-5-methyl-8-phenyl-1,2,3,5,6,7-hexahydroimidazo-
[1,2-a]pyridine 10b
2-Benzyl-1-(3-hydroxypropyl)-4,5-dihydroimidazole 13
To 2-benzyl-4,5-dihydroimidazole 7e (0.25 g, 1.56 mmol) in
toluene (30 cm3) was added but-2-enal (0.19 cm3, 2.34 mmol)
and the resulting solution was heated at reflux for 12 h. The
toluene was removed under reduced pressure and the crude
reaction mixture was purified by column chromatography on
silica gel (0:100→1:99 v/v isopropylamine–chloroform) to give
the title compound as a yellow oil (0.13 g, 37%) (Found: Mϩ
230.1419. C14H18N2O requires: M 230.1419); νmax(film)/cmϪ1
3401, 2968, 2931, 2851, 1636, 1585, 1494, 1249, 1196, 990, 774;
δH (400 MHz) 1.12 (3H, d, J 6.4, CH3CH), 1.88–1.93 (1H, m,
NCHCHH), 2.28–2.34 (1H, m, NCHCHH), 2.80–2.92 and
2.98–3.08 (each 1H, m, NCH2CH2N), 3.28 (1H, m, NCHH),
3.50–3.60 (2H, m, NCHH and NCH), 3.74 (1H, t, J 10.9,
CHOH), 7.20–7.35 (3H, m, Ar-H), 7.40 (2H, m Ar-H), OH
and NH not observed; δC (100 MHz) 20.7 (CH3), 32.9
(NCHCH2), 46.6 (NCH), 49.8 and 52.6 (NCH2), 56.2
To LiAlH4 (38.42 cm3 of a 1.1 M solution in THF, 42.27 mmol)
in THF (100 cm3) at Ϫ78 ЊC under nitrogen was added, via
cannula, methyl 3-(2-benzyl-4,5-dihydroimidazol-1-yl)propano-
ate 11 (5.20 g, 21.13 mmol) in dry THF (150 cm3). The resulting
yellow solution was stirred overnight (Ϫ78 ЊC→20 ЊC). The
reaction mixture was then cooled to 0 ЊC and the excess LiAlH4
destroyed by addition of ethyl acetate (50 cm3). The solvents
were removed under reduced pressure and the crude product
was purified by column chromatography on silica gel (1:2:97→
5:20:75 v/v isopropylamine–methanol–ethyl acetate) to give
the title alcohol as a yellow oil (2.52 g, 55%) (Found: (M Ϫ H)ϩ
217.1339. C13H18N2O requires: M Ϫ H 217.1341); νmax(film)/
cmϪ1 3187 (OH), 2934, 2864, 1600 (C᎐N), 1496, 1455, 1280,
᎐
1169, 1063, 723; δH (300 MHz) 1.54–1.57 (2H, m, CH2CH2OH),
2.43 (1H, br s, OH), 3.09 (2H, t, J 6.7, CH2CH2CH2OH), 3.27
(2H, t, J 9.4, NCH2CH2N), 3.41 (2H, t, J 5.9, CH2OH), 3.57
(2H, s, PhCH2), 3.66 (2H, t, J 9.4, NCH2CH2N), 7.16–7.28
(5H, m, Ar-H); δC (75 MHz) 31.0 (CH2CH2OH), 34.5 (PhCH2),
43.1, 50.0 and 51.9 (NCH2), 59.2 (CH2OH), 126.8, 128.5, 128.6
(Ar-CH), 136.1 (Ar-C), 166.1 (NCN); m/z 218 (Mϩ, 10%), 201
(4), 187 (43), 173 (35), 159 (10), 131 (7), 117 (9), 101 (20), 91
(100), 77 (7), 65 (21), 56 (54).
(NC᎐CPh), 61.3 (CHOH), 126.6, 127.9, 128.1 (Ar-CH), 135.8
᎐
(Ar-C), 163.9 (NCN); m/z 230 (Mϩ, 16%), 213 (29), 199 (26),
185 (46), 170 (5), 157 (25), 143 (7), 129 (14), 115 (12), 105
(38), 91 (12), 77 (31).
Methyl 3-(2-benzyl-4,5-dihydroimidazol-1-yl)propanoate 11
To 2-benzyl-4,5-dihydroimidazole 7e (3.00 g, 18.75 mmol) in
dry dichloromethane (18 cm3) under nitrogen was injected
methyl propenoate (3.37 cm3, 37.5 mmol) and the resulting
solution was heated at reflux overnight. The dichloromethane
was removed under reduced pressure and the crude product was
purified by column chromatography on silica gel (100:0→99:1
ethyl acetate–isopropylamine) to give the title compound as a
yellow oil (3.75 g, 81%) (Found: C, 64.12; H, 7.39; N, 11.11%;
(M Ϫ H)ϩ 245.1288. C14H18N2O2ؒ0.8H2O requires: C, 64.51;
H, 6.91; N, 10.75%; M Ϫ H 245.1290); νmax(film)/cmϪ1 2951,
General method for the synthesis of methyl 3-(2-alkyl-4,5-dihydro-
imidazol-1-yl)propenoates 14
To the 2-alkyl-4,5-dihydroimidazole 7 in dry methanol at 20 ЊC
under nitrogen was injected methyl propynoate. The resulting
yellow solution was stirred overnight at 20 ЊC, before the
methanol was removed under reduced pressure and the crude
product purified by column chromatography on silica gel
(30:70→100:0 v/v ethyl acetate–hexane) to give the enamino-
ester 14.
2862, 1737 (CO), 1615 (C᎐N), 1496, 1456, 1437, 1271, 1175,
᎐
1007; δH (400 MHz) 2.33 (2H, t, J 6.8, CH2CO2CH3),
3.28 (2H, t, J 9.0, NCH2CH2N), 3.32 (2H, t, J 6.8, CH2CH2-
CO2CH3), 3.64 (3H, s, CO2CH3), 3.65 (2H, s, PhCH2), 3.70 (2H,
t, J 9.0, NCH2CH2N), 7.21–7.33 (5H, m, Ar-H); δC (75 MHz)
33.5 and 34.5 (CH2), 42.9 (OCH3), 50.1, 51.7 and 52.4 (NCH2),
126.7, 128.6, 128.7 (Ar-CH), 135.9 (Ar-C), 165.2 (NCN),
171.9 (CO); m/z 246 (Mϩ, 38%), 187 (95), 173 (28), 158 (20),
130 (12), 117 (10), 115 (10), 103 (7), 92 (7), 83 (35), 56 (100),
42 (23).
Methyl (Z)- and (E)-3-(2-benzyl-4,5-dihydroimidazol-1-yl)-
propenoate 14a. Prepared by the general method, using 2-
benzyl-4,5-dihydroimidazole 7e (2.0 g, 12.48 mmol) and methyl
propynoate (1.10 cm3, 18.67 mmol) in methanol (62 cm3), as
(Z)- and (E)-isomers (2:1) of the title compound (1.95 g, 65%).
Data for the (Z)-isomer (Found: C, 66.49; H, 6.73; N,
10.74%; Mϩ 244.1212. C14H16N2O2ؒ0.4H2O requires: C, 66.84;
H, 6.36, N, 11.14%; M 244.1212); νmax(film)/cmϪ1 2948, 1704
(CO), 1610 (C᎐N), 1357, 1268, 1153, 1011, 921, 718; δ (400
᎐
H
MHz) 3.62 (3H, s, CH3), 3.81 (2H, s, PhCH2), 3.97 and 4.04
(each 2H, t, J 8.8, NCH2CH2N), 4.57 and 4.65 (each 1H, d,
8-Phenyl-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridin-7-one 12
sec-Butyllithium (4.43 cm3 of a 1.1 M solution in hexanes, 4.87
mmol) was injected into a solution of methyl 3-(2-benzyl-4,5-
dihydroimidazol-1-yl)propanoate 11 (0.60 g, 2.48 mmol) in dry
THF (25 cm3) at Ϫ78 ЊC under nitrogen. The resulting yellow
muddy solution was stirred at Ϫ78 ЊC for 1 h, allowed to warm
to 20 ЊC and stirred for a further 1 h. The reaction was
quenched with water (25 cm3) and the organic layer extracted
with diethyl ether (3 × 50 cm3). The combined organic extracts
were washed successively with saturated aq. NaHCO3 (100
cm3), water (100 cm3) and brine (100 cm3), dried and concen-
trated. The crude product was purified by column chromato-
graphy on silica gel (1:99→4:96 v/v isopropylamine–ethyl
acetate) to give the title compound as a white solid (0.18 g, 34%),
J 10.0, NCH᎐CHCO Me), 7.20–7.34 (5H, m, Ar-H); δ (100
᎐
2
C
MHz) 34.5 (CH2), 49.4 (NCH2), 50.9 (OCH3), 54.1 (NCH2),
90.9 (NCH᎐CHCO Me), 127.2, 128.7, 128.9 (Ar-CH), 134.2
᎐
2
(Ar-C), 136.0 (NCH᎐CHCO Me), 160.5 (NCN), 165.9 (CO);
᎐
2
m/z 244 (Mϩ, 52%), 229 (3), 213 (20), 185 (84), 171 (64), 159 (8),
128 (34), 117 (16), 105 (20), 91 (100), 77 (19).
