Efficient copper-catalyzed direct intramolecular aminotrifluoromethylation of unactivated alkenes with diverse nitrogen-based nucleophiles

Article abstract of DOI:10.1002/chem.201303387

A mild, convenient, and step-economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen-based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligand

Full text of DOI:10.1002/chem.201303387

DOI: 10.1002/chem.201303387
Full Paper
&
Synthetic Methods
Efficient Copper-Catalyzed Direct Intramolecular
Aminotrifluoromethylation of Unactivated Alkenes with Diverse
Nitrogen-Based Nucleophiles
Jin-Shun Lin, Ya-Ping Xiong, Can-Liang Ma, Li-Jiao Zhao, Bin Tan,* and Xin-Yuan Liu*[a]
Abstract: A mild, convenient, and step-economical intramo-
lecular aminotrifluoromethylation of unactivated alkenes
with a variety of electronically distinct, nitrogen-based nucle-
ophiles in the presence of a simple copper salt catalyst, in
the absence of extra ligands, is described. Many different ni-
trogen-based nucleophiles (e.g., basic primary aliphatic and
aromatic amines, sulfonamides, carbamates, and ureas) can
be employed in this new aminotrifluoromethylation reaction.
The aminotrifluoromethylation process allows straightfor-
ward access to diversely substituted CF3-containing pyrroli-
dines or indolines, in good to excellent yields, through
a direct difunctionalization strategy from the respective acy-
clic starting materials. Mechanistic studies were conducted
and a plausible mechanism was proposed.
Introduction
Recently, transition-metal-mediated or -catalyzed trifluoro-
methylation reactions have emerged as important synthetic
tools for the synthesis of new potential pharmaceutical candi-
dates.[3] In particular, since the pioneering studies in 2011, car-
ried out by the groups of Buchwald,[4a] Liu,[4b] and Wang[4c], effi-
cient trifluoromethylation of simple alkenes with trifluorome-
thylating reagents[5,6] has been successfully established.[7]
Based on this mode of activation, some successful examples
have been shown for the trifluoromethylation of alkenes by
a direct difunctionalization strategy to construct two vicinal
chemical bonds. Consequently, oxytrifluoromethylation[8,9] and
carbotrifluoromethylation[10] of simple alkenes have been ach-
ieved to afford a series of CF3-containing compounds. Specifi-
cally, the groups of Liu[10a] and Sodeoka[10b,c] have independent-
ly developed an elegant intramolecular aryltrifluoromethylation
of alkenes with a palladium/ytterbium catalyst system and
a CuI/Togni’s reagent system, respectively (Scheme 1a). Buch-
wald et al. have successfully demonstrated intramolecular
copper-catalyzed oxytrifluoromethylation of alkenes with
oxygen-based nucleophiles in the presence of a bidentate
ligand, but this catalytic system was incompatible with nitro-
gen-based nucleophiles, such as secondary amides or sulfona-
mides (Scheme 1a).[9a] Thus, compared with oxytrifluoromethy-
lation and carbotrifluoromethylation, it still remains a great
challenge to perform intramolecular difunctionalization-type
trifluoromethylation of unactivated alkenes with different types
of nitrogen-based nucleophiles.[11] Although, during the prepa-
ration of this manuscript, an aminotrifluoromethylation of un-
activated alkenes was reported by the Sodeoka group, only
electron-rich secondary aromatic amines were utilized as the
nitrogen source.[11a] Given the paucity of reports about intra-
molecular aminotrifluoromethylation, we were interested in
the use of transition-metal catalysts in the presence of hyper-
valent iodine CF3 reagents for direct intramolecular aminotri-
fluoromethylation of unactivated alkenes with diverse nitro-
Azaheterocycles, such as pyrrolidine and indoline, are an omni-
present component of a wide range of naturally occurring and
biologically active molecules.[1] Among these molecules, skele-
tons that contain the trifluoromethyl (CF3) group have been
extensively used as important building blocks for the synthesis
of anticholinergic, antiemetic, and antispastic drugs, as well as
enzyme inhibitors, because of their unique properties, such as
increased metabolic stability, lipophilicity, and bioavailability.[2]
As a result, great synthetic efforts have been exerted to devel-
op efficient methods for the incorporation of CF3 into azahe-
terocyclic structures.[3] Despite these important achievements,
most literature methods for the construction of trifluoromethy-
lated pyrrolidines or indolines involve the reaction of precycl-
ized substrates with trifluoromethyl-containing organic com-
pounds.[3] In the context of efficient chemical syntheses with
high step economy and increasing interest in this class of com-
pounds for the exploration of new fluorine-containing pharma-
ceutical candidates, it would be of great synthetic interest to
develop a convenient and step-economical route for facile
access to trifluoromethylated pyrrolidines or indolines, prefera-
bly by using simple catalytic systems and readily available acy-
clic starting materials.
[a] Dr. J.-S. Lin, Y.-P. Xiong, C.-L. Ma, L.-J. Zhao, Prof. Dr. B. Tan,
Prof. Dr. X.-Y. Liu
Department of Chemistry
South University of Science and Technology of China
Shenzhen 518055 (P. R. China)
Fax: (+86)755-8624-5672
E-mail: tanb@sustc.edu.cn
liuxy3@sustc.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303387.
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kenes with different types of nitrogen-based nucleophile to
build a variety of trifluoromethylated five-membered rings, in
good to excellent yields, under mild reaction conditions
(Scheme 1c). Significantly, many different nitrogen-based nu-
cleophiles (e.g., basic primary aliphatic and aromatic amines,
sulfonamides, carbamates, and ureas) can be employed in this
new aminotrifluoromethylation reaction that would be chal-
lenging reagents in related transition-metal-catalyzed hydroa-
mination-type[13] reactions of unsaturated amines. The amino-
trifluoromethylation process allows straightforward access to
diversely substituted CF3-containing pyrrolidines or indolines
through a direct difunctionalization strategy from the respec-
tive acyclic starting materials in a step-economical fashion.
