Copper(II)-Catalyzed Oxidative Cross-Coupling of Anilines, Primary Alkyl Amines, and Sodium Azide Using TBHP: A Route to 2-Substituted Benzimidazoles

Article abstract of DOI:10.1021/acs.joc.6b00186

Copper(II)-catalyzed oxidative cross-coupling of anilines, primary alkyl amines, and sodium azide is described in the presence of TBHP at moderate temperature. This one-pot multicomponent protocol involves a domino C-H functionalization, transimination, ortho-selective amination, and a cyclization sequence. The broad substrate scope and functional group compatibility are the significant practical features. The protocol can be extended to the coupling of benzyl alcohols with moderate yields.

Full text of DOI:10.1021/acs.joc.6b00186

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Article
Copper(II)-Catalyzed Oxidative Cross-Coupling of
Anilines, Primary Alkyl Amines and Sodium Azide
Using TBHP: A Route to 2-Substituted Benzimidazoles
Devulapally Mahesh, Pradeep Sadhu, and Tharmalingam Punniyamurthy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00186 • Publication Date (Web): 18 Mar 2016
Downloaded from http://pubs.acs.org on March 18, 2016
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Page 1 of 26
The Journal of Organic Chemistry
Copper(II)-Catalyzed Oxidative Cross-Coupling of Anilines, Primary Alkyl Amines
and Sodium Azide Using TBHP: A Route to 2-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, Guwahati 781039, India.
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Copper(II)ꢀcatalyzed oxidative crossꢀcoupling of anilines, primary alkyl amines and sodium azide is
described in the presence of TBHP at moderate temperature. This oneꢀpot multicomponent protocol
involves a domino CꢀH functionalization, transimination, ortho selective amination and cyclization
sequence. The broad substrate scope and functional group compatibility are the significant practical
features. The protocol can be extended to the coupling of benzyl alcohols with moderate yields.
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INTRODUCTION
Recent advances in transitionꢀmetalꢀcatalyzed CꢀH functionalization reactions using directing groups
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have led to the development of effective methods for the regioselective carbonꢀcarbon and carbonꢀ
heteroatom bonds formation.1 Among them, the CꢀN bond formation has attracted considerable attention
due to the presence of this moiety in numerous compounds that are of biological, medicinal and material
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2c
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interests.2ꢀ5 More recently, orthoꢀselective CꢀH azidation of arene has been accomplished using ꢀNH2
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and imine2d as the directing groups. Herein, we report an efficient copperꢀcatalyzed oxidative crossꢀ
coupling of anilines¸ primary alkyl amines and sodium azide to afford functionalized benzimidazoles
via a domino transimination, ortho selective amination and cyclization sequence. The utilization of the
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readily accessible simple substrates and the broad substrate scope are the significant practical
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advantages. These reaction conditions can be utilized for the coupling benzyl alcohols in moderate
yields.
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Benzimidazoles are privileged structural scaffolds due to their interesting medicinal and biological
properties.6 For examples, the compounds bearing benzimidazole motifs exhibit a broad spectrum of
biological properties such as antiꢀviral,6a antiꢀcancer,6b antiꢀbacterial,6c antiꢀfungal6d and antiꢀHIV
activities (Figure 1). In addition, benzimidazole structural frameworks are found to be useful for the
fabrication of organic lightꢀemitting diodes (OLEDs).7 Traditionally, the preparation of benzimidazoles
is performed via condensation of 1,2ꢀdiaminoarene with aldehydes or carboxylic acids followed by
oxidative cyclization. However, these methods often suffer due to the limited substrate scope and harsh
reaction conditions.8 To overcome these drawbacks, transitionꢀmetalꢀcatalyzed crossꢀcoupling of aryl
halides and their analogues with NꢀH nucleophiles has been explored.9 More recently, a few studies are
focused on the CꢀH functionalization and CꢀN bond formation of amidines10and benzylamine with 2ꢀ
aminoanilines11 to afford functionalized benzimidazoles (Scheme 1a). These reactions are attractive as
they are effective under relatively mild conditions with broad substrates scope. Development of the
oxidative coupling of the readily accessible substituted anilines, primary alkyl amines and sodium azide
via a domino sp3 and sp2 CꢀH functionalization strategy would thus be valuable (Scheme 1b).
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Figure 1. Examples of Some Biologically Important Benzimidazoles.
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Scheme 1. Methods for Benzimidazoles Using Primary Alkyl Amines via Transimination.
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RESULTS AND DISCUSSION
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First, we commenced the optimization studies using aniline 1a and benzylamine 2a as model substrates
with NaN3 employing different Cuꢀsources, oxidants and solvents (Table 1). Gratifyingly, the oxidative
crossꢀcoupling readily occurred to afford 2ꢀphenylbenzimidazole 3a in a trace amount when the
substrates 1a and 2a were stirred at 80 oC for 10 h with 10 mol % CuI, 3 equiv NaN3 and 2 equiv TBHP
in DMSO (entry 1). The use of CH3COOH as an additive led an increase in the yield to 44%, whereas
CF3COOH and (CH3)3CCOOH produced inferior results (entries 2ꢀ4). Subsequent screening of the
copper sources led to further increase in the yield to 82% using Cu(OAc)2, whereas CuBr, CuCl and
CuCl2 showed moderate catalytic activity (entries 5ꢀ8). In contrast, Cu(SO4)2ꢁ5H2O afforded 3a in a
trace amount (entry 9). Similar results were observed using air, 30% H2O2 and DTBP as the oxidants
(entries 10). DMSO was found to be the solvent of choice, whereas DMF, toluene, 1,4ꢀdioxane and
CH3CN furnished 3a in moderate yields (entries 11ꢀ14), varying the amount of the catalyst (5 mol %) or
additive (10 equiv) led to drop the yield to <38% (entries 15ꢀ16). Control experiments confirmed that
without the copper catalyst or TBHP, the formation of 3a was not observed (entries 17ꢀ18).
