Towards a Series of Chiral Primary Amines Bearing α-Amino Acid and Benzo[d]imidazole Pendants, and Their Application in Asymmetric Aldol Reactions

Article abstract of DOI:10.1055/s-0036-1588107

A straightforward reaction path towards chiral primary amines bearing α-amino acid and benzo[d]imidazole pendants has been developed. Six starting essential α-amino acids were converted into the target chiral amines in a four-step synthesis. The prepared

Full text of DOI:10.1055/s-0036-1588107

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
P. H. Mohite et al.
Paper
Synthesis
Towards a Series of Chiral Primary Amines Bearing α-Amino Acid
and Benzo[d]imidazole Pendants, and Their Application in Asym-
metric Aldol Reactions
Pravinkumar Hansraj Mohite
Me
Pavel Drabina
R
N
R
HO
O
Filip Bureš*
N
NH2
NHBoc
Institute of Organic Chemistry and Technology, Faculty of
Chemical Technology, University of Pardubice, Studentská 573,
Pardubice 53210, Czech Republic
organocatalyst
6 examples
O
filip.bures@upce.cz
O
O
HO
yield 45–74%
dr up to 97:3
ee up to 71%
O
O
organocatalysis
N
N
H
H
Received: 03.10.2016
Accepted after revision: 02.11.2016
Published online: 08.12.2016
oms, acid/base properties, imidazole tautomerism, metal
ion chelating ability, and easy synthesis, may act as an ac-
tive part of a chiral ligand and be applied in asymmetric ca-
talysis.8 Hence, based on our recent preliminary communi-
cation,9 we report herein a straightforward synthetic meth-
odology towards a series of primary amines 5a–h bearing
α-amino acid and benzo[d]imidazole pendants (Figure 1),
and their applications as organocatalysts in asymmetric al-
dol reactions.
DOI: 10.1055/s-0036-1588107; Art ID: ss-2016-z0692-op
Abstract A straightforward reaction path towards chiral primary
amines bearing α-amino acid and benzo[d]imidazole pendants has
been developed. Six starting essential α-amino acids were converted
into the target chiral amines in a four-step synthesis. The prepared
amines were screened as organocatalysts in the direct asymmetric aldol
reaction between 4-nitrobenzaldehyde or isatin and acetone or cyclo-
hexanone. The aldol adducts were obtained in good chemical yields,
diastereoselectivity up to 97:3 (reactions with cyclohexanone), and en-
antioselectivity up to 71% ee. Trifluoroacetic acid and benzoic acid
proved to be the best cocatalysts for the aldol process on 4-nitrobenzal-
dehyde and isatin, respectively.
Me
R
N
N
NH2
5a, R = Me (
)
5e, R = i-Bu (S)
5f, R = s-Bu (S,S)
5g, R = CH2Ph (S)
5h, R = (1-methylindol-3-yl)methyl (S)
Key words α-amino acids, benzo[d]imidazoles, amines, organocataly-
sis, aldol reaction
5b, R = Me (R)
5c, R = Me (S)
5d, R = i-Pr (S)
Figure 1 General structure of target primary amines 5a–h bearing α-
amino acid and benzo[d]imidazole pendants
The field of organocatalyzed asymmetric reactions has
been rapidly developing in the recent years. The methodol-
ogy for such reactions generally involves an optically pure
and readily available organic substance as organocatalyst, is
metal free, and can also be considered as nontoxic and en-
vironmentally friendly.1 Amines represent a group of reac-
tive and valuable organic compounds that can also be used
as organocatalysts.2,3 One of the most widely explored
types of organocatalysts are undoubtedly secondary
amines derived from proline.4 Besides these successful cat-
alysts, various primary amines have also been recently in-
troduced as suitable organocatalysts.5 Their parent back-
bone is often derived from an α-amino acid as a suitable
and readily available source of chirality.6 In this respect, our
recent synthetic attempts were focused on the develop-
ment of new chiral imidazole derivatives bearing various
essential α-amino acid pendants.7 Five-membered imidaz-
ole, which features a variety of useful properties including
the presence of two lone electron pairs on the nitrogen at-
The aldol reaction, known for more than 160 years, is
one of the most-explored fundamental carbon–carbon
bond-forming reactions.10 This synthetic tool allows the
stereoselective formation of aldol products with stereogen-
ic centers at the α- and β-carbon atoms. These aldol prod-
ucts are immensely valuable in the synthesis of architectur-
ally interesting and biologically important natural prod-
ucts, particularly of polyoxygenated compounds. Hence, an
availability of various strategies, protocols, and catalysts for
asymmetric aldol reactions seems to be necessary.1a The
classical aldol reaction is highly atom-economical but suf-
fers from low chemo- and regioselectivity. Besides transi-
tion-metal catalysts, homo-/heterogenous catalysts,
Brønsted and Lewis acids/bases, and biocatalysts, organoca-
talysis utilizing small organic molecules seems to be a suit-
able strategy towards asymmetric aldol reactions. Organo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
P. H. Mohite et al.
Paper
Synthesis
catalyzed aldol reactions have been utilized for the con-
struction of miscellaneous organic substances including
natural products (epothilone), pharmaceuticals (atorvasta-
tin, erythromycin, steroids), explosives (pentaerythritol
tetranitrate), and α,β-unsaturated carbonyl compounds (re-
active substrates). Among these and many others, 3-hy-
droxy-2-oxindole is one of the key structural units found in
a large variety of natural products and drug candidates,
having a wide spectrum of biological activities.11 In partic-
ular, the 3-alkyl-3-hydroxy-2-oxindole structural motif is
of great importance in medicinal chemistry. This motif can
be found in many drugs and natural products, such as TMC-
95A–D,11d,12 donaxaridine,13 the convolutamydines,13 dioxi-
brassinine,14 and 3′-hydroxyglucoisatisin.15 These mole-
cules display diverse biological and pharmacological activi-
ties, such as potent antioxidant, anticonvulsant, anticancer,
anti-HIV, and neuroprotective properties. The most
straightforward synthetic approach towards 3-substituted
3-hydroxy-2-oxindoles is via nucleophilic addition to isatin
(aldol process). In 2005, Tomasini and co-workers reported
the first enantioselective aldol reaction of isatin with ace-
tone using 10% of a dipeptide containing a secondary amine
at the N-terminus.16 Quinidine thiourea may also serve as
an organocatalyst for the reaction of inactivated ketones
and activated carbonyl compounds.17 Primary amines, as
well as carbohydrate-derived alcohols, were successfully
screened as organocatalysts in enantioselective aldol pro-
cesses between isatins and cyclohexanone or acetophe-
none.18,19 Especially primary amines turned out to efficient-
ly catalyze aldol processes of isatin derivatives20–24 and,
therefore, we focused our further attention on utilizing
amines 5a–h in asymmetric aldol reactions to afford 3-sub-
stituted 3-hydroxyindolin-2-ones in a single operational
method.