Results and Discussion
We initiated our study by examination of the reaction of 1a in
the presence of commercially available Togni’s reagent (4a)[5]
with a CuI catalyst. It was interesting to find that CuI
(25 mol%) could catalyze this reaction in dichloroethane (DCE)
at 758C to provide the desired product 2a in 75% yield, along
with a trace amount of allylic trifluoromethylated product 3a
(Table 1, entry 1). Encouraged by this result, we screened differ-
ent Cu salts for this aminotrifluoromethylation reaction
(Table 1, entries 2–7), and found that CuI was most beneficial
for the reaction. Next, a solvent screen revealed DCE to be op-
timal to give maximum yield of 2a (Table 1, entry 1 versus en-
tries 8–10), which suggests a significant solvent effect for this
Scheme 1. Transition-metal catalyzed intramolecular reactions of unactivated
alkenes.
gen-based nucleophiles, which include primary amines, sulfon-
amides, carbamates, and ureas. In this scenario, two major
challenges must be overcome to accomplish the desired reac-
tion:
1) primary electron-rich amines are susceptible to oxidation at
nitrogen in the presence of hypervalent iodine reagents,[12]
which could possibly result in undesirable side reactions
that stem from the free-amine nucleophile.
Table 1. Screening of the reaction conditions.[a]
2) it is very challenging to search for a simple catalytic system
that can accommodate a variety of electronically distinct
amines (from free amines to the various protected amines)
as the nucleophilic component of the reaction due to
a number of factors, which include the different thermody-
namic stabilities of NÀH s-bonds and distinct inherent nu-
cleophilicity of nitrogen atoms,[13] thereby displaying a sig-
nificantly distinct reactivity toward unactivated alkenes.
Catalyst
[CF3] source Solvent
2a [%][b] 3a [%][b]
1
2
3
4
5
6
7
8
9
CuI
CuCl
CuBr
4a
4a
4a
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
dioxane
toluene
DCE
DCE
DCE
75
58
33
60
42
31
14
10
–
6
4
3
18
25
0
To circumvent these potential issues, the development of
direct catalytic aminotrifluoromethylation of unactivated al-
kenes with a wide range of nitrogen-based nucleophiles with
distinct inherent nucleophilicity is still highly desirable.
[Cu(CH3CN)4][BF4] 4a
[Cu(CH3CN)4][PF6] 4a
CuOTf·0.5C6H6
Cu(OTf)2
CuI
CuI
4a
4a
4a
4a
4a
4a
4a
4b
4c
4a
6
In recent years, we have successfully developed a transition-
metal-catalyzed hydroamination of a series of unactivated al-
kenes or alkynes and related tandem reactions (Scheme 1b).[14]
Inspired by these works, and considering the mechanism of
copper-catalyzed trifluoromethylation of alkenes with electro-
philic trifluoromethylating reagents to generate a-CF3-alkyl
radical intermediates,[4,9] we envisioned that an overall copper-
catalyzed direct difunctionalization strategy might be applica-
ble to various nitrogen-based nucleophiles under the right set
of conditions. Herein we describe that a simple copper cata-
lyst, in the absence of extra ligands, efficiently catalyzes direct
intramolecular aminotrifluoromethylation of unactivated al-
7
[c]
[c]
[c]
–
[c]
10
CuI
–
–
11[d] CuI
12[e] CuI
80
71
–
–
–
6
6
–
–
–
[c]
[c]
[c]
[c]
[c]
[c]
13
14
15
CuI
CuI
DCE
DCE
[f]
–
[a] Reaction conditions: 1a (0.05 mmol), 4 (0.1 mmol), catalyst (25 mol%),
solvent (0.4 mL), 758C, 32 h, under argon. [b] Determined by 19F NMR
spectroscopy with PhCF3 as an internal standard. [c] Product was not de-
tected. [d] CuI (50 mol%) was used. [e] CuI (10 mol%) was used. [f] No
catalyst. Ts=p-toluenesulfonyl, Tf=trifluoromethanesulfonyl.
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reaction. We next studied this reaction under the optimal reac-
tion conditions with different loadings of CuI and found that
the load could be reduced to 10 mol% without any remark-
able effect on the yield of 2a (Table 1, entries 11 and 12). To
our surprise, by changing the CF3 reagent from 4a to 4b or
Umemoto’s reagent (4c), only a trace amount of the desired
product was detected (Table 1, entries 13 and 14). A control ex-
periment revealed that none of the desired product was ob-
served in the absence of copper catalyst (Table 1, entry 15),
which unambiguously revealed that the copper catalyst is es-
sential for this reaction. It is also noteworthy that this reaction
could be catalyzed by a simple copper salt without the use of
extra ligands, in sharp contrast to the copper-catalyzed oxytri-
fluoromethylation of alkenes.[9a]
Table 2. CuI-catalyzed aminotrifluoromethylation of unactivated alkenes
with sulfonamides.[a]
1
2
t [h] Yield [%][b]
1
2
3
4
1a
X=H
1b
X=Cl
1c
X=Me
1d
2a
X=H
2b
X=Cl
2c
X=Me
2d
32
10
10
10
75
70
81
75
With an optimized protocol in hand, the substrate scope
was investigated; the results are shown in Table 2. With
a series of substituted N-sulfonyl-2-allylanilines 1 as the sub-
strates, we found that functional groups (X=Cl, Me, OMe) at
the para position of the phenyl ring were well tolerated and
a variety of substituted CF3-containing indolines 2b–d were
obtained in good yields (Table 2, entries 2–4). Furthermore,
a variety of substituents on the nitrogen atom (benzene-,
methane-, and 4-nitrophenyl-sulfonyl, and 4-MeOC6H4SO2),
were also found to be compatible with this catalytic system, to
give the corresponding products 2e–h in good to excellent
yields (Table 2, entries 5–8), although an increased catalyst
loading (CuI [50 mol%]) was required for full substrate conver-
sion in the presence of the Ns substituent (Table 2, entry 7). It
is interesting to note that the protocol could be extended to
the copper-catalyzed aminotrifluoromethylation reaction of 4-
pentenylsulfonamides 1i–k for the synthesis of highly substi-
tuted trifluoromethylated pyrrolidines 2i–k, and the product
yields were relatively insensitive to the nature of the substitu-
tion on the carbon backbone (Table 2, entries 9–11).
