Hypervalent Iodine Mediated Efficient Solvent-Free Regioselective Halogenation and Thiocyanation of Fused N -Heterocycles

Article abstract of DOI:10.1055/s-0037-1611856

A facile, rapid, metal-free regioselective halogenation and thiocyanation of imidazo[1,2- a ]pyridine/pyrimidine heterocycles has been achieved under solvent-free reaction conditions. Halogenations and thiocyanation of the heterocycles could be accomplish

Full text of DOI:10.1055/s-0037-1611856

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–G
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D. R. Indukuri et al.
Letter
Synlett
Hypervalent Iodine Mediated Efficient Solvent-Free Regioselective
Halogenation and Thiocyanation of Fused N-Heterocycles
Divakar Reddy Indukuria,b
Gal Reddy Potugantia,b
Manjula Alla*a,b
a Flouro & Agrochemicals Division, CSIR-Indian Institute of
Chemical Technology, Tarnaka, Hyderabad, 500007, India
b Academy of Scientific and Innovative Research, CSIR-Indian
Institute of Chemical Technology, Tarnaka, Hyderabad
500007, India
manjula@iict.res.in
Received: 18.03.2019
Accepted after revision: 16.05.2019
Published online: 12.06.2019
A diverse range of substitutions can be introduced on
substrates through the reversal of reactivity of reagents
and/or synthons. Hypervalent iodine7 reagents have been
reported to promote this reversal of reactivity to facilitate
hitherto impossible substitutions on electron-rich sub-
strates. A recent flurry of reports on iodobenzenediacetate
(IBD) mediated substitutions on electron-rich aromatic
compounds alkenes,8 carbonyls,9 and enamines10 has
prompted us to investigate hypervalent iodine mediated
functionalisation of the imidazo[1,2-a]pyridine/pyrimidine
framework. Hypervalent iodine reagents are ambiphilic in
nature and behave similar to transition-metal complexes,
facilitating ligand exchange11 and their subsequent transfer
via reductive elimination. Though few synthetic protocols12
have been devised for key substitution on fused N-hetero-
cycles, a versatile metal-free oxidative protocol for C-3 sub-
stitution, incorporating green chemistry principles, is high-
ly desirable.
The reactivity of fused N-heterocycles was assessed
with a range of salts in the presence of iodobenzene diace-
tate (IBD) under various reaction conditions (Table 1,
Scheme 1). To begin with, the strategy was tested by sub-
jecting imidazo[1,2-a]pyridine to IBD-mediated bromina-
tion with NH4Br in H2O at room temperature (entry 1). 3-
Bromo-2-phenylimidazo[1,2-a]pyridine (3a) precipitated
from the reaction mixture within a short time (30 min) and
the product was isolated in 69% yield. Raising the tempera-
ture to 80 °C and performing reaction under solvent-free
conditions not only improved the yield of the reaction
(72%) but also reduced the reaction time by half (entry 2).
The conversion yield (71%) was comparable, when the reac-
tants were subjected to simple grinding in a mortar and
pestle under neat conditions (entry 3). Optimum product
yields were obtained by using 1.5 equivalents of NH4Br and
IBD (entry 4). Having successfully demonstrated the forma-
DOI: 10.1055/s-0037-1611856; Art ID: st-2019-k0155-l
Abstract A facile, rapid, metal-free regioselective halogenation and
thiocyanation of imidazo[1,2-a]pyridine/pyrimidine heterocycles has
been achieved under solvent-free reaction conditions. Halogenations
and thiocyanation of the heterocycles could be accomplished by simple
grinding of reactants and hypervalent iodine reagents with the corre-
sponding alkali metal or ammonium salts. The method has been ex-
trapolated to a cleaner synthesis of brominated imidazo[1,2-a]pyri-
dine/pyrimidine derivatives, starting from the corresponding
heterocyclic amines and substituted -bromoketones, utilising HBr
generated in situ as the source of bromine.
