Copper-Catalyzed Intermolecular Trifluoromethylazidation and Trifluoromethylthiocyanation of Allenes: Efficient Access to CF3-Containing Allyl Azides and Thiocyanates

Article abstract of DOI:10.1021/acs.orglett.5b01677

A mild and efficient method for copper-catalyzed trifluoromethylazidation and trifluoromethylthiocyanation of allenes was explored. A series of CF₃-containing allyl azides and thiocyanates were obtained with high yields and good stereoselectivi

Full text of DOI:10.1021/acs.orglett.5b01677

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Intermolecular Trifluoromethylazidation and
Trifluoromethylthiocyanation of Allenes: Efficient Access to
CF ‑Containing Allyl Azides and Thiocyanates
Na Zhu, Fei Wang, Pinhong Chen, Jinxing Ye,* and Guosheng Liu*
3
†
‡
‡
,†
,‡
†Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China
University of Science and Technology, 130 Meilong Road, Shanghai, China 200237
‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, China 200032
*
S Supporting Information
ABSTRACT: A mild and efficient method for copper-catalyzed trifluoromethyl-
azidation and trifluoromethylthiocyanation of allenes was explored. A series of
CF -containing allyl azides and thiocyanates were obtained with high yields and
3
good stereoselectivities, which can be used for further transformation to some
valuable compounds.
llyl amines and sulfides are versatile building blocks for the1
In the past decade, copper-catalyzed trifluoromethylation of
A
synthesis of organic molecules of higher complexity.
alkenes has been well documented, and an array of new
chemical bonds were incorporated, such as C−X, C−O, C−N,
C−S, and C−C bonds, depending on the nature of the
These structural motifs are frequently found in natural products
and pharmaceuticals and commonly exhibit biological activ-
2
6,7
ities. Generally, the introduction of a trifluoromethyl group
functional group used to trap the key intermediate. The
into lead compounds was considered to modify their activity
related trifluoromethylation of alkynes has also been achieved
3
8
and biocompatibility. Thus, exploration of new methods for
to synthesize various CF -containing vinyl products. In
3
9
introducing the CF group into organic compounds has been of
3
contrast, the trifluoromethylation of allenes is relatively rare.
4
broad interest. Some CF -substituted allyl amines and sulfides
3
In 2013, Ma and Yu disclosed a copper-catalyzed intra-
have been recognized to be biologically active; some of which
molecular trifluoromethyloxygenation of 2,3-allenoic acids to
5
9b
are listed in Figure 1. However, traditional strategies for the
provide CF -substituted butenolides. Later, an intermolecular
3
trifluoromethyloxygenation reaction was explored by Liu and
co-workers, while the substrate scope was limited to
9c
heteroatom substituted allenes. Recently, our group devel-
oped a series of copper-catalyzed intermolecular difunctional-
10
11
ization of alkenes and alkynes, including trifluoromethylated
azidation, arylation, cyanation, and thiocyanation, in which a
mutual activation model between ether-type Togni’s CF3+
reagent and TMSNu or ArB(OH) was presented to be vital
2
for the success of these reactions (Scheme 1a). With our
continuous efforts on this catalytic system, we speculated that if
allenes were subjected to our reaction systems, a battery of
functional groups, such as azide and thiocyanate, would
simultaneously be easily introduced into the products with
Figure 1. Representative bioactive compounds with CF -allylic amines
and sulfides.
CF group. However, the reaction of allenes presented more
3
3
complex reactivity than that of alkenes because of more
reaction sites of allene moiety, which could deliver more
possible trifluoromethylation products (Scheme 1b). The
interesting but questionable selectivity motivated us to
investigate this chemistry.
