Iodoacetic acid is an efficient reagent for the synthesis of amino acid derived 2-aminobenzimidazoles

Article abstract of DOI:10.1055/s-0032-1316849

Chiral, nonracemic, N-unprotected amino acids were converted into the corresponding N-benzimidazol-2-yl derivatives by a sequential procedure involving initial formation of isothiocyanates, their reaction with arene-1,2-diamines, and cyclization-desulfurization of the intermediate thioureas with iodoacetic acid. The simplified workup and the lack of volatile or toxic byproducts in the key desulfurization step renders iodoacetic acid a superior reagent to the usual reagent, iodomethane. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316849

PAPER
▌683
paper
Iodoacetic Acid is an Efficient Reagent for the Synthesis of Amino Acid
Derived 2-Aminobenzimidazoles
Iodoacetic Acid in Synthesis of 2-Aminobenzimidazoles
Andrejs Krasikovs,a Vita Ozola,a Scott L. Dax,b Edgars Suna*a
a
Latvian Institute of Organic Synthesis, Aizkraukles 21, 1006 Riga, Latvia
Fax +371(6)7550338; E-mail: edgars@osi.lv
b
Galleon Pharmaceuticals, 213 Witmer Road, Horsham, PA 19044, USA
Received: 29.11.2012; Accepted after revision: 07.01.2013
cient approach to L-cysteine derivatives 1 containing 2-
(alkylamino)benzimidazole residues (Figure 1). Related
amino acid-containing 2-(alkylamino)benzimidazoles
have been developed as integrin α4β1 antagonists,2 inhib-
Abstract: Chiral, nonracemic, N-unprotected amino acids were
converted into the corresponding N-benzimidazol-2-yl derivatives
by a sequential procedure involving initial formation of isothiocya-
nates, their reaction with arene-1,2-diamines, and cyclization–
desulfurization of the intermediate thioureas with iodoacetic acid. itors of peptidylprolyl isomerase,3 antagonists of fibrino-
gen gpIIb/IIIa,4 and modulators of melanocortin MC4
The simplified workup and the lack of volatile or toxic byproducts
in the key desulfurization step renders iodoacetic acid a superior re-
agent to the usual reagent, iodomethane.
receptors.5
Although a number of methods have been reported for the
Key words: amino acids, cyclization, desulfurization, green chem-
istry, heterocycles
preparation of 2-aminobenzimidazoles,1a,6 the presence of
a chiral nonracemic L-cysteine moiety in benzimidazole 1
limits the choice of suitable synthetic approaches. Intro-
duction of an amine moiety at the 2-position of benzimid-
2-Aminobenzimidazoles are important pharmacophores
azole by nucleophilic substitution of a suitable leaving
and are useful as scaffolds in the development of new
group7 (Figure 2, route A) requires the presence of a
drugs.1 A number of medicines, such as mebendazole, as-
strong base and high temperature, which might cause ra-
temizole, and the drug candidate maribavir, contain a 2-
cemization of the L-cysteine moiety. Likewise, the syn-
aminobenzimidazole subunit (Figure 1). As part of our
thesis of 2-aminobenzimidazoles by a palladium-
drug-discovery efforts, we became interested in an effi-
O
O
NH
OMe
N
N
H
R
mebendazole
N
Tr
N
S
N
O
N
N
O
NH
N
NH
NH2
N
H
R1
R2
F
1
norastemizole: R = H
astemizole: R = 4-MeO(C6H4)(CH2)2
Cl
Cl
N
NH
N
O
HO
OH
HO
maribavir
Figure 1 Pharmacologically active 2-aminobenzimidazoles
SYNTHESIS 2013, 45, 0683–0693
Advanced online publication: 06.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316849; Art ID: SS-2012-T0924-OP
© Georg Thieme Verlag Stuttgart · New York

684
A. Krasikovs et al.
PAPER
catalyzed C–H activation reaction,8 in a Buchwald–
Hartwig C–N bond-forming process9 (Figure 2, route A)
or by an intramolecular copper-catalyzed arylation of
guanidines10 (Figure 2, route B) requires harsh conditions
that would not appear to be compatible with the fragile L-
cysteine moiety.11 We therefore required an approach that
would involve considerably milder conditions for the
preparation of the desired benzimidazole 1, so we chose a
method based on desulfurization and cyclization of the
corresponding substituted thiourea (Figure 2, route C).
R1
NH
NH2
A
C
N
N
X
N
H
NH
N
H
NHR1
S
X = H, Cl, Br, SO2Me
B
Hal
NH
NHR1
R2
N
We obtained the required thiourea as an inseparable mix-
ture of regioisomers 5bA and 5bB by a two-step proce-
dure involving treatment of L-cysteine (2) with
thiophosgene,12 followed by reaction of the intermediate
isothiocyanate 3 with N-methylbenzene-1,2-diamine (4b)
(Scheme 1). We attempted the subsequent conversion of
the thioureas 5bA and 5bB into the target benzimidazole
1b under various published conditions. The use of metal
salts such as mercury(II) oxide13 or copper(I) oxide14 af-
forded poor yields (<20%) of the desired product 1, as did
the use of carbodiimides15 or diacetyl(phenyl)-λ3-iodane16
(Table 1, entries 1–3 and 6). The use of tosyl chloride and
sodium hydroxide17 or of 2-chloro-1,3-dimethyl-1H-im-
idazol-3-ium chloride (DMC) was also unsuccessful, giv-
Figure 2 Options for the synthesis of 2-aminobenzimidazoles
ing a ~40% yield of 1b in each case (entries 4 and 5,
respectively).18
The best results among the literature methods were ob-
tained by using iodomethane19 in methanol or N,N-di-
methylformamide (entries 7 and 8). However, the S-
methylbenzimidazole 7a (3–10%) was obtained as a by-
product in these cases. Presumably, 7a is formed through
decomposition of a transient tetrahedral intermediate 6
(Scheme 1, path B).20
Table 1 Optimization of Conditions for the Desulfurization–Cyclization Reaction
Tr
S
O
Tr
Tr
N
S
O
S
N
O
NHMe
O
desulfurization–
cyclization
H
NH2 Me
N
O
O
N
NH
+
NH
NH
S
S
Me
5bA
5bB
1b
Entry
Reaction conditions
Conversion (%)a
Yield (%) of 1ba
1
HgO, S, EtOH, reflux, 2 h
99
61
33
58
65
96
75
93
97
21
18
<1
19
36
43
10
58
88
92
18
2
PhI(OAc)2, Et3N, MeCN, 0.5 h, r.t.
EDC, DMF, 3 h 80 °C
3
4
TsCl, THF, NaOH, 72 h, r.t.
DMCb, Et3N, CH2Cl2, 4 h, r.t.
5
6
CuCl, DIPEA, toluene–MeCN (4:1), 1 h, 80 °C
MeI, DMF, 3 h, r.t.
7
8
MeI, EtOH, 50 °C, 7 h
9
ICH2CO2H, EtOH, 50 °C, 7 h
ClCH2CO2H, EtOH, 50 °C, 7 h
10
a Yields and conversion were determined by an HPLC method (for details, see below).
b DMC = 2-chloro-1,3-dimethyl-1H-imidazol-3-ium chloride.