Data for the (E)-isomer: mp 74–76 ЊC (Found: C, 67.51; H,
6.59; N, 11.24%; Mϩ 244.1212. C14H16N2O2ؒ0.2H2O requires: C,
67.81; H, 6.45; N, 11.30%; M 244.1212); νmax(film)/cmϪ1 2935,
1693 (CO), 1607 (C᎐N), 1408, 1315, 1261, 1192, 1170, 718;
᎐
δH (400 MHz) 3.57 (2H, t, J 8.8, NCH2CH2N), 3.68 (3H, s,
CH3), 3.94 (2H, s, PhCH2), 3.97 (2H, t, J 8.8, NCH2CH2N),
4.82 (1H, d, J 13.2, NCH᎐CHCO Me), 7.20–7.34 (5H, m,
᎐
2
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342
2337

View Article Online
Ar-H), 7.78 (1H, d, J 13.2, NCH᎐CHCO Me); δ (100 MHz)
Methyl (Z)- and (E)-3-{2-[2-(2-furyl)ethyl]-4,5-dihydroimid-
᎐
2
C
34.0 (CH2), 46.3 (NCH2), 51.1 (OCH3), 53.2 (NCH2), 93.2
azol-1-yl}propenoate 14c. Prepared by the general method,
using 2-[2-(2-furyl)ethyl]-4,5-dihydroimidazole 7g (0.21 g, 1.28
mmol) and methyl propynoate (0.17 cm3, 1.92 mmol) in
methanol (1.20 cm3), as (Z)- and (E)-propenoate isomers (2:1)
of the title compound as white solids (0.19 g, 60%).
(NCH᎐CHCO Me), 127.4, 128.9, 129.1 (Ar-CH), 134.1 (Ar-C),
᎐
2
139.1 (NCH᎐CHCO Me), 159.5 (NCN), 168.6 (CO); m/z 244
᎐
2
(Mϩ, 36%), 213 (25), 185 (50), 171 (30), 159 (10), 128 (40), 117
(20), 105 (17), 91 (100), 77 (26).
Data for (Z)-isomer: mp 58–60 ЊC (Found: C, 62.70; H, 6.54;
N, 11.14%; Mϩ 248.1160. C13H18N2O3 requires: C, 62.89; H,
6.50, N, 11.28%; M 248.1160); νmax(KBr)/cmϪ1 2949, 1699 (CO),
Methyl (Z)- and (E)-3-[2-(hepta-3,5-dienyl)-4,5-dihydroimid-
azol-1-yl]propenoate 14b
1611 (C᎐N), 1474, 1378, 1335, 1213, 1173, 997, 924; δ (400
᎐
H
Prepared by the general method, using 2-(hepta-3,5-dienyl)-4,5-
dihydroimidazole 7f (0.31 g, 1.93 mmol) and methyl propynoate
(0.30 cm3, 2.89 mmol) in methanol (10 cm3), as (Z)- and (E)-
propenoate isomers (2:1) of the title compound (in each case a
3:1 mixture of (E,E):(Z,E) isomers in the heptadienyl
moiety) as yellow oils (0.24 g, 50%).
MHz) 2.69 and 2.99 (each 2H, t, J 7.8, CH2CH2Furyl), 3.59
(3H, s, OCH3), 3.83 and 3.93 (each 2H, t, J 9.0, NCH2CH2N),
4.67 (1H, d, J 10.0, NCH᎐CHCO Me), 5.98 (1H, d, J 2.9,
᎐
2
Furyl-3H), 6.21 (1H, dd, J 1.9 and 2.9, Furyl-4H), 6.52 (1H, d,
J 10.0, NCH᎐CHCO Me), 7.24 (1H, d, J 1.9, Furyl-5H);
᎐
2
δC (100 MHz) 24.5 and 26.6 (CH2CH2Furyl), 49.4 (NCH2), 50.9
Data for (Z)-propenoate isomer (Found: C, 66.95; H, 8.10;
N, 11.03%; Mϩ 248.1534. C14H20N2O2ؒ0.1H2O requires: C,
67.21; H, 8.08; N, 11.20%; M 248.1525); νmax(film)/cmϪ1 2949,
(OCH ), 54.0 (NCH ), 90.9 (NCH᎐CHCO Me), 105.6 and
᎐
3 2 2
110.2 (Furyl-CH), 135.6 (NCH᎐CHCO Me), 141.3 (Furyl-
᎐
2
CH), 153.9 (Furyl-C), 160.9 (NCN), 165.9 (CO); m/z 248 (Mϩ,
25%), 233 (6), 217 (10), 189 (100), 161 (10), 135 (10), 121 (10),
109 (36), 96 (24), 81 (32), 68 (9).
1707 (CO), 1653, 1610 (C᎐N), 1364, 1160, 994, 922; m/z 248
᎐
(Mϩ, 56%), 233 (30), 217 (10), 205 (6), 189 (100), 161 (12), 135
(22), 120 (26), 109 (45), 96 (26), 79 (36), 67 (37), 53 (52); NMR
data for (E,E)-heptadienyl isomer δH (400 MHz) 1.73 (3H, d,
J 6.8, CH CH᎐CH), 2.37–2.45 (4H, m, CH CH CH᎐CH), 3.66
Data for (E)-isomer: mp 96–98 ЊC (Found: C, 62.74; H, 6.54;
N, 11.01%; Mϩ 248.1160. C13H18N2O3 requires: C, 62.89; H,
6.50, N, 11.28%; M 248.1160); νmax(KBr)/cmϪ1 2958, 1693 (CO),
᎐
᎐
3
2
2
(3H, s, OCH3), 3.88 and 3.98 (each 2H, t, J 8.8, NCH2CH2N),
4.74 (1H, d, J 10.0, NCH᎐CHCO Me), 5.56–5.66 and 6.00–
1634 (C᎐N), 1315, 1286, 1217, 1168, 793, 740; δ (400 MHz)
2.66 and 3.01 (each 2H, t, J 7.8, CH2CH2Furyl), 3.48 (2H, t,
J 9.0, NCH2CH2N), 3.65 (3H, s, OCH3), 3.87 (2H, t, J 9.0,
᎐
H
᎐
2
6.10 (each 2H, m, CH᎐CHCH᎐CH), 6.61 (1H, d, J 10.0,
᎐
᎐
NCH᎐CHCO Me); δ (100 MHz) 18.1 (CH CH᎐CH), 27.9
NCH CH N), 4.79 (1H, d, J 13.2, NCH᎐CHCO Me), 6.00
᎐
2 2 2
᎐
᎐
2
C
3
and 28.8 (CH CH CH᎐CH), 49.4 (NCH ), 50.9 (OCH ), 54.1
(1H, d, J 3.1, Furyl-3H), 6.21 (1H, dd, J 2.0 and 3.1, Furyl-
᎐
2
2
2
3
(NCH ), 90.6 (NCH᎐CHCO Me), 128.2, 129.2, 131.2 and
4H), 7.25 (1H, d, J 2.0, Furyl-5H), 7.65 (1H, d, J 13.2, NCH᎐
᎐
᎐
2
2
131.6 (CH᎐CHCH᎐CH), 135.9 (NCH᎐CHCO Me), 161.3
CHCO2Me); δC (100 MHz) 24.5 and 26.2 (CH2CH2Furyl), 46.6
᎐
᎐
᎐
2
(NCN), 166.1 (CO); NMR data for (Z,E)-heptadienyl isomer
δH (400 MHz) 1.11 (3H, d, J 6.8, CH CH᎐CH), 2.37–
(NCH ), 51.4 (OCH ), 53.3 (NCH ), 93.6 (NCH᎐CHCO Me),
᎐
2 3 2 2
105.9 and 110.5 (Furyl-CH), 138.8 (NCH᎐CHCO Me), 141.6
᎐
᎐
3
2
2.45 (4H, m, CH CH CH᎐CH), 3.66 (3H, s, OCH ), 3.88 and
(Furyl-CH), 154.1 (Furyl-C), 160.1 (NCN), 168.9 (CO); m/z
248 (Mϩ, 23%), 233 (5), 217 (9), 205 (5), 189 (100), 175 (2), 161
(8), 135 (6), 121 (8), 109 (36), 96 (21), 81 (27), 68 (8).
