Direct trifluoromethylation of imidazoheterocycles in a recyclable medium at room temperature

Article abstract of DOI:10.1039/c5ra02888d

Regioselective C-H trifluoromethylation of imidazoheterocycles with Langlois' reagent in a recyclable mixed medium of 1-butyl-3-methylimidazoliumtetrafluoroborate ([Bmim]BF₄) and water at room temperature has been developed. In the presence of

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ARTICLE TYPE
Direct Trifluoromethylation of Imidazoheterocycles in a Recyclable
Medium at Room Temperature
XiaoꢀMing Jia,b, Liang Weib, Fan Chenb and RiꢀYuan Tang*a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Regioselective C−H trifluoromethylation of imidazoheterocycles with Langlois` reagent in a recyclable
mixed medium of 1ꢀbutylꢀ3ꢀmethylimidazoliumtetrafluoroborate ([Bmim]BF4) and water at room
temperature has been developed. In the presence of catalytic cupric acetate and 2ꢀmethylꢀ2ꢀ
(methylperoxy)propane (TBHP) , this green strategy tolerates a wide range of functional groups to afford
10 diverse trifluoromethylated imidazoheterocycles in moderate to good yields.
insolubility of imidazoheterocycles in water at room temperature.
We hypothesized that the addition of an ionic liquid to the water
may figure out the insolubility problem of imidazoheterocycles;
50 additionally, ionic liquids are commonly stable, nonꢀvolatile, and
recyclable, which are widely used as green mediums in various
reactions.22 As a part of our continuing interest in the C–H
functionalization of imidazoheterocycles,10h we report a method
Introduction
Imidazoheterocycles are privileged scaffolds with diverse
bioactivity,1 which have been used as SIRT1 activator,2 RSK2
inhibitors,3 anticancer agents,4 and antiviral agents,5 and in the
15 treatment of Cystic Fibrosis.6 Several commercially available
drugs, such as alpidem, olprinone, necopidem, zolimidine, and
saripidem, have been developed by the modification of
imidazoheterocyclic skeletons.7 Thus significant progress has
been made in the functionalization of imidazoheterocycles.8,9
20 C−H bond functionalization strategy is an ideal route to the
for
regioselective
C–H
trifluoromethylation
of
55 imidazoheterocycles in a mixed medium of [Bmim]BF4 and water
at room temperature.
preparation of diverse imidazoheterocycles as it is
a
straightforward, atom economical, and synthetic step economical
method. C−H sulfenylation,10 arylation,11 alkenylation,12 and
carbonylation13 have been employed to the functionalization of
25 imidazoheterocycles. However, little attention has been paid to
the C−H trifluoromethylation of imidazoheterocycles.14
Scheme 1 the trifluoromethylation of imidazoheterocycles.
Results and discussion
The presence of trifluoromethyl group commonly strengthens
the bioactivity of drug candidates,15 which promotes us to focus
on the C−H trifluoromethylation of imidazoheterocycles. Among
30 the trifluoromethylating reagents (including Umemoto`s
reagent,16 Ruppert`s reagent,17 Togni`s reagent,18 and Langlois`
reagent19), Langlois` reagent is a preferable trifluoromethylating
reagent as it is stable, inexpensive, and environmental friendly,
which has been extensively used in the preparation of diverse
60
Initially, we used the trifluoromethylation of 6ꢀ
phenylimidazo[2,1ꢀb]thiazole 1a with sodium
trifluoromethanesulfonate as the model reaction (table 1). Several
organic solvents were investigated in the presence of 5 mol% of
Cu(OAc)2 and 3 equivalents of TBHP at 25 °C: DMSO was
65 preferable for the trifluoromethylation to afford the product 2a in
75% (entry 4); whereas other solvents such as CH3CN, CH3NO2,
and DMF gave low yields (entries 1–3). The trifluoromethylation
of imidazoheterocycles was examined in water as a green
solvent.20k Unfortunately, the insolubility of 1a in water leads to
70 the failure of the trifluoromethylation (entry 5). The
commercially available [Bmim]BF4 ionic liquid is a suitable
reaction medium for the trifluoromethylation at room temperature,
giving product 2a in 62% yield (entry 6). To our delight, the yield
of product 2a was improved to 73% in the mixed medium of
75 [Bmim]BF4 and H2O (v:v = 1:1) (entry 7). Increasing the
proportion of water in the mixed medium decreased the yield of
2a to 46% (entry 8). The reaction of 1a at 40 oC appeared to have
no change in the yield of 2a (entry 9); whereas the reaction at 80
oC produced multiꢀditrifluoromethylated products, leading to
20
20g
35 trifluoromethylated compounds.19,
Baran group20bꢀd,
has
made a great contribution to the field of the trifluoromethylation
of heterocycles using Langlois` reagent. Despite great success has
been achieved, green strategy for the trifluoromethylation
remains scarce. The first example for C−H trifluoromethylation
40 using water as a medium was recently reported by Lipshutz
group.20k
imidazoheterocycles was just carried out in DMSO using silver
nitrate as the development of C−H
catalyst,14b
Despite
the
C−H
trifluoromethylation
of
trifluoromethylation of imidazoheterocycles in an environmental
45 friendly medium is highly desirable, which meets the guiding
principles of green chemistry.21 A challenge we are facing is the
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lower yield of 2a (entry 10). Other copper catalysts, including
favoured the reaction in [Bmim]BF4 to give product 2g in 72%
yield. Difluoroꢀsubstituted substrate also underwent the reaction
successfully to afford product 2h in 45% yield. Different
CuCl, CuCl2·2H2O, Cu(OTf)2, and Cu(TFA)2, were then
o
evaluated in [Bmim]BF4/H2O at 25 C, all of these gave lower
yields than that obtained with Cu(OAc)2 (entries 11–14). The 35 substituents on the thiazole ring were also investigated (products
5
results show that using 2 equivalents of TBHP decreased the
yield of 2a to 61% (entry 15), and no product was obtained in the
absence of TBHP (entry 16). It was demonstrated that only a
small amount of 2a was obtained in the absence of Cu(OAc)2
2i–2k). It is noteworthy that the substrate bearing an ester group
was well tolerated in [Bmim]BF4 to give product 2j in 65% yield,
which enables a further chemical transformation at the ester
group. To our delight, benzo[d]imidazo[2,1ꢀb]thiazole exhibits
(entry 17). These suggest that both TBHP and Cu(OAc)2 are key 40 good reactivity under the standard conditions, affording product
10 to this transformation. The addition of 3 equivalents of 2,2,6,6ꢀ
tetramethylpiperdinꢀ1ꢀoxyl (TEMPO) led to the failure of this
reaction, suggesting that this reaction may undergo a radical
pathway (entry 18).