Synthesis 2013, 45, 683–693
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iodoacetic Acid in the Synthesis of 2-Aminobenzimidazoles
685
NH2
Tr
S
Tr
Tr
Tr
S
O
NHMe
S
S
O
O
S
O
Cl2CS
4b
O
NHMe
NH2 Me
N
O
O
O
H
NaHCO3
CH2Cl2
N
NH
NH
N=C=S
NH2
CH2Cl2–H2O
+
S
2
3
5bA
5bB
R-I
MeOH
50 °C, 6 h
Tr
Tr
S
O
O
–
I
S
R
S
N
N
path A
MeSH
H
N
path B
O
H
+
NH
S
N
+
NH
O
R
Me
N
N
2·HI
H
Me
Me
1a
6
7a: R = Me
7b: R = CH2CO2H
–
I
Scheme 1 Formation of the S-methylbenzimidazole 7a
Because the desired product 1a and the byproduct 7a have Thioureas possessing either electron-donating (entry 5) or
similar solubility profiles and comparable chromato- electron-withdrawing substituents (entries 6–10) at the 4-
graphic properties, the removal of the byproduct 7a re- position of the arene-1,2-diamine moiety were efficiently
quired laborious column chromatography. We reasoned transformed into the corresponding benzimidazoles 1f–j
that the separation of 7a might be simplified by replacing (Table 2). However, thiourea 5k, which contains a strong-
the methyl group on the sulfur atom of benzimidazole 7a ly electron-deficient 2,3-diaminopyridine moiety, was not
by a functional group that would change the solubility compatible with the cyclization conditions, because it
profile of the resulting byproduct. A carboxylic acid moi- formed thiazolidinone 8k in the reaction with iodoacetic
ety was considered to be the most suitable candidate, so acid. Thiazolidinone 8j was similarly formed as a byprod-
we examined the use of haloacetic acids as desulfurization uct from the electron-deficient thiourea 5j. In fact, halo-
agents instead of iodomethane.21 We were pleased to find acetic acids have been routinely used in the synthesis of
that the undesired byproduct 7b (3–5%) that was formed thiazolidinones from thioureas under base-free
in the cyclization of 5bA/B with iodoacetic acid (entry 9) conditions23 or in the presence of base.24 Interestingly, thi-
could be efficiently removed from the reaction mixture by azolidinones such as 8j and 8k were only obtained from
simple extraction with an aqueous base. Chloroacetic acid the strongly electron-deficient thioureas 5j and 5k (entries
was considerably less efficient than iodoacetic acid (entry 10 and 11), and they were not formed in the case of the
10). Furthermore, iodoacetic acid is a more benign reagent other thioureas 5a–i (entries 1–9). Apparently, the lower
than iodomethane, as desulfurization by the iodoacetic nucleophilicity of the aromatic amine group in 5k slows
acid does not generate volatile, foul-smelling, toxic meth- down the conversion of the transient S-alkylthiouronium
anethiol as a byproduct.
iodide 9k into the key tetrahedral intermediate 6k en route
to the target benzimidazole (Scheme 2).25 In the mean-
time, a competitive intramolecular amide-bond formation
reaction occurs, leading to thiazolidinone 8k; similar con-
siderations apply in the case of the conversion of amine 5j
into the thiazolidinone 8j.
To establish the scope of the reaction, we then synthesized
a series of L-cysteine residue-containing benzimidazoles
1a–j by using iodoacetic acid in the desulfurization–cycli-
zation step (Table 2).
N-Unsubstituted benzimidazoles 1a (Table 2, entry 1) and
N-substituted benzimidazoles 1b–d (entries 2–4) were
obtained in good yields.22 The formation of a mixture of
intermediate thioureas 5A and 5B has usually been ob-
The structures of benzimidazole 1b and thiazolidinone 8k
(as its hydroiodide salt) were established by X-ray crystal-
lography (Figure 3).
served in the case of N-substituted diamines 4b–d (Table Note that the iodoacetic acid-based cyclization–desulfur-
2). However, regioisomers 5A and 5B were both convert- ization conditions do not cause detectable levels of race-
ed into the desired benzimidazole 1 in the reaction with io- mization at the chiral center of L-cysteine, as evidenced by
doacetic acid, and therefore no attempt was made to HPLC analysis on a chiral stationary phase of the products
separate the two regioisomers.
of conversion of (R)-3 into (R)-1a and (R)-1b (Table 2,
entries 1 and 2).27
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 683–693

686
A. Krasikovs et al.
PAPER
Table 2 Scope of Aryldiamines Used in Synthesis of L-Cysteine-Derived Benzimidazoles 1
H2N
R2
Tr
Tr
S
N
O
X
S
O
Tr
N
S
N
O
R1HN
X
O
O
I
CO2H
S
NH
O
S
NH
4a–k
+
3
NH
HN
R2
R1
MeOH
R2
R1
R1HN
X
5A
H2N
R2
X
5B
1a–k
Entrya
Product
R1
R2
X
Yield (%)b
1
2
3
1a
1b
1c
H
H
H
H
CH
CH
CH
51
64
67
Me
Bn
4
1d
H
CH
60
5
1e
1f
H
H
H
H
H
H
H
OMe
Cl
CH
CH
CH
CH
CH
CH
N
63
6
60
7
1g
1h
1i
CF3
50
8
CO2Me
CN
61
9
59
10
11
1j
NO2
H
62 (14%)c
0 (72%)d
1k
a Reaction conditions: ICH2CO2H (1.2 equiv), MeOH, 50 °C, 6 h.
b Isolated yields of the >95% pure product determined by HPLC with UV detection at 254 nm.
c Isolated yield of thiazolidinone 8j.
d Isolated yield of thiazolidinone 8k.
Tr
S
O
Tr
S
O
O
O
H2N
O
O
N
N
H2N
N
N
N
S
S
8j
8k
NO2
Tr
S
S
O
NH2
O
H
N
NH
N
5k
ICH2CO2H
DMF
r.t., 4 h
Tr
Tr
Tr
S
S
O
S
S
O
O
O
–
–
I
I
O
NH2
NH2
O
O
H
N
H
NH
S
+
NH
H
N
1k
+
+
H
N
N
N
N
N
CO2H
– H2O
–
NH
I
CO2H
S
6k
9k
8k
Scheme 2 Formation of thiazolidinone 8k
Synthesis 2013, 45, 683–693
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iodoacetic Acid in the Synthesis of 2-Aminobenzimidazoles
687
Figure 3 Single-crystal X-ray structures of 1b (left) and 8k (right).26 Thermal ellipsoids are drawn at the 50% probability level.
We performed additional experiments to examine the suit- In the reaction with iodoacetic acid, intermediate thio-
ability of our procedure for the synthesis of various amino ureas can be transformed into 2-aminobenzimidazoles or
acid-derived benzimidazoles (Table 3). Accordingly, es- thiazolidinones, depending on the electronic properties of
ters of glycine 10a, L-phenylglycine 10b, L-phenylalanine the aryl moiety. Formation of thiazolidinones was ob-
10c, protected L-serine 10d, protected L-lysine 10e and L- served only for certain electron-deficient thioureas. The
glutamic acid 10f were readily converted into the corre- developed approach is sufficiently mild to preserve the
sponding benzimidazol-2-yl derivatives 11a–f and 12a–f stereogenic center of the α-amino acid, permitting the
in good-to-excellent yields in a reaction sequence involv- preparation of the corresponding N-benzimidazol-2-yl de-
ing initial formation of the amino acid isothiocyanate, rivatives in enantiomerically pure forms.
subsequent reaction with a benzene-1,2-diamine and, fi-
The formation of 2-(1H-imidazol-2-ylsulfanyl)acetic acid
nally, cyclization–desulfurization of the intermediate
as a byproduct is presumably the result of a side-track de-
thiourea by iodoacetic acid (Table 3). The conversion of
composition of the transient tetrahedral thiol intermediate
formed by cyclization of the S-alkylated thiourea, which
the amino acids into 11a–f and 12a–f was performed in a
sequential manner without isolation and purification of
subsequently undergoes decomposition to give the de-
the intermediate isothiocyanates and thioureas. In most
sired benzimidazoles. This suggests that the alternative
cases, a byproduct 7b was formed (3–5%), and this was
mechanism for the formation of the 2-aminobenzimid-
separated by simple extraction with an aqueous base. Io-
azole through initial desulfurization of the S-alkylated
doacetic acid-mediated synthesis of benzimidazoles is
thiourea to form a carbodiimide, followed by cyclization
compatible with various protecting groups in the amino
to the benzimidazole, is less likely to have occurred.29
acid residue, for example, acid-sensitive S-trityl and O-
tert-butyl moieties, as well as O-benzyl or N-benzyloxy-
carbonyl groups.28
All reactions were carried out under an argon atmosphere. TLC was
performed on Merck Kieselgel 60F254 plates. Melting points were
In conclusion, we have demonstrated that iodoacetic acid
is an efficient reagent for cyclization–desulfurization of
amino acid-derived thioureas to give 2-aminobenzimid-
azoles. Iodoacetic acid is superior to the usual reagent, io-
domethane, in that the product workup is simpler and
there is no production of the volatile toxic byproduct
methanethiol. All the sulfur-containing byproducts, such
as 2-sulfanylacetic acid and (1H-imidazol-2-ylsulfa-
nyl)acetic acid, are nonvolatile, soluble in basic aqueous
media, and can be readily removed by simple extraction
with an aqueous base. The conversion of N-unprotected
amino acids into the corresponding N-benzimidazol-2-yl-
derivatives can be performed in a sequential manner with-
out isolation and purification of the intermediate isothio-
cyanates and thioureas.
determined by using an OptimMelt automated melting point system
and are uncorrected. NMR spectra were recorded on a Varian Inova
400 MHz spectrometer. 1H and 13C NMR chemical shifts are report-
ed in parts per million (ppm) relative to Me4Si or with the residual
solvent peak as an internal reference. HRMS were obtained with a
Micromass AutoSpec Ultima Magnetic sector mass spectrometer.
