Copper(I)-Catalyzed regioselective amination of N -aryl imines using TMSN3 and TBHP: A route to substituted benzimidazoles

Article abstract of DOI:10.1021/jo502574u

A novel and efficient copper-catalyzed amination of N-aryl imines is described. This one-pot, multicomponent reaction, in which imine acts as a directing group by chelating to the metal center, affords a potential route for the transformation of the commercial aryl amines, aldehydes, and azides into valuable benzimidazole structural units with wide substrate scope and diversity. The synthetic and mechanistic aspects are presented.

Full text of DOI:10.1021/jo502574u

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Article
Copper(I)-Catalyzed Regioselective Amination of N-Aryl Imines
Using TMSN3 and TBHP: A Route to Substituted Benzimidazoles
Devulapally Mahesh, Pradeep Sadhu, and Tharmalingam Punniyamurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502574u • Publication Date (Web): 14 Jan 2015
Downloaded from http://pubs.acs.org on January 15, 2015
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Copper(I)-Catalyzed Regioselective Amination of N-Aryl Imines Using
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TMSN3 and TBHP: A Route to Substituted Benzimidazoles
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Devulapally Mahesh, Pradeep Sadhu, and Tharmalingam Punniyamurthy*
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Department of Chemistry, Indian Institute of Technology Guwahati, Guwahatiꢀ781039, India.
*Eꢀmail: tpunni@iitg.ernet.in
ABSTRACT: A novel and efficient copperꢀcatalyzed amination of Nꢀaryl imines is described. This,
oneꢀpot, multicomponent reaction, in which imine acts as a directing group by chelating to the metal
center, affords a potential route for the transformation of the commercial aryl amines, aldehydes and
azide into valuable benzimidazole structural units with wide substrate scope and diversity. The
synthetic and mechanistic aspects are presented.
INTRODUCTION
Transitionꢀmetalꢀcatalyzed CꢀH functionalization directed by functional groups affords a powerful
tool for the atom economical regioselective construction of carbonꢀcarbon and carbonꢀheteroatom
bonds.1 For the most part, the second row transitionꢀmetals such as Ru2, Rh3, Pt4 and Pd5 have been
studied. Few studies are focused on the copperꢀcatalyzed systems,6 which are particularly attractive
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because of its high abundance and low toxicity. Herein, we report a novel oneꢀpot multiꢀcomponent
copperꢀcatalyzed imine chelated regioselective amination of Nꢀaryl imines using trimethylsilyl azide
(TMSN3) in the presence of tertꢀbutyl hydroperoxide (TBHP) at moderate temperature (Scheme 1,
e). This newly discovered reaction is simple, uses inexpensive copper catalyst and converts the
readily available substrates into important benzimidazole core structures that tolerates an array of
functional groups and substantial steric hindrance, via a sequential tandem condensation, CꢀH
azidation and CꢀN bond formation.
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Scheme 1. The main strategies for benzimidazole syntheses.
(a) Condensation/oxidative cyclization
NH2
N
H+
R
+ RCOX
heat
N
H
NH2
X = O, OH, Cl
(b) Cross-coupling reaction
H
N
R
N
Cu, Pd, Co
X = I, Br
R
NH
N
H
X
(c) Lewis acid assisted intramolecular cyclization
N
R
N
Cu, Fe
R
N
H
N3
(d) C-H functionalization
H
N
R
N
Cu
R
NH
N
H
metal-free
H
This work
(e)
R
NH2
N
H
N
CuI, TMSN3
TBHP
RCHO
R
N
H
DMSO
60 oC
Imine as a directing group
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Benzimidazoles are an important class of compounds for the pharmaceutical industry.7,8 The
benzimidazole scaffold can be found in several commercial drugs such as Nexium, Attacand,
Protonix, Prilosec, and Famvir as well as numerous experimental drug candidates (Figure 1). These
structural frameworks are commonly made by condensation of 1,2ꢀdiaminoarenes with carboxylic
acids or aldehydes followed by oxidative cyclization (Scheme 1, a).9 However, these approaches
often suffer due to limited substrate scope, and sometimes with the requirement of the strong acidic
condition and high reaction temperature. Thus, an effort has been recently made on the development
of new strategies to construct the benzimidazole structural motifs using CꢀN crossꢀcoupling reaction
of 2ꢀhaloarylamidines (Scheme 1, b),10 intramolecular cyclization of 2ꢀazido Nꢀaryl imines (Scheme
1, c)11 and the CꢀH functionalization of Nꢀarylamidines (Scheme 1, d).12 Hence, developing new
ways to obtain benzimidazoles with structural diversity involving the direct CꢀH functionalization
from the readily available simple substrates would be fascinating while challenging at the same time.
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Figure 1. Examples of biologically important substituted 2ꢀarylbenzimidazoles.
RESULTS AND DISCUSSION
We commenced the optimization studies with pꢀtoluidine 1a and benzaldehyde 2a as model
substrates using a series of copper sources with different solvents, azides and oxidants (Table 1).
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Table 1. Optimization of the Reaction Conditionsa
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entry
[Cu] source
[N3]
oxidant
solvent
yield (%)b
1
CuBr
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TsN3
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
30% H2O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
CH3CN
toluene
CH2Cl2
THF
60
5
2
CuBr
3
CuBr
3
4
CuBr
3
5
CuBr
DMF
16
72
n.d.
n.d.
n.d.
40
77
66
63
64
10
68
56c
6
CuBr
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
7
CuBr
8
CuBr
NaN3
9
CuBr
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
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12
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CuCl
CuI
Cu(OAc)2·H2O
CuCl2
CuBr2
Cu2O
Cu(OAc)2
CuI
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CuI
CuI
ꢀ
TMSN3
TMSN3
TMSN3
TMSN3
TBHP
TBHP
TBHP
ꢀ
DMSO
DMSO
DMSO
DMSO
59d
61e
n.d.
n.d.
