Synthesis of Trifluoromethylated Naphthoquinones via Copper-Catalyzed Cascade Trifluoromethylation/Cyclization of 2-(3-Arylpropioloyl)benzaldehydes

Article abstract of DOI:10.1021/acs.orglett.7b00095

A novel copper-catalyzed cascade trifluoromethylation/cyclization of 2-(3-arylpropioloyl)benzaldehydes is described, allowing a direct access to structurally diverse trifluoromethylated naphthoquinones under mild reaction conditions. It represents the first trans-acyltrifluoromethylation of internal alkynes.

Full text of DOI:10.1021/acs.orglett.7b00095

Letter
pubs.acs.org/OrgLett
Synthesis of Trifluoromethylated Naphthoquinones via Copper-
Catalyzed Cascade Trifluoromethylation/Cyclization of 2‑(3-
Arylpropioloyl)benzaldehydes
Yan Zhang,* Dongmei Guo, Shangyi Ye, Zhicheng Liu, and Gangguo Zhu*
Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China
S
* Supporting Information
ABSTRACT: A novel copper-catalyzed cascade trifluoromethyla-
tion/cyclization of 2-(3-arylpropioloyl)benzaldehydes is described,
allowing a direct access to structurally diverse trifluoromethylated
naphthoquinones under mild reaction conditions. It represents the
first trans-acyltrifluoromethylation of internal alkynes.
aphthoquinones are prevalent in a number of natural
products, bioactive molecules, and functionalized materi-
Scheme 1. Methods for the Synthesis of Trifluoromethylated
Naphthoquinones
N
als (Figure 1). Many natural or synthetic naphthoquinones have
Figure 1. Representative bioactive molecules with naphthoquinone
motifs.
been found to exhibit versatile pharmacological properties,
including antimicrobial,1 anti-inflammatory,2 and anticancer
activities.3 Therefore, the development of efficient methods for
the construction of naphthoquinones is of significant importance
in the fields of both synthetic and medicinal chemistry.
On the other hand, the incorporation of a trifluoromethyl
group (CF3) into organic molecules can significantly improve
physical, chemical, and biological properties such as permeability,
bioavailability, and metabolic stability.4 Although a host of
methods have been developed for the preparation of
trifluoromethylated compounds, there are very limited protocols
for introducing CF3 onto naphthoquinones. The traditional
protocol involves a five-step procedure consisting of reduction,
protection, bromination, trifluoromethylation, and oxidation
(Scheme 1a).5 Undoubtedly, the low step-efficiency limits the
the exploration of new protocols for the straightforward synthesis
of naphthoquinones from readily accessible acyclic precursors,
with the concurrent incorporation of a CF3 group, is a highly
attractive alternative to the existing methods.
We have recently developed a methodology for the ketone
synthesis using aldehydes as acceptors for the addition of carbon-
centered radicals.7 Following this concept, we present here a
novel, mild, and direct approach to trifluoromethylated
naphthoquinones via a Cu-catalyzed cascade trifluoromethyla-
tion/cyclization of 2-(3-arylpropioloyl)benzaldehydes using
Togni’s reagent8 as the trifluoromethylation reagent (Scheme
1c). It represents the first trans-acyltrifluoromethylation of
internal alkynes. As compared to the radical trifluoromethylation
of alkenes,9,10 the alkyne trifluoromethylation has been much less
́
synthetic application of this protocol. In 2013, Szabo and Wang
independently discovered an elegant method for the concise
synthesis of trifluoromethylated naphthoquinones featuring a
copper-mediated or catalyzed direct C−H trifluoromethylation
(Scheme 1b).6 Despite this success, the strategy depends on the
utilization of naphthoquinones as the starting materials. As such,
Received: January 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00095
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
explored,11 presumably due to the decreased reactivity of C−C
triple bonds. Therefore, the method described here constitutes a
new advance in the regio- and stereoselective radical
trifluoromethylation of disubstituted alkynes, which may be
valuable for access to polysubstituted trifluoromethylated
alkenes.