Elemental analyses were performed on a Carlo-Erba CHNS-0
EA1108 combustion analysis system.
HPLC Method for Determining the Conversion of 5b and the
Yields of 1b (Table 1)
All the reactions listed in Table 1 were run on a 0.043-mmol scale
of 5b. HPLC analyses were performed on an Alltech Apollo C18
column (5 μm; 4.6 × 150 mm) (Alltech Associates, Inc.) with elu-
tion by a linear gradient from 50% MeOH in 0.01 M aq KH2PO4
(pH 2.5) to 95% MeOH in 0.01 M aq KH2PO4 (pH 2.5) over 24 min.
The flow rate was 0.8 mL/min, and UV-detection was carried out at
254 nm. Compounds 5bA and 5bB co-eluted in a single peak after
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 683–693

688
A. Krasikovs et al.
PAPER
Table 3 Scope for Amino Acids in the Synthesis of Benzimidazoles
H2N
O
O
R3HN
O
R1
R1
N
4a: R3 = H
OR2
OR2
I
CO2H
O
R1
N
O
4b: R3 = Me
OR2
NH
(1.2 equiv)
R1
Cl2CS
R1
S
NH
S
NH
OR2
OR2
–
+
N
NaHCO3
NCS
CH2Cl2
HN
R3HN
NH2
MeOH
R3
+
Cl
CH2Cl2–H2O
R3
50 °C, 6 h
H2N
10a–f
11a–f R3 = H
12a–f R3 = Me
Entry
Products
Yield (%)
O
OBn
11a
12a
88
85
1
NH
N
N
Ph
N
R3
O
OMe
11b
12b
58
75
NH
2
3
4
N
R3
Ph
O
O
11c
12c
84
82
NH
N
N
R3
OBn
O
OMe
11d
12d
74
91
NH
N
N
R3
CbzHN
O
OMe
11e
12e
85
80
5
6
NH
N
N
R3
O
MeO
N
O
OMe
11f
12f
63
59
NH
N
R3
Synthesis 2013, 45, 683–693
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iodoacetic Acid in the Synthesis of 2-Aminobenzimidazoles
689
19.0 min and 1b was eluted after 16.4 min. To compensate for loss
of material during HPLC sample preparation, PhOMe (24 μL, 0.22
mmol) was added to the reaction mixture as an internal standard (re-
tention time: 12.0 min). The conversion of 5b and the yield of 1b
were determined by using three-point calibration curves.
UV, 254 nm; retention times: 8.4 min [(S)–1b] and 14.2 min [(R)–
1b].
tert-Butyl N-(1-Benzyl-1H-benzimidazol-2-yl)-S-trityl-L-cys-
teinate (1c)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 10–15%
EtOAc–PE) to give a white powder; yield: 201 mg (67%); mp 98–
101 °C; [α]D20 –36.8 (c 0.37, acetone); Rf = 0.46 (EtOAc–PE, 1:3).
Benzimidazoles 1a–j; General Procedure
Sat. aq NaHCO3 (3 mL) was added to a soln of cysteine derivative
2 (200 mg, 0.48 mmol) in CH2Cl2 (5 mL) at 0 °C, and the mixture
was stirred for 10 min. Cl2C=S (40 µL, 0.53 mmol, 1.1 equiv) was
added and the mixture was stirred for a further 45 min at 0 °C. The
layers were separated, and the aqueous phase was extracted with
CH2Cl2 (2 × 5 mL). The organic extracts were combined, washed
with H2O (10 mL) and dried (Na2SO4). Removal of the solvent gave
the crude isothiocyanate 3, which was dissolved in dry MeOH (3
mL). The soln was purged with argon, and diamine 4 (0.48 mmol, 1
equiv) was added. The mixture was stirred at r.t. (diamines 4a–e) or
at 50 °C (diamines 4f–h) for 2–20 h until the isothiocyanate 3 was
completely consumed [TLC; Rf = 0.58 (EtOAc–PE, 9:1)].
ICH2CO2H (107 mg, 0.58 mmol, 1.2 equiv) was added and the mix-
ture was heated at 50 °C for 7 h. All volatiles were evaporated, sat.
aq NaHCO3 (10 mL) was added, and the resulting suspension was
extracted with EtOAc (3 × 5 mL). The organic extracts were com-
bined, washed with brine (10 mL), dried (Na2SO4), and concentrat-
ed, and the residue was purified by flash column chromatography.
IR (film): 3328 (NH), 1721 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 7.8 Hz, 1 H), 7.28–
7.21 (m, 11 H), 7.21–7.07 (m, 11 H), 7.06–7.01 (m, 1 H), 5.09 (s, 2
H), 4.91 (d, J = 7.4 Hz, 1 H), 4.74 (dt, J = 7.4, 4.5 Hz, 1 H), 2.86
(dd, J = 11.8, 4.5 Hz, 1 H), 2.61 (dd, J = 11.8, 4.5 Hz, 1 H), 1.39 (s,
9 H).
13C NMR (100.6 MHz, CDCl3): δ = 170.1, 152.4, 144.4, 142.2,
135.4, 134.7, 129.4, 129.1, 128.0, 127.8, 126.9, 126.6, 121.3, 119.8,
116.8, 107.5, 82.6, 66.1, 54.6, 34.2, 27.9, 16.0.
Anal. Calcd for C40H39N3O2S: C, 76.77; H, 6.28; N, 6.71. Found: C,
76.37; H, 6.18; N, 6.66.
tert-Butyl N-[1-(Cyclopropylmethyl)-1H-benzimidazol-2-yl]-S-
trityl-L-cysteinate (1d)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 10–15%
EtOAc–PE) to give a white powder; yield: 170 mg (60%); mp 141–
144 °C; [α]D20 –36.5 (c 0.23, acetone); Rf = 0.42 (EtOAc–PE. 1:3).
tert-Butyl N-1H-Benzimidazol-2-yl-S-trityl-L-cysteinate (1a)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 14–20%
EtOAc–PE) to give a white solid; yield: 130 mg (51%; 98% ee by
IR (film): 3325 (NH), 1722 (C=O) cm–1.
20
1H NMR (400 MHz, CDCl3): δ = 7.43–7.39 (m, 1 H), 7.37–7.32 (m,
6 H), 7.19–7.04 (m, 12 H), 5.08 (d, J = 7.4 Hz, 1 H), 4.88 (dt,
J = 7.4, 4.5 Hz, 1 H), 3.88 (dd, J = 15.4, 6.4 Hz, 1 H), 3.81 (dd,
J = 15.4, 6.4 Hz, 1 H), 2.93 (dd, J = 11.8, 4.5 Hz, 1 H), 2.70 (dd,
J = 11.8, 4.5 Hz, 1 H), 1.47 (s, 9 H), 0.90–0.83 (m, 1 H), 0.66–0.60
(m, 2 H), 0.48–0.42 (m, 2 H).
13C NMR (100.6 MHz, CDCl3): δ = 170.4, 152.3, 144.4, 142.2,
134.7 129.4, 127.8, 126.6, 121.0, 119.5, 116.6, 107.4, 82.7, 66.1,
54.7, 46.4, 34.4, 28.0, 10.5, 4.1, 4.0.
chiral HPLC); mp 78–81 °C; [α]D –17.5 (c 1.36, acetone);
Rf = 0.31 (EtOAc–PE, 1:3).