Key words solvent free, grinding, regioselective substitution, in situ
bromination, atom economy
Fused N-heterocycles are an important class of mole-
cules that exhibit not only unique bioactivities1 but also in-
teresting chemical properties that lead to broad applica-
tions in synthetic2 and material chemistry.3 Consequently,
the synthesis of fused N-heterocycles has received much at-
tention. The utility and activity profile of these molecules,
especially imidazo[1,2-a]pyridine/pyrimidine has been
shown to be greatly influenced by the nature of substitu-
tions on the C-2 and C-3 positions (Figure 1). In these het-
erocycles the C-3 position is normally an electron-rich cen-
tre that is susceptible to electrophilic substitution.4 Substi-
tutions at C-3 carbon of these key substrates via metal-
catalyzed oxidative C–H activation,5 as well as a few organo-
catalyst- and organophotocatalyst-mediated6 oxidative reac-
tions have also been attempted.
1
1
1
S
N
3
N
N
N
2
2
2
N
N
N
3
3
Figure 1 Fused N-heterocycles used in this study
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. R. Indukuri et al.
Letter
Synlett
X
X
N
N
R2
R2
M-X
N
N
R1
R1
IBD
1
X
3/4/5/6
X= Br/Cl/I/ SCN
N
N
N
N
O
O
N
N
N
Br
Br
3b, 79%
4b, 55%
3c, 80%
Br
3a, 84%
N
N
N
N
N
4a, 60%
Cl
Cl
Cl
4c, 57%
N
N
N
N
O
N
N
5a, 78%
I
I
5b. 72%
5c, 70%
I
N
N
N
N
O
N
N
6a, 83%
SCN
SCN
6b, 78%
6e, 75%
SCN
6c, 81%
N
N
N
F
Cl
N
N
N
SCN
6d,78%
SCN
6f, 74%
SCN
N
N
N
N
N
N
Cl
N
N
N
6h, 83%
SCN
SCN
6i, 80%
SCN
6g 84%
SCN
6j, 76%
Scheme 1 Substrate scope of C-3 halogenation and thiocyanation of imidazoheterocycles. Reaction conditions for products 3a–c, 4a–c, 5a–c and 6a–j:
compound 1 (1 mmol), 2 (1.5 mmol), IBD (1.5 mmol), grinding at room temperature. General procedure and data for select compounds are provided in
References and Notes.13
tion of the required product under solvent-free conditions,
other oxidising reagents were tested for their utility in the
current protocol. Reaction was facile with NH4Br and [hy-
droxy(tosyloxy)iodo]benzene (HTIB) (entry 5) by simple
grinding of reactants. On the other hand, the reaction was
not successful under these conditions with K2S2O8 (entry 6).
However, heating the reaction at 80 °C in CH3CN for a longer
time (6 h) resulted in 51% conversion into the desired prod-
uct (entry 7) in the presence of K2S2O8. The results establish
the superiority of hypervalent iodine reagents, unequivo-
cally. Sodium bromide gave slightly higher yield of 3a (en-
try 8). The study was extended to other halide salts. The
chloride salts NH4Cl and NaCl gave the corresponding 3-
chloro-2-phenylimidazo[1,2-a]pyridine (4a; entries 9 and
10), under similar reaction conditions, albeit in much lower
yield. Iodination with NaI in the presence of IBD was also
successful, yielding 3-iodo-2-phenylimidazo[1,2-a]pyridine
(5a; entry 11). The substrate scope of the protocol, investi-
gated with respect to substitutions on C-2 phenyl group of
imidazopyridines, indicated that the unsubstituted phenyl
ring gave the best yields in all halogenations. Among the
various halogenations attempted, the yields were better for
bromination, followed closely by iodination, and chlorina-
tion gave lowest yield of products (Scheme 1, 3a–c, 4a–c,
and 5a–c). Interestingly halogenations with aq. HBr (48%)
and aq. HCl (36.5%) were also successful, and the corre-
sponding products (3a or 4a, respectively) could be ob-
tained in moderate yields (entries 12 and 13).
Extending the protocol to other reagents was explored
in an attempt to further broaden its scope and applicability.
Thiocyanation of the above heterocycles was studied under
a similar set of optimised conditions (Table 1, entry 4).
Gratifyingly, simple grinding of imidazo[1,2-a]pyridine and
KSCN with IBD gave the corresponding 2-phenyl-3-thiocy-
anatoimidazo[1,2-a]pyridine (6a) in 85% yield (entry 14).