X=OMe
X=OMe
5
1e
R=Bs
1 f
R=Ms
1g
2e
R=Bs
2 f
R=Ms
2g
24
16
16
71
90
81
6
7[c]
R=Ns
R=Ns
8
16
77
1h
2h
R=4-MeOC6H4SO2
R=4-MeOC6H4SO2
9
10
16
91
80
1i
1j
2i
2j
10
Encouraged by the aforementioned aminotrifluoromethyla-
tion reaction of alkenes with sulfonamides, we next turned our
attention to expand the scope of the nucleophile to free pri-
mary amines, although we anticipated some challenges associ-
ated with primary amine oxidation in the presence of hyperva-
lent iodine reagents.[12] To our delight, upon optimizing the re-
action conditions by variation of the catalyst, catalyst loading,
hypervalent iodine CF3 reagent, and solvent (Table 3), we iden-
tified the following protocol as optimal: CuI (10 mol%), 4a
(1.5 equiv), DCE, 758C. The reaction of 2-allyl-4-chloroaniline
(1l) gave 2l in 71% yield (Table 3, entry 1).
11
9
76
1k
2k
[a] Reaction conditions: 1 (0.5 mmol), 4a (1.0 mmol), CuI (25 mol%), DCE
(4 mL), 758C, under argon. [b] Isolated yield based on the starting alkene.
[c] CuI (50 mol%) was used. Bs=benzenesulfonyl, Ms=methanesulfonyl,
Ns=4-nitrophenylsulfonyl.
With these optimized reaction conditions in hand, we inves-
tigated the scope of the reaction by using different types of
substituted 2-allylanilines 1 (Table 4). A range of diversely func-
tionalized 2-allylanilines, which included those with electron-
withdrawing and electron-donating groups at different posi-
tions of the phenyl ring, gave the corresponding products 2l–
q in moderate to excellent yields. Additionally, 2-allyl-4,6-di-
chloroaniline (1r), which bears two chloro substituents, gave
2r in 90% yield. To further investigate the scope of application,
we tested aliphatic amines as viable nucleophiles for this reac-
tion. It was found that the copper-catalyzed aminotrifluoro-
methylation reaction of alkenes tolerated aliphatic amines and
substitution at the allylic olefinic carbon atoms to give
trifluoromethylated pyrrolidines 2s and 2t in good yields. In
consideration of the relatively low yields of products 2n, 2q,
and 2t, we improved the results by changing the solvent and
modifying the reaction temperature.[15] We were pleased to
find that when the solvent was changed from DCE to tBuOH,
in all cases, the product yields were remarkably improved,
even when CuI (5 mol%) was used (Table 4, entries 3, 6, and 9).
As an extension to the above aminotrifluoromethylation re-
action, other protected amines could be employed as nucleo-
philes. Our preliminary results showed that, under conditions
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Table 3. Screening of the reaction conditions.[a]
Table 4. CuI-catalyzed aminotrifluoromethylation of unactivated alkenes
with free amines.[a]
Catalyst
Solvent
Yield [%][b]
1
2
t [h]
Yield [%][b]
71
1
2
3
4
5
6
7
8
9
CuI
CuCl
CuBr
[Cu(CH3CN)4][BF4]
[Cu(CH3CN)4][PF6]
CuOTf·0.5C6H6
Cu(OTf)2
CuI
CuI
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
dioxane
toluene
71
52
65
27
10
15
25
38
44
1
2
3
4
16
1l
2l
10
10
9
80
1m
1n
1o
2m
2n
2o
[c]
10
CuI
–
50 (60)[c]
[a] Reaction conditions: 1l (0.05 mmol), 4a (0.1 mmol), catalyst
(10 mol%), solvent (0.4 mL), 758C, 32 h, under argon. [b] Determined by
19F NMR spectroscopy with PhCF3 as an internal standard. [c] Product was
not detected.
83
identical to those of the aminotrifluoromethylation detailed
above, the reaction of alkenyl benzyl carbamates 1u and 1v,
which bear electron-donating (Me) and -withdrawing (Cl)
groups, gave trifluoromethylated products 2u and 2v in 50
and 65% yields, respectively (Scheme 2a). In addition, Boc-pro-
tected alkenyl carbamate 1w showed a similar reactivity to
give 2w in 42% yield (Scheme 2b). Next, we turned our atten-
tion to expand the scope of the nucleophile to include the
more challenging urea protecting group. Because of the pre-
ferred copper(I)-catalyzed intramolecular diamination process
under similar conditions,[16] effective suppression of this reac-
tion was needed to obtain satisfactory chemoselectivity. We
were delighted to find that when 1x was employed under the
standard conditions with 4a the desired trifluoromethylated
product 2x was obtained in 44% isolated yield without any di-
amination product (Scheme 2), which demonstrated that the
aminotrifluoromethylation step is much faster than the diami-
nation process in our catalytic system. Our data indicate that
the present Cu-catalyzed aminotrifluoromethylation process is
a rather general reaction that can be extended to many more
protected amines.
5
6
7
3
10
3
86
1p
1q
2p
2q
42 (50)[c]
90
1r
1s
2r
2s
8
9
16
12
80
53 (70)[d]
1t
2t
[a] Reaction conditions: 1 (0.5 mmol), 4a (0.75 mmol), CuI (10 mol%), DCE
(4 mL), 758C, under argon. [b] Isolated yield based on the starting alkene.
[c] Reaction conditions: 1 (0.5 mmol), 4a (0.6 mmol), CuI (5 mol%), tBuOH
(4 mL), 408C, 10 h, under argon. [d] Reaction conditions: 1 (0.5 mmol), 4a
(0.6 mmol), CuI (5 mol%), tBuOH (4 mL), 12 h, 758C, under argon.
