Synthesis of Benz-Fused Azoles via C-Heteroatom Coupling Reactions Catalyzed by Cu(I) in the Presence of Glycosyltriazole Ligands

Article abstract of DOI:10.1021/acscombsci.9b00004

Glycosyl triazoles are conveniently accessible and contain multiple metal-binding units that may assist in metal-mediated catalysis. Azide derivatives of d-glucose have been converted to their respective aryltriazoles and screened as ligands for the synthesis of 2-substituted benz-fused azoles and benzimidazoquinazolinones by Cu-catalyzed intramolecular Ullmann type C-heteroatom coupling. Good to excellent yields for a variety of benz-fused heterocyles were obtained for this readily accessible catalytic system.

Full text of DOI:10.1021/acscombsci.9b00004

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Article
Synthesis of Benz-fused Azoles via C-Heteroatom Coupling
Reactions Catalysed by Cu(I) in presence of Glycosyltriazole Ligands
Nidhi Mishra, Anoop S Singh, Anand K Agrahari, Sumit K Singh, Mala Singh, and Vinod Kumar Tiwari
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.9b00004 • Publication Date (Web): 03 Apr 2019
Downloaded from http://pubs.acs.org on April 5, 2019
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Synthesis of Benz-fused Azoles via C-Heteroatom Coupling Reactions Catalysed by
Cu(I) in presence of Glycosyltriazole Ligands
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Nidhi Mishraa, Anoop S. Singha, Anand K. Agraharia, Sumit K. Singha, Mala Singha and Vinod
K. Tiwari*a
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a Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi-221005,
INDIA
Abstract:
X
N
R
R
Ar
HN
O
O
O
X
Ar
16 examples
up to 99% yield
R2
NH2CN
X
N
R1
H
R
Ar
N
C
S
X
H2N
R2
CuI
O
N
S
Ar
K2CO3,
N
N
R1
R
H
N
N
N
H
H
10 examples
up to 98% yield
R
N
Ar
2 examples
up to 74% yield
R
Ar
S
ligand
R
N
11 examples
up to 99% yield
X
X
8 examples
up to 97% yield
R
HN
HN
Ar
Ar
S
NH
Glycosyl triazoles are conveniently accessible and contain multiple metal-binding units that may
assist in metal-mediated catalysis. Azide derivatives of D-glucose have been converted to their
respective aryltriazoles and screened as ligands for the synthesis of 2-substituted benz-fuzed
azoles and benzimidazoquinazolinones by Cu-catalyzed intramolecular Ullmann type C-
heteroatom coupling. Good to excellent yields for a variety of benz-fused heterocyles were
obtained for this readily accessible catalytic system.
Key words: Benzazole; Catalysis; Click Chemistry; Cross-coupling; Glycosyl triazole; Ligand
*Corresponding author: E-mail: tiwari_chem@yahoo.co.in, Vinod.Tiwari@bhu.ac.in
Tel.: +91-542-6702466; Fax: +91-542-236817
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INTRODUCTION
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Benz-fused azole derivatives show a broad range of biological activities and constitute the core
structures of a number of marketed drugs (Figure 1).1 Biological and medicinal significance of
benz-fused azoles amplifies the importance of new modified approaches for the synthesis of
these derivatives.2 One of the most efficient and convenient methods for the synthesis of these
derivatives is ligand promoted intramolecular Cu-catalyzed C-heteroatom cross-coupling of (2-
halophenyl)aryl amides/ thioamides/ amidines. A number of conventional ligands,3 as well as
new ligands,4 have been utilized for this purpose, but all ligands are not useful for all the three
types (i.e. C-O, C-N, and C-S) of cross-couplings. Moreover, most of the catalytic systems
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applied for these reactions require high loading of a ligand as well as Cu-source (10-30 mol%).
19F
S
N
O
S
S
N
S
N
S
11CH3
NH
CH3
NH
S
N
NH2
NH2
NH2
F3CO
O
N
O
ETHOXZOLAMIDE
Carbonic Anhydrase Inhibitor
RILUZOLE
Amyotrophic Lateral Sclerosis
Anti-tumor agent
FLUTEMETAMOL
PET scanning
PITTSBURGH COMPD B
PET scanning
Cl
Cl
O
CONH2
H3CO
O
N
S
N
Cl
O
N
NH
N
HO
N
N
N
HN
Me
Me
N
O
NH
N
O
O
N
COOH
Cl
L-697,661
HIV Reverse Tanscriptase Inhibitor
DIMAZOLE
Anti-fungal drug
Tafamidis meglumine
Neurodegenarative drug
BOXAZOMYCIN B
Antibacterial
NSC 693638
Anti-cancer
F
COOH
F
O
O
N
O
H
N
H
H
N
H
N
N
N
N
N
N
O
O
NH
O
S
S
N
O
N
N
N
NH
O
NORASTEMIZOLE
Antihistaminic
Astemizole
Anti-histamin drug
Nocodazole
Anti-neoplastic agent
THIABENDAZOLE
Anti-parasitic drug
CEZOMYCIN
Antibiotic
O
H
CH3
N
CH3
H
N
S
CH3
N
OCH3
N
NH
S
NH
N
N
N
O
OCH3
H3C
H
O
H3CO
N
O
N
S
N
C3H7
OMEPRAZOLE
Anti-ulser agent
Fenbendazole
(Anti-parasitic drug)
ALBENBAZOLE
Antiparasitic
HOOC
TELMISARTAN
Anti-hypertensive drug
Figure 1: Structures of some biologically relevant benzothiazoles, benzoxazoles and
benzimidazoles skeletons.
