Facile conversion of amino acids into 1-alkyl imidazole-2-thiones, and their oxidative desulfurization to imidazoles with benzoyl peroxide

Article abstract of DOI:10.1055/s-2007-983740

Glycine was acylated with isothiocyanates and condensed to 3-alkyl 2-thiohydantoins, which were reduced with a mixture of sodium borohydride and lithium chloride and dehydrated to 1-alkyl imidazole-2-thiones. These were oxidatively desulfurized to imidazoles with benzoyl peroxide. No chromatography was required for model compounds. The methods developed were used to elaborate tyrosine to 1,4-di(p-methoxybenzyl)imidazole, a common intermediate in the syntheses of three imidazoles from the sponge Leucetta. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983740

2002
PAPER
Facile Conversion of Amino Acids into 1-Alkyl Imidazole-2-thiones, and Their
Oxidative Desulfurization to Imidazoles with Benzoyl Peroxide
O
xidative Desulf
u
e
rization of
I
midazol
e
e-2-thiones
k
w
ith Benzoyl Pero
M
xide . Wolfe,a,b Peter R. Schreiner*a,b
a
Institut für Organische Chemie, Justus-Liebig-Universität, Heinrich-Buff-Ring 58, 35392 Gießen, Germany
Fax +49(641)9934309; E-mail: prs@org.chemie.uni-giessen.de
b
Department of Chemistry, University of Georgia, 1001 Cedar St., Athens, GA 30602, USA
Fax +1(706)5429454; E-mail: prs@chem.uga.edu
Received 29 March 2007; revised 2 May 2007
The I2T reagent is classically prepared by acylation of an
a-amino ketone or a 2-amino acetal with a thiocyanate,
followed by cyclization of the intermediate.3,4,16–18 This
entry to an I2T and oxidative desulfurization of it (with
Abstract: Glycine was acylated with isothiocyanates and con-
densed to 3-alkyl 2-thiohydantoins, which were reduced with a mix-
ture of sodium borohydride and lithium chloride and dehydrated to
1-alkyl imidazole-2-thiones. These were oxidatively desulfurized to
imidazoles with benzoyl peroxide. No chromatography was re- nitric acid) dates back at least to Marckwald’s 1892 re-
port.19 Alternative I2T syntheses include condensation of
quired for model compounds. The methods developed were used to
thioureas with a-hydroxycarbonyls,20 and metal hydride
elaborate tyrosine to 1,4-di(p-methoxybenzyl)imidazole, a common
intermediate in the syntheses of three imidazoles from the sponge
reduction of an a-thioureido ester21 or a 2-thiohydantoin
Leucetta.
(2TH)22 followed by dehydration of the intermediate.
Key words: desulfurization, heterocycles, imidazoles, natural
The classical preparation of 2-thiohydantoins (2THs) is
identical in concept to that of I2Ts; acylation of an a-ami-
products, oxidation
no ester or acid with a thiocyanate is followed by cycliza-
tion of the intermediate.22–28 This reaction also traces back
Imidazole-2-thiones (I2Ts, Scheme 1)1,2 undergo oxida-
at least as far as Marckwald and co-workers.29 More re-
tive desulfurization with acidic hydrogen peroxide,3–8
cently it became famous as the basis of the Edman degra-
MCPBA,9 dimethyldioxirane,10 iron(III) chloride,11 and
dation, wherein the unmasked N-terminus of a peptide is
acylated with a thiocyanate; cyclization at the resultant a-
thioureido amide terminus expels a 2TH and a peptide
nitric acid.12–14 Oxidation of 1,3-dialkyl I2Ts by these
methods delivers 1,3-dialkylimidazolium salts, whereas
1-alkyl I2Ts yield neutral imidazoles after work-up. Re-
ductive desulfurization of 1-alkyl I2Ts to neutral imida-
zoles is typically accomplished with Raney nickel.3,15
shortened by one amino acid residue.30 Recent examples
of alternative 2TH syntheses include the reaction of a-
isothiocyanato esters with amines followed by cycliza-
R1HN
R4
NHR2
R3
2
R1
R2
N
R4
N
2
A
R3
O
OH
R3
S
S
R4
R1
R2
R2(1) = H
R1
R2
N
N
N
H
N
H
R3 = R4
R4
R3
I2T
R1(2)
S
N
N
R2
C
N
R4(3)
R3(4)
R1 NH
R4
Z
X
X = OR, Z = O (after [H] / deH2O, R3 = H)
X = R3, Z = (OR)2
X = R3, Z = O
Scheme 1 Major routes to and from I2Ts
SYNTHESIS 2007, No. 13, pp 2002–2008
x
x.
x
x
.