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Table 1. Optimization of the Reaction Conditionsa
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NH2
+
N
10 mol % Cu source
NH2
Ph
NaN3, oxidant
N
H
Additive, 80 °C, 10 h
1a
2a
3a
8
9
entry
1
Cu source
CuI
additive
ꢀ
solvent
DMSO
3a (%)b
trace
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2
CuI
CH3COOH
(CH3)3CCOOH
CF3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
3
CuI
trace
trace
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4
CuI
5
CuBr
CuCl
CuCl2
Cu(OAc)2
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50
7
60
8
82
9
Cu(SO4)2ꢁ5H2O CH3COOH
trace
trace
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10c
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15d
16e
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18f
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
ꢀ
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
toluene
1,4ꢀdioxane
CH3CN
DMSO
DMSO
DMSO
DMSO
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n.d.
n.d.
Cu(OAc)2
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aReaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), [Cu] (10 mol %), NaN3 (1.5 mmol), TBHP (1
b
1
c
mmol), AcOH (2.5 mmol), solvent (0.5 mL), 80 °C, 10 h. Determined by 600 MHz H NMR. Using
air, 30% H2O2 or DTBP. dCu(OAc)2 (5 mol %). eAcOH (5 mmol). No TBHP. n.d. = not detected.
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Scheme 2. Reaction of Substituted Anilines with Benzylaminea
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10 mol % Cu(OAc)2
NH2
N
3.0 equiv NaN3
NH2
R'
R'
5 equiv HOAc
2 equiv TBHP
DMSO, 80 °C
N
H
1b-q
2a
3b-p R' = EDG, EWG
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CH3
N
N
N
N
H
N
H
N
H
H3C
3b, 13 h, 66%
3c, 12 h, 52%
3d,10 h, 79%
N
N
N
H3C
N
H
N
H
N
H
AcHN
Cl
3e, 12 h, 68%
3f, 15 h, 54%
3g, 8 h, 73%
N
N
N
H3C
N
H
N
H
N
H
H3CO
O2N
CH3
3h, 8 h, 72%
3i, 8 h, 63%
3j, 12 h, n.d.
CH3
CH3
N
N
N
H3C
N
H
N
H
N
H
S
H3C
CH3
3k, 12 h, 66%
3l, 10 h, 62%b; 12 h, 70%c
3m, 12 h, 53%
N
N
N
N
N
N
H
N
H
N
H
3n, 15 h, 68%
3o
3p
, 16 h, n.d.
, 16 h, n.d.
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aReaction conditions: amine 1b-q (1 mmol), benzylamine 2a (1.2 mmol), Cu(OAc)2 (10 mol %), NaN3
o
b
c
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(3 mmol), TBHP (2 mmol), AcOH (5 mmol), DMSO (1 mL), 80 C. 3,5ꢀDimethylaniline used. 2,4ꢀ
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Dimethylaniline used.
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Scheme 3. Reaction of Alkyl Amines with Anilinea
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10 mol % Cu(OAc)2
3 equiv NaN3
NH2
N
R'
R'
NH2
+
5 equiv HOAc
2 equiv TBHP
N
H
R' = alkyl, aryl
DMSO, 80 C,
3q-ac
1a
2b-n
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H3C
Cl
MeO
N
N
N
N
H
N
H
N
H
3s, 16 h, 71%
3r, 16 h, 75%
3q, 10 h, 74%
N
N
N
CH3
Cl
F
N
H
N
H
N
H
3v, 10 h, 77%
3t, 11 h, 69%
3u, 10 h, 72%
N
N
O
N
OMe
N
N
H
N
H
N
H
3y, 14 h, 41%
3x, 12 h, 46%
3w, 8 h, 74%
N
N
N
C3H7
C15H31
C5H11
N
N
N
H
H
H
3ab, 16 h, 55%
3aa, 12 h, 46%
3z, 16 h, 35%
N
N
H
3ac, 15 h, 48%
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aReaction conditions: aniline1a (1 mmol), alkyl amines 2b-n (1.2 mmol), Cu(OAc)2 (10 mol %), NaN3
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(3 mmol), TBHP (2 mmol), AcOH (5 mmol), DMSO (1 mL), 80 oC.
Having the optimal conditions, the reaction of substituted anilines 1b-q was next explored using
benzylamine 2a as a standard substrate (Scheme 2). Anilines 1b and 1c with methyl and phenyl groups
at 2ꢀposition underwent reaction to give benzimidazoles 3b and 3c in 66 and 52% yields, respectively.
Similarly, anilines 1d-i bearing acetamide, chloro, ethyl, isopropyl, methoxy and methyl functionalities
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at 4ꢀposition furnished the corresponding benzimidazoles 3d-i in 54ꢀ79% yields, whereas aniline 1j with
strong electron withdrawing nitro group failed to react and the formation of benzimidazole 3j was not
observed. However, the reaction of aniline 1k with 4ꢀthiomethyl group produced benzimidazole 3k in
66% yield, while anilines 1l-n with methyl groups at 2,4ꢀ, 3,5ꢀ and 2,5ꢀpositions provided
benzimidazoles 3l-m in 53ꢀ70% yields. Similar result was observed with 2ꢀaminofluorene 1o affording
benzimidazole 3n in 68% yield. In contrast, the reaction of heterocyclic amines such as 2ꢀaminopyridine
1p and 3-aminopyridine 1q failed to produce benzimidazoles 3o-p and the starting materials were
remain intact.
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Scheme 4. Reaction of Aniline with Benzyl Alcoholsa
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aReaction conditions: aniline 1a (1 mmol), benzyl alcohol 4a-c (1.2 mmol), Cu(OAc)2 (10 mol %),
o
b
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NaN3 (3 mmol), TBHP (2 mmol), AcOH (5 mmol), DMSO (1 mL), 80 C. Alcohol 4a-c (3 mmol)
used.
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Next, the reaction of primary alkyl amines was explored with aniline as the standard substrate
(Scheme 3). Benzylamines 2b-c bearing substitution at 2ꢀposition with methyl and methoxy groups
underwent reaction to furnish benzimidazoles 3q and 3r in 74 and 75% yields, respectively. Similar
result was observed with benzylamine 2d bearing 3ꢀchloro group affording 3s in 71% yield. The
reaction of benzylamines 2e-h bearing substitution at 4ꢀposition with chloro, fluoro, methoxy and
methyl groups produced the corresponding benzimidazoles 3t-w in 69ꢀ77% yields. In addition,
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heterocyclic substrates such as furfurylamine 2i and 4ꢀpicolylamine 2j underwent reaction to give
benzimidazoles 3x and 3y in 46 and 41% yields, respectively. Furthermore, aliphatic amines such as
butylamine 2k, hexylamine 2l, hexadecaneꢀ1ꢀamine 2m and 2ꢀphenyl ethanamine 2n could be crossꢀ
coupled to afford 2ꢀalkyl benzimidazoles 3z-ac in 35ꢀ55% yields.