improved any more even after a number of trials because of the
possible decomposition of trifluoromethylated naphthoquinones
via the haloform reaction under neutral or mild basic reaction
conditions, as reported in the literature.5b,14
With the optimized reaction conditions in hand, we
investigated the scope of this reaction by using various 2-(3-
arylpropioloyl)benzaldehydes, and the results are shown in
Scheme 2. The reaction of 1b, 1c, and 1d afforded
trifluoromethylated naphthoquinones 3b, 3c, and 3d in 61%,
65%, and 63% yield, respectively, indicating that the steric
At the outset, we utilized 1a as the model substrate to optimize
the reaction conditions (Table 1). The possibility of using
a
Table 1. Optimization of the Reaction Conditions
a
Scheme 2. Substrate Scope
b
entry
[CF3]
catalyst
AgNO3
additive
yield (%)
c
1
2a
2b
2c
2d
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
2e
K2S2O8
CsF
25
0
d
2
PhI(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuSO4
CuOAc
Cu(MeCN)4PF6
CuCl
3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
none
trace
trace
33
25
10
28
48
64
10
56
55
40
47
35
0
4
5
6
7
8
9
10
11
12
13
14
CuBr
CuBr
CuBr
Na2CO3
NaHCO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
CuBr
CuBr
e
15
CuBr
f
16
CuBr
g
17
CuBr
18
none
0
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), catalyst (20 mol
b
%), additive (0.2 mmol), MeCN (2.0 mL), 60 °C, 10 h. Isolated
yield. MeCN/DMF (v/v = 2:1) was used instead of MeCN. Run
with PhI(OAc)2 (0.4 mmol) and CsF (0.8 mmol). DCE was used
instead of MeCN. PhCF3 was used instead of MeCN. THF was used
instead of MeCN. DCE = ClCH2CH2Cl.
c
d
e
f
g
CF3SO2Na (2a) as the trifluoromethylation reagent was first
explored. Indeed, the combined use of AgNO3 and K2S2O812 led
to the trifluoromethylated naphthoquinone 3a in 25% yield,
together with the partial decomposition of 1a (Table 1, entry 1).
We then examined the reactivity of TMSCF3 in the presence of
PhI(OAc)2 and CsF,13 but essentially no reaction was observed
(entry 2). When the reaction was performed with the combined
use of 2 equiv of Togni’s reagent 2e, 20 mol % of Cu(OAc)2, and
1 equiv of K2CO3, 3a was obtained in 33% yield (entry 5). The
variation of copper salts indicated that CuBr is the best suitable
catalyst, delivering 3a in 64% yield upon isolation (entries 6−10).
It should be noted that the addition of K2CO3 had a significant
impact on the reaction efficiency, and a very low conversion was
observed in the absence of K2CO3 (entry 11). Replacement of
K2CO3 with Na2CO3, NaHCO3 or K3PO4 led to inferior results
(entries 12−14). In addition, the utilization of other solvents
including DCE, PhCF3, and THF was not able to increase the
yield (entries 15−17). Of note, the reaction yield could not be
a
Reaction conditions: 1 (0.2 mmol), 2e (0.4 mmol), CuBr (20 mol
%), K2CO3 (0.2 mmol), CH3CN (2.0 mL), 60 °C, 5−10 h. Isolated
yields are given. Isolated yield on a 1 mmol scale.