᎐
2
2
3
3.98 (each 2H, t, J 8.8, NCH2CH2N), 4.74 (1H, d, J 10.0,
NCH᎐CHCO Me), 5.01 (1H, dd, J 1.7 and 10.2, CH CH᎐
᎐
᎐
2
3
CHCH᎐CH), 5.14 (1H, dd,
J 1.7 and 17.1, CH CH᎐
᎐
3
᎐
CHCH᎐CH), 5.61–5.66 and 6.25–6.32 (each 1H, m, CH᎐
2-(But-3-enyl)-1-(3-oxobut-1-enyl)-4,5-dihydroimidazole 15a
᎐
᎐
CHCH᎐CH), 6.61 (1H, d, J 10.0, NCH᎐CHCO Me); δ (100
᎐
᎐
But-3-yn-2-one (0.47 cm3, 5.33 mmol) was injected into 2-(but-
3-enyl)-4,5-dihydroimidazole 7b (0.63 g, 5.08 mmol) in dry
methanol (50 cm3) at 20 ЊC under nitrogen and the mixture was
stirred for 14 h. The methanol was removed under reduced
pressure and the residue purified by column chromatography
on silica gel (0.25:99.75→2:98 v/v isopropylamine–ethyl acet-
ate) to give the title compound as a yellow oil (0.81 g, 83%)
(Found: (M Ϫ H)ϩ 191.1184. C11H16N2O requires: M Ϫ H
191.1184); νmax(film)/cmϪ1 2950, 1642, 1572, 1479, 1405, 1354,
1257, 1201, 1005, 964, 927; δH (400 MHz) 2.20 (3H, s, CH3),
2
C
MHz) 20.0 (CH CH᎐CH), 33.8 and 34.9 (CH CH CH᎐CH),
᎐
᎐
3
2
2
49.4 (NCH ), 50.9 (OCH ), 54.1 (NCH ), 90.6 (NCH᎐CH-
᎐
2
3
2
CO2Me), 116.1 and 129.9 (CH᎐CH), 136.0 (NCH᎐CH-
᎐
᎐
CO Me), 136.9 and 138.5 (CH᎐CH), 161.3 (NCN), 166.1 (CO).
᎐
2
Data for (E)-propenoate isomer (Found: Mϩ 248.1523.
C14H20N2O2 requires: M 248.1525); νmax(film)/cmϪ1 2950, 1703
(CO), 1615 (C᎐N), 1410, 1315, 1256, 1197, 1163, 994; m/z 248
᎐
(Mϩ, 28%), 233 (22), 217 (9), 205 (6), 189 (100), 175 (16), 161
(10), 149 (14), 134 (17), 121 (15), 109 (32), 96 (23), 79 (26), 67
(16); NMR data for (E,E)-heptadienyl isomer δH (400 MHz)
2.47–2.52 (4H, m, CH CH CH᎐CH ), 3.57 and 3.95 (each 2H,
᎐
2
2
2
1.73 (3H, d, J 6.8, CH CH᎐CH), 2.41–2.51 (4H, m, CH CH -
᎐
3
2
2
t, J 9.2, NCH2CH2N), 5.00–5.15 (2H, 2 × dd, J 1.7 and 11.2,
1.7 and 19.2, CH᎐CH ), 5.30 (1H, d, J 13.2, NCH᎐CHCOMe),
CH᎐CH), 3.53 (2H, t, J 9.0, NCH CH N), 3.72 (3H, s, OCH ),
᎐
2
2
3
᎐
᎐
2
3.93 (2H, t, J 9.0, NCH CH N), 4.85 (1H, d, J 13.2, NCH᎐
᎐
2
2
5.85–5.94 (1H, m, CH᎐CH ), 7.75 (1H, d, J 13.2, NCH᎐
᎐
᎐
2
CHCO Me), 5.58–5.69 and 5.98–6.10 (each 2H, m, CH᎐
᎐
2
CHCOMe); δC (100 MHz) 26.6 (CH2), 28.7 (CH3), 29.5 (CH2),
46.3 and 53.3 (NCH ), 103.6 (NCH᎐CHCOMe), 116.0 (CH᎐
CHCH᎐CH), 7.74 (1H, d, J 13.2, NCH᎐CHCO Me); δ (100
᎐
᎐
2
C
᎐
᎐
2
MHz), 18.5 (CH CH᎐CH), 27.3 and 28.5 (CH CH CH᎐CH),
᎐
᎐
3
2
2
CH2), 136.5 (CH᎐CH ), 137.7 (NCH᎐CHCOMe), 160.2
᎐
᎐
2
46.2 (NCH2), 50.9 (OCH3), 53.1 (NCH2), 92.9 (NCH᎐
᎐
(NCN), 196.6 (CO); m/z 192 (Mϩ, 27%), 177 (6), 149 (89), 135
(6), 121 (17), 111 (80), 96 (78), 83 (48), 68 (44), 55 (100), 43
(100).
CHCO Me), 128.2, 129.0, 131.6 and 131.7 (CH᎐CHCH᎐CH),
᎐
᎐
2
138.9 (NCH᎐CHCO Me), 160.1 (NCN), 168.7 (CO); NMR
᎐
2
data for (Z,E)-heptadienyl isomer δH (400 MHz) 1.13 (3H, d,
J 6.8, CH CH᎐CH), 2.40–2.51 (4H, m, CH CH CH᎐CH), 3.53
᎐
᎐
3
2
2
2-Benzyl-1-(3-oxobut-1-enyl)-4,5-dihydroimidazole 15b
(2H, t, J 9.0, NCH2CH2N), 3.66 (3H, s, OCH3), 3.95 (2H, t,
J 9.0, NCH CH N), 4.74 (1H, d, J 10.2, NCH᎐CHCO Me),
Prepared as for compound 15a above, using but-3-yn-2-one
(1.45 cm3, 18.75 mmol), 2-benzyl-4,5-dihydroimidazole 7e (2.50
g, 15.62 mmol) in dry methanol (20 cm3) at 0 ЊC under nitrogen
for 30 min and at 20 ЊC for 4 h, to give the title compound as a
pale yellow solid (2.56 g, 72%), mp 104–106 ЊC (Found: C,
71.43; H, 7.09; N, 11.93%; Mϩ 228.1263. C14H16N2Oؒ0.4H2O
requires: C, 71.39; H, 6.79; N, 11.89%; M 228.1262); νmax(KBr)/
cmϪ1 2995, 2919, 1606, 1457, 1360, 1249, 1167, 1001, 942;
δH (400 MHz) 2.10 (3H, s, CH3), 3.56 (2H, t, J 9.3, NCH2-
᎐
2
2
2
5.01 (1H, dd, J 1.7 and 9.8, CH CH᎐CHCH᎐CH), 5.14 (1H,
᎐
᎐
3
dd, J 1.7 and 17.1, CH CH᎐CHCH᎐CH), 5.65–5.70 and 6.24–
᎐
᎐
3
6.31 (each 1H, m, CH CH᎐CHCH᎐CH), 6.61 (1H, d, J 10.2,
᎐
᎐
3
NCH᎐CHCO Me); δ (100 MHz) 20.2 (CH CH᎐CH), 27.9
᎐
᎐
2
C
3
and 28.8 (CH CH CH᎐CH), 49.3 (NCH ), 51.1 (OCH ), 54.1
᎐
2
2
2
3
(NCH ), 90.6 (NCH᎐CHCO Me), 116.1, 131.1, 135.9 and
᎐
2
2
138.3 (CH᎐CHCH᎐CH), 138.8 (NCH᎐CHCO Me), 160.1
᎐
᎐
᎐
2
(NCN), 168.7 (CO).