synthesis of these skeletons suffered from multistep trans-
5
formations and low efficiency. Thus, new methods for
constructing CF -containing allyl amines and sulfides are in
3
To test our hypothesis, the initial investigation was focused
on the reaction of substrate 1a, which was treated with the
high demand. Herein, we report a novel copper-catalyzed
intermolecular trifluoromethyl-azidation and -thiocyanation of
allenes in which azide or thiocyanate and CF group are
3
incorporated simultaneously; a series of CF -containing allyl
Received: June 8, 2015
3
azides and thiocyanates are efficiently synthesized.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01677
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Copper-Catalyzed Intermolecular
Trifluoromethylations
Scheme 2. Substrate Scope for Trifluoromethylazidation of
Allenes
,
a b
10a
previous reaction conditions of alkenes. We were delighted
to find the desired CF -substituted allyl azide product 2a was
3
detected in 17% yield with excellent regioselectivity but poor
stereoselectivity (Table 1, entry 1). Further optimization of the
a
Table 1. Optimization of the Reaction Conditions
a
b
c
All the reactions were run at 0.2 mmol scale. Isolated yield. Ester-
b
b
+
entry
solvent
copper
yield (%)
Z/E
1/1
type Togni’s CF reagent.
3
1
2
3
4
5
6
7
8
9
DMAc
MeOH
Cu(CH CN) PF
17
65
48
30
38
35
18
16
50
35
47
44
48
42
3
4
6
6
6
6
6
Cu(CH CN) PF
1/13
1/23
1/9
3
4
good E-isomer selectivity. Among them, a variety of functional
groups, such as Br, F, alkyl, methoxyl, were compatible with the
reaction conditions. Allene substrates with linear n-pentyl, n-
butyl, and methoxypropyl groups generated the desired
products in good yields with good regio- and stereoselectivities.
However, substrates 1d and 1j with steric bulky groups
provided products 2d and 2j with poor stereoselectivities
around a 2:1 ratio. For the aryl group, both electron-rich and
electron-poor are suitable for the transformation, furnishing the
corresponding products in good yields and stereoselectivities.
In contrast, substrate 1g with an ortho-substituent delivered
product 2g in a slightly lower stereoselectivity. These
observations revealed that the stereoselectivity was sensitive
to the steric hindrance of both alkyl and aryl groups.
Unfortunately, quite limited substrate scope was observed:
the reaction of monosubstituted, 1,3-disubstituted allenes
provided the corresponding products in low yields with poor
regioselectivities. In addition, 1,1-dialkyl substituted allenes also
exhibited unsatisfactory reactivity toward this reaction.
CH CN
Cu(CH CN) PF
3 4
3
THF
Cu(CH CN) PF
3 4
DCM
Cu(CH CN) PF
1/22
1/11
1/17
1/14
1/9
3
4
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Cu(OTf)2
Cu(OAc)2
CuI
CuCl2
1
1
1
1
1
0
1
2
3
4
CuOAc
1/16
1/17
1/15
1/10
1/8
c
d
e
f
Cu(CH CN) PF
3
4
6
6
6
6
Cu(CH CN) PF
3
4
Cu(CH CN) PF
3
4
Cu(CH CN) PF
3
4
aAll the reactions were run at 0.1 mmol scale. b19F-NMR yield with
CF -DMA as an internal standard; E/Z ratio was detected from the
3
c
+
d
crude product. Ester-type Togni’s CF reagent was used. At 0 °C.
At 40 °C. At 60 °C.
3
e
f
solvent revealed that MeOH provided the best result, giving the
corresponding product 2a in 65% yield with excellent regio-
and stereoselectivity (entries 2−5). Later, various Cu(I) and
Cu(II) salts were also examined, and Cu(CH CN) PF was
Inspired by the present results, we turned our attention to
extending such a system to the trifluoromethylthiocyanation
reaction. To our great delight, when substrate 1h was used as a
3
4
6
+
determined to be the best. When ester-type Togni’s CF3
template by treatment with TMSNCS instead of TMSN under
3
reagent was used, the reaction also provided product 2a but
with a slightly lower yield (entry 11). In addition, under the
lower or elevated temperature, the reactions suffered decreased
yields (entries 12−14). It should be noted that the stereo-
selectivity of the reactions varied with the change of reaction
conditions.