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Table 2. Reaction of Aldehyde Precursors with Anilinea
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aReaction conditions: aniline1a (1 mmol), aldehyde precursor 5-10 (1.2 mmol), Cu(OAc)2 (10 mol %),
NaN3 (3 mmol), TBHP (2 mmol), AcOH (5 mmol), DMSO (1 mL), 80 oC.
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The reaction conditions are also compatible for the reaction of analogue benzyl alcohols (Scheme 4).
For examples, benzyl alcohol 4a underwent reaction to furnish benzimidazole 3a in 45% yield. Increase
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in the quantity of benzyl alcohol 4a from 1.2 to 3 equiv led to an improvement in the yield to 61%.
Similar results were observed with benzyl alcohols bearing bromo and chloro functionalities at 4ꢀ
position affording benzimidazoles 3t and 3ad in moderate yields.
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Finally, the utility of the protocol was investigated for the reaction of aldehyde precursors 5ꢀ9 (Table
2). The reaction of acetophenone 5 and styrene 7 exhibited no benzimidazole formation, whereas benzyl
bromide 6 and phenylacetylene 8 and toluene 9 underwent reaction to produce the corresponding
benzimidazoles in 5ꢀ30% yields. These results suggest that broad range of substrates can be crossꢀ
coupled in moderate to good yields.
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Some of these benzimidazoles 3b, 3d-e, 3i, 3l and 3n are formed as a mixture of tautomers. To reveal
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the exact structure, variable temperature H NMR experiments of 3d were pursued as a representative
example (see Supporting Information). As anticipated, the formation of a single tautomer was observed
o
when heated to 50 C, however, the corresponding NOE experiment has failed to suggest the exact
structure of the tautomer due to the lack of NꢀH interaction with aromatic H atom.
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Scheme 5. Kinetic Isotope Experiment
NH2
1.2 equiv 4-MeBnNH2
10 mol % Cu(OAc)2
3 equiv NaN3
5 equiv AcOH
2 equiv TBHP
D
Me
1d
N
3aa
+
Me
+
D
N
H
3aa-d
Me
NH2
D
PH/PD =1.0
DMSO, 80 °C, 2.5 h
Me
1d-d2
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Scheme 6. Radical Scavenger Experiment
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Figure 2. Major Species Identified using ESIꢀMS of the Reaction Mixture of 1a and 2a after 5h (See
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supporting Information).
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To understand the reaction pathway, the intermolecular kinetic isotope experiment was performed
between 1d and 1d-d2 and PH/PD was found to be 1.0 (23% conv., 2.5 h), which suggests that the CꢀH
bond cleavage may not be involved in the productꢀdetermining step (Scheme 5).12 Further, the radical
scavenger experiment using TEMPO exhibited no benzimidazole formation, which suggests that a
radical intermediate may be involved (Scheme 6).13 In addition, the ESIꢀMS analysis of the reaction
mixture of 1a and 2a revealed the presence of three major species, A, B and benzimidazole 3a (Figure
2). Formation of A suggests that the oxidative coupling of benzylamine may be involved via sp3 CꢀH
functionalization,14 while the intermediate B reveals the involvement of transimination15 of A with
aniline followed by imine directed2d ortho selective sp2 CꢀH azidation. The subsequent Cu(OAc)2
catalyzed reduction of –N3 may produce –NH2 under heating.9g The absence of the peaks corresponding
to 2ꢀazidoaniline or 2ꢀaminoaniline suggests that the reaction may not involve ꢀNH2 as the directing
group for the azidation.2c Thus, the copper(II)ꢀcatalyzed oxidative coupling of alkyl amine can give
imine a,14 which can undergo transimination15 with aniline to form b. Coordination16 of b with
Cu(OAc)2 can furnish c, which may subsequently combine with in situ generated N3 radical from HN3
and TBHP to form the intermediate d.2c A single electron transfer17 (SET) from the aryl ring to the metal
center may lead to the formation of e, which can convert into f by azido transfer into the aryl ring.17 The
latter may convert into g via SET process, that could be reduced to h under heating in the presence of
Cu(OAc)2.9g Intramolecular oxidative cyclization of h can produce i that can aromatize to afford 3 and
copper(II) to complete the catalytic cycle (Scheme 7). The role of AcOH is to generate HN3 from NaN3.
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Furthermore, the intermediate b, prepared from aniline and benzaldehyde, underwent reaction to
produce benzimidazole 3a in 77% yield (eq. 1). These results clearly suggest that the reaction may
proceed via the intermediate b using imine as the directing group.
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Scheme 7. Proposed Reaction Pathway
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10 mol % Cu(OAc)2
N
N
3 equiv NaN3
eq. 1
R'
5 equiv HOAc
2 equiv TBHP
N
H
3a, 77%
DMSO, 80 C, 10 h
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CONCLUSIONS
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In summary, copperꢀcatalyzed oxidative crossꢀcoupling of anilines, alkyl primary amines and sodium
azide has been demonstrated using domino sp3 and sp2 CꢀH functionalization, transimination, ortho
selective azidation and cyclization process. The broad substrates scope, functional groups compatibility
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and the oneꢀpot domino process are the significant practical features. This study may open avenue for
the further development of CꢀH functionalization strategy for the regioselective construction of diverse
nitrogen containing heterocycles from the readily available simple substrates at relatively mild reaction
conditions.
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EXPERIMENTAL SECTION
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General Information: Cu(OAc)2 (99%), CuI (98%), CuCl (90%), CuCl2 (97%) and TBHP (~5.5 M in
decane, over molecular sieve 4Å), and NaN3 (99%), CuBr (97%) and CuSO4ꢁ5H2O (99%) purchased
from commercial sources and used as recieved. 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 600 and 400 MHz NMR spectrometers using DMSOꢀd6
and CDCl3 as solvents and Me4Si as an 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 were uncorrected. FTꢀIR spectra were recorded using IR spectrometer. Mass spectra were
recorded on a QꢀTof ESIꢀMS instrument.