The synthesis of benzo[d]imidazole-derived primary
amines 5a–h was carried out via the reaction path shown in
Scheme 1.9 Commercially available, Boc-protected (±)-ala-
nine, (R)-alanine, (S)-alanine, (S)-valine, (S)-leucine, (S,S)-
isoleucine, (S)-phenylalanine, and (S)-1-methyltryptophan
(1a–h) were used as starting materials. These N-Boc-α-ami-
no acids were activated via mixed anhydride (ClCO2Me,
Et3N, DMF) and then treated with o-phenylenediamine to
afford amino amides 2a–h in 71–84% yield. Amides 2a–h
were directly cyclized to the benzo[d]imidazole derivatives
3a–h by treatment with acetic acid. Subsequent N-alkyla-
tion was performed to avoid benzo[d]imidazole tautomer-
ism. Thus, the benzo[d]imidazole derivatives 3a–h were
treated with lithium hexamethyldisilazide and iodometh-
ane to provide the N-methyl derivatives 4a–h in 50–86%
isolated yield. In contrast to products 4a–f and 4h, a partial
racemization of phenylalanine derivative 4g was observed
during this step (52% ee). Unfortunately, all attempted alter-
native N-alkylation systems, including those using Et3N and
Na2CO3, also resulted in partial racemization of 4g.25 Finally,
target amines 5a–g were obtained by Boc group removal
using trifluoroacetic acid. Boc group removal from 4g was
accompanied by further racemization, and 5g was obtained
with only 20% ee. Chemical and optical purities of all target
compounds and intermediates were verified by 1H NMR, 13
C
NMR, HR-MALDI-MS, and chiral-phase HPLC analysis (see
the Supporting Information).
R
H
1. ClCO2Me, Et3N, DMF,
–20 °C, 15 min
N
R
HO
O
NHBoc
O
2. o-phenylenediamine, DMF,
20 °C, 4 h
NHBoc
NH2
2a–h
1a–h
AcOH, 65 °C, 1 h
Me
N
H
1. LHMDS, THF,
R
R
N
0 °C, 30 min
2. MeI, 20 °C, 3 h
NHBoc
N
NHBoc
N
4a–h
3a–h
TFA, 20 °C, 1 h
Me
5a, R = Me (
5b, R = Me (R) 5f, R = s-Bu (S,S)
5c, R = Me (S) 5g, R = CH2Ph (S)
)
5e, R = i-Bu (S)
R
N
N
NH2
5d, R = i-Pr (S) 5h, R = (1-methylindol-3-yl)methyl (S)
5a–h
Scheme 1 Synthesis of primary amines 5a–h
All synthesized primary amines, except 5g, were stud-
ied as organocatalysts in the direct aldol reaction. The ini-
tial screening was carried out utilizing an acid-catalyzed re-
action with 4-nitrobenzaldehyde (6) as acceptor and ace-
tone (7) as donor (Table 1). Trifluoroacetic acid was used as
a proton source. The optimized reaction catalyzed by race-
mic amine (±)-5a derived from alanine afforded aldol prod-
uct 8 in 51% yield and with the anticipated 0% ee (Table 1,
entry 1). The corresponding catalysts (R)-5b and (S)-5c af-
forded aldol product 8 in 40% and 46% yield, respectively,
and modest optical purity of 32% ee in both cases (Table 1,
entries 2 and 3). In general, all organocatalysts having S-
configuration provided the R-configured aldol, while amine
(R)-5b provided the opposite (S)-8 enantiomer. This is in
agreement with the observations of Vincent and co-work-
ers.26 In the series of amines bearing aliphatic residues (5b–
f), the attained enantiomeric excess steadily increased with
increasing bulkiness of the R substituent (Table 1, entries
2–6). Hence, the highest enantiomeric excess of 65% was
achieved with amine 5f derived from isoleucine (Table 1,
entry 6). On the contrary, attachment of a heterocyclic (in-
dolyl) moiety, as in catalyst 5h derived from tryptophan, re-
duced the stereochemical outcome of this aldol process
very significantly (Table 1, entry 7).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
P. H. Mohite et al.
Paper
Synthesis
Table 1 Aldol Reaction of 4-Nitrobenzaldehyde with Acetonea
tained aldol products depends on the configuration of the
catalyst used (e.g., 5b vs 5c). Whereas the attained ee for
the syn-stereoisomers is modest (10–32%), the ee values for
the dominant anti-10 range from 29% to 62%. The highest
enantiomeric excesses of 62% and 39% were achieved with
the aldol reaction catalyzed by amines 5d and 5f derived
from valine and isoleucine, respectively (Table 2, entries 4
and 6). Hence, branching of the R substituent seems to be
crucial.
O
OH
O
O
H
5 (9 mol%)
TFA (4.5 mol%)
O2N
O2N
7
6
8
Entry
Catalyst
Yieldb (%)
Config.c
eed (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
51
40
46
48
51
59
51
±
S
0
32
32
49
59
65
3
In addition, we have investigated the catalytic perfor-
mance of amines 5a–f,h in the direct aldol reaction of isatin
(11). Both acetone (7) and cyclohexanone (9) were used as
donors (Table 3 and 4). In initial optimization attempts, a
model reaction was carried out between 11 and 7 using 10
mol% of catalyst 5 (Table 3). It has been well documented
that additives may improve the catalytic efficiency via fast
enamine formation.28 Accordingly, we examined trifluoro-
acetic, acetic, and benzoic acids as proton sources (30
mol%).5a As seen in Table 3, addition of benzoic acid result-
ed in better catalytic efficiency (attained chemical yields
and enantioselectivities) than the other two acid additives.
Under these conditions, the aldol process between isatin
(11) and acetone (7) utilizing the catalyst 5/PhCO2H system
afforded product 12 in 56–74% yield and 3–24% ee (Table 3).
A clear trend in increasing enantioselectivity, from 4% to
24% ee (Table 3, entries 4 → 7 → 10 → 13 → 16), can be seen
within the series of amines 5b–f with aliphatic residues.
This is in accordance with the observation made for the al-
dol reaction of 4-nitrobenzaldehyde (6) with acetone (Table
1). The highest chemical yields of 12 (74% and 70%) and en-
antioselectivities (16% and 24% ee) were obtained for the
most sterically hindered catalysts 5e and 5f derived from
leucine and isoleucine, respectively (Table 3, entries 13 and
R
R
R
R
R
5h
a Reaction conditions: 6 (1.0 mmol), 7 (7.5 mL), 5 (0.09 mmol), TFA (3.5
μL, 0.045 mmol), 25 °C, 24 h.
b Isolated chemical yield after silica gel column chromatography (EtOAc/
hexane, 1:1).
c Determined from the optical rotation of aldol 8.4a
d Determined by chiral-phase HPLC analysis (Chiralpak AS-H column).9
The catalytic activities of primary amines 5a–f,h were
further evaluated in the aldol process performed with cy-
clohexanone (9) (Table 2). The isolated chemical yields
ranged from 46% to 64% and slightly increased with the ex-
tension of the catalyst R substituent. The aldol process with
9 afforded product 10 as a set of syn- and anti-diastereoiso-
mers with anti-10 dominant, regardless of the structure of
the catalyst used. The reaction catalyzed by amines 5a, 5b,
and 5c derived from alanine afforded 0/0%, 32/29%, and
23/32% ee for the syn/anti-diastereoisomers, respectively
(Table 2, entries 1–3). The absolute configuration of the ob-
Table 2 Aldol Reaction of 4-Nitrobenzaldehyde with Cyclohexanonea
OH
O
O
O
OH
O
H
5 (9 mol%)
TFA (4.5 mol%)
O2N
O2N
O2N
6
9
anti-10
syn-10
Entry
Catalyst
Yieldb (%)
syn/anti,c de
eed (%) (syn)
eed (%) (anti)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
48
46
49
51
60
64
49
2:98, 96
3:97, 94
17:83, 66
7:93, 86
4:96, 92
8:92, 84
12:88, 76
0
0
32 (2S,1′S)
23 (2R,1′R)
32 (2R,1′R)
23 (2R,1′R)
31 (2R,1′R)
10 (2R,1′R)
29 (2R,1′S)
32 (2S,1′R)
62 (2S,1′R)
32 (2S,1′R)
39 (2S,1′R)
36 (2S,1′R)
5h
a Reaction conditions: 6 (1.0 mmol), 9 (7.5 mL), 5 (0.09 mmol), TFA (3.5 μL, 0.045 mmol), 25 °C, 72 h.