IR (film): 3365 (NH), 1739 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.43–8.10 (s, 1 H), 7.38–7.34 (m,
6 H), 7.22–7.12 (m, 10 H), 7.06–6.97 (m, 3 H), 5.40–5.25 (m, 1 H),
4.54–4.44 (m, 1 H), 2.83 (dd, J = 12.2, 4.8 Hz, 1 H), 2.73 (dd,
J = 12.2, 5.4 Hz, 1 H), 1.43 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): δ = 170.6, 152.9, 144.4, 129.5,
127.9, 126.7, 120.6, 82.9, 66.6, 55.2, 34.4, 27.9.
Anal. Calcd for C37H39N3O2S: C, 75.35; H, 6.67; N, 7.12. Found: C,
75.07; H, 6.93; N, 6.80.
Anal. Calcd for C33H33N3O2S: C, 73.99; H, 6.21; N, 7.84. Found: C,
73.61; H, 6.14; N, 7.75.
tert-Butyl N-(5-Methoxy-1H-benzimidazol-2-yl)-S-trityl-L-cys-
teinate (1e)
HPLC: Daicel CHIRALPAK IA, 25 cm × 4.6 mm i.d.; mobile
phase: 20% i-PrOH–80% hexane; flow rate: 0.9 mL/min; detection:
UV, 254 nm; retention times: 7.9 min [(S)–1a] and 21.3 min [(R)–
1a].
This was prepared by following the general procedure with purifi-
cation of the crude product by column chromatography (silica gel,
25% EtOAc–PE) to give a white powder; yield: 172 mg (63%); mp
20
111–113 °C; [α]D –14.6 (c 1.07, acetone); Rf = 0.48 (EtOAc–PE,
tert-Butyl N-(1-Methyl-1H-benzimidazol-2-yl)-S-trityl-L-cys-
teinate (1b)
50:50).
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 5–15%
EtOAc–PE) to give a white powder; yield: 170 mg (64%; 96% ee
by chiral HPLC); mp 86–88 °C (MeOH); [α]D –5.3 (c 0.42, ace-
tone); Rf = 0.41 (EtOAc–PE, 1:3).
IR (film): 3376 (NH), 1733 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.8–8.0 (br s, 1 H), 7.41–7.31 (m,
6 H), 7.24–7.11 (m, 9 H), 7.09–6.91 (m, 1 H), 6.87–6.67 (m, 1 H),
6.65–6.55 (m, 1 H), 5.50 (br s, 1 H), 4.59–4.44 (m, 1 H), 3.76 (s, 3
H), 2.80–2.70 (m, 2 H), 1.42 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): δ = 170.9, 155.1, 153.2, 144.4,
129.5, 127.9, 126.7, 108.2, 82.9, 66.6, 55.8, 55.3, 34.4, 27.9.
20
IR (film): 3319 (NH), 1724 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.39 (m, 1 H), 7.38–7.34 (m,
6 H), 7.21–7.07 (m, 12 H), 4.91 (d, J = 7.4 Hz, 1 H), 4.84 (dt,
J = 7.4, 4.5 Hz, 1 H), 3.51 (s, 3 H), 2.81 (dd, J = 11.8, 4.5 Hz, 1 H),
2.77 (dd, J = 11.8, 4.5 Hz, 1 H), 1.47 (s, 9 H).
Anal. Calcd for C34H35N3O3S: C, 72.19; H, 6.24; N, 7.43. Found: C,
71.95; H, 6.14; N, 7.24.
13C NMR (100.6 MHz, CDCl3): δ = 170.4, 152.6, 144.4, 134.8,
129.4, 127.8, 126.6, 121.1, 119.6, 116.6, 107.1, 82.7, 66.3, 54.8,
34.3, 28.3, 27.9.
tert-Butyl N-(5-Chloro-1H-benzimidazol-2-yl)-S-trityl-L-cys-
teinate (1f)
This was prepared by following the general procedure with purifi-
cation of the crude product by column chromatography (silica gel,
gradient 1–15% EtOAc–PE) to give a white powder; yield: 164 mg
Anal. Calcd for C34H35N3O2S: C, 74.29; H, 6.42; N, 7.64. Found: C,
73.96; H, 6.30; N, 7.56.
20
(60%); mp 122–124 °C; [α]D –14.7 (c 0.47, acetone); Rf = 0.37
HPLC: Daicel CHIRALPAK IA, 25 cm × 4.6 mm i.d.; mobile
phase: 20% i-PrOH–80% hexane, flow rate: 0.9 mL/min; detection:
(EtOAc–PE, 1:3).
IR (film): 3382 (NH), 1733 (C=O) cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 683–693

690
A. Krasikovs et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 7.38–7.32 (m, 6 H), 7.22–7.15 (m,
7 H), 7.15–7.11 (m, 4 H), 6.98 (dd, J = 8.4, 2.0 Hz, 1 H), 4.50–4.44
(m, 1 H), 2.85 (dd, J = 12.6, 5.6 Hz, 1 H), 2.73 (dd, J = 12.6, 5.0 Hz,
1 H), 1.41 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): δ = 171.3, 153.8, 144.3, 129.4,
127.9, 126.8, 120.6, 83.3, 66.8, 55.2, 34.3, 27.9.
gradient CH2Cl2 to 1% EtOH–CH2Cl2) to give a yellow powder;
yield: 174 mg (62%); mp 177–180 °C; [α]D20 –9.4 (c 2.57, acetone);
Rf = 0.30 (EtOAc–PE, 25:75).
IR (film): 3365 (NH), 1729 (C=O), 1516 (NO2) cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.9–8.6 (m, 1 H), 8.2–7.6 (m, 2
H), 7.43–7.29 (m, 6 H), 7.27–7.11 (m, 9 H), 6.92–6.78 (m, 1 H),
6.05–5.72 (m, 1 H), 4.60–4.50 (m, 1 H), 2.88 (dd, J = 12.4, 5.8 Hz,
1 H), 2.71 (dd, J = 12.4, 4.6 Hz, 1 H), 1.47 (s, 9 H).
Anal. Calcd for C33H32ClN3O2S: C, 69.52; H, 5.66; N, 7.37. Found:
C, 69.31; H, 5.81; N, 7.09.
13C NMR (100.6 MHz, CDCl3): δ = 171.3, 144.1, 129.4, 128, 126.9,
83.9, 67.0, 55.1, 34.2, 27.9.
HRMS (ESI): m/z [M + H]+ calcd for C33H33N4O4S: 581.2223;
found: 581.2191.
tert-Butyl N-[5-(Trifluoromethyl)-1H-benzimidazol-2-yl]-S-tri-
tyl-L-cysteinate (1g)
This was prepared by following the general procedure with purifi-
cation of the crude product by column chromatography (silica gel,
gradient 10–20% EtOAc–PE) to give a white powder; yield: 144 mg
20
(50%); mp 115–118 °C; [α]D –12.5 (c 0.41, acetone); Rf = 0.46
tert-Butyl 2-{(2Z)-2-[(2-Amino-4-nitrophenyl)imino]-4-oxo-1,3-
thiazolidin-3-yl}-3-(tritylsulfanyl)propanoate (8j)
(EtOAc–PE, 1:3).
This was prepared by following the general procedure with purifi-
cation of the crude product by column chromatography (silica gel,
gradient CH2Cl2 to 1% EtOH–CH2Cl2) to give a yellow foam; yield:
45 mg (14%); Rf = 0.56 (MeOH–CH2Cl2, 5:95).