2338
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342

View Article Online
CH2N), 3.88 (2H, s, PhCH2), 4.02 (2H, t, J 9.3, NCH2CH2N),
5.20 (1H, d, J 13.2, NCH᎐CHCOMe), 7.20–7.35 (5H, m,
m/z 302 (Mϩ, 13%), 273 (2), 225 (14), 202 (2), 167 (2), 154 (2),
140 (2), 127 (5), 105 (5), 91 (19), 77 (19).
᎐
Ar-H), 7.67 (1H, d, J 13.2, NCH᎐CHCOMe); δ (100 MHz)
᎐
C
28.2 (CH ), 34.3 (PhCH ), 46.6 and 53.7 (NCH ), 104.5 (NCH᎐
CHCOMe), 127.7, 128.7 and 129.1 (Ar-CH), 134.3 (Ar-C),
7-Methyl-8-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyridin-5-
one 16d. Prepared by the general method, using 2-benzyl-4,5-
dihydroimidazole 7e (0.90 g, 5.62 mmol) and ethyl acetoacetate
(1.43 cm3, 11.25 mmol) in toluene (30 cm3), as a white solid
(0.72 g, 56%), mp 161–163 ЊC (lit.,10 161–162 ЊC) (Found: Mϩ
226.1107. C14H14N2O requires: M 226.1106); λmax/nm 333;
νmax(KBr)/cmϪ1 3145 (NH), 1657 (NCO), 1559, 1519, 1493,
1439, 1296, 702; δH (400 MHz) 1.95 (3H, s, CH3), 3.66 and 4.23
(each 2H, t, J 8.2, NCH2CH2N), 4.48 (1H, br s, NH), 5.82 (1H,
s, NCOCH), 7.21–7.41 (5H, m, Ar-H); δC (100 MHz) 20.5
᎐
3
2
2
138.6 (NCH᎐CHCOMe), 159.7 (NCN), 196.7 (CO); m/z 228
᎐
(Mϩ, 29%), 213 (3), 185 (12), 171 (5), 159 (2), 117 (8), 111 (98),
96 (100), 91 (52), 83 (42), 70 (22).
General method for the synthesis of 1,2,3,5-tetrahydroimidazo-
[1,2-a]pyridin-5-ones 16 and 1,2,3,5,6,7,8,9-octahydroimidazo-
[1,2-b]isoquinolin-5-ones 17
The β-ketoester (2 mol equiv.) was injected into the 2-
substituted-4,5-dihydroimidazole 7 (1 mol equiv.) in toluene
and the solution heated to reflux using a Dean–Stark trap for 12
h. The toluene was then removed under reduced pressure and
the crude product purified by column chromatography on silica
gel (98:1:1→85:10:5 v/v ethyl acetate–methanol–isopropyl-
amine) to give the imidazopyridin-5-ones 16 or imidazo-
isoquinolin-5-ones 17.
(CH ), 42.8 and 44.7 (NCH ), 99.7 (NC᎐C), 107.0 (NCOCH),
᎐
3
2
127.3, 129.1 and 130.5 (Ar-CH), 135.2 (Ar-C), 151.2
(CH᎐CCH ), 152.4 (NC᎐C), 160.5 (NCO); m/z 226 (Mϩ,
᎐
᎐
3
100%), 198 (29), 182 (5), 169 (5), 153 (5), 128 (11), 115 (12), 103
(4), 91 (5), 83 (7), 57 (5).
7,8-Diphenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyridin-5-one
16e. Prepared by the general method, using 2-benzyl-4,5-
dihydroimidazole 7e (1.00 g, 6.25 mmol) and ethyl benzoyl-
acetate (2.16 cm3, 12.50 mmol) in toluene (62 cm3), as a yellow
crystalline solid (1.05 g, 58%), mp 279–281 ЊC [lit.,10 270 ЊC
(decomp.)] (Found: Mϩ 288.1259. C19H16N2O requires: M
288.1263); λmax/nm 349; νmax(KBr)/cmϪ1 3234 (NH), 1646
(NCO), 1586, 1531, 1500, 1487, 1469, 1420, 1282, 768, 699;
δH (400 MHz) 3.69 and 4.20 (each 2H, t, J 8.3, NCH2CH2N),
4.98 (1H, br s, NH), 5.95 (1H, s, NCOCH), 7.05–7.28 (10H, m,
7-Methyl-8-(prop-2-enyl)-1,2,3,5-tetrahydroimidazo[1,2-a]-
pyridin-5-one 16a. Prepared by the general method, using 2-
(but-3-enyl)-4,5-dihydroimidazole 7b (0.20 g, 1.61 mmol), ethyl
acetoacetate (0.41 cm3, 3.22 mmol) in toluene (20 cm3), as
a yellow solid (0.14 g, 44%), mp 147–149 ЊC (Found: Mϩ
190.1102. C11H14N2O requires: M 190.1106); λmax/nm 204, 246,
332; νmax(KBr)/cmϪ1 3215 (NH), 3006, 2977, 1657 (NCO), 1545,
1467, 1421, 1399, 1288, 1202, 1106, 994, 909, 809; δH (400 MHz)
Ar-H); δC (100 MHz) 42.8 and 44.9 (NCH ), 98.3 (NC᎐C),
᎐
2
2.09 (3H, s, CH ), 3.04–3.06 (2H, m, CH CH᎐CH ), 3.71 and
᎐
3
2
2
107.4 (NCOCH), 126.7, 127.8, 128.0, 128.6, 128.9 and 130.6
4.20 (each 2H, t, J 8.6, NCH2CH2N), 4.66 (1H, br s, NH), 4.98–
5.08 (2H, m, CH CH᎐CH ), 5.77 (1H, s, NCOCH), 5.76–5.86
(Ar-CH), 135.3 and 139.0 (Ar-C), 151.0 (CH᎐CPh), 155.5
᎐
(NC᎐C), 160.5 (NCO); m/z 288 (Mϩ, 6%), 242 (2), 223 (3), 210
᎐
2
2
᎐
(1H, m, CH᎐CH ); δ (75 MHz) 19.8 (CH3), 30.3 (CH2), 43.0
᎐
2
C
(3), 190 (4), 162 (4), 120 (16), 91 (24), 57 (18).
and 44.7 (NCH ), 94.0 (NC᎐C), 107.4 (NCOCH), 115.3
᎐
2
(CH᎐CH ), 135.4 (CH᎐CH ), 150.6 (CH᎐CCH ), 153.4.4
᎐
᎐
᎐
2
2
3
10-Benzyl-1,2,3,5,6,7,8,9-octahydroimidazo[1,2-b]isoquinolin-
5-one 17a. Prepared by the general method, using 2-(2-
phenylethyl)-4,5-dihydroimidazole 7c (0.10 g, 0.57 mmol) and
ethyl 2-oxocyclohexanecarboxylate (0.18 cm3, 1.15 mmol) in
toluene (20 cm3), as a white solid (0.12 g, 75%), mp 231–233 ЊC
(NC᎐C), 160.6 (NCO); m/z 190 (Mϩ, 81%), 175 (16), 163 (100),
᎐
147 (9), 135 (12), 121 (8), 91 (11), 77 (13).