b Isolated chemical yield after silica gel column chromatography (EtOAc/hexane, 1:1).
c Determined by 1H NMR and chiral-phase HPLC analysis (Chiralpak AD-H column).9
d Absolute configuration was determined by comparison of chiral-phase HPLC analyses with reported data.5h
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
P. H. Mohite et al.
Paper
Synthesis
16). Similar to the aldol reaction of 6 with acetone (Table 1),
amine 5h bearing the tryptophan pendant showed very low
catalytic performance (Table 3, entries 17–19).
line showed the highest diastereoselectivity (94% de), while
the leucine and isoleucine derivatives 5e and 5f afforded
syn-13 with the highest enantioselectivities of 62% and 71%
ee.
Table 3 Optimization Study of the Model Aldol Reaction of Isatin with
Acetonea
Table 4 Aldol Reaction of Isatin with Cyclohexanonea
O
O
O
O
HO
O
O
O
HO
HO
5
5 (10 mol%)
O
O
(10 mol%)
acid (30 mol%)
O
O
O
N
N
PhCO2H
(30 mol%)
H
H
N
H
N
H
N
H
7
11
12
syn-13
anti-13
9
11
Entry
Catalyst
Acid
Yieldb (%)
Config.c eed (%)
Entry Catalyst Yieldb (%) syn/antic, de
eed (%) (anti) eed (%) (syn)
1
2
5a
5b
5b
5b
5c
5c
5c
5d
5d
5d
5e
5e
5e
5f
PhCO2H
TFA
56
58
64
65
64
66
68
57
59
67
62
64
74
67
72
70
61
62
66
±
R
R
R
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
0
1
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
51
48
50
60
46
48
60:40, 20
55:45, 10
80:20, 60
97:3, 94
0
6
0
7 (3S,1′R)
7 (3R,1′S)
36 (3R,1′S)
62 (3R,1′S)
71 (3R,1′S)
3
AcOH
PhCO2H
TFA
2
4
4
4
25
49
45
5
1
89:11, 78
83:17, 66
6
AcOH
PhCO2H
TFA
2
7
4
a Reaction conditions: 11 (0.10 mmol), 9 (1 mL), 5 (0.01 mmol), PhCO2H
(0.03 mmol), 5 °C, 108 h.
8
3
b Isolated chemical yield after silica gel column chromatography (EtOAc/
hexane, 1:1).
9
AcOH
PhCO2H
TFA
5
c Determined by 1H NMR and chiral-phase HPLC analysis (Chiralcel OJ-H col-
umn).27
10
11
12
13
14
15
16
17
18
19
6
d Determined by comparison of chiral-phase HPLC analyses with reported
data.27
12
15
16
18
22
24
1
AcOH
PhCO2H
TFA
Based on our observations and the absolute configura-
tion of obtained aldol 12, a plausible catalytic model for the
reaction of isatin (11) with acetone (7) is proposed (Scheme
2). As a first step, primary amine 5 reacts with ketone 7 to
form an enamine intermediate. In principle, and according
to a recent mechanistic investigation by Kočovský and co-
workers,29 both the syn- and anti-rotamers 14 and 15 can
be envisaged. Whereas the anti-enamine 15 is kinetically
favored, the syn-enamine 14 is thermodynamically more
stable and, under equilibrium conditions, the subsequent
aldol process will proceed mainly via 14. Two principal
roles of the cocatalyst (acid) can be envisaged: i) accelera-
tion of the formation of enamines 14 and 15, and ii) also
protonation of the nitrogen atom of the benzimidazole
backbone to form the benzimidazolium salt. The benzimid-
azolium ion is most likely hydrogen-bonded to the carbonyl
groups of isatin (11), which influences their reactivity and
also brings the reacting species close together for the cross-
aldol reaction. The transition states for both enamines 14
and 15 shown in Scheme 2 suggest easiest access of 14 to
attack 11 via the Re-face (transition state 16), which leads
to the formation of (S)-12. On the contrary, enamine 15
would attack 11 via the Si-face (transition state 19) leading
to (R)-12. These two concurrent modes of attack are reflect-
ed in the low enantioselectivities obtained in the aldol re-
action between acetone and 11 (Table 3, maximal 24% ee).
5f
AcOH
PhCO2H
TFA
5f
5h
5h
5h
AcOH
PhCO2H
1
3
a Reaction conditions: 11 (0.10 mmol), 7 (1 mL), 5 (0.01 mmol), acid cocat-
alyst (0.03 mmol), 5 °C, 96 h.
b Isolated chemical yield after silica gel column chromatography (EtOAc/
hexane, 1:1).
c Absolute configuration was determined by comparison of chiral-phase
HPLC analyses with reported data.27
d Determined by chiral-phase HPLC analysis (Chiralcel OJ-H column).27
In contrast to reactions with acetone, the reaction of
isatin (11) with cyclohexanone (9) required a little longer
reaction time for completion (108 vs 96 h). The aldol prod-
ucts 13 were isolated in 46–60% yield as a set of syn- and
anti-diastereoisomers (Table 4). The attained syn/anti ratio
for the optically pure organocatalysts 5b–f ranged from
97:3 to 55:45 (94% to 10% de). Whereas amines 5a–c de-
rived from alanine provided the aldol adducts 13 in about
50% yield with low diastereo- and enantioselectivity (Table
4, entries 1–3), the valine, leucine, and isoleucine deriva-
tives 5d–f showed significantly improved stereochemical
outcomes (Table 4, entries 4–6). Amine 5d derived from va-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
P. H. Mohite et al.
Paper
Synthesis
transition states
Me
Me
O
R
R
N
N
HO
disfavored
favored
N
H
NH
enamines
N
H
O
NH
Re-face
attack
Me
Re-face
attack
N
H
R
N
O
O
O
O
18
(S)-12
16
N
NH
NH
NH
14
Me
Me
O
Me
R
N
R
N
HO
R
N
favored
disfavored
N
H
NH
N
H
NH
O
N
NH
Si-face
attack
Si-face
attack
N
H
O
O
O
O
15
19
17
(R)-12
HN
HN
Scheme 2 Structure of enamines 14 and 15 and proposed transition states 16–19 for the aldol reaction between isatin and acetone catalyzed by
primary amines 5
In contrast, the reaction of 11 with cyclohexanone (9) af-
forded aldol 13 with up to 71% ee (Table 4). Whereas in
amines 5a–f the aliphatic R substituent is only involved as a
bulky substituent without protonation/coordination capa-
bility, in tryptophan derivative 5h another transition state
involving the indolyl residue can be envisaged. Most likely,
this accounts for the low stereochemical performance of
this derivative.