2
0
0
7
Advanced online publication: 18.06.2007
DOI: 10.1055/s-2007-983740; Art ID: T06007SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Oxidative Desulfurization of Imidazole-2-thiones with Benzoyl Peroxide
2003
tion,28,31,32 condensation of thioureas with 1,2-diones at- were freed of protic impurities by a standard work-up and
tended by alkyl group transfer under microwave dried under vacuum overnight, then treated with DIBAL-
irradiation,28 and thionation of a-amino amides.33
H followed by acid (i.e., Scheme 2, path C, R1 = H,
X = Et).21 The 2THs were only secured by acylating free
glycinate with isothiocyanates and cyclizing the interme-
diate a-thioureido acids with sulfuric acid (Scheme 3).22,23
The reactions proceeded in moderate yields because of
competitive S-acylation,35,36 but the method was suitable
for a multigram preparation, and chromatography was not
necessary. Isolation of 2THs 1–3 required only removal
of acetone, inundation with aqueous sodium bicarbonate,
and filtration; we presume the expected 2-thioamidine by-
products were removed with the mother liquor.
We recently described34 one-pot air- and water-insensitive
syntheses of two 1,3-dialkyl I2Ts from amino esters
(Scheme 2, path A) alongside syntheses through 2THs,
which were accessed in three cases by the thermal cycliza-
tion of intermediate a-thioureido esters (path B,
X = alkyl), and in one case by the acid-catalyzed cycliza-
tion of an a-thioureido acid (path B, X = H).22,23 We also
utilized Markwalder and co-workers’ DIBAL-H reduc-
tion of a-thioureido esters21 in a one-pot reaction from
ethyl N-butylglycinate (path C). The 1,3-dialkyl I2Ts thus
prepared, along with certain 3-alkyl thiazole-2-thiones,
were oxidatively desulfurized to the corresponding salts
with benzoyl peroxide (Equation 1),34 and we expected
the reaction could be applied to the synthesis of neutral
imidazoles from 1-alkyl I2Ts. Intriguingly, this sequence
(amino ester or acid → 2TH → I2T → imidazole) is ap-
parently not well known (if at all) even though the newest
elementary step is almost 40 years old.
S
S
RNCS
3
1
1
3
R
R
2
2
H2SO4
NH2
CO2H
HN
N
H
HN
N
KOH (1 equiv)
H2O–EtOH
4
acetone
α
CO2H
O
precipitated
in crude form
1: R = Bu, 50%
2: R = Bn, 59%
3: R = Ph, 62%
Scheme 3 Synthesis of 3-alkyl I2Ts (yields are from glycine)
S
1. 75% (BzO)2, THF
2. NaA
The conditions used to reduce and dehydrate 1,3-dialkyl
2THs were not applicable to the conversion of 3-alkyl
2THs 1–3 to 1-alkyl I2Ts 4–6 (Table 1). Simple combi-
nation of 2 with 1.1 equivalents sodium borohydride in
ethanol or glyme–ethanol (3:1) at room temperature gave
an incomplete reaction, and the reagent was still not con-
sumed when 2.2 equivalents of sodium borohydride were
used. In TLC analyses of acidified reaction aliquots, the
reagent and product spots were joined by a third spot less
mobile than either of the others. If the reactions were left
long enough at room temperature, both reagent and de-
sired product were undetectable by TLC and only the least
mobile of the three compounds remained. When this prod-
uct was isolated, it could not be adequately characterized.
However, its TLC characteristics are consistent with a 2-
thioureido alcohol, the by-product we would expect from
ring-chain tautomerism and overreduction as discussed by
Scott and Henderson, who also reduced 2THs with boro-
hydrides.22 This overreduction was still observed at 0 °C,
but suppressed at –15 to –5 °C. Application of lithium
chloride22,37,38 at this temperature forced the reaction to
R
R
N
X
N
X
A
R = Me, Bu, Ph
X = NMe, NPh, S
51–86%
A = PhCO2, CF3CO2, BF4, etc.
