Annulation of dihydroimidazoles: A 1,3-dipolar cycloaddition route to pyrrolo[1,2-a]imidazoles, pyrrolidines and pyrroles

Article abstract of DOI:10.1039/a802048e

4,5-Dihydroimidazolium ylides, formed by N-alkylation of 4,5-dihydroimidazoles, undergo diastereoselective endo 1,3-dipolar cycloaddition with electron-deficient alkene dipolarophiles to afford hexahydropyrrolo[1,2-a]imidazoles; reduction of the aminal fu

Full text of DOI:10.1039/a802048e

View Article Online / Journal Homepage / Table of Contents for this issue
Annulation of dihydroimidazoles: a 1,3-dipolar cycloaddition route to
pyrrolo[1,2-a]imidazoles, pyrrolidines and pyrroles
Raymond C. F. Jones,*,a Kevin J. Howard,a John R. Nicholsb and John S. Snaitha
a Department of Chemistry, The Open University, Walton Hall, Milton Keynes, UK MK7 6AA
b Department of Chemistry, University of Nottingham, University Park, Nottingham,
UK NG7 2RD
4,5-Dihydroimidazolium ylides, formed by N-alkylation of 4,5-dihydroimidazoles, undergo
diastereoselective endo 1,3-dipolar cycloaddition with electron-deficient alkene dipolarophiles to afford
hexahydropyrrolo[1,2-a]imidazoles; reduction of the aminal functionality in the cycloadducts leads to
substituted pyrrolidines. Cycloaddition using 2-chloropropenonitrile, followed by base treatment,
affords pyrroles.
CH2Ph
Introduction
N
The use of azomethine ylides 1 as 1,3-dipoles in cycloaddition
reactions to form five-membered nitrogen-containing rings has
N
been the focus of considerable attention.1 Our long-standing
5
interest in the chemistry of 4,5-dihydroimidazoles (2-imid-
azolines),2 including their annulation,3 and the limited reports
BrCHRX
THF
of the use of amidines as sources of azomethine ylides,4
prompted us to investigate the generation and reactions of 4,5-
dihydroimidazolium ylides 2. In our preliminary reports,5 ylides
2 have been shown to undergo diastereoselective cycloaddition
reactions to produce novel hexahydropyrrolo[1,2-a]imidazoles
3, of interest (i) as aza-analogues of naturally occurring
pyrrolizidines, e.g. retronecine 4, the heterocyclic sub-unit of
CH2Ph
N
CH2Ph
H
N
Me
DBU, CH2=C(Me)Y
Y
(6a–e)
N+
N
Br –
X
X
R
R
6a; R = H, X = CO2Me
6b; R = H, X = CO2Et
6c; R = H, X = CO2But
6d; R = Me, X = CO2Et
6e; R = H, X = COPh
6f; R = H, X = CN
7a; R = H, X = Y = CO2Me
CH2Ph
N
OH
CH2Ph
N
7b; R = H, X = CO2Et, Y = CO2Me
7c; R = H, X = CO2But, Y = CO2Me
7d; R = H, X = COPh, Y = CO2Me
7e; R = H, X = CO2Me, Y = CN
7f; R = H, X = CO2Et, Y = CN
7g; R = H, X = CO2But, Y = CN
7h; R = Me, X = CO2Et, Y = CN
7i; R = H, X = COPh, Y = CN
H
Y
CH2OH
RN
X
Z
N
N
N
X
6g; R = H, X = 4-O2NC6H4
X
1
2
3
4
many of the hepatotoxic pyrrolizidine alkaloids,6 and (ii)
because hexahydropyrrolo[1,2-a]imidazoles have been reported
to have antiinflammatory properties.7 Furthermore, reduction
or elimination leads to the formation of pyrrolidines and
pyrroles respectively. We now report in full the results of our
investigations in this area.5
Scheme 1
tion of the imidazoline in THF under nitrogen (Scheme 1).
Isolation by simple filtration or evaporation afforded hygro-
scopic solids or semi-solids which were not fully characterized
and were used immediately.
Selecting as a test reaction 1-benzyl-3-ethoxycarbonylmethyl-
4,5-dihydro-1H-imidazol-3-ium bromide 6b as dipole precur-
sor, and methyl 2-methylpropenoate as dipolarophile, a range
of bases was examined for ylide formation by deprotonation of
the dihydroimidazolium salt. n-Butyllithium in THF at Ϫ78 ЊC
failed to yield any cycloaddition product, as did triethylamine
or diisopropylethylamine at room temperature in the absence
of solvent, or a number of the phosphazene bases in THF.8
Success finally came with the use of 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) at room temperature without solvent,
affording cycloadduct 7b which was isolated as a 10:1 mixture
of stereoisomers after chromatography, although in a dis-
appointingly low yield of 6%. After extensive investigation it
was found that the yield of this test reaction could be raised to
34%, and yields between 29–69% obtained for the range of
cycloadditions examined, with considerable improvement in the
stereoisomer ratio, using one of two protocols: Protocol A:
Dropwise addition of DBU over 10 minutes to a slurry of
freshly prepared quaternary salt in excess dipolarophile; and
Results and discussion
Our strategy for generation of the ylides 2 was the N-alkyl-
ation of a 2-unsubstituted 4,5-dihydroimidazole followed by
C-deprotonation. Initial investigations focussed on stabilised
azomethine ylides, that is those bearing an electron with-
drawing group on the formally negative end of the dipole. In
our early protocol,5a later revised to a one-pot procedure,5b
a
quaternary salt of the dihydroimidazole was formed and
isolated before being subjected to the deprotonation–cyclo-
addition step.
Thus, 1-benzyl-4,5-dihydroimidazole 5 was easily prepared
by treatment of N-benzyl-1,2-diaminoethane with excess tri-
ethyl orthoformate under acidic catalysis. Dihydroimidazole 5
was smoothly N-alkylated to form the quaternary salts 6a–g
using, respectively, the α-bromo esters methyl, ethyl and tert-
butyl bromoacetate, as well as ethyl 2-bromopropionate,
2-bromoacetophenone, bromoacetonitrile, and 4-nitrobenzyl
bromide by dropwise addition of the bromide to a stirred solu-
J. Chem. Soc., Perkin Trans. 1, 1998
2061

View Article Online
Table 1 Cycloaddition of azomethine ylides derived from salts 6a–e (Scheme 1)
Entry
Salt
R
X
Y
Cycloadduct
Yield (%)
Protocol
1
2
3
4
5
6
7
8
9
6a
6b
6c
6e
6a
6b
6c
6d
6e
H
H
H
H
H
H
H
Me
H
CO2Me
CO2Et
CO2But
COPh
CO2Me
CO2Et
CO2But
CO2Et
COPh
CO2Me
CO2Me
CO2Me
CO2Me
CN
CN
CN
7a
7b
7c
7d
7e
7f
7g
7h
7i
29 (64)
34
52 (71)
50
42 (46)
42
69
A (C)
A
B (C)
B
B (C)
B
B
CN
CN
63
46
B
B
CH2Ph
CH2Ph
N
2.5%
H
N
Me
H
7
N
7a
Y
X
N
CO2Me
R
H
5
Me
EtO2C
H
H
Fig. 1
Fig. 2
Protocol B: Addition of DBU by syringe pump over 4 hours to
a solution of the quaternary salt and excess dipolarophile in
THF at reflux.
The proposed transition state is summarised in Fig. 2, and is
consistent with other results involving azomethine ylides gener-
ated from iminium salts.10
The observed regiochemistry of cycloaddition is as expected
for a stabilised azomethine ylide with an electron-deficient
In later experiments it was found unnecessary to isolate the
quaternary salt, and the final preferred protocol,5b Protocol C,
consisted of in situ formation of the quaternary salt by addition
of the bromo compound to a solution of imidazoline 5 in THF
at reflux, followed immediately by addition of excess dipolaro-
phile and then addition of DBU by syringe pump over 4 hours.
Cycloaddition using the salts 6a–c, derived from methyl,
ethyl and tert-butyl bromoacetates, respectively, proceeded
smoothly with both methyl 2-methylpropenoate and 2-methyl-
propenonitrile as dipolarophile, affording endo adducts 7a–c
and 7e–g, respectively (Scheme 1, Table 1). In some early, low-
yielding preparations of 7g performed at room temperature,
significant proportions of a second stereoisomer 8 were
dipolarophile,
with
HOMO-dipole/LUMO-dipolarophile
orbital control;11 there was no evidence of products with the
alternative possible regiochemistry.
1
When the pyrroloimidazoles 7 were analysed by H NMR
spectroscopy immediately after chromatography on silica gel
using ethyl acetate–hexane as eluent, they were found to consist
of a single diastereoisomer. On storage, however, or if chrom-
atography was performed with a basic eluent (dichloromethane–
ethanol–aqueous ammonia or ethyl acetate–triethylamine),
then varying amounts of a new stereoisomer were encountered,
consistent with C-7a epimerisation of the primary cycloadduct;
a plausible rationalization is shown in Scheme 2.
CH2Ph
H
N
CN
Me
CH2Ph
CH2Ph
CH2Ph
NH
N
H
N
H
N
Me
Me
Me
ButO2C
H+
Y
Y
Y
H
N
N
N
H
X
8
X
X
H
H
observed. This allowed for the separation of 7g and 8 and the
characterisation of the latter as the exo adduct, supporting our
postulate that any trace stereoisomer seen in the other cyclo-
additions is indeed the exo cycloadduct. The quaternary salt 6d,
derived from alkylation of 5 by ethyl 2-bromopropionate,
afforded a 63% yield of cycloadduct 7h with 2-methylpropeno-
nitrile. Using the quaternary salts 6f and 6g, from alkylation of
5 with bromoacetonitrile or 4-nitrobenzyl bromide, respectively,
cycloaddition products could not be isolated, although the
benzoylmethyl salt 6e did undergo reaction. Using methyl
2-methylpropenoate and 2-methylpropenonitrile, cycloadducts
7d and 7i were isolated in 50 and 46% yield, respectively.
The relative stereochemistry of the cycloadducts was secured
by 1H NOE difference spectroscopy. For example in cyclo-
adduct 7b, as shown in Fig. 1, observation of an enhancement
of the signal for the bridgehead proton at C-7a on irradiation
of the C-7 methyl group protons confirms that they are on the
same face of the molecule, consistent with an endo approach of
the dipolarophile to the azomethine ylide dipole. Failure to
observe an enhancement at the C-5(H) on irradiation of the C-7
methyl group provides tentative evidence that they are on
opposite faces of the molecule, an observation in agreement
with later findings9 and consistent with an anti dipole geometry.
7
Scheme 2
Extending our studies to α-unsubstituted dipolarophiles,
using Protocol C, treatment of dihydroimidazole 5 with methyl
bromoacetate and three equivalents of methyl propenoate, fol-
lowed by addition of DBU via syringe pump, afforded, after
column chromatography, a 52% yield of cycloadduct as a 2.3:1
ratio of stereoisomers which could not be separated. Spectral
data are consistent with the stereoisomers being epimers at C-7,
i.e. 9 and 10, and considering the stereoselectivity of the earlier
examples, this ratio is unlikely to reflect the endo:exo preference
of the reaction, rather to be a result of the chromatography.
Cycloadducts 9 and 10 could also not be fully separated from a
much more polar material, tentatively postulated to be enamino
1
ester 11, although there was no firm evidence of this in the H
or 13C NMR spectra, suggesting that if 11 is present, it is in
trace amounts or forms only under the acidic conditions of
silica gel (Scheme 3).
Using Protocol C, and methyl bromoacetate to alkylate
dihydroimidazole 5, cycloaddition of N-phenylmaleimide
afforded a 6:1 mixture of endo:exo adducts 12 and 13, respect-
2062
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
acetoxy)pent-2-enoate 16 was prepared using the sequence that
CH2Ph
we have previously outlined.12 Hydration of propenal and in
situ Wittig reaction with ethoxycarbonylmethylenetriphenyl-
phosphorane afforded ethyl 5-hydroxypent-2-enoate, and reac-
tion with bromoacetyl bromide led to the dienophile 16, which
was not stable on storage and had to be used directly. Treatment
of the dihydroimidazole 5 in THF at reflux with one equivalent
of bromo ester 16 followed by addition of DBU via syringe
pump over 4 hours afforded, after chromatography over silica
gel, not the expected cycloadduct 17, but rather lactam 18.
Evidence for the structure of 18, postulated to be formed as
shown in Scheme 6 via collapse of 17 involving elimination (cf.
H
N
CO2Me
H
N
MeO2C
H
10
CH2Ph
CH2Ph
NH
H
N
H
CO2Me
CO2Me
N
N
CH2Ph
MeO2C
MeO2C
H
N
H
H
CO2Et
CH2Ph
N
O
11
9
Br
CO2Et
N
H+
O
16
DBU
CH2Ph
NH
N
O
O
17
H
5
N
H
CO2Me
MeO2C
CO2Et
N
Scheme 3
N
O
CH2Ph
CH2Ph
OH
PhH2C
CH2Ph
N
O
O
H
H
N
N
18
BrCH2CO2Me, DBU
O
+
N
NPh
N
NPh
O
Scheme 6
N
NPh
O
1
MeO2C
O
Scheme 3) and lactam formation, came from the H and 13C
NMR spectra, in particular signals at δH 7.08 and δC 148.10
(methine), and from infrared absorptions at νmax 3376 (br, OH),
MeO2C
5
13
12
Scheme 4
1710 (enamino ester C᎐O), 1657 (lactam C᎐O) and 1629 (C᎐C)
᎐
᎐
᎐
cmϪ1
.
ively, in a combined yield of 31% (Scheme 4). Repeated column
chromatography allowed for their separation, although with
significant loss of material, affording only 8% of 12 and 4% of
13.