On the basis of the well-established reactivity of copper(I)-
catalyzed allylic trifluoromethylation of unactivated alkenes,[4]
a proposed mechanism for this CuI-catalyzed aminotrifluoro-
methylation reaction is depicted in Scheme 3. Reaction of 4a
with CuI generates a CF3 radical,[10d] followed by radical addi-
tion and single-electron oxidation to give intermediate B.[9a]
Subsequent trapping of the resultant carbocation with a nitro-
gen nucleophile (Scheme 3, path A) leads to the desired prod-
uct 2. Several control experiments were conducted to gain
some insight into the mechanism for this CuI-catalyzed amino-
trifluoromethylation reaction. 2,2,6,6-Tetramethyl-1-piperidiny-
loxy (TEMPO), a well-known radical scavenger,[4c,7c,8g] was react-
ed with 4a in the presence of stoichiometric CuI under the
standard reaction conditions (Scheme 4a), and the TEMPO-
trapped complex 5 was obtained in 70% yield on the basis of
19F NMR spectroscopic analysis. Moreover, the inhibition experi-
ment of 1a was conducted with the addition of TEMPO
(2.0 equiv) under the standard reaction conditions and the de-
sired product was afforded in only 9% yield, along with 5 in
60% yield (Scheme 4b), which revealed that the CF3 radical is
likely to be the reactive species under the current reaction
conditions. Considering the fact that a small amount of allylic
trifluoromethylated product 3 was formed through the elimi-
nation of intermediate B[4] in almost all cases, intramolecular
hydroamination of 3 to give the final product 2 may be facili-
tated by copper catalyst in this catalytic system (Scheme 3,
path B).[17] However, no reaction of 3a in the presence of CuI
(25 mol%) under the standard conditions was observed
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present
stage
(Scheme 3,
path C). Therefore, the exact
mechanism for the aminotrifluor-
omethylation reaction remains
unclear at present and deserves
further detailed studies.
Conclusion
We have developed a mild, con-
venient, and step-economical in-
tramolecular aminotrifluorome-
thylation of unactivated alkenes
with a variety of electronically
distinct nitrogen-based nucleo-
philes (from free amines to vari-
Scheme 2. The aminotrifluoromethylation of other protected amines
ous protected amines) in the
presence of a simple copper salt
catalyst, in the absence of extra
ligands. This protocol provides
a highly efficient method for the
synthesis of trifluoromethylated
pyrrolidines or indolines in good
to excellent yields. A very broad
substrate scope from simple
starting materials renders the
method a valuable addition to
the arsenal for the synthesis of
trifluoromethyl-containing aza-
heterocycles. Further studies to
gain insight into the mechanism
and to induce stereocontrol in
the aminotrifluoromethylation of
unactivated alkenes are under-
way in our laboratory.
Scheme 3. Proposed mechanism for the aminotrifluoromethylation reaction of unactivated alkenes.
Experimental Section
General procedure a: CuI-cata-
lyzed aminotrifluoromethyla-
tion of unactivated alkenes
with sulfonamides
Sulfonamide substrate (0.5 mmol,
1.0 equiv),
0.125 mmol,
CuI
25 mol%),
(23.8 mg,
4a
(316.0 mg, 1.0 mmol, 2.0 equiv)
were added to a 25 mL Schlenk
tube equipped with a magnetic
stirrer bar. The tube was evacuated
and backfilled with argon (ꢁ4) and
Scheme 4. Control experiments.
then DCE (4.0 mL) was added to the tube by syringe, under argon.
The sealed tube was stirred at 758C. After reaction completion
(monitored by TLC), the solvent was removed under vacuum and
the residue was purified by silica gel column chromatography (pe-
troleum ether/CH2Cl2 =10:1–1:5) to give the desired products 2a–k
and 2u–x.
(Scheme 4c), which revealed that a mechanism that involves
copper-catalyzed intramolecular hydroamination of 3 to give
the final product is unlikely. On the other hand, an alternative
catalytic mechanism, which proceeds by the formation of a pri-
mary carbon radical C through an aminocupration followed by
homolysis of the CÀCu bond,[18] and subsequent coupling of
this intermediate and a CF3 radical, cannot be ruled out at the
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16.8, 4.0 Hz, 1H), 2.95–2.83 (m, 1H), 2.83 (s, 3H), 2.53–2.39 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=139.50, 132.05, 130.43, 128.57,
125.89, 125.60 (q, J(C,F)=276.0 Hz), 116.75, 57.69 (q, J(C,F)=
3.2 Hz), 40.69 (q, J(C,F)=26.7 Hz), 35.76, 34.39 ppm; 19F NMR
(376 MHz, CDCl3): d=À62.97 ppm (s, 3F); HRMS (ESI): m/z calcd for
C11H10ClF3NO2S: 312.0073 [MÀH]À; found: 312.0078.
Compound 2a:
1H NMR (400 MHz, CDCl3): d=7.69 (d, J=8.4 Hz, 1H), 7.55 (d, J=
8.4 Hz, 2H), 7.26–7.21 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.07–7.03
(m, 2H), 4.47–4.40 (m, 1H), 2.97–2.87 (m, 2H), 2.77 (dd, J=16.4,
2.8 Hz, 1H), 2.51–2.40 (m, 1H), 2.35 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=144.53, 140.89, 134.36, 130.77, 129.90, 128.25,
127.28, 125.79 (q, J(C,F)=275.9 Hz), 125.40, 125.25, 117.40, 56.95
(q, J(C,F)=3.3 Hz), 40.75 (q, J(C,F)=26.6 Hz), 34.29, 21.66 ppm;
19F NMR (376 MHz, CDCl3): d=À63.08 ppm (s, 3F); HRMS (ESI): m/z
calcd for C17H17F3NO2S: 356.0932 [M+H]+; found: 356.0922.