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Carbohydrates provide a suitable skeleton to develop new synthetic tools counting a number of
organocatalysts and ligands.5-8 The spatial arrangement of multiple free hydroxy groups attached
to rigid pyranose and furanose structures of carbohydrate moiety and easy transformation of
these hydroxy groups to various functionalities, offer prospects to modify these molecules into
suitable ligands. Moreover, easy availability and low cost of carbohydrates make it a convenient
source for development of the ligands. A large number of synthetically modified carbohydrate
derivatives have been used as ligands in a broad range of metal-catalyzed reactions.7,8 Along
with other carbohydrate derivatives, glycosylated triazoles have shown tremendous utility in
form of metal-ion ligands and exhibited their efficacy in terms of asymmetric induction, low
catalyst loading, and drug synthesis.6 The success of these ligands lies in the structural benefits
associated with carbohydrate moiety as well as presence of triazole ring which offers an efficient
coordinating site for metal ions and promotes catalysis in many reactions.9 Despite the promising
features of carbohydrate-derived ligands, no such ligand has been used so far for efficient
catalysis of Ullmann-type C-O, C-S, and C-N cross-coupling reactions.
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Here, we have developed triazolyl derivatives of D-glucose as potential ligands for Cu(I)-
catalyzed cross-coupling and employed them for the synthesis of 2-aryl benzoxazoles, 2-
arylbenzothiazoles, 2-arylbenzimidazoles, 2-aminobenzothiazoles, and benzimidazo[2,1-
b]quinazolin-12(6H)-ones.
RESULTS AND DISCUSSION
Keeping in mind the easy remarkable coordination ability of 1,2,3-triazoles with various
metal ions9 and their easy accessibility through high yielding synthetic protocols10, we
tended to modify the structure of D-glucose in such a way that it contains at least one
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triazolyl ring along with its skeletal oxygen atoms either in the form of free hydroxy
group or with protection. Accordingly, we designed three glycoconjugates L1, L2 and L4
containing one 1,2,3-triazolyl ring and at least one free hydroxy group. Ligands L3 and
L7 were designed in a manner that they contain one triazole ring with protected hydroxy
groups of sugar skeleton whereas, L5 contains two triazolyl rings with one free hydroxy
group. Ligand L6 was designed without any triazole ring to compare the effect of triazole
ring in ligands. Another ligand L8, containing benzotriazole ring and a free phenolic
group, was used in the reaction to compare with the sugar-containing ligands and estimate
the role of sugar skeleton in coordination (Figure 2).
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N
N
O
N
N
O
N
O
O
N
O
O
O
HO
HO
O
O
O
O
O
O
N
N
N
L1
L3
L2
HO
HO
O
N
O
N
O
N
O
O
O
HO
HO
O
N
O
O
N
N
N
O
N
L4
N
L6
L5
O
O
O
N
N
N
N
O
N
O
N
OH
L8
L7
Figure 2. Structure of ligands designed and investigated for the intramolecular C-O cross-
coupling.
We instigated strategic synthesis of triazolyl glycoconjugates with classical acetonide protection
of readily available D-glucose resulting into 1,2,5,6-di-O-isopropylidene-α-D-glucofuranose 1
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(Scheme 1).11 3-O-Benzyl protection of diacetonide glucose 1 followed by selective deprotection
of 5,6-isopropylidene group gave glycosyl diol 2.12 Selective tosylation of 6-OH of diol 2
followed by reaction with NaN3 afforded glycosyl azide 3.13 Azide-alkyne cycloaddition of
compound 3 with phenyl acetylene (1.2 equiv.) in presence of CuSO4.5H2O (0.3 equiv.) and
sodium ascorbate (0.6 equiv.) in DCM-water (1:1) at room temperature afforded triazolyl
glycoconjugate L1 in good yields. In a similar pattern, reaction of azido alcohol 3 with 3-
cyclohexylpropyne-1 in presence of Cu-catalyst afforded L2. On the other hand, reaction of
diacetonide glucose 1 with triflic anhydride in presence of pyridine furnished 3-O-triflate
derivative which could be easily converted to 3-azido derivative 4 with inversion at C-3 by
heating with sodium azide in DMF.14 Cu(I)-catalyzed cycloaddition of glycosyl azide 4 with
phenyl acetylene afforded L3 in high yields. Selective isopropylidene deprotection of compound
4 afforded diol 515 which on cycloaddition with phenyl acetylene furnished L4. Similarly,
selective tosylation of diol 5 followed by azidation afforded 3,6-diazido derivative 6 which on
cycloaddition with two equivalents of phenyl acetylene produced a bis-triazolyl glycoconjugate
ligand L5. Oxidation of 5,6-diol of 2 into the corresponding aldehyde followed by reduction
furnished compound L616 with a free alcohol group which was easily converted into
corresponding azide 7 on successive tosylation and azidation.17 Synthesis of L7 was achieved by
Cu-catalyzed reaction of azide 7 with phenylacetylene. Ligand L8 was synthesized by N-
acylation of 1H-benzotriazole by the standard procedure described in literature.18 All the
synthesized ligands were characterized using NMR, IR and mass spectroscopy. Ligand L1 was
also characterized by single crystal X-ray crystallography.
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O
HO
O
O
O
o, p
O
O
O
a, b
O
HO
BnO
HO
BnO
O
O
O
HO
L6
1
g, h
2
q, r
c, d
N3
HO
BnO
O
O
O
O
O
O
O
N3
BnO
O
O
O
O
7
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N3
3
(78%)
4
(68%)
s
e
f
O
O
N
N
N
O
BnO
N
N
N
L7 (73%)
N
N
O
O
N
O
O
HO
HO
O
O
BnO
BnO
L1
(71%)
L2
(67%)
HO
HO
HO
HO
O
O
O
j
k
O
4
glycosyl azide
O
N
O
i
N3
N
L4
(80%)
5
(82%)
N
O
N
l
O
N
N
O
O
R
O
O
O
HO
O
O
N
HO
n
N
O
N
O
N
N3
N
N
L3
(88%)
6a
6b
, R= OTs (95%)
, R= N3 (96%)
L5
(92%)
m
L1
Scheme 1. Synthesis of ligands L1-L7 starting from D-glucose and ORTEP diagram of L1
o
crystal. (a) BnBr, NaH, rt; (b) AcOH/H2O, rt; (C) TsCl, Et3N, DCM, rt; (d) NaN3,DMF, 90 C;
(e) Phenyl acetylene, CuSO4.5H2O, sodium ascorbate, DCM/water (1:1), rt; (f) 3-Cyclohexyl
propyne-1, CuSO4.5H2O, sodium ascorbate, DCM/water (1:1), rt; (g) Tf2O, pyridine, DCM, 0
oC; (h) NaN3, DMF, 90 C; (i) Phenyl acetylene, CuSO4.5H2O, sodium ascorbate, DCM/water
o
(1:1), rt; (j) AcOH/H2O, heat; (k) Phenyl acetylene, CuSO4.5H2O, sodium ascorbate, DCM/water
o
(1:1), rt; (l) TsCl, Et3N, DCM, rt; (m) NaN3, DMF, 90 C; (n) Phenyl acetylene, CuSO4.5H2O,
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sodium ascorbate, DCM/water (1:1), rt; (o) NaIO4, NaHCO3, MeOH, rt; (p) NaBH4, MeOH, rt;
5
6
o
(q) TsCl, Et3N, DCM, rt; (r) NaN3,DMF, 90 C; (s) Phenyl acetylene, CuSO4.5H2O, sodium
7
8
9
ascorbate, DCM/water (1:1), rt.