7-Phenyl-8-(prop-2-enyl)-1,2,3,5-tetrahydroimidazo[1,2-a]-
pyridin-5-one 16b. Prepared by the general method, using 2-
(but-3-enyl)-4,5-dihydroimidazole 7b (0.20 g, 1.61 mmol) and
ethyl benzoylacetate (0.55 cm3, 3.22 mmol) in toluene (20 cm3),
as a yellow solid (0.35, 86%), mp 152–154 ЊC (Found: Mϩ
252.1267. C16H16N2O requires: M 252.1263); λmax/nm 204, 241,
343; νmax(KBr)/cmϪ1 3170 (NH), 2981, 2924, 1656 (NCO), 1547,
1475, 1417, 1375, 1181, 781, 708; δH (300 MHz) 2.87–2.91 (2H,
(Found: Mϩ 280.1575. C18H20N2O requires: M 280.1576); λmax
/
nm 335; νmax(film)/cmϪ1 3240 (NH), 2927, 1652 (NCO), 1533,
1494, 1481, 1290, 1228, 740; δH (400 MHz) 1.65–1.70 (4H, m,
CH2CH2CH2CH2), 2.42 and 2.53 (each 2H, t, J 4.8, CH2CH2-
CH2CH2), 3.57 (2H, t, J 8.4, NCH2CH2N), 3.68 (2H, s, PhCH2),
4.20 (2H, t, J 8.2, NCH2CH2N), 4.30 (1H, br s, NH), 7.10–
7.30 (5H, m, Ar-H); δC (100 MHz) 22.2, 22.5, 23.5, 26.9 and
m, CH CH᎐CH ), 3.70 and 4.20 (each 2H, t, J 8.6, NCH -
31.2 (CH ), 42.7 and 44.8 (NCH ), 94.2 (NC᎐C), 115.4
᎐
2
2
2
᎐
2
2
CH N), 4.75 (1H, br s, NH), 4.91–5.04 (2H, m, CH CH᎐CH ),
(NCOC), 126.3, 127.6 and 128.7 (Ar-CH), 139.6 (Ar-C), 147.6
᎐
2
2
2
(NCOC᎐C), 149.2 (NC᎐C), 160.2 (NCO); m/z 280 (Mϩ, 100%),
5.77 (1H, s, NCOCH), 5.55–5.81 (1H, m, CH CH᎐CH ), 7.15–
᎐
2
2
᎐
᎐
7.21 (2H, m, Ar-H), 7.24–7.33 (3H, m, Ar-H); δC (75 MHz) 31.1
265 (26), 251 (29), 236 (5), 203 (29), 189 (10), 175 (6), 152 (3),
115 (5), 91 (14), 69 (15).
(CH ), 42.9 and 44.6 (NCH ), 92.7 (NC᎐C), 107.2 (NCOCH),
᎐
2
2
115.5 (CH᎐CH ), 127.8, 127.9 and 128.1 (Ar-CH), 136.1
᎐
2
(CH᎐CH ), 139.3 (Ar-C), 151.4 (CH᎐CPh), 157.2 (NC᎐C),
10-(Biphenyl-2-ylmethyl)-1,2,3,5,6,7,8,9-octahydroimidazo-
[1,2-b]isoquinolin-5-one 17b. Prepared by the general method,
using 2-(2-biphenyl-2-ylethyl)-4,5-dihydroimidazole 7d (0.50 g,
2.00 mmol) and ethyl 2-oxocyclohexanecarboxylate (0.64 cm3,
4.00 mmol) in toluene (20 cm3), as a white solid (0.63 g, 88%),
mp 251–253 ЊC (Found: Mϩ 356.1889. C24H24N2O requires: M
356.1889); λmax/nm 206, 244, 338; νmax(film)/cmϪ1 3208 (NH),
2928, 1657 (NCO), 1533, 1494, 1476, 1450, 1288, 1230, 1154,
751; δH (300 MHz) 1.61–1.66 (4H, m, CH2CH2CH2CH2), 2.25
and 2.49 (each 2H, t, J 4.8, CH2CH2CH2CH2), 3.51 (2H, t,
J 8.4, NCH2CH2N), 3.59 (2H, s, ArCH2), 3.86 (1H, br s, NH),
4.17 (2H, t, J 8.2, NCH2CH2N), 7.18–7.46 (9H, m, Ar-H);
δC (75 MHz) 22.2, 22.5, 23.4, 26.8, and 29.6 (CH2), 42.7 and
᎐
᎐
᎐
2
160.2 (NCO); m/z 252 (Mϩ, 100%), 225 (59), 197 (10), 152 (14),
127 (19), 115 (15), 102 (11), 77 (18).
8-Benzyl-7-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyridin-5-
one 16c. Prepared by the general method, using 2-(2-phenyl-
ethyl)-4,5-dihydroimidazole 7c (0.10 g, 0.57 mmol) and ethyl
benzoylacetate (0.20 cm3, 1.14 mmol) in toluene (20 cm3), as a
white solid (0.13 g, 75%), mp 210–212 ЊC (Found: Mϩ 302.1423.
C20H18N2O requires: M 302.1419); λmax/nm 343; νmax(film)/cmϪ1
3246 (NH), 1667 (NCO), 1546, 1526, 1468, 1415, 1289, 1237,
699; δH (400 MHz) 3.60 (2H, s, PhCH2), 3.64 and 4.23 (each 2H,
t, J 8.2, NCH2CH2N), 4.38 (1H, br s, NH), 5.89 (1H, s,
NCOCH), 7.08–7.36 (10H, m, Ar-H); δC (100 MHz) 32.4
44.8 (NCH ), 94.4 (NC᎐C), 115.6 (NCOC), 126.3, 127.2, 127.4,
᎐
2
(CH ), 42.9 and 44.6 (NCH ), 93.9 (NC᎐C), 107.3 (NCOCH),
127.9, 128.3, 129.1 and 136.7 (Ar-CH), 139.6, 141.4 and 142.2
᎐
2
2
126.4, 127.7, 127.8, 127.9, 128.2 and 128.8 (Ar-CH), 139.2 and
(Ar-C), 147.6 (NCOC᎐C), 149.2 (NC᎐C), 160.2 (NCO); m/z
᎐ ᎐
139.5 (Ar-C), 151.45 (CH᎐CPh), 157.4 (NC᎐C), 160.3 (NCO);
356 (Mϩ, 100%), 355 (28), 341 (11), 327 (7), 313 (4), 277 (4), 251
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342 2339
᎐
᎐

View Article Online
(3), 215 (4), 203 (71), 189 (20), 175 (15), 165 (33), 152 (21), 128
(5), 115 (6), 91 (6), 77 (16), 44 (23).
60.08; H, 7.54, N, 9.35%; M 294.1579); νmax(film)/cmϪ1 2983,
1737 (CO), 1694 (CO), 1639 (C᎐N), 1577, 1421, 1372, 1337,
᎐
1160, 1096, 1027, 915, 800; δH (300 MHz) 1.27 (3H, t, J 7.2,
CH3CH2), 1.38 (3H, t, J 7.3, CH3CH2), 2.42 (4H, m, CH2CH2-
10-Phenyl-1,2,3,5,6,7,8,9-octahydroimidazo[1,2-b]isoquinolin-
5-one 17c. Prepared by the general method, using 2-benzyl-4,5-
dihydroimidazole 7e (5.00 g, 31.25 mmol) and ethyl 2-oxo-
cyclohexanecarboxylate (9.98 cm3, 62.50 mmol) in toluene
(150 cm3), as a yellow solid (5.48 g, 66%), mp 233–235 ЊC (lit.,10
240–242 ЊC) (Found: Mϩ 266.1417. C17H18N2O requires: M
266.1419); λmax/nm 334; νmax(film)/cmϪ1 3127 (NH), 2935, 1650
(NCO), 1563, 1523, 1491, 1436, 1096, 698; δH (400 MHz) 1.56–
1.62 and 1.67–1.72 (each 2H, m, CH2CH2CH2CH2), 2.22 and
2.53 (each 2H, t, J 4.8, CH2CH2CH2CH2), 3.59 (2H, t, J 8.4,
NCH2CH2N), 4.11 (1H, br s, NH), 4.22 (2H, t, J 8.2, NCH2-
CH2N), 7.19–7.30 (5H, m, Ar-H); δC (100 MHz) 22.3, 22.5, 23.4
CH᎐CH ), 3.62 and 3.86 (each 2H, t, J 8.9, NCH CH N), 4.12
᎐
2
2
2
(2H, q, J 7.2, CH3CH2), 4.35 (2H, q, J 7.3, CH3CH2), 5.02 (1H,
s, CHCO Et), 5.02–5.15 (2H, m, CH᎐CH ), 5.78–5.88 (1H, m,
᎐
2
2
CH᎐CH ); δ (75 MHz) 13.7 and 14.3 (CH3), 25.4 and 30.1
᎐
2
C
(CH2), 50.0 and 51.9 (NCH2), 60.1 and 62.8 (OCH2), 96.2
(CHCO2Et), 115.5 (CH᎐CH ), 136.9 (CH᎐CH ), 144.5
᎐
᎐
2
2
(NC᎐CH), 159.3 (NCN), 164.5 and 166.4 (CO); m/z 294 (Mϩ,
᎐
7%), 265 (3), 249 (9), 221 (100), 193 (45), 175 (8), 147 (18), 126
(24), 98 (18), 82 (14).