IR (film): 3389 (NH), 3342 (NH), 1717 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1 H), 7.58–7.45 (m, 0.5
H), 7.42–7.28 (m, 6.5 H), 7.22–7.05 (m, 10 H), 6.94–6.72 (m, 1 H),
5.80–5.66 (m, 1 H), 4.58–4.50 (m, 1 H), 2.84 (dd, J = 12.2, 5.6 Hz,
1 H), 2.73 (dd, J = 12.2, 4.6 Hz, 1 H), 1.45 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): δ = 171.7, 154.5, 144.2, 129.4,
127.9, 126.8, 125.0 (d, JC–F = 270 Hz), 83.5, 66.9, 55.1, 34.3, 27.9
IR (film): 3476 (NH), 3368 (NH), 1732 (C=O), 1494 (NO2) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.92 (dd, J = 9.0, 2.6 Hz, 1 H),
7.83 (d, J = 2.6 Hz, 1 H), 7.41–7.36 (m, 6 H), 7.32–7.20 (m, 9 H)
6.60 (d, J = 9.0 Hz, 1 H), 4.91 (dd, J = 11.2, 4.0 Hz, 1 H), 4.46 (s, 2
H), 3.87 (ABq, JAB = 17.2 Hz, 2 H), 3.35 (dd, J = 13.2, 11.2 Hz, 1
H), 2.92 (dd, J = 13.2, 4.0 Hz, 1 H), 1.35 (s, 9 H).
Anal. Calcd for C34H32F3N3O2S: C, 67.64; H, 5.34; N, 6.96. Found:
C, 67.82; H, 5.25; N, 6.79.
13C NMR (100.6 MHz, DMSO-d6): δ = 170.6, 166.4, 156.5, 146.5,
144.2, 138.0, 131.2, 129.6, 128.0, 127.0, 123.0, 116.1, 113.0, 83.3,
67.5, 56.3, 32.6, 30.2, 27.8.
Methyl 2-({(1R)-2-tert-Butoxy-2-oxo-1-[(tritylsulfanyl)meth-
yl]ethyl}amino)-1H-benzimidazole-5-carboxylate (1h)
This was prepared by following the general procedure with purifi-
cation of the crude product by column chromatography (silica gel,
gradient 10–20% EtOAc–PE) to give a white powder; yield: 174 mg
tert-Butyl 2-{2-[(2-Aminopyridin-3-yl)amino]-4-oxo-1,3-thia-
zolidin-3-yl}-3-(tritylsulfanyl)propanoate (8k)
This was prepared by following the general procedure. The product
was isolated as hydroiodide salt; yield: 63 mg (72%). The pure ma-
terial was obtained by crystallization (MeOH); mp 163–165 °C.
20
(61%); mp 116–119 °C; [α]D –30.8 (c 0.82, acetone); Rf = 0.23
(EtOAc–PE, 25:75).
IR (film): 3351 (NH), 1715 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.67 (s, 0.3 H), 8.56 (s, 0.7 H),
8.04 (s, 0.3 H), 7.83–7.69 (m, 0.7 H), 7.60 (s, 1 H), 7.38–7.32 (m,
6.7 H), 7.22–7.11 (m, 9 H), 6.91–6.81 (m, 0.3 H), 5.85–5.60 (m, 1
H), 4.61–4.50 (m, 1 H), 3.89 (s, 3 H), 2.82 (dd, J = 12.4, 5.4 Hz, 1
H), 2.74 (dd, J = 12.4, 4.6 Hz, 1 H), 1.44 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): δ = 171.2, 167.9, 144.2, 129.4,
127.9, 126.8, 83.3, 66.8, 55.1, 51.8, 34.3, 27.9.
1H NMR (400 MHz, DMSO-d6): δ = 14.0–13.0 (br s, 1 H), 7.80 (dd,
J = 6.3, 1.2 Hz, 1 H), 7.62 (dd, J = 7.7, 1.2 Hz, 1 H), 7.36–7.18 (m,
15 H), 6.96 (dd, J = 7.7, 6.3 Hz, 1 H), 5.19 (dd, J = 10.2, 4.7 Hz, 1
H), 4.35 (ABq, JAB = 17.8 Hz, 2 H), 3.76–3.31 (m, 2 H), 2.91 (dd,
J = 12.8, 10.2 Hz, 1 H), 2.82 (dd, J = 12.8, 4.7 Hz, 1 H), 1.28 (s, 9
H).
13C NMR (100.6 MHz, DMSO-d6): δ = 171.5, 166.8, 159.7, 150.2,
144.4, 131.2, 130.6, 129.5, 128.5, 127.3, 113.0, 82.9, 66.9, 55.6,
33.1, 33.0, 27.8.
Anal. Calcd for C35H35N3O4S: C, 70.80; H, 5.94; N, 7.08. Found: C,
70.57; H, 5.88; N, 6.79.
Benzimidazoles 11a–f and 12a–f; General Procedure
CAUTION: Thiophosgene is toxic and causes severe irritation of
the skin, eyes, and respiratory tract.
tert-Butyl N-(5-Cyano-1H-benzimidazol-2-yl)-S-trityl-L-cys-
teinate (1i)
This was prepared by following the general procedure with purifi-
cation of the crude product by column chromatography (silica gel,
gradient CH2Cl2 to 1% EtOH–CH2Cl2) to give a white powder;
yield: 159 mg (59%); mp 138–140 °C; [α]D20 –5.8 (c 1.86, acetone);
Rf = 0.27 (EtOAc–PE, 25:75).
Sat. aq NaHCO3 (5 mL) was added to a suspension of an amino acid
hydrochloride 10 (1.00 mmol) in CH2Cl2 (5 mL) at 0 °C. The mix-
ture was stirred for 10 min then Cl2C=S (100 µL, 1.05 mmol) was
added and the mixture was stirred at 0 °C for 45 min. The layers
were separated and the aqueous phase was extracted with CH2Cl2
(2 × 5 mL). The organic extracts were combined, washed with H2O
(10 mL), and dried (Na2SO4). Removal of the solvent gave the crude
isothiocyanate 3, which was used in the next step without purifica-
tion.
IR (film): 3324 (NH), 2219 (C≡N), 1739 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.05–8.74 (m, 1 H), 7.61–7.24 (m,
8 H), 7.22–6.74 (m, 10 H), 6.12–5.80 (m, 1 H), 4.61–4.50 (m, 1 H),
2.85 (dd, J = 12.4, 5.8 Hz, 1 H), 2.69 (dd, J = 12.4, 4.6 Hz, 1 H),
1.45 (s, 9 H).
Benzene-1,2 diamine 4 (1.00 mmol) was added to a soln of the iso-
thiocyanate in CH2Cl2 (15 mL), and the mixture was stirred at r.t.
for 2 h. The solvent was evaporated to afford the crude thiourea 5.
This was dissolved in MeOH (7 mL) and treated with ICH2CO2H
(223 mg, 1.20 mmol), and the mixture was heated at 50 °C for 5 h.
Volatiles were evaporated, and then sat. aq NaHCO3 (10 mL) was
added. The resulting suspension was extracted with CH2Cl2 (3 × 5
mL). The organic extracts were combined, washed with H2O (10
mL), dried (Na2SO4), and concentrated. The crude product was pu-
rified by flash column chromatography.
13C NMR (100.6 MHz, CDCl3): δ = 171.5, 155.1, 144.1, 129.4,
128.0, 126.9, 118.3, 115.1, 105.0, 83.9, 67.0, 55.1, 34.2, 27.9.
HRMS (ESI): m/z [M + H]+ calcd for C34H33N4O2S: 561.2324;
found: 561.2313.
tert-Butyl N-(5-Nitro-1H-benzimidazol-2-yl)-S-trityl-L-cystein-
ate (1j)
This was prepared by following the general procedure with purifi-
cation of the crude product by column chromatography (silica gel,
Synthesis 2013, 45, 683–693
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iodoacetic Acid in the Synthesis of 2-Aminobenzimidazoles
691
Benzyl N-1H-Benzimidazol-2-ylglycinate (11a)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–7%
EtOH–CH2Cl2) to give a white foam; yield: 248 mg (88%);
Rf = 0.29 (EtOAc).
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O2: 296.1399; found:
296.1403.
HPLC: Daicel CHIRALPAK IA, 25 cm × 4.6 mm i.d.; mobile
phase: i-PrOH–hexane–Et2NH 92:8:0.1%, flow rate: 0.9 mL/min;
detection: UV, 228 nm; retention times: 13.1 min [(R)–12b] and
21.4 min [(S)–12b].
