Efficient Synthesis of Fluoroalkylated Imidazoles via a Metal-Free Cascade Michael Addition/Azidation/Cycloamination Process

Article abstract of DOI:10.1002/ejoc.201801310

In the presence of KI and (diacetoxyiodo)benzene (PIDA), primary amines bearing an α-hydrogen can be efficiently converted to fluoroalkylated imidazoles by reacting with fluoroalkylated alkynes and sodium azide via a cascade Michael addition/azidation/cycloamination process. KI plays a crucial role in this reaction by generating iodine(I) species to promote the cyclization. Substrate scope was explored, and the application of this protocol was demonstrated. Additionally, a plausible reaction mechanism was proposed.

Full text of DOI:10.1002/ejoc.201801310

A Journal of
Accepted Article
Title: Efficient Synthesis of Fluoroalkylated Imidazoles via a Metal-Free
Cascade Michael Additon / Azidation / Cycloamination Process
Authors: Jun Wu, Hui Zhang, Xiao Ding, Xuefei Tan, Hong C Shen, Jie
Chen, Weimin He, Hongmei Deng, Liping Song, and Weiguo
Cao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801310
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10.1002/ejoc.201801310
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Efficient Synthesis of Fluoroalkylated Imidazoles via a Metal-Free
Cascade Michael Additon / Azidation / Cycloamination Process
Jun Wu,‡[a,b] Hui Zhang,‡[c] Xiao Ding,[b] Xuefei Tan,[b] Hong C. Shen,[b] Jie Chen,[c] Weimin He,[c]
Hongmei Deng,[c] Liping Song,*[a,c] and Weiguo Cao*[c,d,e]
Dedication ((optional))
Abstract: In the presence of KI and (diacetoxyiodo)benzene (PIDA),
primary amines bearing an α-hydrogen can be efficiently converted
to fluoroalkylated imidazoles by reacting with fluoroalkylated alkynes
and sodium azide via a cascade Michael addition / azidation /
cycloamination process. KI plays a crucial role in this reaction by
generating iodine (I) species to promote the cyclization. Substrate
scope was explored. The plausible reaction mechanism was
proposed and the application of this protocol was demonstrated.
Yu et al have developed a copper (II)-catalyzed C-H
amination using azides and oxidative cycloamination to
synthesize imidazoles as shown in Scheme 1a.[10] However,
such transition-metal catalyzed reactions may pose difficulties
for their recovery from the effluent or leaching, contamination of
traces of the metal in pharmaceutical products.[12] Therefore, the
development of alternative methods for the metal-free synthesis
of imidazoles is highly desirable.
On considering the introduction of fluorine or fluoroalkylated
groups into an bioactive compound to be a common strategy in
medicinal chemistry,[13] and on the basis of our recent KI/PIDA-
mediated metal-free synthesis of fluoroalkylated quinoxalines
(Scheme 1b),[9] herein, we report an efficient one-pot cascade
synthesis of fluoroalkylated imidazoles using fluoroalkylated
alkynes and primary amines with α-hydrogen as starting
materials without metal catalysts (Scheme 1c). The application
involving API (active pharmaceutical ingredient) synthesis was
also demonstrated.
Introduction
Construction of C-N bonds has attracted wide attention in the
field of organic chemistry.[1-4] Compared to pre-functionalized
cross-coupling such as Buchwald-Hartwig amination[2] and
Ullman-type reaction,[3] C-H amination attracts significant
attention to build N-heterocycles.[4]
Amine derivatives are a major source of building blocks in
medicinal chemistry as they serve as basic scaffolds for the
preparation of biologically active molecules. It is well-known that
amines can readily react with electron-deficient alkynes such as
fluoroalkylated alkynes via Michael addition.
Previous literatures indicate that azides could be employed
to construct heterocycles such as phenanthridines,[5]
quinoxalines[6-9] and imidazoles,[10],[11] etc.
From the perspective of synthetic efficiency, an efficient and
facile cascade of Michael addition / azidation / cycloamination
involving three C-N bonds formation would be highly valuable for
the preparation of N-containing heterocyclic compounds.
[a]
Mr. J. Wu, Prof. Dr. L. Song
School of Materials Science and Engineering, Shanghai University,
Shanghai 200444, P. R. China
E-mail: lpsong@shu.edu.cn; http://www.shu.edu.cn/
Dr. X. Ding, Dr. X. Tan, Dr. H. C. Shen
Roche Innovation Center Shanghai, Roche R&D Center (China) Ltd.
Shanghai 201203, P. R. China
Prof. Dr. H. Zhang, Mr. J. Chen, Mr. W. He, Dr. H. Deng, Prof. Dr.
W. Cao
[b]
[c]
Department of Chemistry, Shanghai University, Shanghai 200444,
P. R. China.
Scheme 1
E-mail: wgcao@staff.shu.edu.cn; http://www.shu.edu.cn/
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, P. R. China
[d]
[e]
Results and Discussion
Firstly, substrate 3a[14] was used as starting material to
validate the feasibility of the cyclization under the optimized
reaction conditions in our previous work,[9] and it was found 92%
yield of 5a (Table 1, entry 1). When TMSN3 was replaced by
cheaper and more stable NaN3, this cyclization also proceeded
‡
Contribute to this work equally
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801310
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smoothly to give 86% yield of 5a (Table 1, entry 2). To further
improve the yield, the quantities of PIDA, NaN3 and KI were
examined (Table 1, entries 2-11). The best result was achieved
when 2.0 equiv of PIDA, 2.0 equiv of NaN3 with 2.0 equiv KI
were applied (Table 1, entry 10). KI was crucial to the reaction.
In the absence of KI, the yield dropped dramatically (Table 1,
entry 10 vs 11). In order to simplify the synthetic procedure, a
one-pot protocol was developed, using 1a and 2a directly as
starting materials (Table 1, entry 12), affording 5a in 88%
isolated yield.
propan-1-amine 1p, propan-2-amine 1u, butan-1-amine 1s or
cyclohexanamine 1v were applied to the reaction, moderate
yields were obtained (5p 44%, 5s 54%, 6u 41%, and 6v 46%).
Heteroaryl substrates such as pyridin-3-ylmethanamine 1q and
(1-methyl-1H-imidazol-2-yl)methanamine 1r both worked well,
providing 5q and 5r in 73% and 86% yield, respectively.
Table 2. One-pot synthesis of fluoroalkylated imidazoles[a],[b]
Table 1. Optimization of reaction conditions for the cyclization of
trifluoromethylated imidazole[a]
Entry
1[9]
[N]
[eq.]
Solvent
DMSO
Oxidant
[eq.]
Additive
[eq.]
Yield[b]
[%]
PIDA (3.0)
TMSN3
(1.5)
KI (3.0)
92
2
PIDA (3.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (1.0)
PIDA (2.0)
PIDA (2.0)
PIDA (2.0)
PIDA (2.0)
PIDA (2.0)
NaN3 (1.5)
NaN3 (1.0)
NaN3 (1.0)
NaN3 (2.0)
NaN3 (2.0)
NaN3 (1.0)
NaN3 (2.0)
NaN3 (2.0)
NaN3 (2.0)
NaN3 (2.0)
KI (3.0)
KI (1.0)
KI (2.0)
KI (1.0)
KI (2.0)
KI (1.0)
KI (1.0)
KI (2.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
86
3
47
5
49
6
45
7
47
8
75
9
85
10
11
12
94, 90[c]
15
KI (2.0)
88[c] [d]
[a] Reactions conditions: at rt, alkyne 2 (0.4 mmol) was added dropwise to the
soln. of amine 1 (0.4 mmol) in DMSO (4 mL), 10 min; NaN3 (0.8 mmol), KI
(0.8 mmol) was added successively, and then PIDA (0.8 mmol) was added
portion wise, 2 h. [b] Isolated yield.
[a] Reaction conditions: 3a (0.4 mmol), additive and [N] source in DMSO (4
mL), PIDA portion-wise at rt, 2 h. [b] The yields were determined by 19F NMR
with PhCF3 as internal standard. [c] Isolated yield. [d] One-pot protocol: at rt,
2a (methyl 4,4,4-trifluorobut-2-ynoate, 0.4 mmol) was added dropwise to the
soln. of 1a (benzylamine, 0.4 mmol) in DMSO (4 mL), 10 min; then NaN3 (0.8
mmol), KI (0.8 mmol) was added successively, and PIDA (0.8 mmol) was
added portion wise, 2h.
Radical scavengers such as tetramethylpiperidine 1-oxyl
(TEMPO) had no significant impact on the reaction of 3a to 5a
,
supporting an ionic pathway of the reaction. When 1.0 eq. PIDA,
2.0 eq. NaN3 and 2.0 eq. KI were applied to the reaction, trace
bis-imine compound 4a was observed on the HRMS, with the
isolation of 46% 5a and 37% recovery of 3a (Scheme 2).
With the established one-pot annulation protocol in hand,
the substrate scope of amines 1 and alkynes 2 was explored. All
of the fluoroalkylated alkynes (2a to 2e) can afford the desired
products 5a-5e in excellent yields. A variety of electron-donating
or withdrawing group-substituted benzyl amines (1a, 1f-1o) all
proceeded smoothly to afford satisfying yields of the desired
products. In addition, when other aliphatic amines such as
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10.1002/ejoc.201801310
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bond in intermediate II via Michael addition resulted in the formation
of azide intermediate III. Releasing N2 of III led to intermediate 4.
Subsequently, iodination of the nitrogen atom linked to C3 in 4 in the
presence of AcOI produced ammonium salt intermediate IV. The
ensuing deprotonation of IV at the ammonium’s α-position led to V,
which underwent a cyclization to generate a neutral intermediate VI.
Finally, the elimination of HI in VI led to the desired product 6. If the
R3 was hydrogen, the aromatization led to product 5.
For reactants with two substituents at the amino’s α-position,
the aryl group stabilized the anion (V) more easily than alkyl group
due to conjugation effect, leading to a higher yield of the former over
the latter (Table 2, for example, 6t 86% vs 6u 41%).
Scheme 2. Reaction to probe the mechanism
Based on the above results and our previous work,[9] we
proposed a plausible mechanism as shown in Scheme 3. Initially,
Michael addition of 1 to 2 generated 3. AcOI, generated from the
reaction of PIDA and KI,[15] reacted with 3, affording intermediate I
(pathway a) or II (pathway b). Subsequently, either cleavage of the
C-I bond in intermediate I via nucleophilic substitution or the N-I
Scheme 3. Proposed mechanism for the formation of 5/6 from 3
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Scheme 4. Gram-scale synthesis of methyl 4-(1,1,2,2,2-pentafluoroethyl)-2-propyl-1H-imidazole-5-carboxylate 5s
(152 mg, 1.0 mmol) dropwise at rt. The mixture was stirred at rt for 10
min. And then, solvent was evaporated in vacuo and the residue was
purified by silica gel flash column chromatography eluted with PE/EA =
20:1 (v/v) to give methyl 3-(benzylamino)-4,4,4-trifluorobut-2-enoate as a
colorless oil (235 mg, 96 %).
DuP-532 (angiotensin II receptor antagonist) could be
synthesized from the intermediate methyl 4-(1,1,2,2,2-
pentafluoroethyl)-2-propyl-1H-imidazole-5-carboxylate
5s
(Scheme 4), which was prepared with only 32% total yield in five
steps by Arnett et al.[16] When our one-pot protocol was applied,
5s could be synthesized directly in one step from 1-butylamine
and methyl 4,4,5,5,5-pentafluoropent-2-ynoate in relative good
yield (52%) in gram-scale. The pleasing efficiency demonstrated
the practicality and promising applicability of this cascade
protocol.
General procedure for the synthesis of 5a to 5s and 6t to 6v: To a
solution of 1 (0.4 mmol) in DMSO (4 mL) was added 2 (0.4 mmol)
dropwise at rt. The mixture was stirred at rt for 10 min. Then, NaN3 (0.8
mmol) and KI (0.8 mmol) were added to the mixture successively. After
that, PIDA (0.8 mmol) was added portionwise. The mixture was stirred at
rt for 2 h. Then, the mixture was poured into ice-water, quenched with
saturated Na2SO3 aq. and neutralized with saturated NaHCO3 aq. The
mixture was extracted with ethyl acetate (20 mL x 3). The combined
organic layer was dried over anhydrous Na2SO4 and concentrated in
vacuo. The residue was purified by silica gel flash column
chromatography to give desired products.
Conclusions
A novel KI/PIDA-mediated cascade Michael addition /
azidation / cycloamination process for the preparation of
fluoroalkylated imidazoles has been developed. The efficient
reaction was proven to be an ionic mechanism. Compared to the
previous report,[10] no metal catalyst is required in this reaction.
This method is suitable for a broad substrate scope of primary
amines with α H and fluoroalkylated alkynes. Importantly, the
high efficiency of gram-scale preparation paved the way to the
potential of commercial production. Further investigations to
exploit the use of KI/PIDA in organic synthesis are under way in
our laboratory.
Gram-scale synthesis of methyl 4-(1,1,2,2,2-pentafluoroethyl)-2-
propyl-1H-imidazole-5-carboxylate (5s)[16]
:
To a solution of 1-
butylamine (1s) (1.10 g, 15 mmol) in DMSO (150 mL) was added methyl
4,4,5,5,5-pentafluoropent-2-ynoate (2b) dropwise (3.03 g, 15 mmol) at rt.
The mixture was stirred at rt for 10 min. To the above solution was added
NaN3 (30 mmol), KI (30 mmol). And then, PIDA (30 mmol) was added
portionwise at rt. The mixture was stirred at rt for 2 h. Then, the mixture
was poured into ice water, quenched with saturated Na2SO3 aq. and
neutralized with saturated NaHCO3 aq. The mixture was extracted with
ethyl acetate (200 mL x 3). The combined organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was purified
by silica gel flash column chromatography (PE/EA = 5:1) to give desired
product (2.25 g, 52%).
Methyl 3-(benzylamino)-4,4,4-trifluorobut-2-enoate (3a)[14]
:
1H NMR
Experimental Section
(400 MHz, CDCl3) δ 8.43 (brs, 1H), 7.38-7.34 (m, 2H), 7.32-7.25 (m, 3H),
5.17 (s, 1H), 4.48 (d, J=6.24 Hz, 2H), 3.68 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ -66.59 (s, CF3); 13C NMR (101 MHz, CDCl3) δ 170.2, 148.3 (q,
J = 31.3 Hz, CF3), 137.7, 128.9, 127.9, 127.3, 120.3 (q, J = 270.5 Hz),
84.8 (q, J = 5.8 Hz), 51.0, 48.1 (q, J = 2.9 Hz); IR (MIR-ATR, 4000–600
cm-1): υmax = 2953, 1672, 1629, 1286, 1180, 1128, 1026, 795, 696; HRMS
(ESI) calcd. for C12H13F3NO2 [(M+H)]+: 260.0893, found: 260.0893.
General information: Reagents and solvents were purchased from
commercially sources and used without further purification.
Fluoroalkynes were prepared according to the known literature.[17]
Melting points were recorded on a X-5 instrument and uncorrected. 1H,
19F and 13C NMR spectra were recorded on a Bruker 400 MHz
spectrometer. All chemical shifts are reported in parts per million
downfield (positive) of the standard: CFCl3 for 19F, TMS for 1H and 13C
NMR spectra. Chemical shifts (δ) are reported in ppm, and coupling
constants (J) are in hertz (Hz). The following abbreviations were used to
explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, br = broad. IR spectra were obtained on a NICOLET iS10
FTIR spectrometer. High-resolution mass spectrometry (HRMS) was
conducted on an Agilent Technologies Q-TOF 6530 unit. All the reactions
in this paper were monitored by UPLC-MS on a UPLC-MS DW3100 unit.
CombiFlash Rf+ was used to purify compounds.
Methyl
2-phenyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate
(5a)[18] : 95 mg (88% yield), (eluent: PE/EA = 5:1), white solid; 1H NMR
(400 MHz, DMSO-d6) δ 14.10 (brs, 1H), 8.22-8.08 (m, 2H), 7.58-7.43 (m,
3H), 3.93 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ -59.67 (s, CF3); 13C
NMR (101 MHz, DMSO-d6) δ 158.7, 148.3, 134.8 (q, J = 38.8 Hz), 130.5,
129.3, 128.8, 127.0, 122.5, 121.6 (q, J = 269.0 Hz), 52.9; IR (MIR-ATR,
4000–600 cm-1): υmax = 3263, 1693, 1446, 1271, 1124, 1045, 960, 781,
690; HRMS (ESI) calcd. for C12H10F3N2O2 [(M+H)]+: 271.0689, found:
271.0707.
Methyl
4-(pentafluoroethyl)-2-phenyl-1H-imidazole-5-carboxylate
(5b): 113 mg (88% yield), (eluent: PE/EA = 5:1), white solid; mp 171-
173C; 1H NMR (400 MHz, DMSO-d6) δ 14.14 (brs, 1H), 8.21-8.09 (m,
2H), 7.58-7.46 (m, 3H), 3.93 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ -
82.25 (s, CF3), -108.57 (s, CF2); 13C NMR (101 MHz, DMSO-d6) δ 158.6,
Procedure for the synthesis of methyl 3-(benzylamino)-4,4,4-
trifluoro-but-2-enoate (3a): To a solution of benzyl amine (93 mg, 1.0
mmol) in MeOH (10 mL) was added methyl 4,4,4-trifluorobut-2-ynoate
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148.7, 133.1 (t, J = 29.3 Hz), 130.6, 129.3, 128.7, 127.0, 124.3, 119.3 (qt,
J = 286.6Hz, 37.8 Hz), 111.3 (tq, J = 251.5 Hz, 38.1 Hz), 52.9; IR (MIR-
ATR, 4000–600 cm-1): υmax = 3279, 1693, 1446, 1274, 1193, 1086, 977,
931, 690; HRMS (ESI) calcd. for C13H10F5N2O2 [(M+H)]+: 321.0657,
found: 321.0664.
8.10 (d, J = 8.80 Hz, 2H), 7.09-7.01 (d, J = 8.80 Hz, 2H), 3.90 (s, 3H),
3.83 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ -59.62 (s, CF3); 13C NMR
(101 MHz, DMSO-d6) δ 161.2, 158.8, 148.5, 134.7(q, J = 38.1 Hz), 128.7,
121.9, 121.5 (q, J = 268.5 Hz), 121.3, 114.7, 55.8, 52.8; IR (MIR-ATR,
4000–600 cm-1): υmax = 3284, 1687, 1452, 1259, 1170, 1113, 1045, 837,
733, 685; HRMS (ESI) calcd. for C13H12F3N2O3 [(M+H)]+: 301.0794,
found: 301.0794.
Methyl 4-(heptafluoropropyl)-2-phenyl-1H-imidazole-5-carboxylate
(5c): 124 mg (84% yield), (eluent: PE/EA = 5:1), white solid; mp 156-
158C; 1H NMR (400 MHz, DMSO-d6) δ 14.13 (brs, 1H), 8.23-8.10 (m,
2H), 7.58-7.43 (m, 3H), 3.92 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ -
79.61 (t, J = 9.54 Hz, CF3), -106.97 (q, J = 8.67 Hz, CF2), -125.27 (s,
CF2); 13C NMR (101 MHz, DMSO-d6) δ 158.6, 148.9, 132.7 (t, J = 28.9
Hz), 130.6, 129.3, 128.7, 127.1, 124.5, 118.2 (qt, J = 287.7 Hz, 34.0 Hz),
111.7 (m), 109.2 (m), 52.8; IR (MIR-ATR, 4000–600 cm-1): υmax = 3288,
1693, 1446, 1269, 1184, 1105, 1059, 877, 694; HRMS (ESI) calcd. for
C14H10F7N2O2 [(M+H)]+: 371.0625, found: 371.0622.
Methyl
2-(3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-
carboxylate (5j): 102 mg (84% yield), (eluent: PE/EA = 5:1), white solid;
mp 173-175C; 1H NMR (400 MHz, DMSO-d6) δ 14.23 (brs, 1H), 8.25 (s,
1H), 8.13-8.05 (m, 1H), 7.60-7.52 (m, 2H), 3.92 (s, 3H); 19F NMR (376
MHz, DMSO-d6) δ -59.71 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ
158.6, 146.8, 134.8(m), 134.2, 131.3, 130.7, 130.3, 126.6, 125.6, 122.9,
121.1(q, J = 268.5 Hz), 53.0; IR (MIR-ATR, 4000–600 cm-1): υmax = 3279,
1697, 1446, 1273, 1176, 1132, 1047, 974, 775, 700; HRMS (ESI) calcd.
for C12H9ClF3N2O2 [(M+H)]+: 305.0299, found: 305.0301.
Methyl 4-(difluoromethyl)-2-phenyl-1H-imidazole-5-carboxylate (5d):
1
Methyl
2-(m-tolyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate
77 mg (76% yield), (eluent: PE/EA = 5:1), white solid; mp 199-200C; H
(5k): 99 mg (87% yield), (eluent: PE/EA = 5:1), white solid; mp 143-
145C; 1H NMR (400 MHz, DMSO-d6) δ 14.03 (brs, 1H), 8.00 (s, 1H),
7.94 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H),
3.92 (s, 3H), 2.39 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ -59.64 (s,
CF3); 13C NMR (101 MHz, DMSO-d6) δ 158.7, 148.4, 138.6, 134.8 (m),
131.2, 129.2, 128.7, 127.5, 124.1, 122.4, 121.6 (q, J = 268.5 Hz), 52.9,
21.4; IR (MIR-ATR, 4000–600 cm-1): υmax = 3284, 1693, 1441, 1281,
1209, 1132, 1049, 955, 795, 702; HRMS (ESI) calcd. for C13H12F3N2O2
[(M+H)]+: 285.0845, found: 285.0836.
NMR (400 MHz, Acetone-d6) δ 8.27-8.02 (m, 2H), 7.56-7.46 (m, 3H),
7.30 (t, J = 52.0 Hz, 1H), 3.92 (s, 3H); 19F NMR (376 MHz, Acetone-d6) δ
-115.52 (d, J = 54.2 Hz, CF2); 13C NMR (101 MHz, Acetone-d6) δ 161.1,
150.8, 142.3 (m), 131.7, 130.9, 130.6, 128.2, 124.1, 111.1 (t, J = 231.8
Hz), 53.3; IR (MIR-ATR, 4000–600 cm-1): υmax = 3290, 1697, 1446, 1271,
1122, 1060, 1014, 779, 690; HRMS (ESI) calcd. for C12H11F2N2O2
[(M+H)]+: 253.0783, found: 253.0778.
Ethyl 2-phenyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (5e) [10]
102 mg (90% yield), ( eluent: PE/EA = 5:1) , white solid; 1H NMR (400
MHz, DMSO-d6) δ 14.07 (brs, 1H), 8.23-8.09 (m, 2H), 7.68-7.36 (m, 3H),
4.39 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 19F NMR (376 MHz,
DMSO-d6) δ -59.51 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ 158.4,
148.3, 134.6 (q, J = 38.8 Hz), 130.5, 129.3, 128.8, 127.0, 122.8, 122.43
(q, J = 268.5 Hz), 61.8, 14.4; IR (MIR-ATR, 4000–600 cm-1): υmax = 3301,
1680, 1427, 1254, 1173, 1105, 1043, 779, 690; HRMS (ESI) calcd. for
C13H12F3N2O2 [(M+H)]+: 285.0845, found: 285.0847.
:
Methyl
2-(2-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-
carboxylate (5l): 85 mg (74% yield), (eluent: PE/EA = 5:1), white solid;
mp 124-125C; 1H NMR (400 MHz, DMSO-d6) δ 14.05 (brs, 1H), 7.85 (dt,
J = 7.6, 1.7 Hz, 1H), 7.63-7.53 (m, 1H), 7.46-7.32 (m, 2H), 3.91 (s, 3H);
19F NMR (376 MHz, DMSO-d6) δ -59.55 (s, CF3), -114.08 (td, J = 11.3,
6.5 Hz, CF); 19F NMR (376 MHz, DMSO-d6) δ -59.55 (s, CF3), -114.08 (td,
J = 11.27, 6.50 Hz, CF); 13C NMR (101 MHz, DMSO-d6) δ 159.8 (q, J =
251.6 Hz), 158.6, 143.8, 134.6 (m), 132.9 (d, J = 8.1 Hz), 131.2 (d, J =
2.2 Hz), 125.2 (d, J = 3.6 Hz), 122.7, 121.6 (q, J = 268.5 Hz), 117.4 (d, J=
13.2 Hz), 116.8 (d, J = 21.2 Hz), 52.9; IR (MIR-ATR, 4000–600 cm-1): υmax
= 3280, 1718, 1470, 1242, 1115, 1043, 951, 768, 741, 688; HRMS (ESI)
calcd. for C12H9F4N2O2 [(M+H)]+: 289.0595, found: 289.0604.
Methyl
2-(4-fluorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-
carboxylate (5f): 98 mg (85% yield), (eluent: PE/EA = 5:1), white solid;
mp 224-225C; 1H NMR (400 MHz, DMSO-d6) δ 14.10 (brs, 1H), 8.32-
8.11 (m, 2H), 7.46-7.25 (m, 2H), 3.93 (s, 3H); 19F NMR (376 MHz,
DMSO-d6) δ -59.70 (s, CF3), -110.64 (m, CF); 13C NMR (101 MHz,
DMSO-d6) δ 163.6 (d, J = 247.9 Hz), 158.7, 147.5, 134.7 (q, J = 38.1 Hz),
129.4 (d, J = 8.8 Hz), 125.4 (d, J = 3.6 Hz), 122.5, 121.6 (q, J = 268.5
Methyl
2-(2-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole-5-
carboxylate (5m): 113 mg (94% yield), (eluent: PE/EA = 4:1), white
solid; mp 174-176C; 1H NMR (400 MHz, DMSO-d6) δ 13.06 (brs, 1H),
7.79 (dd, J = 7.7, 1.7 Hz, 1H), 7.54-7.40 (m, 1H), 7.21 (d, J = 8.1 Hz, 1H),
7.08 (dt, J = 7.7, 1.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H); 19F NMR (376
MHz, DMSO-d6) δ -59.51 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ
158.6, 157.3, 146.0, 134.2 (m), 133.5, 132.2, 130.5, 121.1, 121.7 (q, J =
Hz, ),116.3 (d, J = 22.0 Hz), 52.9; IR (MIR-ATR, 4000–600 cm-1): υmax
=
3280, 1693, 1448, 1277, 1149, 1047, 958, 847, 733; HRMS (ESI) calcd.
for C12H9F4N2O2 [(M+H)]+: 289.0595, found: 289.0597.
Methyl
2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole-5-
267.0 Hz), 117.6, 112.3, 56.3, 52.9; IR (MIR-ATR, 4000–600 cm-1): υmax
=
carboxylate (5g): 114 mg (82% yield), (eluent: PE/EA = 5:1), white solid;
mp 225-226C; 1H NMR (400 MHz, DMSO-d6) δ 14.19 (brs, 1H), 8.09 (d,
3409, 1728, 1479, 1288, 1120, 1051, 949, 748, 677; HRMS (ESI) calcd.
for C13H12F3N2O3 [(M+H)]+: 301.0795, found: 301.0798.
J=8.80 Hz, 2H), 7.72 (d, J=8.80 Hz, 2H), 3.92 (s, 3H); 19F NMR (376 MHz,
DMSO-d6) δ -59.71 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ 158.6,
147.3, 134.8 (q, J = 37.4 Hz), 132.3, 129.0, 127.7, 124.1, 122.8, 121.5 (q,
J = 268.9 Hz), 52.9; IR (MIR-ATR, 4000–600 cm-1): υmax = 3290, 1682,
1448, 1254, 1119, 1045, 831, 719, 682; HRMS (ESI) calcd. for
C12H9BrF3N2O2 [(M+H)]+: 348.9794, found: 348.9810.
Methyl 2-(benzo[d][1,3]dioxol-5-yl)-4-(trifluoromethyl)-1H-imidazole-
5-carboxylate (5n): 103 mg (82% yield), (eluent: PE/EA = 5:1), white
solid; mp 252-253C; 1H NMR (400 MHz, DMSO-d6) δ 13.86 (brs, 1H),
7.74-7.65 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.12 (s, 2H), 3.91 (s, 3H); 19F
NMR (376 MHz, DMSO-d6) δ -59.69 (s, CF3); 13C NMR (101 MHz,
DMSO-d6) δ 158.7, 149.3, 148.2, 148.2, 134.7 (q, J = 38.4 Hz), 122.7,
122.0, 121.8, 121.6 (q, J = 268.5 Hz), 109.1, 107.0, 102.1, 52.8; IR
(MIR-ATR, 4000–600 cm-1): υmax = 3304, 1693, 1460, 1394, 1232, 1105,
1036, 931, 818, 696; HRMS (ESI) calcd. for C13H10F3N2O4 [(M+H)]+:
315.0587, found: 315.0585.
Methyl
2-(4-isopropylphenyl)-4-(trifluoromethyl)-1H-imidazole-5-
carboxylate (5h): 112 mg (90% yield), (eluent: PE/EA = 5:1), white solid;
mp 171-172C; 1H NMR (400 MHz, DMSO-d6) δ 14.00 (brs, 1H), 8.07 (d,
J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 3.91 (s, 3H), 2.99-2.90 (m, 1H),
1.23 (d, J = 6.9 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ -59.61 (s, CF3);
13C NMR (101 MHz, DMSO-d6) δ 158.7, 151.1, 148.5, 134.8 (m), 127.3,
127.1, 126.4, 122.2, 121.7 (q, J = 269.2 Hz), 52.9, 33.8, 24.1; IR (MIR-
ATR, 4000–600 cm-1): υmax = 3271, 1693, 1450, 1259, 1124, 1047, 839,
746, 692; HRMS (ESI) calcd. for C15H16F3N2O2 [(M+H)]+: 313.1158,
found: 313.1176.
Methyl
2-(3,5-dichlorophenyl)-4-(trifluoromethyl)-1H-imidazole-5-
carboxylate (5o): 95 mg (70% yield), (eluent: PE/EA = 5 : 1), white solid;
mp 181-183C; 1H NMR (400 MHz, DMSO-d6) δ 14.31 (brs, 1H), 8.16 (d,
J = 1.8 Hz, 2H), 7.70 (t, J = 1.9 Hz, 1H), 3.93 (s, 3H); 19F NMR (376 MHz,
DMSO-d6) δ -59.83 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ 158.5,
145.3, 135.2, 134.7(q, J = 35.9 Hz), 131.8, 129.7, 125.3, 123.3, 121.4 (q,
J = 268.5 Hz), 53.0; IR (MIR-ATR, 4000–600 cm-1): υmax = 3269, 1693,
1524, 1456, 1271, 1130, 1049, 862, 730, 703; HRMS (ESI) calcd. for
Methyl
2-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole-5-
carboxylate (5i): 104 mg (87% yield), (eluent: PE/EA = 4:1), light yellow
solid; mp 213-214C; 1H NMR (400 MHz, DMSO-d6) δ 13.87 (brs, 1H),
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10.1002/ejoc.201801310
European Journal of Organic Chemistry
FULL PAPER
C12H8Cl2F3N2O2 [(M+H)]+: 338.9909, found: 338.9915.
Acknowledgements ((optional))
Methyl 2-ethyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate (5p):
39 mg (44% yield), (eluent: PE/EA = 3:1), white solid; mp 120-121C; H
1
This work was supported by the National Natural Science Foun-
dation of China (Grant Nos. 21672138, 21542005, 21272152).
NMR (400 MHz, DMSO-d6) δ 13.46 (brs, 1H), 3.85 (s, 3H), 2.68 (q, J =
7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ -
59.37 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ 158.7, 152.8, 133.6 (m),
121.7 (q, J = 268.5 Hz), 120.7, 52.6, 21.4, 12.7; IR (MIR-ATR, 4000–600
cm-1): υmax = 2960, 1740, 1537, 1437, 1286, 1126, 1043, 949, 781, 621;
HRMS (ESI) calcd. for C8H10F3N2O2 [(M+H)]+: 223.0689, found: 223.0692.
Keywords: C-H amination • azidation • potassium iodide •
imidazole • fluoroalkylated alkyne
[1]
(a) J. Jiao, K. Murakami, K. Itami, ACS Catal. 2016, 6, 610-633; (b) M.-
L. Louillat, F. W. Patureau, Chem. Soc. Rev. 2014, 43, 901-910; (c) J. L.
Jeffrey, R. Sarpong, Chem. Sci. 2013, 4, 4092-4106; (d) E. M. Beccalli,
G. Broggini, M. Martinelli, S. Sottocornola, Chem. Soc. Rev. 2007, 107,
5318-5365.
Methyl 2-(3-pyridyl)-4-(trifluoromethyl)-1H-imidazole-5-carboxylate
(5q): 79 mg (73% yield), (eluent: DCM/MeOH = 12:1), yellow solid; mp
211-213C; 1H NMR (400 MHz, DMSO-d6) δ 14.35 (brs, 1H), 9.29 (d, J =
1.6 Hz, 1H), 8.68 (dd, J = 4.7, 1.3 Hz, 1H), 8.47 (td, J = 1.9, 8.0 Hz, 1H),
7.55 (dd, J = 4.9, 8.0 Hz, 1H), 3.94 (s, 3H); 19F NMR (376 MHz, DMSO-
d6) δ -59.64 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ 158.7, 151.1,
148.0, 146.0, 134.9, 134.4 (m), 125.0, 124.2, 123.3, 121.5 (q, J = 268.5
Hz), 52.9; IR (MIR-ATR, 4000–600 cm-1): υmax = 2956, 1732, 1537, 1450,
1304, 1126, 1043, 954,704; HRMS (ESI) calcd. for C11H9F3N3O2
[(M+H)]+: 272.0641, found: 272.0641.
[2]
(a) M. M. Heravi, Z. Kheilkordi, V. Zadsirjan, M. Heydari, M. Malmir, J.
Organomet. Chem. 2018, 861, 17-104; (b) P. R. Castillo, S. L.
Buchwald, Chem. Soc. Rev. 2016, 116, 12564-12649; (c) J. F. Hartwig,
Nature 2008, 455, 314−322; (d) D. S. Surry, S. L. Buchwald, Angew.
Chem. Int. Ed. 2008, 47, 6338−6361; Angew. Chem. 2008, 120,
6438−6461.
Methyl
3'-methyl-4-(trifluoromethyl)-1H,3'H-[2,4'-biimidazole]-5-
[3]
(a) C. Sambiagio, S. P. Marsden, A. J. Blacker, P. C. McGowan, Chem.
Soc. Rev. 2014, 43, 3525−3550; (b) Y. Jiang, D. Ma, In Copper-
carboxylate (5r): 94 mg (86% yield), (eluent: DCM/MeOH = 12:1), white
solid; mp 237-238C; 1H NMR (400 MHz, DMSO-d6) δ 14.06 (brs, 1H),
7.82 (s, 1H), 7.75 (d, J = 0.9 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H); 19F NMR
(376 MHz, DMSO-d6) δ -59.56 (s, CF3); 13C NMR (101 MHz, DMSO-d6) δ
158.8, 141.9, 141.1 (q, J = 35.9 Hz), 134.0, 131.7, 122.1 (q, J = 268.0 Hz),
121.8, 121.5, 52.9, 34.2; IR (MIR-ATR, 4000–600 cm-1): υmax = 2960,
1718, 1572, 1446, 1340, 1203, 1117, 958, 815, 704; HRMS (ESI) calcd.
for C10H10F3N4O2 [(M+H)]+: 275.0750, found: 275.0751.
Mediated Cross-Coupling Reactions; Vol.
1 (EDs.: G. Evano, N.
Blanchard), John Wiley & Sons Inc, Hoboken, NJ, 2013, pp 589−642; (c)
J. Bariwalab; E. V. D. Eycken, Chem. Soc. Rev. 2013, 42, 9283-9303;
(d) G. Evano, N. Blanchard, M. Toumi, Chem. Rev. 2008, 108,
3054−3131; (e) F. Monnier, M. Taillefer, Angew. Chem. Int. Ed. 2009, 48,
6954−6971; Angew. Chem. 2009, 121, 7088−7105.
[4]
(a) E. F. V. Scriven, K. Turnbull, Chem. Rev. 1988, 88, 297-368; (b) S.
Brase, C. Gil, K. Knepper, V. Zimmermann, Angew. Chem. Int. Ed. 2005,
44, 5188-5240; Angew. Chem. 2005, 117, 5320-5374; (c) S. Bräse, K.
Banert, Organic Azides: Syntheses and Applications, Wiley & Sons,
2010; (d) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117, 9247-9310;
C. Tang, Y. Yuan, N. Jiao, Org. Lett. 2015, 17, 2206-2209.
A. Sagar, S. Vidaycharan, A. H. Shinde, D. S. Sharada, Org. Biomol.
Chem. 2016, 14, 4018-4022.
Methyl
(5s)[16]
4-(pentafluoroethyl)-2-propyl-1H-imidazole-5-carboxylate
1H NMR (400 MHz, DMSO-d6) δ 13.53 (brs, 1H), 3.86 (s, 3H),
:
2.67 (t, J = 7.4 Hz, 2H), 1.74-1.64 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 19F
NMR (376 MHz, DMSO-d6) δ -82.51 (s, CF3), -108.47 (s, CF2); 13C NMR
(101 MHz, DMSO-d6) δ 158.5, 152.0, 132.1 (q, J = 28.6 Hz, CF3), 122.4,
119.3 (qt, J = 286.8Hz, 38.1 Hz), 111.3 (tq, J = 250.2Hz, 38.2 Hz), 52.6,
29.6, 21.5, 13.7; IR (MIR-ATR, 4000–600 cm-1): υmax = 2968, 1747, 1537,
1438, 1286, 1198, 1151, 1074, 939, 748; HRMS (ESI) calcd. for
C10H12F5N2O2 [(M+H)]+: 287.0813, found: 287.0819.
[5]
[6]
[7]
[8]
H. Ma, D. Li, W. Yu, Org. Lett. 2016, 18, 868-871.
T. Chen, X. Chen, J. Wei, D. Lin, Y. Xie, W. Zeng, Org. Lett. 2016, 18,
2078-2081.
Methyl
2-methyl-2-phenyl-5-(trifluoromethyl)-2H-imidazole-4-
carboxylate (6t): 98 mg (86% yield), (eluent: PE/EA = 10:1), light yellow
oil; 1H NMR (400 MHz, CDCl3) δ 7.69-7.62 (m, 2H), 7.42-7.29 (m, 3H),
4.02 (s, 3H), 1.88 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -66.63 (s, CF3);
13C NMR (101 MHz, CDCl3) δ 160.0, 153.9 (q, J = 38.1 Hz), 153.3, 136.6,
128.8, 128.7, 127.2, 118.6 (q, J = 273.6 Hz), 108.7, 53.6, 26.5; IR (MIR-
ATR, 4000–600 cm-1): υmax = 2958, 1741, 1440, 1325, 1194, 1149, 1034,
762, 698, 619; HRMS (ESI) calcd. for C13H12F3N2O2 [(M+H)]+: 285.0845,
found: 285.0848.
[9]
J. Wu, H. Zhang, X. Ding, X. Tan, J. Chen, W. He, L. Song, H. C. Shen,
W. Cao, J. Org. Chem. 2018, 83, 9422-9429.
[10] H. Ma, X. Zhang, L. Chen, W. Yu, J. Org. Chem. 2017, 82, 11841-
11847.
[11] S. Arepally, V. N. Babu, M. Bakthadoss, D. S. Sharada, Org. Lett. 2017,
19, 5014-5017.
[12] (a) C. E. Garrett, K. Prasad, Adv. Synth. Catal. 2004, 346, 889-900; (b)
C. Sun, Z. Shi, Chem. Rev. 2014, 114, 9219-9280.
[13] (a) N. A. Meanwell, J. Med. Chem. 2018, 61, 5822-5880; (b) Y. Zhou, J.
Wang, Z. Gu, S. Wang, W. Zhu, J. L. Acena, Chem. Rev. 2016, 116,
422-518.
Methyl 2,2-dimethyl-5-(trifluoromethyl)-2H-imidazole-4-carboxylate
(6u): 36 mg (41% yield), (eluent: PE/EA = 8:1), light yellow oil; 1H NMR
(400 MHz, CDCl3) δ 4.02 (s, 3H), 1.63 (s, 6H); 19F NMR (376 MHz,
CDCl3) δ -66.86 (s, CF3); 13C NMR (101 MHz, CDCl3) δ 159.9, 153.6 (q, J
= 38.8 Hz), 153.0, 118.6 (q, J = 273.6 Hz), 105.0, 53.5, 22.4; IR (MIR-
ATR, 4000–600 cm-1): υmax = 2993, 1745, 1441, 1323, 1144, 1036, 889,
806, 748; HRMS (ESI) calcd. for C8H10F3N2O2 [(M+H)]+: 223.0689, found:
223.0692.
[14] V. A. Soloshonok, V. P. Kukhar, Tetrahedron 1996, 52, 6953-6964.
[15] P. Katrun, S. Chiampanichayakul, K. Korworapan, M. Pohmakotr, V.
Reutrakul, T. Jaipetch, C. Kuhakarn, Eur. J .Org. Chem. 2010, 5633-
5641.
[16] M. E. Pierce, D. J. Carini, G. F. Huhn, G. J. Wells, J. F. Arnett, J. Org.
Chem. 1993, 58, 4642-4645.
Methyl
3-(trifluoromethyl)-1,4-diazaspiro[4.5]deca-1,3-diene-2-
carboxylate (6v): 48 mg (46% yield), (eluent: PE/EA = 10:1), colorless
oil; 1H NMR (400 MHz, CDCl3) δ 4.02 (s, 3H), 1.96-1.66 (m, 10H); 19F
NMR (376 MHz, CDCl3) δ -66.72 (s, CF3); 13C NMR (101 MHz, CDCl3) δ
160.3, 153.4 (q, J = 39.6 Hz), 152.9, 118.7 (q, J = 274.1 Hz), 107.7, 53.4,
33.3, 25.1, 23.4; IR (MIR-ATR, 4000–600 cm-1): υmax = 2937, 1741, 1443,
1319, 1147, 1034, 806, 746; HRMS (ESI) calcd. for C11H14F3N2O2
[(M+H)]+: 263.1002, found: 263.1010.
[17] B. C. Hamper, Org. Synth. 1992, 70, 246-250.
[18] R. Saijo, K.-I. Kurihara, M. Kawase, Heterocycles 2013, 87, 2533-
2553.
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10.1002/ejoc.201801310
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Key Topic*: Cycloamination,
Fluoroalkylated Imidazoles
Jun Wu,‡[a,b] Hui Zhang,‡[c] Xiao Ding,[b]
Xuefei Tan,[b] Hong C. Shen,[b] Jie
Chen,[c] Weimin He,[c] Hongmei Deng,[c]
Liping Song,*[a,c] and Weiguo Cao*[c,d,e]
An efficient cascade one-pot synthesis of fluoroalkylated imidazoles from primary
amines with α-hydrogen and fluoroalkylated alkynes via Michael addition, azidation
and cycloamination was reported. Substrates scope was explored. The mechanism
was elucidated and the application was also demonstrated.
Page No. – Page No.
Efficient synthesis of fluoroalkylated
imidazoles via a metal-free cascade
Michael additon
/
azidation
/
cycloamination process
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