Comparable results were obtained with NH4SCN and imid-
azopyridine as reactants (entry 15). Reaction with alterna-
tive hypervalent reagent HTIB was also facile under simple
grinding conditions (entry 16). However, when K2S2O8 was
used, the formation of the product was possible only on re-
fluxing in solution in dichloroethane (DCE) at 80 °C. Thiocy-
anation failed to progress under simple grinding conditions
(entries 17 and 18). The substrate scope of thiocyanation
was broad, as evident from the examples depicted in
Scheme 1 (6a–j) and products were obtained in good yields.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–G

C
D. R. Indukuri et al.
Letter
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Y
Table 1 Optimization of Conditions for Halogenation and Thiocyana-
tion of 2-Phenylimidazo[1,2-a]pyridine (1a)a
O
N
Y
Acetone
rt
Ar
Br
+
N
Ar
R
R
N
NH2
8
7
HBr
H
9
N
2 M-X
N
Y = CH, N
N
1
N
R1
S
oxidant
S
O
N
N
R1
X=Br/Cl/I/SCN
Acetone
rt
H
NH2
+
X
3/4/5/6
Br
Ar
Ar
N
8
HBr
10
Entry Reagent
Solvent
Oxidant
Time (min) Yield (%)b
11
1
2
NH4Br
NH4Br
NH4Br
NH4Br
NH4Br
NH4Br
NH4Br
NaBr
H2O
IBD (1.2)f
IBD (1.2)f
IBD (1.2)f
IBD (1.5)f
HTIB
30
15
15
15
15
15
360
15
30
30
15
20
20
15
15
15
30
360
69
72
71
84
75
NRc
51
88
60
60
78
55
42
85
70
80
NRc
60
Scheme 2 Synthesis of heterocyclic hydrobromides
neat (80 °C)
grinding
grinding
grinding
grinding
CH3CN
3
A one-pot protocol for the synthesis of 3a by grinding
heterocyclic amine and -bromoketone under solvent-free,
aerobic conditions resulted in hydrolysis of the -bromoke-
tone. Therefore, a completely solvent-free grinding protocol
could not be designed. Suitable conditions for in situ bromi-
nation protocol were arrived at by studying various reac-
tion parameters. It was found that bromination yields were
good when the reaction residue (9/11) was heated neat
(melt) or by simple grinding with IBD (Table 2, entries 1 and
2). Both these conditions gave brominated products in
yields that were comparable to the yields obtained when
brominations were performed in refluxing aprotic solvents
(entries 3 and 4). Protic solvents (entries 5–7) were not
good media for bromination. Brominations in IBD gave bet-
ter yield of the product compared with other oxidising re-
agents (entries 8–10).
4
5
6
K2S2O8
K2S2O8
IBD
7
8
grinding
grinding
grinding
grinding
H2O(rt)
H2O(rt)
grinding
grinding
grinding
grinding
DCE
9
NH4Cl
NaCl
IBD
10
11
12
13
14
15
16
17
18
IBD
NaI
IBD
HBr aq.d
HCl aq.e
KSCN
NH4SCN
KSCN
KSCN
KSCN
IBD
IBD
IBD
IBD
HTIB
K2S2O8
K2S2O8
Table 2 Optimization of Conditions for Bromination of 2-Phenylimid-
azo[1,2-a]pyridine Hydrobromide to 3-Bromo-2-phenylimidazo[1,2-a]-
pyridine (3a)a
a Reaction conditions: 1a (1 mmol), 2 M-X (1.5 mmol), oxidant.
b Isolated yields reported.
c No reaction.
d HBr 48% solution.
N
N
e HCl 36.5% solution.
oxidant
f Equivalents of halide salt and oxidant used are given in parentheses.
N
N
HBr 9a
3a
Br
The success of halogenations with aqueous HCl and HBr
(Table 1, entries 12 and 13) inspired us to investigate a
cleaner and more atom-economical method for the synthe-
sis of 3-bromo-2-phenylimidazo[1,2-a]pyridine (3a). Con-
struction of these fused rings often involves condensation
of a heterocyclic amine and -bromoketone, resulting in
generation of HBr in stoichiometric portions as a by-prod-
uct. It would be an ideal situation if the HBr generated in
situ could be used for bromination. The -bromoketone and
heterocyclic amine were stirred in solvent for the requisite
time (Scheme 2) to complete ring formation and subse-
quently solvent was removed from the reaction mixture.