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Having ligands of our choice in hands, we moved forward for their application in intramolecular
C-heteroatom coupling reaction. For the optimization of reaction conditions and identification of
best ligand and most suitable Cu-source, base and solvent, a prototype reaction was set for the
intramolecular C-O cross-coupling of N-(2-bromophenyl)benzamide 8a to afford 2-phenyl
benzoxazole 9a. Results are summarized in Table 1. For the catalytic screening of ligands,
initially 1 equiv. of N-(2-bromo phenyl)benzamide 8a was heated with 10 mol% of ligand,10
mol% of CuI as Cu-source and 1 equiv. of KOH as a base in dry DMF at 120oC for 10 hours.
The best result in form of product yields was obtained with ligand L1 (Table 1, entry 1). Only
17% yield was obtained when no ligand was used (Table 1, entry 9), whereas no product was
formed in absence of Cu-source (Table 1, entry 10). The formation of the product 9a was
confirmed on the basis of 1H and 13C NMR spectra analysis which was found in agreement with
the literature.4a
Table 1. Screening of ligands L1-L8 for intramolecular C-O cross-coupling and optimization of
the reaction conditions
Br
[Cu] (10 mol%), ligand(10 mol%)
base (1 equiv.), solvent, 120oC
HN
O
N
O
8a
9a
Entry Ligand [Cu]
Base
KOH
KOH
KOH
Solvent Yielda
1
2
3
L1
L2
L3
CuI
CuI
CuI
DMF
DMF
DMF
83%
82%
50%
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8
9
4
5
L4
L5
L6
L7
L8
-
CuI
CuI
CuI
CuI
CuI
CuI
-
KOH
KOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
55%
80%
30%
40%
32%
17%
00
6
KOH
7
KOH
10
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8
KOH
9
KOH
10
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28b
29c
30d
31e
32f
33g
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
KOH
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
Cu2O
K2CO3
Cs2CO3
K3PO4
KOBut
99%
65%
27%
82%
80%
20%
00
NaHCO3 DMF
Na2CO3
DIPEA
Et3N
DMF
DMF
DMF
THF
00
K2CO3
10%
00
K2CO3 Toluene
K2CO3 DMSO 96%
K2CO3 MeOH 70%
K2CO3 CH3CN 43%
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
42%
76%
84%
40%
99%
99%
43%
45%
00
CuOAc K2CO3
CuSO4 K2CO3
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
38%
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Molar ratios: N-(2-bromophenyl) benzamide (1.0 equiv.), ligands (10 mol%), Cu-source (10
5
6
o
a
mol%), base (1.0 equiv.), solvent (2 mL), temperature 120 C, reaction time 10h. Yields
7
8
9
reported after purification by column chromatography (SiO2). bL1 (5 mol%), CuI (5 mol%). cL1
d
e
f
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(2 mol%), CuI (2 mol%). L1 (1 mol%), CuI (1 mol%). K2CO3 (0.5 equiv). Reaction at room
temperature for 24 h. g Temperature 100 oC for 15 h.
The optimized reaction conditions for preparation of 2-phenyl benzoxazole 9a from N-(2-
bromophenyl)benzamide 8a involving 2 mol% CuI, 2 mol% of ligand L1, 1 equiv. of K2CO3 and
120oC temperature were investigated with a variety of N-(2-haloaryl)benzamides containing
different aromatic rings with different substitutions (Scheme 2). Comparatively slower reaction
and slightly lower yield was obtained in case of N-(2-chlorophenyl)benzamide than that of
respective bromo and iodo analogues (Scheme 2, 9a). No remarkable variation in yields were
observed with different substitutions i.e. electron releasing (Scheme 2, 9b, 9i, 9j) or electron
withdrawing groups (Scheme 2, 9c, 9e, 9g, 9h, 9k, 9l) at different positions of phenyl ring
attached to C=O group. Reactions with other aromatic rings, such as, pyridyl and naphthyl in
place of phenyl ring were also good yielding (Scheme 2, 9m, 9n), however low yield was
observed in case of benzyl group (Scheme 2, 9p). Also, the substitution at phenyl ring attached
to nitrogen atom of amide did not alter the expected yield (Scheme 2, 9o).
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X
R2
HN
N
O
L1
CuI (2 mol%),
(2 mol%)
R2
6
7
8
K2CO3 (1 equiv.), DMF, 120oC
O
R1
R1
8
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N
O
N
O
N
O
F3C
9a
9b
9c
X= I, 10 h, 99%
Br, 10 h, 99%
Cl, 15 h, 88%
X=Br, 10 h, 92%
X=Br, 10 h, 95%
N
N
N
O
Cl
O
O
9e
Cl
9d
Br
9f
X=Br, 10 h, 97%
X=Br, 10 h, 95%
X=Br, 10 h, 95%
N
O
N
O
N
O
Br
OH
F
9g
9h
9i
X=Br, 10 h, 99%
X=Br, 10 h, 90%
X=Br, 10 h, 94%
N
O
N
O
N
O
MeO
O2N
NC
9k
9l
9j
X=Br, 10 h, 96%
X=Br, 10 h, 93%
X=Br, 10 h, 95%
N
N
N
O
O
9n
9m
X=Br, 10 h, 95%
X=Br, 10 h, 96%
Cl
N
N
O
Br
O
9o
9p
X=Br, 10 h, 46%
X=Cl, 10 h, 82%
Scheme 2. Synthesis of 2-aryl benzoxazoles via optimized reaction conditions. Yields in %
reported after purification by column chromatography (SiO2).
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After success of glycosyl triazole ligands in the catalysis of intramolecular C-O coupling of N-
(2-haloaryl)benzamide, we further investigated ligands L1, L2 and L5 for intramolecular C-S
and C-N coupling with optimized reaction conditions and molar ratios. In the initial
investigations for the intramolecular C-S coupling of N-(2-bromophenyl)benz-thioamide, all the
three ligands L1, L2 and L5 showed good results for the formation of the respective product 2-
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1
13
aryl benzothiazole 11a which was characterized by its spectral analysis (MS, H and C NMR
spectra) and found in agreement with the literature.20 Likewise, in the investigation for the
intramolecular C-N coupling of N-(2-bromophenyl) benzamidine, all the three ligands L1, L2
and L5 again showed good results for the formation of the product 13a. The respective
1
13
compound 13a was characterized by its spectral analysis (MS, H and C NMR spectra) and
found in agreement with the literature.21 However, for the both intramolecular C-S coupling of
N-(2-bromophenyl)benz-thioamide and intramolecular C-N coupling of N-(2-bromophenyl)
benzamidine, we noticed that ligand L1 again outperform L2 and L3 and produced best yields of
coupling products (Scheme 3 and Scheme 4). We moved forward with L1 for intramolecular C-
S coupling of differently substituted N-(2-haloaryl)benz-thioamides 10(a-k) and achieved
excellent yields (91-99%) of 2-arylbenzothiazoles 11(a-k) (Scheme 3).
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Br
HN
N
L
CuI (2 mol%), (2 mol%)
6
7
8
K2CO3 (1 equiv.), DMF, 120oC
S
R1
S
R1
10 (a-k)
11 (a-k)
9
10
11
12
13
14
15
16
17
18
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N
N
N
Cl
S
S
11b
S
11a
11c
L1
10 h, : 99%
L1
10 h, : >99%
L1
10 h, : 97%
L2
10 h, : 92%
L3
10 h, : 94%
N
N
S
N
S
Br
S
Br
F
11d
11e
11f
L1
10 h, : 98%
L1
10 h, : 91%
L1
10 h, : 93%
N
N
N
S
S
S
11i
NC
F3C
11g
11h
O2N
L1
10 h, : 94%
L1
L1
10 h, : 94%
10 h, : 96%
N
S
11j
L1
N
O
N
S
11k
L1
10 h, : 96%
10 h, : 95%
Scheme 3. Synthesis of 2-aryl benzothiazoles via optimized reaction conditions with ligand L1.
Yields in % reported after purification by column chromatography (SiO2).
On the other hand, the application of ligand L1 in Cu-catalyzed intramoleculer C-N coupling of
N-(2-haloaryl) benzamidines 12(a-h) with optimized reaction conditions and molar ratios
resulted into formation of 2-arylbenzimidazoles 13(a-h) in high yields (88-97%) (Scheme 4).
High product yields in intramolecular C-O, C-S and C-N couplings proved L1 to be a versatile
ligand for Ullmann-type coupling.
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X
R2
H
N
N
L
CuI (2 mol%), (2 mol%)
R2
K2CO3 (1 equiv.), DMF, 120oC
6
7
8
N
R1
NH2
R1
13(a-h)
12(a-h)
9
N
N
N
10
11
12
13
14
15
16
17
18
19
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N
H
N
H
N
H
13a
13b
L1
13c
L1
12 h, : 98%
L1
12 h, : 98%
12 h, : 93%
L2
L5
: 90%
: 88%
Br
Br
N
N
N
N
N
H
N
Br
Br
H
H
F
13f
L1
13e
L1
13d
L1
15 h : 92%
15 h, : 89%
15 h, : 94%
Br
Br
N
N
N
N
H
Br
Br
H
F
13h
L1
13g
L1
15 h, : 87%
15 h, : 90%
13d
Scheme 4. Synthesis of 2-aryl benzimidazoles via optimized reaction conditions and ORTEP
diagram of 13d crystal. Yields in % reported after purification by column chromatography
(SiO2).
We further assessed the effectiveness of ligand L1 in cascade synthesis of 2-phenyl
benzoxazoles from reaction of benzamide and 1,2-dibromobenzene via intermolecular C-N
coupling followed by intramolecular C-O coupling in presence of CuI and K2CO3. Optimization
of the reaction conditions with respect to molar ratios of L1, CuI and K2CO3, temperature and
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reaction time has been summarized in Table S1 (See, supporting information). Best results were
obtained when reaction was catalyzed with 10 mol% L1 and 10 mol% CuI in presence of 2
equiv. K2CO3 in DMF solvent at 130oC temperature and 24 h reaction time (Table S1, entry 5).
Spectral data of developed compound 9a using tandem one-pot reaction of 1,2-dibromobenzene
and benzamide was exactly matched with the compound obtained by intramolecular C-O cross
coupling of N-(2-haloaryl) benzamide 8a. Due to low product yield (up to 45%) in tandem
approach with our ligand, we did not further explore the optimized conditions with other
derivatives.
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60
To check the efficacy of glycosyl triazole ligands for Cu-catalyzed cascade synthesis of N-
phenyl-2-aminobenzothiazole from reaction of phenyl isothiocyanate 14a and 2-iodoaniline 15a,
we optimized the reaction with respect to molar ratios of L1, CuI and K2CO3 and for temperature
and solvent (See, supporting information, Table S2). 5 Mol% L1 with 5 mol% CuI catalyzed the
reaction most effectively in presence of 1.0 equiv. K2CO3 (Table S2, entry 6). Maximum reaction
yield (98%) was obtained at 120 oC in 20 h reaction time (Table S2, entry 6). Ligands L2 and L5
also showed good results for the coupling of phenyl isothiocyanate and 2-iodoaniline under
same reaction conditions but produced slightly lower yields than ligand L1(Table S2, entry 9,
13
10). Formation of product 16a was confirmed by the analysis of MS, NMR (1H and C NMR)
spectra which were found in agreement with the literature data.22
We applied the optimized reaction conditions to coupling of various commercially available aryl
isothiocyanates and 2-halo anilines to develop a series of N-aryl-2-aminobenzothiazoles
(Scheme 5). Among 2-haloanilines, chloroaniline took more time to react and gave lesser yield
as compared to bromo and iodo derivatives (Scheme 5, 16a). Nature of other substitutions at
phenyl ring of isothiocyanate unit did not affect the product yield remarkably. On the other hand,
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halo group substitution on the aryl ring of 2-haloaniline reduced the product yield a little
(Scheme 5, 16g-j) probably due to deactivation of the aromatic ring which restricts its attack on
isothiocyanate to form phenylthiourea intermediate.
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11
12
13
14
15
16
17
18
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H
NCS
N
X
S
L1
CuI (5 mol%), (5 mol%)
R1
R1
R2
N
K2CO3 (2 equiv.), DMF, 120oC
H2N
R2
16
14
15
H
H
H
N
N
S
N
S
S
N
16b
N
N
Cl
16a
16c
X= Br, 20 h, 92%
X= I, 20 h, 98%
Br, 20 h, 91%
Cl, 25 h, 80%
X= Br, 20 h, 93%
H
H
H
N
S
N
S
N
S
N
N
N
16d
O2N
F
MeO
16e
16f
X= Br, 20 h, 92%
X= Br, 20 h, 89%
X= Br, 20 h, 95%
H
N
H
S
N
S
N
Cl
N
Cl
16g
16h
X= Br, 20 h, 86%
H
X= Br, 20 h, 87%
H
N
S
N
S
N
Cl
N
Br
Cl
16i
Br
16j
X= Br, 20 h, 84%
X= Br, 20 h, 81%
O2
C3
C4
C12
N3
C5
C13
C2
N1
C1
C11
C10
O1
C6
C7
C8
N2
C9
S1
16e
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Scheme 5. Synthesis of 2-(N-arylamino) benzothiazoles via optimized reaction conditions and
ORTEP diagram of 16e crystal. Yields in % are reported after purification by column
chromatography (SiO2).
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11
12
13
14
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17
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60
Moving towards some more complex reactions, we considered to employ L1-CuI catalytic
system for the synthesis of benzimidazo[2,1-b]quinazolin-12(6H)-ones from reaction of N-(2-
bromoaryl)-2-bromobenzamide with cyanamide.19 10 Mol% L1 with 10 mol% CuI gave best
catalyzing results for reaction of N-(2-bromophenyl)-2-bromobenzamide 17a with 2 equiv.
cyanamide resulting into benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one 18a with 76% product
yield at 120oC temperature and in 20 h reaction time while taking 2.0 equivalent K2CO3 as base
(See, supporting information, Table S3, entry 4). Optimized reaction conditions also gave good
yield (64%) for synthesis of 2-methylbenzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one 18b
(Scheme 6).
O
NH CN
CuI (10 mol%),
(2 equiv.)
2
O
L1
(10 mol%)
N
N
R
R
H
K2CO3 (2 equiv.), DMF,
120 oC, 20 h
N
Br
N
H
Br
18
17
O
N
O
N
N
N
N
H
N
H
18a (76%)
18b (64%)
Scheme 6. Application of L1 in tandem synthesis of benzimidazo[2,1-b]quinazolin-12(6H)-ones
For quantitative generalization of the reactions catalyzed with the assistance of ligand L1,
we carried out reactions in gram scale and found good yields of 2-phenylbenzoxazole, 2-
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phenylbenzothiazole, 2-phenylbenzimidazole and 2-(N-phenylamino)benzothiazole (Scheme 7).
Moreover we successfully recovered ligand L1 from reaction mixture through column
chromatography (SiO2), in up to 64% recovered yield.
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Br
HN
O
N
L1
CuI (2 mol%), (2 mol%, 158 mg)
K2CO3 (1 equiv.), DMF, 120oC, 10 h
O
8a (
5g)
9a (
3.21 g, 91%)
L1
Recovered
= 98 mg (62%)
Br
HN
S
N
S
L1
CuI (2 mol%), (2 mol%, 150mg)
K2CO3 (1 equiv.), DMF, 120oC, 10 h
10a (
5g)
11a (
3.36 g, 93%)
L1
Recovered
= 96 mg (64%)
Br
HN
N
L1
CuI (2 mol%), (2 mol%, 159 mg)
K2CO3 (1 equiv.), DMF, 120oC, 12 h
N
H
NH
12a (
5g)
13a (
3.05 g, 86%)
L1
Recovered
= 86 mg (54%)
S
C
N
H
N
S
Br
L1
CuI (5 mol%), (5 mol%, 405 mg)
K2CO3 (1 equiv.), DMF, 120oC, 20 h
N
H2N
L1
Recovered
= 251 mg (62%)
14a (
2.5 g)
15a (
3.2 g)
16a (
3.72 g, 89%)
Scheme 7. Gram scale reactions with ligand L1 and recovery of ligand.