Diethyl (E)-2-[2-(biphenyl-2-ylethyl)-4,5-dihydroimidazol-1-
yl]butene-1,4-dioate 19b and its (Z)-isomer. Prepared by the
generalmethod, using2-(2-biphenyl-2-ylethyl)-4,5-dihydroimid-
azole 7d (0.77 g, 3.07 mmol) and diethyl acetylenedicarboxylate
(0.36 cm3, 2.22 mmol), to give after stirring for 8 h the (E)-
isomer of the title compound as a yellow gum, recrystallised
from hexane–ethyl acetate as a white crystalline solid (0.43 g,
54%), mp 85–87 ЊC (Found: C, 71.20; H, 6.70; N, 6.64%;
(M Ϫ H)ϩ 419.1974. C25H28N2O4 requires: C, 71.41; H, 6.71; N,
6.64%; M Ϫ H 419.1971); νmax(film)/cmϪ1 2981, 1741 and 1703
(CO2Et), 1641, 1575, 1479, 1197, 1156, 1046, 752; δH (300 MHz)
1.19 and 1.26 (each 3H, t, J 7.2, CH3CH2), 2.41 and 3.00 (each
2H, t, J 8.0, CH2CH2Ar), 3.56 and 3.79 (each 2H, t, J 9.0,
NCH2CH2N), 4.12 and 4.20 (each 2H, q, J 7.2, CH3CH2), 4.91
(1H, s, CHCO2Et), 7.18–7.43 (9H, m, Ar-H); δC (75 MHz) 13.4
and 14.2 (CH3), 29.4 and 30.1 (CH2), 49.8 and 51.9 (NCH2),
60.0 and 62.6 (OCH2), 96.0 (CHCO2Et), 126.3, 127.0, 127.6,
128.3, 129.1, 130.3, 138.3 (Ar-CH), 141.4 and 141.9 (Ar-C),
and 28.5 (CH ), 42.7 and 44.9 (NCH ), 98.9 (NC᎐C), 114.9
᎐
2
2
(NCOC), 127.3, 128.9 and 130.8 (Ar-CH), 135.2 (Ar-C), 146.8
(NCOC᎐C), 148.3 (NC᎐C), 160.3 (NCO); m/z 266 (Mϩ, 52%),
᎐
᎐
251 (14), 237 (28), 206 (11), 191 (19), 149 (71), 115 (12), 105
(13), 91 (53), 77 (15).
Crystal data for 17c: C17H18N2O, M = 266.33, triclinic, a =
8.831(2), b = 11.534(2), c = 13.182(3) Å, α = 90.34, β = 92.49,
3
¯
γ = 90.79Њ, U = 13441.3(5) Å , T = 150(2) K, space group P1,
monochromated Mo-Kα radiation, λ = 0.71073 Å, Z = 4,
Dc = 1.319 Mg mϪ3, F(000) = 568, yellow crystals, dimensions
0.5 × 0.2 × 0.1 mm, µ(Mo-Kα) = 0.083 mmϪ1, 1.77 < 2θ < 24Њ,
21333 reflections measured, 4182 unique reflections. The struc-
ture was solved by direct methods and refined by full-matrix
least-squares on F2. The final cycle (for 378 parameters)
converged with wR2 = 0.1873 (for all data) and R1 = 0.0661
[I > 2σ(I)].
144.4 (NC᎐CH), 159.1 (NCN), 164.4 and 166.4 (CO); m/z 421
᎐
General method for the synthesis of diethyl 2-(2-substituted-4,5-
dihydroimidazol-1-yl)butene-1,4-dioates 19 and 5-ethoxycarb-
onylmethylene-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-
ones 20
(MHϩ, 2%), 375 (3), 347 (100), 319 (21), 273 (9), 213 (6), 191
(5), 178 (15), 165 (72), 152 (33), 139 (7), 126 (6), 94 (7), 68 (15);
and the (Z)-isomer of the title compound as a thick yellow oil
(0.12 g, 15%) (Found: Mϩ 420.2052. C25H28N2O4 requires: M
420.2049); νmax(film)/cmϪ1 2981, 2939, 1729, 1610, 1480, 1368,
1259, 1172, 1033, 753; δH (300 MHz) 1.24–2.31 (6H, m,
2 × CH3CH2), 2.12 and 2.88 (each 2H, t, J 8.3, CH2CH2Ar),
3.62 and 3.81 (each 2H, t, J 9.9, NCH2CH2N), 4.14 and 4.20
(each 2H, q, J 7.2, CH3CH2), 6.30 (CHCO2Et), 7.14–7.40 (9H,
m, Ar-H); δC (75 MHz) 14.1 and 14.2 (CH3), 29.8 and 30.6
(CH2), 51.5 and 53.7 (NCH2), 60.9 and 62.3 (OCH2), 118.5
(CHCO2Et), 126.1, 126.9, 127.6, 128.2, 129.0, 129.4, 130.2
Diethyl acetylenedicarboxylate (1.2 mol equiv.) was injected
into a solution of 2-substituted-4,5-dihydroimidazole 7 (1
equiv.) in dry dichloromethane (1 M in dihydroimidazole) at
0 ЊC. The reaction was allowed to warm to 20 ЊC and stirred for
the time stated. Any precipitate was collected by filtration to
afford the pyrroloimidazolones 20, the dichloromethane was
removed from the filtrate and the residue chromatographed on
silica gel (ethyl acetate–hexane 3:7 v/v) to give the diethyl
dihydroimidazolylbutene-1,4-dioates 19.
(Ar-CH), 138.4, 141.5 and 141.8 (Ar-C), 140.0 (NC᎐CH), 163.4
᎐
(NCN), 163.9 and 164.0 (CO); m/z 420 (Mϩ, 2%), 391 (1), 375
(2), 364 (1), 347 (100), 319 (20), 275 (6), 249 (5), 238 (2), 178 (7),
165 (29), 152 (12), 128 (3), 115 (2), 91 (5).
Diethyl
(E)-2-[2-(but-3-enyl)-4,5-dihydroimidazol-1-yl]-
butene-1,4-dioate 19a and (Z)-5-ethoxycarbonylmethylene-7-
(prop-2-enyl)-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-
one 20a. Prepared by the general method, using 2-(but-3-enyl)-
4,5-dihydroimidazole 7b (0.83 g, 6.69 mmol) and diethyl acet-
ylenedicarboxylate (1.28 cm3, 8.03 mmol), to give after stirring
for 7 d the pyrroloimidazolone 20a as a yellow solid (0.10 g, 6%),
mp 162–164 ЊC (Found: C, 60.36; H, 6.40; N, 10.30%; MHϩ
249.1239. C13H16N2O3ؒ0.5H2O requires: C, 60.70; H, 6.61, N,
10.89%; MH 249.1235); νmax(KBr)/cmϪ1 3391 (NH), 3317,
2981, 1714 (CO2Et), 1658 (CO), 1554, 1494, 1321, 1150;
δH (300 MHz) 1.29 (3H, t, J 7.1, CH3CH2), 2.97 (2H, d, J 6.4,
Crystal data for 19b: C25H28N2O4, M = 420.49, triclinic,
a = 11.0117(5), b = 10.6661(8), c = 12.2753(9) Å, α = 65.331(3),
β = 65.329(4), γ = 62.908(3)Њ, U = 1119.42(13) Å3, T = 298(2) K,
¯
space group P1, monochromated Mo-Kα radiation, λ =
0.71073 Å, Z = 2, Dc = 1.248 Mg mϪ3, F(000) = 448, colourless
plates, dimensions 0.1 × 0.1 × 0.02 mm, µ(Mo-Kα) = 0.085
mmϪ1, 3.26 < 2θ < 23.25Њ, 8067 reflections measured, 3169
unique reflections. The structure was solved by direct methods
and refined by full-matrix least-squares on F2. The final cycle
(for 283 parameters) converged with wR2 = 0.1373 (for all data)
and R1 = 0.0558 [I > 2σ(I)].
