Cycloaddition of homochiral dihydroimidazoles: A 1,3-dipolar cycloaddition route to optically active pyrrolo[1,2-a]imidazoles

Article abstract of DOI:10.1039/c0ob00529k

N-Alkylation of optically active 1-benzyl-4-phenyl-4,5-dihydroimidazole with active alkyl halides and treatment of the so-formed 4,5-dihydroimidazolium ions with DBU in the presence of a range of electron-deficient alkene dipolarophiles, constitutes a 'on

Full text of DOI:10.1039/c0ob00529k

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PAPER
Cycloaddition of homochiral dihydroimidazoles: A 1,3-dipolar cycloaddition
route to optically active pyrrolo[1,2-a]imidazoles†
Raymond C. F. Jones,*a Kevin J. Howard,b John S. Snaith,‡b Alexander J. Blake,b Wang-Shei Lib and
Peter J. Steelc
Received 2nd August 2010, Accepted 27th September 2010
DOI: 10.1039/c0ob00529k
N-Alkylation of optically active 1-benzyl-4-phenyl-4,5-dihydroimidazole with active alkyl halides and
treatment of the so-formed 4,5-dihydroimidazolium ions with DBU in the presence of a range of
electron-deficient alkene dipolarophiles, constitutes a ‘one-pot’ cascade terminating in a 1,3-dipolar
cycloaddition reaction that affords optically active pyrrolo[1,2-a]imidazoles. Three bonds of the
so-formed pyrrolidine moiety are constructed in this cascade. The cycloaddition follows an endo
approach of dipole and dipolarophile with anti geometry of the dipole and facial selectivity derived
from the phenyl substituent. Inter- and intramolecular cycloaddition modes are observed.
Introduction
The five-membered saturated nitrogen heterocyclic pyrrolidine
ring system is a common sub-unit in many natural products
and synthetic molecules of biological significance.1 The use of
azomethine ylides 1 as 1,3-dipoles in cycloaddition reactions with
alkenes is a valuable method for the assembly of pyrrolidines
(Scheme 1).2 These pericyclic reactions have well-defined tran-
sition states, ideally suited to the asymmetric synthesis of such
molecules. Simple naturally occurring pyrrolidines with interesting
biological properties include the marine metabolites kainic acid 2
and acromelic acid 3,3 and pyrrolidine dicarboxylic acid 4, a potent
inhibitor of glutamate transport.4
Our approach to achieving stereocontrol in such dipolar
cycloadditions is to attach a chiral auxiliary to nitrogen, but
to restrict rotational freedom about the N-to-auxiliary bond by
constraining the auxiliary in a ring, affording optically active 4,5-
dihydroimidazolium (imidazolinium) ylides 5. The facial selectiv-
Scheme 1 1,3-Dipolar cycloaddition of azomethine ylides to generate
pyrrolidines (X, Y usually electron-withdrawing).
ity of the ylides in cycloadditions is thus fully predictable; the
aDepartment of Chemistry, Loughborough University, Loughborough, Leics,
UK LE11 3TU. E-mail: r.c.f.jones@lboro.ac.uk; Fax: +44 1509 223925;
Tel: +44 1509 222557
phenyl substituent facilitates ultimate removal of the templating
atoms. The ylides are generated in situ from dihydroimidazoles
and a suitable alkylating agent, and undergo enantioselective
cycloaddition to afford optically active pyrrolo[1,2-a]imidazoles
as potential precursors to the corresponding pyrrolidines.5,6 In
these sequences three of the bonds in the newly-formed pyrrolidine
ring are made during the alkylation-deprotonation-cycloaddition
cascade. In a previous publication we have detailed the dias-
teroselective cycloadditions of achiral dihydroimidazolium ylides
6;7 we now report in full the results of our investigations in
this area using the optically active ylides 5. Related studies of
bDepartment of Chemistry, University of Nottingham, University Park,
Nottingham, UK NG7 2RD
cDepartment of Chemistry, University of Canterbury, Private Bag 4800,
Christchurch, 8140, New Zealand
† Electronic supplementary information (ESI) available: X-Ray crystallo-
graphic data tables. CCDC reference numbers 787234–787236. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00529k
‡ Present address: School of Chemistry, University of Birmingham,
Birmingham B15 2TT
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asymmetric induction in azomethine ylide cycloaddition by an
auxiliary rotationally constrained at nitrogen have been disclosed
by others.8
Results and Discussion
The precursors to the ylides 5 are the dihydroimidazoles 8a,b.
These were prepared from the enantiomerically pure diamines 7a,b
(themselves prepared from commercially available enantiomers of
phenylglycine as we have reported earlier9) by heating at reflux in
triethyl orthoformate with catalytic p-toluenesulfonic acid. Initial
attempts at quaternisation proved very slow, being incomplete
after several days at 20 ◦C, or 23 h at reflux in THF, even
with active halides such as methyl bromoacetate; addition of KI
had no effect. This led to the development of a revised ‘one-
pot’ procedure whereby the salt is consumed by deprotonation
and cycloaddition as it is formed.10 Thus, imidazolines 8a,b were
separately mixed with an alkylating agent and a dipolarophile
(3 mol equiv.) in dry THF and heated to reflux, when 1 mol equiv.
of 1,8-diazabicyclo[5.4.0]undec-8-ene (DBU) was added dropwise
over 4 h followed by a further 2 h at reflux. Isolation then provided
the hexahydropyrrolo[1,2-a]imidazole cycloadducts, forming three
of the five bonds of the new pyrrolidine ring in one pot (Scheme 2).
Fig. 1 n.O.e correlations to determine relative stereochemistry of cy-
cloadducts 9a and 9e.
configuration of C-3 derived originally from phenylglycine. For
example, for cycloadduct 9a, NOE enhancements were observed
between protons on the following carbon atoms: C-5→C-3,
C-6(pro-S)→C-5, C-7(Me)→C-6(pro-R), C-7(Me)→C-7a. This
stereochemical outcome of the cycloaddition is consistent with an
endo approach of the dipole and dipolarophile, with the dipole
having the anti geometry and facial selectivity provided by the 4-
phenyl substituent in the dipole, as summarised in the transition
state model illustrated in Fig. 2.5 We did not generally observe
any other cycloadduct diastereoisomers with ester-activated dipo-
larophiles, but with nitrile-based dipolarophiles a minor isomer
corresponding to exo approach could sometimes be isolated. Thus,
nitrile 9c was isolated along with small amounts of 9e (endo : exo
8 : 1), and nitrile 9d with small amounts of 9f (endo : exo 11 : 1).
Interestingly, however, 1H NOE difference spectroscopy (e.g. Fig. 1
for adduct 9e) showed that the stereochemistry at C-7a in the
exo adducts was opposite to what would be predicted for exo
addition by our transition state model. It is likely that exo addition
occurs in the expected fashion and is followed by an epimerisation
at C-7a, since the alternative antarafacial addition across the
dipole is energetically disfavoured.11 A possible mechanism for
this reversible epimerisation would involve protonation at N-1 of
the predicted exo-adduct 10 followed by ring opening to produce
an N-substituted pyrrolidinium species. Such species would be
capable of ring closing from the opposite face to the ring opening
and so provide the epimerised exo-adduct 9e (Scheme 3).
Scheme 2 Preparation of pyrroloimidazoles 9 by dipolar cycloaddition
of azomethine ylides derived from optically active dihydroimidazoles 8
Reagents: i, (EtO)3CH, p-TsOH; ii, BrCH2X, CH2 C(Me)Y, THF reflux,
then DBU.
Fig. 2 Transition state model for cycloaddition to give 9a (X = Y =
CO2Me).
A variety of alkylating agents and dipolarophiles were employed
in these reactions. Thus, with methyl bromoacetate as alkylating
agent, smooth reactions occurred with methyl 2-methylpropenoate
as dipolarophile, affording cycloadducts 9a (53%) and 9b (55%)
from 8a and 8b, respectively (Scheme 2; only 3S-series cy-
cloadducts shown). Employing 2-methylpropenonitrile as dipo-
larophile gave cycloadducts 9c (34%) and 9d (56%). The absolute
stereochemistry of the cycloadducts is as illustrated and was
secured by 1H NOE difference spectroscopy to determine relative
stereochemistry, as exemplified in Fig. 1, combined with the fixed
Scheme
pyrroloimidazoles.
3
Mechanism proposed for epimerisation at C-7a of
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Using t-butyl bromoacetate as alkylating agent permitted
smooth cycloaddition with a variety of dipolarophiles. With
methyl 2-methylpropenoate adducts 9g (from 8a) and 9h (from
8b) were isolated as single stereoisomers. Once again the stere-
ochemical outcome of the cycloaddition was in agreement with
our transition state model. It proved possible to crystallise
pyrroloimidazole 9g, and a single crystal X-ray analysis (Fig. 3)
confirmed the structure to be as shown, in agreement with our
1H NOE studies. As in the previous examples, reaction with 2-
methylpropenonitrile was slightly less stereoselective, affording
adducts 9i (from 8a) and 9j (from 8b) along with a small amount
of the product of exo addition: 9i with 9k (endo : exo 8 : 1); 9j with
9l (endo : exo 8 : 1).
Scheme 4 Cycloaddition of azomethine ylides formed from dihydroim-
idazoles 8 using t-butyl bromoacetate as alkylating agent Reagents: i,
BrCH2CO2t-Bu, CH2 CHCO2R, THF reflux, then DBU.
Fig. 4 X-Ray crystal structure of cycloadduct 13a.
Fig. 3 X-Ray crystal structure of cycloadduct 9g.
the range of dipolarophiles to those incorporating sulfone and
ketone activating groups. Hence phenyl ethenyl sulfone gave 14
(33%)12 and but-3-en-2-one afforded 15 (81%), both from (S)-
dihydroimidazole 8a. Employing secondary bromides as alkylating
agents also afforded cycloadducts, although the yields were
low. In cycloadditions with dihydroimidazole 8a and methyl 2-
methylpropenoate, ethyl 2-bromopropanoate afforded the adduct
16a (29%) having quaternary centres at both C-5 and C-7, whilst
t-butyl 2-bromopropanoate afforded adduct 16b (23%). Both of
these cycloadducts were formed as single stereoisomers, with
the more bulky ester function of the dipole adopting an anti
disposition and the dipolarophile approaching endo as in previous
examples.
Seeking an approach to natural products that contain a 2,4-
disubstituted pyrrolidine skeleton, we were interested in achieving
cycloadditions with dipolarophiles lacking a substituent a to
the activating group; in particular, we were concerned about the
stereochemical integrity of the resulting C-7 substituent. Our work
with the achiral imidazoline 11 had shown that cycloadducts
such as 12 existed as an inseparable mixture of epimers at C-7,
presumably via elimination (through ring-opening, cf. Scheme 3,
and proton loss) and conjugate addition across C(7)–C(7a).5
Gratifyingly, methyl and t-butyl propenoates with the appropriate
dihydroimidazoles 8a or 8b and t-butyl bromoacetate as alkylating
agent, gave single stereoisomers of bicycles 13a (65%) and its
enantiomer 13b (63%), and 13c (59%) and its enantiomer 13d
1
(49%) (Scheme 4). Once again we were able to support our H
NOE studies with a single crystal X-ray analysis of adduct 13a
(Fig. 4), which was in agreement with our transition state model.
In the case of t-butyl propenoate, some of the exo isomer was also
produced. Hence 13c was isolated along with 13e (endo : exo 20 : 1)
1
and 13d with 13f (endo : exo 25 : 1). Once again, H NOE studies
showed that the exo adducts had the opposite stereochemistry at
C-7a to that predicted by our transition state model.
A number of key metabolites with interesting biological pro-
files, in particular neuroexcitatory properties, feature a 2,3,4-
trisubstituted pyrrolidine ring.3 Clearly to approach such sys-
tems we needed to achieve cycloaddition with 1,2-disubstituted
alkene dipolarophiles, and we selected methyl (E)-but-2-enoate
It was pleasing to find that these cycloadditions using t-
butyl bromoacetate as alkylating agent were the most efficient
to date. Using this alkylating agent it was possible to extend
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for our initial experiments. Although this dipolarophile af-
forded encouraging yields of bicycles 17a (46%) and 17b (26%,
not optimised) from 8a and 8b, respectively, we were un-
able to obtain cycloadducts with any of the other cyclic and
acyclic 1,2-disubstituted dipolarophiles which were investigated.
These included ethyl (E)-5-hydroxypent-2-enoate, ethyl (E)-5-(t-
butyldimethylsilyloxy)pent-2-enoate, diethyl glutaconate, 2(5H)-
furanone and 5,6-dihydro-2H-pyran-2-one.
Success using 1,2-disubstituted alkene dipolarophiles finally
came with an intramolecular variant of the cycloaddition
reaction.13 Employing one equivalent of ethyl (E)-5-
(bromoacetoxy)pent-2-enoate 18 whose convenient synthesis
we have reported previously13 and which contains, tethered, both
an alkylating agent and a dipolarophile, led to the crystalline
tricyclic cycloadduct 19 from dihydroimidazole 8a (35%) as
a single stereoisomer (Scheme 5); the enantiomer of 19 was
also isolated (30% from 8b) but not fully characterised.14 The
stereochemical outcome of this cycloaddition reaction was
confirmed by an X-ray crystal structure analysis of 19 (Fig. 5).
Once again the stereochemical result of the cycloaddition is
fully consistent with our transition state model, furnishing a
precursor to the desired 2,3,4-trisubstituted pyrrolidines with
complete stereocontrol. Disappointingly the (Z)-bromoacetate
failed to undergo the cycloaddition reaction, with a competing
polymerisation processes appearing to dominate under the
reaction conditions.
Experimental
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 Perkin-
Elmer 1820X FT spectrometers. Mass spectra were recorded using
1
AEI MS902 or VG 8080E spectrometers. H 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 400 MHz.
13C NMR spectra were recorded using the following instruments:
Jeol FX90Q spectrometer at 22.8 MHz; Bruker WM200 at
50.3 MHz; Bruker WM250 at 62.9 MHz; Jeol EX280 at 68 MHz;
Bruker AM400 or Jeol EX400 at 100.6 or 100.4 MHz, respec-
1
tively. H NMR spectra were determined in deuteriochloroform
solution unless indicated, and chemical shifts are quoted in parts
per million (ppm) from tetramethylsilane as internal standard;
coupling constants 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 magnesium sulfate
or sodium sulfate for at least 10 min. Ether refers to diethyl
ether and petroleum ether corresponds to the fraction with b.p.
◦
40–60 C. Tetrahydrofuran (THF) and ether were distilled from
lithium aluminium hydride or potassium immediately prior to use.
Other dry solvents were prepared as described in Perrin et al.16
(S)-1-Benzyl-4-phenyl-4,5-dihydroimidazole
(8a). Prepared
from (S)-1-phenyl-2-benzylaminoethylamine (7a, 7.0 g, 31
mmol) by the method described below for the preparation of
(R)-enantiomer 8b but using triethyl orthoformate (18.34 g, 0.124
mol), to afford the title compound as a colourless oil (1.55 g,
◦
41%): b.p. 148 C/0.1 mmHg; [a]2D3 -172.0 (c 1.03; EtOH);
n
Scheme 5 Intramolecular cycloaddition of a dihydroimidazolium ylide.
max(film)/cm-1 3060, 3027, 2925, 2846, 1672, 1600, 1581, 1493,
1453, 1169, 757; dH (400 MHz; CDCl3) 2.96 (1H, t, J = 9.3,
PhCHCHH), 3.57 (1H, dd, J = 9.3, 10.8, PhCHCHH), 4.20, 4.34
(each 1H, d, J = 14.8, PhCH2), 5.13 (1H, m, PhCHCH2), 7.09
(1H, d, J = 1.6, NCHN), 7.31 (10H, m, Ar–H); dC (100 MHz;
CDCl3) 51.7 (PhCH2), 55.4 (PhCHCH2), 69.95 (PhCHCH2),
126.6, 127.0, 127.7, 127.75, 128.45, 128.7 (6 ¥ Ar-CH), 136.7,
143.8 (2 ¥ Ar-C) and 157.0 (NCHN); m/z 236 (M+, 36%), 120
(53), 91(100). HRMS: (EI) M+ 236.1334; C16H16N2 requires M+
236.1313. Found: C, 81.4; H, 7.1; N, 11.8%; C16H16N2 requires C,
81.3; H, 6.8; N, 11.85%.
(R)-1-Benzyl-4-phenyl-4,5-dihydroimidazole
(8b). (R)-1-
Phenyl-2-benzylaminoethylamine (7b, 6 g, 26.5 mmol) and p-
toluenesulfonic acid (0.04 g, 0.22 mmol) in triethyl orthoformate
(15.72 g, 0.106 mol) was heated at reflux for 20 h. After cooling
to room temperature, aqueous sodium hydroxide (5% w/v, 5 cm3)
was added and the mixture was extracted with chloroform (3 ¥
25 mL). The combined organic phase was dried (Na2SO4) and
evaporated under reduced pressure. The residue was purified by
column chromatography, eluting with ethyl acetate : triethylamine
(99 : 1 v/v) and fractionally distilled under vacuum to yield
the title compound as a colourless oil (5.40 g, 86%): b.p.
Fig. 5 X-Ray crystal structure of cycloadduct 19.
We have thus shown that optically active dihydroimidazoles, via
dihydroimidazolium ylides, are useful precursors to optically ac-
tive pyrrolo[1,2-a]imidazoles though an alkylation-deprotonation-
cycloaddition cascade. The cycloaddition gives predictable stereo-
chemistry and can operate in inter- and intramolecular modes. The
cycloadducts are potential precursors of enantiopure pyrrolidines,
as we have shown in preliminary form and will report in detail.15
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146–148 ◦C/0.08 mmHg; [a]2D3 168.9 (c 1.01; EtOH);
max(film)/cm-1 3061, 3028, 2924, 2844, 1670, 1600, 1581,
64.5 (PhCHCH2), 66.8 (5-CH), 69.2 (PhCHCH2), 96.0 (7a-CH),
126.8, 126.9, 127.0, 127.9, 128.1, 128.7 (6 ¥ Ar-CH), 138.2 141.1
(2 ¥ Ar–C), 174.45, 175.1 (2 ¥ CO); m/z 408 (M+, 2%), 309 (29),
308 (67), 249 (56), 217 (22), 130 (24), 113 (26), 104 (52), 91 (100).
HRMS: (EI) M+ 408.2002; C24H28N2O4 requires M+ 408.2049.
Found: C, 70.6; H, 7.2; N, 6.7%; C24H28N2O4 requires C, 70.6; H,
6.9; N, 6.9%.
n
1493, 1453, 1168, 757; dH (250 MHz; CDCl3) 2.96 (1H, t, J = 9.2,
PhCHCHH), 3.58 (1H, dd, J = 9.2, 10.7, PhCHCHH), 4.20, 4.36
(each 1H, d, J = 14.9, PhCH2), 5.14 (1H, m, PhCHCH2), 7.10 (1H,
d, J = 1.8, NCHN), 7.28 (10H, m, Ar–H); dC (68 MHz; CDCl3)
51.3 (PhCH2), 55.55 (PhCHCH2), 69.7 (PhCHCH2) 126.3, 126.7,
127.4, 127.5, 128.2, 128.4 (6 ¥ Ar-CH), 136.4, 143.5 (2 ¥ Ar–C),
156.7 (NCHN); m/z 236 (M+, 39%), 120 (52), 91(100). HRMS:
(EI) M+ 236.1294; C16H16N2 requires M+ 236.1313. Found: C,
81.3; H, 7.1; N, 11.9%; C16H16N2 requires C, 81.3; H, 6.8; N,
11.85%.
(3S,5S,7R,7aS)-1-Benzyl-7-cyano-5-methoxycarbonyl-7-methyl-
3-phenylhexahydropyrrolo[1,2-a]imidazole (9c). Prepared from
(S)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8a, 0.30 g, 1.27
mmol) by the method described above for the preparation
of 9a but using methyl bromoacetate (0.19 g, 0.12 mL, 1.27
mmol), 2-methylpropenonitrile (0.26 g, 0.32 mL, 3.81 mmol)
and DBU (0.19 g, 0.19 mL, 1.27 mmol). Purification by column
chromatography, eluting with hexane : ethyl acetate (3 : 1 v/v)
yielded the exo-adduct (9e) as a colourless solid (18 mg, 4%):
m.p. 103–105 ◦C; nmax(film)/cm-1 3030, 2951, 2815, 2235, 1747,
1455, 1437, 1206, 1181, 701; dH (250 MHz; CDCl3) 1.51 (3H, s,
CH3), 2.42 (1H, dd, J 6.0, 12.8, 6-CHH), 2.63 (1H, dd, J = 9.2,
10.1, PhCHCHH), 2.81 (1H, dd, J = 10.4, 12.8, 6-CHH), 3.35
(3H, s, OCH3), 3.38 (1H, m, PhCHCHH), 3.46 (1H, d, J = 13.1,
PhCHH), 3.56 (1H, dd, J = 6.0, 10.4, 5-CH), 4.01 (1H, dd, J = 5.5,
10.1, PhCHCH2), 4.08 (1H, d, J = 13.1, PhCHH), 4.75 (1H, s, 7a-
CH), 7.26 (10H, m, Ar–H); dC (68 MHz; CDCl3) 20.0 (CH3), 38.6
(7-C), 43.0 (6-CH2), 51.8 (OCH3), 57.7 (PhCH2), 64.2 (5-CH),
64.3 (PhCHCH2), 69.7 (PhCHCH2), 91.6 (7a-CH), 123.1 (CN),
126.9, 127.4, 127.6, 128.2, 128.5, 128.7 (6 ¥ Ar-CH), 137.4, 140.0
(2 ¥ Ar-C), 172.6 (CO); m/z 375 (M+, 3%), 309 (24), 308 (100),
249 (59), 217 (19), 130 (12), 104 (31), 91 (90). HRMS: (EI) M+
375.1948; C23H25N3O2·0.33H2O requires M+ 375.1947. Found: C,
72.25; H, 6.7; N, 10.9%. C23H25N3O2·0.33H2O requires C, 72.4;
H, 6.8; N, 11.0%; and the title compound (9c) as a colourless oil
(0.16 g, 34%): [a]D22 -43.5 (c 0.69; EtOH); nmax(film)/cm-1 3028,
2950, 2236, 1745, 1495, 1453, 1175; dH (250 MHz; CDCl3) 1.42
(3H, s, CH3), 2.36 (1H, dd, J = 10.1, 13.1, 6-CHH), 2.64 (1H,
t, J = 9.6, PhCHCHH), 2.75 (1H, dd, J = 6.2, 13.1, 6-CHH),
3.36 (3H, s, OCH3), 3.50 (2H, m, PhCHH and PhCHCHH), 3.84
(1H, dd, J = 6.2, 10.1, 5-CH), 4.06 (1H, d, J = 12.8, PhCHH),
4.20 (1H, s, 7a-CH), 4.32 (1H, dd, J = 5.7, 9.9, PhCHCH2), 7.23
(10H, m, Ar–H); dC (68 MHz; CDCl3) 22.1 (CH3), 43.8 (6-CH2),
44.5 (7-C), 51.7 (OCH3), 58.5 (PhCH2), 64.5 (PhCHCH2), 65.1
(5-CH), 69.3 (PhCHCH2), 93.5 (7a-CH), 122.2 (CN), 126.8,
127.3, 127.4, 128.1, 128.4, 128.9 (6 ¥ Ar-CH), 137.9, 140.3 (2 ¥
Ar-C), 172.7 (CO); m/z 375 (M+, 1%), 309 (13), 308 (66), 249 (39),
217 (13), 146 (15), 130 (11), 104 (46), 91 (100). HRMS: (EI) M+
375.1950; C23H25N3O2 requires M+ 375.1947. Found: C, 73.2; H,
6.9; N, 10.9%; C23H25N3O2 requires C, 73.6; H, 6.7; N, 11.1%.
(3S,5S,7R,7aS)-1-Benzyl-5,7-bis(methoxycarbonyl)-7-methyl-
3-phenylhexahydropyrrolo[1,2-a]imidazole (9a). Methyl bromo-
acetate (1.29 g, 0.80 mL, 8.46 mmol) was added to (S)-1-
benzyl-4-phenyl-4,5-dihydroimidazole (8a, 2.00 g, 8.46 mmol) in
tetrahydrofuran (50 mL) stirred at reflux under nitrogen. Methyl
2-methylpropenoate (2.54 g, 2.72 mL, 25.39 mmol) was added in
one portion followed by the dropwise addition over 4 h of DBU
(1.29 g, 1.27 mL, 8.46 mmol). Stirring at reflux was continued
for 2 h. The solvent was evaporated under reduced pressure and
the residue partitioned between chloroform (3 ¥ 40 mL) and
water (40 mL). The combined organic phase was dried (Na2SO4),
evaporated under reduced pressure and the residue purified by
column chromatography eluting with hexane : ethyl acetate (4 : 1
v/v) to afford the title compound as a colourless oil (1.80 g, 52%):
[a]2D2 -15.6 (c 1.04; EtOH); nmax(film)/cm-1 3062, 3028, 2949, 2804,
1731, 1454, 1265, 1205, 1132, 700; dH (250 MHz; CDCl3) 1.50
(3H, s, CH3), 2.20 (1H, dd, J = 9.9, 13.2, 6-CHH), 2.44 (1H,
dd, J = 9.2, 10.0, PhCHCHH), 2.77 (1H, dd, J = 6.8, 13.2, 6-
CHH), 3.21 (2H, m, PhCHH and PhCHCHH), 3.34, 3.81 (each
3H, s, OCH3), 4.08 (1H, dd, J = 6.8, 9.9, 5-CH), 4.13 (2H, m,
PhCHH and PhCHCH2), 4.31 (1H, s, 7a-CH), 7.25 (10H, m,
Ar–H); dC (100 MHz; CDCl3) 23.0 (CH3), 43.3 (6-CH2), 51.5,
51.9 (2 ¥ OCH3), 53.3 (7-C), 58.4 (PhCH2), 64.7 (PhCHCH2),
67.0 (5-CH), 69.4 (PhCHCH2), 96.2 (7a-CH), 127.0, 127.1, 127.2,
128.0, 128.2, 128.8 (6 ¥ Ar-CH), 138.4, 141.3 (2 ¥ Ar-C), 174.6,
175.3 (2 ¥ CO); m/z 408 (M+, 4%), 309 (29), 308 (100), 249 (36),
217 (13), 130 (12), 104 (34), 91 (87). HRMS: (EI) M+ 408.2001;
C24H28N2O4 requires M+ 408.2049. Found: C, 70.85; H, 7.2; N,
6.9%; C24H28N2O4 requires C, 70.6; H, 6.9; N, 6.9%.
(3R,5R,7S,7aR)-1-Benzyl-5,7-bis(methoxycarbonyl)-7-methyl-
3-phenylhexahydropyrrolo[1,2-a]imidazole (9b). Prepared from
(R)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8b, 2.00 g, 8.46
mmol) by the method described above for the preparation of 9a but
using methyl bromoacetate (1.29 g, 0.80 mL, 8.46 mmol), methyl 2-
methylpropenoate (2.54 g, 2.72 mL, 25.39 mmol) and DBU (1.29 g,
1.27 mL, 8.46 mmol). Purification by column chromatography
eluting with hexane : ethyl acetate (4 : 1 v/v) yielded the title
compound as a colourless oil (1.90 g, 55%): [a]2D2 16.8 (c 1.20;
EtOH); nmax(film)/cm-1 3027, 2948, 2804, 1731, 1453, 1265, 1205,
1178, 701; dH (400 MHz; CDCl3) 1.50 (3H, s, CH3), 2.20 (1H,
dd, J = 9.8, 13.3, 6-CHH), 2.44 (1H, t, J = 9.6, PhCHCHH),
2.77 (1H, dd, J = 7.0, 13.3, 6-CHH), 3.22 (2H, m, PhCHH and
PhCHCHH), 3.34, 3.80 (each 3H, s, OCH3), 4.06 (1H, dd, J = 7.0,
9.8, 5-CH), 4.12 (2H, m, PhCHH and PhCHCH2), 4.31 (1H, s,
7a-CH), 7.24 (10H, m, Ar–H); dC (68 MHz; CDCl3) 22.8 (CH3),
43.2 (6-CH2), 51.3, 51.75 (2 ¥ OCH3), 53.1 (7-C), 58.2 (PhCH2),
(3R,5R,7S,7aR)-1-Benzyl-7-cyano-5-methoxycarbonyl-7-me-
thyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (9d). Prepared
from (R)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8b, 0.50 g,
2.12 mmol) by the method described above for the preparation
of 9a but using methyl bromoacetate (0.32 g, 0.20 mL, 2.12
mmol), 2-methylpropenonitrile (0.43 g, 0.53 mL, 6.36 mmol)
and DBU (0.32 g, 0.32 mL, 2.12 mmol). Purification by column
chromatography, eluting with hexane : ethyl acetate (4 : 1 v/v)
yielded the exo-adduct (9f) as a colourless solid (38 mg, 5%), m.p.
◦
100–102 C: nmax KBr/cm-1 3062, 3029, 2950, 2815, 2234, 1745,
1454, 1204, 1180, 700; dH (250 MHz; CDCl3) 1.51 (3H, s, CH3),
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2.42 (1H, dd, J = 6.0, 12.8, 6-CHH), 2.63 (1H, dd, J = 9.2, 10.0,
PhCHCHH), 2.81 (1H, dd, J = 10.4, 12.8, 6-CHH), 3.34 (3H, s,
OCH3) 3.36 (1H, m, PhCHCHH), 3.46 (1H, d, J = 13.1, PhCHH),
3.56 (1H, dd, J = 6.0, 10.4, 5-CH), 4.01 (1H, dd, J = 5.5, 10.0,
PhCHCH2), 4.08 (1H, d, J = 13.0, PhCHH), 4.75 (1H, s, 7a-CH),
7.26 (10H, m, Ar–H); dC (68 MHz; CDCl3) 20.0 (CH3), 38.6
(7-C), 43.0 (6-CH2), 51.8 (OCH3), 57.7 (PhCH2), 64.2 (5-CH),
64.3 (PhCHCH2), 69.7 (PhCHCH2), 91.6 (7a-CH), 123.1 (CN),
126.9, 127.4, 127.55, 128.1, 128.45, 128.7 (6 ¥ Ar-CH), 137.4,
140.0 (2 ¥ Ar-C), 172.6 (CO); m/z 375 (M+, 1%), 308 (82), 249
(52), 217 (19), 130 (13), 104 (39) and 91 (100). HRMS: (EI) M+
375.1951; C23H25N3O2 requires M+ 375.1947. Found: C, 73.7; H,
6.9; N, 11.5%; C23H25N3O2 requires C, 73.6; H, 6.7; N, 11.2%; and
the titl◦e compound (9d) as a colourless solid (1.78 g, 56%), m.p.
67–69 C: [a]2D2 43.5 (c 0.63; EtOH); nmax KBr/cm-1 3028, 2948,
2811, 2236, 1744, 1454, 1204, 1176, 701; dH (250 MHz; CDCl3)
1.41 (3H, s, CH3), 2.35 (1H, dd, J = 10.1, 13.1, 6-CHH), 2.63
(1H, t, J = 9.7, PhCHCHH), 2.72 (1H, dd, J = 6.1, 13.1, 6-CHH),
3.35 (3H, s, OCH3), 3.50 (2H, m, PhCHH and PhCHCHH), 3.83
(1H, dd, J = 6.1, 10.1, 5-CH), 4.04 (1H, d, J = 12.9, PhCHH),
4.18 (1H, s, 7a-CH), 4.30 (1H, dd, J = 5.7, 9.7, PhCHCH2), 7.33
(10H, m, Ar–H); dC (68 MHz; CDCl3) 22.1 (CH3), 43.8 (6-CH2),
44.6 (7-C), 51.75 (OCH3), 58.5 (PhCH2), 64.5 (PhCHCH2), 65.1
(5-CH), 69.4 (PhCHCH2), 93.55 (7a-CH), 122.2 (CN), 126.85,
127.4, 127.4, 128.1, 128.4, 128.9 (6 ¥ Ar-CH), 137.9, 140.3 (2 ¥
Ar-C), 172.8 (CO); m/z 375 (M+, 2%), 309 (26), 308 (94), 249
(59), 217 (21), 104 (54), 91 (100). HRMS: (EI) M+ 375.1977;
C23H25N3O2 requires M+ 375.1947. Found: C, 73.9; H, 6.6; N,
11.3%; C23H25N3O2 requires C, 73.6; H, 6.7; N, 11.2%.
50◦; 299 parameters, wR = 0.1034 for all 2620 data, R = 0.042 for
1393 data with Fo > 4s(Fo).
(3R,5R,7S,7aR)-1-Benzyl-5-t-butoxycarbonyl-7-methoxycar-
bonyl-7-methyl-3-phenylhexahydropyrrolo[1,2-a]imidazole
(9h).
Prepared from (R)-1-benzyl-4-phenyl-4,5-dihydroimidazole
(8b, 1.0 g, 4.23 mmol) by the method described above for the
preparation of 9a but using t-butyl bromoacetate (0.83 g, 0.68 mL,
4.23 mmol), methyl 2-methylpropenoate (1.27 g, 1.36 mL, 12.70
mmol) and DBU (0.64 g, 0.63 mL, 4.23 mmol). Purification
by column chromatography, eluting with petroleum ether (b.p.
40–60 ◦C) : ethyl acetate (5 : 1 v/v) yielded the title compound as
a colourless oil (1.95 g, 51%): nmax(film)/cm-1 2978, 1732, 1455,
1264, 1152, 701; dH (400 MHz; CDCl3) 1.12 (9H, s, C(CH3)3),
1.49 (3H, s, 7-CH3), 2.18 (1H, dd, J = 9.8, 13.2, 6-CHH), 2.41
(1H, t, J = 9.7, PhCHCHH), 2.71 (1H, dd, J = 6.6, 13.2, 6-CHH),
3.21 (2H, m, PhCHH and PhCHCHH), 3.80 (3H, s, OCH3),
3.90 (1H, dd, J = 6.6, 9.8, 5-CH), 4.11 (2H, m, PhCHH and
PhCHCH2), 4.31 (1H, s, 7a-CH), 7.29 (10H, m, Ar–H); dC
(68 MHz; CDCl3) 22.9 (7-CH3), 27.3 (C(CH3)3), 43.2 (6-CH2),
51.6 (OCH3), 53.0 (7-C), 58.2 (PhCH2), 64.8 (PhCHCH2), 68.0
(5-CH), 69.3 (PhCHCH2), 80.1 (C(CH3)3), 96.3 (7a-CH), 126.8,
126.9, 127.1, 127.85, 128.0, 128.6 (6 ¥ Ar-CH), 138.2, 141.65
(2 ¥ Ar-C), 173.2, 175.2 (2 ¥ CO); m/z 450 (M+, 1%), 350 (44),
294 (48), 249 (33), 104 (38), 91 (100). HRMS: (EI) M+ 450.2521;
C27H34N2O4 requires M+ 450.2519. Found: C, 72.1; H, 7.9; N,
6.1%; C27H34N2O4 requires C, 72.0; H, 7.6; N, 6.2%.
(3S,5S,7R,7aS)-1-Benzyl-5-t-butoxycarbonyl-7-cyano-7-me-
thyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (9i). This com-
pound was prepared from (S)-1-benzyl-4-phenyl-4,5-dihy-
droimidazole (8a, 1.0 g, 4.23 mmol) by the method described above
for the preparation of 9a but using t-butyl bromoacetate (0.83 g,
0.68 mL, 4.23 mmol), 2-methylpropenonitrile (0.85 g, 1.07 mL,
12.70 mmol) and DBU (0.64 g, 0.63 mL, 4.23 mmol). Purification
by column chromatography, eluting with petroleum ether (b.p. 40–
(3S,5S,7R,7aS)-1-Benzyl-5-t-butoxycarbonyl-7-methoxycar-
bonyl-7-methyl-3-phenylhexahydropyrrolo[1,2-a]imidazole
(9g).
Prepared from (S)-1-benzyl-4-phenyl-4,5-dihydroimidazole
(8a, 2.0 g, 8.46 mmol) by the method described above for the
preparation of 9a but using t-butyl bromoacetate (1.65 g, 1.37 mL,
8.46 mmol), methyl 2-methylpropenoate (2.54 g, 2.72 mL, 25.39
mmol) and DBU (1.29 g, 1.27 mL, 8.46 mmol). Purification
by column chromatography, eluting with petroleum ether (b.p.
40–60 ◦C) : ethyl acetate (5 : 1 v/v) yielded the title compound as
a colourless oil (1.95 g, 51%): nmax(film)/cm-1 3061, 3027, 2976,
2803, 1731, 1453, 1366, 1263, 1151, 700; dH (250 MHz; CDCl3)
1.12 (9H, s, C(CH3)3), 1.49 (3H, s, 7-CH3), 2.18 (1H, dd, J = 9.8,
13.2, 6-CHH), 2.41 (1H, t, J = 9.7, PhCHCHH), 2.71 (1H, dd,
J = 6.6, 13.2, 6-CHH), 3.20 (2H, m, PhCHH and PhCHCHH),
3.80 (3H, s, OCH3), 3.90 (1H, dd, J = 6.6, 9.8, 5-CH), 4.10 (2H,
m, PhCHH and PhCHCH2), 4.31 (1H, s, 7a-CH), 7.28 (10H,
m, Ar–H); dC (68 MHz; CDCl3) 23.0 (7-CH3), 27.5 (C(CH3)3),
43.3 (6-CH2), 51.8 (OCH3), 53.2 (7-C), 58.4 (PhCH2), 64.9
(PhCHCH2), 68.2 (5-CH), 69.4 (PhCHCH2), 80.3 (C(CH3)3), 96.4
(7a-CH), 127.0, 127.1, 127.3, 128.0, 128.1, 128.8 (6 ¥ Ar-CH),
138.4, 141.8 (2 ¥ Ar-C), 173.5, 175.5 (2 ¥ CO); m/z 450 (M+, 7%),
350 (57), 294 (45), 249 (39), 131 (42), 104 (40), 91 (100). HRMS:
(EI) M+ 450.2491; C27H34N2O4 requires M+ 450.2519. Found: C,
72.1; H, 7.9; N, 6.1%; C27H34N2O4 requires C, 72.0; H, 7.6; N,
6.2%.
◦
60 C) : ethyl acetate (5 : 1 v/v) yielded the exo-adduct (9k) as a
colourless solid (62 mg, 4%), m.p. 100–102 ◦C [from petroleum
ether (b.p. 40–60 ◦C)]: nmax (CHCl3)/cm-1 2822, 2236, 1732, 1369,
1153; dH (250 MHz; CDCl3) 1.13 (9H, s, C(CH3)3), 1.50 (3H, s,
7-CH3), 2.38 (1H, dd, J = 5.8, 12.7, 6-CHH), 2.62 (1H, apparent
t, J = 9.5, PhCHCHH), 2.77 (1H, dd, J = 10.7, 12.7, 6-CHH),
3.35 (1H, dd, J = 5.5, 8.9, PhCHCHH), 3.45 (2H, m, PhCHH
and 5-CH), 3.99 (1H, dd, J = 5.5, 9.9, PhCHCH2), 4.08 (1H, d,
J = 13.0, PhCHH), 4.75 (1H, s, 7a-CH), 7.27 (10H, m, Ar–H);
dC (68 MHz; CDCl3) 20.15 (7-CH3), 27.4 (C(CH3)3), 38.5 (7-C),
43.4 (6-CH2), 57.8 (PhCH2), 64.7 (PhCHCH2), 65.6 (5-CH), 69.8
(PhCHCH2), 81.3 (C(CH3)3), 92.0 (7a-CH), 123.4 (CN), 127.2,
127.4, 127.5, 128.2, 128.4, 128.7 (6 ¥ Ar-CH), 137.6, 140.5 (2 ¥
Ar-C), 171.4 (CO); m/z 350 (39%), 316 (12), 294 (48), 249 (32),
104 (40), 91 (100). Found: C, 74.85; H, 7.7; N, 10.0%; C26H31N3O2
requires C, 74.8; H, 7.5; N, 10.1%; and the title compound (9i) as
a colourless solid◦(0.47 g, 27%), m.p. 118–119 ◦C [from petroleum
ether (b.p. 40–60 C)]: [a]2D2 -15.8 (c 0.48; EtOH); nmax (KBr)/cm-1
3072, 3029, 2981, 2959, 2943, 2234, 1736, 1454, 1443, 1366, 1215,
1152, 1079, 702; dH (400 MHz; CDCl3) 1.13 (9H, s, C(CH3)3),
1.41 (3H, s, 7-CH3), 2.32 (1H, dd, J = 10.1, 13.1, 6-CHH), 2.59
(1H, apparent t, J = 9.5, PhCHCHH), 2.67 (1H, dd, J = 6.0,
13.1, 6-CHH), 3.47 (2H, m, PhCHH and PhCHCHH), 3.71 (1H,
dd, J = 6.0, 10.1, 5-CH), 4.04 (1H, d, J = 12.7, PhCHH), 4.17
Crystal data for 9g: C27H34N2O4, M = 450.6, colourless block,
0.70 ¥ 0.59 ¥ 0.30 mm; orthorhombic, P212121; a = 8.046(1), b =
3
˚
˚
14.280(2), c = 22.646(3) A, U = 2602(1) A ; T = 293 K, m(Mo-
Ka) = 0.08 mm-1, Dc = 1.15 g cm-3; Z = 4, F(000) = 968, 2qmax
=
302 | Org. Biomol. Chem., 2011, 9, 297–306
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m.p. 98–99 ◦C [from petroleum ether (b.p. 40–60 ◦C)]: [a]2D2 -22.8
(c 1.08; EtOH); nmax (KBr)/cm-1 3032, 2980, 2946, 1728, 1367,
1166, 1152, 697; dH (400 MHz; CDCl3) 1.22 (9H, s, C(CH3)3), 2.26
(1H, m, 6-CHH), 2.40 (1H, t, J = 9.6, PhCHCHH), 2.58 (1H, m, 6-
CHH), 3.27 (3H, m, PhCHH, 7-CH and PhCHCHH), 3.72 (3H, s,
OCH3), 3.80 (1H, t, J = 6.8, 5-CH), 4.08 (1H, d, J = 12.9, PhCHH),
4.13 (1H, m, PhCHCH2), 4.68 (1H, d, J = 6.6, 7a-CH), 7.27 (10H,
m, Ar–H); dC (68 MHz; CDCl3) 27.4 (C(CH3)3), 32.6 (6-CH2),
47.9 (7-CH), 51.3 (OCH3), 58.2 (PhCH2), 64.0 (PhCHCH2), 66.8
(5-CH), 68.6 (PhCHCH2), 80.1 (C(CH3)3), 88.4 (7a-CH), 126.7,
126.9, 127.8, 128.0, 128.3 (6 ¥ Ar-CH), 138.2, 141.2 (2 ¥ Ar-
C), 172.7, 173.0 (2 ¥ CO); m/z 436 (M+, 2%), 350 (36), 335 (15)
294 (41), 249 (33), 120 (24), 104 (52), 91 (100). HRMS: (EI) M+
436.2377; C26H32N2O4 requires M+ 436.2362. Found: C, 71.6; H,
7.6; N, 6.4%; C26H32N2O4 requires C, 71.5; H, 7.4; N, 6.4%.
A crystal was mounted on a thin glass fibre and transferred
into the cold stream of the diffractometer low temperature device.
Crystal data for 13a: C26H32N2O4, M = 436.54, monoclinic, P2◦1;
(1H, s, 7a-CH), 4.29 (1H, dd, J = 5.8, 9.8, PhCHCH2), 7.31 (10H,
m, Ar–H); dC (68 MHz; CDCl3) 22.25 (7-CH3), 27.4 (C(CH3)3),
43.9 (6-CH2), 44.4 (7-C), 58.5 (PhCH2), 64.7 (PhCHCH2), 66.4 (5-
CH), 69.4 (PhCHCH2), 81.1 (C(CH3)3), 93.8 (7a-CH), 122.4 (CN),
127.1, 127.3, 127.3, 128.1, 128.3, 128.9 (6 ¥ Ar-CH), 138.0, 140.9
(2 ¥ Ar-C), 171.45 (CO); m/z (FAB) 418 (MH+, 5%), 350 (48),
316 (17), 294 (57), 249 (32), 130 (16), 104 (44), 104 (100). HRMS:
(EI) M+ 417.2424; C26H31N3O2 requires M+ 417.2416. Found: C,
74.75; H, 7.8; N, 10.1%; C26H31N3O2 requires C, 74.8; H, 7.5; N,
10.1%.
(3R,5R,7S,7aR)-1-Benzyl-5-t-butoxycarbonyl-7-cyano-7-me-
thyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (9j). This com-
pound was prepared from (R)-1-benzyl-4-phenyl-4,5-dihy-
droimidazole (8b, 0.50 g, 2.12 mmol) by the method described
above for the preparation of 9a but using t-butyl bromoacetate
(0.41 g, 0.34 mL, 2.12 mmol), 2-methylpropenonitrile (0.43 g,
0.53 mL, 6.35 mmol) and DBU (0.32 g, 0.32 mL, 2.12 mmol).
Purification by column chromatography, eluting with petroleum
ether (b.p. 40–60 ◦C) : ethyl acetate (5 : 1 v/v) yielded the exo-
adduct (9l) as a colourless solid (24 mg, 3%), m.p. 99–101 ◦C: nmax
(KBr)/cm-1 2981, 2233, 1724, 1636, 1366, 1162, 698; dH (400 MHz;
CDCl3) 1.13 (9H, s, C(CH3)3), 1.49 (3H, s, 7-CH3), 2.38 (1H, dd,
J = 5.9, 12.8, 6-CHH), 2.62 (1H, t, J = 9.2, PhCHCHH), 2.76
(1H, dd, J = 10.8, 12.8, 6-CHH), 3.35 (1H, dd, J = 5.5, 9.2,
PhCHCHH), 3.44 (2H, m, PhCHH and 5-CH), 3.99 (1H, dd,
J = 5.5, 10.0, PhCHCH2), 4.07 (1H, d, J = 13.1, PhCHH), 4.75
(1H, s, 7a-CH), 7.39 (10H, m, Ar–H); dC (68 MHz; CDCl3) 20.1
(7-CH3), 27.4 (C(CH3)3), 38.5 (7-C), 43.4 (6-CH2), 57.8 (PhCH2),
64.7 (PhCHCH2), 65.6 (5-CH), 69.8 (PhCHCH2), 81.3 (C(CH3)3),
91.95 (7a-CH), 123.4 (CN), 127.2, 127.4, 127.5, 128.2, 128.4, 128.7
(6 ¥ Ar-CH), 137.6, 140.5 (2 ¥ Ar-C), 171.4 (CO); m/z 350 (15%),
294 (20), 249 (17), 120 (35), 104 (15), 91 (100). Found: C, 75.0;
H, 7.7; N, 10.3%; C26H31N3O2 requires C, 74.8; H, 7.5; N, 10.1%;
and the title compound (9j) as a colourless solid (194 mg, 22%),
m.p. 119–120 ◦C: [a]D22 15.7 (c 1.07; EtOH); nmax (KBr)/cm-1 2978,
1732, 1455, 1264, 1152 and 701; dH (400 MHz; CDCl3) 1.13 (9H, s,
C(CH3)3), 1.45 (3H, s, 7-CH3), 2.35 (1H, dd, J = 9.7, 13.2, 6-CHH),
2.65 (1H, t, J = 9.7, PhCHCHH), 2.78 (1H, dd, J = 6.4, 13.2, 6-
CHH), 3.53 (2H, m, PhCHH and PhCHCHH), 3.78 (1H, dd, J =
6.4, 9.7, 5-CH), 4.12 (1H, d, J = 12.9, PhCHH), 4.23 (1H, s, 7a-
CH), 4.35 (1H, dd, J = 5.9, 9.7, PhCHCH2), 7.29 (10H, m, Ar–H);
dC (68 MHz; CDCl3) 22.1 (7-CH3), 27.2 (C(CH3)3), 43.7 (6-CH2),
44.2 (7-C), 58.3 (PhCH2), 64.55 (PhCHCH2), 66.25 (5-CH), 69.2
(PhCHCH2), 80.8 (C(CH3)3), 93.6 (7a-CH), 122.2 (CN), 126.9,
127.1, 127.15, 128.0, 128.2, 128.7 (6 ¥ Ar-CH), 137.9, 140.75 (2 ¥
Ar-C), 171.25 (CO); m/z (FAB) 418 (MH+, 63%), 350 (100), 316
(19), 294 (37), 249 (17), 208 (22). HRMS: (FAB) MH+ 418.2507;
C26H31N3O2 requires MH+ 418.2494. Found: C, 74.7; H, 7.5; N,
9.9%; C26H31N3O2 requires C, 74.8; H, 7.5; N, 10.1%.
˚
a = 10.276(2), b = 5.799(3), c = 20.259(5) A, b = 103.07(2) ,
3
-1
˚
U = 1175.9(7) A , T = 150(2) K, m(Mo-Ka) = 0.083 mm , Dc =
1.233 g cm-3, Z = 2, 2284 unique data (Rint 0.072) were used in all
calculations. Final R1 [1639 F > 4s(F)] = 0.0734 and wR(all F2)
was 0.146.
(3R,5R,7S,7aR)-1-Benzyl-5-t-butoxycarbonyl-7-methoxycar-
bonyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (13b). Prepared
from (R)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8b, 1.0 g, 4.23
mmol) by the method described above for the preparation of 9a but
using t-butyl bromoacetate (0.83 g, 0.68 mL, 4.23 mmol), methyl
propenoate (1.09 g, 1.14 mL, 12.70 mmol) and DBU (0.64 g,
0.63 mL, 4.23 mmol). Purification by column chromatography,
eluting with petroleum ether (b.p. 40–60 ◦C) : ethyl acetate (5 : 1
v/v) yielded◦the title compound as a colourless solid (1.17 g, 63%),
◦
m.p. 92–94 C [from petroleum ether (b.p. 40–60 C)]: [a]2D2 22.8
(c 1.08; EtOH); nmax (KBr)/cm-1 3032, 2980, 2946, 1728, 1367,
1166, 1152, 697; dH (270 MHz; CDCl3) 1.21 (9H, s, C(CH3)3), 2.27
(1H, m, 6-CHH), 2.40 (1H, t, J = 9.6, PhCHCHH), 2.58 (1H, m, 6-
CHH), 3.28 (3H, m, PhCHH, 7-CH and PhCHCHH), 3.70 (3H, s,
OCH3), 3.82 (1H, t, J = 6.9, 5-CH), 4.08 (1H, d, J = 13.2, PhCHH),
4.13 (1H, m, PhCHCH2), 4.68 (1H, d, J = 6.3, 7a-CH), 7.28 (10H,
m, Ar–H); dC (68 MHz; CDCl3) 27.4 (C(CH3)3), 32.65 (6-CH2),
48.0 (7-CH), 51.4 (OCH3), 58.3 (PhCH2), 64.0 (PhCHCH2), 66.8
(5-CH), 68.7 (PhCHCH2), 80.2 (C(CH3)3), 88.45 (7a-CH), 126.8,
127.0, 127.9, 128.0, 128.3 (6 ¥ Ar-CH), 138.3, 141.3 (2 ¥ Ar-
C), 172.8, 173.1 (2 ¥ CO); m/z 436 (M+, 4%), 350 (43), 335
(16), 294 (48), 249 (37), 120 (32), 104 (58), 91 (100). HRMS:
(EI) M+ 436.2345; C26H32N2O4 requires M+ 436.2362. Found: C,
71.3; H, 7.5; N, 6.3%; C26H32N2O4 requires C, 71.5; H, 7.4; N,
6.4%.
(3S,5S,7R,7aS)-1-Benzyl-5,7-bis(t-butoxycarbonyl)-3-phenyl-
hexahydropyrrolo[1,2-a]imidazole (13c). Prepared from (S)-1-
benzyl-4-phenyl-4,5-dihydroimidazole (8a, 1.0 g, 4.23 mmol) by
the method described above for the preparation of 9a but using
t-butyl bromoacetate (0.83 g, 0.68 mL, 4.23 mmol), t-butyl
propenoate (1.19 g, 1.26 mL, 9.73 mmol) and DBU (0.64 g,
0.63 mL, 4.23 mmol). Purification by column chromatography,
eluting with petroleum ether (b.p. 40–60 ◦C) : ethyl acetate (5 : 1
v/v) yielded the title compound as a colourless solid (1.20 g,
59%), m.p. 102–104 ◦C [from petroleum ether (b.p. 40–60 ◦C)],
(3S,5S,7R,7aS)-1-Benzyl-5-t-butoxycarbonyl-7-methoxycar-
bonyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (13a). Prepared
from (S)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8a, 1.0 g, 4.23
mmol) by the method described above for the preparation of 9a but
using t-butyl bromoacetate (0.83 g, 0.68 mL, 4.23 mmol), methyl
propenoate (1.09 g, 1.14 mL, 12.70 mmol) and DBU (0.64 g,
0.63 mL, 4.23 mmol). Purification by column chromatography,
eluting with petroleum ether (b.p. 40–60 ◦C) : ethyl acetate (5 : 1
v/v) yielded the title compound as a colourless solid (1.21 g, 65%),
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[a]2D2 -27.0 (c 0.97; EtOH): nmax (KBr)/cm-1 2927, 1734, 1628, 1384,
1369, 1145, 702; dH (400 MHz; CDCl3) 1.22, 1.49 (18H, 2 ¥ s, 2 ¥
C(CH3)3), 2.22 (1H, m, 6-CHH), 2.43 (1H, t, J = 9.5, PhCHCHH),
2.52 (1H, m, 6-CHH), 3.16 (1H, dd, J = 6.5, 11.8, 7-CH), 3.26 (2H,
m, PhCHH and PhCHCHH), 3.71 (1H, t, J = 7.0, 5-CH), 4.13 (2H,
m, PhCHH and PhCHCH2), 4.61 (1H, d, J = 6.5, 7a-CH), 7.26
(10H, m, Ar–H); dC (68 MHz; CDCl3) 27.5, 27.75 (2 ¥ C(CH3)3),
33.1 (6-CH2), 49.2 (7-CH), 58.35 (PhCH2), 63.9 (PhCHCH2), 67.0
(5-CH), 68.9 (PhCHCH2), 80.1, 80.5 (2 ¥ C(CH3)3), 88.4 (7a-
CH), 126.8, 126.9, 127.0, 127.9, 129.0 (6 ¥ Ar-CH), 137.9, 141.6
(2 ¥ Ar-C), 171.6, 173.15 (2 ¥ CO); m/z 478 (M+, 5%), 350 (53),
294 (62), 249 (35), 235 (25), 120 (17), 104 (42), 91 (100). HRMS:
(EI) M+ 478.2853; C29H38N2O4 requires M+ 478.2832. Found: C,
72.6; H, 8.25; N, 6.0%; C29H38N2O4 requires C, 72.8; H, 8.0; N,
5.9%; and the exo-adduct (13e) as a colourless oil (70 mg, 3%): nmax
(KBr)/cm-1 3062, 3028, 2977, 2931, 1732, 1628, 1367, 1150, 700;
dH (400 MHz; CDCl3) 1.14, 1.47 (18H, 2 ¥ s, 2 ¥ C(CH3)3), 2.31
(1H, t, J = 9.5, PhCHCHH), 2.46, 2.56 (2H, 2 ¥ m, 6-CH2), 2.99
(1H, m, 7-CH), 3.21 (1H, d, J = 12.9, PhCHH), 3.32 (1H, dd, J =
6.3, 9.3, PhCHCHH), 3.58 (1H, dd, J = 6.2, 9.4, 5-CH), 4.06 (2H,
m, PhCHH and PhCHCH2), 4.39 (1H, d, J = 4.5, 7a-CH), 7.26
(10H, m, Ar–H); dC (68 MHz; CDCl3) 27.5, 28.05 (2 ¥ C(CH3)3),
34.0 (6-CH2), 50.5 (7-CH), 56.6 (PhCH2), 64.0 (PhCHCH2), 68.75
(PhCHCH2), 69.0 (5-CH), 80.7, 81.0 (2 ¥ C(CH3)3), 89.6 (7a-C),
126.9, 126.9, 127.1, 128.1, 128.1, 128.8 (6 ¥ Ar-CH), 138.35, 142.6
(2 ¥ Ar-C), 171.7, 171.9 (2 ¥ CO); m/z 478 (M+, 21%), 350 (85),
294 (71), 249 (38), 235 (30), 104 (27), 91 (100). HRMS: (EI) M+
478.2848; C29H38N2O4 requires M+ 478.2832. Found: C, 72.1; H,
8.1; N, 5.7%; C29H38N2O4·0.2H2O requires C, 72.1; H, 8.2; N,
5.7%.
12.9, PhCHH), 3.32 (1H, dd, J = 6.3, 9.2, PhCHCHH), 3.58 (1H,
dd, J = 6.2, 9.4, 5-CH), 4.09 (2H, m, PhCHH and PhCHCH2),
4.38 (1H, d, J = 4.5, 7a-CH), 7.26 (10H, m, Ar–H); dC (100 MHz;
CDCl3) 27.5, 28.1 (2 ¥ C(CH3)3), 34.05 (6-CH2), 50.7 (7-CH), 56.7
(PhCH2), 64.1 (PhCHCH2), 68.9 (PhCHCH2), 69.1 (5-CH), 80.7,
81.0 (2 ¥ C(CH3)3), 89.6 (7a-CH), 126.85, 126.9, 127.0, 128.1,
128.3, 128.8 (6 ¥ Ar-CH), 138.6, 142.7 (2 ¥ Ar-C), 171.8, 171.9
(2 ¥ CO); m/z 478 (M+, 25%), 350 (96), 294 (83), 249 (42), 235
(33), 104 (29), 91 (100). HRMS: (EI) M+ 478.2837; C29H38N2O4
requires M+ 478.2832.
(3S,5S,7R,7aS)-1-Benzyl-5-t-butoxycarbonyl-3-phenyl-3-phe-
nylsulfonylhexahydropyrrolo[1,2-a]imidazole (14). t-Butyl bro-
moacetate (0.83 g, 0.68 mL, 4.23 mmol) was added to a solution
of (S)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8a, 1.0 g, 4.23
mmol) and phenyl ethenyl sulfone (2.14 g, 12.70 mmol) in dry
tetrahydrofuran (30 mL), stirred at reflux under nitrogen. DBU
(0.64 g, 0.63 mL, 4.23 mmol) was added dropwise over 4 h,
and stirring at reflux was continued for 1.5 h. The solvent was
evaporated under reduced pressure and the residue was partitioned
between chloroform (3 ¥ 30 mL) and water (30 mL). The organic
phase was dried (Na2SO4), evaporated under reduced pressure and
the residue was purified by column chromatography, eluting with
◦
petroleum ether (b.p. 40–60 C) : ethyl acetate (5 : 1 v/v) to yield
the title compound as a colourless solid (0.72 g, 33%), m.p. 142–
145 ◦C (from ethyl acetate): nmax (KBr)/cm-1 2927, 1734, 1628,
1384, 1145; dH (250 MHz; CDCl3) 1.20 (9H, s, C(CH3)3), 2.18 (1H,
m, 6-CHH), 2.46 (2H, m, PhCHCHH and 6-CHH), 3.32 (2H,
m, PhCHH and PhCHCHH), 3.67 (1H, t, J = 6.5, PhCHCH2),
3.98 (1H, dd, J = 6.2, 13.7, 7-CH), 4.18 (1H, dd, J = 5.5, 10.1,
5-CH), 4.62 (1H, d, J = 11.9, PhCHH), 4.97 (1H, d, J = 6.2, 7a-
CH), 7.59 (15H, m, Ar–H); dC (68 MHz; CDCl3) 27.55 (C(CH3)3),
32.0 (6-CH2), 59.1 (PhCH2), 63.45 (PhCHCH2), 64.6 (PhCHCH2),
66.45 (7-CH), 67.8 (5-CH), 81.0 (C(CH3)3), 87.7 (7a-CH), 126.9,
127.2, 128.1, 128.3, 129.1, 129.2 (9 ¥ Ar-CH), 133.2, 138.3, 140.6
(3 ¥ Ar-C), 171.9 (CO); m/z 461 (M+–C4H9, 6%), 417 (11), 350
(61), 294 (63), 249 (45), 235 (36), 120 (50), 104 (59), 91 (100).
HRMS: (EI) M+–C4H9 461.1536; C30H34N2O4S requires M+–C4H9
461.1535. Found: C, 69.4; H, 6.9; N, 5.5%; C30H34N2O4S requires
C, 69.5; H, 6.6; N, 5.4%.
(3R,5R,7S,7aR)-1-Benzyl-5,7-bis(t-butoxycarbonyl)-3-phenyl-
hexahydropyrrolo[1,2-a]imidazole (13d). Prepared from (R)-1-
benzyl-4-phenyl-4,5-dihydroimidazole (8b, 0.50 g, 2.12 mmol)
by the method described above for the preparation of 9a but
using t-butyl bromoacetate (0.41 g, 0.34 mL, 2.12 mmol), t-butyl
propenoate (0.81 g, 0.93 mL, 6.35 mmol) and DBU (0.32 g,
0.32 mL, 2.12 mmol). Purification by column chromatography,
eluting with petroleum ether (b.p. 40–60 ◦C) : ethyl acetate (5 : 1
v/v) yielded the title compound as a colourless so◦lid (0.49 g, 49%),
m.p. 95–98 ◦C [from petroleum ether (b.p. 40–60 C)], [a]2D2 27.1 (c
0.98; EtOH): nmax (KBr)/cm-1 3031, 2975, 2935, 1733, 1369, 1146,
702; dH (400 MHz; CDCl3) 1.21, 1.48 (18H, 2 ¥ s, 2 ¥ C(CH3)3),
2.23 (1H, m, 6-CHH), 2.43 (1H, t, J = 9.6, PhCHCHH), 2.55
(1H, m, 6-CHH), 3.16 (1H, dd, J = 6.5, 11.9, 7-CH), 3.26 (2H, m,
PhCHH and PhCHCHH), 3.73 (1H, t, J = 6.9, 5-CH), 4.13 (2H,
m, PhCHH and PhCHCH2), 4.62 (1H, d, J = 6.5, 7a-CH), 7.27
(10H, m, ArH); dC (68 MHz; CDCl3) 27.5, 28.2 (2 ¥ C(CH3)3),
33.1 (6-CH2), 49.2 (7-CH), 58.4 (PhCH2), 63.9 (PhCHCH2), 67.0
(5-CH), 69.0 (PhCHCH2), 80.2, 80.5 (2 ¥ C(CH3)3), 88.5 (7a-CH),
126.8, 126.95, 127.0, 127.9, 129.0 (6 ¥ Ar-CH), 138.0, 141.6 (2 ¥
Ar-C), 171.6, 173.2 (2 ¥ CO); m/z 478 (M+, 4%), 350 (73), 294 (76),
249 (45), 235 (34), 120 (17), 104 (38), 91 (100). HRMS: (EI) M+
478.2827; C29H38N2O4 requires M+ 478.2832. Found: C, 72.5; H,
8.1; N, 5.8%; C29H38N2O4 requires C, 72.8; H, 8.0; N, 5.9%; and the
exo-adduct (13f) as a colourless oil (22 mg, 2%): nmax(film)/cm-1
2977, 1729, 1367, 1150, 700; dH (400 MHz; CDCl3) 1.14, 1.47
(18H, 2 ¥ s, 2 ¥ C(CH3)3), 2.30 (1H, t, J = 9.5, PhCHCHH), 2.46,
2.57 (2H, 2 ¥ m, 6-CHH), 2.97 (1H, m, 7-CH), 3.20 (1H, d, J =
(3S,5S,7R,7aS)-7-Acetyl-1-Benzyl-5-t-butoxycarbonyl-3-phe-
nylhexahydropyrrolo[1,2-a]imidazole (15). Prepared from (S)-1-
benzyl-4-phenyl-4,5-dihydroimidazole (8a, 1.0 g, 4.23 mmol) by
the method described above for the preparation of 9a but using
t-butyl bromoacetate (0.83 g, 0.68 mL, 4.23 mmol), but-3-en-2-
one (0.89 g, 1.06 mL, 12.70 mmol) and DBU (0.64 g, 0.63 mL,
4.23 mmol). The residue was extracted with petroleum ether (b.p.
40–60 ◦C) to yield the title compound as a yellow oil (1.27 g, 71%):
d
H (270 MHz; CDCl3) 1.14 (9H, s, C(CH3)3), 2.07 (3H, s, COCH3),
2.42 (3H, m, PhCHCHH and 6-CH2), 3.01 (1H, m, 7-CH), 3.41
(2H, m, PhCHH and PhCHCHH), 3.59 (1H, dd, J = 6.3, 8.9,
5-CH), 3.73 (1H, d, J = 12.9, PhCHH), 4.11 (1H, dd, J = 6.3, 9.6,
PhCHCH2), 4.46 (1H, d, J = 4.3, 7a-CH), 7.29 (10H, m, Ar–H); dC
(68 MHz; CDCl3) 27.4 (C(CH3)3), 28.8 (COCH3), 33.9 (6-CH2),
57.0 (PhCH2), 57.1 (7-CH), 64.5 (PhCHCH2), 68.8 (PhCHCH2),
69.1 (5-CH), 80.7 (C(CH3)3), 88.2 (7a-CH), 126.8, 127.1, 128.0,
128.2, 128.8 (6 ¥ Ar-CH), 138.2, 142.5 (2 ¥ Ar-C), 171.5, 173.15
(2 ¥ CO).
304 | Org. Biomol. Chem., 2011, 9, 297–306
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(3S,5S,7R,7aS)-1-Benzyl-5,7-dimethyl-5-ethoxycarbonyl-7-
methoxycarbonyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (16a).
Prepared from (S)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8a,
1.00 g, 4.24 mmol) by the method described above for the
preparation of 9a but using ethyl 2-bromopropanoate (767 mg,
4.24 mmol), methyl 2-methylpropenoate (1.36 mL, 1.27 g, 12.7
mmol) and DBU (0.63 mL, 0.64 g, 4.22 mmol). Purification
by column chromatography, eluting with petroleum ether (b.p.
40–60 ◦C) : ethyl acetate (3 : 1 v/v), yielded the title compound
(530 mg, 29%) as a colourless oil, [a]2D2 12.3 (c 1.00; CHCl3):
40–60 ◦C) : ethyl acetate (10 : 1 v/v) yielded the title compound as
a colourless solid (0.87 g, 46%), m.p. 138–139 ◦C: nmax (KBr)/cm-1
2971, 1724, 1714, 1258, 1156, 1028, 698; dH (400 MHz; C6D6)
1.09 (3H, d, J = 6.8, 6-CH3), 1.29 (9H, s, C(CH3)3), 2.17 (1H,
dd, J = 9.2, 9.9, PhCHCHH), 2.98 (1H, d, J = 13.2, PhCHH),
3.14 (2H, m, PhCHCHH and 6-CH), 3.38 (4H, m, OCH3 and
7-CH), 3.53 (1H, d, J = 7.5, 5-CH), 3.96 (1H, dd, J = 5.3, 9.9,
PhCHCH2), 4.08 (1H, d, J = 13.2, PhCHH), 4.86 (1H, d, J = 6.9,
7a-CH), 7.17 (10H, m, Ar–H); dC (68 MHz; C6D6) 14.1 (6-CH3),
28.0 (C(CH3)3), 36.8 (6-CH), 51.1 (OCH3), 56.45 (7-CH), 59.3
(PhCH2), 62.7 (PhCHCH2), 68.4 (PhCHCH2), 70.75 (5-CH), 80.2
(C(CH3)3), 87.5 (7a-CH), 127.2, 127.2, 127.4, 128.4, 128.5, 128.85
(6 ¥ Ar-CH), 139.5, 141.7 (2 ¥ Ar-C), 171.6, 172.0 (2 ¥ CO); m/z
450 (M+, 3%), 350 (29), 294 (36), 120 (23), 104 (32), 91 (100).
HRMS: (EI) M+ 450.2520; C27H34N2O4 requires M+ 450.2519.
Found: C, 71.9; H, 7.6; N, 6.1%; C27H34N2O4 requires C, 72.0; H,
7.6; N, 6.2%.
n
max(film)/cm-1 2981, 2949, 1733, 1495, 1454, 1252, 1135, 702;
dH (400 MHz; CDCl3) 1.25–1.28 (6H, m, CH3CH2 and 5-CH3),
1.37 (3H, s, 7-CH3), 2.24 (1H, d, J = 13.6, 6-CHH), 2.30-2.32 (1H,
m, PhCHCHH), 2.88 (1H, d, J = 13.6, 6-CHH), 3.16 (1H, dd, J =
5.5, 9.0, PhCHCHH), 3.38 (1H, d, J = 12.7, PhCHH), 3.72 (3H, s,
OCH3), 4.12-4.20 (3H, m, CH3CH2O and PhCHH), 4.33 (1H, s,
7a-CH), 4.54 (1H, dd, J = 5.5, 9.4, PhCHCH2), 7.14–7.28 (8H, m,
Ar–H), 7.42 (2H, d, J = 8.0, Ar–H); dC (100.6 MHz; CDCl3) 14.2,
21.35, 23.95 (3 ¥ CH3), 48.1 (6-CH2), 51.9 (OCH3), 54.3 (7-C), 59.7
(PhCH2), 60.8 (CH3CH2), 62.0 (PhCHCH2), 64.35 (PhCHCH2),
68.0 (5-C), 97.4 (7a-CH), 126.6, 126.9, 128.1, 128.6 (6 ¥ Ar-CH,
overlapping), 138.7, 143.1 (2 ¥ Ar-C), 176.0, 176.4 (2 ¥ CO); m/z
436 (M+, 1%), 405 (6), 363 (9), 337 (33), 336 (100), 263 (49), 91 (89).
HRMS: (EI) M+ 436.2336; C26H32N2O4 requires M+ 436.2362.
(3R,5R,6S ,7S ,7aR)-1-Benzyl-5-t-butoxycarbonyl-7-meth-
oxycarbonyl-6-methyl-3-phenylhexahydropyrrolo[1,2-a]imidazole
(17b). Prepared
from
(R)-1-benzyl-4-phenyl-4,5-dihydro-
imidazole (8b, 1.0 g, 4.23 mmol) by the method described
above for the preparation of 9a but using t-butyl bromoacetate
(0.83 g, 0.68 mL, 4.23 mmol), methyl (E)-but-2-enoate (1.27 g,
1.35 mL, 12.70 mmol) and DBU (0.64 g, 0.63 mL, 4.23 mmol).
Purification by column chromatography, eluting with petroleum
ether (b.p. 40–60 ◦C) : ethyl acetate (10 : 1 v/v) yielded the t◦itle
compound as a colourless solid (0.50 g, 26%), m.p. 139–140 C:
nmax (KBr)/cm-1 3027, 2974, 2960, 1725, 1714, 1258, 1156, 1028,
698; dH (270 MHz; C6D6) 1.09 (3H, d, J = 6.6, 6-CH3), 1.30 (9H, s,
C(CH3)3), 2.17 (1H, dd, J = 8.9, 9.9, PhCHCHH), 2.99 (1H, d,
J = 13.2, PhCHH), 3.18 (2H, m, PhCHCHH and 6-CH), 3.40
(4H, m, OCH3 and 7-CH), 3.52 (1H, d, J = 7.6, 5-CH), 3.96 (1H,
dd, J = 5.3, 9.9, PhCHCH2), 4.08 (1H, d, J = 13.2, PhCHH), 4.85
(1H, d, J = 6.7, 7a-CH), 7.19 (10H, m, Ar–H); dC (68 MHz; C6D6)
14.1 (6-CH3), 28.0 (C(CH3)3), 36.8 (6-CH), 51.1 (OCH3), 56.5
(7-CH), 59.3 (PhCH2), 62.7 (PhCHCH2), 68.4 (PhCHCH2), 70.8
(5-CH), 80.2 (C(CH3)3), 87.5 (7a-CH), 127.2, 127.2, 127.4, 128.5,
128.8, 128.85 (6 ¥ Ar-CH), 139.5, 141.75 (2 ¥ Ar-C), 171.6, 172.0
(2 ¥ CO); m/z (FAB) 451 (MH+, 22%), 350 (15), 210 (14), 154
(37), 136 (35), 120 (23), 107 (27), 91 (78). HRMS: (FAB) MH+
451.2540; C27H34N2O4 requires MH+ 451.2597. Found: C, 72.1;
H, 7.8; N, 6.2%; C27H34N2O4 requires C, 72.0; H, 7.6; N, 6.2%.
(3S,5S,7R,7aS)-1-Benzyl-5-t-butoxycarbonyl-5,7-dimethyl-7-
methoxycarbonyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (16b).
Prepared from (S)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8a,
2.00 g, 8.48 mmol) by the method described above for the
preparation of 9a but using t-butyl 2-bromopropanoate (1.85 g,
8.48 mmol), methyl 2-methylpropenoate (2.72 mL, 2.55 g, 25.4
mmol) and DBU (1.26 mL, 1.28 g, 8.43 mmol). Purification
by column chromatography, eluting with petroleum ether (b.p.
40–60 ◦C) : ethyl acetate (3 : 1 v/v), yielded the title compound
(910 mg, 23%) as a colourless oil, [a]2D2 2.35 (c 2.06; CH2Cl2): nmax
(KBr)/cm-1 3028, 2977, 2876, 2813, 1728 (s, br), 1603, 1498, 1367,
1251, 1137, 1031, 702; dH (400 MHz; CDCl3) 1.15 (3H, s, 5-CH3),
1.40 (3H, s, 7-CH3), 1.47 (9H, s, C(CH3)3), 2.21 (1H, d, J = 13.6,
6-CHH), 2.30 (1H, t, J = 9.3, PhCHCHH), 2.83 (1H, d, J = 13.6,
6-CHH), 3.15 (1H, dd, J = 5.5, 9.3, PhCHCHH), 3.37 (1H, d, J =
12.7, PhCHH), 3.72 (3H, s, OCH3), 4.12 (1H, d, J = 12.7, PhCHH),
4.31 (1H, s, 7a-CH), 4.55 (1H, dd, J = 5.5, 9.3, PhCHCH2), 7.15–
7.45 (10H, m, Ar–H); dC (100.6 MHz; CDCl3) 21.3, 23.9 (2 ¥
CH3), 27.8 (C(CH3)3), 47.9 (6-CH2), 52.0 (OCH3), 54.2 (7-C), 60.2
(PhCH2), 61.9 (PhCHCH2), 64.3 (PhCHCH2), 68.3 (5-C), 80.25
(C(CH3)3), 97.4 (7a-CH), 126.7, 126.7, 126.8, 128.0, 128.1, 128.55
(6 ¥ Ar-CH), 138.7, 143.2 (2 ¥ Ar-C), 175.4, 176.1 (2 ¥ CO); m/z
(FAB) 465 (MH+, 13%), 463 (32), 407 (30), 365 (28), 364 (84), 363
(23), 308 (32), 263 (25), 237 (18), 210 (23), 208 (17), 104 (35), 91
(100). HRMS: (FAB) MH+ 465.2746; C28H36N2O4 requires MH+
465.2753.
Decahydropyrano[3,4-b]pyrrolo[1,2-a]imidazole (19). Prepared
from (S)-1-benzyl-4-phenyl-4,5-dihydroimidazole (8a, 1.69 g, 7.17
mmol) by the method described above for the preparation of 9a
but using ethyl (E)-5-(bromoacetoxy)pent-2-enoate 18 (1.9 g, 7.17
mmol) and DBU (1.09 g, 1.07 mL, 7.17 mmol) added dropwise
over 5 h, followed by stirring at reflux for a further hour. Purifica-
tion by column chromatography, eluting with ethyl acetate : hexane
(3 : 1 v/v) afforded the title compound (1.06 g, 35%) as colourless
◦
(3S,5S,6R,7R,7aS)-1-Benzyl-5-t-butoxycarbonyl-7-methoxycar-
bonyl-6-methyl-3-phenylhexahydropyrrolo[1,2-a]imidazole (17a).
plates, m.p. 109–111 C (from diethyl ether), [a]2D2 34.7 (c 1.23;
CHCl3): nmax (KBr)/cm-1 3026, 2963, 2806, 1754(s), 1724(s),
1496, 1455, 1378, 1304, 1256, 1219, 1175, 1138, 1053, 1038, 758,
703; dH (400 MHz; CDCl3) 1.21 (3H, t, J = 7.2, CH3), 1.63–
1.72, 2.18–2.25 (each 1H, m, CH2CH2O), 2.39 (1H, t, J = 9.0,
PhCHCHH), 2.98 (1H, t, J = 7.0, CHCO2Et), 3.24 (1H, d, J =
13.2, NCHHPh), 3.29 (1H, dd, J = 5.9, 9.0, PhCHCHH), 3.39–
3.47 (1H, m, CHCH2CH2), 3.86 (1H, d, J = 7.8, CHCO2), 4.06
Prepared
from
(S)-1-benzyl-4-phenyl-4,5-dihydroimidazole
(8a, 1.0 g, 4.23 mmol) by the method described above for the
preparation of 9a but using t-butyl bromoacetate (0.83 g, 0.68 mL,
4.23 mmol), methyl (E)-but-2-enoate (1.27 g, 1.35 mL, 12.70
mmol) and DBU (0.64 g, 0.63 mL, 4.23 mmol). Purification
by column chromatography, eluting with petroleum ether (b.p.
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(1H, d, J = 13.2, NCHHPh), 4.10–4.30 (4H, m, PhCHCH2,
CH2CHHO, OCH2CH3), 4.40–4.45 (1H, m, CH2CHHO), 4.65
(1H, d, J = 7.0, NCHN), 7.20–7.30 (8H, m, Ar–H), 7.40
(2H, d, J = 8.1, Ar–H); dC (100.6 MHz; CDCl3) 13.9 (CH3),
27.6 (CH2CH2O), 38.2 (CHCH2CH2), 56.7 (CHCO2Et), 58.2
(PhCH2N), 60.8 (CO2CH2), 62.8 (PhCHCH2), 64.9 (CHCO2),
66.45 (CH2CH2O), 68.3 (PhCHCH2), 86.8 (NCHN), 126.4, 126.9,
127.1, 128.1, 128.15, 128.2 (6 ¥ Ar-CH), 138.1, 140.5 (2 ¥ Ar-C),
170.8, 171.3 (2 ¥ CO); m/z 420 (M+, 28%), 374 (37), 245 (30), 235
(59), 120 (44), 104 (71), 91 (100), 77 (60). Found: C, 71.75; H, 7.0;
N, 6.9; C25H28N2O4 requires C, 71.4; H, 6.7; N, 6.7).
Natural Products, ed. A. Padwa, and W. H. Pearson, Wiley-Interscience:
Hoboken, 2003, p. 169.
3 E. G. McGeer, J. W. Olney, and P. L. McGeer, Kainic Acid as a Tool
in Neurobiology, Raven Press: New York, 1978. For reviews, see: Q.
Wang, S. Yu, A. Simonyi, G. Sun and A. Sun, Mol. Neurobiol., 2005,
31, 3; M. G. Moloney, Nat. Prod. Rep., 2002, 19, 597; A. F. Parsons,
Tetrahedron, 1996, 52, 4149.
4 R. J. Bridges, M. S. Stanley, M. W. Anderson, C. W. Cotman and A. R.
Chamberlin, J. Med. Chem., 1991, 34, 717.
5 R. C. F. Jones, K. J. Howard and J. S. Snaith, Tetrahedron Lett., 1996,
37, 1707.
6 R. C. F. Jones, K. J. Howard and J. S. Snaith, Tetrahedron Lett., 1996,
37, 1711.
7 R. C. F. Jones, K. J. Howard, J. R. Nichols and J. S. Snaith, J. Chem.
Soc., Perkin Trans. 1, 1998, 2061.
A crystal was mounted on a glass fibre and transferred to the
diffractometer. Crystal data for 19: C25H28N2O4, M = 420.49,
8 See, for example: W. N. Draffin and L. M. Harwood, Synlett, 2006,
857; D. J. Aldous, M. G. B. Drew, W. N. Draffin, E. M. N. Hamelin,
L. M. Harwood and S. Thurairatnam, Synthesis, 2005, 3271; K. A.
Ahrendt and R. M. Williams, Org. Lett., 2004, 6, 4539; T. Onishi,
P. R. Sebahar and R. M. Williams, Tetrahedron, 2004, 60, 9503; F. X.
Lery, N. Kunesch, P. George and H.-P. Husson, Heterocycles, 2002, 57,
1599.
˚
monoclinic, a = 11.351(2), b = 9.7612(10), c = 19.942(3) A, b =
3
˚
91.07(2), U = 2209.1(4) A , T = 298(2) K, space group P21 (No.
4), Z = 4, Dc = 1.265 g cm-3,m(Mo-Ka) = 0.050 mm-1, 3081 unique
reflections measured, of which 3072 were used in all calculations.
Final R1 [2091 F > 4s(F)] = 0.0494 and wR(all F2) was 0.141.
9 R. C. F. Jones, I. Turner and K. J. Howard, Tetrahedron Lett., 1993, 34,
6329.
10 R. C. F. Jones and K. J. Howard, J. Chem. Soc., Perkin Trans. 1, 1993,
2391.
Acknowledgements
11 Preliminary molecular mechanics calculations (Macromodel 4.0,
MM2) surprisingly show the isolated product of exo addition, 9e, as
higher in energy than the expected exo-adduct 10, by over 60 kJ mol-1;
cf. R. C. F. Jones, and K. J. Howard, Electronic Conference on Trends in
Organic Chemistry (ECTOC-1) ISBN 0 85404 899 5, ed. H. S. Rzepa,
and J. M. Goodman, (CD-ROM), Royal Society of Chemistry Publi-
cations, 1995, poster 30. See also http://www.ch.ic.ac.uk/ectoc/.
12 For a full discussion of the use of sulfur-activated dipolarophiles, see:
R. C. F. Jones, S. Rafiq, M. R. J. Elsegood, V. McKee and M. J. Slater,
Chem.–Asian J., 2010, 5, 461.
We thank EPSRC for postdoctoral funding (J. S. S., K. J. H.),
University of Nottingham for a studentship (K. J. H.), Rhone-
Poulenc Agriculture for additional financial support (K. J. H.),
Dr D. Hawkins for helpful discussions, and the EPSRC National
Mass Spectrometry Service Centre (Swansea) for some MS data.
13 R. C. F. Jones, K. J. Howard, J. R. Nichols and J. S. Snaith, Tetrahedron
Lett., 1997, 38, 1647.
14 For related intramolecular cycloadditions using a ketone tether, see:
P. M. J. Lory, R. C. F. Jones, J. N. Iley, S. J. Coles and M. B. Hursthouse,
Org. Biomol. Chem., 2006, 4, 3155.
References
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15 R. C. F. Jones, K. J. Howard, J. S. Snaith, A. J. Blake, W.-S. Li, and P. J.
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16 D. R. Perrin, and W. L. F. Armarego, Purification of Laboratory
Chemicals, Pergamon Press: Oxford, 3rd edition, 1988.
306 | Org. Biomol. Chem., 2011, 9, 297–306
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