Direct access to α-trifluoromethyl enones via efficient copper-catalyzed trifluoromethylation of meyer-schuster rearrangement

Article abstract of DOI:10.1021/ol403741m

A novel domino copper-catalyzed trifluoromethylated Meyer-Schuster rearrangement reaction with Togni's reagent was developed, leading to α-trifluormethyl (CF₃) enone products with moderate to good yields. Furthermore, α-CF₃ enones can be transformed toward important trifluoromethyl heterocyclic motifs in a one-pot version.

Full text of DOI:10.1021/ol403741m

Letter
pubs.acs.org/OrgLett
Direct Access to α‑Trifluoromethyl Enones via Efficient Copper-
Catalyzed Trifluoromethylation of Meyer−Schuster Rearrangement
Ya-Ping Xiong,† Ming-Yue Wu,† Xiang-Yu Zhang, Can-Liang Ma, Lin Huang, Li-Jiao Zhao, Bin Tan,*
and Xin-Yuan Liu*
Department of Chemistry South University of Science and Technology of China, Shenzhen, 518055, P. R. China
S
* Supporting Information
ABSTRACT: A novel domino copper-catalyzed trifluorome-
thylated Meyer−Schuster rearrangement reaction with Togni’s
reagent was developed, leading to α-trifluormethyl (CF3)
enone products with moderate to good yields. Furthermore, α-
CF3 enones can be transformed toward important trifluor-
omethyl heterocyclic motifs in a one-pot version.
or 2012, three newly approved drugs bearing a
Scheme 1. General Synthetic Strategies for the Construction
F
trifluoromethyl (CF3) group (Figure 1) have demonstrated
of α-CF3-enones
Figure 1. Newly FDA-approved drugs bearing a CF3 group in 2012.
that the introduction of a CF3 group gives rise to significant
changes in the chemical and physical properties of a potential
drug candidate owing to displaying excellent solubility and
lipophilicity properties.1 Accordingly, the development of new
methods for the construction of a C−CF3 bond has drawn
much attention to synthetic research groups.2,3 On the other
hand, it is well-known that α,β-unsaturated ketones (enones)
could be performed as valuable synthetic building blocks due to
their flexibility in many reactions,4 ranging from Michael
additions, cycloadditions to hydrogenations, and so on.
Therefore, the development of efficient methods for the
incorporation of the CF3 group into the α-position of enone for
the formation of complex polysubstituted α-CF3 enones would
be of particular interest as the effect of trifluoromethyl
introduction on this motif remains, to the best of our
knowledge, thus far widely unexplored (Scheme 1a).5 In this
context, Rasmusson and co-workers5a have reported a photo-
catalyzed reaction of trifluoromethyl iodide with steroidal
dienones with ultraviolet light for up to 6 days with only low
conversion (32−42%). Chen and co-workers5b,c have estab-
lished an elegant strategy for direct trifluoromethylation of
steroidal α-bromo enones with FO2SCF2CO2Me (MFSDA) in
the presence of CuI in DMF with good yields. Despite the
importance of these methods, they all remain fundamentally
limited by the requirement of harsh reaction conditions and
toxic or expensive reagents with a very limited substrate scope
or low conversion. An additional disadvantage of the reported
methods is the required use of prefunctionalized starting
materials suffering from tedious procedures. Thus, the
development of practical, general, and novel transformations
to deliver valuable complex polysubstituted α-CF3 enone
structures from simple starting materials with a broad substrate
scope under mild and simple reaction conditions is highly
desirable, and its realization would improve the wide usefulness
of such compounds in synthetic organic chemistry.
On the basis of the structural analysis, two synthetic
strategies can be envisioned: (1) the direct C−H functionaliza-
tion with CF3 source and (2) trapping the allenol intermediate
through the Meyer−Schuster reaction with electrophilic CF3
source (Scheme 1b). Both strategies are full of challenges
because of the multireactive centers of enone or propargylic
alcohol and the control of selectivity of the active allenol
intermediate. It should be noted that the present preliminary
investigation suggested the direct C−H functionalization with a
CF3 source needs further powerful effort for a successful result.
On the other hand, in our second synthetic proposal, there
have been two recent developments that are related to trap the
allenol intermediate with other electrophiles.6,7 First, the Zhang
group reported an efficient synthesis of α-halogen enones from
propargylic alcohols with NBS or NIS involving cooperative
Au/Mo bimetallic catalysis.6 More recently, Gaunt and co-
Received: December 25, 2013
Published: January 27, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
workers developed a new approach to form a broad range of α-
aryl enones from propargylic alcohols, employing diary-
liodonium salts and copper catalysis.7 Encouraged by these
results and in connection with our continuous efforts devoted
to trifluoromethylation,8 we herein present the first domino
trifluoromethylated Meyer−Schuster rearrangement reaction
catalyzed by simple copper catalyst with Togni’s reagent as CF3
source. A series of readily accessible substituted propargylic
alcohols deliver complicated α-CF3 enone products mainly as
the E-isomers with moderate to good yields. Furthermore, the
highly functionalized α-CF3 enone products can be used as
versatile synthetic intermediates for the transformation into
important heterocyclic motifs in a one-pot version.
In our initial investigation, the reaction of 4-(4-methox-
yphenyl)-2-methylbut-3-yn-2-ol (1a) in the presence of
commercially available Togni’s reagent (I)9 with CuI as the
catalyst was chosen as a model. The different metal salts CuI or
CuBr in the presence of various organic solvents such as
CH3CN or THF all failed to give any desired product. The
disappointing results further demonstrated the existence of
great challenge and forced us to further optimize the reaction
conditions more carefully. It was exciting to find that 25 mol %
of CuI could catalyze this reaction in DCE at 65 °C to provide
the desired product 2a with 45% yield (Table 1, entry 1).
amounts of water in the system may improve the results. To
our disappointment, negative results were obtained when 5
equiv of water or only water was used as solvent (Table 1, entry
4). Further optimization without any improvements involved
the study of catalyst loading and reaction temperature and the
change of CF3 reagent from Togni’s reagent I to II or
Umemoto’s reagent III, probably owing to the coordination of
the thio group of reagent III with the copper catalyst3a (Table
1, entries 5−9). Inspired by the acid-promoted Meyer−
Schuster rearrangement,10 we were delighted to find that the
addition of pyruvic acid could improve the yield to 71% (Table
1, entry 10). After evaluating a range of copper(I) and
copper(II) catalysts, it became clear that CuI salt led to the best
performance (Table 1, entry 10−13). A control experiment
revealed that no desired product was observed in the absence of
copper catalyst (Table 1, entry 14), unambiguously demon-
strating that copper catalyst is essential for this reaction.
To examine the scope of this transformation, the optimized
conditions were applied to the reaction of a variety of
propargylic alcohols prepared from ketone with I. As shown
in Scheme 2, the electronic properties and positions of the
Scheme 2. Trifluoromethylation of Propargylic Alcohols
Prepared from Ketone
a
Table 1. Screening Results of Reaction Conditions
b
entry
[CF3]
cat.
CuI
additive
temp (°C)
yield (%)
1
2
I
none
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
PA
65
65
65
65
65
80
80
80
80
50
50
50
50
50
45
58
52
32
56
45
52
22
8
I
CuI
c
3
I
CuI
d
4
I
CuI
e
5
I
CuI
f
6
I
CuI
7
I
CuI
8
II
III
I
CuI
9
CuI
aromatic ring substituents had a solid effect on reactivity, giving
product yields ranged from 39% to 71%. Interestingly, the
substrates started from different cyclic ketones were found to
be tolerated under the copper-catalyzed domino process to
produce the trifluoromethylated tetrasubstituted enones in
good yields.
10
11
12
13
14
CuI
71
47
trace
62
0
I
CuBr
CuCl
CuOAc
none
PA
I
PA
I
PA
I
PA
a
Reaction conditions: (unless otherwise mentioned) 1a (0.1 mmol), I
To further investigate the scope of this application, we next
turned our attention toward expanding the scope of the
propargylic alcohols prepared from aldehyde, although we
anticipated more challenges associated with E/Z selectivity
during the formation of the double bond.11 To our delight, after
further optimizing the reaction conditions (Supporting
Information, Table S1), we recognized the following protocol
as optimal conditions: only 15 mol % of CuI without any
additive in the presence of 1.7 equiv of I with DCE as solvent at
70 °C, and the reaction of 1-(4-methoxyphenyl)pent-1-yn-3-ol
(1j) gave product 2j in 58% yield with good E-selectivity (E/Z
= 6.9/1).12 After establishing this new protocol, representative
propargylic alcohols were arranged to explore the substrate
scope with the displayed results in Scheme 3. Different
substitution groups showed some influences on the chemical
yields and the double-bond stereoselectivity. For substrates
with a strong electron-donating group on the benzene ring,
excellent E-selectivity was obtained, which may provide an
(0.2 mmol), catalyst (0.025 mmol, 25 mol %), DCE (1.0 mL), 24−48
h, under argon (with additive 1.2 equiv of DTBP for entries 2−9 or 0.2
b
equiv of PA for entries 10−14). Determined by 1H NMR
c
spectroscopy using CH2Br2 as an internal standard. Dry DCE was
d
e
used. Dry DCE in the presence of 5 equiv of water was used. 50 mol
f
% of CuI was used. 10 mol % of CuI was used. (DTBP = 2,6-di-tert-
butylpyridine, PA = pyruvic acid, DCE = 1,2-dichloroethane.)
Encouraged by this result and motivated by Gaunt’s optimal
conditions,7 we then tested the domino trifluoromethylated
Meyer−Schuster rearrangement process with a base DTBP as
an additive. To our delight, the reaction proceeded smoothly
with a better yield of 58% (Table 1, entry 2). The presence of a
trace amount of water was beneficial to the Meyer−Schuster
rearrangement to form the active allenol intermediate, as the
yield was slightly lower when anhydrous DCE was used as
solvent (Table 1, entry 3). As such, we reasoned that larger
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Organic Letters
Letter
reaction of 1a with I in the presence of 2,6-di-tert-butyl-4-
methylphenol (BHT) or 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) under the standard conditions produced the desired
products in only marginal yields, while the TEMPO−CF3
adduct was formed in 45% yield as estimated by 19F NMR
analysis (see the Supporting Information). These results
indicate that the CF3 radical may be involved in the
transformation. Furthermore, with the hope of finding out
whether the C−CF3 bond formation in this reaction follows a
direct C−H activation of enone generated from the exact
Meyer−Schuster rearrangement, enone 6 was subjected to the
standard conditions, but the reaction provided no anticipated
product. The current result revealed that the direct C−H
trifluoromethylation of enone can be ruled out.
Scheme 3. Trifluoromethylation of Propargylic Alcohols
Prepared from Aldehyde
On the basis of the control experimental results and the
previous investigation,6,14 a reaction mechanism was tentatively
proposed (Scheme 6). An initial Cu-catalyzed Meyer−Schuster
efficient example for the synthesis of kinetically favored α-CF3
enones.13a
Scheme 6. Proposed Reaction Mechanism
The synthetic significance of these CF3-containing α,β-
unsaturated ketones lies in their ability to serve as the
precursors for the synthesis of many different classes of organic
molecules, including a variety of heterocycles with medicinal
and biological applications. As such, we spurred to develop a
one-pot process toward the CF3-isoxazole and CF3-pyrazole
compounds. Subjecting propargylic alcohol 1j to the standard
reaction conditions with Togni’s reagent I for 29 h, followed by
trapping the intermediate with hydroxylamine, provided the
desired CF3-isoxazole 4a with 51% yield. This one-pot strategy
can be extended to other substituted aromatic rings for
constructing the desired CF3-isoxazole products in acceptable
results (Scheme 4). Furthermore, CF3-pyrazole 5a was also
obtained in 40% yield with a subsequent treatment of enone
with hydrazine followed by DDQ oxidation (Scheme 4).
rearrangement is well documented to form an active allenol
intermediate A.6,7 The resulting intermediate A can result in the
final α-CF3 enone products via two possible different pathways:
(a) interact directly with active electrophilic CF3 radical species
(path a) or (b) be further activated by the active Cu catalyst to
generate Cu-containing intermediate B (path b).13c Path a
would lead to enone with the CF3 group trans to R1 (E-selective
isomer) selectively as the active species (CF3) should approach
the more electron-rich enolic C−C double bond from the less
hindered face, while the latter (path b) would afford favored
intermediate B to yield the CF3 group cis to R1 (Z-selective
isomer) according to the previous suggested explanation.13 On
the basis of the experimental results with preferred E-selectivity,
path a may be predominant in our current reaction system. The
exact mechanism for the domino process still remains unclear at
present and deserves further detailed studies.
Scheme 4. Application of Copper-Catalyzed
Trifluoromethylation of Meyer−Schuster Rearrangement
In conclusion, a novel approach to transform readily
accessible propargylic alcohols into α-CF3 enones using Togni’s
reagent and copper catalysis has been achieved. This protocol
provided a broad scope of the desired α-CF3 enone products in
moderate to good yields with good E-isomeric selectivity.
Furthermore, the highly functionalized α-CF3 enone products
can be used as versatile synthetic intermediates for further
transformation into important heterocyclic motifs in a one-pot
version.
In order to gain more insight into the reaction mechanism,
several control experiments were performed (Scheme 5). The
Scheme 5. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, Table S1, and NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1002
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Organic Letters
Letter
(4) For selected reviews on reactions of enones, see: (a) Erkkila, A.;
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. (b) Melchiorre,
P. Angew. Chem., Int. Ed. 2012, 51, 9748.
AUTHOR INFORMATION
■
Corresponding Authors
(5) (a) Rasmusson, G. H.; Brown, R. D.; Arth, G. E. J. Org. Chem.
1975, 40, 672. (b) Fei, X.-S.; Tian, W.-S.; Chen, Q.-Y. J. Chem. Soc.,
Perkin Trans. 1 1998, 1139. (c) Chadalapaka, G.; Jutooru, I.; McAlees,
A.; Stefanac, T.; Safe, S. Bioorg. Med. Chem. Lett. 2008, 18, 2633.
(6) Zhang, G.; Peng, Y.; Cui, L.; Zhang, L. Angew. Chem., Int. Ed.
2009, 48, 3112.
*E-mail: tanb@sustc.edu.cn.
*E-mail: liuxy3@sustc.edu.cn.
Author Contributions
†Y.P.X. and M.Y.W. contributed equally to this work.
Notes
(7) Collins, B. S. L.; Suero, M. G.; Gaunt, M. J. Angew. Chem., Int. Ed.
2013, 52, 5799.
The authors declare no competing financial interest.
(8) (a) Lin, J.-S.; Xiong, Y.-P.; Ma, C.-L.; Zhao, L.-J.; Tan, B.; Liu, X.-
Y. Chem.Eur. J. 2014, 20, 1332. (b) Li, L.; Deng, M.; Zheng, S.-C.;
Xiong, Y.-P.; Tan, B.; Liu, X.-Y. Org. Lett. 2014, 16, 504.
(9) For selected examples on trifluoromethylation with Togni’s
reagent: (a) Eisenberger, P.; Gischig, S.; Togni, A. Chem.Eur. J.
2006, 12, 2579. (b) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew.
ACKNOWLEDGMENTS
■
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21302088 and
21302087), Shenzhen special funds for the development of
biomedicine, Internet, new energy, and new material industries
(JCYJ20130401144532131, JCYJ20130401144532137), and
South University of Science and Technology of China (Talent
Development Starting Fund from Shenzhen Government).
Chem., Int. Ed. 2007, 46, 754. (c) Niedermann, K.; Fruh, N.;
̈
Vinogradova, E.; Wiehn, M. S.; Moreno, A.; Togni, A. Angew. Chem.,
Int. Ed. 2011, 50, 1059.
(10) (a) Narasaka, K.; Kusama, H.; Hayashi, Y. Chem. Lett. 1991,
1413. (b) Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71,
3159.
(11) (a) Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7,
4149. (b) Wang, D.; Ye, X.; Shi, X. Org. Lett. 2010, 12, 2088.
(12) The stereoconfiguration of the products was determined by
comparing the NMR spectroscopy of a known compound 2o; see:
Bizet, V.; Pannecoucke, X.; Renaud, J. L.; Cahard, D. J. Fluorine Chem.
2013, 152, 56.
(13) (a) Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147. (b) de
Haro, T.; Nevado, C. Chem. Commun. 2011, 47, 248. (c) Feng, C.;
Loh, T.-P. Angew. Chem., Int. Ed. 2013, 52, 12414.
(14) (a) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc.
2010, 132, 1474. For an in-depth computational study on similar
intermediates, see: (b) Gandon, V.; Lemiere, G.; Hours, A.;
Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2008, 47, 7534.
(c) Garayalde, D.; Go mez-Bengoa, E.; Huang, X.; Goeke, A.; Nevado,
C. J. Am. Chem. Soc. 2010, 132, 4720.
REFERENCES
■
(1) For selected reviews, see: (a) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(2) For selected reviews on trifluoromethylation of organic
compounds, see: (a) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (b) Tomashenko, O.
A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475. (c) Nie, J.; Guo, H.-C.;
Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455. (d) Furuya, T.;
Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (e) Wu, X.-F.;
Neumann, H.; Beller, M. Chem.Asian J. 2012, 7, 1744. (f) Studer, A.
Angew. Chem., Int. Ed. 2012, 51, 8950. (g) Ye, Y.; Sanford, M. S. Synlett
2012, 23, 2005. (h) Liu, H.; Gu, Z.; Jiang, X. Adv. Synth. Catal. 2013,
355, 617. (i) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int.
Ed. 2013, 52, 8214.
(3) For selected representative examples on trifluoromethylation via
C−H bond activation, see: (a) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am.
Chem. Soc. 2010, 132, 3648. (b) Ye, Y.; Ball, N. D.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 14682. (c) Zhang, X.-G.;
Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 11948.
Trifluoromethylation of arenes through a radical process, see:
(d) Nagib, D. A.; MacMillan, D. W. C. Nature 2011, 480, 224.
(e) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14411. Trifluoromethylation of simple alkenes, see: (f) Parsons, A. T.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120. (g) Wang, X.;
Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc.
2011, 133, 16410. (h) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.;
Liu, Z.-J.; Gong, T.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1530.
(i) Feng, C.; Loh, T.-P. Chem. Sci. 2012, 3, 3458. (j) Mizuta, S.;
Verhoog, S.; Engle, K. M.; Khotavivattana, T.; O’Duill, M.;
́
Wheelhouse, K.; Rassias, G.; Medebielle, M.; Gouverneur, V. J. Am.
Chem. Soc. 2013, 135, 2505. (k) Zeng, Y.; Zhang, L.; Zhao, Y.; Ni, C.;
Zhao, J.; Hu, J. J. Am. Chem. Soc. 2013, 135, 2955. (l) Kong, W.;
Casimiro, M.; Merino, E.; Nevado, C. J. Am. Chem. Soc. 2013, 135,
14480. (m) Wu, X.; Chu, L.; Qing, F.-L. Angew. Chem., Int. Ed. 2013,
52, 2198. (n) Egami, H.; Kawamura, S.; Miyazaki, A.; Sodeoka, M.
Angew. Chem., Int. Ed. 2013, 52, 7841. (o) Yasu, Y.; Koike, T.; Akita,
M. Org. Lett. 2013, 15, 2136. (p) Deb, A.; Manna, S.; Modak, A.; Patra,
T.; Maity, S.; Maiti, D. Angew. Chem., Int. Ed. 2013, 52, 9747.
Trifluoromethylation of heteroarenes and terminal alkynes, see:
(q) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262.
(r) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298. For
exploration of the CF3-initiated domino process, see: (s) Chen, Z.-M.;
Bai, W.; Wang, S.-H.; Yang, B.-M.; Tu, Y.-Q.; Zhang, F.-M. Angew.
Chem., Int. Ed. 2013, 52, 9781.
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