CH CH᎐CH ), 3.94 (2H, t, J 7.4, NCH CH N), 4.14–4.26 (4H,
᎐
2
2
2
2
m, CH CH and NCH CH N), 5.01–5.13 (2H, m, CH᎐CH ),
᎐
3
2
2
2
2
5.78–5.88 (1H, m, CH᎐CH ), 5.83 (1H, s, CHCO Et), NH not
Diethyl (E)-2-(2-benzyl-4,5-dihydroimidazol-1-yl)butene-1,4-
dioate 19c and (Z)-5-ethoxycarbonylmethylene-7-phenyl-2,3,5,6-
tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-one 20c. Prepared by
the general method, using 2-benzyl-4,5-dihydroimidazole 7e
(2.00 g, 12.5 mmol) and diethyl acetylenedicarboxylate (2.40
cm3, 15.00 mmol), to give after stirring for 8 h the pyrrolo-
imidazolone 20c as an orange solid recrystallised from methanol
(1.50 g, 42%), mp 230–232 ЊC (Found: C, 67.55; H, 5.64; N,
9.84%; Mϩ 284.1155. C16H16N2O3 requires: C, 67.59; H, 5.67, N,
᎐
2
2
observed; δC (75 MHz) 14.3 (CH3), 25.4 (CH2), 45.4 and 47.6
(NCH ), 60.2 (OCH ), 85.9 (NC᎐C), 93.9 (CHCO Et), 115.1
᎐
2
2
2
(CH᎐CH ), 136.6 (CH᎐CH ), 144.1 (C᎐CHCO Et), 166.5
᎐
᎐
᎐
᎐
2
2
2
(NC᎐C), 168.8 (CO Et), 181.3 (CO); m/z 248 (Mϩ, 15%), 219
2
(4), 202 (10), 191 (13), 173 (15), 161 (14), 147 (17), 135 (5), 121
(8), 105 (12), 84 (62); and the diethyl dihydroimidazolylbutene-
1,4-dioate 19a as a yellow oil (0.34 g, 17%) (Found: C, 60.24; H,
7.46; N, 9.03%; Mϩ 294.1574. C15H22N2O4ؒ0.3H2O requires: C,
2340
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342

View Article Online
9.85%; M 284.1161); νmax(KBr)/cmϪ1 3291 (NH), 2984, 1712
(CO2Et), 1655 (CO), 1603, 1559, 1515, 1482, 1447, 1307, 1189,
1154, 1105, 701; δH [300 MHz; (CD3)2SO], 1.21 (3H, t, J 7.2,
CH3CH2), 4.00 (2H, t, J 7.5, NCH2CH2N), 4.10–4.17 (4H, m,
CH3CH2 and NCH2CH2N), 5.48 (1H, s, CHCO2Et), 7.05 (1H,
t, J 7.5, Ar-H), 7.28 (2H, t, J 7.5, Ar-H), 7.69 (2H, d, J 7.5, Ar-
H), NH not observed; δC [75 MHz; (CD3)2SO] 14.1 (CH3), 44.8
5-Ethoxycarbonylmethylene-7-(biphenyl-2-ylmethyl)-2,3,5,6-
tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-one, the (E)-isomer of
20b. Diethyl (E)-2-[2-(biphenyl-2-ylethyl)-4,5-dihydroimidazol-
1-yl]butene-1,4-dioate 19b (68 mg, 0.16 mmol) in THF (5 cm3)
was added to potassium tert-butoxide (35 mg, 0.31 mmol) in
THF (3 cm3). The yellow solution was stirred at 20 ЊC for 12 h,
the solvent was removed under reduced pressure and the resi-
due chromatographed on silica gel (0:3:7→5:95:0 methanol–
ethyl acetate–hexane) to give the title compound as a yellow oil
(32 mg, 54%) (Found: Mϩ 374.1627. C23H22N2O3 requires: M
374.1630); νmax(film)/cmϪ1 3404 (NH), 1712 (CO2Et), 1659
(CO), 1568, 1480, 1369, 1163; δH (300 MHz) 1.27 (3H, t, J 7.1,
CH3CH2), 3.55 (2H, s, CH2Ar), 3.63 and 4.09 (each 2H, t, J 7.4,
NCH2), 4.14 (2H, q, J 7.1, CH3CH2), 5.77 (1H, s, CHCO2Et),
7.20–7.47 (9H, m, Ar-H), NH not observed; δC (75 MHz) 14.2
(CH3), 25.0 (CH2), 45.3 and 47.3 (NCH2), 60.2 (OCH2), 88.1
and 48.0 (NCH ), 59.8 (OCH ), 88.4 (NC᎐C), 90.9 (CHCO Et),
᎐
2
2
2
123.7, 124.2 and 128.1 (Ar-CH), 132.5 (Ar-C), 144.0 (C᎐CH-
᎐
CO Et), 165.4 (NC᎐C), 168.8 (CO Et), 180.8 (CO); m/z 284
᎐
2
2
(Mϩ, 47%), 238 (42), 211 (28), 183 (32), 168 (9), 154 (27),
143 (27), 128 (48), 115 (88), 103 (31), 89 (100), 77 (48), 63 (35);
and the diethyl dihydroimidazolylbutene-1,4-dioate 19c as an
orange gum (1.42 g, 34%) that was incompletely characterised;
νmax(film)/cmϪ1 2982, 1739 and 1704 (CO2Et), 1577, 1416, 1366,
1161, 1021, 756; δH (300 MHz) 1.23–1.33 (6H, m, 2 × CH3CH2),
3.64 (2H, t, 9.6, NCH2CH2N), 3.69 (2H, s, PhCH2), 3.84 (2H, t,
J 9.6, NCH2CH2N), 4.14 and 4.30 (each 2H, q, J 7.2, CH3CH2),
5.05 (1H, s, CHCO2Et), 7.18–7.34 (5H, m, Ar-H); δC (75 MHz)
13.5 and 14.2 (CH3), 34.7 (CH2), 50.1 and 52.0 (NCH2),
62.0 and 62.7 (OCH2), 96.9 (CHCO2Et), 126.9, 128.4 and 129.1
(NC᎐C), 93.9 (CHCO Et), 126.4, 127.1, 127.9, 128.3, 129.5,
᎐
2
130.3 and 137.6 (Ar-CH), 141.2 and 141.8 (Ar-C), 143.6
(C᎐CHCO Et), 166.5 (NC᎐C), 169.4 (CO Et), 184.4 (CO); m/z
᎐
᎐
2
2
374 (Mϩ, 17%), 345 (3), 328 (2), 317 (2), 299 (9), 271 (22), 247
(2), 221 (2), 203 (11), 189 (8), 178 (16), 165 (100), 152 (66), 128
(9), 115 (13), 94 (8), 7 (42).
(Ar-CH), 134.9 (Ar-C), 144.2 (C᎐CHCO Et), 158.8 (NCN),
᎐
2
164.4 and 166.2 (CO); m/z 331 (MHϩ, 2%), 303 (1), 289 (2), 257
(23), 238 (16), 229 (7), 213 (47), 200 (10), 183 (7), 162 (9), 140
(32), 126 (28), 91 (100).
(Z)-5-Ethoxycarbonylmethylene-7-phenyl-2,3,5,6-tetrahydro-
1H-pyrrolo[1,2-a]imidazol-6-one 20c and its (E)-isomer. Pre-
pared as for pyrroloimidazolone 20b, using diethyl (E)-2-(2-
benzyl-4,5-dihydroimidazol-1-yl)butene-1,4-dioate 19c (68 mg,
0.16 mmol) to give the (Z)- and (E)-isomers of the title com-
pound (0.69 g, 67%; Z:E 5:1) as orange and yellow solids,
respectively, after chromatography. (E)-isomer (less polar
material): mp 172–174 ЊC (Found: Mϩ 284.1161. C16H16N2O3
requires: M 284.1161); νmax(KBr)/cmϪ1 3436 (NH), 1636, 1610,
1543, 1495, 1233, 1216, 1186, 780; δH (300 MHz) 1.36 (3H, t,
J 7.2, CH3CH2), 3.49 (2H, t, J 7.2, NCH2CH2N), 4.25 (2H, q,
J 7.2, CH3CH2), 4.43 (2H, t, J 7.2, NCH2CH2N), 5.06 (1H, s,
CHCO2Et), 7.26 (1H, t, J 7.8, Ar-H), 7.39 (2H, t, J 7.8, Ar-H),
8.22 (2H, d, J 7.8, Ar-H), 13.82 (1H, br s, NH); δC (100 MHz)
Crystal data for 20c: C16H16N2O3, M = 284.32, ortho-
rhombic, a = 7.1760(10), b = 17.805(4), c = 20.947(4) Å, U =
2976.4(9) Å3, T = 150(2) K, space group Pbca, monochromated
Mo-Kα radiation, λ = 0.71073 Å, Z = 8, Dc = 1.411 Mg mϪ3
,
F(000) = 1200, orange needles, dimensions 0.4 × 0.25 × 0.25
mm, µ(Mo-Kα) = 0.099 mmϪ1, 1.94 < 2θ < 27.47Њ, 16412 reflec-
tions measured, 3062 unique reflections. The structure was
solved by direct methods and refined by full-matrix least-
squares on F2. The final cycle (for 191 parameters) converged
with wR2 = 0.1595 (for all data) and R1 = 0.0576 [I > 2σ(I)].