To postulate the most favorable coordination sites of the ligand L1, we did a comparative
analysis of yields obtained with 2 mol% loading of ligands L1, L2, L5, L6, L7 and L8 in Cu-
catalyzed intramolecular C-O crosscoupling of 2-phenylbenzamide in presence of K2CO3
(Figure 3). Ligand L2 which structurally differs with L1 by aliphatic substituent instead of
phenyl ring at position-4 of triazole ring, gave comparable yield to that obtained with L1. This
suggests that the phenyl ring attached to triazole ring has no major contribution in coordination
with Cu(I). Similarly L5 which differs with L1 by the moiety attached at C-3 with inversion of
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stereochemistry at C-3 of sugar skeleton, also furnished high yields of coupling product, which
suggests that the benzyloxy moiety attached to C-3 of glycosyl part of L1 does not play
considerable role in coordination. On the other hand, L6 and L7 which structurally differ with
L1 by lacking free hydroxy group and triazole ring respectively, afforded much lesser yield of
final product in comparison to that obtained with L1, which suggests that the most plausible
effective coordination sites of L1 are triazole ring attached at C-6 and free hydroxy group at C-5
of sugar skeleton. Although ligand L8 which contains a triazole moiety as well as a free hydroxy
group in the proximity of triazole ring, produced poor yield of product which advocates the role
of sugar skeleton in providing most favorable spatial arrangement of triazole ring and hydroxy
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group to offer suitable coordination with Cu(I).
Br
N
O
L
CuI (2 mol%), (2 mol%)
HN
O
K2CO3 (1 equiv.), DMF, 120oC
9a
8a
Ligand
N
N
O
N
O
HO
Plausible
effective
coordination
sites
O
O
L1
9a
Yield of = 99%
N
N
O
O
N
N
HO
N
N
O
O
HO
O
O
O
N
N
N
L5
L2
9a
Yield of = 95%
9a
Yield of = 96%
O
N
O
O
O
O
O
HO
N
N
N
O
O
N
N
O
OH
L6
9a
L7
L8
9a
Yield of = 45%
9a
Yield of = 74%
Yield of = 56%
Figure 3. Comparative analysis to estimate the effective coordination sites of ligand L1.
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A plausible mechanism for the synthesis of benz-fused azoles (9, 11, 13, 13 and 16) and
benzimidazoquinazolinones (18) using L1-Cu(I) catalytic system has been depicted in Scheme 8
and Scheme 9. According to our postulations, our ligand coordinates with Cu(I) as a bi-dentate
ligand through triazole ring and free hydroxy group as probable coordination sites. Ligand-
coordinated Cu(I) reacts with substrate (for example amides 8 or thioamides 10 or benzamidines
12) in presence of base (K2CO3) to form respective coordinated intermediate A. Oxidative
addition converts A into intermediate B which on reductive elimination produces corresponding
2-substituted benz-fused azoles (amides 9 or thioamides 11 or benzamidines 13) as the final
product regenerating the ligand-coordinated Cu(I) (Scheme 8).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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59
60
Y
KHCO3 + KX
N
H
X
K2CO3
+
8
10
12
(Y = O)
(Y = S)
(Y = NH)
L
L
CuI
Coordination
Y
N
A
X
N
N
L
L
O
N
X-CuI
O
HO
= Ar, NHAr
I-CuI
O
O
Y= O, S, and
NH
Oxidative
addition
L1
Reductive
elimination
X
CuIII
Y
Y
N
2-substituted Benz(d)fused-1,3-azole
11 13
N
9
(Y = O);
(Y = S);
(Y = NH)
B
Scheme 8: Plausible mechanism for Cu-L1 catalyzed synthesis of benz-fuzed azoles (9, 11, and
13).
On the other hand, the synthetic route for benzimidazoquinazolinones (18) start from the reaction
of cyanamide with substrate 17 in presence of base which affords intermediate C. Coordination
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of C with Cu(I)-L1 in presence of base produces intermediate D which furnishes adduct E
through catalytic steps of oxidative addition and reductive elimination. Adduct F again
coordinates with ligand coordinated Cu(I) in presence of base to produce intermediate G which
at last gets converted into final product 18 through oxidative addition (via intermediate H) and
reductive elimination (Scheme 9).
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11
12
13
14
15
16
17
18
19
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O
N
Ox
ad
ida
tiv
e
Br
NH2
HN
Br
O
dit
ion
I
Cu
D
N
L
L
Br
Br
K2CO3
N C NH2
O
III
Co
or
din
ati
on
N
O
Br
Cu N NH2
H
N
H
Br
L
Br
X-CuI
Re
du
cti
ve
E
Br
O
L
eli
mi
na
tio
n
17
N
Br
NH2
HN
Br
C
KHCO3 + KX
Co
or
din
ati
on
O
N
O
N
N
N
Br
Br
NH2
NH
F
I
Cu
+
L
K2CO3
L
L
L
X-CuI
G
Ox
ida
tiv
ad
dit
ion
e
Re
eli
mi
na
tio
du
cti
ve
n
O
N
O
N
N
III
Br
Cu
N
N
H
N
H
18
H
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Scheme 9: Plausible mechanism for Cu-L1 catalyzed synthesis of benzimidazoquinazolinones
5
6
18.
7
8
9
CONCLUSIONS
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Conclusively, we have developed glycosyl triazoles as efficient ligands for Cu-catalyzed
Ullmann-type intramolecular cross-coupling to synthesize benz-fuzed azoles. Out of eight
ligands (seven derived from D-glucose and one benzotriazole derivative) screened for the
synthesis of 2-phenyl benzoxazole, ligands L1, L2 and L5 exhibited highest efficacy and
produced excellent yields with as low as 2 mol% loading. Ligand L1 was also employed in
synthesis of a series of 2-substituted benzothiazoles, benzothiazoles and benzimidazoles in high
yields by optimized reaction conditions. A tandem approach for 2-aminobenzothiazoles was also
achieved in high yields with CuI-L1 catalytic system. A tandem approach for synthesis of
benzoxazole from benzamide was
also achieved with L1 in moderate yield. Ligand L1
successfully catalyzed Cu-catalyzed tandem synthesis of benzimidazo[2,1-b]quinazolin-12(6H)-
ones also and produced good yields. A comparative analysis of ligand structures and product
yields produced by them inferred that the triazole moiety and hydroxy group of L1 are the most
probable coordination sites which acquire appropriate spatial arrangement due to suitable sugar
skeleton.