With the optimized reaction conditions in hand, the substrate
scope of the reaction was examined, and the results are
summarized in Scheme 2. Various 1,1-disubstituted aryl allenes
the above system, the desired product 3c was detected in 60%
yield. Further optimization demonstrated that the best yield
was obtained in DMSO at 40 °C (see the Supporting
Information). Next, the scope of the trifluoromethylthio-
cyanation reaction was evaluated under the modified
conditions, and the results are listed in Scheme 3. Generally,
similar to the previous transformation, this reaction furnished
the desired products in good to excellent yields, but with poor
stereoselectivities. Again, the reactions provided E-isomer as the
main products. In contrast, when MeOH was used as the
solvent, the reactions provided a better stereoselectvity, but
1
were suitable for the reaction to yield the corresponding
trifluoromethylated allylazides in moderate to good yields with
B
DOI: 10.1021/acs.orglett.5b01677
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope for the
Trifluoromethylthiocyanation Reaction
Scheme 5. Plausible Mechanism
,
a b
give final products (path b). (2) CF -allyl radical species
3
−
combined with Cu(II)/Nu to give a CF -allyl-Cu(III) species,
3
which underwent reductive elimination to furnish the final
products (path a). Both processes seem to be reasonable;
however, at present, it is difficult to draw a conclusion.
a
b
c
All the reactions were run at 0.2 mmol scale. Isolated yield. MeOH
as solvent, at rt.
We assumed that the addition of CF radical to allene
3
originally generated the corresponding two allyl radical
intermediates (int.I and int.II) with poor selectivity. Then,
species int.II would isomerize to int.I, which is relatively
thermodynamically stable, because of the steric hindrance
with slightly lower yields. Finally, the reactions exhibited good
functional group compatibility, such as Br, F, and alkyl, under
the reaction conditions.
To demonstrate the practicability of the present methods,
further transformation of 2a and 3a were investigated (Scheme
between the aryl and CF group. For the trifluoromethylazi-
3
dation, good stereoselectivity was observed when R is a less
bulky group, while poor selectivty was provided when a
sterically hindered alkyl group was incorporated (such as 2d
and 2j). We reasoned that the poor selectivity may result from
4). We found that 2a could be readily converted to the
Scheme 4. Further Transformations of Products
the steric effect between R and CF groups, which pushed the
3
equilibrium from int.I to int.II (Scheme 5). Compared to the
azidation, the related thiocynation reaction was obtained with
poor stereoselectivities (around 3:1). Although a detailed
mechanistic understanding cannot currently be given to address
these differences, we speculated that trapping CF -allyl radical
3
intermediates by heteroatom radicals or Cu(II) species might
be responsible for the selectivity. When the coupling reaction of
CF -allyl radical is faster than its isomerization (between int.I
3
and int.II), poor stereoselectivity might be expected.
Otherwise, high stereoselectivity will be observed.
With this in mind, we hold that the coupling reaction of
−
corresponding allylamine 4a in 89% yield in the presence of
Cu(II)/SCN with allylic radical should be faster than that of
−
PPh and H O. In addition, treatment of 2a and phenyl-
3
2
Cu(II)/N , resulting in poor stereoselectivity in products 3.
3
acetylene with Cu catalyst delivered the triazole 5a in 95%
To test this hypothesis, the competition reaction was
conducted, and results indicated that the reaction of
thiocynation is indeed much faster than azidation eq 1.
1
0a
yield.
Furthermore, allylthiocyanate 3a could react with
TMSCF through nucleophilic trifluoromethylation to generate
3
related SCF -substituted product 6a in 65% yield. Very
3
interestingly, the reaction of 3a and NaN resulted in the
3
10d
corresponding product 7a in 74% yield. Notably, these CF3-
decorated tetra-substituted olefins were synthesized efficiently
from simple allenes, which was difficult to achieve through
previously reported methods.