Compound 2g:
1H NMR (400 MHz, CDCl3): d=8.25 (d, J=8.8 Hz, 2H), 7.87 (d, J=
8.8 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.31–7.26 (m, 1H), 7.12–7.11 (m,
2H), 4.51–4.45 (m, 1H), 2.98–2.87 (m, 2H), 2.83 (dd, J=16.8, 2.8 Hz,
1H), 2.56–2.42 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=150.68,
142.93, 139.82, 130.65, 128.64, 128.46, 126.09, 125.85, 125.54 (q,
J(C,F)=275.9 Hz), 124.50, 117.27, 57.38 (q, J=3.2 Hz), 40.68 (q,
J(C,F)=27.0 Hz), 34.21 ppm; 19F NMR (376 MHz, CDCl3): d=
À63.06 ppm (s, 3F); HRMS (ESI): m/z calcd for C16H14F3N2O4S:
387.0626 [M+H]+; found: 387.0624.
Compound 2b:
1H NMR (400 MHz, CDCl3): d=7.62 (d, J=8.4 Hz, 1H), 7.55 (d, J=
8.4 Hz, 2H), 7.26–7.20 (m, 3H), 7.03 (s, 1H), 4.46–4.39 (m, 1H),
2.97–2.88 (m, 2H), 2.76 (dd, J=16.8, 3.2 Hz, 1H), 2.52–2.40 (m, 1H),
2.38 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=144.84, 139.66,
133.97, 132.69, 130.52, 130.07, 128.38, 127.27, 125.65 (q, J(C,F)=
275.8 Hz), 125.57, 118.30, 57.26 (q, J(C,F)=3.2 Hz), 40.68 (q, J(C,F)=
29.6 Hz), 34.08, 21.71 ppm; 19F NMR (376 MHz, CDCl3): d=
À63.08 ppm (s, 3F); HRMS (ESI): m/z calcd for C17H16ClF3NO2S:
390.0542 [M+H]+; found: 390.0538.
Compound 2h:
1H NMR (400 MHz, CDCl3): d=7.59–7.57 (m, 3H), 7.18 (dd, J=8.0,
4.0 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J=8.8, 2H), 4.45–4.39 (m, 1H),
3.80 (s, 3H), 2.97–2.87 (m, 2H), 2.75 (dd, J=16.0, 4.0 Hz, 1H), 2.49–
2.39 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=163.70, 139.64,
132.71, 130.33, 129.27, 128.27, 128.18, 125.57 (q, J(C,F)=275.8 Hz),
125.45, 118.18, 114.48, 57.11 (q, J(C,F)=3.2 Hz), 55.61, 40.52 (q,
J(C,F)=26.8 Hz), 34.04 ppm; 19F NMR (376 MHz, CDCl3): d=
À63.09 ppm (s, 3F); HRMS (ESI): m/z calcd for C17H16ClF3NO3S:
406.0492 [M+H]+; found: 406.0492.
Compound 2c:
1H NMR (400 MHz, CDCl3): d=7.48–7.44 (m, 3H), 7.09 (d, J=8.0 Hz,
2H), 6.95 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 4.35–4.30 (m, 1H), 2.85–
2.74 (m, 2H), 2.61 (dd, J=16.8, 2.6 Hz, 1H), 2.38–2.30 (m, 1H), 2.28
(s, 3H), 2.20 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=144.43,
138.44, 135.15, 134.28, 130.98, 129.89, 128.85, 127.30, 126.00,
125.82 (q, J(C,F)=275.8 Hz), 117.28, 57.08 (q, J(C,F)=3.1 Hz), 40.67
(q, J(C,F)=26.7 Hz), 34.22, 21.66, 21.08 ppm; 19F NMR (376 MHz,
CDCl3): d=À63.07 ppm (s, 3F); HRMS (ESI): m/z calcd for
C18H19F3NO2S: 370.1089 [M+H]+; found: 370.1091.
Compound 2i:
1H NMR (400 MHz, CDCl3): d=7.71 (d, J=8.4 Hz, 2H), 7.34 (d, J=
8.0 Hz, 2H), 3.75–3.69 (m, 1H), 3.45–3.39 (m, 1H), 3.19–3.13 (m,
1H), 3.06–2.93 (m, 1H), 2.43 (s, 3H), 2.32–2.16 (m, 1H), 1.80–1.75
(m, 3H), 1.53–1.46 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
144.05, 133.74, 130.02, 127.72, 125.87 (q, J(C,F)=275.8 Hz), 54.75
(q, J(C,F)=3.2 Hz), 49.14, 40.61 (q, J(C,F)=26.3 Hz), 31.72, 24.04,
21.66 ppm; 19F NMR (376 MHz, CDCl3): d=À63.78 ppm (s, 3F);
HRMS (ESI): m/z calcd for C13H17F3NO2S: 308.0932 [M+H]+; found:
308.0922.
Compound 2d:
1H NMR (400 MHz, CDCl3): d=7.59 (d, J=8.8 Hz, 1H), 7.51 (d, J=
8.4 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 6.78 (dd, J=8.8, 2.4 Hz, 1H),
6.60 (d, J=2.4 Hz, 1H), 4.45–4.38 (m, 1H), 3.78 (s, 3H), 2.94–2.77
(m, 2H), 2.67 (dd, J=16.8, 2.4 Hz, 1H), 2.49–2.40 (m, 1H): 2.35 ppm
(s, 3H); 13C NMR (100 MHz, CDCl3): d=157.92, 144.35, 134.24,
134.17, 132.75, 129.85, 127.38, 125.78 (q, J(C,F)=276.0 Hz), 118.76,
113.47, 111.01, 57.31 (q, J(C,F)=3.2 Hz), 55.74, 40.59 (q, J(C,F)=
26.6 Hz), 34.41, 21.66 ppm; 19F NMR (376 MHz, CDCl3): d=
À63.07 ppm (s, 3F); HRMS (ESI): m/z calcd for C18H19F3NO3S:
386.1038 [M+H]+; found: 386.1036.