CuI
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a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), solvent (0.5 mL), 60 °C, 1 h; copper source (10
mol %), azide (1 mmol), TBHP (0.5 mmol), 90 °C, 12 h. b Isolated yield. c 5 mol % CuI was used. d
0.75 mmol TMSN3 was used. e 0.25 mmol TBHP was used. n.d. = not detected.
Gratifyingly, the reaction took place to give 2ꢀphenylbenzimidazole 3a in 60% yield when the
substrates 1a (1 equiv) and 2a (1.2 equiv) were stirred at 60 oC for 1 h to give an imine intermediate
o
that was reacted with CuBr (10 mol %), TMSN3 (2 equiv) and TBHP (1 equiv) at 90 C for 12 h in
CH3CN (entry 1). The use of DMSO as a solvent led to an increase the product yield to 72%,
whereas solvents such as DMF, CH2Cl2, THF and toluene gave inferior results (entries 2ꢀ6). Azides
such as NaN3 and TsN3, and oxidant, 30% H2O2, failed to react (entries 7ꢀ9). Subsequent screening
of the copper sources revealed that CuI exhibited superior results, leading to 3a in 77% yield, while
CuCl, CuBr2, CuCl2, Cu(OAc)2·H2O, Cu(OAc)2 and Cu2O afforded the target molecule in <68%
yield (entries 10ꢀ16). Lowering the amount of the Cuꢀsource (5 mol %), TBHP (0.5 equiv) or
TMSN3 (1.5 equiv) led to the formation of 3a in <61% yield (entry 17ꢀ19). Control experiment
confirmed that, in the absence of either the Cuꢀsource or TBHP, the formation of 3a was not
observed (entries 20ꢀ21).
Having the optimal condition in hand, the scope of the protocol was investigated for the reaction
of a series of substituted anilines and 2ꢀaminofluorene with tolualdehyde 2b as representative
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Table 2. Reaction of Aryl Amines with Tolualdehydea
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5
O
i. DMSO, 60 °C, 1 h
ii. 10 mol % CuI
NH2
H3C
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8
9
N
H
CH3
R'
R'
2 equiv TMSN3
1 equiv TBHP
90 °C
N
H
3b-n
1b-n
2b
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CH3
N
H3C
CH3
N
CH3
N
H
N
H
3b, 13 h, 61%
3c,12 h, 70%c; 14 h, 79%d
N
N
CH3
CH3
N
H
AcHN
N
H
Br
3d, 14 h, 72%
3e, 12 h, 63%
N
N
CH3
CH3
H3C
N
H
N
H
Cl
3g, 12 h, 72%
3f, 14 h, 64%
N
N
CH3
CH3
N
H
N
H
H3CO
F
3i, 12 h, 73%e
3h, 12 h, 59%
N
N
CH3
CH3
F3C
N
H
N
H
O2N
3j, 12 h, n.d.
3k, 12 h, 49%
CH3
N
H3C
N
CH3
CH3
N
H
N
H
H3C
H3C
H3C
3l, 14 h, 59%
3ma, 14 h, 61%f
N
N
CH3
CH3
N
H
N
H
CH3
3n, 9 h, 70%
3mb, 14 h, 10%e,f
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a
o
Reaction conditions: amine 1b-n (1 mmol), aldehyde 2b (1.2 mmol), DMSO (1 mL), 60 C, 1
3
4
h; CuI (10 mol %), TMSN3 (2 mmol), TBHP (1 mmol) and 90 oC. b Isolated yield. c 3ꢀMethylaniline
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d
e
1
was used. 4ꢀMethylaniline was used. Two tautomers were observed in nearly 1:1 ratios by H
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9
NMR. f Obtained as a 1:6 mixture.
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Table 3. Reaction of Aniline with Various Aldehydesa
i. DMSO, 60 °C, 1 h
R'
NH2
N
ii 10 mol % CuI
R'CHO
+
2 equiv TMSN3
1 equiv TBHP
90 °C
N
H
3o-ac
2a-o
1b
Br
H3C
N
N
N
N
H
N
H
N
H
3q, 10 h, 59%
3p, 12 h, 66%
3o, 12 h, 84%
CH3
N
N
N
Br
Cl
N
H
N
H
N
H
3r, 10 h, 65%
3s, 10 h, 63%
3t, 12 h, 67%
N
N
N
CH3
F
OMe
N
H
N
H
N
H
3u, 12 h, 64%
3w, 9 h, 67%
3v, 16 h, 77%
OMe
N
N
N
NO2
OMe
N
H
N
H
N
H
3x, 12 h, 70%
3z, 10 h, 79%
3y, 12 h, 59%
N
S
N
N
N
H
N
H
N
H
3ac, 14 h, 64%
3aa, 12 h, 64%
3ab, 12 h, 68%
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a Reaction conditions: aniline 1b (1 mmol), aldehyde 2a-o (1.2 mmol), DMSO (1 mL), 60 oC, 1 h;
3
4
CuI (10 mol %), TMSN3 (2 mmol), TBHP (1 mmol) and 90 oC. b Isolated yield.