(Z)-5-Methoxycarbonylmethylene-7-phenyl-2,3,5,6-tetra-
hydro-1H-pyrrolo[1,2-a]imidazol-6-one 20d and its (E)-isomer.
Prepared by the general method, using 2-benzyl-4,5-dihydro-
imidazole 7e (3.05 g, 19.06 mmol) and dimethyl acetylenedicarb-
oxylate (2.81 cm3, 22.87 mmol), to give after stirring for 72 h
the (Z)-isomer of the title compound, as an orange precipitate
recrystallised from methanol (1.24 g, 24%), mp 236–238 ЊC
(Found: C, 66.17; H, 5.14; N, 10.25%; Mϩ 270.1002. C15H14-
N2O3 requires: C, 66.66; H, 5.22; N, 10.36%; M 270.1004);
νmax(KBr)/cmϪ1 3255 (NH), 1717 (CO2Me), 1674 (CO), 1604,
1562, 1514, 1309, 1189, 1169, 1154, 1105; δH [300 MHz;
(CD3)2SO] 3.66 (3H, s, CH3), 4.00 and 4.13 (2H, t, J 7.2,
NCH2CH2N), 5.49 (1H, s, CHCO2Me), 7.05 (1H, t, J 7.5,
Ar-H), 7.28 (2H, t, J 7.5, Ar-H), 7.67 (2H, d, J 7.5, Ar-H), 9.58
(1H, br s, NH); δC [75 MHz; (CD3)2SO] 44.8 and 47.9 (NCH2),
14.2 (CH ), 41.1 and 41.5 (NCH ), 61.1 (NC᎐C), 61.7 (OCH ),
᎐
3
2
2
88.4 (CHCO2Et), 127.1, 127.4, 128.3 (Ar-CH), 130.8 (Ar-C),
148.7 (C᎐CHCO Et), 159.3 (NC᎐C), 164.2 (CO Et), 172.7
᎐
᎐
2
2
(CO); m/z 284 (Mϩ, 17%), 238 (100), 209 (15), 181 (10), 167 (1),
153 (5), 143 (6), 128 (6), 115 (17), 103 (4), 89 (7), 77 (4); (Z)-
isomer identical to that reported above.
Acknowledgements
We thank the Open University for a studentship (P. D.), the
EPSRC for its support of the National X-Ray Crystallography
Service Centre, and the EPSRC National Mass Spectrometry
Service Centre (Swansea) for some MS data. One of the
authors (R. C. F. J.) would like to acknowledge his debt of
gratitude to the late Professor Leslie Crombie for help, advice
and guidance at an early stage in his career.
51.2 (OCH ), 88.4 (NC᎐C), 90.6 (CHCO Me), 123.7, 124.2
᎐
3
2
and 128.1 (Ar-CH), 132.4 (Ar-C), 144.1 (C᎐CHCO Me), 165.8
᎐
2
(NC᎐C), 168.2 (CO Me), 180.8 (CO); m/z 270 (Mϩ, 86%), 238
᎐
2
References
(100), 209 (29), 181 (26), 168 (4), 153 (14), 143 (17), 129 (10),
115 (34), 103 (12), 89 (38), 77 (19); the (E)-isomer of the title
compound was obtained from the filtrate, by evaporation and
recrystallision of the residue from methanol–hexane, as an
orange solid (1.70 g, 33%), mp 161–163 ЊC (Found: Mϩ
270.1020. C15H14N2O3 requires: M 270.1004); νmax(KBr)/cmϪ1
3251 (NH), 1716, 1614, 1550, 1511, 1494, 1443, 1421, 1233,
1218, 1183, 797, 776; δH (300 MHz) 3.38 (2H, t, J 7.2, NCH2-
CH2N), 3.78 (3H, s, CH3), 4.36 (2H, t, J 7.2, NCH2CH2N), 4.98
(1H, s, CHCO2Me), 7.26 (1H, t, J 7.6, Ar-H), 7.39 (2H, t, J 7.6,
Ar-H), 8.22 (2H, d, J 7.6, Ar-H), 13.72 (1H, br s, NH); δC (100
1 See for example: R. J. Grout in The Chemistry of Amidines and
Imidates, ed. S. Patai, Wiley Interscience, London, 1975, p. 255;
D. M. Bailey, C. G. Degrazia, D. Wood and J. Siggins, J. Med.
Chem., 1974, 17, 702.
2 R. R. Ruffolo, W. E. Bondinell and J. P. Hieble, J. Med. Chem. 1995,
38, 3681; C. B. Chapleo, Chem. Br., 1986, 313.
3 R. C. F. Jones and P. Dimopoulos, Tetrahedron, 2000, 56, 2061;
R. C. F. Jones, P. Patel, S. C. Hirst and I. Turner, Tetrahedron,
1997, 53, 11781; R. C. F. Jones, J. S. Snaith, M. W. Anderson and
M. J. Smallridge, Tetrahedron, 1997, 53, 1111; M. W. Anderson,
R. C. F. Jones and J. Saunders, J. Chem. Soc., Perkin Trans. 1, 1986,
205; M. W. Anderson, R. C. F. Jones and J. Saunders, J. Chem. Soc.,
Perkin Trans. 1, 1986, 1995.
MHz) 41.3 (NCH2), 51.9 (OCH3), 61.2 (NC᎐C), 87.8
᎐
(CHCO2Me), 127.1, 127.4 and 128.3 (Ar-CH), 130.8 (Ar-C),
4 R. C. F. Jones and J. Schofield, J. Chem. Soc., Perkin Trans. 1, 1990,
375–383.
5 R. C. F. Jones, P. Patel, S. C. Hirst and M. J. Smallridge,
Tetrahedron, 1998, 54, 6191.
148.6 (C᎐CHCO Me), 159.3 (NC᎐C), 163.9 (CO Et), 172.7
᎐
᎐
2
2
(CO); m/z 270 (Mϩ, 25%), 238 (100), 209 (6), 181 (5), 153 (7),
143 (9), 128 (6), 115 (17), 91 (13), 77 (2).
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342
2341

View Article Online
6 See: Z.-T. Huang and M.-X. Wang in The Chemistry of Enamines,
ed. Z. Rappoport, Wiley Interscience, London, 1994, p. 1303, for a
survey of annulations of ketene aminals 2 and analogues.
7 Cf. M.-X. Wang, J.-M. Liang and Z.-T. Huang, J. Chem. Res. (S),
1994, 166; J. Chem. Res. (M), 1994, 1001.
8 R. C. F. Jones and S. C. Hirst, Tetrahedron Lett., 1989, 30,
5361.
mechanism in reactions of ketene aminals having a secondary amino
group.
10 C. V. Magani and F. J. Villani, J. Heterocycl. Chem., 1978, 15, 1021.
11 Crystal data for compounds 17c, 19b and 20c are deposited with the
Cambridge Crystallographic Database, CCDC reference number
207/444. See http://www.rsc.org/suppdata/p1/b0/b001830i/ for
crystallographic files in .cif format.
9 See: J.-H. Zhang, M.-X. Wang and Z.-T. Huang, J. Chem. Soc.,
Perkin Trans. 1, 1999, 2087, for a discussion of the aza-ene
12 Cf. Z.-T. Huang and M.-X. Wang, J. Chem. Soc., Perkin Trans. 1,
1993, 1085.
2342
J. Chem. Soc., Perkin Trans. 1, 2000, 2331–2342