Equation 1 Syntheses of azolium salts from azole-2-thiones, inclu-
ding I2Ts prepared according to Scheme 234
All the 1,3-dialkyl I2T syntheses in Scheme 2 seemed
reasonable for preparation of the 1-alkyl I2Ts necessary
for neutral imidazole syntheses, but, in practice, only one
was suitable. Intermediate a-thioureido esters prepared by
the acylation of ethyl glycinate with isothiocyanates could
not be converted into 2THs under the influence of heat or
sodium ethoxide (i.e., Scheme 2, paths A and B, R1 = H,
X = Et) or sulfuric acid (which we did not previously
evaluate for the cyclization of a-thioureido esters). Note
that the a-thioureido esters we had previously converted
into 2THs were the 1,3-dialkyl varieties, whereas those
that did not carry through were 3-alkyl. We also failed to
recover I2T products when the crude a-thioureido esters
from the reactions of ethyl glycinate and isothiocyanates
R2NCS; then KOH; then NaBH4; then aq HCl
R1 = R2 = Me, 65%
R1 = Bu, R2 = Me, 93%
2. ∆
R1 = R2 = Me, 20%
R1 = Bu, R2 = Me, 79%
path A
X = alkyl
R1 = R2 = Ph, 41%
S
S
S
NaBH4;
aq HCl
X = alkyl
X = H
3
R2
1
1
3
R1
R1
R1
R2
R1
R2
2
1. R2NCS
path B
2
NH
N
N
H
N
N
N
N
2. H2SO4
R1 = R2 = Ph, 39%
4
43–79%
α
CO2X
CO2X
I2T
O
2TH
path C
X = alkyl
R2NCS; then DIBAL-H, –78 °C; then aq HCl
R1 = Bu, R2 = Me, 73%
Scheme 2 Syntheses of 1,3-dialkyl I2Ts on the way to 1,3-dialkylimidazolium salts34
Synthesis 2007, No. 13, 2002–2008 © Thieme Stuttgart · New York

2004
D. M. Wolfe, P. R. Schreiner
PAPER
Table 1 Optimization of the Syntheses of 4–6
S
conditions;
then aq HCl
S
3
1
HN
R
2
1
3
N
R
2
HN
N
4
O
1: R = Bu
2: R = Bn
3: R = Ph
4: R = Bu
5: R = Bn
6: R = Ph
Conditions
R
NaBH4 (equiv) LiCl (equiv)
Solvent
Temp (°C)
Time (h)
Resulta
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bu
Ph
1.1
2.2
2.2
2.2
2.2
1.1
1.1
2.2
2.2
2.2
2.2
1.1
1.1
2.2
0
EtOH or 3:1 DME–EtOH
EtOH or 3:1 DME–EtOH
EtOH or 3:1 DME–EtOH
EtOH or 3:1 DME–EtOH
EtOH or 3:1 DME–EtOH
3:1 DME–EtOH
3:1 DME–EtOH
3:1 DME–EtOH
3:1 DME–EtOH
3:1 DME–EtOH
3:1 DME–EtOH
pyridine
r.t.
16
16
16
16
16
6
DNC; OR starts
DNC; OR starts
DNC; OR starts
DNC; no OR
NR
0
r.t.
0
0
0
–15 to –5
0
–20 to –30
1.1
1.1
2.2
2.2
2.2
2.2
0
r.t.
C; OR starts
DNC; no OR
C; OR starts
C; no OR; 97%
C; no OR; 88%
C; no OR; 71%
NR
0
8
0
6
–15 to –5
–15 to –5
–25 to –15
r.t.
6
6
6
Bu, Bn, or Ph
Bu, Bn, or Ph
Bu, Bn, or Ph
24
24
24
1.1
2.2
pyridine
r.t.
NR
pyridine
r.t.
NR
a Abbreviations: DNC = does not complete; OR = overreduction; NR = no reaction; C = completes.
completion. Refinement of these conditions is reported in nylthioimidazole, which is made from imidazole in two
Table 1 for 2 only, but 1 gave identical results and 3 dif- synthetic steps, both of which require strictly anhydrous
fered only by reducing and overreducing at lower temper- conditions.41,42 We prepared p-methoxybenzyl isothiocy-
atures. The 2THs were not freely soluble in glyme– anate from p-methoxybenzylamine and thiophosgene on a
ethanol (3:1), but disappeared over the course of the reac- large scale, based on the method of Threadgill and co-
tion. They were only appreciably soluble in pyridine. workers,43 and added it to preformed tyrosine dianion
Since molecular borane, liberated during the desired reac- (Scheme 4). Cyclization in sulfuric acid and acetone pro-
tion, could be contributing to overreduction, and because ceeded in low yield, but no chromatography was neces-
pyridine can scavenge borane,39 we expected that a reac- sary and the reaction was amenable to the preparation of
tion in pyridine would be ideal. However, no reaction oc- several grams of 10. Compound 10 was less sensitive to
curred, even with excess sodium borohydride and lithium the conditions of reduction than the model 2THs. Indeed,
chloride at room temperature. Presumably, the 2THs were compound 10 was so sturdy that it was not entirely con-
chelated to or deprotonated by pyridine at N(1), and addi- sumed after several days at room temperature with occa-
tional electron density at C(4) stifled the reduction.22
sional replenishment of lithium and borohydride salts.
Thus, the reduction of 10 was accomplished in moderate
yield and chromatographic purification was necessary.