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example (Table 2). Aniline bearing electron donating and electron withdrawing substituents readily
proceeded reaction, and a substituent at 2ꢀposition had little effect on the yield. Reaction of 2ꢀmethyl
aniline gave benzimidazole 3b in 61% yield, while 3ꢀmethyl aniline underwent reaction to afford the
desired 3c in 70% yield. The reactions of anilines having 4ꢀacetamide, 4ꢀbromo, 4ꢀchloro, 4ꢀethyl, 4ꢀ
fluoro, 4ꢀmethyl, 4ꢀmethoxy and 4ꢀtrifluoromethyl groups produced the corresponding
benzimidazoles 3c-i and 3k in 49ꢀ73% yields. In contrast, in aniline with a strong electron
withdrawing group, 4ꢀnitro, failed to react, which suggests that the electronic nature of the aryl ring
is crucial for the reaction. The reaction conditions are also effective for disubstituted substrates. 2,4ꢀ
Dimethylaniline underwent reaction to furnish benzimidazole 3l in 59% yield, while the reaction of
3,4ꢀdimethylaniline led to the formation of a 1:6 mixture of 3ma and 3mb in 71% yield, which can
be easily separated by column chromatography. In addition, 2ꢀaminofluorene readily underwent
reaction to afford the target product 3n in 70% yield. Recrystallization of 3e yielded single crystals
whose structure was confirmed by Xꢀray analysis (see Supporting Information). Benzimidazoles 3i
and 3mb produced nearly a 1:1 mixture of tautomers.11a,18
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Next, we applied the protocol for the reactions of aldehydes with aniline 1b as a standard
substrate (Table 3). The reaction of benzaldehyde 1a produced benzimidazole 3o in 84% yield.
Substituted aromatic aldehydes with electron donating and electron withdrawing groups, 2ꢀmethyl,
3ꢀbromo, 3ꢀmethyl, 4ꢀbromo, 4ꢀchloro, 4ꢀfluoro, 4ꢀmethoxy, 4ꢀmethyl and 4ꢀnitro substituents,
underwent reaction to give the corresponding benzimidazoles 3p-x in 59ꢀ77% yields. The reaction of
3,4ꢀdimethoxybenzaldehyde afforded 3y in 59% yield, while 2ꢀnaphthaldehyde underwent reaction
to furnish 3z in 79% yield. Anthraceneꢀ9ꢀcarbaldehyde underwent reaction to provide the substituted
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benzimidazole 3aa in 64% yield. The reaction of the heterocyclic aldehyde, thiopheneꢀ2ꢀaldehyde,
occurred to afford the target product 3ab in 68% yield. In addition, an aliphatic aldehyde,
isobutyraldehyde, underwent reaction to give 2ꢀisopropylbenzimidazole 3ac in 64% yield.
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Finally, the scale up of the procedure was investigated using 1a and 2a as representative
examples (Scheme 2). The reaction was efficient and the target product was obtained in 73% yield.
To insight into the reaction pathway, an intermolecular kinetic isotope experiment between
equimolar amounts of 1aꢀd2 and 2b was performed (Scheme 3). At 1 h with 23% conversion, the
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Scheme 2. Gram Scale Synthesis
Scheme 3. Kinetic Isotope Experiment
Scheme 4. Radical Scavenger Experiment
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Figure 2. Major species identified using ESIꢀMS of the reaction mixture of 1a, 2b and TMSN3 after 3 h (see
Supporting Information).6k
Scheme 5. Proposed Reaction Pathway
R
R
R
RCHO
NH2
III
N
N
N
I
TMSN3
CuI
CuI
Cu
TMS
N3
H2O
c
a
b
TBHP
TMSOH
R
R
R
R
III
N
I
N
N
I
I
II
II
I
N
-
I
SET
SET
Cu
.
Cu
OtBu
Cu
Cu
N3
+
OtBu
.
-
OtBu
+
OtBu
N3
N3
N3
H
H
d
g
e
f
-tBuO-, -H+
CuI
CuI
N
R
N
N
H
R
R
N
H
N
N
h
i
CuI
N2
N2
3
reaction afforded PH/PD = 1.14, which suggests that the CꢀH bond cleavage is not involved in the
product determining step.13 In addition, the radical scavenger experiment using TEMPO exhibited no
reaction, which suggests that the reaction involves a radical intermediate (Scheme 4).14 Furthermore,
the ESIꢀMS analyses of the reaction mixture of 1a, 2b and TMSN3 after 3 h revealed the presence of
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four major species A, B, C and 3a (Figure 2).6i,k Thus, the condensation of aldehyde with amine can
give Nꢀaryl imine a that may undergo chelation with CuI to afford b. Oxidative addition of b with
TMSN3 can produce c that can react with TBHP to afford d. The latter can convert into copper(II)
species e by a single electron transfer (SET).6a,f,h Intramolecular N3 transfer to aryl cation radical can
give f that may lead to the formation of h via aryl cation g by SET. Cyclization of h may give i that
can furnish the target product 3 by tautomerization to complete the catalytic cycle.
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CONCLUSIONS
In summary, we have found that copper(I)ꢀcatalyzed imine directed amination of Nꢀaryl imines
proceeds smoothly to afford substituted benzimidazoles. The use of inexpensive copper catalysts, the
commercially available starting material and the broad substrate scope are significant practical
advantages. The tolerance of the functional groups is a synthetically useful feature.
EXPERIMENTAL SECTION
General Information: Cu(OAc)2 (99%), CuCl2 (99%), CuI (98%), CuBr (97%), CuCl (90%), Cu2O
(97%), TMSN3 (95%) and TBHP (98%, 5.5 M in decane) and Cu(OAc)2·H2O (98%) were
purchased from commercial sources. The solvents were purchased and dried according to standard
procedure prior to use.15 Purification of the reaction products was carried out by column
chromatography using silica gel (60ꢀ120 mesh). Analytical TLC was performed on silica gel G/GF
254 plate. NMR spectra were recorded on DRXꢀ400 and 600 MHz using CDCl3 and DMSOꢀd6 as
solvents and Me4Si as internal standard. Chemical shifts (δ) were reported in ppm and spinꢀspin
coupling constants (J) were given in Hz. Melting points were determined using melting point
apparatus and are uncorrected. FTꢀIR spectra were recorded using IR spectrometer. Mass spectra
were recorded on a QꢀTof ESIꢀMS Instrument. XꢀRay data were collected with a CCD area detector
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using Mo/Kα radiation. The structures were solved by direct method using SHELLXꢀ97 (Göttingen,
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Germany).