umn. The aldol reactions with 4-nitrobenzaldehyde were carried out
following our earlier procedure.9 Evaporation and concentration in
vacuo were performed at water aspirator pressure. Column chroma-
tography was carried out with silica gel 60 (particle size 0.040–0.063
mm, 230–400 mesh; Merck) and commercially available solvents. TLC
was conducted on Merck aluminum sheets coated with silica gel 60
F
254, with visualization by UV lamp (254 or 360 nm). Melting points
were measured on a Büchi B-540 melting point apparatus in open
capillaries and are uncorrected. NMR spectra were recorded in
DMSO-d6 or CDCl3 at 500 or 400 MHz (for 1H NMR) and at 125 or 100
MHz (for 13C NMR) with Bruker Avance III 500 or Bruker Avance 400
instruments at 25 °C. Chemical shifts are reported in ppm relative to
the signal for TMS. Coupling constants are given in hertz. Apparent
resonance multiplicities are described as s (singlet), br s (broad sin-
glet), d (doublet), dd (doublet of doublet), dt (doublet of triplet), t
(triplet), q (quartet), and m (multiplet). Residual solvent signals in the
NMR spectra were used as the internal reference (CDCl3: 7.25 and
77.23 ppm for 1H and 13C NMR, respectively; DMSO-d6: 2.55 and
In conclusion, we have developed a facile synthetic ac-
cess to chiral primary amines bearing α-amino acid and
benzo[d]imidazole pendants. Starting from commercially
available Boc-protected α-amino acids, six new derivatives
were synthesized in a four-step reaction sequence. The ala-
nine derivative was prepared as a racemic mixture and as
both optically pure enantiomers. The phenylalanine deriva-
tive 5g underwent racemization during the reaction se-
quence and, therefore, was not further evaluated. The other
prepared amines were investigated as organocatalysts in al-
dol reactions of 4-nitrobenzaldehyde and isatin with ace-
tone and cyclohexanone. Trifluoroacetic acid and benzoic
acid proved to be well-suited proton sources for these two
aldol reactions organocatalyzed by amines 5a–f,h, provid-
ing the products both in good chemical yields and with en-
antiomeric excesses up to 71%. The reaction with cyclohex-
anone provides a set of diastereoisomers with up to 94% de.
Moreover, the prepared amines proved to be tunable or-
ganocatalysts. Whereas their absolute configuration pre-
destines the stereochemical configuration of the formed al-
dol product, their structure, bulkiness of the R substituent,
significantly affects the asymmetric induction.
1
39.51 ppm for H and 13C NMR, respectively). Optical rotation values
were measured on a Perkin Elmer 341 instrument; concentration c is
given in g/100 mL MeOH. IR spectra were recorded on a Thermo Nico-
let iS50 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA).
High-resolution MALDI mass spectra were measured on a MALDI LTQ
Orbitrap XL mass spectrometer (Thermo Fisher Scientific, Bremen,
Germany) equipped with a nitrogen UV laser (337 nm, 60 Hz). The
LTQ Orbitrap instrument was operated in the positive ion mode over a
normal mass range (m/z 50–1500) with the following settings for
tuning parameters: resolution 100000 at m/z = 400, laser energy 17
mJ, number of laser shots 5. 2,5-Dihydroxybenzoic acid (DHB) was
used as the matrix. Mass spectra were averaged over the whole MS
record (30 s) for all measured samples.
Benzo[d]imidazole Derivatives 3a–h; General Procedure
Methyl chloroformate (1.6 mL, 21.2 mmol) was added to a mixture of
a Boc-protected α-amino acid 1a–h (21.2 mmol), Et3N (3.0 mL, 21.2
mmol), and DMF (18 mL) at –20 °C. After 15 min of stirring, o-phenyl-
enediamine (2.3 g, 21.2 mmol) was added and the reaction mixture
was stirred at 20 °C for 4 h. The volatiles were evaporated and the res-
The starting Boc-protected α-amino acids 1a–h are commercially
available. Enantiomeric excesses were determined by HPLC analysis
with a Chiralpak AS-H, Chiralpak AD-H, or Daicel Chiralcel OJ-H col-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
P. H. Mohite et al.
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Synthesis
idue was partitioned between water and EtOAc. The organic layer was
washed with 5% aq NaHCO3, brine, and water, then dried (Na2SO4),
and the solvent was evaporated to afford the corresponding amino
amide 2a–h (71–84% yield).
1H NMR (400 MHz, DMSO-d6): δ = 12.2 (s, 1 H, NHbim), 7.59 (d, J = 7.0
Hz, 1 H, CHAr), 7.50 (d, J = 6.5 Hz, 1 H, NHBoc), 7.22 (d, J = 9 Hz, 1 H,
CHAr), 7.17–7.23 (m, 2 H, CHAr), 4.59 (t, J = 8.2 Hz, 1 H, BocNHCH), 2.23
(m, 1 H, CH(CH3)2), 1.42 (s, 9 H), 0.95 (d, J = 6.7 Hz, 3 H, CH3), 0.83 (d,
J = 6.7 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 155.41, 154.99, 142.90, 133.84,
124.48, 121.67, 120.96, 118.42, 111.18, 78.04, 55.15, 51.87, 32.05,
28.14, 19.28, 18.57.
A solution of crude compound 2a–h (20.0 mmol) in glacial AcOH (10
mL) was heated at 65 °C for 1 h, then the volatiles were evaporated
and the residue was partitioned between water and EtOAc. The or-
ganic layer was washed with water, then dried (Na2SO4), and the sol-
vent was evaporated. Crystallization of the residue (Et2O/hexane) af-
forded the corresponding benzo[d]imidazole derivative 3a–h as a sol-
id (64–82% yield).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C16H24N3O2+: 290.18630;
found: 290.18652.
(S)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)-3-methylbutylcarba-
mate (3e)
(±)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)ethylcarbamate (3a)
Synthesized from (±)-N-Boc-Ala amino amide 2a (5.60 g, 20.0 mmol).
White solid; yield: 4.10 g (78%); mp 232–234 °C; [α]D20 0 (c 1, MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 12.2 (s, 1 H, NHbim), 7.54 (m, 2 H,
CHAr), 7.41 (d, J = 7.8 Hz, 1 H, NHBoc), 7.17 (d, J = 5 Hz, 2 H, CHAr), 4.91
(m, 1 H, BocNHCH), 1.52 (d, J = 7.0 Hz, 3 H, CH3), 1.44 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 156.44, 155.11, 142.93, 134.28,
121.72, 120.98, 118.44, 111.28, 78.25, 45.05, 28.25, 20.17.
Synthesized from (S)-N-Boc-Leu amino amide 2e (6.45 g, 20.0 mmol).
White solid; yield: 4.03 g (66%); mp 186–188 °C; [α]D –32.3 (c 1,
MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 12.1 (s, 1 H, NHbim), 7.53 (m, 2 H,
CHAr), 7.34 (d, J = 8.5 Hz, 1 H, NHBoc), 7.17 (d, J = 5.1 Hz, 2 H, CHAr),
4.86 (q, J = 7.8 Hz, 1 H, BocNHCH), 1.77 (m, 2 H, CH2), 1.62 (m, 1 H,
CH), 1.43 (s, 9 H), 0.95 (t, J = 6.6 Hz, 6 H, CH(CH2)3).
