Coenzyme-inspired chemistry 1: The C-2 alkylation of 4,5-dihydroimidazoles

Article abstract of DOI:10.1016/j.tet.2013.03.040

Alkylation of 4,5-dihydroimidazoles at C-2 is accomplished using a double umpolung of the reactivity of that position, via sulfenylation of a nucleophilic C-2 lithio-species and substitution using an alkyl nucleophile. Arylation via unexpected sulfide con

Full text of DOI:10.1016/j.tet.2013.03.040

Tetrahedron 69 (2013) 4114e4119
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Coenzyme-inspired chemistry 1: the C-2 alkylation
of 4,5-dihydroimidazoles
,
b
Raymond C.F. Jones a , John R. Nichols
*
a Chemistry Department, Loughborough University, Loughborough, Leics LE11 3TU, UK
b Department of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkylation of 4,5-dihydroimidazoles at C-2 is accomplished using a double umpolung of the reactivity of
that position, via sulfenylation of a nucleophilic C-2 lithio-species and substitution using an alkyl nu-
cleophile. Arylation via unexpected sulfide contraction from the arylsulfenylation products has also been
demonstrated. Taken with dihydroimidazole cleavage protocols, this constitutes a tetrahydrofolate-
inspired C1-transfer protocol.
Received 27 November 2012
Received in revised form 20 February 2013
Accepted 11 March 2013
Available online 15 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dihydroimidazole
Alkylation
C1-transfer
Tetrahydrofolate
Coenzyme mimic
1. Introduction
members of FH4 coenzyme family mediate the transfer of single
carbons at the carbonyl and alcohol oxidation levels. The transfer
The use of C-2 ‘azolium’ ylides derived from N-heterocycles has
been of interest for many years, since the discovery by Breslow in
1957 of the involvement of a thiazolium C-2 ylide 1 in the mech-
anism of action of thiamine; the role of a carbene resonance form in
the ‘ylide’ stability was also soon recognised.1 Work by Wanzlick
and others around 1960 investigated similar properties in the
imidazolium system 2, which culminated in the isolation by
Arduengo in 1991 of a stable imidazolium-based carbene.2 This
interest has blossomed in recent years through the application of
related ylides as N-heterocyclic carbenes (NHCs), as ligands for
metals, for example, in metathesis catalysts,3 and in organocatalysis
via analogues of the Breslow intermediate in the thiamine mech-
anism, to provide, for example, carbonyl anions and homoenolate
anions.4
As part of our long-standing interest in the chemistry of
4,5-dihydroimidazole (2-imidazoline),5 we have been concerned
with the C-2 anion 3 derived from this heterocycle, rather than the
ylide/carbene 2. This attracted our interest as a mimic of the tet-
rahydrofolate (FH4) coenzyme N5,N10-methenyl-tetrahydrofolate 4
(5,10-CH]FH4), which mediates transfer of the C-2 carbon atom of
the dihydroimidazolium ring at the carboxyl oxidation level.6 Other
from 5,10-CH]FH4 uses C-2 of the dihydroimidazole sub-unit as an
electrophile, and we have exploited this polarity in methods using
simple dihydroimidazoles for transfer at the carboxyl and carbonyl
oxidation levels.7 We were interested to reverse this reactivity in an
umpolung and employ C-2 of a simple dihydroimidazole as a nu-
cleophile, as an extension of our work with laterally metallated
dihydroimidazole nucleophiles 58 and intrigued by the relationship
of a C-2 anion 3 to the ylide reactivity of NHCs.
PPO(CH2)2
Me
R
N
R
N
S
N
N
N
R
2
N
H2N N Me
1
3
CO2H
H
H2N
N
O
N
R
N
HN
HO2C
N
NH
O
CH2
N
N
5
4
We report here details of our investigation of a direct depro-
tonationealkylation approach using alkyl electrophiles, which was
only partially successful, a successful implementation of the C-2
nucleophile strategy by a sulfenylationealkylation sequence using
* Corresponding author. Tel.: þ44 1509 222557; fax: þ44 1509 223925; e-mail
address: r.c.f.jones@lboro.ac.uk (R.C.F. Jones).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.040

R.C.F. Jones, J.R. Nichols / Tetrahedron 69 (2013) 4114e4119
4115
alkyl nucleophiles rather than electrophiles, and C-2 arylation by an
unexpected sulfide contraction.9 These elaborations at C-2 of
a dihydroimidazole, taken with the cleavage of the ring by hydro-
lysis, complete a C1-transfer at the carboxylate oxidation level in-
spired by 5,10-CH]FH4; we have also reported a cleavage sequence
leading to ketones.7 The exploration of higher oxidation level
electrophiles, using dihydroimidazolium ylides as leaving groups,
will be reported separately.