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General Procedure for Amination of N-Aryl Imines. Aniline 1(1.0 mmol) and benzaldehyde 2
(1.2 mmol) were stirred at 60 °C for 1 h in DMSO (1 mL) under air. The mixture was then cooled to
room temperature and treated with CuI (10 mol %, 0.1 mmol, 19 mg), TMSN3 (2 equiv, 2.0 mmol,
230 mg) and TBHP (1 equiv, 1 mmol, 181µL). The resultant mixture was stirred at 90 °C for the
appropriate time (Table 1 and 2). The progress of the reaction was monitored by TLC using ethyl
acetate and hexane as eluent. The reaction mixture was then cooled to room temperature and was
extracted with ethyl acetate (3 x 10 mL) and washed with brine (2 x 5 mL) and water (2 x 5 mL).
The solution was dried over Na2SO4, passed through a short pad of celite and evaporated on a rotary
evaporator to give a residue that was purified on silica gel column chromatography using nꢀhexane
and ethyl acetate as eluent.
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6-Methyl-2-phenyl-1H-benzo[d]imidazole 3a.11a Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 160 mg, yield 77%; mp 243ꢀ244 °C; H NMR (400
MHz, DMSOꢀd6) δ 12.77 (br s, 1H), 8.17 (d, J = 7.2 Hz, 2H), 7.55ꢀ7.32 (m, 5H), 7.05ꢀ7.00 (m, 1H),
2.43 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ 150.9, 144.2, 142.0, 135.3, 133.1, 131.9, 130.7,
126.1, 123.3, 118.5, 111.1, 21.4; FTꢀIR (KBr) 3447, 3047, 2920, 2110, 1632, 1595, 1460, 1403,
1313, 1272, 1108, 969, 801, 699 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C14H12N2H 209.1079,
found 209.1073.
4-Methyl-2-(p-tolyl)-1H-benzo[d]imidazole 3b. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; liquid; 135 mg, yield 61%; H NMR (600 MHz, DMSOꢀd6) δ 12.74 (br s,
1H), 8.10 (s, 2H), 7.36 (d, J = 7.8 Hz, 3H), 7.08 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 6.6 Hz, 1H), 2.56 (s,
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3H), 2.38 (s, 3H); C NMR (150 MHz, CDCl3) δ 151.5, 140.5, 129.9, 127.4, 126.7, 123.6, 123.0,
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21.6, 17.2; FTꢀIR (neat) 3402, 3029, 2917, 2115, 1620, 1504, 1485, 1439, 1373, 1285, 1117, 958,
827, 748 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C15H14N2H 223.1235, found 223.1234.
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5-Methyl-2-(p-tolyl)-1H-benzo[d]imidazole 3c. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; white solid; 155 mg, yield 70% (using 3ꢀmethylaniline) and 175 mg, yield
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79% (using 4ꢀmethyl aniline); mp 163ꢀ164 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.62 (br s, 1H),
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8.02 (s, 2H), 7.48ꢀ7.32 (m, 4H), 7.05ꢀ6.98 (m, 1H), 2.40 (s, 3H), 2.35 (s, 3H); C NMR (150 MHz,
DMSOꢀd6) δ 152.5, 140.3, 139.2, 138.0, 132.7, 129.9, 127.5, 126.9, 124.4, 115.2, 114.6, 21.8, 21.5;
FTꢀIR (KBr) 3440, 2922, 2852, 1627, 1449, 1385, 1284, 1225, 1109, 1026, 922, 804, 741 cmꢀ1.
HRMS (ESI) m/z: [M+H]+ calcd for C15H14N2H 223.1235, found 223.1230.
N-(2-(p-tolyl)-1H-benzo[d]imidazol-6-yl)acetamide 3d. Analytical TLC on silica gel, 1:2 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 191 mg, yield 72%; mp 273ꢀ274 °C; H NMR (400
MHz, DMSOꢀd6) δ 12.69 (br s, 1H), 9.97 (br s, 1H), 8.09 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 8.0 Hz,
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2H), 7.51 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.20 (s, 1H), 2.36 (s, 3H), 2.07 (s, 3H); C NMR (150
MHz, DMSOꢀd6) δ 167.9, 139.3, 134.6, 129.5, 127.5, 126.1, 118.4, 114.3, 101.5, 24.0, 20.9; FTꢀIR
(KBr) 3439, 3200, 2920, 2854, 1671, 1609, 1563, 1456, 1391, 1272, 1156, 1033, 824, 715 cmꢀ1.
HRMS (ESI) m/z: [M+H]+ calcd for C16H15N3OH 266.1293, found 266.1297.
6-Bromo-2-(p-tolyl)-1H-benzo[d]imidazole 3e.16 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; white solid; 180 mg, yield 63%; mp 232ꢀ233 °C; H NMR (400 MHz,
DMSOꢀd6) δ 13.03 (br s, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.77 (s, 1H), 7.52 (s, 1H), 7.37 (d, J = 6.8
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Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H); C NMR (150 MHz, DMSOꢀd6 + CDCl3) δ 152.0,
139.1, 128.4, 126.1, 125.7, 125.6, 123.8, 20.3; FTꢀIR (KBr) 3449, 3015, 2917, 2110, 1620, 1448,
1378, 1303, 1275, 1112, 1015, 911, 823, 729 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for
C14H11BrN2H 287.0184, found 287.0191.
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6-Chloro-2-(p-tolyl)-1H-benzo[d]imidazole 3f. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; white solid; 155 mg, yield 64%; mp 234ꢀ235 °C; H NMR (600 MHz,
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DMSOꢀd6) δ 13.01 (br s, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.69ꢀ7.65 (m, 1H), 7.53 (d, J = 9.0 Hz, 1H),
7.37 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 2.38 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6 + CDCl3) δ
152.1, 139.0, 128.3, 126.1, 125.9, 125.6, 121.2, 20.2; FTꢀIR (KBr) 3435, 2922, 2857, 2110, 1620,
1583, 1439, 1378, 1308, 1275, 1219, 1061, 963, 809, 725 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for
C14H11ClN2H 243.0689, found 243.0691.