20
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C14H20N3O2+: 262.15500;
13C NMR (100 MHz, DMSO-d6): δ = 174.82, 156.22, 155.36, 121.40,
found: 262.15419.
78.11, 77.94, 51.86, 47.70, 43.07, 28.25, 24.41, 22.94, 22.76, 21.84.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C17H26N3O2+: 304.20195;
found: 304.20100.
(R)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)ethylcarbamate (3b)
Synthesized from (R)-N-Boc-Ala amino amide 2b (5.60 g, 20.0 mmol).
White solid; yield: 4.30 g (82%); mp 220–222 °C; [α]D +13.1 (c 1,
20
(1S,2S)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)-2-methylbutyl-
MeOH).
carbamate (3f)
1H NMR (400 MHz, DMSO-d6): δ = 12.1 (s, 1 H, NHbim), 7.53 (m, 2 H,
CHAr), 7.41 (d, J = 6 Hz, 1 H, NHBoc), 7.17 (s, 2 H, CHAr), 4.90 (br s, 1 H,
BocNHCH), 1.52 (d, J = 6.5 Hz, 3 H, CH3), 1.45 (s, 9 H).
Synthesized from (S,S)-N-Boc-Ile amino amide 2f (6.45 g, 20.0 mmol).
Yellowish solid; yield: 4.65 g (76%); mp 188–190 °C; [α]D20 –17.5 (c 1,
MeOH).
13C NMR (100 MHz, DMSO-d6): δ = 175.35, 157.06, 155.90, 155.73,
121.45, 121.12, 109.21, 108.21, 78.78, 49.45, 45.66, 28.58, 27.00,
20.78, 17.69.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C14H20N3O2+: 262.15500;
found: 262.15388.
1H NMR (400 MHz, DMSO-d6): δ = 12.2 (s, 1 H, NHbim), 7.55 (br s, 2 H),
7.26 (d, J = 8.8 Hz, 1 H, NHBoc), 7.16–7.19 (m, 2 H, CHAr), 7.03 (d,
J = 8.4 Hz, 1 H, CHAr), 4.66 (t, J = 8.3 Hz, 1 H, BocNHCH), 2.00 (m, 1 H,
CH), 1.53 (m, 1 H, CH2), 1.41 (s, 9 H), 1.22 (m, 1 H, CH2), 0.88 (m, 3 H,
CHCH3), 0.77 (d, J = 6.7 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, DMSO-d6): δ = 155.96, 155.65, 143.59, 134.46,
122.33, 121.64, 119.09, 111.86, 78.72, 54.55, 38.95, 28.82, 28.60,
25.46, 16.22, 11.95, 11.65.
(S)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)ethylcarbamate (3c)
Synthesized from (S)-N-Boc-Ala amino amide 2c (5.60 g, 20.0 mmol).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C17H26N3O2+: 304.20195;
20
White solid; yield: 3.94 g (75%); mp 228–230 °C; [α]D –13.5 (c 1,
found: 304.20152.
MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 12.1 (s, 1 H, NHbim), 7.58 (d, J = 6.8
Hz, 1 H, CHAr), 7.48 (d, J = 6.8 Hz, 1 H, CHAr), 7.41 (d, J = 7.8 Hz, 1 H,
NHBoc), 7.14–7.20 (m, 2 H, CHAr), 4.89 (m, 1 H, BocNHCH), 1.51 (d,
J = 7.0 Hz, 3 H, CH3), 1.45 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 156.37, 155.05, 142.89, 134.23,
129.62, 121.68, 120.92, 118.39, 111.22, 108.43, 78.09, 44.99, 28.21,
20.11.
(S)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)-2-phenylethylcarba-
mate (3g)
Synthesized from (S)-N-Boc-Phe amino amide 2g (7.12 g, 20.0 mmol).
20
White solid; yield: 5.35 g (79%); mp 180–182 °C; [α]D –10.4 (c 1,
MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 12.28 (br s, 1 H, NHbim), 7.56 (br, s,
1 H, NHBoc), 7.44 (d, J = 8.7 Hz, 1 H, CHAr), 7.29 (m, 4 H, CHAr), 7.17–
7.25 (m, 4 H, CHAr), 5.04 (m, 1 H, BocNHCH), 2.78–3.22 (m, 2 H,
CHCH2Ph), 1.34 (s, 9 H).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C14H20N3O2+: 262.15500;
found: 262.15504.
13C NMR (100 MHz, DMSO-d6): δ = 155.92, 155.80, 143.59, 138.80,
134.78, 129.86, 128.70, 126.83, 122.45, 121.68, 119.15, 111.96, 78.70,
51.48, 28.80.
(S)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)-2-methylpropylcar-
bamate (3d)
Synthesized from (S)-N-Boc-Val amino amide 2d (6.15 g, 20.0 mmol).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C20H24N3O2+: 338.18630;
20
White solid; yield: 4.12 g (71%); mp 248–250 °C; [α]D –42.4 (c 1,
found: 338.18640.
MeOH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
P. H. Mohite et al.
Paper
Synthesis
(S)-tert-Butyl 1-(1H-Benzo[d]imidazol-2-yl)-2-(1-methyl-1H-in-
dol-3-yl)ethylcarbamate (3h)
1H NMR (400 MHz, CDCl3): δ = 7.71 (m, 1 H, CHAr), 7.22–7.33 (m, 3 H,
CHAr), 5.49 (d, J = 8.6 Hz, 1 H, NHBoc), 5.12–5.19 (m, 1 H, BocNHCH),
3.79 (s, 3 H, NCH3), 1.62 (d, J = 6.8 Hz, 3 H, CH3), 1.42 (s, 9 H).
Synthesized from (S)-N-Boc-1-MeTrp amino amide 2h (8.20 g, 20.0
mmol). Yellowish solid; yield: 5.00 g (64%); mp 204–206 °C; [α]D
20
13C NMR (100 MHz, CDCl3): δ = 155.58, 155.29, 142.23, 135.96,
–30.5 (c 1, MeOH).
122.89, 122.38, 119.67, 109.56, 80.06, 43.02, 29.98, 28.54, 21.05.
1H NMR (400 MHz, DMSO-d6): δ = 12.2 (s, 1 H), 7.48–7.64 (m, 3 H,
CHAr), 7.39 (t, J = 9.5 Hz, 1 H), 7.15–7.22 (m, 3 H, CHAr), 7.02–7.05 (m, 2
H, CHAr), 5.81 (s, 1 H), 5.08 (q, J = 7.5 Hz, 1 H, BocNHCH), 3.73 (s, 3 H,
NCH3), 3.48 (dd, J = 14.5, 5.7 Hz, 1 H, CHCH2Trp), 3.24 (dd, J = 14.5, 8.7
Hz, 1 H, CHCH2Trp), 1.36 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 155.61, 155.27, 143.03, 136.49,
134.20, 127.85, 127.76, 121.80, 121.05, 121.03, 118.68, 118.54,
118.39, 111.34, 109.90, 109.54, 78.07, 50.41, 32.31, 29.76, 28.18.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C15H22N3O2+: 276.17065;
found: 276.16937.