The feature reaction proceeded smoothly and in high
yield; like the model imidazoles, isolation of 12 required
only a simple work-up. Starting from tyrosine required a
methylation to deliver 13. We decided not to acylate O-
methyltyrosine and to complete the synthesis of 13 in four
steps instead of five, because the commercial derivative is
roughly 100 times as expensive as the parent compound.
Desulfurization of the I2Ts with benzoyl peroxide was
straightforward and imidazoles 7–9 were obtained after
simple work-up (Equation 2). To show the utility of this
route, we prepared compound 13, which was previously
prepared by Ohta and co-workers in five synthetic steps
and elaborated to three imidazole alkaloids (isonaamine
A, and isonaamidines A and C) from the sponge Leucet-
ta.40 They commenced with lithiation of 1-SEM-2-phe-
Synthesis 2007, No. 13, 2002–2008 © Thieme Stuttgart · New York

PAPER
Oxidative Desulfurization of Imidazole-2-thiones with Benzoyl Peroxide
2005
S
S
1. KOH (2 equiv), then
PMBNCS
PMB
PMB
PMB
NaBH4, LiCl
DME–EtOH (3:1)
0 °C to r.t.
NH2
CO2H
HN
N
HN
N
N
N
12: X = H
H2O–EtOH
75% (BzO)2
O
LiOH, THF;
then MeI
69%
2. H2SO4, acetone
33%
THF
87%
then aq HCl
54%
11
10
13: X = Me
OH
OH
OX
OH
Scheme 4 Synthesis of 13
in a volume of EtOH roughly equal to the supplied mass of 50% aq
KOH. The mixture was stirred 3 h, then acidified with 1 M HCl (200
mL each). The crude a-thioureido acid was collected by suction fil-
tration, and the filtrate was cooled to 0 °C and refiltered. The com-
bined isolates were taken up in as little acetone as feasible (250 mL
to make 1 and 2, 300 mL to make 3), dried (MgSO4), gravity-
filtered, treated with 96–98% H2SO4 (5 mL each), and followed to
completion by TLC (eluent: Et2O), where the a-thioureido acid ap-
peared as a streak from the origin. When the product (Rf specified
below) was the only mobile component in TLC (3 d to make 1 and
3, 6 d to make 2), the reaction was stripped of acetone, carefully
neutralized with sat. aq NaHCO3 (250 mL each), and suction-
filtered.
In deferring methylation, however, we concluded the syn-
thesis of 13 in 69% yield after a chromatographic purifi-
cation. It is noteworthy that Ohta and co-workers
demethylated both aryl methyl ethers of 13 for their syn-
theses of isonaamine A and isonaamidine A.40 Thus, a
demethylation of 12 at the PMB ether would be an alter-
native formal synthesis of two of the three Leucetta imi-
dazoles. However, our goal was to demonstrate the amino
acid → 2TH → I2T → imidazole sequence; as far as we
can ascertain, these entries to 7–9 and 13 constitute the
first examples.
S
3-Butyl-2-thiohydantoin (1)
After two crystallizations from n-C7H16–toluene (2:1), where 1 was
harvested by simple decantation of the mother liquor, and one more
crystallization from toluene followed by suction filtration, 1 (7.49
g, 50%) was recovered as colorless crystals; Rf = 0.78 (Et2O); mp
106.5–109 °C (Lit.28 mp 109.8–110.7 °C).
R
R
75% (BzO)2
THF
HN
N
N
N
4: R = Bu
5: R = Bn
6: R = Ph
7: R = Bu, 81%
8: R = Bn, 56%
9: R = Ph, 82%
IR (ATR): 3262, 2960, 2926, 2873, 2857, 1708, 1506 cm–1.
Equation 2 Oxidative desulfurization of 1-alkyl I2Ts to neutral
imidazoles with benzoyl peroxide
1H NMR (400 MHz, DMSO-d6): d = 10.15 (s, 1 H), 4.12 (s, 2 H),
3.64 (t, J = 8 Hz, 2 H), 1.52 (quint, J = 8 Hz, 2 H), 1.27 (sext, J = 8
Hz, 2 H), 0.89 (t, J = 8 Hz, 3 H).
This route relies on adapted precedents to deliver 3-alkyl
2THs and 1-alkyl I2Ts.22,23 The oxidative desulfuriza-
tions of 1-alkyl I2Ts to imidazoles with benzoyl peroxide
are new to this report. The syntheses presented highlight
the operational simplicity of the net conversion because
scrupulously dry glassware, reagents, or solvents were not
required at any point, and chromatography following re-
actions characteristic of the sequence was only required
following the incomplete reduction of 10 to 11.
13C NMR (100 MHz, DMSO-d6): d = 183.3, 172.5, 48.2, 39.6, 29.2,
19.3, 13.4.
HRMS (EI): m/z calcd for C7H12N2OS [M+]: 172.06703; found:
172.0666.