With the unreliability of alkylation with electrophiles, we modi-
fied our strategy to utilise the nucleophilic lithio-dihydroimidazole 7
in conjunction with nucleophilic organometallic alkylating agents,
so a double umpolung of the inherent electrophilic reactivity of C-2
of dihydroimidazoles. We thus planned to use the nucleophilic C-2
species to provide an activated electrophilic C-2 for substitution. This
required a C-2 substituent available both as an electrophile and as
a nucleofugal leaving group. To meet these demands we selected the
phenylthio group, available as an electrophile in disulfides or sulfenyl
chlorides, and with leaving group potential as the phenylthiolate
anion. We were pleased to find that the 2-lithio dihydroimidazole 7
(R1¼CH2Ph) formed from 1-benzyl compound 6a reacted efficiently
with diphenyl disulfide to yield the 2-phenylthio compound 9a
(Scheme 1). When isolation of 9a was continued via aqueous
workup, the yield was moderate (56%) but also isolated was 1-
benzyltetrahydroimidazole-2-one 10 (25%), presumably derived by
adventitious hydrolysis during isolation. This process must involve
substitution of 2-phenylthio group by an oxygen nucleophile, so
supporting our choice of sulfenylation. Although tetrahy-
droimidazole 9a was unreactive towards Grignard nucleophiles, it
did react with n-BuLi (THF, ꢀ78 ꢁC) to displace the phenylthio group
and afford 1-benzyl-2-butyl-4,5-dihydroimidazole 11a in good yield
(70%) (Scheme 1).12 The distinctive value of arylthio as leaving group
in this sequence was apparent when di-n-butyl disulfide was used as
electrophile with 7 (R1¼CH2Ph) to prepare 2-butylthio compound 9b
(63%) with no observed hydrolysis to the imidazolone 10, but then 9b
proved inert towards n-butyl-lithium. There was no reaction of 7
(R1¼CH2Ph) with di-tert-butyl disulfide as electrophile.
2. Results and discussion
As substrates we prepared 1-benzyl-4,5-dihydroimidazole 6a
(from N-benzyl-1,2-diaminoethane and triethyl orthoformate or
dimethylformamide diethyl acetal, as previously reported).10 No C-2
proton exchange was observed in D2O solutions of 6a, whereas
treatment with n-BuLi (THF, ꢀ78 ꢁC) afforded an orange-red solution
that was quenched with D2O to show, in the 1H NMR spectrum of the
products taken before further work-up, the disappearance of the
signal at d 6.95 (1H, s) assigned to C-2(H) and no change in intensity
of other signals, confirming exclusive deprotonation at C-2. En-
couraged by this observation, we prepared the 1-(2-phenoxyethyl)-
and 1-(2-methoxyethyl)-4,5-dihydroimidazoles 6b (76%) and 6c
(50%), respectively, from the corresponding diamines and triethyl
orthoformate. We anticipated that these oxygen-containing N-1
substituents might assist lithiation by coordination.11 Deprotonation
at C-2 was observed as for the 1-benzyl compound 6a, however these
systems offered no advantage over 6a so studies were continued
largely using this 1-benzyl-4,5-dihydroimidazole.
R1
N
R1
N
HO2C R2
CH2Ph
N
CH2Ph
CH2Ph
Li
i
ii
N
N
R3
SR1
R2
N
N
7
O C R2
6a; R1 = CH2Ph
N
6a
N
N
9a; R1 = Ph
6b; R1 = CH2CH2OPh
6c; R1 = CH2CH2OMe
11a; R2 = (CH2)3Me
11b; R2 = (CH2)7Me
11c; R2 = Ph
9b; R1 = (CH2)3Me
9c; R
1 = 4-MeC6H4
R1
11d; R2 = 2-furyl
N
CH2Ph
R2
N
CH2Ph
N
O
iii
8a; R1 = CH2Ph, R2 = Me
N
R1
N
H
8b; R1 = CH2CH2OMe, R2 = Me
8c; R1 = CH2CH2OMe, R2 = Et
(from 9a)
N
10
11c; R1 = Ph
12; R1 = 4-MeC6H4
Initial attempts at direct alkylation of the presumed lithio-
dihydroimidazoles 7 with simple haloalkane alkyl electrophiles
offered mixed success. Deprotonation of 6a as described above with
n-BuLi, followed by reaction with iodomethane led to the corre-
sponding 2-methyl derivative 8a (50%). Similar treatment of the 1-
(2-methoxyethyl) heterocycle 6c afforded the 2-methyl compound
8b (34%); in addition a low yield of the 2-ethyl material 8c (7%) was
Scheme 1. Reagents: i, n-BuLi, ꢀ78 ꢁC, THF; R1SSR1; ii, R2Li, ꢀ78 ꢁC, THF; iii, 2 sec-BuLi,
ꢀ78 ꢁC, THF.
We have reported elsewhere on an alternative approach to
1-benzyl-2-methylthio-4,5-dihydroimidazoles by reacting N-ben-
zyl-1,2-diaminoethane with 1,10-thiocarbonyldiimidazole to give
1-benzyl-2,3,4,5-tetrahydroimidazol-2-thione, followed by S-al-
kylation with iodomethane,13 but this is clearly not applicable to
2-phenylthio compound 9a.