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6-Ethyl-2-(p-tolyl)-1H-benzo[d]imidazole 3g. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; liquid; 170 mg, yield 72%; H NMR (600 MHz, DMSOꢀd6) δ 12.66 (br s,
1H), 8.04 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.06ꢀ
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7.04 (m, 1H), 2.71 (s, 2H), 2.37 (s, 3H), 1.26ꢀ1.22 (m, 3H); C NMR (100 MHz, CDCl3) δ 152.8,
140.2, 139.3, 129.8, 127.5, 123.3, 115.2, 113.5, 29.2, 21.4, 16.4; FTꢀIR (neat) 3417, 2962, 2925,
2859, 2103, 165, 1559, 1493, 1449, 1389, 1324, 1378, 1186, 1120, 1019, 965, 821, 728 cmꢀ1. HRMS
(ESI) m/z: [M+H]+ calcd for C16H16N2H 237.1392, found 237.1399.
6-Fluoro-2-(p-tolyl)-1H-benzo[d]imidazole 3h. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; white solid; 134 mg, yield 59%; mp 231ꢀ232 °C; H NMR (600 MHz,
DMSOꢀd6) δ 12.94 (br s, 1H), 8.05 (d, J = 7.8 Hz, 2H), 7.63 (s, 1H), 7.50 (s, 1H), 7.37 (d, J = 7.8
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Hz, 2H), 7.04 (s, 1H), 2.38 (s, 3H); C NMR (150 MHz, DMSOꢀd6) δ 140.4, 130.1, 127.6, 126.9,
112.3, 110.7, 110.3, 21.8; FTꢀIR (KBr) 3058, 2855, 2752, 2113, 1901, 1734, 1653, 1630, 1595,
1577, 1497, 1443, 1422, 1365, 1309, 1220, 1141, 1022, 824, 727 cmꢀ1. HRMS (ESI) m/z: [M+H]+
calcd for C14H11FN2H 227.0985, found 227.0990.
6-Methoxy-2-(p-tolyl)-1H-benzo[d]imidazole 3i. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; liquid; 174 mg, yield 73%; mixture of tautomers (1:1): H NMR (600
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MHz, DMSOꢀd6) δ 12.65 (br s, 2H), 8.02 (s, 4H), 7.52 (s, 1H), 7.38 (s, 1H), 7.33 (s, 4H), 7.18 (s,
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1H), 6.97 (s, 1H), 6.81 (s, 2H), 3.87 (s, 6H), 2.37 (s, 6H); C NMR (100 MHz, CDCl3) δ 156.8,
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152.2, 140.3, 129.9, 127.4, 126.6, 116.2, 112.5, 97.8, 56.0, 21.6; FTꢀIR (neat) 3430, 2927, 2857,
2110, 1630, 1597, 1453, 1425, 1392, 1266, 1201, 1159, 1107, 1033, 949, 823, 729 cmꢀ1. HRMS
(ESI) m/z: [M+H]+ calcd for C15H14N2OH 239.1184, found 239.1189.
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2-(p-Tolyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole 3k.17 Analytical TLC on silica gel, 1:3
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ethyl acetate/hexane Rf = 0.31; white solid; 135 mg, yield 49%; mp 192ꢀ193 °C; H NMR (400
MHz, DMSOꢀd6) δ 13.28 (br s, 2H), 8.10 (d, J = 7.6 Hz, 2H), 7.84ꢀ7.81 (m, 1H), 7.72 (d, J = 8.8 Hz,
1H), 7.54 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H ), 2.39 (s, 3H); 13C NMR (150 MHz, DMSOꢀ
d6) δ 153.9, 140.2, 129.6, 126.7, 119.0; FTꢀIR (KBr) 3464, 3124, 2924, 1889, 1615, 1562, 1509,
1427, 1329, 1239, 1218, 1055, 1022, 936, 826, 728 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for
C15H11N2F3H 277.0953, found 277.0961.
4,6-Dimethyl-2-(p-tolyl)-1H-benzo[d]imidazole 3l. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; liquid; 140 mg, yield 59%; H NMR (600 MHz, DMSOꢀd6) δ 12.57 (br s,
1H), 8.07 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.15 (s, 1H), 6.81 (s, 1H), 2.52 (s, 3H), 2.38
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(s, 6H); C NMR (150 MHz, CDCl3) δ 151.4, 140.2, 132.8, 129.9, 127.6, 126.7, 125.2, 21.8, 21.6,
17.2; FTꢀIR (neat) 3444, 2917, 2857, 1901, 1630, 1593, 1429, 1387, 1257, 1182, 1033, 958, 827,
725 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C16H16N2H 237.1392, found 237.1392.
5,6-Dimethyl-2-(p-tolyl)-1H-benzo[d]imidazole 3ma. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; white solid; 144 mg, yield 61%; mp 233ꢀ224 °C; H NMR (600 MHz,
DMSOꢀd6) δ 12.52 (br s, 1H), 8.03 (d, J = 7.8 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 7.8 Hz, 2H), 7.26
(s, 1H), 2.37 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ 150.5, 142.5,
139.1, 133.4, 130.8, 129.4, 129.1, 127.7, 126.1, 118.8, 111.2, 20.9, 20.0 ; FTꢀIR (KBr) 3435, 3015,
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2917, 2087, 1900, 1625, 1588, 1499, 1448, 1387, 1308, 1289, 1121, 1308, 1121, 1005, 827, 720 cmꢀ
1. HRMS (ESI) m/z: [M+H]+ calcd for C16H16N2H 237.1392, found 237.1390.
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6,7-dimethyl-2-(p-tolyl)-1H-benzo[d]imidazole 3mb. Analytical TLC on silica gel, 1:3 ethyl
acetate/hexane Rf = 0.31; yellow solid; 24 mg, yield 10%; mp 190ꢀ191 °C; mixture of tautomers
(1:1): 1H NMR (400 MHz, DMSOꢀd6) δ 12.64 (br s, 1H), 12.30 (br s, 1H), 8.16 (d, J = 8.0 Hz, 2H),
8.09 (d, J = 7.6 Hz, 2H), 7.38ꢀ7.36 (m, 5H), 7.24 (d, J = 8.0 Hz, 1H), 7.03ꢀ7.00 (m, 2H), 2.53 (s,
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6H), 2.40 (s, 6H), 2.36 (s, 6H); C NMR (150 MHz, CDCl3) δ 151.3, 140.2, 132.0, 129.9, 127.5,
126.7, 126.5, 21.6, 20.6; FTꢀIR (KBr) 3596, 2919, 2102, 1625, 1503, 1437, 1384, 1310, 1260, 1122,
1019, 958, 827, 727 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C16H16N2H 237.1392, found
237.1399.
2-(p-tolyl)-3,9-dihydrofluoreno[2,3-d]imidazole 3n. Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; thick brown gummy liquid; 207 mg, yield 70%; H NMR (400 MHz,
CDCl3) δ 12.91 (br s, 1H), 8.11 (s, 1H), 8.07 (d, J = 7.2 Hz, 2H), 7.94 (s, 1H), 7.79ꢀ7.68 (m, 1H),
7.55 (s, 1H), 7.37 (d, J = 7.2 Hz, 3H), 7.27 (s, 1H), 3.98 (s, 2H), 2.38 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 151.6, 142.4, 139.5, 139.4, 129.5, 127.5, 126.7, 126.4, 126.3, 125.1, 125.0, 57.9, 20.9; FTꢀ
IR (neat) 3435, 2924, 2257, 1644, 1431, 1382, 1272, 1047, 1030, 998, 826, 764 cmꢀ1. HRMS (ESI)
m/z: [M+H]+ calcd for C21H16N2H 297.1392, found 297.1393.
2-Phenyl-1H-benzo[d]imidazole 3o.18 Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
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0.41; pale yellow solid; 163 mg, yield 84%; mp 292ꢀ293 °C; H NMR (600 MHz, DMSOꢀd6) δ
12.92 (br s, 1H), 8.18 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 7.2 Hz, 1H), 7.56ꢀ7.49 (m, 4H), 7.22ꢀ7.19 (m,
2H); 13C NMR (150 MHz, DMSOꢀd6) δ 151.3, 143.8, 135.0, 130.2, 129.9, 129.0, 126.5, 122.6,
121.8, 118.2, 111.4; FTꢀIR (KBr) 3442, 2961, 2919, 2112, 1565, 1440, 1360, 1283, 1120, 1088, 995,
893, 743 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C13H10N2H 195.0922, found 195.0922.
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2-(o-tolyl)-1H-benzo[d]imidazole 3p.18 Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
0.41; white solid; 137 mg, yield 66%; mp 223ꢀ224 °C; 1H NMR (600 MHz, DMSOꢀd6) δ 12.62 (br s,
1H), 7.73 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.41ꢀ7.35 (m, 3H), 7.21 (s, 2H), 2.59 (s,
3H); 13C NMR (150 MHz, DMSOꢀd6) δ 152.0, 143.7, 137.0, 131.3, 130.1, 129.5, 129.4, 126.0,
122.4, 121.5, 119.0, 111.3, 21.0; FTꢀIR (KBr) 3440, 3048, 2973, 2721, 1938, 1619, 1597, 1448,
1406, 1369, 1275, 1229, 1047, 972, 879 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C14H12N2H
209.1079, found 209.1077.
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2-(3-Bromophenyl)-1H-benzo[d]imidazole 3q.18 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 161 mg, yield 59%; mp 223ꢀ224 °C; H NMR (400
MHz, DMSOꢀd6) δ 13.05 (br s, 1H), 8.37 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 6.4 Hz, 2H),
7.56ꢀ7.50 (m, 2H), 7.25ꢀ7.21 (m, 2H); 13C NMR (100 MHz, DMSOꢀd6) δ 149.6, 143.7, 135.0, 132.5,
132.4, 131.1, 128.9, 125.4, 122.9, 122.3, 121.9, 119.1, 111.5; FTꢀIR (KBr) 3326, 3048, 2529, 2112,
1698, 1649, 1595, 1544, 1445, 1315, 1226, 1156, 970, 743 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd
for C13H9BrN2H 273.0027, found 273.0030.
2-(m-tolyl)-1H-Benzo[d]imidazole 3r.19 Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
0.41; white solid; 135 mg, yield 65%; mp 231ꢀ232 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 12.88 (br s,
1H), 8.02 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.53 (d, J = 4.4 Hz, 1H), 7.45 (t, J = 7.6
Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 3.6 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz,
DMSOꢀd6) δ 151.8, 144.2, 138.6, 135.4, 130.9, 130.5, 129.3, 127.4, 124.0, 122.9, 122.0, 119.2,
111.7, 21.5; FTꢀIR (KBr) 3439, 2920, 2859, 2114, 1685, 1554, 1443, 1308, 1239, 1122, 1039, 957,
822, 728 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C14H12N2 H 209.1079, found 209.1088.
2-(4-Bromophenyl)-1H-benzo[d]imidazole 3s.18 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 172 mg, yield 63%; mp 255ꢀ256 °C; H NMR (400
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MHz, DMSOꢀd6) δ 13.00 (br s, 1H), 8.13 (m, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.66 (s, 1H), 7.55 (s,
1H), 7.22 (s, 2H); 13C NMR (150 MHz, DMSOꢀd6) δ 150.2, 143.7, 135.1, 129.4, 129.0, 128.3, 123.4,
123.2, 122.3, 118.9, 111.7; FTꢀIR (KBr) 3449, 3052, 2112, 1622, 1590, 1490, 1427, 1300, 1273,
1224, 1114, 1069, 1009, 963, 828, 745 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C13H9BrN2H
273.0027, found 273.0036.
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2-(4-Chlorophenyl)-1H-benzo[d]imidazole 3t.18 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 153 mg, yield 67%; mp 265ꢀ266 °C; H NMR (600
MHz, DMSOꢀd6) δ 12.97 (br s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.63 (d, J =
8.4 Hz, 2H), 7.54 (d, J = 7.8 Hz, 1H), 7.23ꢀ7.20 (m, 2H); 13C NMR (150 MHz, DMSOꢀd6) δ 150.1,
143.7, 135.0, 134.4, 129.0, 128.7, 128.1, 122.7, 121.8, 118.9, 111.4; FTꢀIR (KBr) 3442, 2997, 2951,
2112, 1630, 1587, 1486, 1429, 1300, 1273, 1225, 1089, 1015, 965, 831, 746 cmꢀ1. HRMS (ESI) m/z:
[M+H]+ calcd for C13H9ClN2H 229.0533, found 229.0533.
2-(4-Fluorophenyl)-1H-benzo[d]imidazole 3u.20 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 136 mg, yield 64%; mp 240ꢀ241 °C; H NMR (400
MHz, DMSOꢀd6) δ 12.93 (br s, 1H), 8.23 (m, 2H), 7.66 (d, J = 6.4 Hz, 1H), 7.53 (d, J = 6.4 Hz,
13
1H), 7.42ꢀ7.38 (m, 2H), 7.20 (s, 2H); C NMR (100 MHz, DMSOꢀd6) δ 164.7, 162.3, 150.8, 144.2,
135.4, 129.2, 127.2, 123, 122.1, 119.2, 111.6, 111.7; FTꢀIR (KBr) 3443, 2917, 2854, 2113, 1603,
1497, 1475, 1433, 1276, 1229, 1157, 1111, 967, 838, 747 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for
C13H9FN2H 213.0828, found 213.0820.
2-(p-tolyl)-1H-benzo[d]imidazole 3v.18 Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
0.41; white solid; 160 mg, yield 77%; mp 275ꢀ276 °C; 1H NMR (400 MHz, DMSOꢀd6) δ 12.85 (br s,
1H), 8.07 (d, J = 7.2 Hz, 2H), 7.63 (s, 1H), 7.52 (s, 1H), 7.36 (d, J = 6.8 Hz, 2H), 7.19 (s, 2H), 2.37
13
(s, 3H); C NMR (150 MHz, DMSOꢀd6) δ 151.4, 143.8, 139.6, 135.0, 129.5, 127.5, 126.4, 122.4,
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121.6, 118.7, 111.2, 21.0; FTꢀIR (KBr) 3440, 2927, 2852, 2106, 1630, 1457, 1261, 1196, 1038, 823,
715 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C14H12N2H 209.1079, found 209.1087.
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acetate/hexane Rf = 0.41; pale yellow solid ; 151 mg, yield 67%; mp 218ꢀ219 °C; H NMR (400
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MHz, DMSOꢀd6) δ 12.76 (br s, 1H), 8.13 (d, J = 7.2 Hz, 2H), 7.56 (s, 2H), 7.17ꢀ7.10 (m, 4H), 3.83
13
(s, 3H); C NMR (150 MHz, DMSOꢀd6) δ 160.6, 151.4, 128.0, 122.7, 121.7, 114.4, 114.3, 111.2,
55.3; FTꢀIR (KBr) 3472, 2921, 2836, 2113, 1611, 1501, 1476, 1453, 1295, 1254, 1179, 1124, 1034,
965, 845, 745 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C14H12N2OH 225.1028, found 225.1033.
2-(4-Nitrophenyl)-1H-benzo[d]imidazole 3x.11b Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; Brown solid; 167 mg, yield 70%; mp 260ꢀ261 °C; H NMR (400 MHz,
13
DMSOꢀd6) δ 13.30 (br s, 1H), 8.40ꢀ8.37 (m, 4H), 7.67 (s, 2H), 7.27 (s, 2H); C NMR (150 MHz,
DMSOꢀd6) δ 150.0, 149.0, 147.7, 136.0, 134.5, 127.32, 127.3, 124.14, 124.1, 122.9, 114.9; FTꢀIR
(KBr) 3451, 2661, 2110, 1667, 1603, 1516, 1433, 1340, 1290, 1101, 1008, 967, 854, 742 cmꢀ1.
HRMS (ESI) m/z: [M+H]+ calcd for C13H9N3O2H 240.0773, found 240.0770.
2-(3,4-Dimethoxyphenyl)-1H-benzo[d]imidazole 3y.21 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane; Rf = 0.41; Pale Yellow solid; 150 mg, yield 59%; mp 181ꢀ182 °C; H NMR (400
MHz, DMSOꢀd6) δ 12.77 (br s, 1H), 7.75 (s, 2H), 7.63 (s, 1H), 7.51 (s, 1H), 7.17 (s, 3H), 3.88 (s,
3H), 3.84 (s, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ 151.6, 150.5, 150.3, 149.0, 122.8, 122.4, 121.8,
119.5, 119.4, 111.8, 109.8, 55.6; FTꢀIR (KBr) 3195, 2987, 2842, 1620, 1508, 1481, 1432, 1264,
1198, 1115, 1039, 945, 847, 743 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C15H14N2O2H 255.1134,
found 255.1140.
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2-(Naphthalen-2-yl)-1H-benzo[d]imidazole 3z.21 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 194 mg, yield 79%; mp 192ꢀ193 °C; H NMR (600
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MHz, DMSOꢀd6) δ 13.07 (br s, 1H), 8.74 (s, 1H), 8.33ꢀ8.29 (m, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.05
(d, J = 6.6 Hz, 1H), 7.99 (d, J = 6.6 Hz, 1H), 7.71 (d, J = 5.4 Hz, 1H), 7.61ꢀ7.58 (m, 3H), 7.23 (s,
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2H); C NMR (150 MHz, DMSOꢀd6 + CDCl3) δ 151.1, 133.1, 133.0, 132.4, 127.7, 127.6, 127.1,
126.9, 126.6, 126.1, 125.9, 125.6, 125.4, 123.3, 121.6, 114.4, 113.4; FTꢀIR (KBr) 3450, 3053, 2111,
1653, 1588, 1504, 1441, 1405, 1334, 1282, 1136, 1096, 982, 907, 18, 742 cmꢀ1. HRMS (ESI) m/z:
[M+H]+ calcd for C17H12N2H 245.1079, found 245.1091.
2-(Anthracen-9-yl)-1H-benzo[d]imidazole 3aa.22 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.71; yellow solid; 188 mg, yield 64%; mp 261ꢀ262 °C; H NMR (600 MHz,
DMSOꢀd6) δ 13.0 (br, s, 1H), 8.85 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 7.2 Hz, 1H), 7.69 (d,
J = 9.0 Hz, 2H), 7.61ꢀ7.57 (m, 3H), 7.53ꢀ7.50 (m, 2H), 7.33ꢀ7.31 (m, 2H); 13C NMR (150 MHz,
DMSOꢀd6) δ 149.5, 130.6, 130.5, 128.8, 128.5, 126.8, 125.8, 125.64, 125.6, 122.5, 121.6, 119.1,
111.4; FTꢀIR (KBr) 3435, 3398, 2922, 2106, 1625, 1448, 1401, 1373, 1331, 1271, 1229, 1033, 921,
883, 790, 743 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C21H14N2 H 295.1235, found 295.1233.
2-(Thiophen-2-yl)-1H-benzo[d]imidazole 3ab.18 Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 136 mg, yield 68%; mp 343ꢀ344 °C; H NMR (600
MHz, DMSOꢀd6) δ 12.95 (br s, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.71 (d, J = 5.4 Hz, 1H), 7.60 (s, 1H),
7.50 (s, 1H), 7.23ꢀ7.19 (m, 3H); 13C NMR (150 MHz, DMSOꢀd6) δ 147.4, 143.9, 135.0, 134.0,
129.1, 128.7, 127.1, 123.0, 122.2, 118.9, 111.5; FTꢀIR (KBr) cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd
for C11H8N2SH 201.0486, found 201.0491.
2-Isopropyl-1H-benzo[d]imidazole 3ac.18 Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf
= 0.31; pale yellow solid; 102 mg, yield 64%; mp 232ꢀ233 °C; 1H NMR (600 MHz, CDCl3) δ 7.31ꢀ
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7.26 (m, 2H), 6.98ꢀ6.92 (m, 2H), 3.04ꢀ2.99 (m, 1H), 1.27ꢀ1.20 (m, 6H); 13C NMR (150 MHz,
DMSOꢀd6) δ160.1, 121.2, 28.7, 21.3; FTꢀIR (KBr) 3441, 2973, 2887, 2114, 1622, 1535, 1455, 1415,
1323, 1273, 1092, 995, 750 cmꢀ1. HRMS (ESI) m/z: [M+H]+ calcd for C10H12N2H 161.1079, found
161.1087.
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Kinetic Isotope Studies:
Preperation of p-Toluidine-d2 (Scheme 6). The titled compound was perpared according to the
reported procedure.2 Deuterium incorporation (82.5%) was determined by H NMR analysis of the
1
mixture. Characterization data for the deuterated product: analytical TLC on silica gel, 1/4 ethyl
1
acetate/hexane Rf = 0.32; pale brown solid; 185 mg, yield 85%; H NMR (400 MHz, CDCl3) δ 6.96
(s, 2H), 3.47 (br s, 2H), 2.23 (s, 3H).
Scheme 6
Intermolecular Kinetic Isotope Study (Scheme 4).23 pꢀToluidine 1a (64 mg), pꢀtoluidineꢀd2 1a-d2
(100 mg) and pꢀtolualdehyde 2b (1.2 equiv, 1.82 mmol, 218 mg) were stirred at 60 °C for 1 h in
DMSO (1 mL) under air. The reaction mixture was then cooled to room temperature and treated with
CuI (10 mol %, 0.152 mmol, 29 mg), TMSN3 (2 equiv, 3.0 mmol, 350 mg) and TBHP (1 equiv, 1.52
mmol, 275 µL). The resultant mixture was stirred at 90 °C for 1 h to give 24% conversion. The
resulting mixture was extracted with ethyl acetate (3 x 10 mL) and washed with brine (2 x 5 mL) and
water (2 x 5 mL). Drying (Na2SO4) and passing through celite gave a clear solution, which was
evaporated on a rotary evaporator to give a residue that was purified on silica gel column
chromatography using nꢀhexane and ethyl acetate as eluent (40 mg, yield 18%). The ratio of
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deuterium to hydrogen was determined from the H NMR relative integration values of Ha (7.47
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ppm) based on Hb (7.05 ppm).
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ASSOCIATED CONTENT
Supporting Information
Mass spectrum of the reaction mixture of 1a and 2b with TMSN3, crystal data of 3e and NMR
spectra (1H and 13C) of the products. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
tpunni@iitg.ernet.in
ACKNOWLEDGMENT
We thank Science and Engineering Research Board (SERB) (SR/S1/OCꢀ55/2011) and Council of Scientific
and Industrial Research (02(0088)/12/EMRꢀII) for financial support. P. S. thanks UGC for SRF Fellowship.
We also thank Central Instrumental Facility, IIT Guwahati for NMR facilities.
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