The residue was taken in a mortar and pestle and the mass
was thoroughly ground along with IBD. Continuous grind-
ing for 15 minutes resulted in formation of the correspond-
ing brominated product in good yields.
Entry
Solvent
Oxidant
Time (min)
Yield (%)b
1
2
neat (80 °C)
grinding
dioxane
CH3CN
H2O
IBD
15
15
15
15
20
15
15
30
6 h
6
80
IBD
85
3
IBD
80
4
IBD
78
5
IBD
65
6
EtOH
IBD
50
7
MeOH
IBD
45
8
grinding
CH3CN
grinding
K2S2O8
K2S2O8
HTIB
NRc
trace
54
9
10
a Reaction Conditions: 9a (1 mmol), oxidant (1.5 mmol).
b Isolated yields were reported.
c No reaction.
The established ideal reaction conditions for in situ bro-
mination [hydrobromide salt 9/11, IBD (1.5 equiv), grind-
ing] were extended to other substrates. The substrate scope
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–G

D
D. R. Indukuri et al.
Letter
Synlett
of the protocol is broad, as a wide range of substituents are
tolerated. The reaction conditions could be used for bromi-
nation of a number of substituted imidazo[1,2-a]pyridine,
imidazo[1,2-a]pyrimidine, as well as other fused N-hetero-
cycles (Scheme 3; 3a–r, 12a–c).
do]benzene17 from IBD and MX (Scheme 5). The species, be-
ing labile, serves as a formal X+ reagent, thereby facilitating
substitution on C-3 carbon.
N
N
IBD, TEMPO/DDQ
NH4Br
N
Having established the scope and utility of the reaction,
the mechanistic aspects of the transformation attracted our
attention. Hypervalent iodine-mediated reactions are
known to adopt two pathways: either a radical pathway15
or ionic pathway.16 Control experiments carried out in the
presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as
radical scavengers were surprisingly successful (Scheme 4).
This unambiguously rules out a radical pathway for the re-
action. The product yield of the reaction was susceptible to
variations in the oxidant quantity and slightly higher than
stoichiometric proportions of IBD and halide/thiocaynate
salts were essential to obtain good product yields. A simple
grinding of the halide salts with IBD resulted in the libera-
tion of distinct acetic acid odour. This indirectly indicates
that a ligand exchange mechanism is probably involved. A
plausible mechanism therefore involves ligand exchange
with acetate to form in situ [acetoxy(halo/thiocyanato)io-
N
3a
Br
N
3a TEMPO 70% yield
3a DDQ 67% yield
H
1
N
IBD, TEMPO
KSCN
N
N
SCN
H
6a 65% yield
1
Scheme 4 Control experiments. Reaction conditions: 1 (1 mmol), IBD
(1.5 mmol) TEMPO or DDQ (1.5 mmol), NH4Br or KSCN (1.5 mmol),
grinding for 15 min at room temperature.
In summary, a highly efficient, rapid, operationally sim-
ple and facile substitution protocol for C–H substitution of
fused N-heterocycles has been established.13,14,18 An inex-
pensive practical halogenation method has been estab-
lished for imidazo[1,2-a]pyridine/ pyrimidine using simple
alkali/ammonium halides, aq. HBr / aq. HCl in the presence
of IBD. The scope of the protocol has been extended to oth-
er reagents, and effective thiocyanation of imidazo[1,2-
X
N
X
N
R2
IBD
R2
N
N
R1
R1
HBr
3
Br
9
S
S
N
IBD
N
N
N
R3
R3
N
R4
R4
N
HBr
Br
12
11
N
N
O
Cl
N
N
N
N
3b, 80%
834mg
70%
3a, 85%
Br
3a
3c, 82%
3d, 84%
Br
Br
Br
N
N
N
N
F
O
Br
N
N
N
N
Cl
3g, 74%
3f, 72%
3h, 81%
Br
Br
Br
3e, 68%
3i, 78%
Br
N
N
N
N
N
N
N
N
Br
Br
3j, 80%
NO2
Br 3k, 79%
3l, 78%
Br
Br
N
N
N
N
S
N
N
N
N
N
N
N
N
3o, 79%
3m, 84%
3p, 80%
O
Br
3n, 68%
Br
Br
Br
S
S
S
N
N
N
N
N
N
O
N
N
N
N
O
N
N
O
Br
Br
3q, 82%
3r, 84%
Br
Br
Br
Br
12c, 70%
12b, 76%
12a, 75%
Scheme 3 Substrate scope of in situ bromination of fused N-heterocycles. Reaction conditions: heterocyclic hydrobromide (9/11; 1 mmol), IBD (1.5
mmol), grinding for 15 min at room temperature. General procedure and data for select compounds is given in References and Notes.14
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–G

E
D. R. Indukuri et al.
Letter
Synlett
O
O
O
O
O
I
O
Br
I
ligand exchange
AcOH
+
HBr
+
O
O
N
N
AcO– +H+
– AcOH
Br
I
N
Br+
Ph
Ph
+
+
N
N
+
– PhI
+
AcO–
N
H
Umpolung
Br
Br
Ph
Scheme 5 Plausible route
a]pyridine/ pyrimidine could be achieved under solvent-
free conditions. The method has been extrapolated to an
atom-economical17 cleaner synthesis of brominated deriva-
tives of fused N-heterocycles starting from heterocyclic
amine and -bromomketone. Additionally, this in situ bro-
mination protocol could be scaled up to a gram level syn-
thesis (Scheme 3, compound 3b). This hypervalent iodine
mediated substitution protocol, which is compatible with a
wide range of substrates, substituents and reagents, is a
valuable tool for substitution of electron-rich arene centres
and N-heterocycles.
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Funding Information
I.D.R. thanks DST and P.G.R. thanks CSIR, for a fellowship.()
(7) (a) Hari, D. P.; Caramenti, P.; Waser, J. Acc. Chem. Res. 2018, 51,
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Acknowledgment
We would like to thank the director, CSIR-IICT, and AcSIR for facilities.
Manuscript communication number IICT/Pubs./2019/018.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611856.
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Yamasaki, M.; Shiro, M.; Shibata, N. J. Am. Chem. Soc. 2013, 135,
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B.; Lingala, S. K.; Yarasi, S. J. Org. Chem. 2012, 77, 10648.
(11) (a) Yusubov, M. S.; Wirth, T. Org. Lett. 2005, 7, 519. (b) Han, H.;
Tsarevsky, N. V. Chem. Sci. 2014, 5, 4599. (c) Ochiai, M.; Sueda,
T.; Miyamoto, K.; Kiprof, P.; Zhdankin, V. V. Angew. Chem. Int.
Ed. 2006, 45, 8203. (d) Sajith, P. K.; Suresh, C. H. Inorg. Chem.
2012, 51, 967.
(4) (a) Zhang, H.; Wei, Q.; Wei, S.; Qu, J.; Wang, B. Eur. J. Org. Chem.
2016, 3373. (b) Bagdi, A. K.; Hajra, A. Chem. Rec. 2016, 16, 1868.
(c) Xiang, S.; Chen, H.; Liu, Q. Tetrahedron Lett. 2016, 57, 3870.
(12) (a) Shakoor, S. M. A.; Mandal, S. K.; Sakhuja, R. Eur. J. Org. Chem.
2017, 2596. (b) Karade, N. N.; Tiwari, G. B.; Shirodkar, S. G.;
Dhoot, B. M. Synth. Commun. 2005, 35, 1197. (c) Chen, Z.; Cao,
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–G

F
D. R. Indukuri et al.
Letter
Synlett
G.; Zhang, F.; Li, H.; Xu, J.; Miao, M.; Ren, H. Synlett 2017, 28,
1795. (d) Rahaman, R.; Das, S.; Barman, P. Green Chem. 2018, 20,
141. (e) Mondal, S.; Samanta, S.; Jana, S.; Hajra, A. J. Org. Chem.
2017, 82, 4504. (f) Yagyu, T.; Takemoto, Y.; Yoshimura, A.;
Zhdankin, V. V.; Saito, A. Org. Lett. 2017, 19, 2506. (g) Xu, D.;
Sun, W.; Xie, Y.; Liu, J.; Liu, B.; Zhou, Y.; Wu, B. J. Org. Chem.
