Copper-catalyzed aminotrifluoromethylation of unactivated alkenes with (TMS)CF3: Construction of trifluoromethylated azaheterocycles

Article abstract of DOI:10.1021/jo5012619

The first example of a copper(I)-catalyzed intramolecular aminotrifluoromethylation of unactivated alkenes using (TMS)CF₃ (trimethyl(trifluoromethyl)silane) as the CF₃ source is described. A broad range of electronically and structurally varied substrates undergo convenient and step-economical transformations for the concurrent construction of a five- or six-membered ring and a C-CF₃ bond toward different types of trifluoromethyl azaheterocycles. The methodology not only circumvents use of expensive electrophilic CF₃ reagents or the photoredox strategy but also expands the scope to substrates that are difficult to access by the existing methods. Mechanistic studies are conducted, and a plausible mechanism is proposed.

Full text of DOI:10.1021/jo5012619

Subscriber access provided by DALHOUSIE UNIV
Article
Copper-Catalyzed Aminotrifluoromethylation of Unactivated Alkenes
with TMSCF3: Construction of Trifluoromethylated Azaheterocycles
Jin-Shun Lin, Xiang-Geng Liu, Xiao-Long Zhu, Bin Tan, and Xin-Yuan Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5012619 • Publication Date (Web): 08 Jul 2014
Downloaded from http://pubs.acs.org on July 14, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Copper-Catalyzed Aminotrifluoromethylation of Unactivated
Alkenes with TMSCF3: Construction of Trifluoromethylated
Azaheterocycles
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
JinꢀShun Lin, XiangꢀGeng Liu, XiaoꢀLong Zhu, Bin Tan,* and XinꢀYuan Liu*
Department of Chemistry, South University of Science and Technology of China,
Shenzhen, 518055, P. R. China
*Eꢀmail: liuxy3@sustc.edu.cn; tanb@sustc.edu.cn
NHR1
NR1
R3
R3
Cat. Cu/oxidant
R2
R2
TMSCF3
n
n
CF3
R3 = H, alkyl, aryl, or n = 1, 2
broader substrate scope compared
with previous methods
improved functional-group tolerance
ABSTRACT: The first example of
a
copper(I)ꢀcatalyzed intramolecular
aminotrifluoromethylation of unactivated alkenes using TMSCF3 as the CF3 source is
described. A broad range of electronically and structurally varied substrates undergo
convenient and stepꢀeconomical transformations for the concurrent construction of
five or sixꢀmembered ring and a CꢀCF3 bond toward different types of trifluoromethyl
azaheterocycles. The methodology not only circumvents use of expensive
electrophilic CF3 reagents or the photoredox strategy but also expands the substrate
scope that is difficult to access by the existed methods. Mechanistic studies are
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 40
1
2
3
4
conducted and a plausible mechanism is proposed.
5
6
7
8
INTRODUCTION
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Trifluoromethyl(CF3)ꢀcontaining azaheterocycles have been recognized as important
building blocks in many bioactive compounds because the presence of a CF3 group in
such biologically active compounds enhances the lipophilicity, metabolic stability,
and bioavailability.1 Toward this end, much attention has been recently paid to the
development of new methods for the synthesis of trifluoromethyl azaheterocycles.2
From the point of highꢀatom and step economy, intramolecular
difunctionalizationꢀtype trifluoromethylation of unactivated alkenes with
nitrogenꢀbased nucleophiles (i.e. aminotrifluoromethylation) has been proven as an
attractive but underꢀexploited strategy for providing easy access to structurally diverse
three or fiveꢀmembered CF3ꢀcontaining compounds.3,4 In this context, Cho and
coꢀworkers have developed elegant visibleꢀlightꢀinduced intramolecular
trifluoromethylation of terminal allylic amines in the presence of Ru complex as a
photocatalyst to produce CF3ꢀcontaining aziridines (Scheme 1a).3a Very recently,
Sodeoka3b and our group4a have independently reported intramolecular
aminotrifluoromethylation of alkenes with diverse nitrogenꢀbased nucleophiles in the
presence of copper catalyst with electrophilic Togni’s reagent as the CF3 source to
give trifluoromethylated aziridines, pyrrolidines or indolines (Scheme 1a and 1b).
Although significant progresses have been made, these reactions have encountered
several major restrictions. For example, the aminotrifluoromethylation of alkenes is
ACS Paragon Plus Environment

Page 3 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
almost limited to not only monosubstituted terminal alkenes but also the only
formation of three or fiveꢀmembered azaheterocycles, thus limiting their synthetic
value and less applicable to largeꢀscale synthesis. It is noteworthy that recent work
from our laboratory has demonstrated that the development of catalytic method that
led to the sixꢀmembered CF3ꢀcontaining azaheterocycles with Togni’s reagent remains
a formidable challenge4a and while the overall transformation can be achieved in a
stepwise fashion.5 Therefore, the development of a convenient and stepꢀeconomical
strategy for expanding aminotrifluoromethylation of unactivated alkenes associated
with the aforementioned challenges is still highly desirable.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Transition-Metal-Catalyzed Aminotrifluoromethylation of Unactivated
Alkenes.
Recently, RuppertꢀPrakash reagent (TMSCF3), which is commercially available
compound, has been widely used as CF3 source in organic synthesis to construct
CF3ꢀcontaining diverse molecules.6ꢀ8 In this area, we have also developed a mild and
general PhI(OAc)2ꢀmediated direct carbotrifluoromethylation of activated alkenes
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 40
1
2
3
4
5
6
7
8
9
using TMSCF3 under metalꢀfree conditions, thus offering a complementary method to
transitionꢀmetalꢀcatalyzed methods.4b However, to our knowledge, there has been no
report on the direct difunctionalization of unactivated alkenes, such as
aminotrifluoromethylation, with nucleophilic TMSCF3 as the CF3 source. In the light
of all of those findings6ꢀ8 and as a part of our continued interest in the area of
trifluoromethylation, herein, we further report the Cu(I)ꢀcatalyzed oxidative
aminotrifluoromethylation of unactivated alkenes using nucleophilic TMSCF3 as the
CF3 source (Scheme 1c), which expands the scope and efficiency of
aminotrifluoromethylation and avoids the use of the expensive electrophilic CF3
reagent or photocatalysts. Significantly, this efficient approach would provide a useful
alternative to the known aminotrifluoromethylation methods, and would prove
especially valuable for the simultaneous formation of five or sixꢀmembered ring and a
CꢀCF3 bond, which should facilitate the development of lateꢀstage introduction of
versatile CF3ꢀcontaining azaheterocycle moieties into complex scaffolds for
diversityꢀoriented synthetic strategies.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCCUSION
Our prior observation4a that substrates bearing gemꢀdisubstituted alkenes or longer
chain groups have displayed less or no efficiency in the presence of electrophilic CF3
reagent as shown in Scheme 1b, and the possibility that nucleophilic TMSCF3 could
be used as CF3 source in the presence of appropriate oxidant for the
aminotrifluoromethylation of simple alkenes inspired by the high reactivity of such
ACS Paragon Plus Environment