Again employing Protocol C and alkylating with methyl
bromoacetate, cycloaddition of methyl (E)-but-2-enoate
afforded a 22% yield of 14 as a single diastereoisomer, but this
epimerised at C-7 on standing (Scheme 5) to afford 15. Con-
Of interest for the potential access to aza-analogues of
retronecine, the cycloaddition using alkynes such as methyl
propynoate as dipolarophiles was investigated, but it was found
that base-catalysed polymerisation processes intervened and
none of the cycloadduct was isolated. An alternative approach,
circumventing the use of alkynes, would be to synthesise
7-halo-substituted cycloadducts which could undergo hydrogen
halide elimination on base treatment to introduce the desired
C-6,7 unsaturation. To this end, the commercially available
2-chloropropenonitrile was found to add to quaternary salts
6a–c and 6e (Protocol B) to produce cycloadducts 19a–d,
respectively, as a 1:1 mixture of stereoisomers in all cases
(Scheme 7). Elimination was effected by treatment of the
CH2Ph
CH2Ph
H
N
N
CO2Me
Me
BrCH2CO2Me, DBU
N
Me
CO2Me
N
MeO2C
CH2Ph
NH
CH2Ph
CH2Ph
N
5
H
N
14
Cl
DBU, CH2=C(Cl)CN
DBU
CN
CN
N
X
N
X
N
CH2Ph
X
H
N
CO2Me
Me
6a; X = CO2Me
6b; X = CO2Et
6c; X = CO2But
6e; X = COPh
19a; X = CO2Me
19b; X = CO2Et
19c; X = CO2But
19d; X = COPh
21a; X = CO2Et
21b; X = CO2But
21c; X = COPh
N
MeO2C
15
Scheme 7
Scheme 5
chloro-cycloadducts with DBU in DMSO at 100 ЊC, but it did
not prove possible to isolate the desired dihydropyrroles 20
which instead underwent a second elimination to form the
N-substituted pyrroles, 18b–d affording 21a–c, respectively.
Also of interest was the cycloaddition of unstabilised ylides,
conveniently prepared by the fluoride-mediated desilylation
protocol developed by Vedejs.13 Quaternary salt 22 was pre-
firmation of stereochemistry in the adducts 12 and 14 came
from H NOE difference experiments, but a combination of
insufficient material and overlapping signals did not permit
rigorous configurational assignment at C-7a in 13 and 15.
We wished to examine an intramolecular variant of the
cycloaddition, to which end the bromo ester ethyl 5-(bromo-
1
J. Chem. Soc., Perkin Trans. 1, 1998
2063

View Article Online
Table 2 Reduction of cycloadducts with sodium cyanoborohydride (Scheme 9)
Entry
R1
R2
X
Y
Cycloadduct
Pyrrolidine
Yield (%)
1
2
3
4
5
6
H
H
H
Me
H
Me
Me
Me
Me
Cl
CO2Et
CO2Et
CO2But
CO2Et
CO2But
H
CO2Me
CN
CN
CN
CN
7b
7f
24a
24b
24c
24d
24e
24f
68
99
86
71
86
82
7g
7h
19c
23b
H
Me
CO2Me
CH2Ph
CH2Ph
R2
H
N
H
N
CN
Y
N
N
X
R1
X
20
7b; R1 = H, R2 = Me, X = CO2Et, Y = CO2Me
7f; R1 = H, R2 = Me, X = CO2Et, Y = CN
7g; R1 = H, R2 = Me, X = CO2But, Y = CN
7h; R1 = R2 = Me, X = CO2Et, Y = CN
19c; R1 = H, R2 = Cl, X = CO2But, Y = CN
23b; R1 = X = H, R2 = Me, Y = CO2Me
pared by alkylating the dihydroimidazole 5 as a solution in
diethyl ether with trimethylsilylmethyl trifluoromethanesulf-
onate; solvent evaporation afforded 22 as a solid. The salt was
taken up in diglyme and added by cannula to a slurry of cae-
sium fluoride and the dipolarophile in diglyme, and the mixture
stirred at room temperature for 20 h. After chromatography
adducts 23a–c were isolated, using methyl propenoate, methyl
2-methylpropenoate and 2-methylpropenonitrile, respectively,
in yields of 43, 47, and 60% (Scheme 8). Adducts 23a and 23b
NaBH3CN, H+
CH2Ph
R2
NH
Y
N
CH2Ph
N
CH2Ph
CH2Ph
N
H
N
R
X
Me3SiCH2SO2CF3
R1
CsF, CH2=C(R)Y
Y
24a; R1 = H, R2 = Me, X = CO2Et, Y = CO2Me
24b; R1 = H, R2 = Me, X = CO2Et, Y = CN
24c; R1 = H, R2 = Me, X = CO2But, Y = CN
24d; R1 = R2 = Me, X = CO2Et, Y = CN
24e; R1 = H, R2 = Cl, X = CO2But, Y = CN
24f; R1 = X = H, R2 = Me, Y = CO2Me
N
N
N
Me3Si
5
22
23a; R = H, Y = CO2Me
23b; R = Me, Y = CO2Me
23c; R = Me, Y = CN
Scheme 8
Scheme 9
were each obtained as a 1:1 mixture of diastereoisomers, and
23c as a 2:1 mixture.
CO2Me
A number of fruitless attempts were made to extend the
scope of the cycloaddition to less electron-poor alkenes. For
example, use of 4-nitro- and 4-cyano-phenylethene, or phenyl-
ethene itself as dipolarophiles met with no success.
N
N
O
PhH2C
25
Treatment of an acidic solution of the cycloadducts 7 with
NaBH3CN smoothly effected aminal cleavage, resulting in good
yields of N-substituted pyrrolidines (Scheme 9, Table 2). Thus
7b and 7f–h were reduced to afford pyrrolidines 24a–d in yields
of 68, 99, 86 and 71%, respectively. 2-Chloropropenonitrile
adduct 19c was similarly reduced in 86% yield to 24e, whilst
5-unsubstituted adduct 23b was reduced to 24f (82%). All of the
pyrrolidines 24 were obtained as a single diastereoisomer after
chromatography, except for chloropyrrolidine 24e which was
obtained as a 1:1 mixture of epimers at C-4, reflecting the
composition of stereoisomers in the precursor cycloadduct 19c.
Whilst tert-butyloxycarbonylpyrrolidines 24c and 24e were
stable towards lactamisation, the ethyl esters 24a, 24b and 24d
were found to lactamise slowly on standing. In contrast, reduc-
tion of methyl ester 9 resulted in an extremely facile cyclisation
to afford lactam 25 (45% over 2 steps from 5 via Protocol C)
as the sole product in an unchanged epimer ratio of 2.3:1.
Chromatography allowed for the separation of pure trans
lactam (10%), although with a considerable accompanying loss
of material; the minor cis isomer could not be isolated in a pure
form.
CH2Ph
CH2Ph
H
N
N
X
Me
CO2Me
H
N
N
X
Me
CH2OH
LiAlH4
7c; X = CO2But
23b; X = H
26a; X = CH2OH
26b; X = H
Scheme 10
We have thus demonstrated the formation of 4,5-dihydro-
imidazolium ylides and their diasteroselective 1,3-dipolar cyclo-
additions with a variety of electron-deficient dipolarophiles to
form pyrrolo[1,2-a]imidazoles and thence, by reduction or
elimination, pyrrolidines and pyrroles. The extension of this
methodology into asymmetric synthesis of the important
pyrrolidine ring system has subsequently been accomplished.9,12
Experimental
Reduction need not necessarily lead to ring opening. Thus,
treatment of 7c with LiAlH4 in Et2O afforded an 87% yield of
diol 26a, whilst similar treatment of 23b gave alcohol 26b in
98% yield (Scheme 10).
Melting points were obtained on a Gallenkamp capillary or a
Reichert hot stage and are uncorrected. IR spectra were
recorded using Pye Unicam SP1000, Pye Unicam SP3-100 or
2064
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
Perkin-Elmer 1720X FT spectrometers. Mass spectra were
recorded using AEI MS902 or VG 7070E spectrometers. H
4.15 (6H, m, NCH2CH2N and OCH2), 4.75 (2H, s, CH2CO2),
4.95 (2H, s, PhCH2), 7.50 (5H, m, Ar-H) and 10.00 (1H, s, CH).
1-Benzyl-3-tert-butoxycarbonylmethyl-4,5-dihydro-1H-
1
NMR spectra were obtained using the following spectrometers:
Perkin-Elmer R32 or JEOL FX90Q at 90 MHz; Bruker WM200
at 200 MHz; Bruker WM250 at 250 MHz; Bruker AM400 or
JEOL EX400 at 400MHz. 13C NMR spectra were recorded
using the following instruments: JEOL FX90Q spectrometer at
22.7 MHz; Bruker WM200 at 50.3 MHz; Bruker WM250 at
62.9 MHz; JEOL EX270 at 68 MHz; Bruker AM400 or JEOL
imidazol-3-ium bromide 6c. This was prepared from 1-benzyl-
4,5-dihydroimidazole 5 (460 mg, 2.87 mmol) by the method
described above for the preparation of 6a but using tert-butyl
bromoacetate (0.48 cm3, 3.02 mmol). This yielded the title
compound 6c (990 mg, 97%) as a hygroscopic solid which was
used without further purification; νmax(film)/cmϪ1 3420, 2980,
1740, 1640, 1380, 1160 and 710; δH(90 MHz) 1.50 (9H, s, 3 ×
CH3), 4.10 (4H, m, NCH2CH2N), 4.55 (2H, s, CH2CO2), 4.95
(2H, s, PhCH2), 7.50 (5H, m, Ar-H) and 10.05 (1H, s, CH).
1-Benzyl-3-(1-ethoxycarbonylethyl)-4,5-dihydro-1H-imidazol-
3-ium bromide 6d. This was prepared from 1-benzyl-4,5-di-
hydroimidazole 5 (840 mg, 5.25 mmol) by the method described
above for the preparation of 6a but using ethyl 2-bromo-
propionate (0.68 cm3, 5.25 mmol). This yielded the title com-
pound 6d (1.79 g, >100%) as a colourless hygroscopic oil which
was used without further purification; δH(60 MHz) 1.30 (3H, t,
J 7.2, CH2CH3), 1.75 (3H, d, J 7.2, CHCH3), 4.0 (4H, m,
NCH2CH2N), 4.25 (2H, q, J 7.2, OCH2), 5.00 (3H, m, PhCH2
and CHCO), 7.40 (5H, m, Ar-H) and 10.10 (1H, s, 2-H).
3-Benzoylmethyl-1-benzyl-4,5-dihydro-1H-imidazol-3-ium
bromide 6e. This was prepared from 1-benzyl-4,5-dihydro-
imidazole 5 (800 mg, 5.0 mmol) by the method described above
for the preparation of 6a but using 2-bromoacetophenone (1.04
g, 5.25 mmol) in dry THF (5 cm3). This yielded the title com-
pound 6e (1.87 g, >100%) as a pale yellow hygroscopic solid
which was used without further purification; δH(60 MHz) 4.00
(4H, m, NCH2CH2N), 4.80 (2H, s, PhCH2), 5.50 (2H, s,
CH2CO2), 7.50 (8H, m, Ar-H), 8.00 (2H, m, Ar-H) and 9.90
(1H, s, CH).
1-Benzyl-3-cyanomethyl-4,5-dihydro-1H-imidazol-3-ium
bromide 6f. This was prepared from 1-benzyl-4,5-dihydro-
imidazole 5 (980 mg, 6.12 mmol) by the method described
above for the preparation of 6a but using bromoacetonitrile
(0.45 cm3, 6.43 mmol). This yielded the title compound 6f
(1.69 g, 99%) as a colourless hygroscopic solid which was used
without further purification; νmax(KBr)/cmϪ1 3400, 2920, 2280,
1640, 1300, 1220, 750 and 700; δH(90 MHz) 3.95 (4H, m,
NCH2CH2N), 4.86 (2H, s, PhCH2), 5.32 (2H, s, CH2CN), 7.38
(5H, m, Ar-H) and 9.90 (1H, s, CH); δC(22.7 MHz) 37.39,
48.33, 48.98 and 52.34 (CH2), 113.78 (CN), 128.73 and 129.05
(Ar-CH), 131.65 (Ar-C) and 158.58 (C-2).
1
EX400 at 100.6 or 100.4 MHz, respectively. H NMR spectra
were determined in deuteriochloroform solution unless indi-
cated, and chemical shifts are quoted in parts per million (ppm)
from tetramethylsilane as internal standard; coupling con-
stants are quoted in Hz. 13C NMR spectra were determined in
deuteriochloroform solution and chemical shifts quoted in
ppm from tetramethylsilane as internal standard or from
tetramethylsilane using CDCl3 as internal standard. Column
chromatography was carried out at medium pressure using
Merck Kieselgel 60 (Art. 9385). Thin layer chromatography
(TLC) was carried out on silica plates (Kieselgel 60, F254, Merck
Art. 5554). Solvent extracts were dried over anhydrous mag-
nesium sulfate or sodium sulfate for at least 10 min. Ether refers
to diethyl ether and light petroleum corresponds to the fraction
with bp 40–60 ЊC. Tetrahydrofuran (THF) and ether were dis-
tilled from lithium aluminium hydride or potassium immedi-
ately prior to use. Other dry solvents were prepared as described
in Perrin et al.14
1-Benzyl-4,5-dihydroimidazole 5
N-Benzyl-1,2-diaminoethane15 (70 g, 0.467 mol), triethyl ortho-
formate (4.0 mol equiv., 276 g, 1.86 mol) and toluene-4-sulfonic
acid (catalytic, 4.0 g, 23 mmol) were heated together under
gentle reflux for 20 h. The resulting solution was cooled, basi-
fied by the addition of aqueous NaOH (5% w/v, 50 cm3) and
extracted with chloroform (2 × 250 cm3). The combined organic
extracts were dried and concentrated in vacuo. Fractional distil-
lation of the resulting liquor gave the title compound 5 (53.61 g,
72%), bp 120 ЊC at 2 mmHg (Found: Mϩ, 160.0987; C10H12N2
requires M, 160.1000); νmax(film)/cmϪ1 3205, 2835, 2800, 1681,
1614, 1591, 1357 and 980; δH(80 MHz) 3.13 and 3.82 (each 2H,
t, J 9.9, NCH2CH2N), 4.28 (2H, s, PhCH2), 6.97 (1H, s, CH)
and 7.31 (5H, s, Ar-H); δC(100.6 MHz) 47.92 and 51.49
(NCH2CH2N), 54.91 (PhCH2), 127.40, 127.53 and 128.48
(Ar-CH), 136.78 (Ar-C) and 157.27 (C-2); m/z 160 (Mϩ, 75%),
159 (5), 120 (7), 92 (26), 91 (100), 69 (25) and 65 (16). Com-
pound 5 solidified on standing and a portion was recrystallised
from cyclohexane–hexane to yield a colourless hygroscopic
solid, mp 46 ЊC.