In order to avoid the losses of 2-phenylthiodihydroimidazole 9a
due to hydrolysis during isolation and to generate a direct C-2 al-
kylation protocol, the sulfenylation and substitution were tele-
scoped and performed in a one-pot protocol. Thus 1-benzyl-4,5-
dihydroimidazole 6a was treated in succession with n-BuLi and
diphenyl disulfide (THF, ꢀ78 ꢁC), the solution warmed to 20 ꢁC to
complete sulfenylation and then recooled to ꢀ78 ꢁC before addition
of an alkyl-lithium. The sequence was completed by conventional
work-up and chromatography, and used to prepare the 2-butyl-, 2-
octyl- and 2-phenyl-4,5-dihydroimidazoles 11aec (72, 76 and 52%,
respectively, based on 6a). 2-Furyl compound 11d was also pre-
pared in a low, unoptimised yield.
also recovered indicating a lateral
proton-exchange of the 2-methyl group of the first-formed 8b with
the corresponding 2-lithio derivative 7, followed by an -methyl-
a-deprotonation, presumably by
a
ation before the desired C-2 alkylation was complete.11 The use of
haloalkanes other than the reactive iodomethane was unsuccessful,
and there was no improvement by addition of dipolar aprotic sol-
vent (HMPA), or by changing to toluene-4-sulfonate or trifluoro
methanesulfonate electrophiles. Alkylation of 6a was successful
with dimethyl sulfate to produce 8a (60%) but this did not translate
to other dialkyl sulfates. Transmetallation from lithium with pen-
tynylcopper or chlorotitanium triisopropoxide did not improve the
alkylation, and 2-triakylsilyl or 2-trialkylstannyl derivatives (po-
tential masked carbanions) were not recovered from reaction of 7
(R1¼CH2Ph) with chlorosilanes or -stannanes.

4116
R.C.F. Jones, J.R. Nichols / Tetrahedron 69 (2013) 4114e4119
An unexpected result was observed when we attempted to ex-
spectrometers as indicated: PerkineElmer 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 de-
termined in CDCl3 solution and chemical shifts dC quoted in parts
per million (ppm) from TMS as internal standard. Coupling con-
stants J are quoted in hertz with multiplicities: s-singlet, d-doublet,
t-triplet, q-quartet, m-multiplet and br-broad. 13C NMR spectra
were determined in CDCl3 solution and chemical shifts dC quoted in
ppm from TMS as internal standard or from TMS using CDCl3 as
internal standard. 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 60e80 ꢁ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.15 Alkyl-lithiums were
standardised by the diphenylacetic acid method.16
tend this protocol to a secondary alkyl-lithium. Treatment of the 2-
phenylthio compound 6a with sec-BuLi (2 mol equiv, THF, ꢀ78 ꢁC)
did not give a substitution product but afforded 1-benzyl-2-phenyl-
4,5-dihydroimidazole 11c (69%) (Scheme 1). This suggested that the
phenylthio compound had undergone a sulfur extrusion. We next
prepared the 2-(4-methylphenyl)thio-4,5-dihydroimidazole 9c
(55%) from the 2-H compound 6a by lithiation and sulfenylation (n-
BuLi, THF, ꢀ78 ꢁC; bis(4-methylphenyl) disulfide); some urea 10 was
again also isolated (21%). Sulfide contraction of 9c using sec-BuLi as
above gave 1-benzyl-2-(4-methylphenyl)-4,5-dihydroimidazole 12
(46%). The position of the methyl substitution could be easily de-
termined by from the diagnostic doublet signals (J¼7) for a 1,4-
disubstituted benzene in the 1H NMR spectrum at
each 2H.
d 7.3 and 7.5,
The regiospecific nature of this sulfide contraction leads us to
suggest the mechanism outlined in Scheme 2. We propose a single
electron transfer from the secondary alkyl-lithium to the C-2 sub-
stituent aryl ring to afford a radical anion in a process analogous to
the Birch reduction.14 In the absence of a proton source, the radical
anion can rearrange to an episulfide, thus transferring the negative
charge to an electronegative nitrogen atom. A further one-electron
reduction and aromatisation by expulsion of the sulfur atom leads
to an N,S-dianion that on aqueous work-up we propose will un-
dergo protonation and elimination of H2S to regenerate the dihy-
droimidazole ring.
4.2. Preparation of dihydroimidazoles (6)
4.2.1. 1-Benzyl-4,5-dihydroimidazole (6a). N-Benzyl-1,2-diaminoe
thane (42.9 g, 0.290 mol), triethyl orthoformate (169 g, 1.14 mol)
and toluene-4-sulfonic acid (1.00 g, 5.75 mmol) were heated to-
gether under reflux for 20 h. The cooled solution was basified with
aqueous NaOH solution (5% w/v, 50 mL) and extracted with CHCl3
(2ꢂ250 mL). The organic extracts were dried and concentrated un-
der reduced pressure and the residue was distilled to afford to afford
the title compound 6a (34.3 g, 75%) as a colourless oil that solidified
on standing, mp 45e46 ꢁC having data as reported.10
4.2.2. 1-(2-Phenoxyethyl)-4,5-dihydroimidazole (6b). 2-Bromoethyl
phenyl ether (21.1 g, 0.105 mol) was added dropwise to 1,2-
diaminoethane (32.0 g, 0.520 mol) and the mixture heated under
reflux for 8 h. The cooled mixture was extracted with ether
(2ꢂ200 mL) and the organic extracts were dried, concentrated
under reduced pressure and the residue was distilled to afford N-
(2-phenoxyethyl)-1,2-diaminoethane (13.7 g, 72%) as a colourless
oil, bp 126 ꢁC at 1.5 mmHg; nmax (film)/cmꢀ1 3300, 3020, 2930,
1600, 1490, 1460, 1250, 1050, 750; dC 7.30e7.34 (2H, m, AreH),
6.94e6.96 (3H, m, AreH), 4.02 (2H, t, J¼5.5, OCH2), 2.95 (2H, t,
J¼5.5, NCH2), 2.70e2.73 (4H, m, NCH2CH2N), 1.31 (3H, s, NH, NH2);
m/z (Mþ not present) 150 (100%), 121 (14), 94 (10), 66 (36), 77 (24),
56 (76), 44 (73). N-(2-Phenoxyethyl)-1,2-diaminoethane (13.0 g,
72.5 mmol) was treated with triethyl orthoformate and toluene-4-
sulfonic acid according to the method described above for the
preparation of 6a to afford the title compound 6b (10.5 g, 76%) as
a colourless oil after distillation, bp 160 ꢁC at 2.5 mmHg; nmax (CCl4)/
cmꢀ1 3040, 2970, 2930, 1600, 1220, 1050; dC 7.33e7.36 (2H, m,
AreH), 6.90e6.94 (4H, m, AreH, 2-CH), 4.11 (2H, t, J¼5.3, OCH2),
3.78 (2H, t, J¼9.2, NCH2CH2N), 3.52 (2H, t, J¼5.3, OCH2CH2), 3.30
(2H, t, J¼9.2, NCH2CH2N); dC 158.4, 157.6 (AreC), 129.5, 121.2, 114.6
(AreCH), 66.1 (OCH2), 55.2, 47.0, 46.7 (CH2); m/z 190 (Mþ, 49%), 63
(100), 77 (12), 56 (69). HRMS: Mþ 190.1112; C11H14N2O requires Mþ
190.1106.
Scheme 2. Proposed mechanism for sulfide contraction of 2-arylthio-4,5-
dihydroimidazoles using sec-BuLi.
3. Conclusions
We have therefore discovered a route to the alkylation of 4,5-
dihydroimidazoles at C-2 (unreliable using direct methods) using
a double umpolung of the inherent reactivity of that position, via
sulfenylation of a nucleophilic C-2 lithio-species and substitution
using an alkyl nucleophile. Arylation via an unexpected sulfide
contraction from the arylsulfenylation products has also been
demonstrated. When these 2-(aryl/alkyl)-4,5-dihydroimidazoles
are cleaved as we have reported, to carboxylic acids or ketones,
this completes a single-carbon transfer that mimics the tetrahy-
drofolate coenzyme family. Our studies using higher oxidation level
electrophiles, that mimic the actions of thiamine, will be reported
separately.
4.2.3. 1-(2-Methoxyethyl)-4,5-dihydroimidazole (6c). The method
described above for preparation of N-(2-phenoxyethyl)-1,2-
diaminoethane was followed, but using 2-chloroethyl methyl
ether (14.0 g, 0.150 mol) and 1,2-diaminoethane (30.0 g, 0.60 mol)
to afford N-(2-methoxyethyl)-1,2-diaminoethane (14.6 g, 83%) as
a colourless oil after distillation, bp 66 ꢁC at 2 mmHg; nmax (film)/
cmꢀ1 3300, 2880,1460,1115; dC 3.55 (2H, t, J¼5.3, OCH2), 3.42 (3H, s,
CH3), 3.28e3.35 (6H, m, CH2NCH2CH2N), 1.35 (3H, s, NH, NH2); m/z
(Mþ not present) 88 (100%), 73 (17), 59 (26), 44 (51). N-(2-
Methoxyethyl)-1,2-diaminoethane (11.8 g, 0.100 mol) was treated
4. Experimental section
4.1. General
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 spectrometers.
Mass spectra were recorded using AEI MS902 or VG 7070E spec-
trometers. 1H NMR spectra were obtained using the following

R.C.F. Jones, J.R. Nichols / Tetrahedron 69 (2013) 4114e4119
4117
with triethyl orthoformate (59.2 g, 0.400 mol) and toluene-4-
sulfonic acid (0.350 g, 2.00 mmol) according to the method de-
scribed above for the preparation of 6a to afford the title compound
6c (6.89 g, 50%) as a colourless oil after distillation, bp 84 ꢁC at
0.5 mmHg; nmax (film)/cmꢀ1 2920, 2860, 1600, 1200, 1120; dC 6.95
(1H, s, 2-CH), 3.91 (2H, t, J¼9.0, NCH2CH2N), 3.35e3.43 (9H, m,
CH3OCH2CH2N, NCH2CH2N); dC 157.8 (C-2), 70.75 (OCH3), 58.8, 55.0,
49.0, 47.3 (CH2); m/z 128 (Mþ, 28%), 101 (13), 88 (25), 83 (100), 56
(55). HRMS: Mþ 128.0947; C6H12N2O requires Mþ 128.0950.
pressure and partitioned between CHCl3 (2ꢂ50 mL) and water
(50 mL). The combined organic extracts were dried, concentrated
under reduced pressure and the residue was purified by column
chromatography eluting with CHCl3/2-aminopropane (99.5:0.5 v/v)
to afford the title compound 9a (2.05 g, 56%) as a colourless oil; nmax
(film)/cmꢀ1 3060, 2950, 2860, 1560, 1160, 1030, 750, 705; dC
7.58e7.62 (2H, m, AreH), 7.25e7.35 (8H, m, AreH), 4.35 (2H, s,
CH2Ph), 3.69e3.71, 3.24e3.26 (each 2H, m, NCH2CH2N); dC 162.7 (C-
2), 136.5, 133.4 (AreC), 128.4, 128.2, 128.0, 127.2, 127.1, 126.9
(AreCH), 52.9, 51.0, 50.0 (CH2); m/z 268 (Mþ, 36%), 267 (92), 207
(15), 121 (23), 91 (100), 65 (21), 51 (82). HRMS: Mþ 268.1027;
C16H16N2S requires Mþ 268.1034. Also isolated was 1-benzyl-
2,3,4,5-tetrahydroimidazol-2-one 10 (0.60 g, 25%) as a colourless
needles, mp 129e130 ꢁC (lit.12 mp 124e127 ꢁC); nmax (KBr)/cmꢀ1
3350, 2980,1720,1520,1220,1040, 710; dC 7.37e7.43 (5H, m, AreH),
6.10 (1H, br s, NH), 4.45 (2H, s, CH2Ph), 3.38e3.43 (4H, m,
NCH2CH2N); dC 162.9 (CO), 136.9 (AreC), 128.2, 127.6, 127.0
(AreCH), 47.3, 44.2, 37.7 (CH2); m/z 176 (Mþ, 87%), 175 (23), 147
(25), 105 (14), 104 (34), 99 (24), 91 (100), 85 (26), 65 (26), 51 (10).
HRMS: Mþ 176.0946; C10H12N2O requires Mþ 176.0950.
4.3. C-2 Alkylation products (8)
4.3.1. 1-Benzyl-2-methyl-4,5-dihydroimidazole (8a)
4.3.1.1. Method A. n-Butyl-lithium (1.42 M solution in hexanes;
7.00 mL, 10.0 mmol) was added dropwise to a solution of 1-benzyl-
4,5-dihydroimidazole 6a (1.60 g, 10.0 mmol) in dry THF (50 mL),
precooled to ꢀ78 ꢁC under an atmosphere of nitrogen. After 20 min
at this temperature, iodomethane (1.42 g, 10.0 mmol) was added
dropwise and the mixture was allowed to warm to 20 ꢁC and stirred
for a further 4 h. The mixture was concentrated under reduced
pressure, the residue was partitioned between CHCl3 (50 mL) and
water (50 mL) and the organic layer was dried and concentrated
under reduced pressure to afford, after Kugelrohr distillation, the
title compound 8a (0.87 g, 50%) as a pale yellow oil, bp 120 ꢁC (oven
temperature) at 2 mmHg (lit.,17 bp 102e106 ꢁC at 1 mmHg); nmax
(film)/cmꢀ1 2920, 2850, 1600, 1430, 1270, 940, 740, 710; dC
7.2.9e7.31 (5H, m, AreH), 4.30 (2H, s, CH2Ph), 3.75, 3.25 (each 2H, t,
J¼8.9, NCH2CH2N), 2.01 (3H, s, CH3). HRMS: Mþ 174.1151; C11H14N2
requires Mþ 174.1157.
4.4.2. 1-Benzyl-2-butylthio-4,5-dihydroimidazole (9b). Compound
(9b) was prepared by the method described above for the prepa-
ration of 9a but using 1-benzyl-4,5-dihydroimidazole 6a (1.00 g,
6.25 mmol) and di-n-butyl disulfide (1.23 g, 6.87 mmol) to afford
the title compound 9b (0.98 g, 63%) as a pale yellow oil; nmax (film)/
cmꢀ1 3030, 2960, 2930, 2860, 1565, 1460, 1300, 1190, 710; dC
7.22e7.28 (5H, m, AreH), 4.25 (2H, s, CH2Ph), 3.75 (2H, t, J¼9.0,
NCH2CH2N), 3.16e3.24 (4H, m, NCH2CH2N, SCH2), 1.52e1.58 (4H, m,
CH2CH2CH3), 0.90 (3H, t, J¼7.1, CH3); dC 164.6 (C-2), 137.2 (AreC),
128.4, 127.6, 127.2 (AreCH), 53.2, 51.2, 50.7, 31.3, 31.2, 21.8 (CH2),
13.5 (CH3); m/z 248 (Mþ, 6%), 192 (100), 191 (53), 159 (15), 91 (47),
44 (11). HRMS: Mþ 248.1343; C14H20N2S requires Mþ 248.1347.
4.3.1.2. Method B. Performed according to method A described
above but using 1-benzyl-4,5-dihydroimidazole 6a (0.62 g,
3.88 mmol) in dry THF (30 mL), n-butyl-lithium (1.50 M solution in
hexanes; 2.78 mL, 4.16 mmol) and dimethyl sulfate (0.525 g,
4.16 mmol), purification by column chromatography eluting with
CHCl3/2-aminopropane (99.5:0.5 v/v) afforded the title compound
8a (0.41 g, 60%) as a colourless oil identical to a sample prepared by
method A.
4.4.3. 1-Benzyl-2-(4-methylphenyl)-4,5-dihydroimidazole
(9c). Compound (9c) was prepared by the method described above
for the preparation of 9a but using 1-benzyl-4,5-dihydroimidazole
6a (0.770 g, 4.81 mmol) and di-(4-methylphenyl) disulfide (1.30 g,
5.30 mmol) to afford the title compound 9c (0.74 g, 55%) as a pale
yellow oil; dC 7.45 (2H, d, J¼7, AreH), 7.23e7.27 (5H, m, AreH), 7.10
(2H, J¼7, AreH), 4.30 (2H, s, CH2Ph), 3.65, 3.15 (each 2H, t, J¼9.2,
NCH2CH2N), 2.3 (3H, s, CH3); dC 153.3 (C-2), 133.8, 137.0, 125.0
(AreC),134.3,129.7,128.3,127.5,127.2 (AreCH), 53.3, 51.4, 50.6 (CH2),
20.9 (CH3); m/z 282 (Mþ, 22%), 281 (31), 246 (100), 161 (18),123 (98),
91 (99), 83 (19), 77 (20), 65 (16). HRMS: Mþ 282.1180; C17H18N2S
requires Mþ 282.1191. Also isolated was 1-benzyl-2,3,4,5-
tetrahydroimidazol-2-one 10 (0.18 g, 21%) identical to the sample
described above.
4.3.2. 1-(2-Methoxyethyl)-2-methyl-4,5-dihydroimidazole
(8b). Compound (8b) was prepared by method A described above
for the preparation of 8a but using 1-(2-methoxyethyl)-4,5-
dihydroimidazole 6c (2.61 g, 20.0 mmol), n-butyl-lithium (1.40 M
solution in hexanes; 16.5 mL, 23.0 mmol) and iodomethane (3.20 g,
22.0 mmol). Column chromatography eluting with CHCl3/2-
aminopropane (99.5:0.5 v/v) afforded the title compound 8b
(1.01 g, 34%) as a colourless oil that was not further purified; nmax
(film)/cmꢀ1 2940, 2860, 1650, 1600, 1400, 1200, 1120; dC 3.36e3.42
(11H, m, CH3OCH2CH2N, NCH2CH2N), 2.00 (3H, s, CH3). Also isolated
was 1-(2-methoxyethyl)-2-ethyl-4,5-dihydroimidazole 8c (0.20 g,
7%) that was not further purified; dC 3.37e3.43 (11H, m,
CH3OCH2CH2N, NCH2CH2N), 2.24 (2H, q, J¼7.5, CH2CH3), 1.20 (3H, t,
J¼7.5, CH2CH3).
4.5. 1-Benzyl-2-butyl-4,5-dihydroimidazole (11a)
To a solution of 1-benzyl-2-phenylthio-4,5-dihydroimidazole 9a
(0.710 g, 2.65 mmol) in dry THF (15 mL) cooled to ꢀ78 ꢁC under an
atmosphere of nitrogen, was added n-butyl-lithium (1.47 M solu-
tion in hexanes; 2.00 mL, 2.92 mmol). The mixture was stirred at
this temperature for 2 h, the reaction was quenched by the addition
of water (0.5 mL) and allowed to warm to 20 ꢁC. The mixture was
partitioned between CHCl3 (2ꢂ30 mL) and water (30 mL), the
combined organic extracts were dried and concentrated under re-
duced pressure and the residue was purified by column chroma-
tography eluting with CHCl3/2-aminopropane (99.5:0.5 v/v) to
afford the title compound 11a (0.40 g, 70%) as a colourless oil; nmax
(film)/cmꢀ1 3040, 2950, 1610, 1450, 1420, 1250, 750; dC 7.23e7.27
(5H, m, AreH), 4.25 (2H, s, CH2Ph), 3.70, 3.15 (each 2H, t, J¼9.1,
NCH2CH2N), 2.30 (2H, t, J¼7.0, CH2), 1.46e1.52 (4H, m, CH2CH2CH3),
0.90 (3H, t, J¼7.1, CH3); dC 167.1 (C-2), 137.9 (AreC), 128.7, 127.3,
4.4. 2-Aryl- and 2-alkylthiodihydroimidazoles (9)
4.4.1. 1-Benzyl-2-phenylthio-4,5-dihydroimidazole
(9a). To
1-
benzyl-4,5-dihydroimidazole 6a (2.18 g, 13.6 mmol) in dry THF
(30 mL) stirred at ꢀ78 ꢁC under an atmosphere of nitrogen was
added n-butyl-lithium (1.5 M solution in hexanes; 9.75 mL,
14.6 mmol). After 20 min diphenyl disulfide (3.20 g, 14.6 mmol) in
dry THF (5 mL) was added dropwise and the mixture was main-
tained at ꢀ78 ꢁC for 2 h, then allowed to warm to 20 ꢁC, stirred for
a further 30 min and the reaction was quenched by the addition of
water (2 mL). The mixture was concentrated under reduced

4118
R.C.F. Jones, J.R. Nichols / Tetrahedron 69 (2013) 4114e4119
127.2 (AreCH), 52.2, 50.8, 50.3 (CH2N), 28.7, 27.6, 22.6 (CH2), 13.8
(CH3); m/z (Mþ, 19%), 187 (18), 175 (10), 174 (80), 173 (100), 91 (98),
65 (15), 56 (11), 42 (11). HRMS: Mþ 216.1627; C14H20N2 requires Mþ
216.1626.
FureH), 7.28e7.32 (5H, m, AreH), 6.90 (1H, d, J¼3.3, FureH), 6.45
(1H, dd, J¼3.3. 1.1, FureH), 4.60 (2H, s, CH2Ph), 3.90, 3.40 (each 2H, t,
J¼8.8, NCH2CH2N); dC 157.2 (C-2), 145.7 (FureC), 143.6 (FureCH),
138.1 (AreC), 128.7, 127.4, 127.2 (AreCH), 113.0, 111.3 (FureCH),
53.4, 52.3, 51.3 (CH2); m/z 226 (Mþ, 50%), 225 (11), 135 (15), 108
(26), 107 (36), 91 (100), 65 (14). HRMS: Mþ 226.1102; C14H14N2O
requires Mþ 226.1106.
4.6. One-pot C-2 alkylation of 1-benzyl-4,5-dihydroimidazole
(6a)
4.6.1. 1-Benzyl-2-butyl-4,5-dihydroimidazole (11a). To 1-benzyl-
4,5-dihydroimidazole 6a (0.750 g, 4.68 mmol) in dry THF (30 mL)
stirred at ꢀ78 ꢁC under an atmosphere of nitrogen was added n-
butyl-lithium (1.47 M solution in hexanes; 3.20 mL, 4.68 mmol).
After 20 min diphenyl disulfide (1.02 g, 4.68 mmol) in dry THF
(5 cm3) was added dropwise and the solution was maintained at
ꢀ78 ꢁC for 1 h then allowed to warm to 20 ꢁC, stirred for a further
10 min and cooled to ꢀ78 ꢁC before n-butyl-lithium (1.47 M solu-
tion in hexanes; 3.50 mL, 5.16 mmol) was added dropwise and the
mixture stirred for a further 1.5 h at ꢀ78 ꢁC. The mixture was
allowed to warm to 20 ꢁC, the reaction was quenched by the ad-
dition of water (2.0 mL) and concentrated under reduced pressure.
The residue was partitioned between CHCl3 (2ꢂ75 mL) and water
(75 mL) and the combined organic extracts were dried and con-
centrated under reduced pressure. The crude product was purified
by column chromatography eluting with CHCl3/2-aminopropane
(99.25:0.75 v/v) to afford the title compound 11a (0.73 g, 72%) as
pale yellow oil, identical to the sample described above.
4.7. Sulfur extrusion reactions using sec-butyl-lithium
4.7.1. 1-Benzyl-2-phenyl-4,5-dihydroimidazole (11c). To 1-benzyl-
2-phenylthio-4,5-dihydroimidazole 9a (450 mg, 1.68 mmol) in dry
THF (10 mL) stirred at ꢀ78 ꢁC under an atmosphere of nitrogen was
added sec-butyl-lithium (1.40 M solution in cyclohexane; 2.60 mL,
3.67 mmol). The mixture was maintained at ꢀ78 ꢁC for 1.5 h,
allowed to warm to 20 ꢁC and stirred for a further 5 min when the
reaction was quenched by the addition of water (2.0 mL) and the
mixture was partitioned between CHCl3 (2ꢂ50 mL) and water
(50 mL). The combined organic extracts were dried, concentrated
under reduced pressure and the residue was purified by column
chromatography eluting with CHCl3/2-aminopropane (99.5:0.5 v/v)
to afford the title compound 11c (274 mg, 69%) as a colourless solid
identical to the sample described above.
4.7.2. 1-Benzyl-2-(4-methylphenyl)-4,5-dihydroimidazole
(12). Compound (12) was prepared using the method described
above for the preparation of 11c but using 1-benzyl-2-(4-
methylphenylthio)-4,5-dihydroimidazole (492 mg, 1.74 mmol)
and sec-butyl-lithium (1.40 M solution in cyclohexane; 2.75 mL,
3.88 mmol) to afford the title compound 12 (198 mg, 46%) as a pale
yellow waxy solid; nmax (film)/cmꢀ1 3040, 290, 2880, 1605, 1410,
1285, 1260, 1020, 845, 760; dC 7.50 (2H, d, J¼7.0, AreH), 7.28e7.32
(2H, d, J¼7.0, & 5H, m, AreH), 4.25 (2H, s, CH2Ph), 3.90, 3.30 (each
2H, t, J¼9.0, NCH2CH2N), 2.35 (3H, s, CH3); dC 167.3 (C-2), 139.7,
138.1, 128.3 (AreC), 129.0, 123.5, 128.0, 127.1, 126.0 (AreCH), 53.2,
53.1, 50.9 (CH2), 21.2 (CH3); m/z 250 (Mþ, 72%), 249 (22), 131 (100),
91 (93), 65 (12). HRMS: Mþ 250.1461; C17H18N2 requires M,
250.1470.
4.6.2. 1-Benzyl-2-octyl-4,5-dihydroimidazole
(11b). Compound
(11b) was prepared using the method described above for the ‘one-
pot’ preparation of 11a but using 1-benzyl-4,5-dihydroimidazole 6a
(0.750 g, 4.68 mmol) and n-octyl-lithium (0.41 M solution in pen-
tane; 16.0 mL, 6.55 mmol) to afford after column chromatography
eluting with CHCl3/2-aminopropane (99.5:0.5 v/v), the title com-
pound 11b (0.97 g, 76%) as a colourless oil; nmax (film)/cmꢀ1 3040,
2940, 2860, 1670, 1610, 1460, 1420, 1250, 740; dC 7.27e7.32 (5H, m,
AreH), 4.30 (2H, s, CH2Ph), 3.70, 3.20 (each 2H, t, J¼8.9, NCH2CH2N),
2.30 (2H, t, J¼7.0, CH2), 1.26e1.34 (12H, m, 6ꢂ CH2), 0.90 (3H, t,
J¼7.1, CH3); dC 166.4 (C-2),137.3 (AreC), 128.0, 126.8,126.6 (AreCH),
51.6, 50.2, 49.7, 31.2, 28.9, 28.7, 28.6, 27.3, 26.0, 22.0 (CH2), 13.5
(CH3); m/z 272 (Mþ, 19%), 229 (23), 188 (17), 187 (17), 174 (96), 173
(89), 120 (10), 91 (100), 83 (10), 51 (10). HRMS: Mþ 272.2254;
C18H28N2 requires Mþ 272.2252.
Acknowledgements
The authors thank EPSRC and AstraZeneca Pharmaceuticals for
support (J.R.N.) and Dr. M. Cox for helpful discussions.
4.6.3. 1-Benzyl-2-phenyl-4,5-dihydroimidazole
(11c). Compound
(11c) was prepared using the method described above for the ‘one-
pot’ preparation of 11a but using 1-benzyl-4,5-dihydroimidazole 6a
(0.750 g, 4.68 mmol) and phenyl-lithium (1.70 M solution in cy-
clohexane/ether; 8.80 mL, 15.0 mmol) to afford after column
chromatography eluting with CHCl3/2-aminopropane (99.25:0.75
v/v), the title compound 11c (1.52 g, 52%) as a colourless solid, mp
64e65 ꢁC; dC 7.70e7.72 (2H, m, AreH), 7.38e7.42 (8H, m, AreH),
4.30 (2H, s, CH2Ph), 3.95, 3.40 (each 2H, t, J¼9.0, NCH2CH2N); dC
166.7 (C-2), 137.6, 131.0 (AreC), 129.3, 128.1, 127.9, 127.6, 126.8,
126.6 (AreCH), 53.0, 52.6, 50.6 (CH2); m/z 236 (Mþ, 53%), 235 (12),
117 (100), 91 (50), 77 (16). HRMS: Mþ 236.1319; C16H16N2 requires
Mþ 236.1313.
References and notes
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4.6.4. 1-Benzyl-2-(2-furyl)-4,5-dihydroimidazole (11d). Compound
(11d) was prepared using the method described above for the ‘one-
pot’ preparation of 11a but using 1-benzyl-4,5-dihydroimidazole 6a
(1.00 g, 6.25 mmol) and 2-furyl-lithium prepared from furan
(0.638 g, 9.38 mmol) and n-butyl-lithium (1.40 M solution in hex-
anes; 6.70 mL, 9.38 mmol) in dry THF (25 mL) to afford after column
chromatography eluting with CHCl3/2-aminopropane (99.5:0.5 v/
v), the title compound 11d (0.15 g, 11%) as a colourless oil; nmax
(CHCl3)/cmꢀ1 2920, 1580, 1410, 1200, 1030; dC 7.48 (1H, d, J¼1.1,
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A. R.; Rewcastle, G. W.; Fan, W.-Q. J. Org. Chem. 1988, 53, 5685 and refs. therein.

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