2016, 81, 11081. (h) Zhang, X.; Hou, W.; Zhang-Negrerie, D.;
Zhao, K.; Du, Y. Org. Lett. 2015, 17, 5252.
7.29–7.25 (m, 2 H), 6.70 (dd, J = 7.0, 1.5 Hz, 1 H), 2.40 (s, 6 H).
13C NMR (125 MHz, CDCl3):  = 145.64, 142.27, 137.95, 136.02,
130.04, 129.08, 127.60, 122.98, 115.81, 115.49, 90.41, 77.00,
21.28. HRMS-ESI: m/z [M + H]+ calcd. for C15H14BrN2: 301.0348;
found: 301.0340.
3-Bromo-2-(thiophen-2-yl)imidazo[1,2-a]pyrimidine (3m)
Yield: 232 mg (84%); white solid; mp 150–152 °C; 1H NMR (400
MHz, CDCl3):  = 8.56 (dd, J = 4.0, 1.8 Hz, 1 H), 8.40 (dd, J = 6.8,
1.8 Hz, 1 H), 7.95 (d, J = 3.6 Hz, 1 H), 7.45 (d, J = 5.0 Hz, 1 H),
7.20–7.14 (m, 1 H), 6.99 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (125
MHz, CDCl3):  = 150.23, 147.99, 140.28, 135.12, 131.15, 127.74,
127.28, 126.71, 109.36, 89.31, 77.00. HRMS-ESI: m/z [M + H]+
calcd. for C10H7BrN3S: 279.9543; found: 279.9544.
3-Bromo-2-(3-nitrophenyl)imidazo[1,2-a]pyrimidine (3n)
Yield: 214 mg (68%); white solid; mp 224–226 °C; 1H NMR (300
MHz, CDCl3+DMSO):  = 9.12 (s, 1 H), 8.67 (dd, J = 4.1, 1.9 Hz,
1 H), 8.65–8.57 (m, 2 H), 8.27 (dd, J = 8.2, 1.2 Hz, 1 H), 7.72 (t, J =
8.0 Hz, 1 H), 7.15 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (75 MHz,
CDCl3+DMSO):  = 150.36, 147.28, 147.06, 139.91, 133.11,
132.40, 131.32, 128.71, 122.07, 121.29, 109.15, 90.40, 77.00.
HRMS-ESI: m/z [M + H]+ calcd. for C12H8BrN4O2: 317.9749;
found: 317.9752.
(13) Synthesis of 3-Halo/thiocyanato-2-phenylimidazo[1,2-a]pyr-
idine Derivatives; General Procedure
A mixture of 2-phenylimidazo[1,2-a]pyridine (1; 1 mmol), M-X
(2a–d; 1.5 mmol) and IBD (1.5 mmol) were taken in a mortar
and the mixture was ground with a pestle until the solids
melted (ca. 15 min). A distinction odour of acetic acid was
noted. The progress of the reaction was monitored by TLC and
grinding was continued until the starting materials disap-
peared. The reaction mixture was extracted with ethyl acetate
(30 mL) and washed with water (10 mL) to remove remnant
inorganic salts. The organic layer was separated and dried over
Na2SO4. Solvent was removed in vacuo. The crude product thus
obtained was purified by column chromatography for all halo-
genations (silicon 60–120 mesh; EtOAc/hexane, 5:95). Thiocya-
nation products could be obtained in pure form without further
purification.
3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyrimidine (3p)
Yield: 241 mg (80%); brown solid; mp 180–182 °C; 1H NMR
(400 MHz, CDCl3):  = 8.28 (d, J = 7.0 Hz, 1 H), 8.14–8.10 (m,
2 H), 7.29 (d, J = 8.0 Hz, 2 H), 6.85–6.82 (m, 1 H), 2.66 (s, 3 H),
2.41 (s, 3 H). 13C NMR (125 MHz, CDCl3):  = 160.32, 148.05,
143.39, 138.52, 130.58, 129.60, 129.13, 127.73, 110.08, 88.91,
(14) Synthesis
of
3-Bromo-2-phenylimidazo[1,2-a]pyri-
dine/pyrimidine/benzo[d]imidazo[2,1-b]thiazole
Deriva-
tives via in Situ Bromination; General Procedure
A mixture of heterocyclic hydrobromide (9/11; 1 mmol), and
IBD (1.5 mmol) were taken in a mortar and the mixture was
ground with a pestle until the solids melted (ca. 15 min). The
progress of the reaction was monitored by TLC and grinding
was continued until the starting materials disappeared. The
solid residue was washed with n-pentane and dried under high
vacuum to afford the product
77.00, 24.84, 21.35. HRMS-ESI: m/z [M
+
H]+ calcd. for
C
13H11BrN3: 288.0140; found: 288.0136. HRMS-ESI: m/z [M +
H]+, calcd. for C14H13BrN3: 302.0293; found: 302.0287.