Compound 2j:
1H NMR (400 MHz, CDCl3): d=7.61 (d, J=8.0 Hz, 2H), 7.23 (d, J=
8.0 Hz, 2H), 3.62–3.54 (m, 1H), 3.29–3.24 (m, 1H), 3.07 (d, J=
10.8 Hz, 1H), 2.94 (dd, J=10.6, 1.0 Hz, 1H), 2.32 (s, 3H), 2.26–2.11
(m, 1H), 1.75 (dd, J=12.8, 7.2 Hz, 1H), 1.48 (dd, J=12.8, 8.4 Hz,
1H), 0.93 (s, 3H), 0.33 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
144.09, 133.82, 129.93, 127.79, 126.10 (q, J(C,F)=275.6 Hz), 61.21,
54.64 (q, J(C,F)=3.3 Hz), 46.92, 41.05 (q, J(C,F)=26.4 Hz), 37.59,
26.37, 25.56, 21.65 ppm; 19F NMR (376 MHz, CDCl3): d=
À63.76 ppm (s, 3F); HRMS (ESI): m/z calcd for C15H21F3NO2S:
336.1245 [M+H]+; found: 336.1220; m/z calcd for C15H20F3NNaO2S:
358.1065 [M+Na]+; found: 358.1055.
Compound 2e:
1H NMR (400 MHz, CDCl3): d=7.63–7.57 (m, 3H), 7.46–7.44 (m, 1H),
7.34–7.30 (m, 2H), 7.18–7.14 (m, 1H), 6.98 (d, J=4.0 Hz, 2H), 4.41–
4.34 (m, 1H), 2.90–2.78 (m, 2H), 2.68 (dd, J=16.4, 3.0 Hz, 1H),
2.43–2.29 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=140.71,
137.27, 133.59, 130.80, 129.32, 128.31, 127.23, 125.76 (q, J(C,F)=
275.9 Hz), 125.47, 125.42, 117.44, 57.02 (q, J(C,F)=3.2 Hz), 40.69 (q,
J(C,F)=26.6 Hz), 34.24 ppm; 19F NMR (376 MHz, CDCl3): d=
À63.06 ppm (s, 3F); HRMS (ESI): m/z calcd for C16H15F3NO2S:
342.0776 [M+H]+; found: 342.0778.
Compound 2k:
1H NMR (400 MHz, CDCl3): d=7.71 (d, J=8.4 Hz, 2H), 7.32 (d, J=
8.0 Hz, 2H), 3.65–3.57 (m, 1H), 3.42–3.29 (m, 1H), 3.24 (d, J=
10.8 Hz, 1H), 3.12 (d, J=10.8 Hz, 1H), 2.41 (s, 3H), 2.33–2.21 (m,
1H), 1.91 (dd, J=12.4, 6.8 Hz, 1H), 1.52 (dd, J=12.0, 8.8 Hz, 1H),
1.43–1.03 (m, 8H), 0.73–0.67 (m, 1H), 0.54–0.48 ppm (m, 1H);
Compound 2 f:
1H NMR (400 MHz, CDCl3): d=7.35 (d, J=8.4 Hz, 1H), 7.19–7.16 (m,
2H), 4.60–4.53 (m, 1H), 3.51 (dd, J=16.8, 9.8 Hz, 1H), 3.02 (dd, J=
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13C NMR (100 MHz, CDCl3): d=144.05, 133.72, 129.89, 127.51,
126.13 (q, J(C,F)=275.6 Hz), 58.33, 53.90 (q, J=3.0 Hz), 45.26,
41.47, 41.20 (q, J(C,F)=26.4 Hz), 36.36, 33.89, 25.84, 23.74, 22.90,
21.64 ppm; 19F NMR (376 MHz, CDCl3): d=À63.70 ppm (s, 3F);
HRMS (ESI): m/z calcd for C18H25F3NO2S: 376.1558 [M+H]+; found:
376.1547.
(376 MHz, CDCl3): d=À64.15 ppm (s, 3F); HRMS (ESI): m/z calcd for
C11H10F3N2: 227.0796 [M+H]+; found: 227.0793.
Compound 2p:
1H NMR (400 MHz, CDCl3): d=7.04 (dd, J=8.0, 0.4 Hz, 1H), 6.97
(dd, J=7.2, 0.8 Hz, 1H), 6.68–6.64 (m, 1H), 4.30 (s, 1H), 4.28–4.20
(m, 1H), 3.33 (dd, J=16.0, 8.8 Hz, 1H), 2.85 (dd, J=16.0, 9.2 Hz,
1H), 2.61–2.36 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=147.36,
129.00, 127.57, 126.37 (q, J(C,F)=275.5 Hz), 122.90, 120.02, 114.88,
54.06 (q, J=2.9 Hz), 40.48 (q, J(C,F)=26.5 Hz), 37.15 ppm; 19F NMR
(376 MHz, CDCl3): d=À64.26 ppm (s, 3F). HRMS (ESI): m/z calcd for
C10H10ClF3N: 236.0454 [M+H]+; found: 236.0444.
General procedure b: CuI-catalyzed aminotrifluoromethyla-
tion of unactivated alkenes with free amines
CuI (10 or 5 mol%), 4a (237.0 mg, 0.75 mmol, 1.5 equiv) were
added to a 25 mL Schlenk tube equipped with a magnetic stirrer
bar. The tube was evacuated and backfilled with argon (ꢁ4), then
the solution of substrate (0.50 mmol, 1.0 equiv) in DCE or tBuOH
(4.0 mL) was added to the tube by syringe, under argon. The con-
tents of the sealed tube were stirred at 40 or 758C. Upon comple-
tion of the reaction (monitored by TLC), the solvent was removed
under vacuum and the residue was purified by silica gel column
chromatography (petroleum ether/CH2Cl2 =50:1–1:1) to give the
desired products 2l–t.