3-Benzyl-2-thiohydantoin (2)
Crystallization from EtOAc, which required a hot gravity filtration,
afforded 2 (8.86 g, 59%) as large amber crystals; Rf = 0.78 (Et2O);
mp 176–177 °C (Lit.26 mp 154–156 °C).
IR (ATR): 3268, 2904, 1709, 1507 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.31 (s, 1 H), 7.32 – 7.24 (m,
5 H), 4.87 (s, 2 H), 4.20 (s, 2 H).
All reagents were used as received from commercial sources. Melt-
ing points were recorded on a MelTemp apparatus and are uncor-
rected. NMR spectra were recorded on a Varian Mercury 400
spectrometer with TMS as internal standard. Mass spectra were col-
lected on a Hewlett-Packard 5970 (EI). IR spectra were taken in
ATR mode on a BioRad Excalibur Series FTS 4000 fitted with a
Specac Golden Gate Diamond accessory. High-resolution mass
spectra were taken on a Bruker Daltonics 4.7T FTMS (EI).
13C NMR (100 MHz, DMSO-d6): d = 183.1, 172.5, 136.3, 128.2,
127.4, 127.1, 48.4, 43.2.
HRMS (EI): m/z calcd for C10H10N2OS [M+]: 206.05138; found:
206.0509.
3-Phenyl-2-thiohydantoin (3)
Crystallization from nitromethane, which required a hot gravity fil-
tration, afforded 3 (9.37 g, 62%) as bright yellow crystals; Rf = 0.62
(Et2O); mp 248–252 °C (dec.) (Lit.28 mp 258.3–259.7 °C; Lit.44 mp
243 °C).
2-Thiohydantoins 1–3; General Procedure
Based on the procedure of Johnson and Buchanan,23 glycine (6.54
g, 87 mmol to make 1; 5.46 g, 73 mmol to make 2; 5.86 g, 78 mmol
to make 3) was dissolved in 1 equiv of 50% aq KOH (9.78 g, 87
mmol to make 1; 8.16 g, 73 mmol to make 2; 8.76 g, 78 mmol to
make 3), the soln was diluted with EtOH (1.2 mL per 1 g of 50% aq
KOH), cooled to 0 °C, then treated dropwise with 1 equiv of the ap-
propriate isothiocyanate (10.03 g, 87 mmol n-butyl to make 1; 10.85
g, 73 mmol benzyl to make 2; 10.55 g, 78 mmol phenyl to make 3)
IR (ATR): 3140, 3000, 2953, 2913, 1758, 1516 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.40 (s, 1 H), 7.48 (t, J = 8
Hz, 2 H), 7.41 (t, J = 8 Hz, 1 H), 7.27 (d, J = 8 Hz, 2 H), 4.28 (s, 2
H).
Synthesis 2007, No. 13, 2002–2008 © Thieme Stuttgart · New York

2006
D. M. Wolfe, P. R. Schreiner
PAPER
13C NMR (100 MHz, DMSO-d6): d = 183.2, 172.0, 133.3, 128.7,
128.5, 128.4, 49.0.
MS (EI): m/z (%) = 176 (69, [M+]), 175 (100, [M+ – H]), 77 (10,
[Ph+]).
HRMS (EI): m/z calcd for C9H8N2OS [M+]: 192.03573; found:
192.0353.
HRMS (EI): m/z calcd for C9H8N2S [M+]: 176.04082; found:
176.0404.
Imidazole-2-thiones 4–6; General Procedure
Oxidative Desulfurization of Imidazole-2-thiones to Imidazoles
7–9; General Procedure
A stock soln of 0.50 M LiCl/NaBH4 in 3:1 DME–EtOH was pre-
pared by vigorously stirring NaBH4 (7.56 g, 200 mmol) into a fresh
soln of LiCl (8.47 g, 200 mmol) in 3:1 DME–EtOH (300 mL). The
soln was made up to 400 mL total with 3:1 DME–EtOH. NaCl
formed as a fine precipitate45 that was smoothly transferred in the
necessary volume (128 mL, 64 mmol for 1; 108 mL, 54 mmol for 2;
116 mL, 58 mmol for 3) for reduction of the appropriate 2TH (5 g,
29 mmol 1, 26 mmol 2, 28 mmol 3). The prepared soln was cooled
to the temperature range specified in Table 1 before 2TH was added
in one portion. The reaction was followed by TLC analysis (eluent:
Et2O) of Et2O extracts of acidified reaction aliquots. After 6 h, only
I2T was visible. The reaction was quenched with concd HCl (50
mL), stirred 30 min, diluted with H2O (50 mL), and washed with
CH2Cl2 (3 × 50 mL). The combined organic extracts were washed
with H2O and brine (1 × 50 mL each), dried (MgSO4), filtered, and
concentrated to leave 4–6 as specified.
