Diastereoselective Synthesis of Enantioenriched Trifluoromethylated Ethylenediamines and Isoindolines Containing Two Stereogenic Carbon Centers by Nucleophilic Trifluoromethylation Using HFC-23

Article abstract of DOI:10.1021/acs.joc.0c00796

Fluoroform, HFC-23, is an industrial byproduct from the synthesis of polytetrafluoroethylene and is a vastly underused resource; however, its physicochemical properties have hindered progress toward synthetic uses. Herein, we describe the use of HFC-23 as a cheap trifluoromethylating agent in two reactions for the highly diastereoselective synthesis of medicinally attractive chiral amines with two stereogenic carbon centers: A base-dependent, stereodivergent nucleophilic addition to synthesize enantioenriched vicinal diamines and a tandem nucleophilic addition/aza-Michael sequence toward enantioenriched isoindolines.

Full text of DOI:10.1021/acs.joc.0c00796

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Article
Diastereoselective Synthesis of Enantioenriched Trifluoromethylated
Ethylenediamines and Isoindolines Containing Two Stereogenic
Carbon Centers by Nucleophilic Trifluoromethylation Using HFC-23
Kazuki Hirano, Takuya Saito, Yamato Fujihira, Daniel M. Sedgwick, Santos Fustero, and Norio Shibata
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00796 • Publication Date (Web): 18 May 2020
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Page 1 of 11
The Journal of Organic Chemistry
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Diastereoselective Synthesis of Enantioenriched Trifluoromethylated
Ethylenediamines and Isoindolines Containing Two Stereogenic Carbon
Centers by Nucleophilic Trifluoromethylation Using HFC-23
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Kazuki Hirano,† Takuya Saito,† Yamato Fujihira, Daniel M. Sedgwick,‡ Santos Fustero,‡ and Norio
Shibata*†‖
† Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-5888,
Japan.
‡ Departmento de Química Orgánica, Universitat de València, 46100 Burjassot, Spain
‖ Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University,
688 Yingbin Avenue, 321004 Jinhua, China
*E-mail: nozshiba@nitech.ac.jp
Supporting Information Placeholder
ABSTRACT: Fluoroform, HFC-23, is an industrial by-product
O
S-tBu
(
O
X
in the synthesis of polytetrafluoroethylene and a vastly un-
derused resource, although its physicochemical properties
have hindered progress towards synthetic uses. Herein, we
describe the use of HFC-23 as a cheap trifluoromethylating
agent in two reactions for the highly diastereoselective syn-
thesis of medicinally attractive chiral amines with two stere-
ogenic carbon centers: a base-dependent, stereodivergent
nucleophilic addition to synthesize enantioenriched vicinal
CF3
O
S-tBu
Bn2N
S-
tBu
)
N
N
Bn2N
S
)
R
(
N
)
H
S
-
R
(
CF3
P4 tBu
CO2R
R
X
(
R
(
)
1
Rs
O
(
)-
3
)-
Ss
-
(
2
S
)-
HCF3
-23
Rs
(
,
to 99:1
up
CF3
N
S-tBu
P4 tBu
toluene
(HFC
)
toluene
−
R
( )
º
78
C
O
S-tBu
−
CO2
R
º
Bn2N
78
C
4
R R
,
S
up
,
s
N
)-
to 99:1
R
)
(
H
KHMDS
to 93:7
R
2
R
)-
Rs
up
(
,
diamines, and a tandem nucleophilic addition/aza-Michael sequence towards enantioenriched isoindolines.