Compound 2q:
1H NMR (400 MHz, CDCl3): d=6.96 (s, 1H), 6.89 (d, J=8.0 Hz, 1H),
6.57 (d, J=7.6 Hz, 1H), 4.21–4.13 (m, 1H), 3.94 (brs, 1H), 3.23 (dd,
J=15.4, 8.4 Hz, 1H), 2.75 (dd, J=15.4, 8.8 Hz, 1H), 2.55–2.38 (m,
2H), 2.30 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=147.93,
128.69, 128.09, 127.85, 126.37 (q, J(C,F)=275.4 Hz), 125.50, 109.31,
54.36 (q, J=2.9 Hz), 40.54 (q, J(C,F)=26.3 Hz), 36.56, 20.90 ppm;
19F NMR (376 MHz, CDCl3): d=À64.21 ppm (s, 3F); HRMS (ESI): m/z
calcd for C11H13F3N: 216.1000 [M+H]+; found: 216.0997.
Compound 2l:
1H NMR (400 MHz, CDCl3): d=7.04 (d, J=0.4 Hz, 1H), 6.99 (dd, J=
8.0, 2.0 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 4.23–4.15 (m, 1H), 4.04
(brs, 1H), 3.22 (dd, J=15.8, 8.4 Hz, 1H), 2.74 (dd, J=15.8, 9.2 Hz,
1H), 2.55–2.33 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=148.94,
129.43, 127.57, 126.46 (q, J(C,F)=275.7 Hz), 124.89, 123.72, 110.01,
54.53 (q, J(C,F)=2.4 Hz), 41.40 (q, J(C,F)=26.5 Hz), 36.29 ppm;
19F NMR (376 MHz, CDCl3): d=À64.24 ppm (s, 3F); HRMS (ESI): m/z
calcd for C10H10ClF3N: 236.0454 [M+H]+; found: 236.0451.
Compound 2r:
1H NMR (400 MHz, CDCl3): d=7.04–7.03 (m, 1H), 6.93 (s, 1H), 4.28–
4.20 (m, 2H), 3.30 (dd, J=16.0, 8.8 Hz, 1H), 2.82 (dd, J=16.0,
9.2 Hz, 1H), 2.59–2.35 ppm (m, 2H). 13C NMR (100 MHz, CDCl3): d=
146.19, 130.20, 127.10, 126.25 (q, J(C,F)=275.5 Hz), 123.76, 123.36,
114.80, 54.30 (q, J=2.8 Hz), 40.34 (q, J(C,F)=26.7 Hz), 36.98 ppm;
19F NMR (376 MHz, CDCl3): d=À64.28 ppm (s, 3F); HRMS (ESI): m/z
calcd for C10H9Cl2F3N: 270.0064 [M+H]+; found: 270.0057.
Compound 2m:
1H NMR (400 MHz, CDCl3): d=7.17 (s, 1H), 7.13 (d, J=8.4 Hz, 1H),
6.48 (d, J=8.4 Hz, 1H), 4.22–4.15 (m, 1H), 4.11 (s, 1H), 3.22 (dd, J=
15.8, 8.4 Hz, 1H), 2.74 (dd, J=15.8, 8.8 Hz, 1H), 2.52–2.36 ppm (m,
2H); 13C NMR (100 MHz, CDCl3): d=149.36, 130.46, 129.87, 127.68,
126. 42 (q, J(C,F)=275.5 Hz), 110.72, 110.57, 54.43 (q, J=2.7 Hz),
40.39 (q, J(C,F)=26.4 Hz), 36.21 ppm; 19F NMR (376 MHz, CDCl3):
d=À64.20 ppm (s, 3F); HRMS (ESI): m/z calcd for C10H10BrF3N:
279.9949 [M+H]+; found: 279.9950.
Compound 2s:
1H NMR (400 MHz, CDCl3): d=7.34–7.17 (m, 10H), 3.79 (d, J=
11.2 Hz, 1H), 3.55–3.58 (m, 1H), 3.43 (d, J=11.6 Hz, 1H), 2.92 (dd,
J=12.8, 6.4 Hz, 1H), 2.37–2.25 (m, 2H), 2.18–2.11 (m, 1H),
1.99 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=147.06, 145.94,
128.77, 128.58, 127.09, 126.87, 126.56 (q, J(C,F)=275.7 Hz), 126.50,
126.41, 57.53, 56.44, 51.63 (q, J=2.6 Hz), 44.92, 41.36 ppm (q,
J(C,F)=25.9 Hz); 19F NMR (376 MHz, CDCl3): d=À64.14 (s, 3F);
HRMS (ESI): m/z calcd for C18H19F3N: 306.1470 [M+H]+; found:
306.1465.
Compound 2n:
1H NMR (400 MHz, CDCl3): d=6.83–6.81 (m, 1H), 6.76–6.71 (m, 1H),
6.53 (dd, J=8.4, 4.4 Hz, 1H), 4.22–4.18 (m, 1H), 3.88 (brs, 1H), 3.23
(dd, J=15.6, 8.4 Hz, 1H), 2.75 (dd, J=15.6, 9.2 Hz, 1H), 2.57–
2.35 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=157.29 (q, J(C,F)=
234.3 Hz), 146.27, 129.23 (d, J(C,F)=8.1 Hz), 126.48 (q, J(C,F)=
275.5 Hz), 113.77 (d, J(C,F)=23.1 Hz), 112.15 (d, J(C,F)=23.8 Hz),
109.56 (d, J(C,F)=8.3 Hz), 54.80 (q, J(C,F)=2.7 Hz), 40.43 (q, J(C,F)=
26.5 Hz), 36.63 ppm; 19F NMR (376 MHz, CDCl3): d=À64.28 (s, 3F),
À125.91 ppm (s, 1F); HRMS (ESI): m/z calcd for C10H10F4N: 220.0749
[M+H]+; found: 220.0741.
Compound 2t:
1H NMR (400 MHz, CDCl3): d=3.43 (brs, 1H), 2.75–2.85 (m, 2H),
2.38–2.17 (m, 4H), 1.89 (s, 1H), 1.44–1.41 ppm (m, 10H); 13C NMR
(100 MHz, CDCl3): d=126.64 (q, J(C,F)=275.3 Hz), 58.24, 52.11,
45.25, 42.98, 40.52 (q, J(C,F)=26.6 Hz), 38.43, 37.00, 26.14, 24.04,
23.60 ppm; 19F NMR (376 MHz, CDCl3): d=À64.31 ppm (s, 3F);
HRMS (ESI): m/z calcd for C11H19F3N: 222.1470 [M+H]+; found:
222.1461.