IR (film): 3366 (NH), 1742 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.5–7.8 (br s, 1 H), 7.37–7.23 (m,
7 H), 7.07–7.02 (m, 2 H), 5.53–5.24 (m, 1 H), 5.16 (s, 2 H), 4.30 (s,
2 H).
13C NMR (100.6 MHz, CDCl3): δ = 171.2, 154.1, 135.0, 128.6,
128.5, 128.2, 120.9, 112.6, 67.3, 44.8.
tert-Butyl N-1H-Benzimidazol-2-yl-L-phenylalaninate (11c)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–5%
EtOH–CH2Cl2) to give a yellow powder; yield: 283 mg (84%);
[α]D20 +34.4 (c 0.25, acetone); Rf = 0.48 EtOAc–PE (50:50).
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3O2: 282.1243; found:
IR (film): 3345 (NH), 1729 (C=O) cm–1.
282.1233.
1H NMR (400 MHz, DMSO-d6): δ = 10.8–10.6 (br s, 1 H), 7.33–
7.25 (m, 4 H), 7.24–7.18 (m, 1 H), 7.17–7.11 (m, 2 H), 6.93–6.84
(m, 3 H), 4.62–4.51 (m, 1 H), 3.11 (dd, J = 13.7, 6.2 Hz, 1 H), 3.05
(dd, J = 13.7, 8.0 Hz, 1 H), 1.33 (s, 9 H).
13C NMR (100.6 MHz, DMSO-d6): δ = 172.1, 154.7, 137.9, 129.7,
128.6, 126.9, 119.8, 81.1, 57.4, 37.9, 28.0.
Benzyl N-(1-Methyl-1H-benzimidazol-2-yl)glycinate (12a)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–3%
EtOH–CH2Cl2) to give a white foam; yield: 252 mg (85%);
Rf = 0.25 (EtOAc–PE, 50:50).
IR (film): 3280 (NH), 1731 (C=O) cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C20H24N3O2: 338.1869; found:
1H NMR (400 MHz, CDCl3): δ = 7.50–7.45 (m, 1 H), 7.39–7.30 (m,
5 H), 7.15–7.06 (m, 3 H), 5.24 (s, 2 H), 4.85–4.77 (m, 1 H), 4.41 (d,
J = 4.6 Hz, 2 H), 3.53 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): δ = 171.0, 153.4, 141.5, 135.2,
134.9, 128.6, 128.4, 128.2, 121.4, 119.9, 116.5, 107.3, 67.3, 44.9,
28.2.
338.1869.
tert-Butyl N-(1-Methyl-1H-benzimidazol-2-yl)-L-phenylalani-
nate (12c)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–3%
EtOH–CH2Cl2) to give a foam; yield: 266 mg (85%). The analyti-
cally pure compound was obtained by column chromatography (sil-
HRMS (ESI): m/z [M + H]+ calcd for C17H18N3O2: 296.1399; found:
296.1393.
20
ica gel, 20–40% EtOAc–petroleum ether); [α]D +4.2 (c 0.86,
acetone); Rf = 0.48 (EtOAc–PE, 25:75).
IR (film): 3324 (NH), 1714 (C=O) cm–1.
Methyl (2S)-(1H-Benzimidazol-2-ylamino)(phenyl)acetate
(11b)
1H NMR (400 MHz, CDCl3): δ = 7.51–7.47 (m, 1 H), 7.30–7.20 (m,
3 H), 7.19–7.15 (m, 2 H), 7.15–7.09 (m, 1 H), 7.09–7.05 (m, 2 H),
5.04–4.98 (m, 1 H), 4.73 (d, J = 7.5 Hz, 1 H), 3.45 (s, 3 H), 3.36 (dd,
J = 13.8, 6.1 Hz, 1 H), 3.26 (dd, J = 13.8, 4.9 Hz, 1 H), 1.44 (s, 9 H).
13C NMR (100.6 MHz, CDCl3): δ = 172.2, 153.0, 141.8, 136.4,
134.8, 129.6, 128.2, 126.9, 121.2, 119.7, 116.4, 107.3, 82.5, 56.7,
37.9, 28.0, 27.9.
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 10–50%
EtOAc–PE) to give a white powder; yield: 162 mg (58%; 91% ee,
20
chiral HPLC); mp 170–172 °C; [α]D +108.8 (c 1.02, acetone);
Rf = 0.32 (EtOAc–PE, 50:50).
IR (film): 3359 (NH), 1743 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.56 (br s, 1 H), 7.55 (d,
J = 8.2 Hz, 1 H), 7.52–7.47 (m, 2 H), 7.43–7.32 (m, 3 H), 7.21–7.15
(m, 2 H), 6.94–6.85 (m, 2 H), 5.59 (d, J = 8.0 Hz, 1 H), 3.65 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H26N3O2: 352.2025; found:
352.2033.
13C NMR (100.6 MHz, DMSO-d6): δ = 172.6, 154.5, 137.6, 129.1,
128.6, 128.0, 119.9, 59.6, 52.7.
HRMS (ESI): m/z [M + H]+ calcd for C16H16N3O2: 282.1243; found:
282.1243.
Methyl N-1H-Benzimidazol-2-yl-O-benzyl-L-serinate (11d)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–5%
EtOH–CH2Cl2) to give a foam; yield: 240 mg (74%). The pure com-
20
pound was obtained by crystallization (CCl4); [α]D –2.0 (c 0.27,
HPLC: Daicel CHIRALPAK IA, 25 cm × 4.6 mm i.d.; mobile
phase: i-PrOH–hexane–Et2NH (10:90:0.1), flow rate: 0.9 mL/min;
detection: UV, 228 nm; retention times: 17.0 min [(R)-11b] and
27.7 min [(S)-11b].
MeOH); Rf = 0.21 (EtOAc–PE, 50:50).
IR (film): 3350 (NH), 1744 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.63 (s, 1 H) 7.38–7.26 (m, 5
H), 7.20–7.14 (m, 2 H), 6.97 (d, J = 8.5 Hz, 1 H), 6.92–6.86 (m, 2
H), 4.77–4.70 (m, 1 H), 4.57 (d, J = 12.2 Hz, 1 H), 4.51 (d, J = 12.2
Hz, 1 H), 3.88 (dd, J = 9.6, 4.3 Hz, 1 H), 3.81 (dd, J = 9.6, 4.0 Hz,
1 H), 3.66 (s, 3 H).
13C NMR (100.6 MHz, DMSO-d6): δ = 172.1, 154.8, 138.3, 128.7,
128.0, 127.9, 119.9, 72.6, 70.2, 56.0, 52.5.
HRMS (ESI): m/z [M + H]+ calcd for C18H20N3O3: 326.1505; found:
326.1487.
Methyl (2S)-[(1-Methyl-1H-benzimidazol-2-yl)amino](phenyl)-
acetate (12b)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 10–50%
EtOAc–PE) to give a white powder; yield: 221 mg (75%; 87% ee
by chiral HPLC); mp 143–146 °C; Rf = 0.35 (EtOAc–PE, 50:50);
[α]D20 +76.8 (c 1.32, acetone).
IR (film): 3349 (NH), 1742 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.56–7.53 (m, 2 H), 7.45–7.34
(m, 4 H), 7.26–7.18 (m, 2 H), 7.02–6.94 (m, 2 H), 5.65 (d, J = 8.0
Hz, 1 H), 3.66 (s, 3 H), 3.60 (s, 3 H).
13C NMR (100.6 MHz, DMSO-d6): δ = 172.6, 154.6, 142.2, 137.2,
135.8, 129.0, 128.6, 128.5, 120.9, 119.4, 116.0, 108.2, 60.2, 52.6,
29.1.
Methyl O-Benzyl-N-(1-methyl-1H-benzimidazol-2-yl)-L-seri-
nate (12d)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–3%
EtOH–CH2Cl2) to give a white foam; yield: 310 mg (91%); [α]D
–6.5 (c 1.09, acetone); Rf = 0.39 (EtOAc–PE, 50:50).