Solid imidazole-2-thione (0.50 g, 3.2 mmol 4, 2.6 mmol 5, 2.8
mmol 6) was added to a stirred slurry of 75% (BzO)2 (5.17 g, 16
mmol for 4; 4.24 g, 13 mmol for 5; 4.58 g, 14 mmol for 6) in THF
(10 mL), which brought the reaction to spontaneous reflux. After
cooling to r.t., the mixture was diluted with H2O (20 mL) and Et2O
(20 mL). The aqueous layer was separated, and the organic layer
was washed with H2O (1 × 10 mL). The combined aqueous layers
were washed with CH2Cl2 (3 × 10 mL), then treated with aq 6 M
NaOH (2 mL), and stirred until (BzO)2 was not detectable by TLC
anymore (less than 1 h). The aqueous soln was washed with Et2O
(3 × 10 mL), the combined organic extracts were washed with H2O
and brine (1 × 10 mL each), dried (MgSO4), filtered, and concen-
trated to leave 7–9 as specified below.
1-Butylimidazole (7)
Yield: 0.32 g (81%); colorless oil, which was authenticated with
commercial 1-butylimidazole by 1H and 13C NMR spectra, and TLC
(Rf = 0.10, Et2O).
1-Butylimidazole-2-thione (4)
Yield: 4.35 g (97%); Rf = 0.44 (Et2O); mp 80–81.5 °C (Lit.17 mp
80–81 °C).
1-Benzylimidazole (8)
Yield: 0.23 g (56%); colorless crystals; mp 69.5–72 °C, which were
authenticated with commercial 1-benzylimidazole (mp 68–70 °C)
IR (ATR): 3092, 2954, 1571 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.13 (br s, 1 H), 6.74 (d, J = 1.6
Hz, 1 H), 6.71 (d, J = 1.6 Hz, 1 H), 4.01 (t, J = 8 Hz, 2 H), 1.76
(quint, J = 8 Hz, 2 H), 1.38 (sext, J = 8 Hz, 2 H), 0.95 (t, J = 8 Hz,
3 H).
1
by mp, mixed mp, H and 13C NMR spectra, and TLC (Rf = 0.10,
Et2O).
13C NMR (100 MHz, CDCl3): d = 159.4, 117.7, 114.3, 46.6, 31.0,
19.6, 13.5.
1-Phenylimidazole (9)
Yield: 0.33 g (82%); colorless oil, which was authenticated with
commercial 1-phenylimidazole by H and 13C NMR spectra, and
TLC (Rf = 0.25, Et2O).
1
MS (EI): m/z (%) = 156 (100, [M+]), 127 (27, [M+ – Et]), 123 (45,
[M+ – SH]), 114 (30, [M+ – propene]), 100 (73, [M+ – butene]).
HRMS (EI): m/z calcd for C7H12N2S [M+]: 156.07212; found:
156.0718.
3-(p-Methoxybenzyl)-5-(p-hydroxybenzyl)-2-thiohydantoin
(10)
A mixture of tyrosine (8.14 g, 45 mmol) and 50% aq KOH (10.08
g, 90 mmol) was diluted with H2O to a total volume of 50 mL and
thoroughly dissolved before the addition of EtOH (150 mL). The
soln was cooled to 0 °C, then treated dropwise with PMBNCS (8.05
g, 45 mmol, prepared based on a report from Threadgill and co-
workers43) in EtOH (10 mL), stirred 3 h, treated with 1 M HCl (400
mL), stirred 1 h, and frozen at –30 °C overnight. The mixture was
then allowed to reach r.t. again, and an aqueous layer separated from
an orange solid. The aqueous layer was decanted and the orange sol-
id was concentrated twice from acetone (200 mL each), redissolved
in acetone (300 mL), dried (MgSO4), filtered, and treated with 96–
98% H2SO4 (10 mL). The cyclization required 3 d, whereupon ace-
tone was removed in vacuo, the residue was treated with sat. aq
NaHCO3 (500 mL), and the mixture was washed with CH2Cl2
(3 × 100 mL). The combined organic extracts were washed with
H2O and brine (1 × 50 mL each), dried (MgSO4), filtered, and evap-
orated to leave a dark-brown oil (19.98 g), which released crude 10
as yellow crystals upon standing. The dark supernatant was re-
moved by pipette, and the separated material (6.54 g) was recrystal-
lized from i-PrOH to deliver 10 (5.05 g, 33%); Rf = 0.78 (Et2O); mp
163–165 °C.
1-Benzylimidazole-2-thione (5)
Yield: 4.31 g (88%); Rf = 0.44 (Et2O); mp 145–148 °C (Lit.17 mp
145–146 °C).