Introduction
Since then, the same idea has been applied to the devel-
opment of other reagents bearing similar fluorinated alkyl
groups such as difluoromethyltrimethylsilane (Me3SiCF2H)
or pentafluoroethyltrimethylsilane (Me3SiC2F5). To date,
these reagents have been exploited in nucleophilic addi-
tions to a wide array of electrophiles, including carbonyls
and imines.5 However, the preparation of these reagents is
costly, and their use in reactions is not atom economical.6 In
this sense, fluoroform represents the “ideal” reagent for the
introduction of the trifluoromethyl group (Figure 1b). Fluo-
roform (HFC-23, CF3H and trifluoromethane), is ubiquitous
in a massive amount globally as an industrial by-product in
the synthesis of polytetrafluoroethylene (PTFE), and is also
a potent greenhouse gas that promotes global warming.7 It
would, therefore, be extremely beneficial to exploit this in-
expensive and vastly underused resource in chemical reac-
tions and industrial applications. Unfortunately, advances
in methodologies using HFC-23 have been somewhat scarce
despite its simple structure, largely due to its undesirable
physicochemical properties; it has a low boiling point of –
82 °C and a high pKa value of 27.8 Furthermore, the result-
ing trifluoromethyl anion is highly unstable, and spontane-
The introduction of fluorine and fluorinated functional
groups into pharmaceuticals and agrochemicals has be-
come commonplace.1 The unique characteristics of the C—
F bond allow us to fine-tune properties such as metabolic
stability, lipophilicity and acidity/basicity of a given com-
pound as necessary.2 The development of new methodolo-
gies to introduce these groups into different structures of
biological and synthetic interest is therefore of great inter-
est to the synthetic community. Historically, the trifluoro-
methyl (CF3) group has been introduced using electrophilic
reagents, generally in conjunction with a transition metal
such as copper.3 The field was revolutionalized in 1989,
however, when Prakash et al. described how trifluorome-
thyltrimethylsilane (Me3SiCF3) could be used as a trifluoro-
methyl anion equivalent in conjunction with a fluoride
source (Figure 1a).4
a)
Me
b)
-23
3 (HFC )
3Si-CF3
HCF
vs
examples
well-developed
expensive
limited
cheap
Figure 1. Sources of the CF3 anion; Me3SiCF3 vs HFC-23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 11
ously loses a fluoride ion to form the corresponding difluo- more economical means of synthesizing such structures
1
romethyl carbene (:CF2). Due to this, the counterion used in
the reaction is of great significance. HFC-23 was first used
as a trifluoromethyl anion source in 1991 by Shono et al.,8a
by deprotonating with a strong electrogenerated base and
capturing the trifluoromethyl anion with dimethylforma-
mide (DMF) as a hemiaminal. Several advances were made
in this field using the same DMF-derived hemiaminal as the
trifluoromethylating agent in nucleophilic additions to alde-
hydes and ketones,8b-h but it wasn’t until the seminal report
by Grushin et al. in 2011 that the anion was trapped in an
air-stable copper complex that was capable of carrying out
aromatic trifluoromethylations.9 They later made a break-
through in HFC-23 research with the direct cupration of
HFC-23 using CuCl and tBuOK to generate CuCF3,10 expand-
ing the utility of HFC-23 for trifluoromethylations.11 A sec-
ond breakthrough in this field came from Prakash et al. in
2012, when they used HFC-23 directly under more accessi-
ble conditions for the potassium hexamethyldisilazide
(KHMDS)-mediated addition of HFC-23 to a variety of sili-
con, boron, sulfur and carbonyl-based electrophiles.12
Thanks to these developments, the use of HFC-23 is now
emerging as a powerful alternative to other traditional
methods of introducing the trifluoromethyl group into or-
ganic substrates, without having to rely on electrochemical
methods or expensive reagents.13 During our own studies
into trifluoromethylation reactions,14 we found that the un-
should be a highly attractive goal.
2
3
4
5
6
7
8
9
Herein we wish to report the use of HFC-23 as a much
cheaper alternative in reported diastereoselective addition
reactions of the trifluoromethyl anion to industrially rele-
vant imines (Schemes 1c, d).16 More interestingly, enanti-
oenriched α-trifluoromethyl amines 2 can be synthesized in
a stereodivergent manner depending on the base used
(Scheme 1c). Specifically, the trifluoromethylation of (Rs)-
α-amino N-tert-butanesulfinimines (Rs)-1 by HFC-23 in the
presence of P4-tBu superbase produced (Rs, S)-2 (via a non-
chelated transition state), whereas the use of KHMDS fur-
nished trifluoromethylated N-sulfinamides (Rs, R)-2 (via a
chelated transition state). A complex tandem nucleophilic
addition/intramolecular aza-Michael sequence of N-(tert-
butanesulfinyl)imines (Ss)-3 to form enantioenriched tri-
fluoromethylated isoindolines (Ss, R, R)-4 was also achieved
diastereoselectively by using HFC-23 in conjunction with
P4-tBu via a non-chelated transition state (Scheme 1d).
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. The application of HFC-23 as a benign alter-
native to Me3SiCF3.
work
Previous
et al.
)
work
b)
(Fustero
Previous
et al.
)
a)
(Prakash
O
S-tBu
O
S-tBu
X
Bn2N
N
R
(
)
N
CF3
R
X
(
)
S
O
S-tBu
(
(
)
)
CF3
O
R
(
CO2R
S-tBu
(
1
Rs
Rs
3
)-
N
Bn2N
)-
N
)
H
Me3Si-CF3
S
(
TBAT
TMAF
S
,
R
−
−
CO2R
- r.t.
THF, 55 ºC
THF, 35 ºC
Rs
S
2
R
S
4
-
,
S
)-
s
(
)-
(
,
stable trifluoromethyl anion (CF3 ) generated from HFC-23
can be stabilized by ion paring with highly sterically de-
manding cations, such as the polyaminophosphazene su-
perbase P4-tBu,14 allowing similar reactions to be carried
out using stoichiometric or catalytic amounts of P4-tBu, as
well as extending the addition of HFC-23 to imines.14d More
recently, we described a simpler system for the stabilization
-
N
H
P4 tBu/H
O
R'
CF3
work
This
d)
work
This
c)
Non-chelated
transition state
O
S-tBu
(
-
P4 tBu
X
CF3
O
N
S-tBu
Bn2N
S)
N
)
H
S
(
CF3
-
of CF3 with the potassium cation (K+) capsulized by polyeth-
(
CO2R
R
)
X
R
O
Rs
1
Ss
3
(
)-
(
)-
HCF3
-23
Rs
(
,
S
2
to 99:1
up
CF3
S-tBu
)-
N
-
ers such as dimethoxyethanes. Specifically, when stabilized
(HFC
)
P4 tBu
toluene
78 ºC
toluene
−
R
)
(
78 ºC
O
S-tBu
-
with glyme-capsuled K+, the CF3 anion efficiently reacts
−
CO2
R
Bn2N
4
)-
Ss, R, R
N
(
R
)
(
H
KHMDS
with a wide variety of carbonyl compounds to furnish the
corresponding trifluoromethyl carbinols in good to high
yields.15 Although the taming of HFC-23 is improving, when
compared with the versatile utility of Me3SiCF3, HFC-23 re-
mains an immature source of a trifluoromethylation rea-
gent, and examples of reactions carried out with HFC-23 re-
main limited. In particular, one of the more important chal-
lenges left to overcome is the use of HFC-23 in stereoselec-
tive reactions toward pharmaceutically useful trifluoro-
methylated compounds bearing multiple stereogenic car-
bon centers. In this sense, Prakash et al. reported the nucle-
ophilic trifluoromethylation of sterically crowded α-amino
N-tert-butanesulfinimines (Rs)-1 by Me3SiCF3 in the pres-
ence of tetrabutylammonium difluorotriphenylsilicate
(TBAT) to furnish trifluoromethylated vicinal ethylenedia-
mines (Rs, S)-2 with high diastereoselectivity (Scheme
1a).16a Fustero et al. reported the highly stereoselective syn-
thesis of trifluoromethylated 1,3-disubstituted isoindolines
(Rs, S, S)-4 through a tandem reaction consisting of dia-