2k in 81% yield.
Table 2. The Scope of Trifluoromethylation of Imidazoheterocycles a
Table 1. Screening of Optimal Conditions a
S
N
S
N
S
N
S
N
O
Cl
N
N
N
N
CF3
2a, 73%
CF3
2b, 74%
CF3
2c, 70%
CF3
2d, 71%
15
Entry
1
[Cu]
Solvent
T (oC)
25
25
25
25
25
25
25
25
40
80
25
25
25
25
25
25
25
Isolated yield (%)
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl
CH3CN
46
47
S
N
S
N
S
N
S
N
Br
F
CN
F
N
N
N
S
N
2
CH3NO2
F
CF3
CF3
2f, 78%
CF3
CF3
3
DMF
43
2e, 74%
2g, 72%b
2h, 45%
4
DMSO
75
O
O
S
N
S
N
N
N
5
H2O
0
N
N
N
N
CF3
CF3
2j, 65%b
CF3
CF3
6
[Bmim]BF4
62
2i, 78%
2k, 81%
2l, 74%
7
8b
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
[Bmim]BF4/H2O
73
N
N
N
N
46
Cl
Br
N
N
N
N
9
73
CF3
2m, 68%
CF3
2n, 60%
O
CF3
CF3
2p, 56%
2o
, 61%
10
11
12
13
14
15c
16d
17
56
N
N
N
N
53
Ph
N
N
N
N
F
CuCl2·2H2O
Cu(OTf)2
Cu(TFA)2
Cu(OAc)2
Cu(OAc)2
―
41
CF3
CF3
CF3
2r, 51%
CF3
2q, 70%
2s, 60%
2t, 62%
52
Cl
Br
53
N
N
N
N
N
N
N
N
N
61
CF3
CF3
CF3
CF3
trace
＜10
trace
2x, 65%
2u, 67%
2v, 75%
2w, 38%
a
45 Reaction conditions: 1 (0.2 mmol), CF3SO2Na (0.4 mmol, 2 equiv),
Cu(OAc)2 (5 mol%), TBHP (3 equiv), [Bmim]BF4/H2O (v:v = 1:1, 2 mL),
at 25 oC, reaction for 24 h. b in [Bmim]BF4 (2 mL).
18e
Cu(OAc)2
[Bmim]BF4/H2O
25
a
Reaction conditions: 1a (0.2 mmol), CF3SO2Na (0.4 mmol, 2 equiv),
To
trifluoromethylation strategy, the scope of imidazo[1,2ꢀ
50 a]pyridines was investigated (products 2l–2w). 2ꢀ
further
demonstrate
the
versatility
of
this
[Cu] (5 mol%), TBHP (3 equiv, 5ꢀ6 M solution in decane), solvent (2
mL), [Bmim]BF4/H2O (v:v = 1:1), at 25 oC, reaction for 24 h.
b
[Bmim]BF4/H2O (v:v = 1:2). c TBHP (2 equiv). d in the absence of TBHP.
20 e TEMPO (3 equiv) was added.
Arylimidazo[1,2ꢀa]pyridines with a methyl, methoxyl, chloro,
bromo, or phenyl group on the benzene ring were well tolerated
under the standard conditions, giving the corresponding product
in moderate yield (products 2l–2q). A 51% yield of 2r was also
With this optimized reaction conditions in hand, the scope of
imidazothiazoles was investigated (Table 2). 6ꢀarylimidazo[2,1ꢀ
b]thiazoles containing a methyl, methoxyl, chloro, bromo, fluoro,
or cyano group on the benzene ring were well tolerated under the 55 obtained despite the hindrance of the naphthyl group. The results
25 standard conditions. For example, both methyl and methoxyl
substituted substrates underwent the reaction smoothly to give the
corresponding products 2b and 2c in 74% and 70% yields,
respectively. The haloꢀsubstituted substrates have good reactivity
show that substrates with a halo group on the pyridine ring are
suitable for this transformation (products 2t–2v). For example, a
75% yield of product 2v was obtained in the reaction of 8ꢀbromoꢀ
2ꢀphenylimidazo[1,2ꢀa]pyridine, to which various functional
in the trifluoromethylation giving products 2d–2f in good yields. 60 groups can be introduced by the disconnection of C−Br bond.
30 These products are synthetically useful for further modification
by coupling reaction at the halo groups. Cyano group also
The reaction of 2ꢀethylimidazo[1,2ꢀa]pyridine was also carried
out under the standard conditions, albeit with a low yield of
2
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product 2w that cannot be obtained in the previous work14b
.
imidazoheterocycles has potential for industrial applications.
Finally, 2ꢀphenylimidazo[1,2ꢀa]pyrimidine was reacted with
sodium trifluoromethanesulfonate to give product 2x in 65%
yield.
Next, we focused on the trifluoromethylation of imidazoles to
expand the scope of application of this methodology (table 3).
The results showed that the reactions of 1Hꢀimidazole and
methylꢀsubstituted 1Hꢀimidazoles did not proceed under the
standard conditions. To our delight, a small amount of product 4d
10 was observed in the trifluoromethylation of 1ꢀphenylꢀ1Hꢀ
imidazole. Encouraged by this result, other phenylꢀsubstituted
imidazoles such as 2ꢀphenylꢀ1Hꢀimidazole and 4ꢀphenylꢀ1Hꢀ
imidazole were reacted with sodium trifluoromethanesulfonate,
both reactions proceeded smoothly, giving products 4e and 4f in
15 42% and 51% yields, respectively. Based on these results, we can
conclude that the phenyl substituent is essential to the
trifluoromethylation of imidazoles. The presence of a phenyl
group as a conjugated group in substrates 3e and 3f can stabilize
the imidazole ring, which may facilitate the trifluoromethylation.
20 Whereas the phenyl group on the nitrogen has weaker
conjugation effect on the imidazole ring, leading to the bad result.
Substrates 3aꢀc did not work at all under the standard conditions
may result from the absence of a conjugated group.
45 Table 4. Recycling of the reaction medium
Entry
Cycle
1b
2b
3b
4b
Yield (%)
5
1
2
3
4
5
70
70
65
53
48
5
a Reaction conditions: 1a (10 mmol), CF3SO2Na (20 mmol, 2 equiv), [Cu]
(5 mol%), TBHP (3 equiv, 5ꢀ6 M solution in decane), [Bmim]BF4/H2O
(v:v = 1:1, 30 mL), at 25 oC, reaction for 24 h. b Extracted with Et2O;
[Bmim]BF4/H2O medium was recycled for next reaction.
Table 3. The Scope of Trifluoromethylation of Imidazoles a
50
25
Scheme 2 A Possible Mechanism.
According to the present results and previous reports,14b, 19, 20
a
possible mechanism is proposed in scheme 2. The copper
catalysts may facilitate the generation of tꢀbutoxyl radical from
55 TBHP,
the
tꢀbutoxyl
radical
reacts
with
sodium
trifluoromethanesulfonate to afford a trifluoromethyl radical in
situ. The trifluoromethyl radical then reacts with compound 1 to
produce intermediate A. The intermediate A is oxidized to a
carboncation B, followed by an oxidative dehydrogenation
60 process to afford target product 2.
a
Reaction conditions: 3 (0.2 mmol), CF3SO2Na (0.4 mmol, 2 equiv),
Conclusions
Cu(OAc)2 (5 mol%), TBHP (3 equiv), [Bmim]BF4/H2O (v:v = 1:1, 2 mL),
at 25 oC, reaction for 24 h.
In summary, the mixture of [Bmim]BF4 and H2O has been
found to be an effective reaction medium for the
trifluoromethylation of imidazoheterocycles with Langlois`
65 reagent at room temperature. In the presence of catalytic cupric
acetate and TBHP, a wide range of functional groups were well
30
To test their potential in large scale synthesis, the reaction of
1a was conducted at 2.0 g (10 mmol) scale, and it performed well
under the standard conditions to give 2a in 70% yield (table 4). In
the treatment of the reaction mixture with Et2O, threeꢀphase
(from top to bottom is ether, water, and [Bmim]BF4) can be
tolerated
to
afford
diverse
trifluoromethylated
35 observed. Thus product 2a is readily isolated from the reaction
medium, and cupric acetate was mainly distributed in [Bmim]BF4
and water phases for the reaction cycle (table 4). The results show
that the 1th−3th recycles appear to have no obvious change in term
of yield of 2a (entries 1−3); whereas the yield was reduced to 53%
40 and 48% in the 4th and 5th recycles, respectively (entries 4 and 5).
It is noteworthy that Et2O used for extraction can be easily
recovered for next extraction. These results suggest that the
newly established strategy for the trifluoromethylation of
imidazoheterocycles in moderate to good yields. Moreover,
several phenylꢀsubstituted 1Hꢀimidazoles are also suitable for the
70 trifluoromethylation under the standard conditions. This strategy
has several advantages: (1) using green and recyclable reaction
medium, (2) room temperature reactions, and (3) good toleration
with various functional groups.
Experimental Section
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45.3 Hz). IR (ATR, cmꢀ1): 1538, 1453, 1385, 1126, 1075, 986.
LRMS (EI, 70 eV) m/z (%): 302 (100), 283 (9), 267 (6), 207 (11),
60 58 (8). HRMS (ESI) for C12H7ClF3N2S (M+H)+: calcd 302.9965,
found 302.9960.
General remarks
1H and 13C NMR spectra were measured on a Bruker AvanceꢀⅢ
500 instrument (500 MHz for 1H, 125 MHz for 13C NMR
spectroscopy) using CDCl3 or DMSOꢀd6 as the solvent.
referenced to internal TMS (0.0 ppm) as the standard. Mass
spectra were measured on a Shimadzu GCꢀMSꢀQP2010 Plus
spectrometer (EI). HRMS (ESI) analysis was measured on a
Bruker micrOTOFꢀQ II instrument. IR analysis was measured on
Nicolet IS10 spectrometer (ATR).
6ꢀ(4ꢀbromophenyl)ꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazole
5
1
(2e). Light yellow solid. H NMR (500 MHz, CDCl3) δ 7.59 –
7.58 (m, 5H), 7.01 (d, J = 4.5 Hz, 1H). 13C NMR (125 MHz,
65 CDCl3) δ 151.6, 147.9, 131.6, 131.6, 130.4, 123.3, 121.5 (q, JC–F
= 265.3 Hz), 119.0 (q, JC–F = 2.8 Hz), 114.6, 111.9 (q, JC–F = 42.3
Hz). IR (ATR, cmꢀ1): 1528, 1437, 1218, 1182, 1120, 973. LRMS
(EI, 70 eV) m/z (%): 348 (100), 346 (93), 268 (6), 169 (9). HRMS
(ESI) for C12H7BrF3N2S (M+H)+: calcd 346.9460, found
70 346.9456.
10 General procedure for C−H trifluoromethylation of
imidazoheterocycles.
A 15ꢀmL tube with a Teflon cap, equipped with a magnetic
stirring bar, was charged with substrate 1a (0.20 mmol),
CF3SO2Na (0.40 mmol, 2.0 equiv), Cu(OAc)2 (5 mol%), TBHP
15 (0.60 mmol, 3.0 equiv), and [Bmim]BF4/H2O (v:v = 1:1, 2 mL)
was then added sequentially. The tube was then capped and
stirred at 25 °C for 24 h. The product was extracted by Et2O (3 ×
10 mL), the ether phase was collected and dried (Na2SO4),
filtered through a Celite pad, and washed with Et2O. The filtrate
20 was concentrated in vacuo (Et2O was recovered for next
extraction), and the resulting residue was purified by column
chromatography (hexaneꢀEtOAc) to afford product 2a as a light
yellow solid; yield: 39.1 mg (73%).
6ꢀ(4ꢀfluorophenyl)ꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazole
1
(2f). Light yellow solid. H NMR (500 MHz, CDCl3) δ 7.69 (dd,
J = 8.4, 5.3 Hz, 2H), 7.59 (d, J = 4.5 Hz, 1H), 7.13 (t, J = 8.7 Hz,
2H), 7.00 (d, J = 4.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ
75 163.2 (d, JC–F = 247.1 Hz), 151.5, 148.1, 130.7 (d, JC–F = 8.4 Hz),
128.78 (d, JC–F = 3.3 Hz), 121.6 (q, JC–F = 265.4 Hz), 119.0 (q,
JC–F = 2.8 Hz), 115.4 (d, JC–F = 21.6 Hz), 114.4, 111.7 (q, JC–F
=
41.4 Hz). IR (ATR, cmꢀ1): 1487, 1243, 1187, 1169, 819, 765.
LRMS (EI, 70 eV) m/z (%): 286 (100), 265 (7), 133 (6), 121 (7),
80 58 (6). HRMS (ESI) for C12H7F4N2S (M+H)+: calcd 287.0261,
found 287.0276.
4ꢀ(5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazolꢀ6ꢀyl)benzonitrile
(2g). Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J
= 7.5 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H), 7.68 – 7.64 (m, 1H), 7.14
85 – 7.10 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 152.0, 146.7,
6ꢀphenylꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazole (2a). Light
25 yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 7.5 Hz,
2H), 7.58 (d, J = 4.5 Hz, 1H), 7.46 – 7.39 (m, 3H), 6.98 (d, J =
4.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 151.6, 149.3, 132.8,
137.0, 132.2, 129.3, 121.4 (q, JC–F = 265.6 Hz), 119.0 (q, JC–F
=
129.0, 128.9, 128.5, 121.8 (q, J C–F = 265.3 Hz), 119.1 (q, J C – F
=
2.8 Hz), 114.4, 112.0 (q, JC–F = 41.6 Hz). IR (ATR, cmꢀ1): 1576,
30 1433, 1335, 1187, 1132, 785. LRMS (EI, 70 eV) m/z (%): 268
(100), 249 (11), 229 (6), 134 (6), 58 (7). HRMS (ESI) for
C12H8F3N2S (M+H)+: calcd 269.0355, found 269.0350.
2.8 Hz), 118.70, 115.4, 112.7 (q, JC–F = 41.0 Hz), 112.4. IR
(ATR, cmꢀ1): 2226, 2098, 1517, 1480, 1175, 1149, 1082, 986,
971. LRMS (EI, 70 eV) m/z (%): 293 (100), 281 (17), 243 (7), 73
90 (7), 58 (7). HRMS (ESI) for C13H7F3N3S (M+H)+: calcd
294.0307, found 294.0309.
6ꢀ(pꢀtolyl)ꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazole
(2b).
Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 8.0
35 Hz, 2H), 7.56 (d, J = 4.5 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 6.94
(d, J = 4.5 Hz, 1H), 2.40 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
151.4, 149.2, 138.8, 129.8, 129.1, 128.6, 121.7 (q, JC–F = 265.6
Hz), 119.0 (q, JC–F = 2.8 Hz), 114.0, 111.5 (q, JC–F = 40.6 Hz),
21.3. IR (ATR, cmꢀ1): 2921, 1528, 1327, 1169, 1090, 832. LRMS
40 (EI, 70 eV) m/z (%): 282 (100), 207 (14), 133 (8), 116 (7), 115
(8). HRMS (ESI) for C13H10F3N2S (M+H)+: calcd 283.0511,
found 283.0520.
6ꢀ(3,4ꢀdifluorophenyl)ꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀ
b]thiazole (2h). Light yellow solid. 1H NMR (500 MHz, CDCl3)
δ 7.61 – 7.46 (m, 3H), 7.26 – 7.04 (m, 2H). 13C NMR (125 MHz,
95 CDCl3) δ 151.5, 150.8 (dd, JC–F = 242.4, 11.5 Hz), 150.2 (dd, JC–F
= 244.9, 11.7 Hz), 146.8, 129.5, 125.0, 121.4 (q, JC–F = 265.5
Hz), 118.9, 117.8 (d, JC–F = 18.5 Hz), 117.3 (d, JC–F = 17.4 Hz),
114.7, 112.0 (q, JC–F = 43.4 Hz). IR (ATR, cmꢀ1): 3037, 1518,
1398, 1178, 1150, 1090, 969. LRMS (EI, 70 eV) m/z (%): 304
100 (100), 285 (17), 265 (7), 187 (9), 58 (8). HRMS (ESI) for
C12H6F5N2S (M+H)+: calcd 305.0166, found 305.0186.
6ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀ
1
2ꢀmethylꢀ6ꢀphenylꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazole
(2i). Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.69 (d, J
b]thiazole (2c). Light yellow solid. H NMR (500 MHz, CDCl3)
45 δ 7.65 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 4.0 Hz, 1H), 6.98 – 6.96
= 7.4 Hz, 2H), 7.45 – 7.39 (m, 3H), 7.30 (s, 1H), 2.46 (s, 3H). 13
C
(m, 3H), 3.85 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 160.2,
105 NMR (125 MHz, CDCl3) δ 150.9, 147.9, 132.8, 128.8, 128.7,
128.4, 128.4, 121.7 (q, JC–F = 265.5 Hz), 115.5 (q, JC–F = 2.8 Hz),
111.5 (q, JC–F = 40.4 Hz), 14.1. IR (ATR, cmꢀ1): 2931, 1435,
1352, 1183, 1150, 837. LRMS (EI, 70 eV) m/z (%): 282 (100),
263 (7), 261 (7), 103 (5), 72 (3). HRMS (ESI) for C13H10F3N2S
110 (M+H)+: calcd 283.0511, found 283.0508.
151.4, 149.0 (d, JC–F = 2.4 Hz), 130.1, 125.2, 121.8 (q, JC–F
265.3 Hz), 119.0 (q, JC–F = 2.8 Hz), 114.0, 113.9, 111.2 (q, JC–F
=
=
40.5 Hz), 55.4. IR (ATR, cmꢀ1): 3059, 2966, 1428, 1353, 1275,
50 1182, 865. LRMS (EI, 70 eV) m/z (%): 298 (100), 283 (3), 281
(7), 73 (8). HRMS (ESI) for C13H9F3N2NaOS (M+Na)+: calcd
321.0280, found 321.0301.
Ethyl 6ꢀphenylꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazoleꢀ2ꢀ
carboxylate (2j). Light yellow solid. 1H NMR (500 MHz,
CDCl3) δ 8.19 (s, 1H), 7.64 (d, J = 6.5 Hz, 2H), 7.38 – 7.37 (m,
3H), 4.35 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). 13C NMR
115 (125 MHz, CDCl3) δ 159.5, 151.0, 149.2, 130.8, 128.2, 127.7,
6ꢀ(4ꢀchlorophenyl)ꢀ5ꢀ(trifluoromethyl)imidazo[2,1ꢀb]thiazole
1
(2d). Light yellow solid. H NMR (500 MHz, CDCl3) δ 7.66 –
55 7.60 (m, 3H), 7.42 (d, J = 6.5 Hz, 2H), 7.05 – 7.02 (m, 1H). 13
C
NMR (125 MHz, CDCl3) δ 151.6, 147.9, 135.0, 131.1, 130.1,
128.7, 121.6 (q, JC–F = 265.5 Hz), 119.0, 114.6, 111.9 (q, JC–F
=
4
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127.4, 123.3, 122.7, 120.2 (q, JC–F = 265.7 Hz), 110.9 (q, JC–F
=
= 3.5 Hz), 123.5, 121.9 (q, JC–F = 265.3 Hz), 118.1, 114.2, 109.7
40.4 Hz), 61.4, 13.1. IR (ATR, cmꢀ1): 1735, 1600, 1563, 1387, 60 (q, JC–F = 39.4 Hz). IR (ATR, cmꢀ1): 1530, 1398, 1181, 1139, 726,
1162, 1139, 1089, 975. LRMS (EI, 70 eV) m/z (%): 340 (100),
312 (62), 207 (21), 267 (8), 73 (11). HRMS (ESI) for
C15H12F3N2O2S (M+H)+: calcd 341.0566, found 341.0559.
628. LRMS (EI, 70 eV) m/z (%): 340 (100), 342 (97), 261 (30),
207 (21), 73 (11). HRMS (ESI) for C14H9BrF3N2 (M+H)+: calcd
340.9896, found 340.9891.