EXPERIMENTAL
General
All the reactions were performed under argon atmosphere using anhydrous solvents except for
those in which water was used as solvent. All the reagents and solvents used were of analytical
grade. Glasswares were dried in an oven at 100 °C for one hour and cooled in a desiccator before
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use. 60 F254 Silica gel pre-coated aluminum plates were used for thin layer chromatography
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(TLC) and spots were located either under a UV lamp (λmax = 254 nm) or by charring after 5%
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H2SO4-MeOH solution spray. H and 13C NMR were recorded at 500 MHz and 125 MHz,
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respectively. Chemical shifts given in ppm are relative to that of TMS as internal standard; J
values are given in Hz. Mass spectra were recorded by electron spray ionization mass
spectrometry (ESI-MS). IR spectra were recorded as Nujol mulls in KBr pellets. C, H, N
Analyzer was used for elemental analysis and results were found to be within 0.4% of the
calculated values. Single-crystal X-ray data collected on CCD-diffractometer.
General experimental procedure for the synthesis of glycosylated triazole ligands
4-Phenyl-1-(3-O-benzyl-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranos-6-yl)-1H-1,2,3
triazole (L1):
Glycosyl azide 3 (1.0 g, 2.98 mmol) was taken in 50 ml 1:1 mixture of dichloromethane and
water. 1 Equiv. of phenyl acetylene (304 mg, 2.98 mmol, 327 µl) was added to this mixture
followed by an addition of 0.3 equiv. of CuSO4.5H2O (223 mg, 0.89 mmol) and 0.6 equiv. of
sodium ascorbate (354 mg, 1.79 mmol). The resultant suspension was stirred at room
temperature for 10 hours. The completion of reaction was confirmed by TLC using 5% H2SO4-
MeOH solution spray as locating agent followed by charring. The reaction mixture was filtered
through a sintered funnel and the filtrate was extracted three times with dichloromethane. The
collected organic layer was given brine wash, dried over anhydrous Na2SO4 and concentrated
under reduced pressure to afford the crude compound. Purification of the crude by silica gel
(230-400 mesh) column chromatography using gradient mixtures of n-hexane/ethylacetate (7:3)
afforded pure compound L1 in 71% yield (930 mg).
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White solid, yield 71%; Rf = 0.4 (30% ethyl acetate/n-hexane); m.p. = 146-148°C; 1H NMR (500
MHz, CDCl3): δ 7.71 (s, 1H), 7.53 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 7.5 Hz, 2H), 7.28-7.24 (m,
6H), 5.97 (d, J = 3.0 Hz, 1H), 4.79 (d, J = 13.5 Hz, 2H), 4.70-4.63 (m, 4H), 4.32-4.28 (m, 1H),
4.15 (s, 1H), 4.02 (d, J = 6.5 Hz, 1H), 1.42 (s, 3H), 1.31 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
146.9, 137.4, 130.1, 128.7, 128.6, 128.1, 128.0, 125.3, 121.6, 112.0, 105.3, 82.5, 81.3, 80.9, 72.6,
67.3, 54.6, 26.8 and 26.3 ppm; HRMS m/z [M+H]+ calculated for C24H27N3O5Na+ 460.1843,
found 460.1841.
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General procedure for the synthesis of 2-substituted benzoxazoles (9) by intramolecular C-
O cross coupling of N-(2-haloaryl) benzamides (8)
N-(2-bromophenyl) benzamide 8a (500 mg, 1.81 mmol) was taken in 1.5 ml of dry DMF and
ligand L1 (2 mol%, 16 mg, 0.036 mmol), CuI (2 mol%, 7 mg 0.036 mmol) and K2CO3 (1.0
equiv., 250 mg, 1.81 mmol) were added to it. The mixture was heated at 120oC in a sealed vessel
under argon atmosphere for 10-15 hrs. Completion of reaction was confirmed by TLC and the
reaction mass was cooled to room temperature followed by evaporation of DMF under reduced
pressure. Crude was purified by silica gel (230-400 mesh) column chromatography using
gradient mixtures of n-hexane/ethylacetate (50:1) to afford pure compound 9a (350 mg, 99%).
2-Phenylbenzo[d]oxazole (9a):4a White solid, yield 99%; Rf = 0.6 (2% ethyl acetate/n-hexane);
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m.p. = 103-104°C; H NMR (500 MHz, CDCl3): δ 8.26-8.24 (m, 2H), 7.79-7.76 (m, 1H), 7.58-
7.55 (m, 1H), 7.52-7.49 (m, 3H), 7.35-7.33 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 163.1,
150.8, 142.2, 131.5, 128.9, 127.7, 127.2, 125.1, 124.6, 120.1 and 110.6 ppm.
General procedure for synthesis of 2-substituted benzothiazoles (11a-i) by intramolecular
C-S cross coupling of N-(2-haloaryl) benzthiamides (10a-i)
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N-(2-Haloaryl) benzthiaamide 10a (500 mg, 1.71 mmol) was taken in 1.5 ml of dry DMF and
ligand L1 (2 mol%, 15 mg, 0.034 mmol), CuI (2 mol%, 7 mg, 0.034 mmol) and K2CO3 (1
equiv., 236 mg, 1.71 mmol) were added to it. The mixture was heated at 120oC in a sealed vessel
under argon atmosphere for 10 hrs. Completion of reaction was confirmed by TLC and the
reaction mass was cooled to room temperature followed by evaporation of DMF under reduced
pressure. Crude was purified by silica gel (230-400 mesh) column chromatography using
gradient mixtures of n-hexane/ethylacetate (30:1) to afford pure compound 11a (359 mg, >99%).
2-Phenylbenzo[d]thiazole (11a)20: White solid, yield >99%; Rf = 0.5 (2% ethyl acetate/n-
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hexane); m.p. = 100-104oC; H NMR (500 MHz, CDCl3): δ 8.10-8.08 (m, 3H), 7.88 (d, J = 8.5
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Hz, 1H), 7.50-7.47 (m, 4H), 7.37 (t, J = 8.5 Hz, 1H); C NMR (125 MHz, CDCl3): δ 168.1,
154.2, 135.1, 133.7, 131.0, 129.1, 127.6, 126.4, 125.2, 123.3 and 121.7 ppm.