Based on our previous reports on the mutual activation
1
0
model, the proposed mechanism is provided in Scheme 5: the
+
activated CF3 reagent by TMSNu could react with Cu(I)
−
In conclusion, we have developed a novel copper-catalyzed
catalyst to release Cu(II), Nu , and CF radical species, which
3
trifluoromethylazidation and trifluoromethylthiocyanation of
was then trapped by allenes, giving a CF -allyl radical species
3
1
2
with high regioselectivity. For the further process of CF -allyl
radical with Cu(II)/Nu , two scenarios could be used to
allenes. Various CF -allyl azides and thiocyanates were obtained
3
3
−
with good yields and regioselectivities, which can be readily
transformed to some valuable compounds. Further inves-
tigation into the mechanism and application is in progress.
address final C−N and C−S bonds formation: (1) The N or
3
SCN radical species might be generated from the oxidation of
−
Nu with Cu(II) then coupled with CF -allyl radical species to
3
C
DOI: 10.1021/acs.orglett.5b01677
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
5
2
1
1, 8221. (g) Yasu, Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed.
012, 51, 9567. (h) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2012,
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ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures, characterization, and additional data.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01677.
́
K. M.; O’Duill, M.; Wheelhouse, K.; Rassias, G.; Medebielle, M.;
Gouverneur, V. J. Am. Chem. Soc. 2013, 135, 2505. (j) Wu, X.; Chu, L.;
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Kawamura, S.; Miyazaki, A.; Sodeoka, M. Angew. Chem., Int. Ed. 2013,
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2, 7841. (l) Feng, C.; Loh, T.-P. Angew. Chem., Int. Ed. 2013, 52,
1
2414. (m) Kong, W.; Casimiro, M.; Merino, E.; Nevado, C. J. Am.
AUTHOR INFORMATION
Corresponding Authors
■
*
*
Chem. Soc. 2013, 135, 14480. (n) Liu, X.; Xiong, F.; Huang, X.; Xu, L.;
Li, P.; Wu, X. Angew. Chem., Int. Ed. 2013, 52, 6962. (o) Chen, Z.-M.;
Bai, W.; Wang, S.-H.; Yang, B.-M.; Tu, Y.-Q.; Zhang, F.-M. Angew.
Chem., Int. Ed. 2013, 52, 9781. (p) Li, L.; Deng, M.; Zheng, S.-C.;
Xiong, Y.-P.; Tan, B.; Liu, X.-Y. Org. Lett. 2014, 16, 504.
E-mail: yejx@ecust.edu.cn.
E-mail: gliu@mail.sioc.ac.cn.
Notes
(
8) (a) Xiao, Z.; Hu, H.; Ma, J.; Chen, Q.; Guo, Y. Chin. J. Chem.
The authors declare no competing financial interest.
2013, 31, 939. (b) Xu, T.; Cheung, C. W.; Hu, X. Angew. Chem., Int.
Ed. 2014, 53, 4910. (c) Iqbal, N.; Jung, J.; Park, S.; Cho, E. J. Angew.
Chem., Int. Ed. 2014, 53, 539. (d) Maji, A.; Hazra, A.; Maiti, D. Org.
Lett. 2014, 16, 4524. (e) 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. (f) Xu, J.; Wang,
Y.-L.; Gong, T.-J.; Xiao, B.; Fu, Y. Chem. Commun. 2014, 50, 12915.
(9) (a) Tsuchii, K.; Imura, M.; Kamada, N.; Hirao, T.; Ogawa, A. J.
Org. Chem. 2004, 69, 6658. (b) Yu, Q.; Ma, S. Chem. - Eur. J. 2013, 19,
13304. (c) Wang, Y.; Jiang, M.; Liu, J.-T. Adv. Synth. Catal. 2014, 356,
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the Na-
tional Nature Science Foundation of China (21225210,
2
1421091, and 21472219), and the Science Technology
Commission of the Shanghai Municipality (12ZR1453400).
We thank Xiaojian Liu at Shanghai Institute of Technology for
his initial studies on the project.
2
907.
(10) (a) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem.,
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P.; Liu, G. J. Fluorine Chem. 2014, 167, 55. (d) Liang, Z.; Wang, F.;
Chen, P.; Liu, G. Org. Lett. 2015, 17, 2438.
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DOI: 10.1021/acs.orglett.5b01677
Org. Lett. XXXX, XXX, XXX−XXX