Page 5 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reagent toward unactivated alkenes8 and other transformations,7 led us to further
expand the substrate scope of such reaction. To do so and further improve the product
yield in our previous report,4a we initiated these investigations by examining the
reaction of Nꢀbenzyloxycarbonylꢀ2ꢀallyl aniline 1a by using TMSCF3 as the CF3
source in the present of CuI (25 mol %), AgNO3 as the oxidant and KF as the base or
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
initiator. We found that CuI could catalyze this reaction in DMF at 80 C for 16 h to
form the desired product 2a in 58% yield (Table 1, entry 1). Encouraged by this result,
we turned our attention to screen different copper catalysts, and Cu(CH3CN)4BF4 was
found to provide 2a in 62% yield (Table 1, entries 1ꢀ7). The product yield could be
further improved to 68% by reducing the catalyst loadings of Cu(CH3CN)4BF4 from
25 to 15 mol % (Table 1, entry 8). Among different organic solvents examined, it
turned out that the reaction with DMF gave the best results (Table 1, entries 8ꢀ13).
Further investigation revealed that AgNO3 behaved as the most efficient oxidant
among the screened oxidants (Table 1, entries 14ꢀ16); and the negative result was
obtained by lowering the amount of AgNO3 (Table 1, entry 17). In contrast, control
experiments demonstrated that the reaction did not occur in the presence of Cu
catalyst or AgNO3 alone (Table 1, entries 18 and 19), unambiguously revealing that
copper catalyst with the combination of AgNO3 is essential for this reaction. It should
be noted that the product yield was remarkably improved under the current system as
compared to our previous result.4a
Table 1. Screening of the Reaction Conditionsa
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 40
1
2
3
4
5
6
7
8
9
entry
1
Cu
oxidant
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgF
solvent
DMF
time (h)
16
16
16
16
16
16
16
16
4
yield (%)b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CuI
58
35
60
55
62
ꢀꢀd
61
68
65
63
ꢀꢀd
ꢀꢀd
ꢀꢀd
14
ꢀꢀd
9
2
CuBr
DMF
3
CuTcc
DMF
4
CuOTf.0.5C6H6
Cu(CH3CN)4BF4
Cu(OTf)2
DMF
5
DMF
6
DMF
7
Cu(CH3CN)4PF6
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
DMF
8
DMF
9
DMSO
NMP
10
11
12
13
14
15
16
8
EtOAc
CH3OH
dioxane
DMF
16
16
16
16
16
16
Ag2CO3
DMF
Cu(CH3CN)4BF4 PhI(OAc)2
DMF
ACS Paragon Plus Environment

Page 7 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
17e
18
19
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
ꢀꢀ
AgNO3
ꢀꢀ
DMF
DMF
DMF
16
16
16
38
ꢀꢀd
ꢀꢀd
AgNO3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reaction conditions (unless otherwise mentioned): 1a (0.05 mmol), solvent (0.3 mL),
TMSCF3 (4.0 eq), oxidant (1.0 eq), KF (4.0 eq), Cu catalyst loading (entries 1ꢀ7: 25 mol %,
entries 8ꢀ18: 15 mol %), under argon. b Determined by 19F NMR spectroscopy using PhCF3 as an
internal standard. c CuTc = copper(I)ꢀthiopheneꢀ2ꢀcarboxylate. A trace amount of product was
d
observed. e 0.5 eq of AgNO3 was used. Cbz = carbobenzyloxy.
With an optimized set of reaction conditions in hand, we next turned our attention
to assessing the scope of aminotrifluoromethylation of alkenes. As can be seen in
Table 2, regardless of the position and nature of the substituent, various 2ꢀallyl aniline
derivatives reacted efficiently with TMSCF3 to afford the desired products in
moderate to good yields. Reactions of 2ꢀallyl aniline derivatives 1aꢀ1f having
electronꢀdonating and ꢀneutral substituents on the aryl ring at the different positions
worked well, furnishing 2aꢀ2f in 46ꢀ61% yields. Notably, electronꢀwithdrawing
substituents including F, Cl and Br at the different aryl positions were proved to be
wellꢀtolerated under the standard reaction conditions, giving the corresponding
products 2gꢀ2j in good yields. These results are significant since aryl halides are
reactive and, thus, are difficult to be retained in many copperꢀcatalyzed
trifluoromethylation reactions,7d,9 which offer opportunities for further modifications
at these positions.10 Interestingly, a good yield of 2k containing threeꢀrings was
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 40
1
2
3
4
5
6
7
8
9
achieved when exchanging the phenyl moiety for a naphthyl group under similar
reaction conditions. It is more encouraging to note that products that are more difficult
to prepare via Cu(I)ꢀcatalyzed aminotrifluoromethylation with Togni’s reagent,4a such
as 1l and 1m that contain gemꢀdisubstituted alkenes bearing methyl or phenyl group,
can also be accessed by using this method. Furthermore, the protocol could be
extended to the reaction of pentenylcarbamate 1nꢀ1p for the synthesis of highly
substituted trifluoromethylated pyrrolidine 2nꢀ2p; and the product yields were
relatively insensitive to the nature of the substitution on the carbon backbone. Most
importantly, a variety of substituents on the nitrogen atom including Boc and Ts are
compatible under the reaction conditions, giving the desired products 2q and 2r in 60
and 47% yields, respectively.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Aminotrifluoromethylation of Alkenes to Form Five-Membered Ringa,b
ACS Paragon Plus Environment

Page 9 of 40
The Journal of Organic Chemistry
1
2
3
4
O
N
CF3
5
6
7
N
N
CF3
CF3
Cbz
Cbz
Cbz
2a
16 h, 56%
2b
2c
15 h, 61%
28 h, 46%
8
9
Ph
N
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
Cbz
CF3
Cbz
N
CF3
2e
Cbz
2d
2f
44 h, 59%
20 h, 50%
12 h, 57%
F
Cl
N
N
CF3
CF3
N
Cbz
CF3
Cbz
Cbz
2h
15 h, 58%
2g
2i
Cl
15 h, 58%
36 h, 51%
Br
N
CF3
N
N
CF3
CF3
Cbz
Cbz
Cbz
2j
15 h, 50%
2k
2l
34 h, 60%
32 h, 62%
Ph
N
N
CF3
CF3
N
CF3
CF3
Cbz
Cbz
2m
2n
Cbz
2o
24 h, 40%
18 h, 34%
16 h, 42%
Ph
Ph
N
N
Boc
CF3
N
CF3
Ts
2q
36 h, 60%
2r
Cbz
2p
48 h, 47%
16 h, 40%
a Reaction conditions (Unless otherwise mentioned): 1 (0.5 mmol),
TMSCF3 (4.0 eq), KF (4.0 eq), Cu(CH3CN)4BF4 (15 mol %), AgNO3
(1.0 eq) in DMF under argon. b Yield based on the starting alkene. Boc
= tert-butyloxycarbonyl. Ts = p-toluenesulfonyl.
To further investigate the scope of application, we tested the use of more
challenging 2ꢀallyl benzylamine derivatives as substrates, since the expected
sixꢀmembered products could not also be obtained with the previous Cuꢀcatalyzed
aminotrifluoromethylation with Togni’s reagent.4a We are delighted to find that, when
3a was employed under the current reaction system in the presence of TMSCF3, the
desired trifluoromethylated product 4a with the formation of sixꢀmembered ring was
obtained in 52% yield. With regard to the scope of such substrates, monosubstituted
and gemꢀdisubstituted alkenes bearing electronꢀdonating and electronꢀwithdrawing
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 40
1
2
3
4
5
6
7
8
9
groups on the aryl ring also proved to be suitable substrates (3bꢀ3e), furnishing the
corresponding products 4bꢀ4e in 44ꢀ60% yields. Given the broad substrate scope, this
approach is clearly complementary to the previous metalꢀcatalyzed and photoredox
trifluoromethylated methods.3,4a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Aminotrifluoromethylation of Alkenes to Form Six-Membered Ringa,b
It is interesting to note that the current protocol in the presence of TMSCF3 could
be extended to direct intramolecular carbotrifluoromethylation of alkenes. Thus, our
preliminary result showed that, under the similar conditions to those of
aminotrifluoromethylation
reaction
detailed
above,
the
reaction
of
NꢀmethylꢀNꢀphenylacrylamide 3f gave trifluoromethylated product 4f in 40% yield
(Scheme 2).
Scheme 2. Direct Intramolecular Carbotrifluoromethylation of Alkenes
ACS Paragon Plus Environment