Compound 2o:
Compound 2u:
1H NMR (400 MHz, CDCl3): d=7.28 (d, J=8.4 Hz, 1H), 7.24 (s, 1H),
6.55 (d, J=8.4 Hz, 1H), 4.72 (s, 1H), 4.31–4.24 (m, 1H), 3.28 (dd, J=
16.0, 9.2 Hz, 1H), 2.77 (dd, J=16.0, 8.4 Hz, 1H), 2.54–2.34 ppm (m,
2H); 13C NMR (100 MHz, CDCl3): d=154.17, 133.52, 128.12, 127.97,
126.27 (q, J(C,F)=275.5 Hz), 120.64, 108.44, 100.31, 53.98 (q,
J(C,F)=2.9 Hz), 40.45 (q, J(C,F)=26.5 Hz), 35.39 ppm; 19F NMR
1H NMR (400 MHz, CDCl3): d=7.76 (brs, 1H), 7.48–7.36 (m, 5H),
7.02 (s, 2H), 5.34 (s, 2H), 4.80–4.78 (m, 1H), 3.40 (dd, J=16.4,
9.6 Hz, 1H), 2.97 (d, J=16.4 Hz, 1H), 2.66 (brs, 1H), 2.40–2.26 ppm
(m, 4H); 13C NMR (100 MHz, CDCl3): d=152.32, 138.68, 136.05,
133.03, 129.20, 128.66, 128.51, 128.36, 128.22, 125.95 (q, J(C,F)=
275.9 Hz), 125.76, 115.27, 67.54, 54.34, 38.18, 33.74, 20.82 ppm;
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19F NMR (376 MHz, CDCl3): d=À63.24 ppm (brs, 3F); HRMS (ESI):
m/z calcd for C19H18F3NNaO2: 372.1187 [M+Na]+; found: 372.1182.
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Angew. Chem. Int. Ed. 2011, 50, 9120–9123; b) J. Xu, Y. Fu, D.-F. Luo, Y.-Y.
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Compound 2v:
1H NMR (400 MHz, CDCl3): d=7.73 (brs, 1H), 7.42–7.35 (m, 5H),
7.14 (brs, 2H), 5.29 (s, 2H), 4.81–4.76 (m, 1H), 3.39 (dd, J=16.8,
9.6 Hz, 1H), 2.96 (d, J=16.8 Hz, 1H), 2.64 (brs, 1H), 2.38–2.24 ppm
(m, 1H); 13C NMR (100 MHz, CDCl3): d=152.31, 139.79, 135.76,
131.07, 128.77, 128.57, 128.43, 128.34, 127.87, 125.82 (q, J(C,F)=
275.8 Hz), 125.27, 116.45, 67.88, 54.60, 38.10, 33.58 ppm; 19F NMR
(376 MHz, CDCl3): d=À63.29 ppm (brs, 3F); HRMS (APCI): m/z
calcd for C17H16ClF3N: 326.0923 [MÀCO2+H]+; found: 326.0856.
Compound 2w:
1H NMR (400 MHz, CDCl3): d=7.66 (brs, 1H), 7.13 (d, J=10.8 Hz,
2H), 4.70 (s, 1H), 3.38 (dd, J=16.8, 9.6 Hz, 1H), 2.92 (d, J=16.8 Hz,
1H), 2.64 (s, 1H), 2.37–2.23 (m, 1H), 1.56 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=151.55, 140.18, 130.96, 127.90, 127.71, 125.85
(q, J(C,F)=275.7 Hz), 125.14, 116.26, 82.11, 54.43 (q, J=3.1 Hz),
38.34, 33.60, 28.33 ppm; 19F NMR (376 MHz, CDCl3): d=
À63.62 ppm (brs, 3F); HRMS (APCI): m/z calcd for C10H10ClF3N:
236.0454 [MÀCO2ÀC4H8+H]+; found: 236.0441.
Compound 2x:
1H NMR (400 MHz, CDCl3): d=7.30 (d, J=7.6 Hz, 2H), 7.21–7.17 (m,
2H), 6.95 (t, J=7.2 Hz, 1H), 6.21 (s, 1H), 4.19–4.11 (m, 1H), 3.30 (d,
J=9.2 Hz, 1H), 3.15–3.08 (m, 1H), 3.03 (d, J=9.2 Hz, 1H), 2.11 (dd,
J=13.0, 7.6 Hz, 1H), 2.03–1.91 (m, 1H), 1.51–1.30 ppm (m, 11H);
13C NMR (100 MHz, CDCl3): d=154.69, 138.89, 129.04, 126.41 (q,
J(C,F)=275.8 Hz), 123.31, 119.91, 57.24, 51.74 (q, J(C,F)=3.1 Hz),
43.21, 42.42, 38.60 (q, J(C,F)=26.2 Hz), 36.61, 34.83, 26.07, 23.85,
22.98 ppm; 19F NMR (376 MHz, CDCl3): d=À63.20 ppm (s, 3F);
HRMS (ESI): m/z calcd for C18H24F3N2O: 341.1841 [M+H]+; found:
341.1834.
Acknowledgements
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21302088,
21302087), the Shenzhen Bureau of Science, Technology & In-
formation (JCYJ20130401144532131, JCYJ20130401144532137),
and South University of Science and Technology of China
(Talent Development Starting Fund from Shenzhen Govern-
ment).
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Keywords: alkenes · aminotrifluoromethylation · copper ·
nitrogen-based nucleophiles · nitrogen heterocycles
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Full Paper
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Received: August 29, 2013
Published online on December 20, 2013
Chem. Eur. J. 2014, 20, 1332 – 1340
www.chemeurj.org
1340
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim