Copper-mediated trifluoroacetylation of indoles with ethyl trifluoropyruvate

Article abstract of DOI:10.1039/c7ob01335c

Direct trifluoroacetylation of indoles with ethyl trifluoropyruvate as a trifluoroacetylating reagent has been developed. This novel protocol provides an attractive route for the preparation of 3-trifluoroacetylindole derivatives, due to its operational simplicity and practicability as well as mild reaction conditions.

Full text of DOI:10.1039/c7ob01335c

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: G. Yan, X. Cao, W.
Zheng, Q. Ke, J. Zhang and D. huang, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB01335C.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Organic & Biomolecular Chemistry
Page 1 of 5Journal Name
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C7OB01335C
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Copper-Mediated Trifluoroacetylation of Indoles with Ethyl
Trifluoropyruvate
‡
‡
Guobing Yan*, Xihan Cao , Wanbin Zheng , Qiumin Ke, Jieyu Zhang and Dayun Huang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Direct
trifluoroacetylation
of
indoles
with
ethyl
trifluoroacetylating reagent.8 The radical mechanism is proposed
trifluoropyruvate as a trifluoroacetylating reagent has been 50 for the reaction, in which the acyl Cu(I) species could be involved
developed. This novel protocol provides an attractive route to
the preparation of 3-trifluoroacetylindole derivatives, due to
through the process of decarboxylation. To the best of our
knowledge, this compound is firstly employed as
a
10 its operational simplicity and practicability as well as the mild
reaction conditions.
trifluoroacetylating reagent. Based on our continuous interest in
the CꢀH bond functionalization of indoles,9 our idea for realizing
55
a new copperꢀcatalyzed approach to 3ꢀtrifluoroacetylindole
Fluorineꢀcontaining compounds have received extensive attention
in the fields of pharmaceutical industry and material science, due
15 to their unique physical and biological properties induced by the
fluorine atom.1 In particular, the trifluoromethyl group can be
derivates was inspired by recent Weng’s work. Herein, we report
a simple and efficient copperꢀmediated trifluoroacetylation of
indoles with ethyl trifluoropyruvate as a trifluoroacetylating
reagent.
found in many drugs or drug candidates, which can improve the 60 On the outset of this investigation, we used Nꢀmethylindole 1a as
properties of bioactive molecules, such as metabolic stability,
lipophilicity, and selectivity.2 Therefore, great efforts have been
20 devoted to the development of new methodologies for the
selective incorporation of trifluoromethyl group into organic
model substrate with ethyl trifluoropyruvate as
trifluoroacetylating reagent to screen suitable reaction conditions
and the results were summarized in Table 1. No product was
a
detected without any catalyst in dimethyl sulfoxide (DMSO) as
o
compounds. On the other hand, indoles represent an important 65 solvent at 80 C (entry 1). When 20 mol% CuCl was used as the
class of nitrogenꢀcontaining heterocyclic compounds frequently
encountered in natural products and pharmaceuticals.3 From the
25 molecular design point of view, the combination of two
pharmacophores into a single molecule often enhances the
biological properties of the resultant hybrid molecules.
3ꢀtrifluoroacetylindole derivates is an important structural motif
of bioactive compounds and intermediates for the synthesis of
30 useful compounds.4 FriedelꢀCrafts acylation of indoles at their Cꢀ
3 position is one of the most important and fundamental
catalyst, the aldolꢀtype reaction took place and gave the
corresponding product 3a in 63% yield (entry 2). To our surprise,
the trifluoroacetylation product 2a could be excusively obtained
by increasing the loading of catalyst (entries 3ꢀ7). The reaction
70 could provide 85% yield with 0.6 equivalent catalyst, but the
yield could not be further improved by increasing catalyst loading
(entries 4ꢀ7). Encouraged by these initial results, we proceeded
to optimize the reaction conditions. Several other solvents were
tested. The reaction gave the desired product with moderate yield
transformation, in which trifluoroacetic anhydride (TFAA), 75 in N,NꢀDimethylformamide (DMF) (entry 8). Acetonitrile
trifluoroacetyl chloride and trifluoroacetic acid (TFA) are used as
the trifluoroacetylating reagents.5 Recently, Williams and Guan
35 etc. reported the similar fluoroacetylation of indoles with sodium
chlorodifluoroacetate and fluorinated acetic acids as the acylating
(MeCN) and tetrahydrofuran (THF) also afforded the product 2a
in approximately same yields (entries 9ꢀ10), whereas the yield of
reaction slightly dropped in toluene (PhMe) (entry 11). Next,
various copper salts were further tested for the
reagents under catalyst and additiveꢀfree conditions.6 However, 80 trifluoroacetylation reaction. It was found that most copper(I)
these reactions suffer from some issues of imperfect functional
group tolerance, strict anhydrous conditions and instability of
40 indole derivates under strongly acidic conditions. Therefore, the
development of a mild and efficient strategy for their preparation
from readily available reagents is highly desirable.
In the past decades, ethyl trifluoropyruvate has been used
extensively in asymmetric FriedelꢀCrafts reactions of indoles for
45 the synthesis of chiral 2ꢀ(3’ꢀindolyl)ꢀ3,3,3ꢀtrifluoroꢀ2ꢀ
hydroxypropanoates.7 More recently, Weng and coꢀworkers
salts could promote the reaction with different efficiency (entries
12ꢀ16), whereas the reaction can not occur with the copper(II)
salts as catalysts. The effect of temperature on the reaction was
also investigated. Only trace amount of the desired product could
85 be detected at 60°C (entry 17). The yield of the reaction was
slightly improved by increasing reaction temperature (entry 18).
Finally, we attempted to reduce the amount of trifluoroacetylating
reagent, but the yield decreased gradually with the decrease of
ethyl trifluoropyruvate (entries 19ꢀ20). After extensive screening
of 90 of the reaction conditions, the optimal reaction condition was: the
a
reported
the
copperꢀmediated
trifluoroacetylation
arenediazonium salts with ethyl trifluoropyruvate as
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C7OB01335C
ratio of indole to ethyl trifluoropyruvate is 1:2, 0.6 equivalent
amount of CuCl in DMSO at 80 oC.
low yields (2b, 2c, 2g), even a trace amount of product and the
starting material recovered (2h).
35
Table 1. Optimization of the reaction conditions[a].
O
CF3
O
CuCl(0.6 eq.)
OEt
R2
R2
+
F3C
DMSO, 80 oC, 12 h
N
R1
N
O
R1
1a-t
2a-t
5
O
O
O
O
Me
CF3
CF3
CF3
CF3
Temp.
[oC]
Yield %
Entry
[Cu](eq.)
Solvent
(2a) [b]
Me
ꢀ
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19[d]
20[e]
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
ꢀ
63[c]
68
85
84
82
85
43
38
36
26
56
73
66
24
35
Trace
86
N
Me
N
N
Me
N
Me
Me
2b, 70%
CuCl (0.2)
CuCl (0.4)
CuCl (0.6)
CuCl (0.8)
CuCl (1.0)
CuCl (1.2)
CuCl (0.6)
CuCl (0.6)
CuCl (0.6)
CuCl (0.6)
CuBr (0.6)
CuI (0.6)
CuCN (0.6)
CuSCN (0.6)
Cu2O (0.6)
CuCl (0.6)
CuCl (0.6)
CuCl (0.6)
CuCl (0.6)
2a, 85%
2c, 65%
2d, 86%
O
O
N
O
O
CF3
MeO
Br
CF3
CF3
CF3
Ph
N
N
N
Me
Me
Me
Me
Me
2e, 78%
2f, 89%
2g, 65%
2h, Trace
MeCN
THF
PhMe
O
O
O
O
CF3
CF3
CF3
CF3
Br
Cl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
N
Me
N
Me
N
N
Me
Me
Br
Cl
2i, 72%
2j, 70%
2k, 80%
2l, 71%
O
O
O
N
O
CN
CF3
OHC
CF3
O2N
CF3
CF3
F
N
N
N
Me
Me
Me
Me
74
68
2o, Trace%
2m, 83%
2n, 57%
2p, Trace%
O
O
O
[a] Unless otherwise noted, the reaction conditions are as follows:
1a (0.3 mmol ), ethyl trifluoropyruvate (2.0 eq.), 12 h.
[b] Isolated yield.
O
CF3
CF3
CF3
CF3
N
N
N
[c] aldolꢀtype product 3a.
N
H
Bn
Ac
Ts
10 [d] ethyl trifluoropyruvate (1.5 eq.).
[e] ethyl trifluoropyruvate (1.2 eq.).
2q, 65%
2r, 68%
2s, Trace%
2t, Trace%
Scheme 1. Trifluoroacetylation of indole derivates。Reaction
conditions：1a-t (0.3 mmol), ethyl trifluoropyruvate (2.0 eq.),
CuCl (0.6 eq.), DMSO (1.5 mL), 80 oC, 12h.
Under the optimized conditions, the substrate scope of this
reaction was investigated. The results were summarized in
15 Scheme 1. It was observed that the electronic effects of
substituent seriously affected the reaction. The Nꢀmethylindoles
bearing various electronꢀdonating groups worked well and
afforded the corresponding trifluoroacetylation products in good
yields (2a-e). However, the Nꢀmethylindoles bearing electronꢀ
20 deficient groups showed different efficiency (2h-p). Except for
this substrate, 4ꢀbromoꢀNꢀmethylindole, haloꢀsubstituted indoles
worked smoothly and gave the moderate to good yields, which is
advantageous for further transformations (2i-m). Formylꢀ
substituted indoles provided the 57% yield (2n), whereas nitroꢀ
25 and cyanoꢀsubstituted indoles only gave the trace amount of
products and the starting material recovered (2o, 2p). The
reaction was compatible with Nꢀunprotected and Nꢀbenzylindole,
abliet relatively low yields (2q, 2r), whereas the indoles with Nꢀ
acetyl, and Nꢀphenylsulfonyl substituents were inactive under the
30 same conditions (2s, 2t). In addition, the steric effects of
substituent were obvious. The substituents on the C2 or C4
position of indoles affected the reaction and gave the relatively
40
To
demonstrate
the
practical
usefulness
of
this
trifluoroacetylation strategy, the reaction of Nꢀmethylindole was
carried out in gramꢀscale for the synthesis of 3ꢀtrifluoroacetylꢀNꢀ
methylindole at standard conditions (Scheme 2). To our delight,
45 the product 2a could be obtained with 76% yield.
Scheme 2. Gramꢀscale for the synthesis of 2a.
During the screening reaction conditions, we found that the
different product could be excusively obtained by changing the
50 amount of catalyst loading. The reaction progress was also
monitored by TLC and GCꢀMass, but the aldolꢀtype product
could not be detected with 0.6 equivalent CuCl as catalyst. On the
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB01335C
Path a
one hand, the reaction of the isolated prodcut 3a using as starting
material was carried out with 0.6 equivalent CuCl in the absence
or presence of Nꢀmethylindole (Scheme 3). The results showed
that the trace amount of 2a could be obtained in the presence of
Nꢀmethylindole, whereas no reaction occurred and the starting
material recovered in the absence of Nꢀmethylindole. These
results suggested that the aldolꢀtype reaction and subsequent
cleavage of carbonꢀcarbon bond was ruled out for the reaction.
On the other hand, we have performed the radicalꢀtrap
O
CF3
5
N
O
O
Me
Air
F3C
OEt
CF3
Cu(II)
Cu(I)
O
10 experiment. When stoichiometric amount of the radical scavenger
2,2,6,6ꢀtetramethylpiperidineꢀNꢀoxide (TEMPO) was added to
the reaction mixture under the same reaction conditions, the yield
of the reaction slightly decreased. The result suggested that a
freeꢀradical process for the reaction was also ruled out.
15
O
Cu(I)
N
Me
F3C
C
A
O
Cu(II)
Air
OH
CO2Et
F3C
F3C
B
CuCl(0.6 eq.)
No product
N
Me
DMSO, 80 oC, 12 h
N
Me
3a
Pathb
O
OH
CO2Et
CF3
F3C
O
N
Me
CF3
O
O
O
CuCl
Cl
CuCl(0.6 eq.)
DMSO, 80 oC, 12 h
1a/3a
F3C
OEt
+
F3C
N
N
N
N
Me
HCl
35
Me
Me
Me
= 1.5/1
Figure 1. Proposed mechanism.
1a
3a
2a
, 8%
In conclusion, we have developed a novel copperꢀmediated
trifluoroacetylation method for the synthesis of 3ꢀ
O
CF3
CuCl(0.6 eq.)
TEMPO(1.0 eq.)
O
40 trifluoroacetylindole derivates. The electronic and steric effects of
substituent were obvious in this reaction. The Nꢀmethylindoles
bearing electronꢀdonating groups worked well than those bearing
electronꢀdeficient groups. In addition, the substituents on the C2
or C4 position of indoles affected the yields of the reaction.
45 Further studies to elucidate the mechanism is currently underway
in our lab.
OEt
+
F3C
DMSO, 80 oC, 12 h
N
Me
N
O
Me
2a
, 82%
1a
Scheme 3. Control experiments.
On the basis of our preliminary observations and literature
20 reports8, a plausible mechanism for the trifluoroacetylation of
indoles is proposed in Figure 1(Path a). Firstly, the acyl Cu(I)
We thank the National Natural Science Foundation of China
(No.21572094) and NewꢀShoot Talented Man Plan Project of
50 Zhejiang Province (No.201410352004) for financial support.
species
A could be generated through the process of
decarboxylation, which was oxidized under air atmosphere to
acyl Cu(II) species B. Subsequently, the reaction of Nꢀ
25 methylindole with acyl Cu(II) species B took palce to provide the
intermediate C, followed by the reductive elimination to the
desired product, along with a Cu(0) species, which was oxidized
to Cu(I) by air to complete the catalytic cycle. On the other hand,
considering the fact that the FriedelꢀCrafts trifluoroacetylation of
30 indoles has been established6, an alternative pathway could not be
ruled out in Figure 1(Path b). Trifluoracetyl chloride (CF3COCl)
could be in situ generated from the reaction of CuCl and
CF3COCO2Et, followed by the FriedelꢀCrafts acylation of indoles
by the Lewis acidic interaction of copper salt.
Notes and references
55 Department of Chemistry, Lishui University, Lishui 323000, People’s
Republic of China, Fax: +86-578-2271458; E-mail: gbyan@lsu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
60 ‡ X. Cao, and W. Zheng contributed equally.
1
(a) K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford,
2006; (b) T. Hiyama, Organofluorine Compounds: Chemistry and
Applications; Springer: Berlin, New York, 2000; (c) Biomedical
Frontiers of Fluorine Chemistry (Eds.: I. Ojima, J. R. McCarthy, J.
T. Welch), ACS Symposium Series, 1996; (d) Fluorine-containing
Amino Acids, Synthesis and Properties (Eds.: V. P. Kukhar, V. A.
Soloshonok), Wiley, New York, 1995; (e) G. A. Olah, R.
Khrisnamurti, G. Surya Prakash in Organofluorine Chemistry-
65
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Organic & Biomolecular Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C7OB01335C
Principle and Commerical Application (Eds.: R. E. Banks, B. E.
Smart, J. C. Tatlow), Plenum Press, New York, 1994; f) Fluorine-
Containing Molecules, Structure, Reactivity, Synthesis and
Applications (Eds.: J. F. Liebman, A. Greenberg, W. R. Dolbier, Jr.),
VCH, Weinheim, 1988.
(a)K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881; (b)S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320.
For comprehensive reviews, see: (a) D. Crich, A. Banerjee, Acc.
Chem. Res. 2007, 40, 151; (b) G. R. Humphrey, J. T. Kuethe, Chem.
Rev. 2006, 106, 2875; (c) S. Cacchi, G. Fabrizi, Chem. Rev. 2005,
105, 2873.
(a) C.ꢀH. Ma, T.ꢀR. Kang, L. He, Q.ꢀZ. Liu, Eur. J. Org. Chem. 2014,
2014, 3981; (b) T. Kawanami, A. S. Karns, C. M. Adams, M.
SerranoꢀWu, Tetrahedron Lett. 2013, 54, 7202; (c) A. S. Rowan, T.
S. Moody, R. M. Howard, T. J. Underwood, I. R. Miskelly, Y. He, B.
Wang, Tetrahedron: Asymmetry 2013, 24, 1369.
For selective examples: (a) A. Delgado, J. Clardy, J. Org. Chem.
1993, 58, 2862; b) A. S. Kiselyov, R. G. Harvey, Tetrahedron Lett.
1995, 36, 4005; (c) G. W. Gribble, H. L. Fraser, J. C. Badenock,
Chem. Commun. 2001, 805; (d) J. H. Wynne, C. T. Lloyd, S. D.
Jensen, S. Boson, W. M. Stalick, Synthesis 2004, 14, 2277; (e) C. M.
Park, S. Y. Kim, W. K. Park, N. S. Park, C. M. Seong, Bioorg. Med.
Chem. Lett. 2008, 18, 3844; (f) S. Bovens, A. S. Elfringhoff, M.
Kaptur, D. Reinhardt, M. Schäfers, M. Lehr, J. Med. Chem. 2010, 53,
8298.
5
10
15
20
25
30
35
40
45
2
3
4
5
6
7
(a) T. J. Williams, M. F. Greaney, Org. Lett. 2014, 16, 4024; (b) S.ꢀJ.
Yao, Z.ꢀH. Ren, Y.ꢀY. Wang, Z.ꢀH. Guan, J. Org. Chem. 2016, 81,
4226.
For selective examples: (a) M. P. A. Lyle, N. D. Draper, P. D.
Wilson, Org. Lett. 2005, 7, 901; (b) S. Nakamura, K. Hyodo, Y.
Nakamura, N. Shibata, T. Torua, Adv. Synth. Catal. 2008, 350, 1443;
(c) J. Nie, G.ꢀW. Zhang, L. Wang, D.ꢀH. Zheng, Y. Zheng, J.ꢀA. Ma,
Eur. J. Org. Chem. 2009, 3145; (d) G. Grach, A. Dinut, S. Marque, J.
Marrot, R. Gil, D. Prim, Org. Biomol. Chem. 2011, 9, 497; (e) X.
Han, B. Liu, H.ꢀB. Zhou, C. Dong, Tetrahedron: Asymmetry 2012,
23, 1332; (f) X. Han, W. Ouyang, B. Liu, W. Wang, P. Tien, S. Wu,
H.ꢀB. Zhou, Org. Biomol. Chem. 2013, 11, 8463; (g) X. Han, H. Wu,
W. Wang, C. Dong, P. Tien, S. Wu, H.ꢀB. Zhou, Org. Biomol. Chem.
2013, 11, 8463.
8
9
W. Wu, Q. Tian, T. Chen, Z. Weng, Chem.-Eur. J. 2016, 22, 16455.
G. Yan, C. Kuang, Y. Zhang, J. Wang, Org. Lett. 2010, 12, 1052.
10 Q. Xing, P. Li, H. Lv, R. Lang, C. Xia, F. Li, Chem. Commun. 2014,
50, 12181.
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB01335C
Graphical Abstract
Copper-Mediated Trifluoroacetylation of Indoles with Ethyl
Trifluoropyruvate
Guobing Yan a,*, Xihan Cao a, ‡, Wanbin Zheng a, ‡, Qiumin Kea, Jieyu Zhang
a, Dayun Huang a,*
a
Department of Chemistry, Lishui University, Lishui 323000, People’s Republic of China
Fax:+86-578-2271458; E-mail: gbyan@lsu.edu.cn
Contributed equally to this work
‡