Page 11 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Preliminary mechanistic investigations on this reaction have been carried out
(Scheme 3). Firstly, under the standard conditions but with the addition of 1.0 or 2.0
equivalents of 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO), the yield of the
reaction between 1a and TMSCF3 was significantly dropped (eq. 1). However, neither
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
an allylicꢀTEMPO adduct nor a TEMPOꢀCF3 adduct were observed, as judged by F
1
and H NMR analysis of the crude product. It is noteworthy that no TEMPOꢀCF3
adduct was also observed in the reaction mixture of TMSCF3, KF, AgNO3,
Cu(CH3CN)4BF4 (15 mol %) and TEMPO in the absence of 1a (eq. 2). Collectively,
these results reveal that the CF3 radical or the allylic radical is unlikely involved as
the reactive species under the current reaction conditions, which is in agreement with
the observation involving oxidative trifluoromethylation of unactivated alkenes with
TMSCF3 reported by Qing and coꢀworkers.8a Moreover, the reaction was found to be
mostly inhibited by 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) under the standard
conditions (eq. 3). These control experiments possibly suggest that the involvement of
in situ generated CuCF3 or AgCF3 intermediate followed by a single electron transfer
(SET) radical pathway is possible, also based on recent reports involving such
reagents for the trifluoromethylation reactions with SET pathway.7g,7k,11 To further
gain some insights about this hypothesis, under the standard reaction conditions we
examined the aminotrifluoromethylation reaction of 1a with CuCF3 or AgCF3 in situ
generated from TMSCF3, Cu(CH3CN)4BF4 or AgNO3, and KF according to the
reported procedures.7g,7i Interestingly, no detectable amounts of the product 2a was
observed with CuCF3 as reagent (eq. 4), whereas the product 2a was observed with
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 40
1
2
3
4
5
6
7
8
9
AgCF3 as reagent with 57% yield determined by 19F NMR (eq. 5). These observations
clearly indicated that the reaction should proceed with the intermediacy of AgCF3,
which is presumably in situ generated from AgNO3 and TMSCF3 assisted with KF.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Mechanistic Studies
On the basis of the above experimental observations and the previous investigation
on copperꢀcatalyzed hydroamination or aminotrifluoromethylation of alkenes,4,8,11
a
plausible mechanism for our methodology was proposed (Scheme 4), which first
involves outerꢀsphere attack of the nitrogen atom on the Cu(I)ꢀcomplexes alkene of A
to generate the neutral alkylꢀcopper complex B.12 Second, the reaction of TMSCF3,
AgNO3 and KF in situ generates AgCF3, which then reacts with intermediate B via
singleꢀelectron transfer13 to produce the final product 2 and regenerate the cationic
copper catalyst and silver. It is worth noting that a silver mirror was observed at the
ACS Paragon Plus Environment

Page 13 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
end of most of the aminotrifluoromethylation reactions. On the other hand, an
alternative catalytic mechanism, which proceeds by the formation of αꢀCF3ꢀalkyl
radical intermediate initiated from alkene8 followed by the subsequent coupling of
this intermediate and the carbamate nitrogen atom,4a cannot be ruled out at the present
stage. Therefore, rigorous investigations are necessary to unambiguously elucidate the
detailed mechanism.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Proposed Mechanism for the Aminotrofluoromethylation Reaction of
Unactivated Alkenes.
NHR1
NHR1
NR1
Cu(CH3CN)4BF4
Cu+
R2
R2
R2
Cu
n
n
n
A
B
1
in situ
+
KF
+
AgNO3
TMSCF3
SET
AgCF3
NR1
R2
Ag0, Cu+
+
CF3
n
2
CONCLUSION
In summary, we have demonstrated the first example of a copper(I)ꢀcatalyzed
aminotrifluoromethylation of unactivated alkenes with nucleophilic TMSCF3 as the
CF3 source. The methodology furnishes a diverse collection of synthetically valuable
trifluoromethylated azoheterocyles under mild reaction conditions. Furthermore, it has
significant advantages over the conventional aminotrifluoromethylation, because this
approach not only circumvents the use of expensive electrophilic CF3 reagents or the
photoredox strategy, but also expands the substrate scope that is difficult to access by
known methods, thus reflecting the synthetic utility of this method in medicinal
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 40
1
2
3
4
chemistry and materials science related fields.
5
6
7
8
Experimental Section
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General information. All reactions were carried out under Ar using Schlenk
techniques. Reagents were purchased at the highest commercial quality and used
without further purification, unless otherwise stated. KF was activated by
mufflefurnace in high temperature. Analytical thin layer chromatography (TLC) was
performed on precoated silica gel 60 GF254 plates. Flash column chromatography
was performed using silica gel (60, particle size 0.040ꢀ0.063 mm). Visualization on
TLC was achieved by use of UV light (254 nm) or iodine. NMR spectra were
1
recorded on a 400 MHz spectrometer for H NMR, 100 MHz for 13C NMR and 376
MHz for 19F NMR (CFCl3 as an external reference (0 ppm)) in CDCl3 with
tetramethylsilane (TMS) as internal standard. The chemical shifts are expressed in
1
ppm and coupling constants are given in Hz. Data for H NMR are recorded as
follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quarter;
m, multiplet; br, broad), coupling constant (Hz), integration. Highꢀresolution mass
spectrometry (HRMS) was conducted on a TOF mass spectrometer.
General synthesis of carbamate substrates:
Carbamate substrates 1a,4a 1c,14 1e,14 1g,14 1h4a were synthesized according to the
procedures previously reported. The 2ꢀallylaniline substrate15 was synthesized
according to the procedures previously reported.
Synthesis of substrates 1b, 1f, 1i, 1k and 1j.
ACS Paragon Plus Environment

Page 15 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
To a stirred solution of 2ꢀallylaniline substrates (2.0 mmol) and pyridine (0.3 mL, 4.0
mmol) in CH2Cl2 (8 mL) was added CbzCl (0.3 mL, 2.4 mmol) in an iceꢀwater bath,
and the solution was left to warm to room temperature and stirred for additional 4ꢀ8
hours. After complete conversion (monitored by TLC), the reaction was quenched
with H2O (10 mL), and the reaction mixture was extracted with CH2Cl2 (3 x 10 mL).
The combined organic layers were brined, dried (Na2SO4), concentrated in vacuo. The
residue was purified by silica gel column chromatography (eluent: petroleum
ether/EtOAc = 80:1ꢀ30:1) to give 1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Benzyl (2ꢀallylꢀ6ꢀmethylphenyl)carbamate (1b). 450 mg, 80% yield; H NMR (400
MHz, CDCl3) δ 7.43ꢀ7.07 (m, 8H), 6.28 (s, 1H), 5.93ꢀ5.89 (m, 1H), 5.21 (s, 2H), 5.06
(d, J = 9.6 Hz, 1H), 5.00 (d, J = 17.2 Hz, 1H), 3.37 (d, J = 5.6 Hz, 2H), 2.29 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 154.4, 136.8, 136.6, 136.5, 133.6, 129.1, 128.6, 128.2,
127.7, 127.5, 116.0, 67.1, 36.9, 18.4; HRMS (ESI) m/z calcd. for C18H19NNaO2
[M+Na]+ 304.1313, found 304.1309.
Benzyl (2ꢀallylꢀ3,5ꢀdimethylphenyl)carbamate (1f). 461 mg, 78% yield; 1H NMR (400
MHz, CDCl3) δ 7.52ꢀ7.37 (m, 6H), 6.87 (s, 1H), 6.63 (br s, 1H), 6.00ꢀ5.91 (m, 1H),
5.25 (s, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.94 (d, J = 17.2 Hz, 1H), 3.38 (d, J = 4.8 Hz,
2H), 2.36 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.1, 136.9, 136.5,
136.3, 135.8, 135.0, 128.5, 128.2, 128.2, 127.6, 125.1, 121.2, 115.6, 66.9, 31.5, 21.1,
19.9; HRMS (ESI) m/z calcd. for C19H22NO2 [M+H]+ 296.1651, found 296.1643.
1
Benzyl (2ꢀallylꢀ6ꢀchlorophenyl)carbamate (1i). 453 mg, 75% yield; H NMR (400
MHz, CDCl3) δ 7.42ꢀ7.17 (m, 8H), 6.41 (br s, 1H), 5.96 ꢀ5.87 (m, 1H), 5.28 (m, 4H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 40
1
2
3
4
5
6
3.41ꢀ3.33 (m, 2H); HRMS (ESI) m/z calcd. for C17H16ClNNaO2 [M+Na]+ 324.0767,
found 324.0763.
7
8
9
1
Benzyl (2ꢀallylꢀ4ꢀbromophenyl)carbamate (1j). 609 mg, 88% yield; H NMR (400
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3) δ 7.74 (br s, 1H), 7.48ꢀ7.33 (m, 6H), 7.30 (d, J = 2.4 Hz, 1H), 6.66 (br s,
1H), 5.91 (ddt, J = 17.2, 10.0, 6.0 Hz, 1H), 5.20ꢀ5.17 (m, 3H), 5.06 (dd, J = 17.2, 1.6
Hz, 1H), 3.31 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 153.6, 136.0, 135.2,
134.8, 132.8, 131.2, 130.4, 128.7, 128.5, 128.8, 123.5, 117.5, 117.2, 67.2, 36.1;
HRMS (ESI) m/z calcd. for C17H16BrNNaO2 [M+Na]+ 368.0262, found 368.0257.
1
Benzyl (2ꢀallylnaphthalenꢀ1ꢀyl)carbamate (1k). 546 mg, 86% yield; H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz,
1H), 7.55ꢀ7.09 (m, 8H), 6.66 (s, 1H), 6.01ꢀ5.97 (m, 1H), 5.30ꢀ5.05 (m, 4H), 3.56 (d, J
= 5.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 155.1, 136.3, 136.2, 134.8, 133.1,
131.2, 129.8, 128.6, 128.4, 128.1, 128.0, 127.8, 126.7, 125.6, 122.7, 116.2, 67.3, 36.7;
HRMS (ESI) m/z calcd. for C21H20NO2 [M+H]+ 318.1494, found 318.1488.
Synthesis of carbamate substrate 1d. To a solution of 1j (346.2 mg, 1.0 mmol),
phenylboronic acid (183.0 mg, 1.5 mmol), K2CO3 (414.0 mg, 3.0 mmol), and
2ꢀdicyclohexylphosphinoꢀ2′,4′,6′ꢀtriisopropylbiphenyl (XꢀPhos, 9.5 mg, 0.02 mmol)
in CH3CN/H2O (6 mL/4 mL) was added Pd(OAc)2 (2.3 mg 0.01 mmol). The flask and
its contents were put under reduced pressure and then backfilled with argon three
times. The mixture was stirred at 60 °C for 12 h under argon atmosphere, then cooled,
and extracted with CH2Cl2, and the combined organic layer was washed with brine
and dried (Na2SO4). The solvent was removed in vacuo to afford a crude product,
ACS Paragon Plus Environment

Page 17 of 40
The Journal of Organic Chemistry
1
2
3
4
which was purified by flash chromatography (eluent: petroleum ether/EtOAc = 60:1)
5
6
7
to 1d as a white solid.
8
9
1
Benzyl (3ꢀallylꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀyl)carbamate (1d). 268 mg, 78% yield; H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(400 MHz, CDCl3) δ 7.93 (br s, 1H), 7.61ꢀ7.34 (m, 12H), 6.75 (br s, 1H), δ 6.01 (ddt,
J = 17.2, 10.4, 6.0 Hz, 1H), 5.25 (s, 2H), 5.20 (dd, J = 10.0, 1.2 Hz, 1H), 5.12 (dd, J =
17.2, 1.2 Hz, 1H), 3.44 (d, J = 5.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 153.9,
140.6, 137.4, 136.2, 135.7, 135.4, 128.9, 128.8, 128.7, 128.4, 127.2, 127.0, 126.2,
122.2, 117.1, 67.1, 36.7; HRMS (ESI) m/z calcd. for C23H22NO2 [M+H]+ 344.1651,
found 344.1645.
Synthesis of carbamate substrates 1l and 1m. The 2ꢀallylaniline substrate16 was
synthesized according to the procedures previously reported. Benzyl
(2ꢀ(2ꢀmethylallyl)phenyl)carbamate
(1l)
and
benzyl
(2ꢀ(2ꢀphenylallyl)phenyl)carbamate (1m) were obtained by the procedure described
above.
1
Benzyl (2ꢀ(2ꢀmethylallyl)phenyl)carbamate (1l). 239 mg, 85% yield; H NMR (400
MHz, CDCl3) δ 7.89 (br s, 1H), 7.46ꢀ7.36 (m, 5H), 7.32ꢀ7.28 (m, 1H), 7.18 (d, J = 6.8
Hz, 1H), 7.13ꢀ7.09 (m, 1H), 6.87 (br s, 1H), 5.25 (s, 2H), 4.94 (s, 1H), 4.74 (s, 1H),
3.36 (s, 2H), 1.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9, 143.8, 136.5, 136.3,
130.8, 128.6, 128.3, 128.3, 127.6, 124.3, 121.9, 112.5, 66.9, 41.3, 22.4; HRMS (ESI)
m/z calcd. for C18H19NNaO2 [M+Na]+ 304.1313, found 304.1309.
1
Benzyl (2ꢀ(2ꢀphenylallyl)phenyl)carbamate (1m). 282 mg, 82% yield; H NMR (400
MHz, CDCl3) δ 7.81 (br s, 1H), 7.46ꢀ7.28 (m, 12H), 7.20 (d, J = 7.6 Hz, 1H), 7.09 (t,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 40
1
2
3
4
5
6
7
8
9
J = 7.2 Hz, 1H), 6.64 (s, 1H), 5.48 (s, 1H), 5.20 (s, 2H), 4.86 (s, 1H), 3.78 (s, 2H); 13C
NMR (100 MHz, CDCl3) δ 154.1, 145.7, 140.7, 136.2, 136.1, 130.9, 129.1, 128.7,
128.6, 128.5, 128.4, 128.3, 128.0, 127.7, 126.0, 124.7, 114.4, 67.1, 37.9; HRMS (ESI)
m/z calcd. for C23H21NNaO2 [M+Na]+ 366.1470, found 366.1463.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of carbamate substrates 1nꢀ1p. Carbamate substrates 1nꢀ1p were
synthesized according to the procedures previously reported.17
Synthesis of tertꢀbutyl (2ꢀallylꢀ4ꢀmethylphenyl)carbamate (1q). To a stirred solution of
1a (441.6 mg, 3.0 mmol) in tetrahydrofuran (10 mL) was added
diꢀtertꢀbutylꢀdicarbonate (786.0 mg, 3.6 mmol) and triethylamine (TEA, 6.3 ml, 9.0
mmol). The reaction mixture was refluxed for 12 hours, during which time a white
precipitate formed. The solvent was removed in vacuo and ethyl acetate (10 ml) was
added to the residue. The mixture was washed with 1 M citric acid (aq) (3 x 10 ml),
brined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica
gel column chromatography (eluent: petroleum ether/EtOAc = 60/1) to give 1q as a
while solid.
Tertꢀbutyl (2ꢀallylꢀ4ꢀmethylphenyl)carbamate (1q). 608 mg, 82% yield; 1H NMR (400
MHz, CDCl3) δ 7.60 (s, 1H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H),
6.35 (s, 1H), 5.95 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.15 (dq, J = 10.0, 1.6 Hz, 1H),
5.06 (dq, J = 17.2, 1.6 Hz, 1H), 3.33 (d, J = 6.0 Hz, 2H), 2.29 (s, 3H), 1.51 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 153.5, 136.1, 133.8, 133.8, 130.6, 129.5, 127.9, 122.6,
116.4, 80.2, 36.5, 28.4, 20.8; HRMS (ESI) m/z calcd. for C15H21NNaO2 [M+Na]+
270.1470, found 270.1465.
ACS Paragon Plus Environment

Page 19 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of carbamate substrates 3aꢀ3e. Carbamate substrate 3a18 was synthesized
according to the procedures previously reported. 2ꢀIodoꢀ4ꢀmethylbenzonitrile19 was
prepared according to literature procedure. To a suspension of Pd2(dba)3 (183.1 mg,
0.2 mmol), triphenylphosphine (419.7 mg, 1.6 mmol) and lithium chloride (1.3 g, 30.0
mmol) in DMF (30 mL) was added 2ꢀiodoꢀ4ꢀmethylbenzonitrile (2.4 mg, 10.0 mmol)
at room temperature under a argon atmosphere. After 15 minutes, allyl indium reagent
which is generated from allyl iodide (2.5 g, 15.0 mmol) and indium (1.1 g, 10.0 mmol)
in DMF (5 mL) was added and the mixture was stirred at 100 °C for 8 hours. The
reaction mixture was quenched with NaHCO3 (sat. aq.). The aqueous layer was
extracted with EtOAc (3 ×50 mL), and the combined organics were washed with
water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was
purified by silica gel column chromatography (eluent: petroleum ether/EtOAc = 80/1)
to afford 2ꢀallylꢀ4ꢀmethylbenzonitrile (1.1 g, 68 %).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To a suspension of LiAlH4 (LAH, 425.4 mg, 11.2 mmol) in THF (15 mL) at 0 °C was
slowly added a solution of 2ꢀallylꢀ4ꢀmethylbenzonitrile (440.2 mg, 2.8 mmol) in THF
(10.0 mL). After being stirred for 3 hours at 0 °C, the reaction mixture was quenched
by slow, sequential addition of water (0.5 mL) in Na2SO4 (3.0 g). The reaction
mixture was warmed to room temperature, stirred for an additional 30 minutes,
filtered, and concentrated in vacuo. The crude material was directly used in the next
reaction. Benzyl 2ꢀallylꢀ4ꢀmethylbenzylcarbamate (3b) was obtained by the procedure
described above.
Benzyl 2ꢀallylꢀ4ꢀmethylbenzylcarbamate (3b). 414 mg, 50% yield, two steps; 1H NMR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 40
1
2
3
4
5
6
7
8
9
(400 MHz, CDCl3) δ 7.39ꢀ732 (m, 5H), 7.22 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz,
2H), 6.02ꢀ5.94 (m, 1H), 5.15ꢀ.501 (m, 5H), 4.38 (d, J = 5.6 Hz, 2H), 3.42 (d, J = 6.0
Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.1, 137.7, 137.6, 137.1,
136.6, 133.1, 130.8, 128.9, 128.5, 128.1, 127.4, 115.9, 66.7, 42.4, 36.9, 21.0; HRMS
(ESI) m/z calcd. for C19H21NNaO2 [M+Na]+ 318.1470, found 318.1467.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀBromoꢀ5ꢀfluorobenzonitrile (400.0 mg, 2.0 mmol) was treated with allyltributyl tin
(0.81 mL, 2.6 mmol) and palladium tetrakistriphenylphosphine (462.2 mg 0.4 mmol)
in degassed, dry toluene (10 mL) and the mixture was refluxed for 24 hours.20 Then
cooled, the crude mixture was directly filtered through SiO2 and the solvent was
removed in vacuo, the residue was purified by a silica gel column chromatography
(eluent: petroleum ether/EtOAc = 80/1) to give 2ꢀallylꢀ5ꢀfluorobenzonitrile (177.3 mg,
55%) as a liquid. Benzyl 2ꢀallylꢀ4ꢀfluorobenzylcarbamate (3c) was obtained by the
procedure described above.
1
Benzyl 2ꢀallylꢀ4ꢀfluorobenzylcarbamate (3c). 185 mg, 65% yield, two steps; H NMR
(400 MHz, CDCl3) δ 7.36ꢀ7.31 (m, 5H), 7.27ꢀ7.23 (m, 1H), 6.90 (d, J = 9.2 Hz, 2H),
5.93 (ddt, J = 17.2, 10.4, 6.0 Hz, 1H), 5.12ꢀ4.98 (m, 5H), 4.35 (d, J = 5.6 Hz, 2H),
3.40 (d, J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 162.3 (d, J = 244.4 Hz),
156.2, 140.3 (d, J = 7.1 Hz), 136.4, 136.1, 131.9, 130.5 (d, J = 8.4 Hz), 128.6, 128.2,
128.2, 116.8, 116.7 (d, J = 21.2 Hz), 113.4 (d, J = 21.0 Hz), 66.9, 42.1, 36.8; 19F
NMR (376 MHz, CDCl3) δ ꢀ114.85 (dd, J = 14.9, 8.8 Hz); HRMS (ESI) m/z calcd. for
C18H18FNNaO2 [M+Na]+ 322.1219, found 322.1214.
2ꢀAllylꢀ4ꢀchlorobenzonitrile and 2ꢀ(2ꢀmethylallyl)benzonitrile was prepared
ACS Paragon Plus Environment

Page 21 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
according to literature procedure.21 3d-3e were obtained by the procedure described
above.
7
8
9
Benzyl 2ꢀallylꢀ4ꢀchlorobenzylcarbamate (3d). 196 mg, 62% yield, two steps; 1H NMR
(400 MHz, CDCl3) δ 7.36ꢀ7.32 (m, 5H), 7.26ꢀ7.17 (m, 3H), 5.92(ddt, J = 17.2, 10.4,
6.0 Hz, 1H), 5.12ꢀ4.97 (m, 5H), 4.35 (d, J = 5.6 Hz, 2H), 3.39 (d, J = 6.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 156.2, 139.7, 136.4, 136.0, 134.8, 133.5, 130.0, 129.9,
128.6, 128.2, 128.2, 126.8, 116.9, 67.0, 42.1, 36.7; HRMS (ESI) m/z calcd. for
C18H18ClNNaO2 [M+Na]+ 338.0924, found 338.0917.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Benzyl 2ꢀ(2ꢀmethylallyl)benzylcarbamate (3e). 171 mg, 58% yield, two steps; H
NMR (400 MHz, CDCl3) δ 7.39ꢀ7.19 (m, 9H), 5.22 (s, 1H), 5.16 (s, 2H), 4.88 (s, 1H),
4.55 (s, 1H), 4.41 (d, J = 6.0 Hz, 2H), 3.40 (s, 2H), 1.79 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 156.2, 144.8, 137.4, 136.5, 130.6, 128.6, 128.4, 128.0, 127.6, 126.7, 111.9,
66.6, 42.5, 41.0, 22.7; HRMS (ESI) m/z calcd. for C19H21NNaO2 [M+Na]+ 318.1470,
found 318.1463.
Experiments to remove Cbz group.
A solution of 2o (35.5 mg, 0.1 mmol) in CH3OH (5.0 mL) was stirred in the presence
of 10% Pd(OH)2/C (60.0 mg) under H2 (H2 balloon) at room temperature for 24 h. The
catalyst was filtered through celite and washed with EtOAc, the filtrate was
concentrated in vacuo and the residue was purified by a silica gel column
chromatography (eluent: CH2Cl2/CH3OH = 100/1ꢀ30/1) to give 5 (18 mg, 81%) as a
liquid. The present spectrum is consistent with our previous reported.4a
1
3ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ2ꢀazaspiro[4.5]decane (5). H NMR (400 MHz, CDCl3) δ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 40
1
2
3
4
5
6
7
8
9
3.43 (s, 1H), 2.75ꢀ2.85 (m, 2H), 2.38ꢀ2.17 (m, 4H), 1.89 (s, 1H), 1.44ꢀ1.41 (m, 10H).
13C NMR (100 MHz, CDCl3) δ 126.6 (q, J = 275.3 Hz), 58.2, 52.1, 45.3, 43.0, 40.5 (q,
J = 26.6 Hz), 38.4, 37.0, 26.1, 24.0, 23.6; 19F NMR (376 MHz, CDCl3) δ ꢀ64.31 (s,
3F); HRMS (ESI) m/z calcd. for C11H19F3N [M+H]+ 222.1470, found 222.1461.
General procedure: copper-catalyzed intramolecular aminotrifluoromethylation
of unactivated alkenes with TMSCF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Under argon, an ovenꢀdried resealable Schlenk tube equipped with a magnetic stir bar
was charged with activated KF (116.0 mg, 2.0 mmol, 4.0 equiv), Cu(CH3CN)4BF4
(26.0 mg, 0.075 mmol, 15 mol %), carbamate substrates (0.5 mmol, 1.0 equiv),
AgNO3 (85.0 mg, 0.5 mmol, 1.0 equiv), DMF (super dry, 3.0 mL),
trimethyl(trifluoromethyl)silane (TMSCF3, 0.3 mL, 2.0 mmol, 4.0 equiv). The sealed
tube was then stirred at 80 °C. Upon completion (monitored by TLC), solvent was
removed in vacuo, and the residue was purified by a silica gel column
chromatography (eluent: petroleum ether/EtOAc = 80/1ꢀ15/1) to give the desired
products. (NOTE: the reaction was waterꢀsensitive, the reagents and Schlenk tube
must be dried prior to use).
Benzyl 5ꢀmethylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2a) 4a
98 mg, 56%
.
yield; 1H NMR (400 MHz, CDCl3) δ 7.76 (br s, 1H), 7.48ꢀ7.36 (m, 5H), 7.02 (s, 2H),
5.34 (s, 2H), 4.80ꢀ4.78 (m, 1H), 3.40 (dd, J = 16.4, 9.6 Hz, 1H), 2.97 (d, J = 16.4 Hz,
13
1H), 2.66 (br s, 1H), 2.40ꢀ2.26 (m, 4H); C NMR (100 MHz, CDCl3) δ 152.3 (br s),
138.7 (br s), 136.1, 133.0, 129.2, 128.7, 128.5, 128.4, 128.2, 126.0 (q, J = 275.9 Hz),
125.8, 115.3, 67.5, 54.3, 38.2 (br s), 33.7 (br s), 20.8; 19F NMR (376 MHz, CDCl3,
ACS Paragon Plus Environment

Page 23 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
observed as a mixture of rotamers, major and minor) δ ꢀ62.86 (br s, 3F, minor), ꢀ63.24
(br s, 3F, major); HRMS (ESI) m/z calcd. for C19H18F3NNaO2 [M+Na]+ 372.1187,
found 372.1182.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 7ꢀmethylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2b). 80 mg, 46% yield;
1H NMR (400 MHz, CDCl3) δ 7.43ꢀ7.34 (m, 5H), 7.08ꢀ7.02 (m, 3H), 5.27 (q, J = 12.4
Hz, 2H), 5.02 (dd, J = 14.8, 7.2 Hz, 1H), 3.47 (dd, J = 16.0, 8.0 Hz, 1H), 2.66 (d, J =
16.0 Hz, 1H), 2.50ꢀ2.39 (m, 1H), 2.31ꢀ2.19 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
153.9, 139.6, 136.0, 131.9, 130.3, 128.9, 128.6, 128.3, 128.2, 125.8 (q, J = 275.7 Hz),
125.2, 122.3, 67.8, 56.6, 38.4 (q, J = 27.0 Hz), 35.1, 20.0; 19F NMR (376 MHz,
CDCl3) δ ꢀ63.44 (t, J = 10.6 Hz, 3F); HRMS (ESI) m/z calcd. for C19H19F3NO2
[M+H]+ 350.1368, found 350.1362
Benzyl 5ꢀmethoxyꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2c). 111 mg, 61%
1
yield; H NMR (400 MHz, CDCl3) δ7.78 (br s, 1H), 7.46ꢀ7.33 (m, 5H), 6.76 (s, 2H),
5.31 (s, 2H), 4.79 (s, 1H), 3.77 (s, 3H), 3.40 (dd, J = 16.4, 9.6 Hz, 1H), 2.95 (d, J =
16.4 Hz, 1H), 2.62 (br s, 1H), 2.39ꢀ2.25 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
156.3, 152.1 (br s), 136.0, 134.8 (br s), 130.3 (br s), 128.7, 128.4, 128.2, 125.9 (q, J =
275.8 Hz), 116.0, 112.5, 111.3, 67.4 (br s), 55.6, 54.2 (br s), 38.4 (br s), 34.2 (br s);
19F NMR (376 MHz, CDCl3, observed as a mixture of rotamers, major and minor) δ
ꢀ62.87 (br s, 3F, minor), ꢀ63.27 (br s, 3F, major); HRMS (ESI) m/z calcd. for
C19H18F3NNaO3 [M+Na]+ 388.1136, found 388.1128.
Benzyl 5ꢀphenylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2d). 103 mg, 50%
yield; 1H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1H), 7.66ꢀ7.27 (m, 12H), 5.36 (s, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 40
1
2
3
4
5
6
7
8
9
4.89ꢀ4.84 (m, 1H), 3.51 (dd, J = 16.4, 9.6 Hz, 1H), 3.08 (d, J = 16.4 Hz, 1H),
2.88ꢀ2.64 (m, 1H), 2.46ꢀ2.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 152.4 (br s),
140.7, 136.8, 135.8, 128.9, 128.8, 128.5, 128.3, 127.1, 126.9, 126.9, 125.9 (q, J =
273.7 Hz), 123.9, 115.7, 67.8 (br s), 54.6 (br s), 38.5 (br s), 34.0 (br s); 19F NMR (376
MHz, CDCl3, observed as a mixture of rotamers, major and minor) δ ꢀ62.88 (br s, 3F,
minor), ꢀ63.28 (br s, 3F, major); HRMS (ESI) m/z calcd. for C24H20F3NNaO2
[M+Na]+ 434.1344, found 434.1337.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Benzyl 2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2e). 99 mg, 59% yield; H
NMR (400 MHz, CDCl3) δ 7.86 (br s, 1H), 7.47ꢀ7.35 (m, 5H), 7.20 (d, J = 7.2 Hz,
2H), 7.02 (t, J = 7.6 Hz, 1H), 5.33 (s, 2H), 4.83ꢀ4.78 (m, 1H), 3.43 (dd, J = 16.8, 9.6
Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.64 (br s, 1H), 2.40ꢀ2.26 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 152.1 (br s), 140.9 (br s), 135.9, 128.7, 128.4, 128.3, 127.9, 125.9 (q,
J = 275.7 Hz), 125.1, 123.4, 115.5, 67.6 (br s), 54.2 (br s), 38.3 (br s), 33.9 (br s); 19F
NMR (376 MHz, CDCl3, observed as a mixture of rotamers, major and minor) δ
ꢀ62.92 (br s, 3F, minor), ꢀ63.28 (br s, 3F, major); HRMS (ESI) m/z calcd. for
C18H16F3NNaO2 [M+Na]+ 358.1031, found 358.1026.
Benzyl 4,6ꢀdimethylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2f). 103 mg, 57%
1
yield; H NMR (400 MHz, CDCl3) δ 7.61ꢀ7.25 (m, 6H), 6.70 (s, 1H), 5.33 (s, 2H),
4.85ꢀ4.79 (m, 1H), 3.26 (dd, J = 16.4, 9.6 Hz, 1H), 2.88 (d, J = 16.4 Hz, 1H), 2.65 (br
s, 1H), 2.39ꢀ2.27 (m, 4H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.3 (br s),
141.0 (br s), 138.0, 136.0, 134.2, 128.7, 128.4, 128.2, 125.9 (q, J = 275.8 Hz), 125.3,
124.7, 113.7, 67.5 (br s), 54.4 (br s), 38.7 (br s), 32.6 (br s), 21.6, 18.6, 18.5; 19F NMR
ACS Paragon Plus Environment