(S)-tert-Butyl 2-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-
yl)propylcarbamate (4d)
Synthesized from (S)-N-Boc-Val BIM 3d (1.10 g, 3.8 mmol). Yellow
20
solid; yield: 0.67 g (58%); mp 114–116 °C; [α]D –62.1 (c 1, MeOH);
Rf = 0.7.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C23H27N4O2+: 391.21285;
found: 391.21269.
1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1 H, CHAr), 7.78–7.80 (m, 1 H,
CHAr), 7.33–7.42 (m, 2 H, CHAr), 5.49 (d, J = 9.6 Hz, 1 H, NHBoc), 4.86 (t,
J = 5.8 Hz, 1 H, BocNHCH), 3.89 (s, 3 H, NCH3), 2.30–2.39 (m, 1 H,
CH(CH3)2), 1.48 (s, 9 H), 1.12 (d, J = 6.7 Hz, 3 H, CH3), 0.99 (d, J = 6.7 Hz,
3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 155.91, 155.23, 142.47, 135.53,
122.69, 122.37, 119.57, 109.68, 79.87, 52.47, 33.66, 30.18, 28.51,
19.77, 18.58.
N-Methylbenzo[d]imidazole Derivatives 4a–h; General Procedure
The appropriate benzo[d]imidazole 3a–h (3.8 mmol) dissolved in an-
hydrous THF (20 mL) was treated with 1 M LHMDS in THF (3.8 mL, 3.8
mmol) at 0 °C for 30 min, whereupon MeI (0.25 mL, 4.0 mmol) was
added and the reaction mixture was stirred at 20 °C for 3 h. Then, the
mixture was diluted with water and extracted with EtOAc. The organ-
ic layer was dried (Na2SO4), the solvents were evaporated, and the res-
idue was purified by silica gel column chromatography (EtOAc/
hexane, 1:1) to afford the N-methyl derivative 4a–h as a solid (50–
86% yield).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C17H26N3O2+: 304.20195;
found: 304.20202.
(S)-tert-Butyl 3-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-
yl)butylcarbamate (4e)
Synthesized from (S)-N-Boc-Leu BIM 3e (1.16 g, 3.8 mmol). White
solid; yield: 0.79 g (65%); mp 102–104 °C; [α]D –41 (c 1, MeOH);
Rf = 0.6.
(±)-tert-Butyl 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethylcarba-
mate (4a)
20
Synthesized from (±)-N-Boc-Ala BIM 3a (1.00 g, 3.8 mmol). White sol-
id; yield: 0.90 g (86%); mp 134–136 °C; [α]D20 0 (c 1, MeOH); Rf = 0.5.
1H NMR (400 MHz, CDCl3): δ = 7.78 (m, 1 H, CHAr), 7.29–7.40 (m, 3 H,
CHAr), 5.56 (d, J = 8.5 Hz, 1 H, NHBoc), 5.19–5.26 (m, 1 H, BocNHCH),
3.86 (s, 3 H, NCH3), 1.69 (d, J = 6.8 Hz, 3 H, CH3), 1.49 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 155.58, 155.27, 142.22, 135.94,
122.88, 122.37, 119.65, 109.54, 80.03, 42.99, 29.97, 28.52, 21.02.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.73 (m, 1 H, CHAr), 7.29–7.34 (m,
1 H, CHAr), 7.23–7.29 (m, 2 H, CHAr), 5.19 (d, J = 9.3 Hz, 1 H, NHBoc),
5.12 (m, 1 H, BocNHCH), 3.83 (s, 3 H, NCH3), 1.86 (m, 2 H, CH2), 1.70
(m, 1 H, CH), 1.40 (s, 9 H), 0.99 (d, J = 6.5 Hz, 3 H, CH(CH2)3), 0.95 (d,
J = 6.6 Hz, 3 H, CH(CH2)3).
13C NMR (100 MHz, CDCl3): δ = 155.80, 135.68, 134.61, 129.62,
122.78, 122.35, 119.66, 109.64, 79.99, 45.10, 44.29, 30.03, 28.51,
24.93, 23.13, 22.44.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C15H22N3O2+: 276.17065;
found: 276.16979.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C18H28N3O2+: 318.21760;
found: 318.21729.
(R)-tert-Butyl 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethylcarba-
mate (4b)
(1S,2S)-tert-Butyl 2-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-
yl)butylcarbamate (4f)
Synthesized from (R)-N-Boc-Ala BIM 3b (1.00 g, 3.8 mmol). Yellowish
solid; yield: 0.80 g (76%); mp 138–140 °C; [α]D +84.1 (c 1, MeOH);
Rf = 0.5.
1H NMR (400 MHz, CDCl3): δ = 7.77–7.80 (m, 1 H, CHAr), 7.29–7.40 (m,
3 H, CHAr), 5.61 (d, J = 8.7 Hz, 1 H, NHBoc), 5.19–5.26 (m, 1 H, BocN-
HCH), 3.85 (s, 3 H, NCH3), 1.69 (d, J = 6.8 Hz, 3 H, CH3), 1.50 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 155.55, 155.25, 142.15, 135.89,
122.85, 122.33, 119.60, 109.53, 80.00, 42.95, 29.95, 28.49, 20.98.
20
Synthesized from (S,S)-N-Boc-Ile BIM 3f (1.16 g, 3.8 mmol). Yellow
20
solid; yield: 0.78 g (64%); mp 104–106 °C; [α]D –73.5 (c 1, MeOH);
Rf = 0.6.
1H NMR (400 MHz, CDCl3): δ = 7.71 (m, 1 H, CHAr), 7.34 (m, 1 H, CHAr),
7.23–7.29 (m, 2 H, CHAr), 5.39 (d, J = 9.5 Hz, 1 H, NHBoc), 4.82 (t, J = 9.0
Hz, 1 H, BocNHCH), 3.82 (s, 3 H, NCH3), 2.05 (m, 1 H, CH), 1.71 (m, 1 H,
CH2), 1.39 (s, 9 H), 1.20 (m, 1 H, CH2), 0.91 (t, J = 7.4 Hz, 3 H, CHCH3),
0.85 (d, J = 6.7 Hz, 3 H, CH2CH3).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C15H22N3O2+: 276.17065;
13C NMR (100 MHz, CDCl3): δ = 155.84, 155.45, 142.53, 135.46,
122.66, 122.37, 119.56, 109.72, 79.88, 51.51, 39.95, 30.20, 28.51,
24.99, 15.97, 11.40.
found: 276.16956.
(S)-tert-Butyl 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethylcarba-
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C18H28N3O2+: 318.21760;
mate (4c)
Synthesized from (S)-N-Boc-Ala BIM 3c (1.00 g, 3.8 mmol). Yellowish
solid; yield: 0.70 g (66%); mp 128–130 °C; [α]D –84.8 (c 1, MeOH);
found: 318.21717.
20
Rf = 0.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
P. H. Mohite et al.
Paper
Synthesis
(S)-tert-Butyl 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-phenyl-
ethylcarbamate (4g)
1H NMR (400 MHz, DMSO-d6): δ = 7.61 (d, J = 7.4 Hz, 1 H, CHAr), 7.54
(d, J = 7.5 Hz, 1 H, CHAr), 7.18–7.27 (m, 2 H, CHAr), 4.33 (q, J = 6.7 Hz, 1
H, NH2CH), 3.86 (s, 3 H, NCH3), 1.49 (d, J = 6.5 Hz, 3 H, CH3).