20
IR (film): 3342 (NH), 1744 (C=O) cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 683–693

692
A. Krasikovs et al.
PAPER
20
1H NMR (400 MHz, CDCl3): δ = 7.46–7.43 (m, 1 H), 7.36–7.25 (m,
5 H), 7.15–7.04 (m, 3 H), 5.11 (d, J = 8.5 Hz, 1 H), 4.98 (dt, J = 8.5,
3.0 Hz, 1 H), 4.59 (d, J = 12.2 Hz, 1 H), 4.51 (d, J = 12.2 Hz, 1 H),
4.03 (dd, J = 9.5, 3.0 Hz, 1 H), 3.96 (dd, J = 9.5, 3.0 Hz, 1 H), 3.77
(s, 3 H), 3.53 (s, 3 H).
13C NMR (100.6 MHz, CDCl3): δ = 171.7, 153.2, 141.9, 137.6,
135.0, 128.4, 127.8, 127.6, 121.2, 119.7, 116.5, 107.2, 73.3, 69.9,
56.2, 52.6, 28.3.
EtOAc–PE) to give a foam; yield: 193 mg (63%); [α]D –48.4 (c
1.12, acetone); Rf = 0.19 (EtOAc–PE, 50:50).
IR (film): 3342 (NH), 1739 (C=O), 1733 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.44 (m, 1 H), 7.13–7.03 (m,
3 H), 5.08 (d, J = 7.9 Hz, 1 H), 4.85 (td, J = 7.9, 5.0 Hz, 1 H), 3.78
(s, 3 H), 3.66 (s, 3 H), 3.51 (s, 3 H), 2.60–2.34 (m, 3 H), 2.24–2.13
(m, 1 H).
13C NMR (100.6 MHz, CDCl3): δ = 173.7, 173.7, 153.3, 141.9,
134.9, 121.2, 119.8, 116.7, 107.3, 55.2, 52.6, 51.8, 30.3, 28.2, 27.4.
Anal. Calcd for C19H21N3O3: C, 67.24; H, 6.24; N, 12.38. Found: C,
67.02; H, 6.16; N, 12.33.
HRMS (ESI): m/z [M + H]+ calcd for C15H20N3O4: 306.1454; found:
Methyl N2-1H-Benzimidazol-2-yl-N6-[(phenylacetyl)oxy]-L-ly-
sinate (11e)
306.1442.
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–3%
EtOH–CH2Cl2) to give a foam; yield: 350 mg (85%). The analyti-
cally pure compound was obtained by column chromatography (sil-
ica gel, 40% EtOAc–petroleum ether); [α]D –10.3 (c 0.54,
acetone); Rf = 0.32 (EtOAc).
Acknowledgment
The authors thank Dr. S. Belyakov for X-ray crystallographic ana-
lysis and Dr. James Mannion, CEO & President, Galleon Phar-
maceuticals for support.
20
IR (film): 3332 (NH), 1696 (C=O) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.60 (s, 1 H) 7.34–7.17 (m, 4
H) 7.13–7.06 (m, 2 H) 6.94 (d, J = 8.7 Hz, 1 H) 6.90–6.77 (m, 2 H)
4.96 (s, 2 H) 4.35 (td, J = 8.7, 5.2 Hz, 1 H) 3.60 (s, 3 H) 2.99–2.91
(m, 2 H) 1.82–1.62 (m, 2 H) 1.47–1.30 (m, 4 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
References
13C NMR (100.6 MHz, CDCl3): δ = 174.1, 156.8, 154.1, 136.5,
128.6, 128.2, 128.0, 120.8, 66.7, 55.4, 52.4, 40.4, 31.8, 29.3, 22.2.
HRMS (ESI): m/z [M + H]+ calcd for C22H27N4O4: 411.2032; found:
411.2007.
(1) (a) Alamgir, M.; Black, D. St. C.; Kumar, N. Top.
Heterocycl. Chem 2007, 9, 87. (b) Boiani, M.; Gonzalez, M.
Mini-Rev. Med. Chem. 2005, 5, 409. (c) Wang, J.; Hou, T.
J. Chem. Inf. Model. 2010, 50, 55.
(2) Grant, F. S.; Konradi, A. W.; Pleiss, M. A.; Thorsett, E. D.
US 6,545,003, 2003.
Methyl N2-(1-Methyl-1H-benzimidazol-2-yl)-N6-[(phenylace-
tyl)oxy]-L-lysinate (12e)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 1–3%
EtOH–CH2Cl2) to give a foam; yield: 365 mg (80%); [α]D20 –26.5
(c 0.58, acetone); , Rf = 0.16 (EtOAc–PE, 50:50).
(3) Wythes, M. J.; Palmer, M. J.; Kemp, M. I.; Mackenny, M.
C.; Maguire, R. J.; Blake, J. F. WO 0005231, 2000.
(4) Keenan, R. M.; Miller, W. H. WO 9412478 1994.
(5) Poitout, L.; Brault, V.; Sackur, V.; Pierre, C. R.; Pascale, P.
US 20090270372, 2009.
IR (film): 3335 (NH), 1724 (C=O) cm–1.
(6) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893.
1H NMR (400 MHz, CDCl3): δ = 7.48–7.44 (m, 1 H), 7.37–7.26 (m,
5 H), 7.12–7.04 (m, 3 H), 5.09–5.06 (m, 2 H), 4.89–4.76 (m, 3 H),
3.77 (s, 3 H), 3.53 (s, 3 H), 3.24–3.15 (m, 2 H), 2.09–1.98 (m, 1 H),
1.93–1.80 (m, 1 H), 1.65–1.37 (m, 4 H).
13C NMR (100.6 MHz, CDCl3): δ = 174.4, 156.5, 153.4, 141.9,
136.5, 134.9, 128.5, 128.1, 128.0, 121.2, 119.7, 116.6, 107.2, 66.5,
55.4, 52.5, 40.5, 32.2, 29.5, 28.2, 22.3.
(7) For selected recent examples of nucleophilic replacements
of Cl, see: (a) Sun, A.; Ndungu, J. M.; Krumm, S. A.; Yoon,
J.-J.; Thepchatri, P.; Natchus, M.; Plemper, R. K.; Snyder, J.
P. ACS Med. Chem. Lett. 2011, 2, 798. (b) Peddibhotla, S.;
Shi, R.; Khan, P.; Smith, L. H.; Mangravita-Novo, A.;
Vicchiarelli, M.; Su, Y.; Okolotowicz, K. J.; Cashman, J. R.;
Reed, J. C.; Roth, G. P. J. Med. Chem. 2010, 53, 4793.
(c) Almasi, D.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera,
C. J. Org. Chem. 2009, 74, 6163. (d) Lahue, B. R.; Ma, Y.;
Shipps, G. W.; Seghezzi, W.; Herbst, R. Bioorg. Med. Chem.
Lett. 2009, 19, 3405. (e) Moriya, M.; Kishino, H.; Sakuraba,
S.; Sakamoto, T.; Suga, T.; Takahashi, H.; Suzuki, T.; Ito,
M.; Ito, J.; Moriya, R.; Takenaga, N.; Iwaasa, H.; Ishihara,
A.; Kanatani, A.; Fukami, T. Bioorg. Med. Chem. Lett. 2009,
19, 3568. (f) Bonfanti, J-F.; Meyer, C.; Doublet, F.; Fortin,
J.; Muller, P.; Queguiner, L.; Gevers, T.; Janssens, P.; Szel,
H.; Willebrords, R.; Timmerman, P.; Wuyts, K.; van
Remoortere, P.; Janssens, F.; Wigerinck, P.; Andries, K.
J. Med. Chem. 2008, 51, 875. (g) Arienzo, R.; Cramp, S.;
Dyke, H. J.; Lockey, P. M.; Norman, D.; Roach, A. G.;
Smith, P.; Wong, M.; Wren, S. P. Bioorg. Med. Chem. Lett.
2007, 17, 1403. (h) Martin, R. E.; Green, L. G.; Guba, W.;
Kratochwil, N.; Christ, A. J. Med. Chem. 2007, 50, 6291.
(i) Ognyanov, V. I.; Balan, C.; Bannon, A. W.; Bo, Y.;
Dominguez, C.; Fotsch, C.; Gore, V. K.; Klionsky, L.; Ma,
V. V.; Qian, Y.-X.; Tamir, R.; Wang, X.; Xi, N.; Xu, S.; Zhu,
D.; Gavva, N. R.; Treanor, J. J. S.; Norman, M. H. J. Med.
Chem. 2006, 49, 3719. For replacement of a methylsulfonyl
HRMS (ESI): m/z [M + H]+ calcd for C23H29N4O4: 425.2189; found:
425.2137.
Dimethyl N-1H-Benzimidazol-2-yl-L-glutamate (11f)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 10–25%
20
EtOAc–PE) to give a foam; yield: 172 mg (59%); [α]D –24.6 (c
0.86, acetone); Rf = 0.16 (EtOAc–PE, 50:50).
IR (film): 3355 (NH), 1739 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.6–8.6 (br s, 1 H), 7.36–7.24 (m,
2 H), 7.08–7.01 (m, 2 H), 5.8–5.4 (br s, 1 H), 4.71–4.65 (m, 1 H),
3.76 (s, 3 H), 3.68 (s, 3 H), 2.54 (t, J = 7.0 Hz, 2 H), 2.35–2.24 (m,
1 H), 2.19–2.08 (m, 1 H).
13C NMR (100.6 MHz, CDCl3): δ = 173.9, 173.5, 154.1, 120.7,
55.1, 52.6, 51.9, 30.1, 27.7.
HRMS (ESI): m/z [M + H]+ calcd for C14H18N3O4: 292.1297; found:
292.1285.
Dimethyl N-(1-Methyl-1H-benzimidazol-2-yl)-L-glutamate
(12f)
This was prepared by following the general procedure with purifi-
cation by column chromatography (silica gel, gradient 10–25%
Synthesis 2013, 45, 683–693
© Georg Thieme Verlag Stuttgart · New York

PAPER
group, see: (j) Lan, P.; Romero, F. A.; Malcolm, T. S.;
Iodoacetic Acid in the Synthesis of 2-Aminobenzimidazoles
693
R.; Pick, T. E.; Poon, D. J.; Ryckman, D.; Siesel, D. A.;
Stevens, B. D.; Wodka, D.; Makara, G. M. Tetrahedron Lett.
2008, 49, 1910.
Stillwell, B. S.; Swiftney, T.; van Dyck, J. P.; Zhang, C.; Ji,
N. Tetrahedron Lett. 2010, 51, 5319.
(8) (a) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178.
(b) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A.
Org. Lett. 2009, 11, 1607.
(19) (a) Hamley, P.; Tinker, A. C. Bioorg. Med. Chem. Lett.
1995, 5, 1573. (b) Taniguchi, K.; Shigenaga, S.; Ogahara,
T.; Fujitsu, T.; Matsuo, M. Chem. Pharm. Bull. 1993, 41,
301.
(20) A tetrahedral intermediate in the formation of 2-amino-
benzimidazoles has been proposed: see ref. 15c.
(21) To the best of our knowledge, iodoacetic acid has never been
used as desulfurizing agent in the synthesis of benzimid-
azoles.
(22) The structure of 1b was supported by a single-crystal X-ray
analysis.
(23) Meng, G.; Zheng, M.; Dong, M.; Qu, Q. Org. Prep. Proced.
Int. 2012, 44, 184.
(9) (a) Hong, Y.; Tanoury, G. J.; Wilkinson, H. S.; Bakale, R.
P.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 1997,
38, 5607. (b) Hong, Y. P.; Senanayake, C. H.; Xiang, T. J.;
Vandenbossche, C. P.; Tanoury, G. J.; Bakale, R. P.; Wald,
S. A. Tetrahedron Lett. 1998, 39, 3121. (c) Hooper, M. W.;
Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68,
2861. (d) Wang, X.; Bhatia, P. A.; Daanen, J. F.; Latsaw, S.
P.; Rohde, J.; Kolasa, T.; Hakeem, A. A.; Matulenko, M. A.;
Nakane, M.; Uchic, M. E.; Miller, L. N.; Chang, R.;
Moreland, R. B.; Brioni, J. D.; Steward, A. O. Bioorg. Med.
Chem. 2005, 13, 4667.
(24) For selected examples of the use of NaOAc as a base, see:
(a) Erol, S.; Dogan, I. J. Org. Chem. 2007, 72, 2494.
(b) Obushak, N. D.; Matiichuk, V. S.; Martyak, R. L. Chem.
Heterocycl. Comp. 2003, 39, 878. (c) Choubey, V. N.;
Singh, H. Bull. Chem. Soc. Jpn. 1970, 43, 2233.
(25) (a) Presumably, the proton of the 9k·HI salt resides mainly
on the 2-aminopyridine moiety, thereby further decreasing
its nucleophilicity [pKa (DMSO) = 27.72 for 2-amino-
pyridine (ref. 25a) and pKa (DMSO) = 21.0 for thiourea (ref.
25b)]: (b) Bordwell, F. G.; Algrim, D. J. J. Am. Chem. Soc.
1988, 110, 2964. (c) Bordwell, F. G.; Ji, G. Z. J. Am. Chem.
Soc. 1991, 113, 8398; Note, however, that in the crystal
lattice, the proton of 8k•HI is located on the pyridine
nitrogen, as evidenced by single-crystal X-ray analysis.
(26) Crystallographic data for compounds 1b and 8k have been
deposited with the accession numbers CCDC 912871 and
912872, respectively, and can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033;
E-mail: deposit@ccdc.cam.ac.uk; Web site:
(10) (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(b) Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.;
Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (c) Deng,
X.; McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74,
5742. (d) Lv, X.; Bao, W. J. Org. Chem. 2009, 74, 5618.
(11) L-Cysteine is especially susceptible to racemization in
solution-phase peptide synthesis, see: (a) Barber, M.; Jones,
J. H.; Witty, M. J. J. Chem. Soc., Perkin Trans. 1 1979, 2425.
It is also susceptible to racemization in solid-phase peptide
synthesis, see: (b) Han, Y.; Albericio, F.; Barany, G. J. Org.
Chem. 1997, 62, 4307.
(12) Kokotos, C. G.; Kokotos, G. Adv. Synth. Catal. 2009, 351,
1355.
(13) (a) Floch, L.; Uher, M.; Leško, J. Collect. Czech. Chem.
Commun. 1989, 54, 206. (b) Perkins, J. L.; Zartman, A. E.;
Meissner, R. S. Tetrahedron Lett. 1999, 40, 1103.
(14) (a) Wang, X.; Zhang, L.; Xu, Y.; Krishnamurthy, D.;
Senanayake, C. H. Tetrahedron Lett. 2004, 45, 7167.
(15) (a) Carpenter, R. D.; Andrei, M.; Lau, E. Y.; Lightstone, F.
C.; Liu, R.; Lam, K. S.; Kurth, M. J. J. Med. Chem. 2007, 50,
5863. (b) Carpenter, R. D.; DeBredt, P. B.; Lam, K. S.;
Kurth, M. J. J. Comb. Chem. 2006, 8, 907. (c) Cee, V. J.;
Downing, N. S. Tetrahedron Lett. 2006, 47, 3747.
(d) Krchňák, V.; Smith, J.; Vágner, J. Tetrahedron Lett.
2001, 42, 1627.
(16) (a) Ghosh, H.; Yella, R.; Nath, J.; Patel, B. K. Eur. J. Org.
Chem. 2008, 6189.
(17) (a) Heinelt, U.; Schulthesis, D.; Jäger, J.; Lindenmaier, M.;
Pollex, A.; Beckmann, H. G. S. Tetrahedron 2004, 60, 9883.
(18) Artman, G. D. III; Solovay, C. F.; Adams, C. M.; Diaz, B.;
Dimitroff, M.; Ehara, T.; Gu, D.; Ma, F.; Liu, D.; Miller, B.
www.ccdc.cam.ac.uk/conts/retrieving.html.
(27) Determined by HPLC on a chiral stationary phase; see the
experimental section for details. tert-Butyl S-trityl-l-cys-
teinate of 98% ee optical purity was used as the starting
material in all experiments.
(28) Partial racemization of an asymmetric center occurred in the
l-phenylglycine-derived benzimidazoles 11b (91% ee) and
12b (87% ee), as evidenced by chiral HPLC assay (see the
experimental section for details).
(29) Omar, A.-M. M. E.; Habib, N. S.; Aboulwafa, O. M.
Synthesis 1977, 864.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 683–693