5
2ꢀphenylꢀ3ꢀ(trifluoromethyl)benzo[d]imidazo[2,1ꢀb]thiazole
2ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀ
1
(2k)14a. Light yellow solid. H NMR (500 MHz, CDCl3) δ 7.79 65 a]pyridine (2q). Light yellow solid. 1H NMR (500 MHz, CDCl3)
(d, J = 8.0 Hz, 1H), 7.59 – 7.54 (m, 3H), 7.37 – 7.31 (m, 4H),
7.25 (t, J = 7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 149.9,
10 149.1, 131.9, 131.1, 129.1, 128.6, 127.9, 127.1, 125.8, 124.6,
δ 8.31 (d, J = 6.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.76 – 7.64
(m, 5H), 7.46 (t, J = 7.3 Hz, 2H), 7.36 (d, J = 6.5 Hz, 2H), 6.97 (t,
J = 7.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 147.8, 146.2,
141.8, 140.6, 131.8, 130.0, 128.8, 127.6, 127.2, 127.0, 126.9,
123.3, 120.5 (q, JC–F = 265.3 Hz), 113.7 (q, JC–F = 4.6 Hz), 111.5
(q, JC–F = 40.5 Hz). IR (ATR, cmꢀ1): 3072, 1551, 1478, 1296, 70 125.4 (q, JC–F = 3.6 Hz), 122.0 (q, JC–F = 265.5 Hz), 118.0, 114.0,
1178, 1157, 1093, 976, 773. LRMS (EI, 70 eV) m/z (%): 318
109.6 (q, JC–F = 39.3 Hz). IR (ATR, cmꢀ1): 1506, 1421, 1368,
1261, 1017, 729. LRMS (EI, 70 eV) m/z (%): 338 (100), 317 (5),
281 (5), 169 (4), 78 (7). HRMS (ESI) for C20H13F3N2Na
(M+Na)+: calcd 361.0923, found 361.0940.
(100), 297 (10), 159 (11), 108 (10), 69 (10).
15 2ꢀphenylꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 3.0
(2l)14a
.
Hz, 1H), 7.61 – 7.60 (m, 3H), 7.35 – 7.22 (m, 4H), 6.82 (t, J = 6.5 75 2ꢀ(naphthalenꢀ2ꢀyl)ꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀ
Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 147.0, 145.1, 131.9,
128.5, 127.9, 127.1, 125.9, 124.5, 121.9 (q, JC–F = 265.2 Hz),
20 117.0, 112.9, 108.5 (q, JC–F = 38.4 Hz). IR (ATR, cmꢀ1): 3059,
1580, 1510, 1405, 1385, 1198, 1116, 1062, 995, 781. LRMS (EI,
70 eV) m/z (%): 262 (100), 241 (15), 212 (10), 192 (5), 78 (13).
a]pyridine (2r). Light yellow solid. 1H NMR (500 MHz, CDCl3)
δ 8.30 (d, J = 7.0 Hz, 1H), 8.21 (s, 1H), 7.93 – 7.81 (m, 4H), 7.75
(d, J = 9.0 Hz, 1H), 7.51 – 7.50 (m, 2H), 7.36 – 7.33 (m, 1H),
6.94 (t, J = 6.8 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 148.0,
80 146.2, 133.5, 133.1, 130.3, 129.3, 128.6, 127.8, 127.7, 127.0,
126.7, 126.3, 125.5 (q, JC–F = 3.5 Hz), 122.0 (q, JC–F = 265.4 Hz),
118.1, 114.0, 109.8 (q, JC–F = 39.1 Hz). IR (ATR, cmꢀ1): 3019,
1526, 1366, 1157, 1075, 971. LRMS (EI, 70 eV) m/z (%): 312
(100), 291 (13), 273 (8), 156 (5), 73 (5). HRMS (ESI) for
2ꢀ(pꢀtolyl)ꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
(2m).
Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 7.2
25 Hz 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 6.5 Hz, 2H), 7.35
(s, 1H), 7.27 (d, J = 7.0 Hz, 2H), 6.94 (d, J = 6.5 Hz, 1H), 2.41 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 148.2, 146.2, 139.0, 130.0, 85 C18H12F3N2 (M+H)+: calcd 313.0947, found 313.0962.
129.5, 129.0, 126.9, 125.5, 122.1 (q, JC–F = 265.5 Hz), 118.0,
113.9, 109.4 (q, JC–F = 40.6 Hz), 21.4. IR (ATR, cmꢀ1): 3045,
30 2973, 1539, 1462, 1327, 1251, 1152, 1073, 983, 754. LRMS (EI,
70 eV) m/z (%): 276 (100), 255 (5), 205 (7), 103 (5), 78 (11).
6ꢀmethylꢀ2ꢀphenylꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
(2s). Light yellow solid. H NMR (500 MHz, CDCl3) δ 8.08 (s,
1
1H), 7.69 (d, J = 6.0 Hz, 2H), 7.62 (d, J = 9.0 Hz, 1H), 7.45 (d, J
= 7.5 Hz, 3H), 7.22 (d, J = 9.0 Hz, 1H), 2.38 (s, 3H). 13C NMR
HRMS (ESI) for C15H12F3N2 (M+H)+: calcd 277.0947, found 90 (125 MHz, CDCl3) δ 147.9, 145.3, 133.2, 130.1, 129.6, 128.9,
277.0960.