3-Bromo-2-(4-methoxyphenyl)imidazo[1,2-a]pyrimidine
(3q)
Yield: 249 mg (82%); white solid; mp 154–156 °C; 1H NMR (400
MHz, CDCl3):  = 8.57 (dd, J = 4.1, 2.0 Hz, 1 H), 8.45 (dd, J = 6.8,
2.0 Hz, 1 H), 8.22–8.16 (m, 2 H), 7.05–6.96 (m, 3 H), 3.88 (s,
3 H). 13C NMR (100 MHz, CDCl3):  = 160.16, 149.79, 148.14,
144.22, 131.18, 129.44, 124.79, 113.95, 109.14, 89.38, 77.00,
(15) (a) Selvakumar, S.; Kang, Q.-K.; Arumugam, N.; Almansour, A. I.;
Kumar, R. S.; Maruoka, K. Tetrahedron 2017, 73, 5841. (b) Zhao,
F.; Sun, T.; Sun, H.; Xi, G.; Sun, K. Tetrahedron Lett. 2017, 58,
3132. (c) Wang, X.; Studer, A. Acc. Chem. Res. 2017, 50, 1712.
(d) Wang, X.; Studer, A. Acc. Chem. Res. 2017, 50, 1712. (e) Bose,
D. S.; Idrees, M. J. Org. Chem. 2006, 71, 8261.
55.33. HRMS-ESI: m/z [M
+
H]+ calcd. for C13H10BrN3O:
304.0086; found: 304.0085.
(16) (a) Yoshimura, A.; Middleton, K. R.; Todora, A. D.; Kastern, B. J.;
Koski, S. R.; Maskaev, A. V.; Zhdankin, V. V. Org. Lett. 2013, 15,
4010. (b) Boye, A. C.; Meyer, D.; Ingison, C. K.; French, A. N.;
Wirth, T. Org. Lett. 2003, 5, 2157.
(17) (a) Tang, S.-Z.; Zhao, W.; Chen, T.; Liu, Y.; Zhang, X.-M.; Zhang,
F.-M. Adv. Synth. Catal. 2017, 359, 4177. (b) Akula, R.; Galligan,
M.; Ibrahim, H. Chem. Commun. 2009, 6991.
3-Bromo-7-methoxy-2-(4-methoxyphenyl)benzo[d]imidazo
[2,1-b]thiazole (12b)
Yield: 251 mg (65%); white solid; mp 206–208 °C; 1H NMR (300
MHz, CDCl3):  = 8.30 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 2 H),
7.20 (d, J = 2.4 Hz, 1 H), 7.05–6.92 (m, 3 H), 3.87 (d, J = 4.5 Hz,
6 H). 13C NMR (100 MHz, CDCl3):  = 159.34, 157.31, 147.08,
143.31, 131.54, 128.46, 127.18, 125.18, 114.26, 113.87, 113.06,
108.54, 90.89, 77.00, 55.88, 55.31. HRMS-ESI: m/z [M + H]+
calcd. for C17H14BrN2O2S: 388.9958; found: 388.9959.
3-Bromo-7-methoxy-2-(p-tolyl)benzo[d]imidazo[2,1-b]thi-
azole (12c)
(18) Analytical data and copies of spectra of all compounds are given
in the Supporting Information.
Analytical data of a selection of new compounds are given
below.