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General Procedure for the Synthesis of Benzimidazoles. To a stirred solution of aniline 1 (1.0 mmol),
Cu(OAc)2 (10 mol %, 0.1 mmol, 18 mg), NaN3 (3 equiv, 3.0 mmol, 195 mg), AcOH (5 equiv, 5.0 mmol,
300 mg) and TBHP (2 equiv, 2 mmol, 360 µL) in DMSO (1 mL) was added alkyl amine 2 or alcohol 4
(1.2 mmol), and the resultant mixture was stirred at 80 °C for the appropriate time. The progress of the
reaction was monitored by TLC using ethyl acetate and hexane as an eluent. After completion, the
reaction mixture was cooled to room temperature and treated with saturated NaHCO3 (5 mL). The
solution was then extracted with ethyl acetate (3 x 10 mL) and washed with brine (2 x 5 mL) and water
(1 x 5 mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica
gel column chromatography using nꢀhexane and ethyl acetate as an eluent to afford analytically pure
products.
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2-Phenyl-1H-benzo[d]imidazole 3a.2dAnalytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.41;
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white solid; 137 mg, yield 70%; mp 290ꢀ291 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.92 (br s, 1H),
8.19 (d, J = 7.8 Hz, 2H), 7.67 (s, 1H), 7.56ꢀ7.48 (m, 4H), 7.20 (s, 2H); 13C {1H} NMR (150 MHz,
DMSOꢀd6) δ 151.2, 143.8, 135.0, 130.1, 129.8, 128.9, 126.4, 122.5, 121.6, 118.9, 111.3; FTꢀIR (KBr)
3436, 3048, 2962, 2922, 2114, 1623, 1591, 1462, 1411, 1374, 1276, 1120, 1029, 971, 744, 703 cmꢀ1.
HRMS (ESI) m/z: [M+H] calcd for C13H10N2H 195.0922, found 195.0913.
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4-Methyl-2-phenyl-1H-benzo[d]imidazole 3b.18aAnalytical TLC on silica gel, 1:3 ethyl acetate/hexane
Rf = 0.42; white solid; 137 mg, yield 66%; mp 247ꢀ248 °C; mixture of tautomers (1.2:1 ): 1H NMR (600
MHz, DMSOꢀd6) δ 12.83 (br s, 1H), 12.57 (br s, 1H), 8.26ꢀ8.18 (m, 4H), 7.55ꢀ7.49 (m, 7H), 7.35 (d, J =
7.2 Hz, 1H), 7.11ꢀ7.07 (m, 2H), 6.99 (s, 2H) 2.59 (s, 3H), 2.57 (s, 3H); 13C {1H} NMR (150 MHz,
CDCl3) δ 151.2, 150.4, 143.5, 143.2, 134.7, 134.5, 130.3, 129.74, 129.7, 128.9, 128.8, 128.4, 126.7,
126.5, 126.4, 123.1, 122.5, 121.9, 121.8, 121.3, 116.3, 108.8, 17.2, 16.7; FTꢀIR (neat) 3435, 3051, 2921,
2854, 2717, 2115, 1619, 1537, 1481, 1458, 1371, 1287, 785, 746, 703 cmꢀ1. HRMS (ESI) m/z: [M+H]
calcd for C14H12N2H 209.1078, found 209.1057.
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2,4-Diphenyl-1H-benzo[d]imidazole 3c. Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
0.42; white solid; 141 mg, yield 52%; mp 256ꢀ257 °C;1H NMR (400 MHz, DMSOꢀd6) δ 13.06 (br s,
1H), 8.21ꢀ8.16 (m, 4H), 7.59ꢀ7.50 (m, 6H), 7.44 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.33 (t, J =
8.0 Hz, 1H);13C {1H} NMR (100 MHz, DMSOꢀd6) δ 151.2, 141.3, 138.3, 135.8, 130.6, 130.1, 129.8,
128.9, 128.8, 128.5, 128.2, 127.0, 126.5, 122.9, 120.5, 110.6; FTꢀIR (neat) 3435, 3057, 2921, 2851,
2114, 1617, 1457, 1415, 1390, 1316, 1244, 1112, 1027, 750, 697 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd
for C19H14N2H 271.1235, found 271.1229.
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6-Methyl-2-phenyl-1H-benzo[d]imidazole 3d.2d Analytical TLC on silica gel, 1:3 ethyl acetate/hexane
Rf = 0.42; white solid; 164 mg, yield 79%; mp 246ꢀ247 °C; mixture of tautomers (1:1.3):1H NMR (600
MHz, DMSOꢀd6) δ 12.77 (br s, 1H), 12.74 (br s, 1H), 8.16 (d, J = 7.8 Hz, 4H), 7.55ꢀ7.52 (m, 5H), 7.48ꢀ
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7.45 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4Hz, 1H),
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2.43 (s, 3H), 2.41 (s, 3H); C {1H} NMR (150 MHz, DMSOꢀd6) δ 150.8, 142.0, 131.8, 130.3, 129.6,
128.9, 126.3, 123.9, 123.3, 118.5, 111.0, 21.3; FTꢀIR (KBr) 3435, 3047, 2921, 2856, 2110, 1631, 1595,
1463, 1401, 1308, 1276, 1112, 972, 804, 702, 689 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C14H12N2H
209.1078, found 209.1071.