IR (ATR): 3137, 3084, 3008, 2920, 1573 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.25 (br s, 1 H), 7.36–7.30 (br m,
5 H), 6.72 (d, J = 1.8 Hz, 1 H), 6.58 (d, J = 1.8 Hz, 1 H), 5.23 (s, 2
H) .
13C NMR (100 MHz, CDCl3): d = 160.4, 135.6, 128.8, 128.11,
128.10, 117.7, 114.7, 50.2.
MS (EI): m/z (%) = 190 (84, [M+]), 157 (28, [M+ – SH]), 91 (100,
[Bn+]).
HRMS (EI): m/z calcd for C10H10N2S [M+]: 190.05647; found:
190.0559.
1-Phenylimidazole-2-thione (6)
Yield: 3.48 g (71%); Rf = 0.38 (Et2O); mp 182–183 °C (Lit.17 mp
179–180 °C; Lit.18 mp 181 °C).
IR (ATR): 3071, 3005, 2894, 1574 cm–1.
IR (ATR): 3390, 3207, 3010, 2923, 2845, 1731, 1512 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.45 (br s, 1 H), 7.59 (d, J = 8
Hz, 2 H), 7.50 (t, J = 8 Hz, 2 H), 7.42 (t, J = 8 Hz, 1 H), 6.86 (d,
J = < 2 Hz, 1 H), 6.82 (d, J = < 2 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6): d = 10.47 (s, 1 H, NH), 9.36 (s, 1
H, OH), 6.92 (d, J = 8 Hz, 2 H, ArH), 6.72 (d, J = 8 Hz, 2 H, ArH),
6.64–6.61 (m, 4 H, ArH), 4.62 (s, 2 H, NCH2C6H4OMe), 4.59 (t,
J = 4 Hz, 1 H, H-5), 3.70 (s, 3 H, OCH3), 2.95 (d, J = 4 Hz, 2 H,
CH2C6H4OH).
13C NMR (100 MHz, CDCl3): d = 160.9, 137.4, 129.1, 128.4, 125.9,
119.4, 115.1.
Synthesis 2007, No. 13, 2002–2008 © Thieme Stuttgart · New York

PAPER
Oxidative Desulfurization of Imidazole-2-thiones with Benzoyl Peroxide
2007
13C NMR (100 MHz, DMSO-d6): d = 182.1, 173.7, 157.9, 156.2,
130.6, 127.7, 127.6, 124.2, 114.9, 113.3, 59.8, 54.8, 42.3, 34.5.
persion while stirring overnight. Addition of MeI (84 mL, 0.19 g,
1.35 mmol) gave a clear soln in 2 h, which was stirred another 4 h
before the addition of H2O (30 mL). The mixture was extracted with
CH2Cl2 (3 × 15 mL), the combined organic extracts were washed
with H2O and brine (1 × 20 mL each), dried (MgSO4), filtered, and
concentrated. After chromatography over 230–400 mesh silica gel
(20 g) with a solvent gradient (EtOAc → 5:1 EtOAc–EtOH), the
crude product (Rf = 0.40, 5:1 EtOAc–EtOH) still contained phenol
12. The residue was redissolved in Et2O (50 mL), washed with aq 3
M NaOH (3 × 25 mL), H2O and brine (1 × 25 mL each), dried
(MgSO4), filtered, and concentrated to afford 13 (0.2200 g, 69%)
with 1H and 13C NMR spectra matching those in the literature;40 mp
83.5–86 °C (Lit.40 mp 84–85 °C).
HRMS (EI): m/z calcd for C18H18N2O3S [M+]: 342.10381; found:
342.1031.
1-(p-Methoxybenzyl)-4-(p-hydroxybenzyl)imidazole-2-thione
(11)
2-Thiohydantoin 10 (2.21 g, 6.5 mmol) was less sensitive to the
conditions of reduction than the model compounds, and was added
to a soln of NaBH4 (0.54 g, 14 mmol) and LiCl (0.60 g, 14 mmol)
in 3:1 DME–EtOH (30 mL) at 0 °C. The reaction was allowed to
reach r.t. overnight. A TLC analysis showed incomplete consump-
tion of 10, but no overreduction. The reaction was stopped by the
addition of concd HCl (10 mL). The mixture was stirred 30 min, di-
luted with H2O (150 mL), and washed with CH2Cl2 (3 × 50 mL).
The combined organic extracts were washed with H2O and brine
(1 × 20 mL each), dried (MgSO4), filtered, plugged with 230–400
mesh silica gel (3 g), and concentrated. The silica gel plug was load-
ed on a silica gel column (230–400 mesh, 60 g) packed in EtOAc;
elution with the same delivered 11 (1.14 g, 54%); Rf = 0.76
(EtOAc); mp 198–204 °C.