b
B
DOI: 10.1021/acs.orglett.7b00095
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Letter
hindrance of Ar2 has little impact on the reaction. The
chlorinated substrate 1k was effective for the production of 3k,
which may offer an opportunity for further derivatizations via the
transition-metal-catalyzed cross-coupling reaction. Heteroaryl
substituents like thiophene were also compatible with the
reaction, albeit in moderate yields (3m and 3n). In the meantime,
the Ar1 group was varied. Substrates bearing either electron-
withdrawing or -donating groups readily underwent this Cu-
catalyzed cascade trifluoromethylation/cyclization reaction. The
fluorinated substrate 1o was converted into the corresponding
product 3o in 60% yield, whereas the reaction of 1q produced 3q
in 47% yield. There results implied that the electronic effect of
Ar1 had a correlation with the reaction efficiency, which could
also be deduced from the transformation of 1y and 1z (3y and
3z). In contrast, no reaction took place when 1aa was used as the
starting material, presumably due to the reduced reactivity of the
C−C triple bond (3aa). Overall, a wide range of functional
groups such as F, CF3, Cl, OMe, OPh, and OCH2O were
tolerated rather well, which is attractive for the synthetic
application. The structure of trifluoromethylated naphthoqui-
none 3w was unambiguously identified by single-crystal X-ray
analysis (Figure 2).15
Scheme 4. Proposed Catalytic Cycle
Cu-catalyzed cascade trifluoromethylation/cyclization reaction.
First, the CF3 radical (A) is generated by a single-electron
transfer (SET) from Cu(I) to 2e, with the release of Cu(II)
species. Since the α-position of the carbonyl group has a higher
electron density than the β-position, the CF3 radical (A)
regioselectively adds to the α-carbon of 1 to deliver an alkenyl
radical B.6c Subsequent addition of alkenyl radical to the
intramolecular aldehyde provides an alkoxyl radical C, which can
be converted into the radical D via a 1,2-hydrogen atom transfer
(1,2-HAT).7,19 Then, oxidation of D by the Cu(II) species
results in a cationic intermediate E, accompanied by the
regeneration of Cu(I) catalyst. Finally, trifluoromethylated
naphthoquinones 3 are generated from E via the K2CO3-
promoted deprotonation.
Figure 2. ORTEP representation of the X-ray crystal structure of 3w.
The synthetic utility of this methodology was then explored
(Scheme 3). In the presence of 1.5 equiv of H2O2 and Na2CO3,
Scheme 3. Derivatization of Compound 3a
3a was smoothly transformed to the naphthoquinone epoxide 4
in 80% yield. This is noteworthy as it has been reported that this
type of compound exhibits significant biological activities in the
metabolic processes.16 Moreover, the reduction of 3a with i-
Bu2AlH at a low temperature afforded the diol product 5 in 70%
yield.
In summary, we have developed a novel copper-catalyzed
cascade trifluoromethylation/cyclization of 2-(3-arylpropioloyl)-
benzaldehydes, providing straightforward access to structurally
diverse trifluoromethylated naphthoquinones under mild
reaction conditions. The reaction represents the first trans-
acyltrifluoromethylation of internal alkynes, which offers a novel
approach to direct synthesis of polysubstituted trifluoromethy-
lated alkenes.
In order to gain insight into the reaction mechanism, the
standard reaction was carried out in the presence of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO). As a result, 3a was not
formed, and the TEMPO−CF3 adduct 69c was detected by 19
F
NMR analysis (16% yield) (eq 1). The radical clock reaction
using (1-cyclopropylvinyl)benzene (1′) as the radical-trapping
reagent provided the known product 717 in 43% yield, estimated
from the 19F NMR spectroscopy (eq 2). Furthermore,
compound 818 was subjected to the reaction conditions, and
no detectable product 3c was observed (eq 3), thus ruling out the
possibility of forming a naphthoquinone intermediate. Con-
sequently, a radical mechanism is depicted in Scheme 4 for this
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00095.
■
S
Detailed experimental procedures, characterization data
for all new products 3−5, and NMR spectra (PDF)
X-ray data for 3w (ZIP)
C
DOI: 10.1021/acs.orglett.7b00095
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Li, L.; Zheng, S.-C.; Xiong, Y.-P.; Zhao, L.-J.; Tan, B.; Liu, X.-Y. Angew.