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N-(2-Phenyl-1H-benzo[d]imidazol-6-yl)acetamide 3e. Analytical TLC on silica gel, 1:2 ethyl
acetate/hexane Rf = 0.41; pale yellow solid; 171 mg, yield 68%; mp 262ꢀ263 °C; mixture of tautomers
(1:2.1): 1H NMR (600 MHz, DMSOꢀd6) δ 12.85 (br s, 1H), 12.79 (br s, 1H), 10.03 (br s, 1H), 9.93 (br s,
1H), 8.16ꢀ8.13 (m, 4H), 8.02 (s, 1H), 7.58ꢀ7.52 (m, 5H), 7.47ꢀ7.45 (m, 2H), 7.39ꢀ7.37 (m, 2H), 7.21ꢀ
13
7.19 (m, 2H), 2.09 (s, 3H), 2.07 (s, 3H); C {1H} NMR (150 MHz, DMSOꢀd6) δ 168.1, 168.0, 151.7,
151.0, 143.9, 140.0, 135.1, 134.9, 131.3, 130.2, 129.6, 129.0, 126.4, 126.2, 118.7, 115.8, 114.5, 110.9,
109.3, 101.5, 24.1; FTꢀIR (KBr) 3436, 2957, 2922, 2851, 2130, 1643, 1497, 1463, 1313, 1259, 1178,
1025, 994, 822, 694 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C15H13N3OH 252.1137, found 252.1146.
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6-Chloro-2-phenyl-1H-benzo[d]imidazole 3f.9c Analytical TLC on silica gel, 1:3 ethyl acetate/hexane
Rf = 0.48; white solid; 123 mg yield 54%; mp 200ꢀ201 °C; 1H NMR (600 MHz, DMSOꢀd6) δ 13.12 (br
s, 1H), 8.17 (d, J = 7.8 Hz, 2H), 7.69ꢀ7.50 (m, 5H), 7.23 (d, J = 7.8 Hz, 1H); 13C {1H} NMR (150 MHz,
DMSOꢀd6) δ 152.7, 130.2, 129.7, 129.0, 126.6, 126.5, 122.4; FTꢀIR (KBr) 3444, 2920, 2119, 1624,
1584, 1462, 1450, 1438, 1384, 1275, 1107, 1062, 808, 692 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for
C13H9ClN2H229.0532, found 229.0512.
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6-Ethyl-2-phenyl-1H-benzo[d]imidazole 3g. Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf
= 0.43; brown liquid; 162 mg, yield 73%;1H NMR (400 MHz, DMSOꢀd6) δ 12.82 (br s, 1H), 8.20 (d, J
= 8.4 Hz, 2H), 7.57ꢀ7.47 (m, 3H), 7.46ꢀ7.41 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 2.74 (q, J = 7.6 Hz, 2H),
1.25 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ 130.4, 129.7, 128.9, 126.3, 28.5, 16.4; FTꢀ
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IR (neat) 3390, 3064, 2963, 2928, 2106, 1628, 1595, 1453, 1431, 1405, 1374, 1280, 1055, 814, 776, 692
cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C15H14N2H 223.1235, found 223.1235.
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6-Isopropyl-2-phenyl-1H-benzo[d]imidazole 3h. Analytical TLC on silica gel, 1:3 ethyl
acetate/hexane Rf = 0.45; liquid; 170 mg, yield 72%; 1H NMR (600 MHz, DMSOꢀd6) δ 12.82 (br s, 1H),
8.20 (s, 2H), 7.59ꢀ7.52 (m, 3H), 7.47ꢀ7.36 (m, 2H), 7.09 (s, 1H), 2.99 (s, 1H), 1.26 (d, J = 7.2 Hz, 6H);
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tautomers (1:1): C {1H} NMR (100 MHz, CDCl3) δ 151.0, 143.2, 142.3, 135.2, 130.4, 129.6, 128.9,
126.3, 121.6, 120.7, 118.6, 115.8, 110.9, 108.3, 33.7, 24.4; FTꢀIR (neat) 3400, 3067, 2959, 2927, 2256,
2104, 1628, 1541, 1463, 1431, 1364, 1288, 1047, 815, 776 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for
C16H16N2H 237.1392, found 237.1393.
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6-Methoxy-2-phenyl-1H-benzo[d]imidazole 3i.9cAnalytical TLC on silica gel, 1:3 ethyl acetate/hexane
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Rf = 0.35; liquid; 141 mg, yield 63%; tautomers (1:1): H NMR (600 MHz, DMSOꢀd6) δ 12.82 (br s,
2H), 8.18ꢀ8.17 (m, 4H), 7.57ꢀ7.52 (m, 6H), 7.46ꢀ7.44 (m, 2H), 7.31ꢀ7.20 (m, 1H), 7.04 (s, 1H), 6.86 (s,
2H), 3.81 (s, 6H); tautomers (1:1): 13C {1H} NMR (100 MHz, CDCl3) δ 156.1, 150.5, 138.4, 130.4,
129.5, 128.9, 128.3, 127.3, 126.7, 126.2, 119.4, 112.3, 111.6, 111.2, 101.4, 94.5, 55.5; FTꢀIR (neat)
3414, 2924, 2854, 2255, 1631, 1594, 1539, 1490, 1455, 1434, 1159, 1117, 1026, 823, 778 cmꢀ1. HRMS
(ESI) m/z: [M+H] calcd for C14H12N2OH 225.1028, found 225.1031.
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6-(Methylthio)-2-phenyl-1H-benzo[d]imidazole 3k.18bAnalytical TLC on silica gel, 1:3 ethyl
acetate/hexane Rf = 0.31; liquid; 158 mg, yield 66%; 1H NMR (600 MHz, DMSOꢀd6) δ 12.97 (br s, 1H),
8.19 (d, J = 7.8 Hz, 2H), 7.55ꢀ7.53 (m, 3H), 7.49ꢀ7.46 (m, 2H), 7.17 (d, J = 4.8 Hz, 1H), 2.52 (s, 3H);
13C {1H} NMR (150 MHz, DMSOꢀd6) δ 151.4, 130.0, 129.9, 129.0, 126.5, 122.9, 121.9, 119.2, 117.2,
111.9, 109.4, 16.5; FTꢀIR (KBr) 3400, 2920, 2856, 2255, 2126, 1624, 1582, 1537, 1463, 1441, 1422,
1278, 1025, 1004, 806, 777 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C14H12N2SH 241.0799, found
241.0796.
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4,6-Dimethyl-2-phenyl-1H-benzo[d]imidazole 3l.9c Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; white solid; 138 mg, yield 62% (3,5ꢀdiMe aniline) and 155 mg, 70% (2,4ꢀ
1
diMe aniline); mp 190ꢀ191 °C; tautomers (1:0.6); H NMR (600 MHz, DMSOꢀd6) δ 12.67 (br s, 1H),
12.46 (br s, 1H), 8.23 (d, J =7.8 Hz, 2H), 8.16 (d, J = 7.2 Hz, 2H), 7.54ꢀ7.45 (m, 6H), 7.26 (s, 1H), 7.12
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(s, 1H), 6.83ꢀ6.82 (m, 2H) 2.54ꢀ2.50 (m, 6H), 2.50ꢀ2.37 (m, 6H); C {1H} NMR (150 MHz, CDCl3) δ
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151.0, 149.9, 143.9, 141.4, 134.8, 132.7, 131.7, 130.6, 130.5, 129.6, 129.4, 128.9, 128.8, 127.8, 126.6,
126.2, 124.7, 123.6, 120.7, 116.0, 108.5, 21.4, 21.2, 17.1, 16.6; FTꢀIR (neat) 3456, 3146, 2922, 2853,
2108, 1683, 1627, 1456, 1406, 1332, 1254, 1031, 838, 701, 682 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd
for C15H14N2H 223.1235, found 223.1231.
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4,7-Dimethyl-2-phenyl-1H-benzo[d]imidazole 3m. Analytical TLC on silica gel, 1:3 ethyl
acetate/hexane Rf = 0.41; white solid; 118 mg, yield 53%; mp 231ꢀ232 °C; 1H NMR (400 MHz, DMSOꢀ
d6) δ 12.63 (br s, 1H), 8.37ꢀ8.35 (m, 2H), 7.68ꢀ7.60 (m, 3H), 7.02ꢀ7.00 (m, 2H), 2.68ꢀ2.62 (m, 6H); 13C
{1H} NMR (150 MHz, CDCl3) δ 150.4, 134.2, 130.5, 129.6, 128.8, 126.7, 125.5, 123.0, 121.9,
118.5,112.8, 17.0, 16.5; FTꢀIR (neat) 3435, 2922, 2852, 2108, 1625, 1457, 1410, 1313, 1264, 1029,
963, 705 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C15H14N2H 223.1235, found 223.1241.
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2-Phenyl-3,9-dihydrofluoreno[2,3-d]imidazole 3n. Analytical TLC on silica gel, 1:3 ethyl
1
acetate/hexane Rf = 0.45; white solid; 192 mg, yield 68%; mixture of tautomers (1:1); H NMR (600
MHz, CDCl3) δ 13.05 (br s, 1H), 12.97 (br s, 1H), 8.24ꢀ8.20 (m, 4H), 7.96ꢀ7.87 (m, 2H), 7.77ꢀ7.69 (m,
13
2H), 7.64ꢀ7.48 (m, 10H), 7.39ꢀ7.36 (m, 2H), 7.28ꢀ7.26 (m, 2H), 4.15ꢀ 4.11 (m, 1H), 3.99 (s, 1H); C
{1H} NMR (150 MHz, CDCl3) δ 151.5, 130.2 129.7, 128.9, 126.7, 126.5, 126.3, 125.0, 115.1; FTꢀIR
(neat) 3433, 2922, 1629, 1457, 1433, 1403, 1311, 1107, 962, 854, 768, 725, 751, 698 cmꢀ1. HRMS (ESI)
m/z: [M+H] calcd for C20H14N2H 283.1235, found 283.1235.
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2-(o-Tolyl)-1H-benzo[d]imidazole 3q.2d Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
1
0.41; white solid; 154 mg, yield 74%; mp 223ꢀ224 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.63 (br s,
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1H), 7.75 (d, J = 7.2 Hz, 1H), 7.67 (s, 1H), 7.54 (s, 1H), 7.41ꢀ7.35 (m, 3H), 7.21 (s, 2H), 2.61 (s, 3H);
13C {1H} NMR (150 MHz, DMSOꢀd6) δ 151.9, 143.6, 137.0, 134.3, 131.3, 130.1, 129.4, 129.3, 126.0,
122.3, 121.4, 118.9, 111.3, 21.0; FTꢀIR (KBr) 3435, 3052, 2959, 2786, 2111, 1620, 1542, 1454, 1409,
1367, 1216, 1092, 900, 765, 746, 733 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C14H12N2H 209.1079,
found 209.1085.
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2-(2-Methoxyphenyl)-1H-benzo[d]imidazole 3r. Analytical TLC on silica gel, 1:3 ethyl
acetate/hexane Rf = 0.41; white solid; 168 mg, yield 75%; mp 236ꢀ237 °C; 1H NMR (600 MHz, DMSOꢀ
d6) δ 12.13 (br s, 1H), 8.33 (d, J = 7.2 Hz, 1H), 7.65ꢀ7.60 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.25 (d, J =
13
8.4 Hz, 1H), 7.20 (t, J = 7.8 Hz, 2H) 7.13 (t, J = 7.2 Hz, 1H), 4.02 (s, 3H); C {1H} NMR (150 MHz,
DMSOꢀd6) δ 156.8, 149.0, 142.8, 134.8, 131.2, 129.8, 122.1, 121.6, 120.9, 118.5, 118.1, 112.1, 55.7;
FTꢀIR (KBr) 3436, 3007, 2964, 2111, 1604, 1584, 1474, 1435, 1373, 1281, 1244, 1089, 1022, 966, 746
cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C14H12N2OH 225.1027, found 225.1027.
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2-(3-Chlorophenyl)-1H-benzo[d]imidazole 3s.9c Analytical TLC on silica gel, 1:3 ethyl acetate/hexane
Rf = 0.41; white solid; 162 mg, yield 71%; mp 239ꢀ240 °C;1H NMR (600 MHz, DMSOꢀd6) δ 13.06 (br
s, 1H), 8.23ꢀ8.22 (m, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60ꢀ7.54 (m, 3H), 7.26ꢀ
13
7.20 (m, 2H); C {1H} NMR (150 MHz, DMSOꢀd6) δ 149.8, 143.7, 135.0, 133.8, 132.2, 130.9, 129.5,
126.1, 125.0, 122.9, 122.0, 119.1, 111.6; FTꢀIR (KBr) 3434, 3045, 2964, 2877, 2788, 2113, 1602, 1591,
1541, 1442, 1403, 1285, 1229, 1079, 998, 925, 743 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C13H9ClN2
H 229.0533, found 229.0518.
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2-(4-Chlorophenyl)-1H-benzo[d]imidazole 3t.2d Analytical TLC on silica gel, 1:3 ethyl acetate/hexane
1
Rf = 0.41; pale yellow solid; 157 mg, yield 69%; mp 266ꢀ267 °C; H NMR (600 MHz, DMSOꢀd6) δ
13
13.0 (br s, 1H), 8.19 (d, J = 7.2 Hz, 2H), 7.63ꢀ7.56 (m, 4H), 7.21 (s, 2H); C {1H} NMR (150 MHz,
DMSOꢀd6) δ 150.2, 134.5, 129.0, 128.1, 122.3, 118.9, 111.5; FTꢀIR (KBr) 3445, 2996, 2957, 2116,
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1635, 1583, 1482, 1421, 1323, 1256, 1234, 1095, 1025, 966, 835, 757 cmꢀ1. HRMS (ESI) m/z: [M+H]
calcd for C13H9ClN2H 229.0532, found 229.0529.
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2-(4-Fluorophenyl)-1H-benzo[d]imidazole 3u.2d Analytical TLC on silica gel, 1:3 ethyl acetate/hexane
1
Rf = 0.41; yellow solid; 153 mg, yield 72%; mp 239ꢀ240 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.92
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(br s, 1H), 8.22 (s, 2H), 7.65 (s, 1H), 7.53 (s, 1H), 7.40 (s, 2H), 7.20 (s, 2H); 13C {1H} NMR (150 MHz,
DMSOꢀd6) δ 164.0 (d, J = 247.0 Hz,), 150.5, 143.8, 135.1, 128.8 (d, J = 7.5 Hz), 126.9, 122.6, 121.8,
118.9, 116.2 (d, 22.5 Hz), 111.4; FTꢀIR (KBr) 3435, 3052, 2960, 2854, 2116, 1603, 1497, 1475, 1433,
1276, 1228, 1156, 1110, 837, 747 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C13H9FN2H 213.0828,
found 213.0821.
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2-(p-Tolyl)-1H-benzo[d]imidazole 3v.2d Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
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0.41; white solid; 160 mg, yield 77%; mp 275ꢀ276 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.85 (br s,
1H), 8.08 (d, J = 9 Hz, 2H), 7.65ꢀ7.63 (m, 1H), 7.52 (s, 1H), 7.36 (d, J = 9 Hz, 2H), 7.20ꢀ7.17 (m, 2H),
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2.38 (s, 3H); C {1H} NMR (150 MHz, DMSOꢀd6) δ 151.4, 143.9, 139.6, 135.0, 129.5, 127.5, 126.4,
122.4, 121.6, 118.7, 111.2, 21.0; FTꢀIR (KBr) 3435, 3053, 2961, 2919, 2855, 2115, 1621, 1588, 1448,
1430, 1226, 1122, 1042, 821, 747 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C14H12N2H 209.1079, found
209.1065.
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2-(4-Methoxyphenyl)-1H-benzo[d]imidazole 3w.2d Analytical TLC on silica gel, 1:3 ethyl
1
acetate/hexane Rf = 0.41; white solid ; 166 mg, yield 74%; mp 217ꢀ218 °C; H NMR (600 MHz,
DMSOꢀd6) δ 12.75 (br s, 1H), 8.12 (s, 2H), 7.62 (s, 1H), 7.49 (s, 1H), 7.17ꢀ7.11 (m, 4H), 3.84 (s, 3H);
13C {1H} NMR (150 MHz, DMSOꢀd6) δ 160.6, 151.4, 143.9, 135.0, 128.1, 122.7, 122.1, 121.5, 118.5,
114.4, 111.0, 55.3; FTꢀIR (KBr) 3472, 3054, 2923, 2855, 2113, 1611, 1500, 1476, 1453, 1295, 1254,
1179, 1124, 1033, 965, 845, 745 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C14H12N2OH 225.1027,
found 225.1026.
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2-(Furan-2-yl)-1H-benzo[d]imidazole 3x.9f Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
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1
0.35; white solid ; 85 mg, yield 46%; mp 284ꢀ285 °C; H NMR (400 MHz, DMSOꢀd6) δ 12.94 (br s,
1H), 7.95 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.20ꢀ7.19 (m, 3H), 6.73 (s, 1H); 13C
{1H} NMR (100 MHz, DMSOꢀd6) δ 145.6, 144.7, 143.7, 134.2, 122.7, 121.8, 118.8, 112.4, 111.4,
110.5; FTꢀIR (KBr) 3434, 3059, 2924, 2853, 2663, 1630, 1525, 1443, 1416, 1364, 1278, 1234, 1014,
979, 906, 883, 738, 589 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C11H8N2OH 185.0715, found
185.0715
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2-(Pyridin-4-yl)-1H-benzo[d]imidazole 3y.9h Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf
1
= 0.20; pale yellow solid; 80 mg, yield 41%; mp 220ꢀ221 °C; H NMR (600 MHz, DMSOꢀd6) δ 13.27
(br s, 1H), 8.76 (s, 2H), 8.10 (s, 2H), 7.74 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.30ꢀ7.25 (m,
13
2H); C {1H} NMR (150 MHz, DMSOꢀd6) δ 150.5, 149.8, 148.8, 143.6, 137.1, 135.0, 123.6, 122.3,
120.3, 119.5, 111.8; FTꢀIR (KBr) 3418, 2925, 2255, 2128, 1646, 1609, 1433, 1384, 1317, 1234, 1048,
1025, 1001, 765 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C12H9N3H 196.0875, found 196.0875.
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2-Pentadecyl-1H-benzo[d]imidazole 3z. Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
0.35; white solid; 115 mg, yield 35%; mp 91ꢀ92 °C;1H NMR (600 MHz, DMSOꢀd6) δ 12.14 (br s, 1H),
13
7.44 (s, 2H), 7.09 (s, 2H), 2.77 (s, 2H), 1.74 (s, 2H), 1.22 (s, 24H) 0.84 (s, 3H); C {1H} NMR (150
MHz, DMSOꢀd6 ) δ 31.3, 29.0, 28.9, 28.73, 28.7, 28.5, 27.6, 22.1, 14.0; FTꢀIR (KBr) 3435, 3089, 2954,
2920, 2849, 2101, 1625, 1541, 1470, 1458, 1206, 1155, 753, 744 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd
for C22H36N2H 329.2956, found 329.2936.