1-Benzyl-3-(p-nitrobenzyl)-4,5-dihydro-1H-imidazol-3-ium
bromide 6g. This was prepared from 1-benzyl-4,5-dihydro-
imidazole 5 (1.0 g, 6.25 mmol) by the method described above
for the preparation of 6a but using 4-nitrobenzyl bromide (1.48
g, 6.875 mmol) in dry THF (5 cm3). This yielded the title com-
pound 6g (2.53 g, >100%) as a colourless hygroscopic solid
which was used without further purification; νmax(film)/cmϪ1
2900, 1640, 1510, 1350, 1210, 800 and 730; δH(90 MHz) 3.85
(4H, m, NCH2CH2N), 4.90 (2H, s, PhCH2), 5.20 (2H, s,
CH2C6H4NO2), 7.40 (5H, m, Ar-H), 7.80 and 8.30 (each 2H, d,
J 9, Ar-H) and 10.50 (1H, s, CH).
Preparation of imidazolium bromides 6a–g
1-Benzyl-3-methoxycarbonylmethyl-4,5-dihydro-1H-imidazol-
3-ium bromide 6a. Methyl bromoacetate (0.60 cm3, 6.36 mmol)
was added dropwise to a stirred solution of 1-benzyl-4,5-
dihydroimidazole 5 (970 mg, 6.06 mmol) in dry THF (30 cm3)
under an atmosphere of nitrogen. The mixture was stirred for a
further 30 min and the resulting liquor was then concentrated in
vacuo yielding the title compound 6a (1.89 g, 100%) as a viscous
hygroscopic colourless oil which was used without further
purification; νmax(film)/cmϪ1 3420, 3070, 2900, 1740, 1640, 1425,
1295, 1220, 1125 and 705; δH(90 MHz) 3.76 (3H, s, CH3), 4.07
(4H, m, NCH2CH2N), 4.75 (2H, s, CH2CO2), 4.88 (2H, s,
PhCH2), 7.40 (5H, m, Ar-H) and 10.05 (1H, s, CH).
1-Benzyl-3-ethoxycarbonylmethyl-4,5-dihydro-1H-imidazol-3-
ium bromide 6b. This was prepared from 1-benzyl-4,5-dihydro-
imidazole 5 (520 mg, 3.25 mmol) by the method described
above for the preparation of 6a but using ethyl bromoacetate
(0.40 cm3, 3.57 mmol). This yielded the title compound 6b (1.17
g, >100%) as a hygroscopic semi-solid which was used without
further purification; νmax(film)/cmϪ1 3450, 2950, 1745, 1650,
1210, 1030 and 710; δH(90 MHz) 1.30 (3H, t, J 7, CH2CH3),
1-Benzyl-5,7-bis(methoxycarbonyl)-7-methylhexahydro-1H-
pyrrolo[1,2-a]imidazole 7a via cycloaddition Protocol A
To
1-benzyl-3-methoxycarbonylmethyl-4,5-dihydro-1H-
imidazol-3-ium bromide 6a, prepared from 1-benzyl-4,5-
dihydroimidazole 5 (970 mg, 6.06 mmol) and methyl bromo-
acetate (0.60 cm3, 6.36 mmol), was added methyl 2-methyl-
propenoate (0.97 cm3, 9.09 mmol) and the mixture stirred for 5
min to produce a slurry. DBU (1.01 cm3, 6.67 mmol) was then
added dropwise over 10 min and the resulting mixture stirred
for a further 16 h. After concentration in vacuo and partitioning
between chloroform (2 × 30 cm3) and water (30 cm3), the com-
bined organic extracts were dried and concentrated in vacuo.
The crude product was purified by column chromatography
eluting with dichloromethane–ethanol–conc. aq. ammonia
J. Chem. Soc., Perkin Trans. 1, 1998
2065

View Article Online
(400:8:1 v/v/v) to afford the title compound 7a (580 mg, 29%) as
a colourless oil (Found: Mϩ, 332.1742; C18H24N2O4 requires M,
332.1736); νmax(film)/cmϪ1 2949, 2842, 2802, 1730, 1453, 1435,
1202, 1159, 1137 and 701; δH(400 MHz) 1.42 (3H, s, CH3), 2.10
(1H, dd, J 13.2 and 10.1, CHCHH), 2.57 (1H, m, NCHH-
CH2N), 2.77 (2H, m, NCH2CHHN and CHCHH), 3.00 (1H,
m, NCHHCH2N), 3.20 (1H, m, NCH2CHHN), 3.25 (1H, d,
J 12.8, PhCHH), 3.72 and 3.74 (6H, 2 × s, 2 × CH3), 4.04 (3H,
m, 7a-H, PhCHH and CHCO2) and 7.27 (5H, m, Ar-H);
δC(100.6 MHz) 23.10 (CH3), 42.59 (CHCH2), 51.68 and 51.96
(OCH3), 52.69 (quaternary C), 53.07 and 54.70 (NCH2CH2N),
58.55 (PhCH2), 67.72 (CHCO), 95.09 (C-7a), 126.87, 128.19
and 128.53 (Ar-CH), 138.72 (Ar-C), 174.29 and 174.86 (CO);
m/z 332 (Mϩ, 2%), 301 (6), 273 (8), 232 (100), 141 (89), 114 (13)
and 91 (58). A portion of the title compound was converted to
the oxalate salt, m.p. 64–66 ЊC, and recrystallised from ethanol–
ether (Found: C, 54.6; H, 6.4; N, 6.1%; C20H26N2O8ؒH2O
requires C, 54.5; H, 6.4; N, 6.4%).
1-Benzyl-5-ethoxycarbonyl-7-methoxycarbonyl-7-methyl-
hexahydro-1H-pyrrolo[1,2-a]imidazole 7b. Prepared from 1-
benzyl-4,5-dihydroimidazole 5 (740 mg, 4.625 mmol) by the
method described above for the preparation of 7a via Protocol
A but using ethyl bromoacetate (810 mg, 4.85 mmol), methyl
2-methylpropenoate (1.0 cm3, 9.25 mmol) and DBU (0.86 cm3,
5.78 mmol). The crude product was purified by column
chromatography eluting with dichloromethane–ethanol–conc.
aq. ammonia (400:8:1 v/v/v) to yield the title compound 7b
(537 mg, 33.5%) as a colourless oil (Found: Mϩ, 346.1882;
C19H26N2O4 requires M, 346.1892); νmax(film)/cmϪ1 2980, 2810,
1730, 1450, 1200, 1040, 750 and 700; δH(250 MHz) 1.28 (3H, t,
J 7.1, CH2CH3), 1.42 (3H, s, CH3), 2.10 (1H, dd, J 10.2 and
13.2, CHCHH), 2.57 (1H, m, NCH2CHHN), 2.77 (2H, m,
NCH2CHHN and CHCHH), 3.01 and 3.22 (each 1H, m,
NCH2CH2N), 3.24 (1H, d, J 12.8, PhCHH), 3.72 (3H, s,
OCH3), 4.02 (3H, m, 7a-H, PhCHH and CHCO2), 4.20 (2H,
dq, J 2.4 and 7.1, OCH2) and 7.25 (5H, m, Ar-H); δC(22.7
MHz) 14.15 (CH2CH3), 23.14 (CCH3), 42.37 (CHCH2), 51.47
(OCH3), 52.67 (quaternary C), 52.94 and 54.56 (NCH2CH2N),
58.57 (PhCH2), 60.52 (OCH2), 67.62 (CHCO), 95.14 (C-7a),
126.78, 127.97 and 128.46 (Ar-CH), 138.75 (Ar-C), 173.58 and
174.72 (CO); m/z 346 (Mϩ, 2%), 315 (6), 273 (10), 246 (100), 174
(26), 155 (65), 100 (11) and 91 (69).
5-Benzoyl-1-benzyl-7-methoxycarbonyl-7-methylhexahydro-
1H-pyrrolo[1,2-a]imidazole 7d. Prepared from 1-benzyl-4,5-
dihydroimidazole 5 (800 mg, 5.0 mmol) by the method
described above for the preparation of 7c via Protocol B
but using 2-bromoacetophenone (1.04 g, 5.25 mmol), methyl
2-methylpropenoate (2.0 g, 20.0 mmol) and DBU (800 mg, 5.25
mmol) and heating the mixture under reflux for 1 h. Column
chromatography eluting with ether–hexane (3:1 v/v) afforded
the title compound 7d (947 mg, 50%) as a colourless oil (Found:
Mϩ, 378.1917; C23H26N2O3 requires M, 378.1943); νmax(film)/
cmϪ1 3020, 2940, 2800, 1725, 1685, 1450, 1205, 1140 and 705;
δH(250 MHz) 1.42 (3H, s, CH3), 2.00 (1H, dd, J 12.9 and 10.7,
CHCHH), 2.61 and 2.77 (each 1H, m, NCH2CH2N), 2.92 (1H,
dd, J 12.9 and 6.5, CHCHH), 3.12 (2H, m, NCH2CH2N), 3.29
(1H, d, J 13.0, PhCHH), 3.78 (3H, s, OCH3), 4.13 (2H, m,
PhCHH and 7a-H), 4.99 (1H, dd, J 10.6 and 6.5, CHCO),
7.39 (8H, m, Ar-H) and 8.06 (2H, m, Ar-H); δC(22.7 MHz)
22.93 (CH3), 43.68 (CHCH2), 51.53 (CH3O), 52.40 (NCH2-
CH2N), 52.83 (quaternary C), 54.51 (NCH2CH2N), 58.52
(PhCH2), 70.92 (CHCO), 95.14 (C-7a), 126.62, 127.92, 128.24
and 132.74 (Ar-CH), 135.99 and 138.70 (Ar-C), 174.94 (ester
CO) and 199.26 (ketone CO); m/z 378 (Mϩ, 0.5%), 376 (3),
317 (8), 278 (100), 273 (14), 187 (63), 161 (11), 105 (33) and 91
(89).
1-Benzyl-7-cyano-5-methoxycarbonyl-7-methylhexahydro-
1H-pyrrolo[1,2-a]imidazole 7e. Prepared from 1-benzyl-4,5-
dihydroimidazole 5 (660 mg, 4.125 mmol) by the method
described above for the preparation of 7c via Protocol B but
using methyl bromoacetate (0.63 g, 4.125 mmol), 2-methyl-
propenonitrile (1.04 cm3, 12.37 mmol) and DBU (0.62 cm3,
4.125 mmol). Column chromatography eluting with ethyl
acetate–hexane (1:1 v/v) afforded the title compound 7e (519
mg, 42%) as a colourless oil (Found Mϩ, 299.1569; C17H21N3O2
requires M, 299.1634); νmax(film)/cmϪ1 2960, 2820, 2255, 1740,
1450, 1200, 760 and 705; δH(250 MHz) 1.35 (3H, s, CH3), 2.23
(1H, dd, J 10.9 and 13.1, CHCHH), 2.75 (2H, m, NCH2CHHN
and CHCHH), 2.91 (1H, m, NCH2CHHN), 3.27 (2H, m,
NCH2CH2N), 3.52 (1H, d, J 12.9 PhCHH), 3.76 (3H, s, OCH3),
3.80 (1H, dd, J 10.9 and 5.9, CHCO2), 3.91 (1H, s, 7a-H), 4.00
(1H, d, J 12.9, PhCHH), 7.30 (3H, m, Ar-H) and 7.45 (2H,
m, Ar-H); δC(22.7 MHz) 22.55 (CH3), 43.62 (CHCH2), 44.11
(quaternary C), 52.29 (OCH3), 53.05 and 54.67 (NCH2CH2N),
58.84 (PhCH2), 66.10 (CHCO), 93.08 (C-7a), 122.06 (CN),
127.43, 128.46 and 129.00 (Ar-CH), 138.48 (Ar-C) and 172.66
(CO); m/z 299 (Mϩ, 1%), 298 (2), 232 (83), 173 (17), 141 (100),
114 (22) and 91 (84). A portion of the title compound was
converted to the oxalate salt and recrystallised from ethanol–
ether (Found: C, 56.4; H, 6.4; N, 10.2%; C19H23N3O6ؒH2O
requires C, 56.0; H, 6.2; N, 10.3%).
1-Benzyl-7-cyano-5-ethoxycarbonyl-7-methylhexahydro-1H-
pyrrolo[1,2-a]imidazole 7f. Prepared from 1-benzyl-4,5-di-
hydroimidazole 5 (750 mg, 4.69 mmol) by the method described
above for the preparation of 7c via Protocol B but using ethyl
bromoacetate (0.52 cm3, 4.69 mmol), 2-methylpropenonitrile
(1.18 cm3, 14.06 mmol) and DBU (0.70 cm3, 4.69 mmol).