Synthesized from (S)-N-Boc-Phe BIM 3g (1.29 g, 3.8 mmol). White
20
13C NMR (100 MHz, DMSO-d6): δ = 158.91, 141.76, 136.06, 121.67,
solid; yield: 0.67 g (50%); mp 132–134 °C; [α]D –18.8 (c 1, MeOH);
52% ee; Rf = 0.8.
121.22, 118.60, 109.82, 43.62, 29.63, 22.93.
1H NMR (400 MHz, CDCl3): δ = 7.80–7.83 (m, 1 H, CHAr), 7.23–7.34 (m,
7 H, CHAr), 7.09 (m, 1 H, CHAr), 5.72 (d, J = 8.8 Hz, 1 H, NHBoc), 5.24 (m,
1 H, BocNHCH), 3.4–3.55 (m, 2 H, CHCH2Ph), 3.33 (s, 3 H, NCH3), 1.47
(s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 154.56, 142.43, 136.90, 129.62,
128.65, 127.03, 122.77, 122.41, 119.55, 109.55, 49.14, 42.73, 29.40,
28.52.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C10H14N3+: 176.11823;
found: 176.11766.
(S)-1-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethanamine (5c)
Synthesized from (S)-N-Boc-Ala BIM-N-Me 4c (0.64 g, 2.3 mmol). Yel-
low oil; yield: 0.18 g (45%); [α]D20 –4.2 (c 1, MeOH); Rf = 0.2.
IR (HATR): 3100, 3030, 2933, 1680, 1457, 1335, 1128, 741 cm–1
.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C21H26N3O2+: 352.20195;
found: 352.20187.
1H NMR (400 MHz, DMSO-d6): δ = 7.61 (d, J = 7.4 Hz, 1 H, CHAr), 7.54
(d, J = 7.4 Hz, 1 H, CHAr), 7.14–7.27 (m, 2 H, CHAr), 4.31 (q, J = 6.7 Hz, 1
H, NH2CH), 3.86 (s, 3 H, NCH3), 1.49 (d, J = 6.6 Hz, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 159.10, 141.75, 136.05, 121.61,
121.16, 118.57, 109.77, 43.63, 29.61, 23.05.
(S)-tert-Butyl 1-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-(1-meth-
yl-1H-indol-3-yl)ethylcarbamate (4h)
Synthesized from (S)-N-Boc-1-MeTrp BIM 3h (1.49 g, 3.8 mmol).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C10H14N3+: 176.11823;
found: 176.11816.
20
Brown solid; yield: 0.99 g (64%); mp 164–166 °C; [α]D –20.1 (c 1,
MeOH); Rf = 0.5.
1H NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 1 H, CHAr), 7.49 (d,
J = 7.8 Hz, 1 H, CHAr), 7.15–7.28 (m, 5 H, CHAr), 6.99 (t, J = 7.5 Hz, 1 H,
CHAr), 6.66 (s, 1 H, NHBoc), 5.78 (br s, 1 H), 5.34 (q, J = 7.8 Hz, 1 H,
BocNHCH), 3.61 (s, 3 H, NCH3), 3.54 (dd, J = 14.0, 5.4 Hz, 1 H,
CHCH2Trp), 3.40 (dd, J = 14.0, 9.4 Hz, 1 H, CHCH2Trp), 3.20 (s, 3 H,
NCH3), 1.41 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 155.49, 155.36, 136.98, 135.32,
129.94, 128.10, 127.82, 122.78, 122.51, 121.83, 119.34, 118.98,
109.73, 109.41, 109.29, 79.99, 48.13, 32.82, 32.16, 29.75, 28.54.
(S)-2-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-
amine (5d)
Synthesized from (S)-N-Boc-Val BIM-N-Me 4d (0.70 g, 2.3 mmol). Yel-
low solid; yield: 0.29 g (61%); mp 80–82 °C; [α]D20 –11.4 (c 1, MeOH);
Rf = 0.3.
IR (HATR): 3060, 2961, 2860, 1683, 1612, 1467, 1200, 1126, 740 cm–1
1H NMR (500 MHz, DMSO-d6): δ = 7.61 (d, J = 7.4 Hz, 1 H, CHAr), 7.55
(d, J = 7.7 Hz, 1 H, CHAr), 7.19–7.26 (m, 2 H, CHAr), 3.90 (d, J = 7.0 Hz, 1
H, NH2CH), 3.84 (s, 3 H, NCH3), 2.05–2.13 (m, 1 H, CH(CH3)2), 1.01 (d,
J = 6.7 Hz, 3 H, CH3), 0.88 (d, J = 6.7 Hz, 3 H, CH3).
.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C24H29N4O2+: 405.22850;
found: 405.22849.
13C NMR (125 MHz, DMSO-d6): δ = 158.25, 141.93, 135.75, 121.55,
121.28, 118.52, 109.97, 53.52, 33.33, 29.76, 19.87, 18.23.
Primary Amines 5a–h; General Procedure
The appropriate Boc derivative 4a–h (2.3 mmol) was treated with TFA
(1 mL) at 20 °C for 1 h. Then, Et2O/hexane (1:1) was added to the reac-
tion mixture until the product precipitated. The crude product was
collected by filtration and purified by silica gel column chromatogra-
phy (EtOAc/CH2Cl2/MeOH, 1:1:0.2) to afford 5a–h as a viscous oil or as
a solid (36–61% yield).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C12H18N3+: 204.14952;
found: 204.14897.
(S)-3-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)butan-1-
amine (5e)
Synthesized from (S)-N-Boc-Leu BIM-N-Me 4e (0.73 g, 2.3 mmol).
Viscous oil; yield: 0.20 g (39%); [α]D20 –15 (c 1, MeOH); Rf = 0.2.
(±)-1-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethanamine (5a)
IR (HATR): 3040, 3030, 2958, 2810, 1678, 1454, 1201, 1133, 746 cm–1
.
Synthesized from (±)-N-Boc-Ala BIM-N-Me 4a (0.64 g, 2.3 mmol). Yel-
low oil; yield: 0.19 g (45%); [α]D20 0 (c 1, MeOH); Rf = 0.2.
1H NMR (500 MHz, DMSO-d6): δ = 7.61 (d, J = 7.7 Hz, 1 H, CHAr), 7.55
(d, J = 7.9 Hz, 1 H, CHAr), 7.19–7.27 (m, 2 H, CHAr), 4.23 (t, J = 6.8 Hz, 1
H, NH2CH), 3.86 (s, 3 H, NCH3), 1.75 (m, 2 H, CH2), 1.67 (m, 1 H, CH),
0.93 (d, J = 6.0 Hz, 6 H, CH(CH3)2).
13C NMR (125 MHz, DMSO-d6): δ = 158.39, 141.86, 135.97, 121.79,
121.39, 118.63, 110.00, 46.14, 45.52, 29.75, 24.43, 23.06, 22.29.
IR (HATR): 3100, 3050, 2998, 1681, 1479, 1458, 1335, 1258, 1128, 742
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.73 (m, 1 H, CHAr), 7.22–7.32 (m,
3 H, CHAr), 4.33 (q, J = 6.7 Hz, 1 H, NH2CH), 3.79 (s, 3 H, NCH3), 1.57 (d,
J = 6.7 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 159.09, 141.76, 136.06, 121.64,
121.19, 118.59, 109.79, 43.64, 29.62, 23.34, 23.04.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C13H20N3+: 218.16517;
found: 218.16497.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C10H14N3+: 176.11823;
found: 176.11749.