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2-Pentyl-1H-benzo[d]imidazole 3aa.18d Analytical TLC on silica gel, 1:3 ethyl acetate/hexane; Rf =
1
0.35; brown solid; 86 mg, yield 46%; mp 140ꢀ141 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.16 (br s,
1H), 7.44 (s, 2H), 7.10ꢀ7.09 (m, 2H), 2.79 (t, J = 7.2 Hz, 2H), 1.77ꢀ1.74 (m, 2H), 1.32ꢀ1.30 (m, 4H),
13
0.87ꢀ0.84 (m, 3H); C {1H} NMR (150 MHz, DMSOꢀd6) δ 155.3, 121.1, 30.9, 28.5, 27.3, 21.9, 13.9;
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FTꢀIR (KBr) 3390, 3050, 2951, 2924, 2852, 2773, 2257, 2128, 1647, 1537, 1447, 1418, 1233, 1024,
998, 766 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C12H16N2H 189.1392, found 189.1394.
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2-Propyl-1H-benzo[d]imidazole 3ab.18a Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
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0.35; brown solid; 88 mg, yield 55%; mp 230ꢀ231 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.15 (br s,
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1H), 7.45 (s, 2H), 7.10 (s, 2H), 2.78 (t, J = 7.2 Hz, 2H), 1.80ꢀ1.76 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C
{1H} NMR (150 MHz, DMSOꢀd6) δ 155.0, 121.1, 30.5, 21.0, 13.7; FTꢀIR (KBr) 3434, 2257, 2129,
1646, 1047, 1025, 996, 827, 766, 688 cmꢀ1. HRMS (ESI) m/z: [M+H] calcd for C10H12N2H 161.1079,
found 161.1078.
2-Benzyl-1H-benzo[d]imidazole 3ac.9c Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
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344
0.41; white solid; 100 mg, yield 48%; mp 221ꢀ222 °C; H NMR (600 MHz, DMSOꢀd6) δ 12.29 (br s,
345
1H), 7.46 (s, 2H), 7.34ꢀ7.30 (m, 4H), 7.24ꢀ7.21 (m, 1H), 7.13ꢀ7.10 (m, 2H), 4.16 (s, 2H); 13C {1H}
NMR (150 MHz, DMSOꢀd6) δ 153.3, 137.4, 128.5, 128.2, 126.3, 121.1, 34.7; FTꢀIR (KBr) 3436, 3049,
2923, 2683, 1623, 1536, 1493, 1456, 1426, 1270, 1222, 1147, 1024, 748, 722 cmꢀ1. HRMS (ESI) m/z:
[M+H] calcd for C14H12N2H 209.1078, found 209.1071.
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2-(4-Bromophenyl)-1H-benzo[d]imidazole 3ad.2d Analytical TLC on silica gel, 1:3 ethyl
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acetate/hexane Rf = 0.41; pale yellow solid; 95 mg, yield 35%; mp 260ꢀ261 °C; H NMR (400 MHz,
DMSOꢀd6) δ 13.00 (br s, 1H), 8.13ꢀ8.08 (m, 2H), 7.78 (d, J = 7.2 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H),
7.54 (d, J = 8.0 Hz, 1H), 7.23ꢀ7.19 (m, 2H); 13C {1H} NMR (100 MHz, DMSOꢀd6) δ 150.0, 143.5,
134.8, 131.8, 129.2, 128.1, 123.0, 122.6, 121.6, 118.7, 111.2; FTꢀIR (KBr) 3435, 3056, 2120, 1619,
1584, 1485, 1423, 1297, 1270, 1221, 1197, 1064, 1005, 960, 820, 742 cmꢀ1. HRMS (ESI) m/z: [M+H]
calcd for C13H9BrN2H 273.0027, found 273.0028.
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Kinetic Isotope Study
12b
To a stirred solution of pꢀtoluidine 1d (0.18 mmol, 20 mg), pꢀtoluidine 1d-d2 (0.32 mmol, 35 mg),
Cu(OAc)2 (10 mol %, 0.05 mmol, 9 mg), NaN3 (3 equiv, 1.5 mmol, 97 mg), AcOH (5 equiv, 2.5 mmol,
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150 mg) and TBHP (2 equiv, 1 mmol, 90 µL) in DMSO (0.5 mL) was added 4ꢀMeBnNH2 2j (1.2 equiv,
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o
0.6 mmol, 73 mg), and the resultant mixture was stirred at 80 C (Scheme 8). After 2.5 h, the reaction
mixture was cooled to room temperature and treated with saturated NaHCO3 (3 mL). The mixture was
then extracted with ethyl acetate (3 x 5 mL) and washed with brine (2 x 3 mL) and water (1 x 5 mL).
Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica gel column
chromatography using hexane and ethyl acetate as an eluent to afford a mixture of 3ae-d and 3ae as a
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white solid in 19% (21 mg) yield. The ratio of deuterium to hydrogen was determined by the H NMR
relative integration values of Ha (7.95 ppm) based on Hb (7.51 ppm).
1.2 equiv 4-MeBnNH2
D
10 mol % Cu(OAc)2
D
N
NH2
NH2
3 equiv NaN3
Me
3aa
+
+
N
H
Me
5 equiv AcOH
2 equiv TBHP
DMSO, 80 °C, 2.5 h
Me
D
Me
PH/PD =1.0
1d-d2
1d
3ae-d
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Scheme 8
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
37371
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*Eꢀmail: tpunni@iitg.ernet.in
ACKNOWLEDGMENT
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We thank Science and Engineering Research Board (SERB) (EMR/2015/43) 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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SUPPORTING INFORMATION
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ESIꢀMS spectrum of the reaction mixture of 1a and 2a, variable temperature NMR spectra of 3d and
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13
NMR spectra (1H and C) of the products. This material is available free of charge via the Internet at
http://pubs.acs.org.
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REFERENCES
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Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K., 1984; Vol. 5,
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