Page 25 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(376 MHz, CDCl3, observed as a mixture of rotamers, major and minor) δ ꢀ62.91 (br s,
3F, minor), ꢀ63.27 (br s, 3F, major); HRMS (ESI) m/z calcd. for C20H20F3NNaO2
[M+Na]+ 386.1344, found 386.1337.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 5ꢀfluoroꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2g). 102 mg, 58%
yield; 1H NMR (400 MHz, CDCl3) δ 7.79 (br s, 1H), 7.45ꢀ7.34 (m, 5H), 6.90 (s, 1H),
6.88 (s, 1H), 5.31 (s, 2H), 4.81 (s, 1H), 3.41 (dd, J = 16.8, 9.6 Hz, 1H), 2.97 (d, J =
16.8 Hz, 1H), 2.63 (br s, 1H), 2.40ꢀ2.26 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
159.3 (d, J = 241.8 Hz), 152.2 (br s), 137.3 (br s), 135.7, 130.8 (br s), 128.7, 128.5,
128.3, 125.6 (q, J = 275.9 Hz), 116.2 (d, J = 8.3 Hz), 114.2 (d, J = 23.1 Hz), 112.4 (d,
J = 23.9 Hz), 67.7 (br s), 54.5 (br s), 38.4 (br s), 33.9 (br s); 19F NMR (376 MHz,
CDCl3, observed as a mixture of rotamers, major and minor) δ ꢀ62.91 (br s, 3F, minor),
ꢀ63.29 (br s, 3F, major); ꢀ119.91 (br s, 1F, major), ꢀ120.29 (br s, 1F, minor); HRMS
(ESI) m/z calcd. for C18H15F4NNaO2 [M+Na]+ 376.0937, found 376.0931.
Benzyl 5ꢀchloroꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2h).4a 107 mg, 58%
1
yield; H NMR (400 MHz, CDCl3) δ 7.73 (br s, 1H), 7.42ꢀ7.35 (m, 5H), 7.14 (br s,
2H), 5.29 (s, 2H), 4.81ꢀ4.76 (m, 1H), 3.39 (dd, J = 16.8, 9.6 Hz, 1H), 2.96 (d, J = 16.8
Hz, 1H), 2.64 (br s, 1H), 2.38ꢀ2.24 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 152.3,
139.8, 135.8, 131.1, 128.8, 128.6, 128.4, 128.3, 127.9, 125.8 (q, J = 275.8 Hz), 125.3,
116.5, 67.9, 54.6, 38.1, 33.6; 19F NMR (376 MHz, CDCl3, observed as a mixture of
rotamers, major and minor) δ ꢀ62.93 (br s, 3F, minor), ꢀ63.27 (br s, 3F, major); HRMS
(APCI) m/z calcd. for C17H16ClF3N [MꢀCO2+H]+ 326.0923, found 326.0856.
Benzyl 7ꢀchloroꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2i). 94 mg, 51% yield;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 40
1
2
3
4
5
6
7
8
9
1H NMR (400 MHz, CDCl3) δ 7.50ꢀ7.33 (m, 5H), 7.26 (d, J = 8.0 Hz, 1H), 7.14 (d, J
= 7.2 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 5.31 (s, 2H), 4.99 (td, J = 8.4, 5.2 Hz, 1H),
3.51 (dd, J = 16.0, 8.4 Hz, 1H), 2.78 (d, J = 16.0 Hz, 1H), 2.59ꢀ2.48 (m, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
2.37ꢀ2.25 (m, 1H); C NMR (100 MHz, CDCl3) δ 153.4, 138.4, 135.6, 134.6, 129.7,
128.6, 128.4, 126.2, 125.7 (q, J = 275.7 Hz), 124.7, 123.4, 68.2, 57.4 (q, J = 2.6 Hz),
38.5 (q, J = 27.0 Hz), 35.2; 19F NMR (376 MHz, CDCl3) δ ꢀ63.38 (t, J = 10.6 Hz, 3F);
HRMS (ESI) m/z calcd. for C18H15ClF3NNaO2 [M+Na]+ 392.0641, found 392.0633.
Benzyl 5ꢀbromoꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2j). 104 mg, 50%
yield; 1H NMR (400 MHz, CDCl3) δ 7.74 (br s, 1H), 7.46ꢀ7.28 (m, 7H), 5.33 (s, 2H),
4.84ꢀ4.79 (m, 1H), 3.43 (dd, J = 16.8, 9.6 Hz, 1H), 3.00 (d, J = 16.8 Hz, 1H), 2.63 (br
s, 1H), 2.41ꢀ2.27 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 152.2 (br s), 140.3 (br s),
135.6, 131.3, 130.8, 128.7, 128.6, 128.3, 128.2, 125.7 (q, J = 275.7 Hz), 116.9, 115.8,
67.9 (br s), 54.5 (br s), 38.2 (br s), 33.6 (br s); 19F NMR (376 MHz, CDCl3, observed
as a mixture of rotamers, major and minor) δ ꢀ62.86 (br s, 3F, minor), ꢀ63.26 (br s, 3F,
major); HRMS (ESI) m/z calcd. for C18H15BrF3NNaO2 [M+Na]+ 436.0136, found
436.0130.
Benzyl 2ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ2,3ꢀdihydroꢀ1Hꢀbenzoꢀ[g]indoleꢀ1ꢀcarboxylate (2k).
1
119 mg, 62% yield; H NMR (400 MHz, CDCl3) δ 7.97ꢀ7.92 (m, 1H), 7.87ꢀ7.82 (m,
1H), 7.68 (d, J = 8.4 Hz, 1H), 7.52ꢀ7.33 (m, 8H), 5.39 (d, J = 12.4 Hz, 1H), 5.25 (d, J
= 12.4 Hz, 1H), 5.19 (q, J = 7.2 Hz, 1H), 3.67 (dd, J = 16.0, 8.0 Hz, 1H), 2.82 (d, J =
16.0 Hz, 1H), 2.62ꢀ2.48 (m, 1H), 2.36ꢀ2.23 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
154.5, 136.6, 135.9, 134.0, 128.6, 128.3, 128.2, 126.6, 125.9 (q, J = 275.8 Hz), 125.5,
ACS Paragon Plus Environment

Page 27 of 40
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
125.2, 124.8, 122.5, 68.0, 57.4 (q, J = 3.8 Hz), 38.7 (q, J = 26.9 Hz), 35.6; 19F NMR
(376 MHz, CDCl3) δ ꢀ63.28 (t, J = 10.5 Hz, 3F); HRMS (ESI) m/z calcd. for
C22H19F3NO2 [M+H]+ 386.1368, found 386.1364.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 2ꢀmethylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2l). 105 mg, 60%
yield; 1H NMR (400 MHz, CDCl3) δ 7.45ꢀ7.34 (m, 6H), 7.13 (d, J = 7.6 Hz, 2H), 6.98
(t, J = 7.6 Hz, 1H), 5.31 (dd, J = 18.4, 12.0 Hz, 2H),3.46 (d, J = 16.4 Hz, 1H), 3.05 (d,
J = 16.4 Hz, 1H), 2.89 (br s, 2H), 1.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.1,
141.6 (br s), 135.8, 128.8, 128.5, 128.4, 127.9, 126.0 (q, J = 275.8 Hz), 124.7, 123.2,
19
115.8, 67.6, 63.9, 42.7, 41.1 (br s), 26.5 (br s); F NMR (376 MHz, CDCl3) δ ꢀ60.83
(s, 3F); HRMS (ESI) m/z calcd. for C19H19F3NO2 [M+H]+ 350.1368, found 350.1361.
Benzyl 2ꢀphenylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)indolineꢀ1ꢀcarboxylate (2m). 70 mg, 34%
1
yield; H NMR (400 MHz, CDCl3, observed as a mixture of rotamers, major and
minor) δ 8.16 (d, J = 6.4 Hz, 1H, major), 7.67 (s, 1H, minor), 7.56ꢀ6.98 (m, 13H,
major + minor), 6.74 (d, J = 14.4 Hz, 1H, major + minor), 5.32ꢀ4.93 (m, 2H, major +
minor), 3.95 (br s, 1H, minor), 3.76 (d, J = 17.2 Hz, 1H, major + minor), 3.56ꢀ3.45 (m,
1H, major), 3.39 (d, J = 16.8 Hz, 1H, major + minor), 3.05ꢀ2.94 (m, 1H, major +
minor); 13C NMR (100 MHz, CDCl3, observed as a mixture of rotamers, major and
minor) δ 152.7, 147.4, 143.2, 135.3, 129.1, 128.6, 128.5
(major), 128.5 (minor), 128.3,
128.0, 127.8, 127.3, 127.1 (overlap), 126.0, 124.2 (overlap), 123.4
(
major , 123.1
)
(minor), 115.3, 67.2 (major), 66.2 (minor), 46.5, 45.1, 41.6 (q, J = 26.2 Hz); 19F NMR
(376 MHz, CDCl3, observed as a mixture of rotamers, major and minor) δ ꢀ60.54 (br s,
3F, minor), ꢀ60.93 (br s, 3F, major); HRMS (ESI) m/z calcd. for C24H21F3NO2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 40
1
2
3
4
[M+H]+ 412.1524, found 412.1518.
5
6
7
Benzyl 4,4ꢀdimethylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)pyrrolidineꢀ1ꢀcarboxylꢀate (2n). 66 mg, 42%
8
9
1
yield; H NMR (400 MHz, DMSO, observed as a mixture of rotamers, major and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
minor) δ 7.40ꢀ7.31 (m, 5H, major + minor), 5.11ꢀ5.09 (m, 2H, major + minor), 4.03ꢀ
3.95 (m, 1H, major + minor), 3.35ꢀ3.33 (m, 1H, major + minor), 3.06ꢀ2.96 (m, 2H,
major + minor), 2.84ꢀ2.75 (m, 1H, minor), 2.48ꢀ2.36 (m, 1H, major + minor),
1.96ꢀ1.91 (m, 1H, major + minor), 1.64ꢀ1.59 (m, 1H, major + minor), 1.06 (s, 3H,
major + minor), 0.93 (s, 3H, major + minor); 13C NMR (100 MHz, DMSO, observed
as a mixture of rotamers, major and minor) δ 154.8 (major), 154.7 (minor), 137.4
(major), 137.4 (minor), 128.9, 128.3, 127.9, 127.0 (q, J = 275.3 Hz), 66.8 (minor),
66.4 (major), 58.9 (minor), 58.7 (major), 52.4 (major), 51.8 (minor), 46.1 (minor),
45.1 (major), 38.6 (q, J = 25.6 Hz, minor), 37.2 (q, J = 25.6 Hz, major), 37.8 (major),
37.5 (minor), 26.1, 25.7; 19F NMR (376 MHz, CDCl3, observed as a mixture of
rotamers, major and minor) δ ꢀ63.26 (t, J = 11.6 Hz, 3F, major), ꢀ63.50 (t, J = 11.6 Hz,
3F, minor).
1H NMR (500 MHz, DMSO, 60 oC) δ 7.51ꢀ7.43 (m, 5H), 5.28ꢀ5.19 (dd, J = 18.5, 10.5,
Hz, 2H), 4.18ꢀ4.12 (m, 1H), 3.49 (d, J = 10.5 Hz, 1H), 3.15 (d, J = 10.5 Hz, H), 3.07
(br s, 1H), 2.63ꢀ2.45 (m, 1H), 2.09 (dd, J = 12.5, 7.5 Hz, 1H), 1.76 (dd, J = 12.5, 8.5
o
Hz, 1H), 1.21 (s, 3H), 1.08 (s, 3H); 13C NMR (126 MHz, DMSO, 60 C) δ 154.9,
137.4, 128.8, 128.3, 127.9, 127.0 (q, J = 278.1 Hz), 66.7, 59.1, 52.3, 45.6, 37.6, 26.2,
25.9; HRMS (ESI) m/z calcd. for C16H20F3NNaO2 [M+Na]+ 338.1344, found
338.1339.
ACS Paragon Plus Environment

Page 29 of 40
The Journal of Organic Chemistry
1
2
3
4
Benzyl 3ꢀ(2,2,2ꢀtrifluoroethyl)ꢀ2ꢀazaspiro[4.5]decaneꢀ2ꢀcarboxylate (2o). 71 mg, 40%
5
6
7
1
yield; H NMR (400 MHz, CDCl3 observed as a mixture of rotamers, major and
8
9
minor) δ 7.37ꢀ7.32 (m, 5H, major + minor), 5.21ꢀ5.09 (m, 2H, major + minor),
4.09ꢀ4.02 (m, 1H, major + minor), 3.69 (d, J = 10.8 Hz, 1H, major), 3.58 (d, J = 10.8
Hz, 1H, minor), 3.25ꢀ3.13 (m, 1H, minor), 2.96 (d, J = 11.2 Hz, 1H, major + minor),
2.92ꢀ2.80 (m, 1H, major), 2.18ꢀ2.00 (m, 2H, major + minor), 1.49ꢀ1.38 (m, 11H,
major + minor); 13C NMR (100 MHz, CDCl3, observed as a mixture of rotamers,
major and minor) δ 155.3 (major), 155.1 (minor), 136.8 (major), 136.4 (minor), 128.6,
128.2 (minor), 128.1 (major), 127.8, 126.3 (q, J = 275.3 Hz), 67.3 (minor), 66.9
(major), 56.7 (minor), 56.5 (major), 51.8 (major), 51.2 (minor), 44.5 (minor), 43.3
(major), 41.6 (major), 41.4 (minor), 39.6 (q, J = 25.1 Hz, minor), 38.1 (q, J = 26.4 Hz,
major), 36.3, 34.4 (minor), 34.3 (major), 26.1, 23.8, 22.9 (minor), 22.8 (major); 19F
NMR (376 MHz, CDCl3, observed as a mixture of rotamers, major and minor) δ
ꢀ63.24 (t, J = 10.9 Hz, 3F, major), ꢀ63.62 (t, J = 10.9 Hz, 3F, minor); HRMS (ESI)
m/z calcd. for C19H24F3NNaO2 [M+Na]+ 378.1657, found 378.1653.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Benzyl 4,4ꢀdiphenylꢀ2ꢀ(2,2,2ꢀtrifluoroethyl)pyrrolidineꢀ1ꢀcarboxylate (2p). 88 mg, 40%
1
yield; H NMR (400 MHz, CDCl3 observed as a mixture of rotamers, major and
minor) δ 7.44ꢀ7.16 (m, 15H, major + minor), 5.35ꢀ5.11(m, 2H, major + minor), 4.73
(dd, J = 11.6, 2.0 Hz, 1H, major), 4.59 (dd, J = 11.6, 1.6 Hz, 1H, minor), 4.01ꢀ3.91 (m,
1H, major + minor), 3.73 (d, J = 11.6 Hz, 1H, major + minor), 3.28ꢀ3.15 (m, 1H,
minor), 3.08ꢀ3.00 (m, 1H, major + minor), 2.97ꢀ2.84 (m, 1H, major), 2.59ꢀ2.49 (m,
1H, major + minor), 2.18ꢀ2.01 (m, 1H, major + minor); 13C NMR (100 MHz, CDCl3,
ACS Paragon Plus Environment