Column chromatography eluting with ethyl acetate–hexane
(1:1 v/v) afforded the title compound 7f (621 mg, 42%) as a
colourless oil (Found: Mϩ, 313.1786; C18H23N3O2 requires M,
313.1790); νmax(film)/cmϪ1 2990, 2820, 2240, 1740, 1450, 1190,
750 and 700; δH(400 MHz) 1.28 (3H, t, J 7.1, CH2CH3), 1.35
(3H, s, CH3), 2.25 (1H, dd, J 10.8 and 13.0, CHCHH), 2.73
(2H, m, NCH2CHHN and CHCHH), 2.91 (1H, m, NCH2-
CHHN), 3.26 (2H, m, NCH2CH2N), 3.50 (1H, d, J 12.9,
PhCHH), 3.77 (1H, dd, J 10.8 and 5.9, CHCO2), 3.90 (1H, s,
7a-H), 4.00 (1H, d, J 12.9, PhCHH), 4.20 (2H, q, J 7.1, OCH2),
7.30 (3H, m, Ar-H) and 7.48 (2H, m, Ar-H); δC(22.7 MHz)
14.10 (CH2CH3), 22.44 (CH3), 43.41 (CHCH2), 43.89 (quater-
nary C), 52.83 and 54.46 (NCH2CH2N), 58.63 (PhCH2), 61.01
(OCH2), 66.05 (CHCO), 92.86 (C-7a), 121.96 (CN), 127.21,
128.29 and 128.84 (Ar-CH), 138.37 (Ar-C) and 171.96 (CO);
1-Benzyl-5-tert-butoxycarbonyl-7-methoxycarbonyl-7-methyl-
hexahydro-1H-pyrrolo[1,2-a]imidazole 7c via cycloaddition
Protocol B
1-Benzyl-3-tert-butoxycarbonylmethyl-4,5-dihydro-1H-imid-
azol-3-ium bromide 6c, prepared from 1-benzyl-4,5-dihydro-
imidazole 5 (820 mg, 5.125 mmol) and tert-butyl bromoacetate
(0.83 cm3, 5.125 mmol), was taken up in dry THF (30 cm3),
heated to reflux and methyl 2-methylpropenoate (1.54 g, 15.37
mmol) added in one portion. DBU (0.77 cm3, 5.125 mmol) was
then added dropwise to the refluxing mixture over a period of
4 h. After a further 20 h of heating at reflux the reaction was
cooled, concentrated in vacuo and partitioned between chloro-
form (2 × 30 cm3) and water (30 cm3). The combined organic
extracts were dried and concentrated in vacuo, and the crude
product was purified by column chromatography eluting with
hexane–ethyl acetate (1:3 v/v) to yield the title compound 7c
(993 mg, 52%) as a colourless oil (Found: Mϩ, 374.2202;
C21H30N2O4 requires M, 374.2206); νmax(film)/cmϪ1 2980, 2800,
1730, 1450, 1370, 1150, 750 and 705; δH(250 MHz) 1.41 (3H, s,
CH3), 1.47 [9H, s, C(CH3)3], 2.04 (1H, dd, J 13.2 and 10.0,
CHCHH), 2.55 (1H, m, NCHHCH2N), 2.72 (1H, dd, J 13.3
and 7.1, CHCHH), 2.79 (1H, m, NCHHCH2N), 3.00 and 3.17
(each 1H, m, NCH2CH2N), 3.22 (1H, d, J 12.8, PhCHH), 3.71
(3H, s, OCH3), 3.88 (1H, dd, J 10.0 and 7.0, CHCO2), 4.01 (1H,
s, 7a-H), 4.05 (1H, d, J 12.8, PhCHH) and 7.28 (5H, m, Ar-H);
m/z 374 (Mϩ, 1%), 274 (48), 218 (100), 186 (9), 140 (6), 127 (60)
and 91 (62).
2066
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
m/z 313 (Mϩ, 3%), 246 (85), 240 (13), 174 (26), 155 (92), 100 (18)
and 91 (100).
345.1784; C22H23N3O requires M, 345.1841); νmax(film)/cmϪ1
3050, 3020, 2980, 2940, 2840, 2240, 1685, 1445, 1225, 740 and
700; δH(400 MHz) 1.34 (3H, s, CH3), 2.23 (1H, dd, J 10.7 and
13.1, CHCHH), 2.77 (2H, m, NCH2CHHN and CHCHH),
2.92 (1H, m, NCH2CHHN), 3.22 and 3.30 (each 1H, m,
NCH2CH2N), 3.52 (1H, d, J 12.8, PhCHH), 3.97 (1H, s, 7a-H),
4.03 (1H, d, J 12.8, PhCHH), 4.73 (1H, dd, J 10.7 and 5.8,
CHCO), 7.42 (8H, m, Ar-H) and 7.98 (2H, m, Ar-H); δC(22.7
MHz) 22.22 (CH3), 43.95 (CHCH2), 44.16 (quaternary C),
52.61 and 54.62 (NCH2CH2N), 58.52 (PhCH2), 68.54 (CHCO),
92.81 (C-7a), 122.28 (CN), 127.10, 128.19, 128.51, 128.67 and
133.17 (Ar-CH), 135.77 and 138.32 (Ar-C) and 197.53 (CO);
m/z 345 (Mϩ, 2%), 343 (6), 278 (100), 240 (11), 187 (56), 173
(16), 161 (10), 105 (18) and 91 (72).
1-Benzyl-5-tert-butoxycarbonyl-7-cyano-7-methylhexahydro-
1H-pyrrolo[1,2-a]imidazole 7g. Prepared from 1-benzyl-4,5-
dihydroimidazole 5 (790 mg, 4.944 mmol) by the method
described above for the preparation of 7c via Protocol B but
using tert-butyl bromoacetate (0.80 cm3, 4.94 mmol), 2-methyl-
propenonitrile (1.24 cm3, 14.81 mmol) and DBU (0.74 cm3, 4.94
mmol). Column chromatography eluting with ethyl acetate–
hexane (1:2 v/v) afforded the title compound 7g (1.17 g, 69%),
mp 73–77 ЊC, as a colourless solid (Found: C, 70.5; H, 8.2; N,
12.4%; Mϩ, 341.2075: C20H27N3O2 requires C, 70.35; H, 8.0; N,
12.3%; M, 341.2103); νmax(KBr)/cmϪ1 2980, 2940, 2810, 2240,
1735, 1455, 1370, 1150 and 700; δH(400 MHz) 1.35 (3H, s, CH3),
1.47 [9H, s, C(CH3)3], 2.17 (1H, dd, J 13.0 and 10.8, CHCHH),
2.67 (1H, dd, J 13.0 and 5.8, CHCHH), 2.75 and 2.90 (each 1H,
m, NCH2CH2N), 3.25 (2H, m, NCH2CH2N), 3.50 (1H, d,
J 12.9, PhCHH), 3.68 (1H, dd, J 10.8 and 5.8, CHCO2),
3.88 (1H, s, 7a-H), 4.00 (1H, d, J 12.9, PhCHH), 7.27 (1H, m,
Ar-H), 7.33 and 7.46 (each 2H, m, Ar-H); δC(22.7 MHz) 22.55
(CH3), 28.02 [C(CH3)3], 43.51 (CHCH2), 43.89 (CCN), 52.83
and 54.51 (NCH2CH2N), 58.63 (PhCH2), 66.75 (CHCO2),
81.38 (CMe3), 92.92 (C-7a), 122.17 (CN), 127.27, 128.29 and
128.89 (Ar-CH), 138.48 (Ar-C) and 171.20 (CO); m/z 341 (Mϩ,
8%), 274 (51), 240 (27), 218 (100), 186 (8), 173 (11), 127 (62) and
91 (63). Also isolated from some experiments was exo isomer 8:
δH(250 MHz) 1.42 (3H, s, CH3), 1.49 [9H, s, C(CH3)3], 2.39
(1H, dd, J 12.9 and 6.1, CHCHH), 2.72 (3H, m, NCHHCHHN
and CHCHH), 3.17 (1H, m, NCH2CHHN), 3.25 (1H, m,
NCHHCH2N), 3.40 (1H, dd, J 10.9 and 6.1, CHCO2), 3.47 and
4.04 (each 1H, d, J 13.3, PhCH2), 4.43 (1H, s, 7a-H) and 7.33
(5H, m, Ar-H); δC(22.7 MHz) 19.95 (CH3), 28.17 [C(CH3)3],
38.37 (CCN), 43.03 (CHCH2), 53.64 and 55.11 (NCH2CH2N),
57.98 (PhCH2), 65.78 (CHCO2), 81.65 (CMe3), 91.02 (C-7a),
123.42 (CN), 127.37, 128.51 and 128.67 (Ar-CH), 137.99
(Ar-C) and 171.26 (CO).
1-Benzyl-7-cyano-5-ethoxycarbonyl-5,7-dimethylhexahydro-
1H-pyrrolo[1,2-a]imidazole 7h. Prepared from 1-benzyl-4,5-
dihydroimidazole 5 (750 mg, 4.69 mmol) by the method
described above for the preparation of 7c via Protocol A but
using ethyl 2-bromopropionate (0.64 cm3, 4.57 mmol), 2-methyl-
propenonitrile (1.0 cm3, 11.72 mmol) and DBU (0.68 cm3, 4.57
mmol). Column chromatography eluting with hexane–ethyl
acetate (7:3 v/v) afforded the title compound 7h (960 mg, 63%)
as a colourless oil (Found: Mϩ, 327.1917; C19H25N3O2 requires
M, 327.1946); νmax(film)/cmϪ1 2980, 2930, 2805, 2240, 1730,
1455, 1150, 1030, 750 and 705; δH(250 MHz) 1.28 (6H, m, 2 ×
CH3), 1.59 (3H, s, CH3), 2.53 (2H, s, CCH2), 2.69 and 3.00 (each
1H, m, NCH2CH2N), 3.19 (2H, m, NCH2CH2N), 3.50 (1H, d,
J 12.6, PhCHH), 3.87 (1H, s, 7a-H), 4.06 (1H, d, J 12.6,
PhCHH), 4.17 (2H, q, J 7.1, OCH2), 7.31 (3H, m, Ar-H) and
7.48 (2H, m, Ar-H); δC(22.7 MHz) 14.21 (CH2CH3), 20.81 and
24.50 (2 × CH3), 42.65 (CCN), 45.68 (CCH2C), 49.42 and 54.56
(NCH2CH2N), 59.17 (PhCH2), 61.34 (OCH2), 67.13 (CCO2),
93.35 (C-7a), 123.80 (CN), 127.37, 128.46 and 129.22 (Ar-CH),
138.64 (Ar-C) and 174.83 (CO); m/z 327 (Mϩ, 2%), 261 (21),
260 (90), 254 (14), 187 (25), 169 (100), 120 (11) and 91 (82). A
portion of the title compound was converted to the oxalate salt,
m.p. 86–87 C and recrystallised from ethanol–ether (Found: C,
57.9; H, 6.85; N, 9.4%: C21H27N3O6ؒH2O requires C, 57.9;
H, 6.7; N, 9.6%).
1-Benzyl-5,7-bis(methoxycarbonyl)hexahydro-1H-pyrrolo[1,2-
a]imidazole stereoisomers 9 and 10 via cycloaddition Protocol C
To a solution of 1-benzyl-4,5-dihydroimidazole 5 (1.00 g, 6.25
mmol) stirred at reflux under an atmosphere of nitrogen in
THF (30 cm3) was added methyl bromoacetate (956 mg, 6.25
mmol) followed by methyl propenoate (1.613 g, 18.75 mmol).
DBU (950 mg, 6.25 mmol) was then added dropwise (syringe
pump) to the refluxing mixture over a period of 4 h. The solu-
tion was heated at reflux for a further 2 h, after which it was
cooled to room temperature and partitioned between chloro-
form (3 × 30 cm3) and water (30 cm3). The combined organic
phase was dried, evaporated under reduced pressure, and the
residue purified by column chromatography eluting with ethyl
acetate to yield the title compounds 9 and 10 as a colourless oil
(1.04 g, 52%) identified as a 2.3:1 mixture of epimers at C-7
(Found: Mϩ, 318.1580. C17H22N2O4requires M, 318.1579);
νmax(film)/cmϪ1 2951, 2843, 1738, 1680, 1601, 1453, 1438, 1199
and 1169; δH(400 MHz) 2.23 (1H, dt, J 7.2 and 13.2, CHCHH),
2.56 (2H, m, NCHHCH2N and CHCHH), 2.74 (0.3H, dt, J 6.4
and 6.8, NCH2CHHN), 2.81 (0.7H, dt, J 6.0 and 5.6, NCH2-
CHHN), 2.95 (0.3H, m, 7-H), 3.06 (1H, m, NCHHCH2N), 3.23
(0.7H, m, 7-H), 3.25 (1H, m, NCH2CHHN), 3.30 (1H, d,
J 13.2, PhCHH), 3.61 (0.3H, m, 5-H), 3.66 (0.9H, s, CH3), 3.69
(2.1H, s, CH3), 3.74 (3H, s, CH3), 3.97 (0.7H, m, 5-H), 4.03 (1H,
d, J 13.2, PhCHH), 4.17 (0.3H, d, J 3.6, 7a-H), 4.42 (0.7H, d,
J 6.4, 7a- H) and 7.20 (5H, m, Ar-H); δC(100.4 MHz) 32.52
(C-6, major isomer), 33.51 (C-6, minor isomer), 46.98 (C-7,
major isomer), 48.45 (C-7, minor isomer), 51.52, 51.65, 51.70
(3 × CH3O), 52.03 (NCH2CH2N, minor isomer), 52.58
(NCH2CH2N, major isomer), 53.28 (NCH2CH2N, minor iso-
mer), 53.95 (NCH2CH2N, major isomer), 56.37 (PhCH2, minor
isomer), 57.96 (PhCH2, major isomer), 66.30 (C-5, major iso-
mer), 68.02 (C-5, minor isomer), 87.24 (C-7a, major isomer),
88.17 (C-7a, minor isomer), 126.43, 126.59, 128.02, 128.20,
128.33, 128.44 (Ar-CH), 138.04 (Ar-C, minor isomer), 138.31
(Ar-C, major isomer), 172.46, 172.73 and 173.67 (CO); m/z 318
(Mϩ, 3%), 317 (7), 287 (11), 259 (8), 233 (13), 232 (85), 141 (93),
114 (22) and 91 (100).
Cycloadducts with N-phenylmaleimide, 12 and 13. Prepared
from 1-benzyl-4,5-dihydroimidazole 5 (2.0 g, 12.5 mmol) by the
method described above for the preparation of 9 and 10 via
Protocol C but using methyl bromoacetate (1.92 g, 1.18 cm3,
12.5 mmol), N-phenylmaleimide (6.50 g, 37.5 mmol) and DBU
(1.90 g, 1.86 cm3, 12.5 mmol). Column chromatography eluting
with toluene–ether (3:2 v/v) followed by ether afforded the title
compound 12 as an off-white solid (190 mg, 8%), mp 52–55 ЊC
(Found: Mϩ Ϫ H, 404.1558. C23H23N3O4 requires M Ϫ H,
404.1610); νmax(film)/cmϪ1 3028, 2951, 2846, 1777, 1713, 1496,
1377, 1186 and 694; δH(250 MHz) 2.57 (1H, m, NCHHCH2N),
2.89 (2H, m, NCHHCH2N and NCH2CHHN), 3.24 (1H, m,
NCH2CHHN), 3.31 (1H, d, J 12.3, PhCHH), 3.78 (5H, m,
COCHCHCO and OCH3), 4.27 (1H, d, J 12.3, PhCHH), 4.32
(1H, d, J 1.3, NCHCO), 4.61 (1H, d, J 6.3, NCHN), 7.26 (7H,
m, Ar-H) and 7.41 (3H, m, Ar-H); δC(68 MHz) 50.28 and 50.86
(COCHCHCO), 51.97 (NCH2CH2N), 52.42 (OCH3), 52.58
5-Benzoyl-1-benzyl-7-cyano-7-methylhexahydro-1H-pyrrolo-
[1,2-a]imidazole 7i. Prepared from 1-benzyl-4,5-dihydro-
imidazole 5 (940 mg, 5.875 mmol) by the method described
above for the preparation of 7c via Protocol B but using
2-bromoacetophenone (1.23 g, 6.17 mmol), 2-methylpropeno-
nitrile (1.57 g, 23.50 mmol) and DBU (980 mg, 6.46 mmol) and
heating the mixture under reflux for 1 h. Column chroma-
tography eluting with ether–hexane (1:1 v/v) afforded the title
compound 7i (930 mg, 46%) as a pale yellow oil (Found: Mϩ,
J. Chem. Soc., Perkin Trans. 1, 1998
2067

View Article Online
(NCH2CH2N), 58.55 (PhCH2), 66.85 (NCHCO), 87.08
(NCHN), 126.49, 126.90, 127.81, 128.45, 128.82 and 128.97
(Ar-CH), 131.82 and 137.81 (Ar-C), 171.77, 174.29 and 174.86
(CO); m/z 404 (Mϩ Ϫ H 6%), 232 (86), 141 (79) and 91 (100);
and the exo adduct 13 as a colourless solid (90 mg, 4%); δH(400
MHz) 2.43 (1H, m, NCHHCH2N), 2.84 (1H, m, NCH2-
CHHN), 3.22 (1H, m, NCHHCH2N), 3.31 (1H, m, NCH2-
CHHN), 3.41 (1H, d, J 8.3, CHCONPh), 3.51 (1H, d, J 12.3,
PhCHH), 3.82 (4H, m, CHCONPh and OCH3), 4.09 (2H, m,
NCHN and PhCHH), 4.18 (1H, d, J 7.8, NCHCO) and 7.37
(10H, m, Ar-H); δC(68 MHz) 47.80 and 48.45 (COCHCHCO),
50.06 and 51.48 (NCH2CH2N), 52.33 (OCH3), 55.81 (PhCH2),
69.44 (NCHCO), 88.45 (NCHN), 126.27, 127.31, 128.43,
128.54, 128.61 and 128.99 (Ar-CH), 131.48 and 137.46 (Ar-C),
170.44, 174.59 and 174.82 (CO).
1-Benzyl-5,7-bis(methoxycarbonyl)-6-methylhexahydro-1H-
pyrrolo[1,2-a]imidazole 14. Prepared from 1-benzyl-4,5-di-
hydroimidazole 5 (1.0 g, 6.25 mmol) by the method described
above for the preparation of 9 and 10 via Protocol C but using
methyl bromoacetate (0.96 g, 0.59 cm3, 6.25 mmol), methyl (E)-
but-2-enoate (1.87 g, 1.99 cm3, 18.75 mmol) and DBU (0.95 g,
0.93 cm3, 6.25 mmol). Column chromatography eluting with
light petroleum–ethyl acetate (1:1 v/v) yielded the title com-
pound 14 as a pale yellow sticky solid (0.450 g, 22%) (Found:
Mϩ, 332.1737. C18H24N2O4 requires M, 332.1736); νmax(film)/
cmϪ1 3027, 2950, 2843, 1738, 1436, 1198, 1170 and 701; δH(400
MHz; C6D6) 0.99 (3H, d, J 6.9, CH3), 2.17 (1H, m, CHH-
CH2N), 2.48 (1H, m, CH2CHHN), 2.76 (1H, m, CHHCH2N),
2.95 (1H, m, CH2CHHN), 3.01 (2H, m, PhCHH and CHCH3),
3.10 (1H, dd, J 6.5 and 7.7, CHCHCO2Me), 3.31 and 3.34 (each
3H, s, OCH3), 3.81 (1H, d, J 7.2, NCHCO), 3.96 (1H, d, J 13.3,
PhCHH), 4.47 (1H, d, J 6.5, 7a-H) and 7.18 (5H, m, Ar-H);
δC(68 MHz; C6D6) 14.70 (CH3), 36.67 (CHCH3), 51.32 and
51.41 (2 × OCH3), 52.99 and 53.64 (NCH2CH2N), 54.58
(CHCHCO2Me), 58.53 (PhCH2), 71.48 (NCHCO), 86.63
(C-7a), 126.67, 128.00 and 128.07 (Ar-CH), 138.71 (Ar-C),
172.02 and 172.90 (CO); m/z 332 (Mϩ, 2%), 232 (55), 213 (15),
154 (24), 141 (50), 120 (29) and 91 (100).
cycloaddition reaction, see below; δH(400 MHz) 1.29 (3H, t,
J 7.2, CH2CH3), 2.59 (2H, m, CH2CH), 3.84 (2H, s, CH2Br),
4.20 (2H, q, J 7.2, CH2CH3), 4.30 (2H, t, J 6.6, CH2OCO-
CH Br), 5.92 (1H, d, J 16.0, CH᎐CHCO) and 6.91 (1H, dt,
᎐
2
J 16.0 and 7.0, CH᎐CHCO).
᎐
2-Benzyl-7-ethoxycarbonyl-8-(2-hydroxyethyl)-1,2,3,4,8,8a-
hexahydropyrrolo[1,2-a]pyrazin-1-one 18. Prepared from 1-
benzyl-4,5-dihydroimidazole 5 (302 mg, 1.89 mmol) by the
method described above for the preparation of 9 and 10 via
Protocol C but using ethyl (E)-5-(bromoacetoxy)pent-2-enoate
16 (500 mg, 1.89 mmol) and DBU (287 mg, 1.89 mmol).
Column chromatography eluting with ethyl acetate afforded the
title compound 18 (100 mg, 15%) as a colourless oil (Found: Mϩ,
344.1736. C19H24N2O4requires M, 344.1736); νmax(CDCl3)/cmϪ1
3376 (br), 2983, 2933, 2876, 1710, 1657, 1629, 1554, 1455, 1441,
1351, 1254, 1088, 1055 and 1029; δH(400 MHz) 1.25 (3H, t,
J 7.2, CH3), 1.68 and 2.03 (each 1H, m, CH2CH2OH), 3.1–3.7
(7H, m, CH2OH, NCH2CH2N, NCHCH), 4.15 (2H, m,
CH2CH3), 4.48 (1H, d, J 10, NCHCH), 4.65 (2H, dd, J 14.8,
13.2, PhCH ), 7.08 (1H, s, NCH᎐C) and 7.30 (5H, m, Ar-H);
᎐
2
δC(100.4 MHz) 14.36 (CH3), 31.79 (CH2CH2OH), 40.59
(NCHCH), 43.68 (NCH2CH2N), 46.84 (NCH2CH2N), 50.12
(PhCH2), 59.70 (CH2CH3), 60.27 (CH2OH), 67.16 (NCHCH),
106.43 (CH᎐C), 127.73, 128.04 and 128.68 (Ar-CH), 135.70
᎐
(Ar-C), 148.10 (CH᎐C), 166.32 and 166.81 (CO); m/z 344
᎐
(Mϩ, 4%), 253 (1) and 91 (100).
1-Benzyl-7-chloro-7-cyano-5-methoxycarbonylhexahydro-1H-
pyrrolo[1,2-a]imidazole 19a. Prepared from 1-benzyl-4,5-di-
hydroimidazole 5 (890 mg, 5.56 mmol) by the method described
above for the preparation of 7c via Protocol B but using methyl
bromoacetate (890 mg, 5.84 mmol), 2-chloropropenonitrile
(1.95 g, 22.25 mmol) and DBU (930 mg, 6.12 mmol) and heat-
ing the resulting mixture under reflux for 1 h. Column chrom-
atography eluting with ethyl acetate–hexane (1:2 v/v) afforded
the title compound 19a (582 mg, 33%) as a pale yellow oil
identified as a 1:1 mixture of diastereoisomers (Found: Mϩ,
319.1099; C16H1835ClN3O2 requires M, 319.1088); νmax(film)/
cmϪ1 3020, 2960, 2860, 2250, 1740, 1440, 1200, 740 and 700;
δH(400 MHz) 2.87 (3.5H, m, NCH2CH2N, CHCHH and
CHCHH), 3.12 (0.5H, dd, J 13.4 and 6.4, CHCHH), 3.21
(0.5H, m, NCHHCH2N), 3.30 (1.5H, m, NCHHCH2N and
NCHHCH2N), 3.55 (0.5H, d, J 13.1, PhCHH), 3.67 (0.5H, d,
J 13.3, PhCHH), 3.78 (4H, m, OCH3 and CHCO2), 4.13 (0.5H,
d, J 13.3, PhCHH), 4.30 (0.5H, d, J 13.1, PhCHH), 4.39 and
4.59 (each 0.5H, s, 7a-H) and 7.35 (5H, m, Ar-H); δC(22.7
MHz) 45.14, 53.16, 53.70, 53.81, 54.62, 57.49 and 57.87 (CH2),
52.29 (OCH3), 59.98 and 60.79 (quaternary C), 64.37 and 64.86
(CHCO2), 91.78 and 94.06 (C-7a), 116.92 and 117.03 (CN),
127.21, 128.24, 128.56 and 128.67 (Ar-CH), 137.40 (Ar-C),
171.09 and 171.53 (CO); m/z 319 (Mϩ, 3%), 260 (7), 232 (100),
173 (13), 114 (14) and 91 (93).
1-Benzyl-7-chloro-7-cyano-5-ethoxycarbonylhexahydro-1H-
pyrrolo[1,2-a]imidazole 19b. Prepared from 1-benzyl-4,5-
dihydroimidazole 5 (880 mg, 5.50 mmol) by the method
described above for the preparation of 7c via Protocol B but
using ethyl bromoacetate (960 mg, 5.77 mmol), 2-chloro-
propenonitrile (1.32 cm3, 16.5 mmol) and DBU (880 mg, 5.77
mmol) and heating the resulting mixture at reflux for 1 h.
Column chromatography eluting with ethyl acetate–hexane
(1:1 v/v) afforded the title compound 19b (709 mg, 39%) as a
yellow oil identified as a 1:1 mixture of diastereoisomers
(Found: Mϩ, 333.1194, 335.1240; C17H20 35,37ClN3O2 requires
M, 333.1244, 335.1215); νmax(film)/cmϪ1 2980, 2830, 2250, 1730,
1190, 1030, 760, 760 and 705; δH(400 MHz) 1.30 (3H, t, J 7.2,
CH3), 2.85 (3.5H, m, NCH2CH2N, CHCHH and CHCHH),
3.12 (0.5H, dd, J 13.4 and 6.4, CHCHH), 3.21 (0.5H, m,
NCHHCH2N), 3.30 (1.5H, m, NCHHCH2N and NCHH-
CCH2N), 3.55 (0.5H, d, J 13.1, PhCHH), 3.67 (0.5H, d, J 13.2,
PhCHH), 3.76 (1H, dd, J 9.8 and 6.6, CHCO2), 4.13 (0.5H, d,
J 13.2, PhCHH), 4.23 (2H, m, OCH2), 4.30 (0.5H, d, J 13.1,
Ethyl (E)-5-(Bromoacetoxy)pent-2-enoate 16
Propenal (50 cm3, 0.66 mol), sulfuric acid (1.5 , 66 cm3) and
water (120 cm3) were heated together at 45–60 ЊC for 2 h before
the solution was cooled to 0 ЊC and brought to pH 8 by the
addition of sodium carbonate. Ethoxycarbonylmethylenetri-
phenylphosphorane (83.3 g, 0.195 mol) and water (50 cm3) were
added, followed by portionwise addition of sodium carbonate
(37.1 g, 0.35 mol) with stirring over 2 h. After stirring for a
further 0.5 h, the solution was extracted with ether (3 × 300
cm3), the combined organic extract dried and evaporated under
reduced pressure, and the residue purified by column chroma-
tography eluting with light petroleum–ethyl acetate (3:1 v/v) to
yield ethyl (E)-5-hydroxypent-2-enoate as a colourless oil (10.94
g, 39%) that was used directly; δH(400 MHz) 1.29 (3H, t, J 7.2,
CH2CH3), 2.48 (2H, m, CH2CH), 3.55 (2H, t, J 6.4, CH2OH),
4.19 (2H, q, J 7.2, CH2CH3), 4.2 (1H, br s, OH), 5.89 (1H,
d, J 15.6, CH᎐CHCO) and 6.96 (1H, dt, J 15.6 and 6.8,
᎐
CH᎐CHCO). To ethyl (E)-5-hydroxypent-2-enoate (2 g, 13.9
᎐
mmol) in dry dichloromethane (40 cm3) at Ϫ10 ЊC (ice–salt
bath) were added with stirring triethylamine (4.2 g, 41.7 mmol)
followed dropwise by bromoacetyl bromide (8.4 g, 41.7 mmol).
The solution was allowed to warm to 20 ЊC and stirred for a
further 10 min before the addition of saturated aqueous sodium
hydrogen carbonate (50 cm3). The mixture was stirred for 30
min, the layers separated, and the aqueous phase extracted
with dichloromethane (3 × 50 cm3). The combined organic
phases were dried, evaporated under reduced pressure and the
residue was distilled (Kugelrohr apparatus, 3 mmHg, oven temp.
200 ЊC) to afford the title compound 16 as a colourless oil (2.5 g,
68%), bp 110 ЊC at 0.05 mmHg, that deteriorated on storage
and was used directly, without further characterization, in the
2068
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
PhCHH), 4.39 and 4.59 (each 0.5H, s, 7a-H) and 7.35 (5H, m,
Ar-H); δC(22.7 MHz) 14.15 (CH3), 45.41, 53.37, 53.91, 54.08,
54.84, 57.71 and 58.09 (CH2), 60.25 and 61.01 (quaternary C),
61.50 (CH2), 64.75 and 65.18 (CH), 92.00 and 94.27 (C-7a),
117.19 and 117.30 (CN), 127.43, 128.46, 128.78 and 128.89
(Ar-CH), 137.67 (Ar-C), 170.82 and 171.26 (CO); m/z 335 and
333 (Mϩ, 0.2 and 1%), 297 (5), 246 (57), 174 (17), 155 (63), 120
(8) and 91 (100).
v/v) to yield the title compound 21a (108 mg, 73%) as a colour-
less oil (Found: Mϩ, 297.1485; C17H19N3O2 requires M,
297.1477); νmax(film)/cmϪ1 3350, 3125, 2980, 2230, 1710, 1550,
1490, 1400, 1270, 1205, 1100 and 740; δH(250 MHz) 1.34 (3H, t,
J 7.2, CH3), 1.43 (1H, br s, NH), 2.97 (2H, t, J 5.9, NCH2-
CH2N), 3.75 (2H, s, PhCH2), 4.27 (2H, q, J 7.1, OCH2), 4.43
(2H, t, J 5.9, NCH2CH2N) and 7.26 (7H, m, Ar-H); δC(22.7
MHz) 14.32 (CH3), 49.25 and 50.07 (NCH2CH2N), 53.59
(PhCH2), 60.69 (OCH2), 92.76 (Ar-C), 115.35 (CN), 120.66
(Ar-CH), 123.58 (Ar-C), 127.16, 127.97, 128.51 and 133.98
(Ar-CH), 140.00 (Ar-C) and 160.10 (CO); m/z 297 (Mϩ, 6%),
251 (5), 147 (5), 121 (9), 120 (100), 106 (5) and 92 (97).
1-Benzyl-5-tert-butoxycarbonyl-7-chloro-7-cyanohexahydro-
1H-pyrrolo[1,2-a]imidazole 19c. Prepared from 1-benzyl-4,5-
dihydroimidazole 5 (1.43 g, 8.94 mmol) by the method
described above for the preparation of 7c via Protocol B but
using tert-butyl bromoacetate (1.51 cm3, 9.38 mmol), 2-
chloropropenonitrile (2.85 cm3, 35.75 mmol) and DBU (1.40
cm3, 9.38 mmol) and heating the resulting mixture at reflux for
1 h. Column chromatography eluting with ether–hexane (4:1
v/v) afforded the title compound 19c (1.76 g, 55%) as a pale
yellow oil, identified as a 1:1 mixture of diastereoisomers
(Found: Mϩ, 361.1530; C19H2435ClN3O2 requires M, 361.1557);
νmax(film)/cmϪ1 2990, 2850, 2250, 1730, 1460, 1370, 1160 and
710; δH(400 MHz) 1.47 [9H, s, C(CH3)3], 2.82 (3H, m, NCH2-
CHHN, NCH2CHHN, CHCHH and CHCHH), 2.95 (0.5H, m,
NCH2CHHN), 3.07 (0.5H, dd, J 13.4 and 6.3, CHCHH), 3.20
(0.5H, m, NCHHCH2N), 3.29 (1.5H, m, NCHHCH2N and
NCHHCH2N), 3.54 (0.5H, d, J 13.1, PhCHH), 3.67 (1.5H, m,
PhCHH and CHCO2), 4.13 (0.5H, d, J 13.4, PhCHH), 4.28
(0.5H, d, J 13.1, PhCHH), 4.38 and 4.58 (each 0.5H, s, 7a-H)
and 7.36 (5H, m, Ar-H); δC(22.7 MHz) 28.02 [C(CH3)3], 45.52
(CHCH2), 53.32, 53.86, 54.08 and 54.84 (NCH2CH2N), 57.71,
58.09 (PhCH2), 60.31 and 61.12 (quaternary C), 65.45 and
65.83 (CH), 82.03 and 82.14 (CMe3), 92.00 and 94.33 (C-7a),
117.30 and 117.41 (CN), 127.37, 128.40, 128.78 and 128.89
(Ar-CH), 137.78 (Ar-C), 169.90 and 170.44 (CO); m/z 363 and
361 (Mϩ, 0.6 and 2%), 274 (31), 262 (8), 260 (22), 218 (100), 173
(9), 127 (74) and 91 (94).
5-Benzoyl-1-benzyl-7-chloro-7-cyanohexahydro-1H-pyrrolo-
[1,2-a]imidazole 19d. Prepared from 1-benzyl-4,5-dihydro-
imidazole 5 (660 mg, 4.125 mmol) by the method described
above for the preparation of 7c via Protocol B but using
2-bromoacetophenone (860 mg, 4.33 mmol), 2-chloropropeno-
nitrile (1.08 cm3, 13.6 mmol) and DBU (0.63 g, 4.125 mmol)
and heating the resulting mixture under reflux for 1 h. Column
chromatography eluting with ether–hexane (1:1 v/v) afforded
the title compound 19d (536 mg, 36%) as a yellow oil identified
as a 1:1 mixture of diastereoisomers that was used directly in
the preparation of pyrrole 21c (see below); νmax(film)/cmϪ1 3050,
3025, 2940, 2840, 2250, 1690, 1600, 1450, 1270, 910 and 740;
δH(60 MHz) 3.10 (6H, m, NCH2CH2N and CHCH2), 3.60
(0.5H, d, J 6.0, PhCHH), 3.75 (0.5H, d, J 6.0, PhCHH), 4.45
(3H, m, PhCHH, 7a-H and CHCO), 7.55 (8H, m, Ar-H) and
8.05 (2H, m, Ar-H); δC(22.7 MHz) 45.52 (CHCH2), 53.25,
53.75, 54.28 and 54.83 (NCH2CH2N), 57.87 and 58.19
(PhCH2), 60.69 and 61.66 (quaternary C), 66.48 and 67.24
(CHCO), 92.16 and 94.33 (C-7a), 117.24 and 117.57 (CN),
127.32, 128.35, 128.46, 128.78 and 133.55 (Ar-CH), 135.55,
135.88 and 137.67 (Ar-C), 196.12 and 196.45 (CO); m/z (Mϩ
not observed) 327 (3%), 221 (61), 220 (54), 192 (20), 126 (20),
91 (100) and 77 (46).
1-(2-Benzylaminoethyl)-2-tert-butoxycarbonyl-4-cyanopyrrole
21b. Prepared from 1-benzyl-5-tert-butoxycarbonyl-7-chloro-7-
cyanohexahydro-1H-pyrrolo[1,2-a]imidazole 19c (508.6 mg,
1.41 mmol) by the method described above for the preparation
of 21a but using DBU (0.23 cm3, 1.55 mmol). Column chroma-
tography eluting with ether afforded the title compound 21b (272
mg, 59%) as a yellow oil (Found: Mϩ Ϫ C4H9OH, 251.1081;
C19H23N3O2 Ϫ C4H10O requires M, 251.1059); νmax(film)/cmϪ1
3320, 3010, 2975, 2230, 1710, 1550, 1490, 1400, 1280, 1170,
1140 and 1100; δH(60 MHz) 1.45 (1H, br, s, NH), 1.55 [9H, s,
C(CH3)3], 2.95 (2H, t, J 4.0, NCH2CH2N), 3.75 (2H, s, PhCH2),
4.40 (2H, t, J 4.0, NCH2CH2N), 7.10 (1H, d, J 1.7, Ar-H)
and 7.30 (6H, m, Ar-H); δC(22.7 MHz) 28.18 [C(CH3)3], 49.15
and 49.90 (NCH2CH2N), 53.48 (PhCH2), 81.70 (CMe3), 92.27
(Ar-C), 115.46 (CN), 120.28 (Ar-CH), 124.77 (Ar-C), 126.99,
127.92, 128.40 and 133.55 (Ar-CH), 139.94 (Ar-C) and 159.34
(CO); m/z (Mϩ not observed) 251 (Mϩ Ϫ C4H9OH, 7%), 120
(66), 91 (100) and 41 (13).
2-Benzoyl-1-(2-benzylaminoethyl)-4-cyanopyrrole 21c. Pre-
pared from 5-benzoyl-1-benzyl-7-chloro-7-cyanohexahydro-
1H-pyrrolo[1,2-a]imidazole 19d (539.3 mg, 1.47 mmol) by the
method described above for the preparation of 21a but using
DBU (0.24 cm3, 1.62 mmol). Column chromatography eluting
with ethyl acetate–triethylamine (99.5:0.5 v/v) afforded the title
compound 21c (242 mg, 50%) as a yellow oil (Found: Mϩ,
329.1505; C21H19N3O requires M, 329.1528); νmax(film)/cmϪ1
3350, 3130, 3070, 2850, 2240, 1640, 1400, 1280, 1140, 910, 740
and 700; δH(60 MHz) 1.65 (1H, br s, NH), 3.05 (2H, t, J 4.0,
NCH2CH2N), 3.80 (2H, s, PhCH2), 4.55 (2H, t, J 4.0, NCH2-
CH2N), 7.00 (1H, m, Ar-H), 7.35 (5H, m, Ar-H), 7.60 (4H,
m, Ar-H) and 7.85 (2H, m, Ar- H); δC(22.7 MHz) 49.31 and
50.07 (NCH2CH2N), 53.43 (PhCH2), 92.65 (Ar-C), 115.14
(CN), 124.29, 126.99, 127.86, 128.35 and 129.16 (Ar-CH),
130.57 (Ar-C), 132.36 and 135.34 (Ar-CH), 138.53 and 139.94
(Ar-C) and 185.94 (CO); m/z 329 (Mϩ, 2%), 327 (5), 311 (25),
234 (26), 220 (16), 219 (11), 120 (28) and 91 (100).
1-Benzyl-3-(trimethylsilylmethyl)-4,5-dihydro-1H-imidazol-3-
ium trifluoromethanesulfonate 22
Trimethylsilylmethyl trifluoromethanesulfonate (0.465 cm3,
2.33 mmol) was added dropwise to a stirred solution of 1-
benzyl-4,5-dihydroimidazole 5 (340 mg, 2.12 mmol) in dry
acetonitrile (10 cm3) under an atmosphere of nitrogen. After 2 h
the liquor was concentrated in vacuo and on standing yielded
the title compound 22 as a colourless hygroscopic solid (760
mg, 98%) which was used without further purification; νmax
-
(film)/cmϪ1 3060, 2950, 1650, 1260, 1150, 1030 and 850; δH(400
MHz) 0.13 (9H, s, 3 × CH3), 3.10 (2H, s, CH2Si), 3.78 and 3.88
(each 2H, m, NCH2CH2N), 4.60 (2H, s, PhCH2), 7.33 (5H, m,
Ar-H) and 8.38 (1H, s, 2-H); m/z (FAB ϩve) 643 [(2M Ϫ OTf)ϩ,
2%], 247 (100), 155 (20), 130 (15), 91 (95), 73 (95) and 59 (85).
Preparation of pyrroles 21a–c
1-(2-Benzylaminoethyl)-4-cyano-2-ethoxycarbonylpyrrole
21a. To 1-benzyl-7-chloro-7-cyano-5-ethoxycarbonylhexa-
hydro-1H-pyrrolo[1,2-a]imidazole 19b (165.7 mg, 0.497 mmol)
in dry DMSO (10 cm3) stirred at 100 ЊC was added DBU (83.2
mg, 0.547 mmol). The mixture was maintained at this temper-
ature for 3 h, then allowed to cool and the liquor partitioned
between chloroform (2 × 30 cm3) and water (30 cm3). The com-
bined organic extract was washed with water (5 × 30 cm3), dried
and concentrated in vacuo. The crude product was purified by
column chromatography eluting with ethyl acetate–hexane (1:1
Preparation of pyrroloimidazoles 23a–c
1-Benzyl-7-methoxycarbonylhexahydro-1H-pyrrolo[1,2-a]-
imidazole 23a. 1-Benzyl-3-(trimethylsilylmethyl)-4,5-dihydro-
1H-imidazol-3-ium trifluoromethanesulfonate 22, prepared (see
above) from 1-benzyl-4,5-dihydroimidazole 5 (505 mg, 3.18
mmol) and trimethylsilylmethyl trifluoromethanesulfonate
J. Chem. Soc., Perkin Trans. 1, 1998
2069

View Article Online
(0.66 cm3, 3.32 mmol), was taken up in dry diglyme (15 cm3)
and added by cannula to a slurry of caesium fluoride (2.40 g,
15.79 mmol) and methyl propenoate (285 mg, 3.32 mmol) in
dry diglyme (20 cm3) under an atmosphere of nitrogen. The
resulting mixture was stirred at room temperature for 5 h and
then concentrated in vacuo. The semi-solid was partitioned
between chloroform (2 × 40 cm3) and water (40 cm3), and the
combined organic extracts were dried and concentrated in
vacuo. Column chromatography of the crude product eluting
with chloroform–isopropylamine (99.5:0.5 v/v) yielded the title
compound 23a (351 mg, 43%) as a colourless oil identified as a
1:1 mixture of diastereoisomers; νmax(film)/cmϪ1 2950, 2820,
1730, 1670, 1600, 1160, 750 and 700; δH(200 MHz) 2.20 and
2.66 (each 2.5H, m), 3.12 (5H, m), 3.57 and 3.61 (3H, 2 × s,
OCH3), 3.70 (1H, m), 3.84 (0.5H, d, J 15.6, PhCHH), 3.95
(0.5H, d, J 5.0, 7a-H) and 7.19 (5H, m, Ar-H); δC(62.9 MHz)
29.54 and 34.75 (CHCH2), 41.40 and 44.41 (CHCO2), 49.61
and 51.70 (OCH3), 52.71, 53.15, 53.52, 54.01, 55.16, 57.36,
57.70 and 58.40 (4 × CH2), 85.62 and 88.82 (C-7a), 127.95,
128.14, 128.63 and 128.91 (Ar-CH), 138.68 (Ar-C), 173.94 and
174.38 (CO); m/z 261 (Mϩ ϩ H, 20%), 260 (Mϩ, 30), 259 (45),
229 (10), 201 (8), 174 (42), 91 (100) and 83 (65). A small portion
of the title compound was converted to the bis(oxalate) salt
(Found: C, 51.7; H, 5.8; N, 6.7%; C19H24N2O10 requires C, 51.8;
H, 5.5; N, 6.3%).