Acknowledgment
This work was supported by the National Science Foundation
(CHE-0209857). We thank Prof. James de Haseth and Mr. J. Brian
Loudermilk for the use of their IR spectrophotometer and for tech-
nical assistance.
IR (ATR): 3128, 3069, 3013, 2964, 2924, 1511 cm–1.
References
1H NMR (400 MHz, CDCl3/DMSO-d6): d = 11.80 (s, 1 H, NH),
8.76 (s, 1 H, OH), 7.24 (d, J = 8 Hz, 2 H, ArH), 6.97 (d, J = 8 Hz, 2
H, ArH), 6.84 (d, J = 8 Hz, 2 H, ArH), 6.74 (d, J = 8 Hz, 2 H, ArH),
6.17 (s, 1 H, H-5), 5.06 (s, 2 H, NCH2C6H4OMe), 3.77 (s, 3 H,
OCH3), 3.60 (s, 2 H, CH2C6H4OH).
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13C NMR (100 MHz, CDCl3/DMSO-d6): d = 160.5, 159.0, 155.9,
129.4, 129.3, 129.1, 128.3, 127.4, 115.3, 113.8, 113.6, 55.0, 49.1,
30.2.
HRMS (EI): m/z calcd for C18H18N2O2S [M+]: 326.10890; found:
326.1090.
1-(p-Methoxybenzyl)-4-(p-hydroxybenzyl)imidazole (12)
Solid 11 (1.0 g, 3.1 mmol) was added in one portion to a slurry of
75% (BzO)2 (4.95 g, 15 mmol) in THF (5 mL). The reaction came
to spontaneous reflux; after cooling back to r.t., the mixture was di-
luted with H2O (20 mL) and Et2O (20 mL). The aqueous layer was
collected, and the organic layer was washed with H2O (1 × 10 mL).
The combined aqueous layers were washed with CH2Cl2 (3 × 5
mL), then treated with aq 6 M NaOH (5 mL) and stirred until no
(BzO)2 was visible by TLC (less than 1 h). The pH was lowered to
8 with sat. aq NH4Cl (25 mL) before extraction with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with H2O and brine
(1 × 20 mL each), dried (MgSO4), filtered, and concentrated to
leave 12 (0.79 g, 87%); mp 131–133 °C.
IR (ATR): 3106, 3034, 2996, 2903, 2829, 2787, 2669, 2580, 1609,
1509 cm–1.
1H NMR (400 MHz, CDCl3/CD3OD): d = 7.44 (s, 1 H, ImH), 7.11
(d, J = 8 Hz, 2 H, ArH), 7.05 (d, J = 8 Hz, 2 H, ArH), 6.87 (d, J = 8
Hz, 2 H, ArH), 6.74 (d, J = 8 Hz, 2 H, ArH), 6.51 (s, 1 H, ImH), 4.95
(s, 2 H, NCH2C6H4OMe), 4.47 (br s, 1 H, OH), 3.79 (s, 3 H, OCH3),
3.77 (s, 2 H, CH2C6H4OH).
(16) Schoenherr, H. J.; Wanzlick, H. W. Chem. Ber. 1970, 103,
1037.
(17) Jones, R. G.; Kornfeld, E. C.; McLaughlin, K. C.; Anderson,
R. C. J. Am. Chem. Soc. 1949, 71, 4000.
13C NMR (100 MHz, CDCl3/CD3OD): d = 159.7, 155.3, 142.9,
136.5, 131.0, 129.9, 129.2, 128.2, 116.4, 115.4, 114.5, 55.4, 50.6,
33.8.
(18) Kister, J.; Assef, G.; Mille, G.; Metzger, J. Can. J. Chem.
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3749.
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2006, 8, 141.
MS (EI): m/z (%) = 294 (26, [M+]), 121 (100, [p-MeOBn+]).
HRMS (EI): m/z calcd for C18H18N2O2 [M+]: 294.13683; found:
294.1367.
1,4-Di(p-methoxybenzyl)imidazole (13)
A soln of 12 (0.3053 g, 1.04 mmol) in THF (10 mL) was treated
with LiOH·H2O (0.0447 g, 1.07 mmol) and turned into a fine dis-
Synthesis 2007, No. 13, 2002–2008 © Thieme Stuttgart · New York

2008
D. M. Wolfe, P. R. Schreiner
PAPER
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(175 mL), and H2O (175 mL). The isolate was distilled (bp
92.5–94 °C/0.2–0.3 Torr) to afford p-methoxybenzyl
isothiocyanate (30.24 g, 89%) with spectral properties
matching those of the chromatographed material from the
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Synthesis 2007, No. 13, 2002–2008 © Thieme Stuttgart · New York