Chem., Int. Ed. 2014, 53, 11890. (s) Yu, P.; Zheng, S.-C.; Yang, N.-Y.;
Tan, B.; Liu, X.-Y. Angew. Chem., Int. Ed. 2015, 54, 4041. (t) Li, Z.-L.; Li,
X.-H.; Wang, N.; Yang, N.-Y.; Liu, X.-Y. Angew. Chem., Int. Ed. 2016, 55,
15100. (u) Yu, L.-Z.; Xu, Q.; Tang, X.-Y.; Shi, M. ACS Catal. 2016, 6,
526. (v) Cheng, C.; Liu, S.; Lu, D.; Zhu, G. Org. Lett. 2016, 18, 2852.
(11) Selected examples of trifluoromethylation of terminal alkynes:
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangyan001@zjnu.edu.cn.
*E-mail: gangguo@zjnu.cn.
ORCID
Gangguo Zhu: 0000-0003-4384-824X
Notes
́
(a) Janson, P. G.; Ghoneim, I.; Ilchenko, N. O.; Szabo, K. Org. Lett.
2012, 14, 2882. (b) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew. Chem.,
Int. Ed. 2014, 53, 539. (c) Wang, F.; Zhu, N.; Chen, P.; Ye, J.; Liu, G.
Angew. Chem., Int. Ed. 2015, 54, 9356. (d) Ji, Y.-L.; Luo, J.-J.; Lin, J.-H.;
Xiao, J.-C.; Gu, Y.-C. Org. Lett. 2016, 18, 1000. For internal alkynes, see:
(e) Ge, G.-C; Huang, X.-J.; Ding, C.-H; Wan, S.-L.; Dai, L.-X.; Hou, X.-
H. Chem. Commun. 2014, 50, 3048. (f) Xu, J.; Wang, Y.-L.; Gong, T.-J.;
Xiao, B.; Fu, Y. Chem. Commun. 2014, 50, 12915. (g) Gao, P.; Shen, Y.-
W.; Fang, R.; Hao, X.-H.; Qiu, Z.-H.; Yang, F.; Yan, X.-B.; Wang, Q.;
Gong, X.-J.; Liu, X.-Y.; Liang, Y.-M. Angew. Chem., Int. Ed. 2014, 53,
7629. (h) Xiong, Y.-P.; Wu, M.-Y.; Zhang, X.-Y.; Ma, C.-L.; Huang, L.;
Zhao, L.-J.; Tan, B.; Liu, X.-Y. Org. Lett. 2014, 16, 1000. (i) Ji, Y.-L.; Lin,
J.-H.; Xiao, J.-C.; Gu, Y. C. Org. Chem. Front. 2014, 1, 1280.
(12) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D.
Angew. Chem., Int. Ed. 2013, 52, 9747.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the National Natural Science
Foundation of China (21672191) and the Natural Science
Foundation of Zhejiang Province (LQ17B020001).
REFERENCES
■
(1) Didry, N.; Dubreuil, L.; Pinkas, M. Pharm. Acta Helv. 1994, 69, 25.
(2) Fujii, S.; Shimizu, A.; Takeda, N.; Oguchi, K.; Katsurai, T.;
Shirakawa, H.; Komai, M.; Kagechika, H. Bioorg. Med. Chem. 2015, 23,
2344.
(3) Teiten, M. H.; Mack, F.; Debbab, A.; Aly, A. H.; Dicato, M.;
Proksch, P.; Diederich, M. Bioorg. Med. Chem. 2013, 21, 3850.
(4) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320. (b) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed.
(13) Mu, X.; Wu, T.; Wang, H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc.
2012, 134, 878.
(14) As an example, the decomposition of 3s was observed by GC and
HRMS analysis; for details, see Figures S1 and S2 of the Supporting
Information.
(15) CCDC 1515077 (3w) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(16) Miyashita, K.; Imanishi, T. Chem. Rev. 2005, 105, 4515.
(17) Egami, H.; Shimizu, R.; Usui, Y.; Sodeoka, M. J. Fluorine Chem.
2014, 167, 172.
2005, 44, 214. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317,
̈
1881.