(0.33H, d, J 13.4, PhCHH), 4.12 (0.66H, d, J 12.7, PhCHH),
4.22 (0.33H, s, 7a-H) and 7.30 (5H, m, Ar-H); δC(22.7 MHz)
19.40 and 22.93 (CH3), 38.80 and 39.23 (CH2CCN), 39.56 and
43.30 (CCN), 51.58, 52.72, 53.10, 53.70, 54.08 and 54.51 (CH2),
58.52 and 58.95 (PhCH2), 91.19 and 93.08 (C-7a), 122.93 (CN),
127.21, 128.29, 128.46 and 129.00 (Ar-CH), 138.21 and 138.53
(Ar-C); m/z 241 (Mϩ, 22%), 174 (80), 91 (89), 83 (100) and 56
(59).
Synthesis of tetrahydropyrroles 24a–f
1-(2-Benzylaminoethyl)-2-ethoxycarbonyl-4-methoxy-
carbonyl-4-methyltetrahydropyrrole 24a.
A solution of 1-
benzyl-5-ethoxycarbonyl-7-methoxycarbonyl-7-methylhexa-
hydro-1H-pyrrolo[1,2-a]imidazole 7b (347.1 mg, 1.0 mmol) in
dry ethanol (20 cm3) was made acidic to methyl green indicator
by the dropwise addition of hydrochloric acid (2 ). Sodium
cyanoborohydride (69 mg, 1.10 mmol) was added portionwise
while maintaining the acidic pH. The resulting mixture was
stirred at room temperature for 3 h, made basic by the addition
of solid potassium hydrogen carbonate and partitioned
between chloroform (2 × 50 cm3) and water (50 cm3). The com-
bined organic extract was dried, concentrated in vacuo, and the
crude product purified by column chromatography eluting with
ethyl acetate–triethylamine (99.5:0.5 v/v) to yield the title
compound 24a (237 mg, 68%) as a colourless oil (Found: Mϩ,
348.2024; C19H28N2O4 requires M, 348.2039); νmax(film)/cmϪ1
3320, 2950, 2810, 1730, 1460, 1180 and 750; δH(250 MHz) 1.25
(3H, t, J 7.1, CH2CH3), 1.40 (3H, s, CH3), 1.78 (1H, dd, J 13.2
and 7.0, CHCHH), 2.05 (1H, br s, NH), 2.70 (5H, m, NCH2-
CH2N and CHCHH), 2.87 and 2.95 (each 1H, d, J 9.3, NCH2-
CCO2), 3.37 (1H, dd, J 9.0 and 7.0, CHCO2), 3.66 (3H, s,
OCH3), 3.73 and 3.83 (each 1H, d, J 13.2, PhCH2), 4.15 (2H, q,
J 7.1, OCH2) and 7.30 (5H, m, Ar-H); δC(22.7 MHz) 14.10
(CH2CH3), 24.23 (CH3), 40.43 (CHCH2), 47.41 (NCH2CH2N),
47.85 (quaternary C), 51.96 (OCH3), 53.70 (NCH2CH2N),
53.81 (PhCH2), 60.47 (NCH2), 62.69 (OCH2), 65.62 (CH),
126.67, 128.02 and 128.19 (Ar-CH), 140.59 (Ar-C), 173.58 and
176.73 (CO); m/z 348 (Mϩ, 9%), 302 (21), 273 (16), 229 (16), 228
(100), 211 (33), 174 (15), 156 (44) and 91 (55).
1-Benzyl-7-methoxycarbonyl-7-methylhexahydro-1H-pyrrolo-
[1,2-a]imidazole 23b. Prepared according to the method
described above for the preparation of 23a but using 1-benzyl-
3-(trimethylsilylmethyl)-4,5-dihydro-1H-imidazol-3-ium
tri-
fluoromethanesulfonate 22 prepared from 1-benzyl-4,5-
dihydroimidazole 5 (720 mg, 4.50 mmol) and trimethylsilyl-
methyl trifluoromethanesulfonate (1.12 g, 4.725 mmol) in dry
diglyme (15 cm3), caesium fluoride (2.05 g, 13.5 mmol) and
methyl 2-methylpropenoate (900 mg, 9.0 mmol) in dry diglyme
(40 cm3), and stirring for 20 h at room temperature before con-
centration in vacuo. The resulting semi-solid was partitioned
between chloroform (2 × 50 cm3) and water (50 cm3), and the
combined organic extracts were dried and concentrated in
vacuo. Column chromatography of the crude product eluting
with ethyl acetate–triethylamine (99.5:0.5 v/v) afforded the title
compound 23b (575 mg, 47%) as a colourless oil identified as a
1:1 mixture of diastereoisomers (Found: Mϩ, 274.1660; C16H22-
N2O2 requires M, 274.1681); νmax(film)/cmϪ1 2950, 2820, 1730,
1450, 1270, 1140 and 1090; δH(200 MHz) 1.37 and 1.39 (3H, 2 ×
s, CH3), 1.72 and 1.88 (each 0.5H, m, CHHCCO2), 2.64 and
3.07 (each 3.5H, m), 3.28 and 3.36 (each 0.5H, d J 10.8,
PhCHH), 3.68 and 3.70 (3H, 2 × s, OCH3), 3.90 (0.5H, s, C-7a
H), 4.03 and 4.09 (each 0.5H, d, J 10.8, PhCHH), 4.25 (0.5H, s,
7a-H) and 7.25 (5H, m, Ar-H); δC(50.3 MHz) 18.90 and 23.11
(CH3), 36.24 and 38.15 (CH3CCH2), 51.45, 51.52, 51.82, 52.46,
52.88, 53.31, 53.62, 53.71 and 54.74 (C), 58.34 and 59.35
(PhCH2), 90.18 and 95.34 (C-7a), 126.63, 126.74, 128.03,
128.11, 128.23 and 128.38 (Ar-CH), 139.22 and 139.42 (Ar-C),
175.24 and 176.81 (CO); m/z 274 (Mϩ, 13%), 174 (57), 96 (10),
91 (32) and 83 (100).
1-(2-Benzylaminoethyl)-4-cyano-2-ethoxycarbonyl-4-methyl-
tetrahydropyrrole 24b. Prepared from 1-benzyl-7-cyano-5-
ethoxycarbonyl-7-methylhexahydro-1H-pyrrolo[1,2-a]imid-
azole 7f (295.2 mg, 0.943 mmol) by the method described above
for the preparation of 24a but using sodium cyanoborohydride
(65 mg, 1.04 mmol). Column chromatography eluting with
ethyl acetate–triethylamine (99.5:0.5 v/v) afforded the title
compound 24b (295 mg, 99%) as a colourless oil (Found: Mϩ Ϫ
C2H5OH, 269.1495; C18H25N3O2
Ϫ C2H6O requires M,
269.1528); νmax(film)/cmϪ1 3320, 2980, 2950, 2820, 2240, 1730,
1450, 1190, 740 and 700; δH(250 MHz) 1.25 (3H, t, J 7.1,
CH2CH3), 1.50 (3H, s, CH3), 1.97 (1H, dd, J 13.7 and 6.4,
CHCHH), 2.05 (1H, br s, NH), 2.70 (5H, m, NCH2CH2N and
CHCHH), 2.94 and 3.02 (each 1H, d, J 9.4, NCH2CCO2), 3.54
(1H, dd, J 9.4 and 6.4, CHCO2), 3.72 and 3.82 (each 1H, d,
J 13.7, PhCH2), 4.13 (2H, q, J 7.2, OCH2) and 7.30 (5H, m,
Ar-H); m/z (Mϩ not observed), 269 (Mϩ Ϫ C2H5OH, 46%), 240
(32), 202 (17), 178 (79), 174 (41), 136 (20), 122 (19) and 91 (100).
1-(2-Benzylaminoethyl)-2-tert-butoxycarbonyl-4-cyano-4-
1-Benzyl-7-cyano-7-methylhexahydro-1H-pyrrolo[1,2-a]-
imidazole 23c. Prepared from 1-benzyl-4,5-dihydroimidazole 5
(750 mg, 4.68 mmol) by the method described above for the
preparation of 23a but using trimethylsilylmethyl trifluoro-
methanesulfonate (1.16 g, 4.92 mmol), caesium fluoride (2.14 g,
14.06 mmol) and 2-methylpropenonitrile (470 mg, 7.03 mmol).
Column chromatography eluting with dichloromethane–
ethanol–conc. aq. ammonia (800:8:1 v/v/v) afforded the title
compound 23c (680 mg, 60%) as a colourless oil identified as a
2:1 mixture of diastereoisomers (Found: Mϩ, 241.1576;
C15H19N3 requires M, 241.1579); νmax(film)/cmϪ1 3025, 2925,
2840, 2250, 1500, 1450, 750 and 700; δH(250 MHz) 1.40 and
1.45 (3H, 2 × s, CH3), 1.95 (0.66H, m, CHHCCN), 2.05 (0.33H,
m, CHHCCN), 2.40, 2.60, 2.75 and 2.85 (each 1H, m), 3.15
(3H, m), 3.43 (1H, m, PhCHH), 3.70 (0.66H, s, 7a-H), 4.04
methyltetrahydropyrrole 24c. Prepared from 1-benzyl-5-tert-
butoxycarbonyl-7-cyano-7-methylhexahydro-1H-pyrrolo[1,2-a]-
imidazole 7g (241 mg, 0.71 mmol) by the method described
above for the preparation of 24a but using sodium cyanoboro-
hydride (45 mg, 0.706 mmol). Column chromatography eluting
with chloroform–isopropylamine (99.5:0.5 v/v) afforded the
title compound 24c (208 mg, 86%) as a colourless oil (Found:
Mϩ, 343.2251; C20H29N3O2 requires M, 343.2260); νmax(film)/
cmϪ1 3280, 2975, 2820, 2230, 1730, 1450, 1360, 1150 and 750;
δH(250 MHz) 1.45 [9H, s, C(CH3)3], 1.50 (3H, s, CH3), 1.93 (1H,
dd, J 13.3 and 6.2, CHCHH), 2.07 (1H, br s, NH), 2.75 (5H, m,
NCH2CH2N and CHCHH), 2.93 and 3.00 (each 1H, d, J 9.6,
2070
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
NCH2CCN), 3.42 (1H, dd, J 8.9 and 6.3, CHCO2), 3.72 and
3.82 (each 1H, d, J 13.2, PhCH2) and 7.30 (5H, m, Ar-H);
δC(22.7 MHz) 24.17 (CH3), 28.07 [C(CH3)3], 35.82 (quaternary
C), 42.11 (CHCH2), 47.30 and 53.21 (NCH2CH2N), 53.86
(PhCH2), 63.45 (NCH2), 65.40 (CH), 81.43 (CMe3), 124.50
(CN), 126.83, 128.13 and 128.35 (Ar-CH), 140.54 (Ar-C) and
172.01 (CO); m/z 343 (Mϩ, 5%), 242 (34), 167 (70), 134 (18), 123
(43), 120 (36), 109 (10) and 91 (100).
as described above from 1-benzyl-4,5-dihydroimidazole 5 (1.00
g, 6.25 mmol) but using methyl bromoacetate (0.96 g, 0.59 cm3,
6.25 mmol), methyl propenoate (1.61 g, 1.69 cm3, 18.75 mmol)
and DBU (0.95 g, 0.93 cm3, 6.25 mmol). The solvent was
removed in vacuo and the residue partitioned between chloro-
form (3 × 30 cm3) and water (30 cm3). The combined organic
phase was dried and evaporated in vacuo, and the residue taken
up in ethanol (20 cm3) and made acidic to methyl green indica-
tor by the dropwise addition of 2  hydrochloric acid. Sodium
cyanoborohydride (0.43 g, 6.88 mmol) was added portionwise
and stirring at room temperature was continued for 16 h. The
mixture was basified to pH 8 by the portionwise addition of
solid potassium hydrogen carbonate and partitioned between
dichloromethane (3 × 20 cm3) and water (50 cm3). The organic
phase was dried, concentrated in vacuo, and the residue purified
by column chromatography eluting with ethyl acetate–triethyl-
amine (95:5 v/v) to yield the title compound 25 (183 mg, 10%) as
a pale yellow oil (Found: Mϩ, 288.1460. C16H20N2O3 requires
M, 288.1474); νmax(film)/cmϪ1 3028, 2951, 1732, 1650, 1494,
1452, 1356, 1203, 1175 and 703; δH(400 MHz) 2.30 and 2.57
(each 1H, m, CHCH2CH), 2.79 (1H, m, NCHHCH2N), 2.88
(1H, dd, J 10.1 and 7.1, NCHHCH), 2.95 (1H, m, NCHH-
CH2N), 3.10 (1H, m, CHCO2Me), 3.20 (2H, m, NCH2CHHN
and NCHHCH), 3.37 (1H, m, NCH2CHHN), 3.45 (1H, t,
J 8.4, NCHCO), 3.71 (3H, s, OCH3), 4.52 and 4.65 (each 1H, d,
J 14.6, PhCH2) and 7.29 (5H, m, Ar-H); δC(68 MHz) 30.73
(CHCH2CH), 40.15 (CHCO2Me), 44.76 and 46.24 (CH2CH2),
48.97 (PhCH2), 51.61 (OCH3), 55.58 (NCH2CH), 63.38
(NCHCO), 127.08, 127.60 and 128.23 (Ar-CH), 136.28 (Ar-C),
169.11 (NCO) and 171.97 (CO2Me); m/z 288 (Mϩ, 28%), 259
(33), 197 (81), 174 (25), 137 (18) and 91 (100).