1
3-Bromo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyr-
idine (3c)
Yield: 260 mg (70%); pale-pink solid; mp 204–206 °C; H NMR
(400 MHz, CDCl3):  = 8.31 (d, J = 9.1 Hz, 1 H), 7.90 (d, J = 8.2 Hz,
2 H), 7.26 (t, J = 4.0 Hz, 2 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.01 (dd, J =
9.0, 2.4 Hz, 1 H), 3.88 (s, 3 H), 2.40 (s, 3 H). 13C NMR (125 MHz,
CDCl3):  = 157.27, 147.20, 143.74, 137.63, 131.56, 129.96,
129.11, 127.22, 126.99, 114.26, 112.96, 108.54, 91.33, 77.00,
55.86, 21.31. HRMS-ESI: m/z [M + H]+ calcd. for C17H14BrN2OS:
372.9967; found: 372.9954.
1
Yield: 253 mg (80%); yellow solid; mp 92–94 °C; H NMR (500
MHz, CDCl3):  = 8.08–8.04 (m, 1 H), 8.02 (d, J = 7.0 Hz, 1 H),
7.38 (s, 1 H), 7.03–6.99 (m, 2 H), 6.74 (dd, J = 7.0, 1.5 Hz, 1 H),
3.86 (s, 3 H), 2.42 (s, 3 H). 13C NMR (100 MHz, CDCl3):  =
159.57, 145.52, 141.94, 136.15, 129.02, 125.35, 122.96, 115.65,
115.50, 113.81, 89.96, 77.00, 55.24, 21.28. HRMS-ESI: m/z [M +
H]+ calcd. for C15H14BrN2O: 317.0284; found: 317.0290.
3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (3l)
Yield: 234 mg (78%); white solid; mp 176–178 °C; 1H NMR (400
MHz, CDCl3):  = 8.00 (dd, J = 7.5, 5.8 Hz, 3 H), 7.37 (s, 1 H),
3-Chloro-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyr-
idine (4c)
Yield: 155 mg (57%); brown solid; mp 122–124 °C; 1H NMR
(400 MHz, CDCl3):  = 8.09–8.04 (m, 2 H), 7.97 (d, J = 7.0 Hz,
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–G

G
D. R. Indukuri et al.
Letter
Synlett
1 H), 7.39 (s, 1 H), 7.03–6.98 (m, 2 H), 6.75 (dd, J = 7.0, 1.5 Hz,
1 H), 3.87 (s, 3 H), 2.43 (d, J = 0.6 Hz, 3 H). 13C NMR (125 MHz,
CDCl3):  = 159.60, 143.98, 139.23, 135.94, 128.75, 125.19,
121.82, 115.80, 115.45, 113.99, 104.16, 55.34, 21.41. HRMS-ESI:
m/z [M + H]+ calcd. for C15H14OClN2: 273.0792; found: 273.0789.
3-Iodo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyri-
dine (5c)
159.56, 148.23, 147.52, 136.37, 129.59, 126.16, 125.43, 115.71,
115.45, 113.66, 77.00, 57.33, 55.22, 21.19. HRMS-ESI: m/z [M +
H]+ calcd. for C15H14IN2O: 365.0146; found: 365.0151.
3-Thiocyanato-2-(p-tolyl)imidazo[1,2-a]pyrimidine (6g)
Yield: 223 mg (84%); white solid; mp 208–210 °C; 1H NMR (300
MHz, CDCl3+DMSO):  = 8.81 (ddd, J = 6.1, 5.5, 1.9 Hz, 2 H), 8.07
(d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.27 (dd, J = 6.7,
4.3 Hz, 1 H), 2.46 (s, 3 H). 13C NMR (75 MHz, CDCl3+DMSO):  =
151.94, 138.92, 131.87, 128.45, 127.67, 126.76, 109.65, 77.00,
20.38. HRMS-ESI: m/z [M + H]+ calcd. for C14H11IN4S: 267.0695;
found: 267.0699.
Eluent: hexane/ethyl acetate, 90:10.
Yield: 254 mg (70%); white solid; mp 118–120 °C; 1H NMR (400
MHz, CDCl3):  = 8.06 (d, J = 7.0 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 2 H),
7.35 (s, 1 H), 7.01 (d, J = 8.7 Hz, 2 H), 6.73 (d, J = 6.9 Hz, 1 H),
3.86 (s, 3 H), 2.43 (s, 3 H). 13C NMR (125 MHz, CDCl3):  =
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–G