(5) (a) Van Tuyen, N.; Kesteleyn, B.; De Kimpe, N. Tetrahedron 2002,
58, 121. (b) Lanfranchi, D. A.; Belorgey, D.; Muller, T.; Vezin, H.;
Lanzer, M.; Davioud-Charvet, E. Org. Biomol. Chem. 2012, 10, 4795.
̈
́
(6) (a) Ilchenko, N. O.; Janson, P. G.; Szabo, K. J. Chem. Commun.
2013, 49, 6614. (b) Wang, X.; Ye, Y.; Ji, G.; Xu, Y.; Zhang, S.; Feng, J.;
Zhang, Y.; Wang, J. Org. Lett. 2013, 15, 3730. (c) Fang, Z.; Ning, Y.; Mi,
P.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 1522.
(18) Wang, D.; Ge, B.; Du, L.; Miao, H.; Ding, Y. Synlett 2014, 25,
2895.
(19) Gilbert, B. C.; Holmes, R. G. G.; Laue, H. A. H.; Norman, R. O. C.
(7) (a) Che, C.; Huang, Q.; Zheng, H.; Zhu, G. Chem. Sci. 2016, 7,
4134. (b) Zhu, H.; Nie, X.; Huang, Q.; Zhu, G. Tetrahedron Lett. 2016,
57, 2331.
J. Chem. Soc., Perkin Trans. 2 1976, 1047.
(8) Charpentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115, 650.
̈
(9) Selected reviews: (a) Studer, A. Angew. Chem., Int. Ed. 2012, 51,
8950. (b) Chen, P.; Liu, G. Synthesis 2013, 45, 2919. (c) Chu, L.; Qing,
F.-L. Acc. Chem. Res. 2014, 47, 1513. (d) Barata-Vallejo, S.; Lantano, B.;
̃
Postigo, A. Chem. - Eur. J. 2014, 20, 16806. (e) Egami, H.; Sodeoka, M.
Angew. Chem., Int. Ed. 2014, 53, 8294. (f) Merino, E.; Nevado, C. Chem.
Soc. Rev. 2014, 43, 6598. (g) Alonso, C.; Martínez de Marigorta, E.;
Rubiales, G.; Palacios, F. Chem. Rev. 2015, 115, 1847.
(10) Selected reports: (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2011, 50, 9120. (b) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc.
2012, 134, 12462. (c) Wang, X.; Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.;
Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 16410. (d) Yasu, Y.;
Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2012, 51, 9567. (e) Wallentin,
C. J.; Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc.
2012, 134, 8875. (f) Shimizu, R.; Egami, H.; Hamashima, Y.; Sodeoka,
M. Angew. Chem., Int. Ed. 2012, 51, 4577. (g) Egami, H.; Shimizu, R.;
Kawamura, S.; Sodeoka, M. Angew. Chem., Int. Ed. 2013, 52, 4000.
(h) Wu, X.; Chu, L.; Qing, F.-L. Angew. Chem., Int. Ed. 2013, 52, 2198.
(i) Jiang, X.-Y.; Qing, F.-L. Angew. Chem., Int. Ed. 2013, 52, 14177.
(j) Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D. Angew.
Chem., Int. Ed. 2013, 52, 9747. (k) 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.
(l) Kong, W.; Casimiro, M.; Merino, E.; Nevado, C. J. Am. Chem. Soc.
2013, 135, 14480. (m) Kong, W.; Casimiro, M.; Fuentes, N.; Merino, E.;
Nevado, C. Angew. Chem., Int. Ed. 2013, 52, 13086. (n) Chen, Z.-M.; Bai,
W.; Wang, S.-H.; Yang, B.-M.; Tu, Y.-Q.; Zhang, F.-M. Angew. Chem., Int.
Ed. 2013, 52, 9781. (o) Xu, T.; Cheung, C. W.; Hu, X. Angew. Chem., Int.
Ed. 2014, 53, 4910. (p) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G.
Angew. Chem., Int. Ed. 2014, 53, 1881. (q) Wang, F.; Wang, D.; Mu, X.;
Chen, P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 10202. (r) Yu, P.; Lin, J.-S.;
D
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