128.2, 123.9, 123.2 (q, JC–F = 3.5 Hz), 122.1 (q, JC–F = 265.6 Hz),
117.3, 109.2 (q, JC–F = 32.9 Hz), 18.4. IR (ATR, cmꢀ1): 2931,
1540, 1259, 1165, 1098, 825, 796. LRMS (EI, 70 eV) m/z (%):
276 (100), 237 (4), 226 (8), 128 (4), 92 (10). HRMS (ESI) for
2ꢀ(3ꢀmethoxyphenyl)ꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀ
35 a]pyridine (2n). Light yellow solid. 1H NMR (500 MHz, CDCl3)
δ 8.32 (d, J = 4.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.39 – 7.36
(m, 2H), 7.28 – 7.25 (m, 2H), 7.00 (d, J = 6.0 Hz, 2H), 3.87 (s, 95 C15H12F3N2 (M+H)+: calcd 277.0947, found 277.0964.
3H). 13C NMR (125 MHz, CDCl3) δ 159.4, 147.9, 146.1, 134.2,
129.3, 127.1, 125.6, 122.1, 121.9 (q, JC–F = 265.4 Hz), 118.1,
40 115.1, 114.7, 114.1, 109.7 (q, JC–F = 36.0 Hz), 55.4. IR (ATR,
cmꢀ1): 3021, 2962, 1538, 1458, 1397, 1263, 1082, 767. LRMS
6ꢀfluoroꢀ2ꢀphenylꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
(2t). Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.26 (s,
1H), 7.78 – 7.62 (m, 3H), 7.46 – 7.45 (m, 3H), 7.33 – 7.29 (m,
1H). 13C NMR (125 MHz, CDCl3) δ 153.8 (d, JC–F = 238.4 Hz),
(EI, 70 eV) m/z (%): 292 (100), 273 (10), 241(10), 78 (3). HRMS 100 149.1, 143.8, 132.6, 129.5, 129.2, 128.3, 121.7 (q, JC–F = 265.5
(ESI) for C15H12F3N2O (M+H)+: calcd 293.0896, found 293.0898.
2ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
45 (2o). Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J
= 6.5 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H),
Hz), 119.1 (d, JC–F = 25.2 Hz), 118.6 (d, JC–F = 8.9 Hz), 112.8
(dq, JC–F = 42.5, 3.75 Hz), 111.0 (q, JC–F = 39.4 Hz). IR (ATR,
cmꢀ1): 1510, 1483, 1386, 1265, 1173, 916. LRMS (EI, 70 eV) m/z
(%): 280 (100), 261 (10), 259 (17), 210 (6), 96 (17). HRMS (ESI)
7.44 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 6.5 105 for C14H9F4N2 (M+H)+: calcd 281.0696, found 281.0709.
Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 146.7, 146.0, 135.0,
131.3, 130.8, 128.3, 127.1, 125.4 (q, JC–F = 3.3 Hz), 121.7 (q, JC–F
50 = 265.6 Hz), 117.9, 114.0, 109.5 (q, JC–F = 39.0 Hz). IR (ATR,
cmꢀ1): 1567, 1436, 1332, 1189, 1109, 1116, 752. LRMS (EI, 70
8ꢀchloroꢀ2ꢀphenylꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
(2u). Light green solid. 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J
= 7.0 Hz, 1H), 7.62 (d, J = 6.0 Hz, 2H), 7.42 – 7.37 (m, 4H), 6.85
(t, J = 7.1 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 147.5, 142.6,
eV) m/z (%): 296 (100), 277 (9), 241 (6), 138 (7), 51 (14). HRMS 110 131.4, 128.7, 128.2, 127.2, 124.9, 123.1 (q, JC–F = 3.6 Hz), 123.0,
(ESI) for C14H9ClF3N2 (M+H)+: calcd 297.0401, found 297.0414.
2ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
55 (2p). Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J
= 7.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.60 – 7.57 (m, 4H), 7.40
120.5 (q, JC–F = 265.4 Hz), 112.6, 110.2 (q, JC–F = 39.6 Hz). IR
(ATR, cmꢀ1): 3029, 1550, 1376, 1187, 1117, 1090, 783, 687.
LRMS (EI, 70 eV) m/z (%): 296 (100), 298 (33), 275 (12), 138
(8), 76 (10). HRMS (ESI) for C14H8ClF3N2Na (M+Na)+: calcd
(t, J = 8.0 Hz, 1H), 7.00 (t, J = 6.5 Hz, 1H). 13C NMR (125 MHz, 115 319.0220, found 319.0227.
CDCl3) δ 146.9, 146.2, 131.9, 131.5, 131.2, 127.3, 125.6 (q, JC–F
8ꢀbromoꢀ2ꢀphenylꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
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(2v). Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J
60
Sugimoto and N. Toyooka, Bioorg. Med. Chem. Lett., 2013, 2317,
4907.
A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M.
Rambaldi, L. Varoli, D. Lannigan, J. Smith, D. Scudiero, S.
Kondapaka and R. H. Shoemaker, Eur. J. Med. Chem., 2011, 46,
4311.
Selected references, see: (a) J.ꢀH. Park, M. I. ElꢀGamal, Y. Su. Lee
and Ch.ꢀH. Oh, Eur. J. Med. Chem., 2011, 46, 5769. (b) A. R. Ali,
E. R. ElꢀBendary, M. A. Ghaly and I. A. Shehata, Eur. J. Med.
Chem., 2014, 75, 492.