General procedure for synthesis of 2-substituted benzimidazoles (13a-h) by intramolecular
C-N cross coupling of N-(2-haloaryl) benzamidines (12a-h)
N-(2-Haloaryl) benzamidine 12a (500 mg, 1.81 mmol) was taken in minimum 1.5 ml of dry
DMF and ligand L1 (2 mol%, 16 mg, 0.036 mmol), CuI (2 mol%, 7 mg, 0.036 mmol) and
K2CO3 (1 equiv., 251 mg, 1.81 mmol) were added to it. The mixture was heated at 120oC in a
sealed vessel under argon atmosphere for 15 hrs. Completion of reaction was confirmed by TLC
and the reaction mass was cooled to room temperature followed by evaporation of DMF under
reduced pressure. Crude was purified by silica gel (230-400 mesh) column chromatography
using gradient mixtures of n-hexane/ethylacetate (7:1) to afford pure compound 13a (346 mg,
98%).
2-Phenyl-1H-benzo[d]imidazole (13a)21: White solid, yield 98%; Rf = 0.5 (30% ethyl acetate/n-
hexane); m.p. = 292-294oC; 1H NMR (500 MHz, CDCl3+DMSO-d6): δ 12.7 (s, 1H), 8.19 (d, J =
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7.5 Hz, 2H), 7.59-7.42 (m, 5H), 7.19 (t, J = 3.0 Hz, 2H); C NMR (125 MHz, CDCl3+DMSO-
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d6): δ 151.9, 135.7, 130.5, 129.9, 128.9, 126.8, 122.4, 118.9 and 111.7 ppm.
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General procedure for synthesis of N-aryl-2-aminobenzothiazoles (16a-j) by tandem
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reaction of aryl isothiocyanate (14) and 2-haloaniline (15)
Phenyl isothiocyanate 14a (200 mg, 1.48 mmol, 177 µl) and 2-iodoaniline 15a (1 equiv., 324
mg, 1.48 mmol) were taken in 1.5 ml of dry DMF and ligand L1 (5 mol%, 32 mg, 0.074 mmol),
CuI (5 mol%, 14 mg, 0.074 mg) and K2CO3 (1.0 equiv., 204 mg, 1.48 mmol) were added to it.
The mixture was heated at 120oC in a sealed vessel under argon atmosphere for 20 hrs.
Completion of reaction was confirmed by TLC and the reaction mass was cooled to room
temperature followed by evaporation of DMF under reduced pressure. Crude was purified by
silica gel (230-400 mesh) column chromatography using gradient mixtures of n-
hexane/ethylacetate (6:1) to afford pure compound 16a (328 mg, 98%)
N-Phenylbenzo[d]thiazol-2-amine (16a)22: White solid, yield 98%; Rf = 0.7 (30% ethyl
acetate/n-hexane); m.p. = 156-158oC; 1H NMR (500 MHz, DMSO d6+CD3OD): δ 10.34 (s, 1H),
7.71-7.69 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.30-7.24 (m, 3H), 7.08 (t, J = 7.5 Hz, 1H), 6.97-
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6.94 (m, 1H); C NMR (125 MHz, DMSO d6+CD3OD): δ 162.3, 152.5, 141.0, 140.9, 130.4,
129.4, 126.3, 122.7, 122.6, 121.3 119.6 and 118.2 ppm.
General procedure for tandem synthesis of benzimidazo[2,1-b]quinazolin-12(6H)-ones
(18a,b)
Compound 17a (150 mg, 0.42 mmol) was dissolved in 1.5 ml dry DMF and cyanamide (2 equiv.,
35 mg, 0.84 mmol), ligand L1 (10 mol%, 18 mg, 0.04 mmol), CuI (10 mol%, 8 mg, 0.04 mmol)
and K2CO3 (2 equiv., 116 mg, 0.84 mmol) were added to it. The mixture was heated at 120oC in
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a sealed vessel under argon atmosphere for 20 hours. Completion of reaction was confirmed by
TLC and the reaction mass was cooled to room temperature followed by evaporation of DMF
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under reduced pressure.
Crude was purified by silica gel (230-400 mesh) column
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chromatography using gradient mixtures of n-hexane/ethylacetate (3:2) to afford pure compound
18a (100 mg, 76%).
Benzo[4,5]imidazo[2,1-b]quinazolin-12(6H)-one (18a)19: White solid, yield 76%; Rf = 0.4
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(80% ethyl acetate/n-hexane); m.p. >300o C; H NMR (500 MHz, DMSO-d6): δ 12.42 (s, 1H),
8.40 (d, J = 9.0 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H), 7.76 (t, J = 7.5 Hz, 1H), 7.51-7.40 (m, 3H),
7.33-7.26 (m, 2H); 13C NMR (125 MHz, DMSO-d6): δ 174.5, 160.0, 159.0, 147.0, 134.6, 128.1,
127.1, 126.7, 125.7, 122.1, 121.0, 114.9 and 113.0 ppm.
ACKNOWLEDGEMENTS
NM thanks University Grants Commission (UGC) for JRF and SRF. AKA thanks Council of
Scientific and Industrial Research (CSIR), New Delhi for JRF. VKT sincerely thanks Science and
Engineering Research Board (SERB), New Delhi for the financial support (Grant No.
EMR/2016/001123). Authors gratefully acknowledge Indian Institute of Technology, Kanpur;
TCG Chembioteck, Kolkata and CISC, Department of Chemistry, Institute of Science, Banaras
Hindu University (BHU) for providing spectroscopic studies of the developed molecules and
BHU for the basic infrastructure.
Supporting Information
1
13
Copies of H and C NMR spectra for all compounds and X-ray crystallographic data for L1,
13d and 16e (CIF) are given. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Authors *E-mail: Vinod.Tiwari@bhu.ac.in; VTIWARI@ucdavis.edu
ORCID: 0000-0001-9244-8889
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