1-(2-Benzylaminoethyl)-4-cyano-2-ethoxycarbonyl-2,4-di-
methyltetrahydropyrrole 24d. Prepared from 1-benzyl-7-cyano-
5-ethoxycarbonyl-5,7-dimethylhexahydro-1H-pyrrolo[1,2-a]-
imidazole 7h (303.5 mg, 0.93 mmol) by the method described
above for the preparation of 24a but using sodium cyanoboro-
hydride (64.2 mg, 1.03 mmol). Column chromatography eluting
with ethyl acetate–triethylamine (99.5:0.5 v/v) afforded the title
compound 24d (217 mg, 71%) as a colourless oil (Found: Mϩ,
329.2097; C19H27N3O2 requires M, 329.2103); νmax(film)/cmϪ1
3320, 2980, 2840, 2250, 1730, 1460, 1200, 1150 and 750; δH(250
MHz) 1.23 (3H, t, J 7.1, CH2CH3), 1.41 and 1.45 (each 3H, s,
CH3), 2.08 (1H, br s, NH), 2.26 and 2.32 (each 1H, d, J 13.8,
CCH2C), 2.60 (4H, m, NCHHCH2N and NCHHCCN), 2.85
(1H, m, NCHHCH2N), 3.21 (1H, d, J 9.4, NCHHCCN), 3.75
and 3.85 (each 1H, d, J 13.4, PhCH2), 4.12 (2H, q, J 7.1, OCH2)
and 7.25 (5H, m, Ar-H); δC(22.7 MHz) 14.10 (CH2CH3), 22.49
and 22.92 (CH3), 35.01 (quaternary C), 46.60, 47.25, 49.58,
53.42, 60.47 and 61.28 (CH2), 67.19 (quaternary C), 125.37
(CN), 126.56, 127.81 and 128.13 (Ar-CH), 140.21 (Ar-C) and
173.58 (CO); m/z 329 (Mϩ, 2%), 256 (13), 209 (96), 183 (10), 181
(18), 137 (64), 120 (53) and 91 (100).
1-(2-Benzylaminoethyl)-2-tert-butoxycarbonyl-4-chloro-4-
cyanotetrahydropyrrole 24e. Prepared from 1-benzyl-5-tert-
butoxycarbonyl-7-chloro-7-cyanohexahydro-1H-pyrrolo[1,2-a]-
imidazole 19c (249 mg, 0.69 mmol) by the method described
above for the preparation of 24a but using sodium cyanoboro-
hydride (43 mg, 0.69 mmol). Column chromatography eluting
with chloroform–isopropylamine (99.5:0.5 v/v) afforded the
title compound 24e (208 mg, 86%) as a yellow oil identified as
a 1:1 mixture of diastereoisomers (Found Mϩ, 363.1721;
C19H2635ClN3O2 requires M, 363.1713); νmax(film)/cmϪ1 3320,
2980, 2250, 1725, 1455, 1370, 1150 and 750; δH(60 MHz) 1.45
[9H, s, C(CH3)3], 2.10 (1H, br s, NH), 3.20 (9H, m), 3.80 (2H, s,
PhCH2) and 7.35 (5H, m, Ar-H); δC(22.7 MHz) 28.02 (CH3),
45.63, 45.79, 47.20, 47.58 and 52.94 (CH2), 53.42 (quaternary
C), 53.86 and 54.46 (CH2), 55.05 (quaternary C), 64.21 and
65.13 (CH), 65.72 and 66.70 (NCH2), 82.14 and 82.25 (CMe3),
117.95 and 119.09 (CN), 126.89, 128.13 and 128.40 (Ar-CH),
140.38 (Ar-C) and 170.71 (CO); m/z 363 (Mϩ, 1%), 264 (3), 262
(8), 226 (13), 187 (10), 152 (17), 120 (80) and 91 (100).
1-(2-Benzylaminoethyl)-3-methoxycarbonyl-3-methyltetra-
hydropyrrole 24f. Prepared from 1-benzyl-7-methoxycarbonyl-
7-methylhexahydro-1H-pyrrolo[1,2-a]imidazole 23b (155.4 mg,
0.567 mmol) by the method described above for the preparation
of 24a but using sodium cyanoborohydride (37 mg, 0.595
mmol). Column chromatography eluting with ethyl acetate–
triethylamine (99.5:0.5 v/v) afforded the title compound 24f
(128 mg, 82%) as a colourless oil (Found: Mϩ, 276.1875;
C16H24N2O2 requires M, 276.1838); νmax(film)/cmϪ1 3310, 2950,
2800, 1725, 1450, 1200, 1125, 740 and 700; δH(250 MHz) 1.33
(3H, s, CH3), 1.64 (1H, m, CH2CHH), 1.95 (1H, br s, NH), 2.37
(2H, m, NCHHCCO2 and CH2CHHC), 2.65 (6H, m, NCH2-
CH2NCH2), 2.95 (1H, d, J 9.2, NCHHCCO2), 3.70 (3H, s,
OCH3), 3.83 (2H, s, PhCH2) and 7.30 (5H, m, Ar-H); δC(22.7
MHz) 25.36 (CH3), 36.09 (CH2CH2C), 47.58 (CH2), 48.39
(quaternary C), 51.96 (OCH3), 53.81, 54.08, 55.38 and 64.21
(CH2), 126.83, 128.08 and 128.35 (Ar-CH), 140.70 (Ar-C) and
177.76 (CO); m/z 276 (Mϩ, 1%), 273 (2), 156 (100) and 91 (37).
1-Benzyl-5,7-bis(hydroxymethyl)-7-methylhexahydro-1H-
pyrrolo[1,2-a]-imidazole 26a
1-Benzyl-5-tert-butoxycarbonyl-7-methoxycarbonyl-7-methyl-
hexahydro-1H-pyrrolo[1,2-a]imidazole 7c (479 mg, 1.28 mmol)
in dry ether (10 cm3) was added to a slurry of lithium alu-
minium hydride (107 mg, 2.82 mmol) in dry ether (20 cm3). The
resulting slurry was stirred for a further 2 h, quenched by the
addition of ethyl acetate and partitioned between chloroform
(2 × 40 cm3) and water (40 cm3). The combined organic extract
was dried, concentrated in vacuo and the crude product purified
by column chromatography eluting with chloroform–isopropyl-
amine (99.5:0.5 v/v) to yield the title compound 26a (308 mg,
87%) as a pale yellow viscous oil (Found: Mϩ, 276.1834;
C16H24N2O2 requires M, 276.1838); νmax(film)/cmϪ1 3400, 2930,
2870, 1460, 1050, 770 and 700; δH(250 MHz) 1.15 (3H, s, CH3),
1.80 (1H, dd, J 13.0 and 10.3, CHCHHC), 1.95 (1H, dd, J 6.5
and 13.0, CHCHHC), 2.61 and 2.81 (each 1H, m, NCH2-
CH2N), 3.10 (3H, m, NCH2CH2N and CHCH2OH), 3.37 (2H,
m, CHCHHOH and PhCHH), 3.58 (1H, dd, J 10.8 and 3.8,
CHCHHOH), 3.63 and 3.65 [each 1H, d, J 11.8, C(CH3)-
CH2OH], 3.90 (1H, s, 7a-H), 4.00 (1H, d, J 12.6, PhCHH) and
7.32 (5H, m, Ar-H); δC(22.7 MHz) 23.79 (CH3), 41.51, 44.43,
51.42, 54.08, 60.14, 63.88, 66.16 and 69.68 (C), 95.74 (C-7a),
127.54, 128.62 and 128.89 (Ar-CH) and 137.83 (Ar-C); m/z 276
(Mϩ, 2%), 275 (2), 246 (15), 245 (26), 204 (25), 187 (100), 126
(12), 113 (14) and 91 (94).
1-Benzyl-7-hydroxymethyl-7-methylhexahydro-1H-pyrrolo[1,2-
a]imidazole 26b
This compound was prepared from 1-benzyl-7-methoxy-
carbonyl-7-methylhexahydro-1H-pyrrolo[1,2-a]imidazole 23b
(1.72 g, 6.28 mmol) by the method described above for the prep-
aration of 26a but using lithium aluminium hydride (286 mg,
7.54 mmol). Column chromatography eluting with chloroform–
isopropylamine (99.5:0.5 v/v) afforded the title compound 26b
(1.52 g, 98%) as a yellow gum identified as a 1:1 mixture of
diastereoisomers (Found: Mϩ, 246.1738; C15H22N2O requires
M, 246.1732); νmax(film)/cmϪ1 3350, 3020, 2950, 2860, 2820,
2-Benzyl-7-methoxycarbonyloctahydropyrrolo[1,2-a]pyrazin-1-
one 25
Pyrroloimidazole stereoisomer mixture 9 and 10 was prepared
J. Chem. Soc., Perkin Trans. 1, 1998
2071

View Article Online
4 R. Smith and T. Livinghouse, Tetrahedron, 1985, 41, 3559; O. Tsuge,
1460, 1350, 1050 and 750; δH(250 MHz) 1.10 and 1.12 (3H,
2 × s, CH3), 1.55, 2.00, 2.20 and 2.40 (each 0.5H, m), 3.20 (12H,
br m) and 7.45 (5H, m, Ar-H); m/z 246 (Mϩ, 11%), 245 (26),
216 (18), 215 (36), 174 (47), 91 (67) and 83 (100).
S. Kanesma and K. Matsuda, J. Org. Chem., 1986, 51, 1997.
5 For preliminary communication of part of this work, see: (a) R. C.
F. Jones, J. R. Nichols and M. T. Cox, Tetrahedron Lett., 1990, 31,
2333; (b) R. C. F. Jones and K. J. Howard, J. Chem. Soc., Perkin
Trans. 1, 1993, 2391.
6 For example, see: I. R. Stirling, I. K. A. Freer and D. J. Robins,
J. Chem. Soc., Perkin Trans. 1, 1997, 677.
Acknowledgements
7 T. F. Gallagher and J. L. Adams, Tetrahedron Lett., 1989, 30, 6599.
8 R. Schwesinger and H. Schlemper, Angew. Chem., Int. Ed. Engl.,
1987, 26, 1167.
9 Single crystal X-ray analysis of the related 3-phenylpyrrolo-
imidazoles confirms the trans relationship between the ester
functions at C-5 and C-7: R. C. F. Jones, K. J. Howard and J. S.
Snaith, Tetrahedron Lett., 1996, 37, 1707.
We thank EPSRC for a CASE studentship (J. R. N.) and a
postdoctoral fellowship (J. S. S), University of Nottingham
for a studentship (K. J. H.), ICI Pharmaceuticals and Rhone-
Poulenc Agriculture for financial support, Drs M. T. Cox and
D. Hawkins for helpful discussions, and the EPSRC National
Mass Spectrometry Service (Swansea) for some MS data.
10 For example, see: G. Tóth, J. Frank, Z. Bende, L. Weber and
K. Simon, J. Chem. Soc., Perkin Trans. 1, 1983, 1961; O. Tsuge,
S. Kanemasa and S. Takenaka, Bull. Chem. Soc. Jpn., 1985, 58,
3137; H. Ardill, M. J. R. Dorrity, R. Grigg, M.-S. Leon-ling, J. F.
Malone, V. Sridharan and S. Thianpatanagul, Tetrahedron, 1990,
46, 6433; H. Ardill, X. L. R. Fontaine, R. Grigg, D. Henderson,
J. Montgomery, V. Sridharan and S. Surendrakumar, Tetrahedron,
1990, 46, 6449.
References
1 For examples and leading references, see: J. Rouden, J. Royer and
H.-P. Husson, Tetrahedron Lett., 1989, 30, 5133; R. M. Williams,
W. Zhai, D. J. Aldous and S. C. Aldous, J. Org. Chem., 1992, 57,
6527; L. M. Harwood and I. A. Lilley, Tetrahedron Lett., 1993, 34,
537; J. A. Monn and M. J. Valli, J. Org. Chem., 1994, 59, 2773; A. R.
Katritzky, J. Koditz and H. Y. Lang, Tetrahedron, 1994, 50, 12 571;
I. Coldham, A. J. Collis, R. J. Mould and D. E. Robinson, Synthesis,
1995, 1147; R. Grigg, Tetrahedron: Asymmetry, 1995, 6, 2475; M. E.
Kopach, A. H. Fray and A. I. Meyers, J. Am. Chem. Soc., 1996, 118,
9876; Z. Ma, S. Wang, C. S. Cooper, A. K. L. Fung, J. K. Lynch,
F. Plagge and D. T. W. Chu, Tetrahedron: Asymmetry, 1997, 8,
883.
2 For leading references, see: R. C. F. Jones, P. Patel, S. C. Hirst and
I. Turner, Tetrahedron, 1997, 53, 11 781; R. C. F. Jones, J. S. Snaith,
M. W. Anderson and M. J. Smallridge, Tetrahedron, 1997, 53, 1111.
3 R. C. F. Jones and M. J. Smallridge, Tetrahedron Lett., 1988, 29,
5005; R. C. F. Jones and S. C. Hirst, Tetrahedron Lett., 1989, 30,
5361, 5365.
11 R. Sustmann, Tetrahedron Lett., 1971, 2717.
12 R. C. F. Jones, K. J. Howard and J. S. Snaith, Tetrahedron Lett.,
1997, 38, 1647.
13 E. Vedejs, S. Larsen and F. G. West, J. Org. Chem., 1985, 50, 2170.
14 D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of
Laboratory Chemicals, Pergamon Press, second edition, 1980.
15 D. E. Goldberg and K. C. Patel, J. Inorg. Nucl. Chem., 1972, 34,
3583.
Paper 8/02048E
Received 13th March 1998
Accepted 12th May 1998
2072
J. Chem. Soc., Perkin Trans. 1, 1998