(a) J. S. Barradas, M. I. Errea, N. B. D'Accorso, C. S. Sepulveda and
E. B. Damonte, Eur. J. Med. Chem., 2010, 46, 259. (b) T. Juspin, M.
Laget, T. Terme, N. Azas and P. Vanelle, Eur. J. Med. Chem., 2010,
45, 840.
= 7.0 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.58 – 7.52 (m, 1H), 7.40 –
7.32 (m, 3H), 6.77 (t, J = 7.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 147.7, 143.3, 131.6, 128.9, 128.5, 128.3, 127.3, 123.9,
120.7 (q, JC–F = 265.3 Hz), 113.1, 111.4, 110.5 (q, JC–F = 39.6
Hz). IR (ATR, cmꢀ1): 1538, 1472, 1335, 1156, 980, 712. LRMS
(EI, 70 eV) m/z (%): 340 (100), 342 (98), 321 (12), 170 (9), 158
(10). HRMS (ESI) for C14H8BrF3N2Na (M+Na)+: calcd 362.9715,
found 362.9738.
3
4
5
5
65
70
10 2ꢀethylꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyridine
(2w).
Brown oil. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 5.5 Hz,
1H), 7.65 (d, J = 9.0 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 6.94 (t, J =
7.5 Hz, 1H), 2.94 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 147.8, 135.9, 129.8, 126.3, 125.2,
15 120.7 (q, JC–F = 265.5 Hz), 117.4, 113.4, 31.1, 13.7. IR (ATR,
cmꢀ1): 2931, 1512, 1255, 1221, 1186, 1122, 726. LRMS (EI, 70
eV) m/z (%): 214 (51), 213 (100), 195 (7), 145 (6), 78 (22).
HRMS (ESI) for C10H10F3N2 (M+H)+: calcd 215.0791, found
215.0795.
6
7
R. Budriesi, P. Ioan, A. Leoni, N. Pedemonte, A. Locatelli, M.
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Biehl, Tetrahedron Lett., 2012, 53, 6008.
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Gevorgyan, Angew. Chem., Int. Ed., 2010, 49, 2743. (b) E.
Kianmehr, M. Ghanbari, M. N. Niri and R. Faramarzi, J. Comb.
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Xu, Y. Mo, H. Liu, J. Han and A. Lei, Chem. Commun., 2012, 48,
11073. (k) J. Zeng, Y. J. Tan, M. L. Leow and X.ꢀW. Liu, Org. Lett.,
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80
20 2ꢀphenylꢀ3ꢀ(trifluoromethyl)imidazo[1,2ꢀa]pyrimidine
(2x).
Light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.74 – 8.64 (m,
2H), 7.78 (d, J = 4.0 Hz, 2H), 7.59 – 7.39 (m, 3H), 7.13 – 7.10
(m, 1H). 13C NMR (125 MHz, CDCl3) δ 152.2, 149.5, 148.6,
133.5, 132.1, 129.6, 129.5, 128.3, 121.5 (q, JC–F = 265.5 Hz),
25 110.2, 108.1 (q, JC–F = 39.6 Hz). IR (ATR, cmꢀ1):1636, 1510,
1483, 1381, 1215, 1172, 1086, 980, 712. LRMS (EI, 70 eV) m/z
(%): 263 (100), 242 (19), 79 (2), 73 (11). HRMS (ESI) for
C13H8F3N3Na (M+Na)+ : calcd 286.0563, found 286.0562.
2ꢀphenylꢀ4ꢀ(trifluoromethyl)ꢀ1Hꢀimidazole (4e).23 White solid.
30 1H NMR (500 MHz, Acetone) δ 12.19 (brs, 1H), 7.88 (d, J = 7.5
Hz, 2H), 7.61 (s, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.5
Hz, 1H). 13C NMR (125 MHz, Acetone) δ 148.7, 130.7, 130.1,
129.7, 127.0, 126.5, 123.4 (q, JC–F = 265.3 Hz), 118.9. IR (ATR,
cmꢀ1): 2932, 2306, 1578, 1556, 1359, 1172, 1148, 975. LRMS
35 (EI, 70 eV) m/z (%): 212 (100), 192 (18), 165 (49), 116 (36), 77
(23).
85
8
9
90
95
100
105
110
115
120
5ꢀphenylꢀ4ꢀ(trifluoromethyl)ꢀ1Hꢀimidazole (4f).23 Light yellow
1
solid. H NMR (500 MHz, DMSO) δ 13.22 (brs, 1H), 7.97 (s,
1H), 7.61 – 7.41 (m, 5H). 13C NMR (125 MHz, DMSO) δ 136.5,
40 131.4, 128.8, 128.6, 128.4, 122.6 (q, JC–F = 265.5 Hz). IR (ATR,
cmꢀ1): 2928, 1567, 1263, 1178, 1152, 798. LRMS (EI, 70 eV) m/z
(%): 212 (100), 192 (18), 165 (23), 109 (21), 89 (29).
Notes and references
a College of Science, South China Agricultural University, Guangzhou
45 510642, China. Tel:+86577-8668-9615; E-mail: try00312@163.com
b College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou 325035, China. Tel:+86577-8668-9615; E-mail:
try@wzu.edu.cn
1
† Electronic Supplementary Information (ESI) available: [coppies of H
50 and 13C spectra for all compounds.]. See DOI: 10.1039/b000000x/
1
2
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