Coenzyme-inspired chemistry 2: 4,5-dihydroimidazolium ylides (NHCs) and the reactions of 2-(1-hydroxyalkyl)-4,5-dihydroimidazoles

Article abstract of DOI:10.1039/c3ob40884a

Ketones are prepared from aldehydes via 1-benzyl-2-(1-hydroxyalkyl)-4,5- dihydroimidazoles (adducts of the aldehydes with 1-benzyl-2-lithio-4,5- dihydroimidazoles) whereas 1-benzyl-2-(1-oxoalkyl)-4,5-dihydroimidazoles are shown to act as acyl transfer reagents via C-C bond cleavage. 4,5-Dihydroimidazolium ylides (NHCs) are intermediates in both processes, which constitute thiamine-inspired C-C bond formation and cleavage protocols.

Full text of DOI:10.1039/c3ob40884a

Organic &
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PAPER
Coenzyme-inspired chemistry 2: 4,5-dihydro-
imidazolium ylides (NHCs) and the reactions of
2-(1-hydroxyalkyl)-4,5-dihydroimidazoles
Cite this: Org. Biomol. Chem., 2013, 11,
5926
Raymond C. F. Jones*a and John R. Nicholsb
Ketones are prepared from aldehydes via 1-benzyl-2-(1-hydroxyalkyl)-4,5-dihydroimidazoles (adducts of
the aldehydes with 1-benzyl-2-lithio-4,5-dihydroimidazoles) whereas 1-benzyl-2-(1-oxoalkyl)-4,5-dihydro-
imidazoles are shown to act as acyl transfer reagents via C–C bond cleavage. 4,5-Dihydroimidazolium
ylides (NHCs) are intermediates in both processes, which constitute thiamine-inspired C–C bond for-
mation and cleavage protocols.
Received 29th April 2013,
Accepted 17th July 2013
DOI: 10.1039/c3ob40884a
www.rsc.org/obc
Introduction
As part of a study of coenzyme-inspired chemistry using the
4,5-dihydroimidazole nucleus, we have focussed on the reacti-
vity of the C-2 anion 1 formed from 4,5-dihydroimidazoles, as
an extension of our earlier work on laterally metallated nucleo-
philes 21 and other aspects of 4,5-dihydroimidazole chem-
istry.2 We have recently reported full details of C-2 alkylation
processes of anions 1 which form part of a carbon transfer
sequence that mimics the single carbon transfers mediated by
the tetrahydrofolate (FH4) coenzyme N5,N10-methenyltetra-
hydrofolate.3 In an extension of this chemistry to higher oxi-
dation level electrophiles, we were inspired by the azolium
ylides that form part of the mechanism of action of thiamine
as the thiazolium species 3,4 reinforced by the recent upsurge
in the use of N-heterocyclic carbenes (NHCs) as ligands for
metals, for example in metathesis.5 These two aspects,
azolium ylide and carbene, are also seen combined in various
organocatalytic procedures that utilise analogues of the
Breslow intermediate in the thiamine mechanism to display
carbonyl anion and homoenolate reactivity.6 Key intermediates
in the thiamine-catalysed processes are the 2-(1-hydroxyalkyl)
adducts 4.
We therefore determined to investigate the reactivity of
2-lithio-4,5-dihydroimidazoles 5 with carbonyl electrophiles.
This paper reports in detail our investigation of the reactions
of lithio-derivatives 5 with aldehydes, ketones and esters,
and the reactivities of the 2-(1-hydroxyalkyl)-4,5-dihydro-
imidazoles and 2-(1-oxoalkyl)-4,5-dihydroimidazoles so pro-
duced.7 The 2-(hydroxyalkyl) adducts allow ketones to be
prepared from aldehydes, whereas the 2-(oxoalkyl) adducts
act as acyl transfer reagents. Both protocols utilise dihydro-
imidazolium ylides (NHCs) 6 as leaving groups via C–C
bond cleavage, in this way mimicking thiamine-mediated
processes.
aChemistry Department, Loughborough University, Loughborough, Leics. LE11 3TU,
UK. E-mail: r.c.f.jones@lboro.ac.uk; Fax: +44 (0) 1509 223925;
Tel: +44 (0) 1509 222557
bDepartment of Chemistry, University of Nottingham, University Park, Nottingham
NG7 2RD, UK
Results & discussion
The substrate for our studies was 1-benzyl-4,5-dihydroimida-
zole 7, prepared as we have reported previously.8 Metallation
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using our standard protocol (n-BuLi, THF, −78 °C)2 and treat-
ment of the 2-lithio-derivative with aldehydes (freshly distilled)
afforded the 2-(1-hydroxyalkyl)-4,5-dihydroimidazoles 8a–f in
good yields (Scheme 1). Originally we had planned to deproto-
nate adducts 8 at the α-position to parallel the Breslow inter-
mediate in the thiamine series,4 so we prepared three
O-protected derivatives 9a–c of alcohols 8. The tert-butyldi-
methylsilyl (TBDMS) ether 9a was prepared by two methods: (i)
from 8a using TBDMSCl, 4-(dimethylamino)pyridine, CH2Cl2
(48%), or (ii) by direct treatment with TBDMSCl of the lithium
alkoxide intermediate in the preparation of 8a (66% from 7).
The former approach was also employed to prepare TBDMS
ether 9b (TBDMSCl; 84%), and benzyl carbonate 9c (PhCH2O-
COCl; 64%) from alcohol 8c. However, whilst treatment of
ethers 9a, b with various strong bases (n-BuLi, s-BuLi or LDA,
THF, −78 °C) gave the red colouration normally characteristic
of deprotonation, quenching with a range of electrophiles
(D2O, haloalkanes or aldehydes) failed to afford any substi-
tution products, and the only reaction observed was some de-
silylation to alcohols 8a, b; carbonate 9c likewise failed to
provide any substitution products. It is reasonable to speculate
that the lithiated species exists as a stabilised lithio-enamine
10 but we have no firm evidence concerning reasons for these
failures.
We next proposed that the target tertiary alcohols that
would have arisen from a deprotonation-alkylation of 8 or 9
could be accessed by reversal of polarity at the α-carbon centre,
from nucleophile to electrophile. The hydroxyalkyl adducts 8a, c
were therefore oxidised (MnO2, CH2Cl2, 20 °C) to the corres-
ponding 2-(1-oxoalkyl)-4,5-dihydroimidazoles 11a, b (53 &
67%, respectively). The IR absorptions of the carbonyl groups
were observed at 1700 & 1670 cm−1, respectively, supporting
the presence of the conjugated carbonyl group. The 2-oxoalkyl-
4,5-dihydroimidazoles 11 could be more directly prepared by
acylation of the lithio-derivative of 7, formed as already
described. The most effective acylating agents from a range
surveyed proved to be ethyl esters; other acylating agents exam-
ined included acyl chlorides, acid anhydrides, N-acylpyrroli-
dines and thioesters. The acylations were performed by inverse
Scheme 1 Formation and reactions of 2-(1-hydroxyalkyl)-4,5-dihydromidazoles 8 and 12.
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addition of the lithio-dihydroimidazole solution, cooled to to obtain ketones from the tertiary alcohols 12. We were grati-
−100 °C, to a solution of the ethyl esters. Normal addition fied to find that these alcohols collapsed readily to ketones on
afforded low yields; we presume that this may result from com- heating in solution in CHCl3 containing catalytic conc. hydro-
peting enolisation of the 2-acyl group and/or a second addition chloric acid. Thus 2-(1-hydroxyalkyl)dihydroimidazoles 12a–c,
of the lithio-derivative of 7 to the initial 2-acyl-4,5-dihydroimi- e, f afforded the ketones 13a–e in good yields (Scheme 1), iso-
dazole. Using the inverse addition protocol, 2-acyl compounds lated simply by filtration over silica. These mild conditions
11b–d were obtained (67, 41 & 44%, respectively) (Scheme 1).
contrast with the reported properties of analogous 2-(1-hydroxy-
With the 2-oxoalkyl-4,5-dihydroimidazoles 11 in hand, the alkyl)imidazoles which are stable to acidic conditions and
tertiary alcohols 12 were prepared by addition of organometal- require quaternisation and base treatment to cleave the C2–Cα
lic C-nucleophiles. Reaction of 2-benzoyl compound 11b with bond. We presume that this bond cleavage proceeds by proto-
methyl-, n-butyl- and phenyl-lithiums (THF, −78 °C) led to the nation of the amidine function at N-3 and elimination to give
tertiary alcohols 12a–c (69, 59 & 92%, respectively) (Scheme 1); the ketone and the dihydroimidazolium ylide 14a, that sub-
no adduct was observed using s-BuLi as nucleophile. Ethenyl- sequently protonates at C-2, so that the requirement for acid is
magnesium bromide reacted effectively with 11b at 20 °C to catalytic. This pathway is lent support by the observation that
give 12d (89%), whilst lower yields of 12e, f were obtained stoichiometric quaternisation of 12a, c (MeI, THF, 20 °C)
using ethyl- and octylmagnesium bromides, respectively. led directly to in situ bond cleavage to afford crystals of the
In these latter cases, isolation of the secondary alcohol 8c 1-benzyl-3-methyl-4,5-dihydroimidazolium iodide 15a with iso-
demonstrated that reduction accounted for the remaining lation of the ketones 13a, c from the mother liquors. Here the
material. If the addition of alkyl-lithiums to 11c was performed likely pathway is quaternisation and elimination to give the
at −78 °C, the 2-(1-oxoalkyl)-4,5-dihydroimidazole was recovered ketone and ylide 14b which protonates. The acid-promoted
unchanged, implying that these very basic reagents were enolising cleavage requires tertiary alcohols 12 as the secondary alcohols
the 2-acyl substituent when α-protons were present. In contrast, 8 were found to be stable to acidic CHCl3; similarly prolonged
the less basic Grignard reagents methyl- and phenylmagnesium treatment of 8c with iodomethane led only to the quaternary
bromides with acyl compound 11c did provide the adducts 12g, salt 15b. Taken overall, these processes have produced ketones
h, respectively; ethylmagnesium bromide did, however, afford from aldehydes with the catalytic intervention of a dihydroimi-
only the reduction product 8g (R1 = (CH2)4Me; 54%).
dazole, which mimics the C–C bond formations mediated by
The direct addition of the lithio-dihydroimidazole formed thiamine, e.g. in transketolase,9 albeit with reversed polarity.
from 7 to ketones would provide an alternative approach to the
tertiary alcohols 12. When this was attempted using the lithio-
derivative of 7 prepared in the usual way, with the methyl
ketones propan-2-one and pentan-2-one, only recovered
ketone and dihydroimidazole 7 were isolated, presumably
because of ketone enolisation. A successful addition of the
lithio-derivative of 7 to benzophenone to afford alcohol 12c
(50%) supported this conclusion. The competition between
nucleophilicity and basicity of the lithio-derivative of dihydro-
Encouraged by the obvious ability of dihydroimidazolium
imidazole 7 was also shown by the isolation of adducts 12e, i–k ylides such as 14 to act as leaving groups, we investigated the
that were isolated in moderate yields from the ketones 1-phe- 2-(1-oxoalkyl)-dihydroimidazoles (2-acyldihydroimidazoles) 11
nylpropan-1-one, pentan-3-one, pent-1-en-3-one and cyclohexa- as acylating agents with non-carbon nucleophiles. The
none, respectively, along with recovered starting materials. 2-benzoyl compound 11b was treated with excess iodomethane
Interestingly, there appears to be little or no competing enoli- (20 °C, 2 h) and the quaternary salt reacted without purifi-
sation with aldehyde electrophiles where it would be possible, cation with a heteroatom nucleophile to afford in good yields
as demonstrated by the successful additions of lithio-7 to alde- benzoic acid 16a (NaOH aq, 25 °C), ester 16b (EtOH reflux),
hydes to afford hydroxyalkyl adducts 8 described above and thioester 16c (BuSH, THF reflux) and the amides 16c, d
listed in Scheme 1. We have therefore shown two routes to the (PhCH2NH2 or BuNH2, respectively, THF reflux) (Scheme 1).
tertiary alcohols 12: (i) via the direct addition of the lithio- Presumably ylide 14b is the by-product from these acylations:
derivative of 7 to ketones; and (ii) as an alternative, and in consistent with this supposition is the isolation of quaternary
particular in those cases not accessible by direct addition salt 15a (94%) from the preparation of thioester 16c. Further
to enolisable ketones, via the addition of organometallic support for an ylide as leaving group was obtained when 11b
C-nucleophiles to 2-acyldihydroimidazoles 11 (themselves avail- was treated in MeOH with NH4Cl as a proton source to afford
able either from addition of the anion from 7 to aldehydes methyl benzoate 16f (71%) and dihydroimidazole 7. In an
followed by oxidation, or from direct acylation of lithio-7 unoptimised reaction, the quaternary salt formed from 11b
using esters).
was treated with n-BuLi to generate 1-phenylpentan-1-one
Having made the necessary carbon–carbon bond, i.e. 11 →12, (30%) to validate the potential of these salts to undergo
that was prompted by analogy with the action of thiamine,4 to acyl transfer to C-nucleophiles, in contrast to the carbonyl
complete the sequence mimicking thiamine it was necessary additions observed (see earlier) with non-quaternised
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dihydroimidazoles 11. We have demonstrated clearly the appli- was added n-butyl-lithium (1.58 M solution in hexanes;
cation of 2-acyl-4,5-dihydroimidazoles in acyl transfer pro- 4.35 mL, 6.87 mmol). After 20 min to allow complete anion
cesses involving C–C bond cleavage, which is much less formation, freshly distilled butanal (0.61 mL, 6.87 mmol) was
common than C–heteroatom cleavage.10
added dropwise and the mixture stirred for a further 1 h at
−78 °C, allowed to warm to 20 °C and then concentrated
under reduced pressure. The resulting red oil was partitioned
between chloroform (2 × 50 mL) and water (50 mL), the com-
bined organic extract dried and concentrated under reduced
pressure. Purification by column chromatography, eluting with
CHCl3–2-aminopropane (95 : 5 v/v) afforded the title compound
8a (0.87 g, 60%) as a waxy solid; νmax(film)/cm−1 3050, 2960,
2860, 1600, 1430, 1230, 1120, 750, 700; δH (200 MHz) 7.22–7.26
(5H, m, Ar-H.), 4.18–4.22 (3H, 2 × d and m, PhCH2 and
CHOH), 3.68–3.71 (3H, m, NCH2CH2N and OH), 3.24–3.26 (2H,
m, NCH2CH2N), 1.48–1.53 (4H, m, CH2CH2), 0.90 (3H, t, J =
7.1, CH3); m/z 232 (M+, 5%), 190 (25), 180 (12), 120 (20), 99
(33), 91 (100). HRMS: M+ 232.1583; C14H20N2O requires M+
232.1576. A sample recrystallised from EtOH–H2O gave colour-
less needles, mp 105 °C (Found: C, 67.2; H, 9.1; N, 11.0%;
C14H20N2O·H2O requires C, 67.2; H, 8.9; N, 11.2%).
Conclusions
We have reported a synthesis of 2-(1-hydroxyalkyl)-4,5-dihy-
droimidazoles by reaction of a 2-lithio-dihydroimidazole with
aldehydes. The oxidation of these 2-hydroxylalkyl dihydroimi-
dazoles to 2-(1-oxoalkyl)-4,5-dihydroimidazoles (also available
from direct acylation of the 2-lithio-dihydroimidazoles) fol-
lowed by addition of organometallic C-nucleophiles afforded
tertiary alcohols in which the C–C bond formation parallels
that in thiamine-mediated processes in Nature.4 Facile C–C
bond cleavage of these tertiary alcohols led to ketones with a
dihydroimidazolium ylide (NHC) as a leaving group; in this
way we have developed a route from aldehydes to ketones
mediated by dihydroimidazoles, thus mimicking the action of
thiamine. The application of dihydroimidazolium ylides as
leaving groups has also allowed us to demonstrate that 2-acyl-
dihydroimidazoles can act as acylating agents via the less
common C–C bond cleavage.
1-Benzyl-2-(1-hydroxydecyl)-4,5-dihydroimidazole (8b). Pre-
pared by the method described above for the preparation of 8a
but using 1-benzyl-4,5-dihydroimidazole 7 (2.00 g, 12.5 mmol),
n-butyl lithium (1.42
M solution in hexanes; 9.50 mL,
13.5 mmol) and decanal (2.15 g, 13.8 mmol) to afford after
column chromatography eluting with CHCl3–2-aminopropane
(96 : 4 v/v), the title compound 8b (1.38 g, 70%) as a waxy solid;
νmax(CHCl3)/cm−1 3400, 2950, 2860, 1600, 1120; δH 7.29–7.33
(5H, m, Ar-H), 4.29–4.32 (3H, 2 × d and m, PhCH2 and CHOH),
3.73–3.76 (2H, m, NCH2CH2N), 3.33–3.37 (2H, m, NCH2CH2N),
1.46–1.53 (16H, m, (CH2)8), 0.90 (3H, t, J = 7.0, CH3).
Experimental
Melting points were obtained on a Gallenkamp capillary or a
Reichert hot stage apparatus and are uncorrected. IR spectra
were recorded using Pye Unicam SP1000 or SP3-100 spec-
trometers. Mass spectra were recorded using AEI MS902 or VG
7070E spectrometers. 1H NMR spectra were obtained using the
following spectrometers as indicated: Perkin-Elmer R32 or Joel
FX90Q spectrometers at 90 MHz. 13C NMR spectra were
recorded using a Jeol FX90Q spectrometer at 22.7 MHz. 1H
NMR spectra were determined in CDCl3 solution and chemical
shifts δH quoted in parts per million (ppm) from TMS as
internal standard. Coupling constants J are quoted in Hz with
multiplicities: s-singlet, d-doublet, t-triplet, q-quartet, m-multi-
plet, and br-broad. 13C NMR spectra were determined in CDCl3
solution and chemical shifts δC quoted in ppm from TMS as
internal standard or from TMS using CDCI3 as internal stan-
dard. Column chromatography was carried out at medium
pressure using Merck Kieselgel 60 (Art. 9385); TLC was carried
out on silica plates (Kieselgel 60, F254, Merck Art. 5554).
Solvent extractions were dried over anhydrous MgSO4 or
Na2SO4 for at least 10 min. Ether refers to diethyl ether and
light petroleum to the fraction of bp 60–80 °C. THF and ether
were distilled from LiAlH4 or potassium immediately prior to
use. Other dry solvents were prepared as described in Perrin
et al.11 Alkyl-lithiums were standardised by the diphenylacetic
acid method.12
1-Benzyl-2-(phenylhydroxymethyl)-4,5-dihydroimidazole (8c).
Prepared by the method described above for the preparation of
8a but using 1-benzyl-4,5-dihydroimidazole
7
(1.60 g,
10.0 mmol), n-butyl-lithium (1.58 M solution in hexanes;
7.00 mL, 11.1 mmol) and benzaldehyde (1.17 g, 11.0 mmol) to
afford after column chromatography eluting with CHCl3–
2-aminopropane (96 : 4 v/v), the title compound (1.89 g, 71%) as a
pale yellow gum; νmax(film)/cm−1 3040, 2860, 1600, 1450, 1250,
1000, 920, 750; δH (250 MHz) 7.54–7.56 (2H, m, Ar-H),
7.28–7.32 (3H, m, Ar-H), 7.18–7.22 (3H, m, Ar-H), 6.89–6.91
(2H, m, Ar-H), 6.65 (1H, br s, OH), 5.65 (1H, s, CHOH), 4.15
(2H, s, PhCH2), 3.63–3.67 and 3.13–3.16 (each 2H, m,
NCH2CH2N); δC 168.1 (C-2), 140.4, 137.2 (Ar-C), 128.2, 128.1,
127.5, 127.4, 127.0, 126.9 (Ar-CH), 69.2 (CHOH), 51.0, 50.5
(CH2); m/z 266 (M+, 2%), 149 (7), 120 (19), 105 (11), 91 (100), 71
(10). HRMS: M+ 266.1413; C17H18N2O requires M+ 266.1419.
1-Benzyl-2-(3-methoxyphenylhydroxymethyl)-4,5-dihydroimi-
dazole (8d). Prepared by the method described above for the
preparation of 8a but using 1-benzyl-4,5-dihydroimidazole 7
(1.00 g, 6.25 mmol), n-butyl-lithium (1.54 M solution in
hexanes; 4.50 mL, 6.87 mmol) and 3-methoxybenzaldehyde
(0.94 g, 6.87 mmol) to afford after column chromatography
1-Benzyl-2-(1-hydroxybutyl)-4,5-dihydroimidazole (8a). To eluting with CHCl3–2-aminopropane (99.5 : 0.5 v/v), the title
1-benzyl-4,5-dihydroimidazole 7 (1.00 g, 6.25 mmol) in dry THF compound 8c (1.08 g, 58%) as a yellow oil; νmax(film)/cm−1
(30 mL), stirred at −78 °C under an atmosphere of nitrogen, 3050, 2950, 2840, 1600, 1260, 780, 700; δH 7.23–7.27 (6H, m,
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Ar-H), 6.99–7.02 (3H, m, Ar-H), 5.70 (1H, s, CHOH), 4.70 (1H,
Method B: Prepared by the method described earlier for the
br s, OH), 4.20 (2H, s, PhCH2), 3.66–3.72 (5H, m, OCH3 and preparation of 8a but using 1-benzyl-4.5-dihydroimidazole 7
NCH2CH2N), 3.08–3.12 (2H, m, NCH2CH2N). (1.0 g, 6.25 mmol) in dry THF (40 mL), n-butyl-lithium (1.50 M
1-Benzyl-2-(4-methoxyphenylhydroxymethyl)-4,5-dihydroimi- solution in hexanes; 4.60 mL, 6.87 mmol) and butanal (0.52 g,
dazole (8e). Prepared by the method described above for the 7.20 mmol) After the yellow solution allowed to warm to 20 °C,
preparation of 8a but using 1-benzyl-4,5-dihydroimidazole 7 tert-butyldimethylsilyl chloride (1.13 g, 7.50 mmol) in dry THF
(0.77 g, 4.81 mmol), n-butyl-lithium (1.55 M solution in (5 mL) was added and the mixture stirred for a further 16 h
hexanes; 3.25 mL, 5.05 mmol) and 4-methoxybenzaldehyde before the addition of water (2.0 mL). The mixture was parti-
(0.61 ml, 5.05 mmol) to afford after column chromatography tioned between water (50 mL) and CHCl3 (2 × 50 mL) and the
eluting with CHCl3–2-aminopropane (99.5 : 0.5 v/v) to afford combined organic extracts were dried and concentrated under
after column chromatography eluting with CHCl3–2-aminopro- reduced pressure. The residue was purified by column chrom-
pane (99.5 : 0.5 v/v), the title compound 8e (0.82 g, 57%) as a atography, eluting with CHCl3–2-aminopropane (99.5 : 0.5 v/v),
colourless oil; νmax(film)/cm−1 3000, 2950, 2840, 1600, 1510, yielding the title compound 9a (1.43 g, 66%) as a pale yellow oil
1460, 1250, 1180, 1040, 770, 700; δH 7.23–7.27 (6H, m, Ar-H), identical to the sample prepared by Method A.
6.89–7.02 (3H, m, Ar-H), 5.40 (1H, s, CHOH), 4.60 (1H, br s,
1-Benzyl-2-[phenyl(tert-butyldimethylsilyloxy)methyl]-4,5-
OH), 4.09–4.11 (2H, m, PhCH2), 3.77–3.84 (5H, m, OCH3 and dihydroimidazole (9b). Prepared by Method A described above
NCH2CH2N), 3.23–3.27 (2H, m, NCH2CH2N); m/z 296 (M+, 7%), for the preparation of 9a but using 1-benzyl-2-(phenylhydroxy-
294 (10), 265 (11), 205 (15), 197 (36), 160 (31), 135 (60), 91 methyl)-4,5-dihydroimidazole 8c (555 mg, 2.01 mmol), tert-
(100). HRMS: M+ 296.1521; C18H20N2O requires M+ 296.1525.
butyldimethylsilyl chloride (378 mg, 2.50 mmol) and 4-(di-
1-Benzyl-2-(3,4-dimethoxyphenylhydroxymethyl)-4,5-dihy- methylamino)pyridine (255 mg, 2.01 mmol) to afford after
droimidazole (8f). Prepared by the method described above column chromatography eluting with CHCl3–2-aminopropane
for the preparation of 8a but using 1-benzyl-4,5-dihydroimida- (99.5 : 0.5 v/v), the title compound 9b (670 mg, 84%) as a colour-
zole 7 (1.00 g, 6.25 mmol), n-butyl-lithium (1.54 M solution in less oil; δH 7.26–7.34 (8H, m, Ar-H), 6.78–6.81 (2H, m, Ar-H),
hexanes; 4.25 mL, 6.54 mmol) and 3,4-dimethoxybenzaldehyde 5.80 (1H, s, CHO), 4.40, 4.05 (each 1H, d, J = 15, PhCH2),
(1.09 g, 6.54 mmol) to afford after column chromatography 3.78–3.82, 3.08–3.12 (each 2H, m, NCH2CH2N), 1.00 (9H, s, 3 ×
eluting with CHCl3–2-aminopropane (99.25 : 0.75 v/v), the title CH3), and 0.25 (6H, s, 2 × CH3); δC 166.1 (C-2), 140.2, 137.8 (Ar-
compound (1.22 g, 60%) as a colourless gum; νmax(film)/cm−1 C), 128.2, 128.1, 128.0, 127.6, 127.2, 126.9 (Ar-CH), 72.1 (CHO),
3000, 1600, 1450, 1350, 1260, 1230, 760, 700; δH 7.18–7.22 (4H, 52.2, 51.0, 50.6 (CH2), 25.9 (C(CH3)3), 18.3 (C(CH3)3), −4.70,
m, Ar-H), 6.93–6.97 (4H, m, Ar-H), 5.45 (1H, s, CHOH), 4.60 −5.35 (Si(CH3)2); m/z 380 (M+, 24%), 324 (29), 323 (100), 133
(1 H, br s, OH), 4.15 (2H, s, PhCH2), 3.80 (6H, s, 2 × OCH3), (12), 91 (75), 75 (18), 73 (25). HRMS: M+ 380.2278;
3.67–3.70, 3.18–3.21 (each 2H, m, NCH2CH2N); δC 168.0 (C-2), C23H32N2OSi requires M+ 380.2283.
149.2, 148.9, 136.9, 132.6 (Ar-C), 128.2, 127.2, 127.1, 119.3,
1-Benzyl-2-[phenyl(benzyloxycarbonyloxy)methyl]-4,5-dihy-
111.1, 110.2 (Ar-CH), 69.1 (CHOH), 55.8, 51.3, 51.0, 50.2 (CH2 droimidazole (9c). To 1-benzyl-2-(phenylhydroxymethyl)-4,5-
and CH3); m/z 326 (M+, 19%), 235 (11), 227 (37), 165 (33), 159 dihydroimidazole 8c (2.04 g, 7.67 mmol) in dry pyridine
(20), 120 (14), 91 (100), 77 (10), 65 (13). HRMS: M+ 326.1630; (6.2 mL), stirred at −20 °C under an atmosphere of nitro-
C19H22N2O requires M+ 326.1630.
gen, was added benzyl chloroformate (1.4 eq., 1.53 mL,
1-Benzyl-2-(1-tert-butyldimethylsilyloxybutyl)-4,5-dihydro- 10.74 mmol). The resulting solution was stirred at −20 °C for
imidazole (9a). Method A: To 1-benzyl-2-(1-hydroxybutyl)-4,5- 2 h then allowed to warm to 20 °C. After a further 24 h the
dihydroimidazole 8a (1.13 g, 4.87 mmol) in dry CH2Cl2 reaction mixture was poured into water (40 mL) and extracted
(10 mL) was added tert-butyldimethylsilyl chloride (0.88 g, with CHCl3 (2 × 30 mL). The combined organic extracts were
5.84 mmol) and 4-(dimethylamino)pyridine (0.71 g, dried and concentrated under reduced pressure. The residue
5.84 mmol) and the resulting mixture stirred at 20 °C for 72 h. was purified by column chromatography eluting with EtOAc–
The reaction mixture was concentrated under reduced pressure Et3N (99.25 : 0.75 v/v) to afford the title compound 9c (1.96 g,
and purified by column chromatography, eluting with CHCl3– 64%) as a colourless solid, mp 104–105 °C; νmax(KBr)/cm−1
2-aminopropane (99.5 : 0.5 v/v) to afford the title compound 9a 3027, 2950, 2880, 1750, 1610, 1260, 960, 750, 705; δH 7.35–7.44
(0.81 g, 48%) as a colourless oil; νmax(film)/cm−1 2970, 2940, (13H, m, Ar-CH), 7.08–7.12 (2H, m, Ar-CH), 6.50 (1H, s, CHO),
2860, 1605, 1260, 1080, 845, 780, 760, 700; δH 7.32–7.36 (5H, 5.25, 4.20 (each 2H, s, PhCH2O), 3.83–3.87, 3.17–3.22 (each 2H,
m, Ar-H), 5.0 (1H, d, J = 15.0, PhCHH), 4.60 (1H, t, J = 7.0, m, NCH2CH2N); m/z 400 (M+, 3%), 250 (12), 249 (19), 175 (15),
CHO), 4.30 (1H, d, J = 15.0, PhCHH), 3.73–3.77, 3.27–3.33 (each 167 (11), 107 (28), 105 (63), 91 (100). HRMS: M+ 400.1774;
2H, m, NCH2CH2N), 1.74–1.76, 1.39–1.43 (each 2H, m, CH2), C25H24N2O3 requires M+ 400.1785.
0.97–1.00 (12H, m, 4 × CH3), 0.20 (6H, s, 2 × CH3); δC 166.3
1-Benzyl-2-butanoyl-4,5-dihydroimidazole (11a). Prepared by
(C-2), 137.8 (Ar-C), 127.8, 126.4 (Ar-CH), 70.9 (CHO), 51.6, 50.9, Method A described below for the preparation of 11b but using
50.6, 37.4 (CH2), 25.2 (C(CH)3), 18.6 (CH2), 17.3 (C(CH)3), 13.1 1-benzyl-2-hydroxybutyl-4,5-dihydroimidazole 8a (1 07 mg,
(CH3), −5.1, −6.0 (Si(CH3)2); m/z 346 (M+, 13%), 317 (13), 0.460 mmol) and manganese dioxide (200 mg, 2.30 mmol),
304 (38), 289 (99), 287 (11), 91 (100). HRMS: M+ 346.2428; and stirring the mixture for 24 h, to afford after column
C20H34N2OSi requires M+ 346.2440.
chromatography eluting with EtOAc–Et3N (99.5 : 0.5 v/v), the
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title compound 11a (56 mg, 53%) as a colourless oil that was
1-Benzyl-2-decanoyl-4,5-dihydroimidazole (11d). Prepared
not further characterised; νmax(film)/cm−1 2960, 2880, 1700, by Method B described above for the preparation of 11b but
1575, 1250, 1130, 1000, 740, 700; δH (200 MHz) 7.18–7.23 (5H, using 1-benzyl-4,5-dihydroimidazole 7 (0.51 g, 3.19 mmol),
m, Ar-CH), 4.50 (2H, s, PhCH2), 3.75, 3.23 (each 2H, t, J = 9.1, n-butyl-lithium (1.55
M solution in hexanes; 2.26 ml,
NCH2CH2N), 2.85 (2H, t, J = 7.0, COCH2), 1.60 (2H, sextet, J = 3.50 mmol) and ethyl decanoate (1.34 g, 6.70 mmol) to afford
7, COCH2CH2), 0.90 (3H, t, J = 7, CH3); m/z 230 (M+, 15%), 159 after column chromatography, eluting with EtOAc–light pet-
(20), 91 (100).
roleum–Et3N (89.5 : 1 0 : 0.5 v/v/v), the title compound 11d
2-Benzoyl-1-benzyl-4,5-dihydroimidazole (11b). Method A: (0.44 g, 44%) as a colourless oil; νmax(film)/cm−1 2920, 2860,
Manganese dioxide (8.00 g) was added to a solution of 1700, 1575, 1450, 740; δH 7.32–7.36 (5H, m, Ar-H), 4.60 (2H, s,
1-benzyl-2-(phenylhydroxymethyl)-4,5-dihydroimidazole 8c PhCH2), 3.74–3.77, 3.28–3.31 (each 2H, m, NCH2CH2N), 2.95
(1.16 g, 4.36 mmol) in dry CH2Cl2 (50 mL). The slurry was (2H, t, J = 7.0, COCH2), 1.58–1.61 (2H, m, COCH2CH2), 1.25
stirred at 20 °C for 2 h before the manganese salts were (12H, m, 6 × CH2), 0.84–0.86 (3H, m, CH3); δC 197.6 (CO),
removed by filtration through celite, washing the filter pad 161.1 (C-2), 137.8 (Ar-C), 128.5, 127.7, 137.5 (Ar-CH), 52.7, 51.0,
with a further portion of CH2Cl2 (100 mL). The combined fil- 50.7, 40.3, 31.8, 29.3, 29.2, 29.1, 29.0, 23.6, 22.6 (CH2), 14.0
trate was concentrated under reduced pressure and the residue (CH3); m/z 315 (MH+, 14%), 314 (M+, 26), 223 (19), 202 (41),
purified by column chromatography eluting with EtOAc–Et3N 133 (70), 91 (100). HRMS: M+ 314.2361; C20H30N2O requires
(99.5 : 0.5 v/v), to afford the title compound 11b (0.77 g, 67%) as M+ 314.2356.
a yellow oil; νmax(film)/cm−1 3060, 3040, 2950, 2860, 1670,
1-Benzyl-2-(1-hydroxy-1-phenylethyl)-4,5-dihydroimidazole
1580, 1450, 1385, 1200, 1180, 990, 900, 740, 700; δH 8.19–8.21 (12a). To 1-benzyl-2-benzoyl-4,5-dihydroimidazole 11b (370 mg,
(2H, m, Ar-CH), 7.58–7.61 (3H, m, Ar-CH), 7.27–7.32 (5H, m, 1.40 mmol) in dry THF (10 mL), stirred at −78 °C under an
Ar-CH), 4.40 (2H, s, PhCH2), 3.98, 3.40 (each 2H, t, J = 8.9, atmosphere of nitrogen, was added methyl-lithium (1.60 M
NCH2CH2N); δC 188.8 (CO), 161.7 (C-2), 140.0, 135.4 (Ar-C), solution in ether; 1.10 mL, 1.75 mmol). The mixture was main-
133.9, 130.1, 128.4, 128.3, 127.8, 127.3 (Ar-CH), 53.8, 51.0, 49.5 tained at −78 °C for 30 min before the addition of water
(CH2); m/z 264 (M+, 36%), 235 (32), 159 (10), 133 (14), 132 (35), (2 mL), warmed to 20 °C and partitioned between water
105 (68), 91 (100), 77 (81). HRMS: M+ 264.1270; C17H16N2O (25 mL) and CHCl3 (2 × 25 mL). The combined organic extracts
requires M+ 264.1262.
were dried, concentrated under reduced pressure and the
Method B: To 1-benzyl-4,5-dihydroimidazole 7 (2.41 g, residue was washed with ether (4 × 10 mL) to afford the title
15.06 mmol) in dry THF (50 mL), stirred at −78 °C under an compound 12a (186 mg, 69%) as a colourless solid, mp 143 °C;
atmosphere of nitrogen, was added n-butyl-lithium (1.50 M νmax(KBr)/cm−1 3050, 2850, 1600, 1400, 1240, 1210, 1150, 1120,
solution in hexanes; 10.8 mL, 16.2 mmol). After 20 min, the 1020, 750, 710; δH (250 MHz) 7.54–7.56 (2H, m, Ar-H),
solution was cooled to −100 °C and added by cannula to a 7.28–7.33 (6H, m, Ar-H). 6.89–6.91 (2H, m, Ar-H), 4.03, 3.87
stirred solution of ethyl benzoate (4.07 g, 27.1 mmol) in dry (each 1H, d, J = 14.8, PhCH2), 3.76–3.79, 3.23–3.26 (each 2H,
THF (50 mL) cooled to −78 °C under an atmosphere of nitro- m, NCH2CH2N), 1.9 (3H, s, CH3); m/z 280 (M+, 4%), 189 (23),
gen. The mixture was maintained at −78 °C for 1 h, allowed to 160 (10), 120 (6), 113 (25), 105 (29), 91 (100), 77 (46). HRMS:
warm to 20 °C and stirred for a further 3 h before the addition M+ 280.1572; C18H20N2O requires M+ 280.1575.
of water (4 mL). The mixture was partitioned between CHCl3
1-Benzyl-2-(1-hydroxy-1-phenylpentyl)-4,5-dihydroimidazole
(2 × 100 mL) and water (100 mL). The combined organic extracts (12b). Prepared by the method described above for the prepa-
were dried and concentrated under reduced pressure and the ration of 12a but using 1-benzyl-2-benzoyl-4,5-dihydroimida-
residue purified by column chromatography, eluting with zole 11b (82.0 mg, 0.310 mmol), n-butyl-lithium (1.40 M
EtOAc–Et3N (99.5 : 0.5 v/v) to afford the title compound 11b solution in hexanes; 0.27 mL, 0.390 mmol) to afford after
(2.66 g, 67%) as a colourless oil identical to the sample pre- column chromatography eluting with EtOAc–Et3N (99.5 : 0.5 v/v),
pared by Method A.
the title compound 12b (86 mg, 59%) as a colourless oil; δH
1-Benzyl-2-hexanoyl-4,5-dihydroimidazole (11c). Prepared by 7.46–7.54 (8H, m, Ar-H), 7.38–7.41 (2H, m, Ar-H), 4.30 (1H. br
Method B described above for the preparation of 11b but using s, OH), 3.99–4.01 (2H, m, PhCH2), 3.78–3.81, 3.29–3.32 (each
1-benzyl-4,5-dihydroimidazole 7 (1.49 g, 9.32 mmol), n-butyl- 2H, m, NCH2CH2N), 2.29–2.32 (2H, m, C(OH)CH2), 1.38–1.42
lithium (1.60 M solution in hexanes; 6.40 mL, 10.3 mmol) and (4H, m, 2 × CH2), 0.94–0.96 (3H, m, CH3); m/z 322 (M+, 2%),
ethyl hexanoate (2.69 g, 18.6 mmol) to afford after column 266 (13), 175 (30), 160 (21), 120 (33), 105 (60), 91 (100), 77 (55),
chromatography, eluting with EtOAc–Et2O (40 : 60 v/v), the title 51 (15). HRMS: M+ 322.2017; C21H26N2O requires M+ 322.2045.
compound 11c (0.98 g, 41%) as a colourless oil that was not
1-Benzyl-2-(diphenylhydroxymethyl)-4,5-dihydroimidazole
further characterised; νmax(film)/cm−1 2920, 2860, 1705, 1575, (12c). Method A: Prepared by the method described above for
1450, 1275; δH (200 MHz) 7.28–7.32 (5H, m, Ar-CH), 4.60 (2H, the preparation of 12a but using 1-benzyl-2-benzoyl-4,5-dihy-
s, PhCH2), 3.71–3.73, 3.32–34 (each 2H, m, NCH2CH2N), 2.95 droimidazole 11b (600 mg, 2.27 mmol), phenyl-lithium (1.70 M
(2H, t, J = 7.1, COCH2), 1.59–1.61 (2H, m, COCH2CH2), solution in cyclohexane–Et2O; 2.0 mL, 3.41 mmol) to afford
1.34–1.37 (4H, m, 2 × CH2), 0.89–0.91 (3H, m, CH3); m/z after purification by crystallisation from CHCl3–Et2O the title
259 (MH+, 43%), 258 (M+, 32), 202 (30), 133 (45), 91 (100), compound 12c (71 0 mg, 92%) as a colourless solid, mp
60 (87).
115 °C, identical to the sample prepared by Method B below.
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Method B: To 1-benzyl-4,5-dihydroimidazole 7 (1.08 g, the title compound 12e (653 mg, 50%) as a colourless solid, mp
6.73 mmol) in dry THF (40 mL), stirred at −78 °C under an 123–124 °C (Found: C, 77.3; H, 7.4; N, 9.6%; C19H22N2O
atmosphere of nitrogen, was added n-butyl-lithium (1.50 M requires C, 77.5; H, 7.5; N, 9.5%); νmax(KBr)/cm−1 3100, 2850,
solution in hexanes; 4.95 mL, 7.40 mmol). After 20 min, benzo- 1600, 1400, 1230, 995, 770, 710; δH (250 MHz) 7.44–7.46 (2H,
phenone (1.35 g, 7.40 mmol) in dry THF (5 ml) was added m, Ar-H), 7.13–7.17 (6H, m, Ar-H), 6.7–6.9 (2H, m, Ar-H), 4.80
dropwise and the mixture stirred at −78 °C for 1 h then (1H, br s, OH), 3.95, 3.75 (each 1H, d, J = 14.7, PhCH2),
allowed to warm to 20 °C and stirred for a further 1 h before 3.65–3.69, 3.08–3.12 (each 2H, m, NCH2CH2N), 2.20–2.23 (2H, m,
addition of water (2 mL). The mixture was concentrated under CH2CH3), 0.90 (3H, t, J = 7.3, CH3); m/z 294 (M+, 4%), 266 (14),
reduced pressure and partitioned between water (50 mL) and 203 (11), 175 (26), 160 (23), 134 (11), 127 (18), 105 (74), 91 (100),
CHCl3 (2 × 50 mL). The combined organic extract was dried 77 (34). HRMS: M+ 294.1749; C19H22N2O requires M+ 294.1732.
and concentrated under reduced pressure to leave a waxy solid
1-Benzyl-2-(1-hydroxy-1-phenylnonyl)-4,5-dihydroimidazole
purified by trituration from CHCl3–Et2O to afford the title com- (12f). Prepared by the method described above for the prepa-
pound 12c (1.13 g, 50%) as a colourless solid, mp 115–116 °C ration of 12a but using 1-benzyl-2-benzoyl-4,5-dihydroimida-
(Found: C, 80.8; H, 6.7; N, 6.1%; C23H22N2O requires C, 80.7; zole 11b (540 mg, 2.05 mmol) and octylmagnesium bromide
H, 6.5; N, 6.2%); νmax(KBr)/cm−1 3100, 2850, 1590, 1365, 1260, (1.03 M solution in THF; 3.0 mL, 3.07 mmol) at 20 °C to afford
1235, 1190, 1000, 750, 705; δH (400 MHz) 7.56–7.60 (4H, m, Ar- after column chromatography eluting with CHCl3–2-aminopro-
H), 7.44–7.49 (6H, m, Ar-H), 7.15–7.17 (3H, m, Ar-H), 6.69–6.71 pane (99.5 : 0.5 v/v), the title compound 12f (326.5 mg, 42%) as
(2H, m, 2 × Ar-H), 3.96 (2H, s, PhCH2), 3.80, 3.35 (each 2H, t, a colourless solid, mp 83–85 °C (Found: C, 78.9; H, 9.1; N,
J = 9.9, NCH2CH2N); δC (100 MHz) 169.6 (C-2), 142.7, 137.1 (Ar- 7.4%; C25H34N2O requires C, 79.3; H, 9.0; N, 7.4%); νmax(KBr)/
C), 128.3, 128.3, 128.0, 127.5, 127.4, 127.3 (Ar-CH), 78.0 (COH), cm−1 3080, 2920, 2850, 1580, 1450, 1420, 1280, 1250, 700; δH
52.7, 52.4, 51.1 (NCH2); m/z (M+ not observed), 182 (39), 160 7.27–7.32 (8H, m, Ar-H), 6.89–6.91 (2H, m, Ar-H), 4.7 (1H, br s,
(24), 105 (1 00), 91 (89), 77 (73), 51 (55).
OH), 3.95 (2H, s, PhCH2), 3.68–3.71, 3.19–3.22 (each 2H, m,
1-Benzyl-2-(1-hydroxy-1-phenylprop-2-enyl)-4,5-dihydro- NCH2CH2N), 2.24–2.26 (2H, m, C(OH)CH2), 1.30–1.38 (10H, m,
imidazole (12d). Prepared by the method described above for 5 × CH2), 0.88–0.90 (3H, m, CH3); δC 169.3 (C-2), 143.2, 137.8
the preparation of 12a but using 1-benzyl-2-benzoyl-4,5-dihy- (Ar-C), 128.2, 128.0, 127.5, 127.4, 127.1, 125.9 (Ar-CH), 74.8
droimidazole 11b (600 mg, 2.27 mmol), ethenylmagnesium (COH), 52.1, 52.0, 51.2, 39.2, 31.8, 29.9, 29.5, 29.2, 23.3, 22.6
bromide (1.0 M solution in THF; 3.40 mL, 3.40 mmol) at 20 °C (CH2); m/z 378 (M+, 0.4%), 218 (10), 160 (22), 133 (12), 120
to afford after column chromatography eluting with CHCl3– (100), 105 (94), 91 (72), 77 (36). HRMS: M+ 378.2700;
2-aminopropane (99.5 : 0.5 v/v), the title compound 12d (588 mg, C25H34N2O requires M+ 378.2671.
89%) as a colourless solid, mp 99–101 °C; νmax(KBr)/cm−1
1-Benzyl-2-(1-hydroxy-1-methylhexyl)-4.5-dihydroimidazole
3050, 2870, 1590, 1280, 1250, 1200, 1000, 750, 700; δH (12g). Prepared by the method described above for the prepa-
7.27–7.33 (8H, m, Ar-H), 6.89–6.91 (2H, m, Ar-H), 6.5 (1H, dd, ration of 12a but using 1-benzyl-2-hexanoyl-4,5-dihydroimida-
J = 10.0, 17.1, CHvCH2), 5.55 (1H, dd, J = 1.0, 17.1, CHvCHH), zole 11c (136 mg, 0.530 mmol) and methylmagnesium
5.35 (1H, dd, J = 1.0, 10.0, CHvCHH), 4.60 (1H, br s, OH), 3.95 bromide (3.0 M solution in Et2O; 0.300 mL, 0.790 mmol) at
(2H, s, PhCH2), 3.78–3.81, 3.19–3.22 (each 2H, m, NCH2CH2N); 20 °C to afford the title compound 12g (81 mg, 56%) as a col-
δC 168.7 (C-2), 142.2, 137.6 (Ar-C), 140.3 (CHvCH2), 128.5, ourless solid, mp 96–98 °C (Found: C, 74.0; H, 9.6; N, 9.9%;
128.3, 127.8, 127.6, 127.2, 126.3 (Ar-CH), 114.9 (CHvCH2), C17H26N2O requires C, 74.4; H, 9.6; N, 10.2%); νmax(KBr)/cm−1
75.7 (COH), 52.0, 51.9, 51.5 (CH2); m/z 292 (M+, 5%), 275 (7), 3120, 2940, 2850, 1590, 1405, 1360, 1270, 1140, 1000, 950, 850;
160 (28), 132 (19), 105 (56), 91 (100), 77 (33). HRMS: δH 7.27–7.32 (5H, m, Ar-H), 4.44–4.46 (2H, m, PhCH2), 3.70,
M+ 292.1562; C19H20N2O requires M+ 292.1575.
3.30 (each 2H, t, J = 9.0, NCH2CH2N), 1.70–1.72 (2H, m, C(OH)
1-Benzyl-2-(1-hydroxy-1-phenylpropyl)-4,5-dihydroimidazole CH2), 1.55 (3H, s, COHCH3), 1.28–1.33 (6H, m, 3 × CH2),
(12e). Method A: Prepared by the method described above for 0.88–0.90 (3H, m, CH3); m/z 275 (MH+, 15%), 274 (M+, 10), 259
the preparation of 12a but using 1-benzyl-2-benzoyl-4,5-di- (6), 204 (25), 113 (1 00), 91 (70).
hydroimidazole 11b (1.047 g, 3.97 mmol) and ethylmagnesium
1-Benzyl-2-(1-hydroxy-1-phenylhexyl)-4,5-dihydroimidazole
bromide (4.77 mmol in THF) at 20 °C, to afford after column (12h). Prepared by the method described above for the prepa-
chromatography eluting with EtOAc–Et3N (99.5 : 0.5 v/v), the ration of 12a but using 1-benzyl-2-hexanoyl-2-imidazoline 11c
title compound 12e (366 mg, 31%) as a colourless solid, mp (237 mg, 0.920 mmol) and phenylmagnesium bromide (3.0 M
123–124 °C, identical to the sample prepared by Method B solution in Et2O; 0.380 mL, 1.15 mmol) at 20 °C to afford after
below. Also isolated from this reaction was 1-benzyl-2-(phenyl- column chromatography eluting with EtOAc–Et2O–Et3N
hydroxymethyl)-4,5-dihydroimidazoline 8c (420 mg, 40%), (79.5 : 20 : 0.5 v/v), the title compound 12h (142 mg, 46%) as a
identical to the sample described earlier.
colourless solid, mp 104 °C (Found: C, 77.9; H, 8.5; N, 8.2%;
Method B: Prepared by Method B described above for the C22H28N2O requires C, 78.4; H, 8.4; N, 8.3%); νmax(KBr)/cm−1
preparation of 12c but using 1-benzyl-4,5-dihydroimidazole 7 3060, 2940, 1570, 1440, 1280, 1150, 700; δH (200 MHz)
(0.70 g, 4.38 mmol), n-butyl-lithium (1.50 M solution in 7.48–7.52 (2H, m, Ar-H), 7.27–7.33 (6H, m, Ar-H), 6.88–6.91
hexanes; 3.20 mL, 4.81 mmol) and 1-phenylpropan-1-one (2H, m, Ar-H), 4.55 (1H, br s, OH), 4.00, 3.85 (each 1H, d,
(0.64 mL, 4.81 mmol) to afford trituration from CHCl3–Et2O, J = 15, PhCH2), 3.78–3.81, 3.24–3.27 (each 2H, m, NCH2CH2N),
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2.23–2.26 (2H, m, C(OH)CH2), 1.42–1.47 (6H, m, 3 × CH2), Preparation of ketones (13) from tertiary alcohols (12) by
0.89–0.91 (3H, m, CH3); m/z 336 (M+, 8%), 266 (20), 245 (5), acidification
175 (35), 160 (10), 120 (20), 105 (60), 91 (100), 77 (45).
General method A. The appropriate 1-benzyl-2-(1-hydroxy-
alkyl)-4,5-dihydroimidazole 12 in alumina-washed chloro-
form (20 mL) was heated under gentle reflux with conc.
hydrochloric acid (36% w/w, 4 drops) for 4 h. The mixture was
cooled, concentrated under reduced pressure and the crude
product purified by column chromatography eluting with
EtOAc–Et3N (99.5 : 0.5 v/v).
Acetophenone (13a). Prepared from 1-benzyl-2-(1-hydroxy-1-
phenylethyl)-4,5-dihydroimidazole 12a (175 mg, 0.624 mmol)
by the general method to afford the title compound (70 mg,
94%) as a colourless oil, identical to a commercial sample.
1-Phenylpentan-1-one (13b). Prepared from 1-benzyl-2-
(1-hydroxy-1-phenylpentyl)-4,5-dihydroimidazole 12b (152 mg,
0.470 mmol) by the general method to afford the title com-
pound 13b (60 mg, 79%) as a colourless oil; νmax(film)/cm−1
3060, 2980, 2870, 1680, 1460, 1270, 1210, 700; δH 7.92–7.95
(2H, m, Ar-H), 7.48–7.53 (3H, m, Ar-H), 3.90 (2H, t, J = 7.2,
CH2CO), 1.47–1.52 (4H, m, 2 × CH2), 0.93–0.96 (3H, m, CH3);
δC 200.4 (CO), 137.3 (Ar-C), 132.8, 128.6, 128.1 (Ar-CH), 38.3
(CH2CO), 26.6, 22.5 (CH2), 13.9 (CH3); m/z 162 (M+, 9%), 120
(47), 105 (100), 85 (7), 77 (41). HRMS: M+ 162.1055; C11H14O
requires M+ 162.1045.
1-Benzyl-2-(1-ethyl-1-hydroxypropyl)-4,5-dihydroimidazole
(12i). Prepared by Method B described above for the pre-
paration of 12c but using 1-benzyl-4,5-dihydroimidazole 7
(1.00 g, 6.25 mmol), n-butyllithium (1.50 M solution in
hexanes; 4.55 mL, 6.80 mmol) and pentan-3-one (0.59 g,
6.80 mmol) to afford after column chromatography eluting
with CHCl3–2-aminopropane (99.5 : 0.5 v/v) the title compound
12i (560 mg, 38%) as a colourless gum; νmax(KBr)/cm−1 3100,
2980, 2960, 1600, 1370, 1280, 705; δH 7.37–7.42 (5H, m, Ar-H),
4.70 (1H, br s, OH), 4.45 (2H, s, PhCH2), 3.70, 3.30 (each 2H, t,
J = 8.9, NCH2CH2N), 1.80 (4H, q, J = 7, 2 × CH2CH3), 0.95 (6H,
t, J = 7.0, 2 × CH3); δC 169.4 (C-2), 137.7 (Ar-C), 128.7, 127.5,
127.3 (Ar-CH), 72.3 (COH). 52.8, 52.2, 50.6 (NCH2), 32.1
(CH2CH3), 8.02 (CH3); m/z 246 (M+, 9%), 229 (9), 217 (24), 127
(81), 91 (100), 65 (13), 57 (16). HRMS: M+ 246.1730; C15H22N2O
requires M+ 246.1732.
1-Benzyl-2-(1-ethyl-1-hydroxyprop-2-enyl)-4,5-dihydroimida-
zole (12j). Prepared by Method B described above for the
preparation of 12c but using 1-benzyl-4,5-dihydroimidazole 7
(1.00 g, 6.25 mmol), n-butyllithium (1.50 M solution in
hexanes; 4.55 mL, 6.80 mmol) and pent-1-en-3-one (0.58 g,
6.88 mmol) to afford after column chromatography eluting
with CHCl3–2-aminopropane (99.5 : 0.5 v/v) the title compound
(540 mg, 35%) as a colourless solid, mp 68–72 °C; νmax(KBr)/
cm−1 3150, 2980, 2940, 2880, 1590, 1410, 1360, 1250, 1180,
1000, 970, 740, 700; δH (250 MHz) 7.33–7.37 (5H, m, Ar-CH),
6.13 (1 H, dd, J = 10.6, 17.3, CHvCH2), 5.50 (1H, dd, J = 1.1,
Benzophenone (13c). Prepared from 1-benzyl-2-(diphenyl-
hydroxymethyl)-4,5-dihydroimidazole 12c (429 mg, 1.25 mmol)
by the general method to afford the title compound 13c
(227 mg, 99%) as a pale yellow solid, mp 46–48 °C (lit.,13
48 °C), identical with a commercial sample.
1-Phenylpropan-1-one (13d). Prepared from 1-benzyl-2-
17.3, CHvCHH), 5.30 (1H, dd, J = 1.1, 10.6, CHvCHH), 4.65 (1-hydroxy-1-phenylpropyl)-4,5-dihydroimidazole 12e (150 mg,
(1H, br s OH), 4.45, 4.30 (each 1H, d, J = 15, PhCH2), 3.73–3.77, 0.510 mmol) by the general method to afford the title com-
3.28–3.32 (each 2H, m, NCH2CH2N), 1.94–1.6 (2H, m, CH2), pound 13d (36 mg, 52%) as a colourless oil; νmax(film)/cm−1
1.05 (3H, t, J = 7.4, CH3); δC 168.9 (C-2), 140.4 (CHvCH2), 3060, 2960, 2940, 1675, 1600, 1450, 1350, 1220, 950, 760, 700;
137.8 (Ar-C), 128.6, 127.4, 127.3 (Ar-CH), 115.5 (CHvCH2), δH 7.94–7.97 (2H, m, Ar-H), 7.48–7.52 (3H, m, Ar-H), 3.0 (2H, q,
74.0 (COH), 52.7, 52.3, 51.0 (NCH2), 31.2 (CH2CH3), 7.7 (CH3); J = 7.2, CH2), 1.25 (3H, t, J = 7.2, CH3); δC 200.4 (CO), 137.2 (Ar-
m/z 244 (M+, 2%), 227 (17), 216 (13), 215 (14), 160 (21), 153 C), 132.9, 128.6, 128.1 (Ar-CH), 31.9 (CH2), 8.4 (CH3); m/z 134
(17), 125 (10), 91 (100). HRMS: M+ 244.1585; C15H20N2O (M+, 25%), 113 (15), 105 (100), 77 (37), 51 (11). HRMS: M+
requires M+ 244.1574.
134.0714; C9H10O requires M+ 134.0731.
1-Benzyl-2-(1-hydroxycyclohex-1-yl)-4,5-dihydroimidazole
1-Phenylnonan-1-one (13e). Prepared from 1-benzyl-2-
(12k). Prepared by Method
B described above for the (1-hydroxy-1-phenylnonyl)-4,5-dihydroimidazole 12f (297 mg,
preparation of 12c but using 1-benzyl-4,5-dihydroimidazole 7 0.807 mmol) by the general method but using CDCl3 as the
(0.58 g, 3.63 mmol), n-butyl-lithium (1.60 M solution in solvent, acidic impurities in this solvent as the catalyst and
hexanes; 2.50 mL, 4.0 mmol) and cyclohexanone (0.45 mL, heating under reflux for 48 h, to afford the title compound 13e
4.35 mmol) to afford after trituration from CHCl3-Et2O, the (147 mg, 83%) as a colourless oil; νmax(film)/cm−1 3060, 2930,
title compound 12k (302 mg, 35%) as a colourless solid, mp 2860, 1680, 1600, 1450, 1225, 700; δH 7.98–8.01 (2H, m, Ar-H),
133–135 °C (Found: C, 74.35; H, 8.9; N, 10.7%; C16H22N2O 7.54–7.57 (3H, m, ArH), 2.95 (2H, t, J = 7.0, COCH2), 1.69–1.72
requires C, 74.4; H, 8.6; N, 10.8%); νmax(KBr)/cm−1 3100, 1960, (2H, m, COCH2CH2), 1.30 (10H, m, 5 × CH2), 0.89–0.91 (3H, m,
2880, 1600, 705; δH (250 MHz) 7.22–7.27 (5H, m, Ar-CH), 4.60 CH3); δC 200.4 (CO), 137.3 (Ar-C), 132.8, 128.6, 128.1 (Ar-CH),
(2H, s, PhCH2), 3.70 (2H, t, J = 10.3, NCH2CH2N), 3.48 (1H, br s, 38.6, 31.9, 29.5, 29.2, 24.5, 22.7 (CH2), 14.0 (CH3); m/z 318
OH), 3.30 (2H, t, J = 10.3, NCH2CH2N), 1.77–1.82 (9H, m, 4 × (M+, 10%), 133 (13), 120(100), 105 (98), 77 (40). HRMS:
CH2, CHH), 1.24–1.26 (1H, m, CHH); δC 170.9 (C-2), 138.4 (Ar- M+ 218.1672; C15H22O requires M+ 218.1670.
C), 128.6, 128.5, 127.1 (Ar-CH), 71.2 (COH), 52.5, 52.1, 51.4
1-Benzyl-3-methyl-4,5-dihydroimidazolium iodide 15a. Iodo-
(NCH2), 36.1, 25.5, 21.6 (CH2); m/z 258 (M+, 21%), 242 (10), 241 methane (6.24 mL, 100 mmol) was added to 1-benzyl-4,5-dihy-
(58), 203 (36), 167 (50), 91 (100), 71 (12). HRMS: M+ 258.1760; droimidazole 7 in dry THF (40 mL) and the mixture stirred
C16H22N2O requires M+ 258.1732.
at 20 °C for 1.5 h. The colourless crystals were collected by
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filtration, washed with dry THF (100 mL) and dried under above, was heated under reflux in EtOH (20 mL) for 20 h. The
reduced pressure to afford the title compound 15a (7.20 g, mixture was cooled, concentrated under reduced pressure, and
96%), mp 127–128 °C (Found: C, 43.6; H, 5.1; N, 9.2%; the residue purified by column chromatography eluting with
C11H15N2I requires C, 43.7; H, 5.0; N, 9.3%); νmax(KBr)/cm−1 EtOAc to afford the title compound 16b (206 mg, 73%) as a col-
3050, 2980, 1660, 1440, 1310, 1230, 1140, 760, 710; δH 9.50 ourless oil, identical to a commercial sample.
(1H, s, 2-CH), 7.32–7.37 (5H, m, Ar-H), 4.80 (2H, s, PhCH2),
3.85–3.95 (4H, m, NCH2CH2N), 3.30 (3H, s, CH3).
S-Butyl thiobenzoate (16c). 2-Benzoyl-1-benzyl-3-methyl-4,5-
dihydroimidazolium iodide prepared from 2-benzoyl-1-benzyl-
4,5-dihydroimidazole 11b (169 mg, 0.64 mmol) as described
above, was heated with butanethiol (0.350 mL, 3.20 mmol).
Under reflux in dry THF (10 mL) for 40 h. The mixture was
Preparation of ketones (13) from tertiary alcohols (12) by
quaternisation
General method B. To the appropriate 1-benzyl-2-(1-hydro- cooled, concentrated under reduced pressure, and the residue
xyalkyl)-4,5-dihydroimidazole 12 in dry THF was added excess purified by column chromatography eluting with Et3N–EtOAc
iodomethane and the mixture stirred at 20 °C for 24 h. After (0.5 : 99.5 v/v) to afford the title compound 16c (183 mg, 95%)
filtration and concentration of the filtrate under reduced as a pale yellow oil; νmax(film)/cm−1 2980, 1665, 1440, 1215,
pressure, the residue was purified by column chromatography 920, 790; δH 7.94–79.6 (2H, m, Ar-H), 7.43–7.46 (3H, m, Ar-H),
eluting with CHCl3–2-aminopropane (99.5 : 0.5 v/v). The fil- 3.05 (2H, t, J = 7.0, SCH2), 1.48–1.53 (4H, m, SCH2CH2CH2),
tered solid was dried and identified as 1-benzyl-3-methyl-4,5- 0.95 (3H, t, J = 7.0, CH3); δC 191.8 (CO), 137.4 (Ar-C), 133.1,
dihydroimidazolium iodide 15a (85–90%), identical to the 128.5, 127.2 (Ar-CH), 31.7 (SCH2), 28.7, 22.1 (CH2), 13.6 (CH3);
sample described above.
m/z 194 (M+, 4%), 105 (100), 77 (23), 57 (10). HRMS: M+
Acetophenone (13a). Prepared from 1-benzyl-2-(1-hydroxy-1- 194.0774; C11H14OS requires M+ 194.0765. Also isolated from
phenylethyl)-4,5-dihydroimidazole 12a (70.5 mg, 0.252 mmol) the column after eluting with MeOH, was 1-benzyl-3-methyl-
in dry THF (15 mL) and iodomethane (0.31 mL, 5.04 mmol) by 4,5-dihydroimidazolium iodide 15a (182.6 mg, 95%) identical
the general method to afford the title compound 13a (27.5 mg, to the sample described above.
91%) as a colourless oil identical to a sample prepared from
N-Benzylbenzamide (16d). 2-Benzoyl-1-benzyl-3-methyl-4,5-
12a by acidification using General Method A.
dihydroimidazolium iodide prepared from 2-benzoyl-1-benzyl-
Benzophenone (13c). Prepared from 1-benzyl-2-(diphenylhy- 4,5-dihydroimidazole 11b (456 mg, 1.73 mmol) as described
droxymethyl)-4,5-dihydroimidazole 12c (290 mg, 0.850 mmol) above, was heated with benzylamine (0.37 mL, 1.73 mmol)
in dry THF (15 mL) and iodomethane (1.50 g, 6.80 mmol) by under reflux in dry THF (20 mL) for 20 h. The mixture was
the general method to afford the title compound 13c (155 mg, cooled, concentrated under reduced pressure, and the residue
83%) as a colourless solid, identical to a sample prepared from purified by column chromatography eluting with EtOAc–Et3N
12c by acidification using General Method A.
(99.5 : 0.5 v/v) to afford the title compound 16d (293 mg, 80%)
as a pale yellow solid, mp 104–106 °C (lit.,15 104–106 °C).
Acyl transfer to nucleophiles from 2-benzoyl-1-benzyl-4,5-
dihydroimidazole (11b)
N-Butylbenzamide
(16e). 2-Benzoyl-1-benzyl-3-methyl-4,5-
dihydroimidazolium iodide prepared from 2-benzoyl-1-benzyl-
2-Benzoyl-1-benzyl-3-methyl-4,5-dihydroimidazolium iodide. 4,5-dihydroimidazole 11b (379 mg, 1.43 mmol) as described
Iodomethane (0.360 mL, 5.73 mmol) was added dropwise to above, was heated with butan-1-amine (0.71 mL, 2.86 mmol)
2-benzoyl-1-benzyl-4,5-dihydroimidazole 11b (505 mg, 1.91 mmol) under reflux in dry THF (20 mL) for 8 h. The mixture was
in dry THF (10 mL) under an atmosphere of nitrogen and the cooled, concentrated under reduced pressure, and the residue
mixture stirred at 20 °C for 2 h before being concentrated purified by column chromatography eluting with EtOAc–light
under reduced pressure to afford the title compound (745 mg, petroleum (1 : 2 v/v) to afford the title compound 16d (147 mg,
100%) as a foamy orange solid that was used directly; 58%) as a colourless oil; νmax(film)/cm−1 3320, 2940, 1630,
νmax(CHCl3)/cm−1 2950, 1680, 1620, 1450, 1310, 1200; δH 1550, 1300; δH 7.74–7.76 (2H, m, Ar-H). 7.38–7.41 (3H, m, Ar-H),
8.48–8.52 (2H, m, Ar-H), 7.79–7.83 (3H, m, Ar-H), 7.27–7.33 (5H, 6.75 (1H, br s, NH), 3.40 (2H, q, J = 6.5, NHCH2), 1.49–1.53 (4H,
m, Ar-H), 4.52–4.57 (6H, m, CH2NCH2CH2N), 3.15 (3H, s, CH3).
m, NCH2CH2), 0.9 (3H, t, J = 6, CH3); δC 167.6 (CO), 134.9 (Ar-
Benzoic acid (16a). 2-Benzoyl-1-benzyl-3-methyl-4,5-dihy- C), 131.0, 128.2, 126.9 (Ar-CH), 39.7 (NHCH2), 31.6, 20.0 (CH2),
droimidazolium iodide (745 mg, 1.91 mmol) was stirred at 13.6 (CH3); m/z 177 (M+, 16%), 135 (13), 134 (13), 105 (100),
20 °C in aqueous NaOH (2% w/v, 20 mL) for 4 h. The solution 77 (27). HRMS: M+ 177.1169; C11H15NO requires M+ 177.1154.
was washed with CHCl3 (25 mL), acidified using hydrochloric
Methyl benzoate (16f). 2-Benzoyl-1-benzyl-4,5-dihydroimida-
acid (5% w/v, 20 mL), and the acidic solution extracted with zole 11b (358 mg, 1.37 mmol) and ammonium acetate
CHCl3 (2 × 25 mL). The combined organic extracts were dried (115 mg, 1.49 mmol) were stirred in dry MeOH (10 mL) at
and concentrated under reduced pressure to yield the title com- 20 °C for 3 h before being concentrated under reduced
pound 16a (175 mg, 75%) as a colourless solid, mp 121–122 °C pressure, partitioned between CHCl3 (2 × 30 mL) and hydro-
(lit.,14 122 °C), identical with a commercial sample.
chloric acid (5% w/v, 30 mL). The combined organic extract
Ethyl benzoate (16b). 2-Benzoyl-1-benzyl-3-methyl-4,5-dihy- was dried and concentrated under reduced pressure to afford
droimidazolium iodide prepared from 2-benzoyl-1-benzyl-4,5- the title compound 16f (131 mg, 71%), identical to a commercial
dihydroimidazoline 11b (497 mg, 1.88 mmol) as described sample.
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Paper
1-Phenylpentan-1-one (13b). To 2-benzoyl-1-benzyl-3-methyl-
4,5-dihydroimidazolium iodide prepared from 2-benzoyl-1-
benzyl-4,5-dihydroimidazole 11b (365 mg, 1.38 mmol) as
described above, stirred under an atmosphere of nitrogen at
−78 °C in dry THF (15 mL), was added n-butyl-lithium (1.50 M
solution in hexanes; 1.10 mL, 1.66 mmol). After 30 min the
mixture was warmed to 20 °C before the addition of water
(2.0 mL) and partially concentration under reduced pressure.
The residue was partitioned between CHCl3 (2 × 30 mL) and
water (30 mL), the combined organic extract dried and concen-
trated under reduced pressure, and the residue purified by
column chromatography eluting with EtOAc to afford the title
compound (67 mg, 30%) as a colourless oil, identical to the
sample described above.
3 R. C. F. Jones and J. R. Nichols, Tetrahedron, 2013, 63, 4114.
4 H. Zhao, F. W. Foss and R. Breslow, J. Am. Chem. Soc., 2008,
130, 12590; R. Breslow, J. Am. Chem. Soc., 1957, 79, 1762;
R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
5 See for example: C. Samojlowicz, M. Bieniek and K. Greal,
Chem. Rev., 2009, 109, 3708; S. Diez-Gonzalez, N. Marion
and S. P. Nolan, Chem. Rev., 2009, 109, 3612.
6 For leading references, see: D. Enders, O. Niemeier and
A. Henseler, Chem. Rev., 2007, 107, 5606; E. M. Phillips,
T. E. Reynolds and K. A. Scheidt, J. Am. Chem. Soc., 2008,
130, 2417; V. Nair, S. Vellalath and B. P. Babu, Chem. Soc.
Rev., 2008, 37, 2691; C. D. Campbell, C. Concellon and
A. D. Smith, Tetrahedron: Asymmetry, 2011, 22, 797.
7 R. C. F. Jones and J. R. Nichols, Tetrahedron Lett., 1990, 31,
1771.
8 R. C. F. Jones, K. J. Howard, J. R. Nichols and J. S. Snaith,
J. Chem. Soc., Perkin Trans. 1, 1998, 2061.
Acknowledgements
9 For example: R. H. Garrett and C. M. Grisham, Biochemis-
try, Brooks/Cole, Boston, 2010, ch. 22, pp. 688–689.
10 For example: J. Clayden, N. Greeves and S. Warren,
Organic Chemistry, OUP, Oxford, 2nd edn, 2012, ch. 10,
pp. 198–213.
The authors thank EPSRC and AstraZeneca Pharmaceuticals
for support (J. R. N.) and Dr M. Cox for helpful discussions.
11 D. D. Perrin and W. F. Armarego, Purification of Laboratory
Chemicals, Pergamon Press, Oxford, 3rd edn, 1988.
12 W. G. Kofron and L. M. Baclawski, J. Org. Chem., 1976, 41,
1879.
13 CRC Handbook of Chemistry and Physics, ed. D. R. Lide, CRC
Press, 76th edn, 1995–1996, pp. 3–209.
Notes and references
1 R. C. F. Jones and P. Dimopoulos, Tetrahedron, 2000, 56,
2061; R. C. F. Jones, J. S. Snaith, M. W. Anderson and
M. J. Smallridge, Tetrahedron, 1997, 53, 1111; R. C. F. Jones
and J. Schofield, J. Chem. Soc., Perkin Trans. 1, 1990, 375;
R. C. F. Jones, M. J. Smallridge and C. B. Chapleo, J. Chem.
Soc., Perkin Trans. 1, 1990, 385.
14 CRC Handbook of Chemistry and Physics, ed. D. R. Lide, CRC
Press, 76th edn, 1995–1996, pp. 3–69.
15 Handbook of Fine Chemicals, Aldrich Chemical Company,
2009–2010, p. 254.
2 For leading references, see: R. C. F. Jones, Adv. Heterocycl.
Chem., 2010, 101, 125.
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