(1S,2S)-2-Methyl-1-(1-methyl-1H-benzo[d]imidazol-2-yl)butan-1-
amine (5f)
Synthesized from (S,S)-N-Boc-Ile BIM-N-Me 4f (0.73 g, 2.3 mmol).
Viscous oil; yield: 0.18 g (36%); [α]D20 –21.8 (c 1, MeOH); Rf = 0.2.
(R)-1-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethanamine (5b)
Synthesized from (R)-N-Boc-Ala BIM-N-Me 4b (0.64 g, 2.3 mmol). Yel-
low oil; yield: 0.20 g (48%); [α]D20 +4.0 (c 1, MeOH); Rf = 0.2.
IR (HATR): 3330, 3250, 2965, 1678, 1558, 1471, 1202, 1180, 1130,
744, 721 cm–1
.
IR (HATR): 3100, 3050, 2932, 1684, 1630, 1456, 1395, 1331, 740 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
P. H. Mohite et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 7.62 (d, J = 7.0 Hz, 1 H, CHAr), 7.56
(d, J = 7.0 Hz, 1 H, CHAr), 7.20–7.55 (m, 2 H, CHAr), 4.03 (d, J = 7.6 Hz, 1
H, NH2CH), 3.85 (s, 3 H, NCH3), 1.90 (m, 1 H, CH), 1.19 and 1.75 (2 × m,
2 × 1 H, CH2), 0.90 (t, J = 7.2 Hz, 3 H, CHCH3), 0.85 (d, J = 6.4 Hz, 3 H,
CH2CH3).
13C NMR (100 MHz, DMSO-d6): δ = 157.67, 141.92, 135.68, 121.62,
121.35, 118.51, 110.02, 52.30, 39.92, 29.80, 24.06, 15.78, 11.20.
reaction catalyzed by 5f. The absolute configuration of compound 12
was assigned by comparison of chiral-phase HPLC analyses with re-
ported data.27
1H NMR (400 MHz, DMSO-d6): δ = 10.2 (s, 1 H), 7.28 (d, J = 7.4 Hz, 1
H), 7.22 (dt, Jt = 7.6 Hz, Jd = 1.3 Hz, 1 H), 6.95 (dt, Jt = 7.5 Hz, Jd = 1.0 Hz,
1 H), 6.82 (d, J = 7.6 Hz, 1 H), 6.03 (s, 1 H), 3.32 (d, J = 16.6 Hz, 1 H),
3.04 (d, J = 16.6 Hz, 1 H), 2.04 (s, 3 H).
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C13H20N3+: 218.16517;
13C NMR (100 MHz, DMSO-d6): δ = 205.86, 178.81, 143.14, 132.12,
found: 218.16473.
129.63, 124.30, 121.89, 110.07, 73.27, 50.86, 31.18.
+
HR-MALDI-MS (DHB): m/z [M + Na]+ calcd for C11H11NNaO3
:
(S)-1-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-phenylethanamine
228.06311; found: 228.06326.
(5g)
Synthesized from (S)-N-Boc-Phe BIM-N-Me 4g (0.81 g, 2.3 mmol). Oil;
yield: 0.22 g (38%); [α]D20 –6.2 (c 1, MeOH); 20% ee; Rf = 0.3.
Aldol Product 13
The enantiomeric excess of product 13 was determined by HPLC anal-
ysis (Daicel Chiralcel OJ-H column; flow 0.8 mL·min–1; n-hexane/
i-PrOH, 85:15): tR (major diastereoisomer) = 21.2 (major), 28.1 (mi-
nor) min; 71% ee for the reaction catalyzed by 5f; tR (minor diastereo-
isomer) = 16.7 (major), 18.6 (minor) min; 45% ee for the reaction cat-
alyzed by 5f.
1H NMR (400 MHz, DMSO-d6): δ = 10.19 (s, 1 H), 7.12–7.20 (m, 1 H),
6.73–6.84 (m, 2 H), 5.81 (s, 1 H), 3.05 (dd, J = 13.2, 5.2 Hz, 1 H), 2.55–
2.58 (m, 1 H), 2.25–2.31 (m, 1 H), 1.3–1.8 (m, 5 H), 1.23 (m, 1 H).
IR (HATR): 3100, 3050, 2926, 1676, 1460, 1261, 1122, 733, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.85 (m, 1 H, CHAr), 7.27–7.35 (m,
6 H, CHAr), 7.13–7.15 (m, 2 H, CHAr), 4.44 (t, J = 7.2 Hz, 1 H, NH2CH),
3.45 (s, 3 H, NCH3), 3.23–3.34 (m, 2 H, CHCH2Ph).
13C NMR (100 MHz, CDCl3): δ = 157.04, 142.19, 137.79, 129.53,
128.84, 127.07, 122.71, 122.39, 119.56, 109.46, 50.96, 44.77, 29.58.
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C16H18N3+: 252.14952;
found: 252.14904.
13C NMR (100 MHz, DMSO-d6): δ = 209.75, 179.35, 144.06, 131.49,
129.22, 125.44, 121.46, 110.04, 74.50, 58.01, 42.11, 34.02, 27.27,
25.09, 24.66.
(S)-1-(1-Methyl-1H-benzo[d]imidazol-2-yl)-2-(1-methyl-1H-in-
dol-3-yl)ethanamine (5h)
+
HR-MALDI-MS (DHB): m/z [M + Na]+ calcd for C14H15NNaO3
:
Synthesized from (S)-N-Boc-1-MeTrp BIM-N-Me 4h (0.94 g, 2.3
268.09441; found: 268.09464.
20
mmol). Yellow oil; yield: 0.38 g (53%); [α]D –7.5 (c 1, MeOH);
Rf = 0.2.
IR (HATR): 3070, 2924, 1612, 1520, 1470, 1326, 1123, 1006, 844, 738
Acknowledgment
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.80 (m, 1 H, CHAr), 7.53 (d, J = 7.8 Hz, 1
H, CHAr), 7.22–7.32 (m, 5 H, CHAr), 7.08 (t, J = 7.4 Hz, 1 H, CHAr), 6.86 (s,
1 H), 4.51 (t, J = 7.1 Hz, 1 H, NH2CH), 3.73 (s, 3 H, NCH3), 3.56 (s, 3 H,
NCH3), 3.45 (dd, J = 16.0, 7.1 Hz, 1 H, CHCH2Trp), 3.35 (dd, J = 14.2, 8.2
Hz, 1 H, CHCH2Trp).
This research was supported by the Ministry of Education, Youth, and
Sport of the Czech Republic.
Supporting Information
13C NMR (125 MHz, CDCl3): δ = 157.41, 142.13, 137.24, 135.90,
128.24, 127.91, 122.67, 122.34, 121.94, 119.58, 118.70, 110.08,
109.39, 109.04, 49.66, 33.92, 32.87, 31.94, 29.88.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588107.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
HR-MALDI-MS (DHB): m/z [M + H]+ calcd for C19H21N4+: 305.17783;
found: 305.17652.
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