stereoselective trifluoromethylation of N-tert-butanesulfin-
imines (Rs)-3 by Me3SiCF3, followed by intramolecular aza-
Michael reaction (Scheme 1b).16b Both 2 and 4 represent
particularly relevant classes of compounds in medicinal
chemistry as chiral amine building blocks (Figure 2), given
their prevalence in pharmaceuticals and agrochemicals,17
to 99:1
up
R
2
Rs
R
)-
to 93:7
up
(
,
H
H
N
-
P4 tBu/H
R'
SiMe3
R'
N
HCF3
S
N
S
tBu
O
N
tBu
K
K
CF3
O
R"
H
F3C
O
SiMe3
HMDS
Non-chelated
transition state
Chelated transition state
O
NHAc
N
N
N
H
N
O
O
O
Cl
HN
HN
Me
O
NH2
O
Cl
(-)-Epiquinamide
O
O
ICI-199,441
agonist)
Oseltamivir
(Tamiflu)
antiviral
k
(
F3C
Rolapitant
(NK1
CF3
NH
Cl
OMe
receptor)
O
O
N
MeO
N
O
NH
N
N
N
O
O
O
N
O
NH
H
O
M
e
NH2
Me
Fumaridine
(alkaloid)
Lenalidomide
(multiple myeloma)
R
172939
D
Pagoclone
(anxiolytic)
(
)-PD
Me2N
(Dopamine 4 antagonist)
Figure 2. Natural products and biologically active com-
pounds containing vicinal diamino moeity (red) and
isoindolin-1-one framework (blue).
Results and Discussion
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Page 3 of 11
The Journal of Organic Chemistry
We first explored the use of HFC-23 in the synthesis of
to this was pyrrolidine-based 1e (89:11), perhaps due to the
higher rigidity of the starting imine. On the other hand, the
KHMDS-based reaction gave more consistently high yields
but more variable diastereoselectivities with (RS, R)-2 selec-
tivity. Longer aliphatic chains such as those in imines 1a and
1b gave higher diastereoselectivities (8:92-7:93), whereas
the shorter chain in 1c resulted in a slightly lower 13:87.
Again, the aromatic and pyrrolidine-based imines 1d and 1e
reacted with a lower diastereoselectivity (16:84). Nonethe-
less, a small library of trifluoromethylated enantioenriched
vicinal diamines were synthesized in good yields, and with
high diastereoselectivities comparable to those previously
described.16a It should be mentioned that our HFC-23 meth-
odology was applicable to the synthesis of both diastereoi-
somers of chiral trifluoromethylated diamines 2, whereas
the reported Me3SiCF3 strategy affords only one. Thus, the
use of HFC-23 has advantages over Me3SiCF3 not only in
terms of cost and atom economy, but also makes stereodi-
vergent synthesis possible. The stereochemistry of all the
products 2 was determined through spectral data analysis
using data from 1H and 19F NMR spectroscopy of litera-
ture.16a
enantioenriched trifluoromethylated ethylenediamines.16a
We began by testing reaction conditions with varying bases
and solvents (Table 1). In this case, both KHMDS and P4-tBu
gave the desired 1,2-diamine 2a (entries 1—2). However,
we found that the diastereoselectivities varied greatly be-
tween the two bases, and even resulted in the opposite ste-
reochemistry at the newly formed chiral carbon center. This
phenomenon has been described previously;14d the high ste-
ric bulk of P4-tBu prevents the formation of a six-membered
chair-like transition state and forces the addition of the tri-
fluoromethyl anion to take place via an open-chain transi-
tion state. Other bases such as tBuOK provided less effective
in this reaction (entry 3). Changing the solvent to THF failed
to improve the yields, although it did produce a switch in
stereochemistry when using KHMDS as the base (16:84 to
64:36), most likely due to the coordinating nature of THF
(entries 4—5). Increasing the reaction temperature from
−78 °C to −50 °C resulted in lower yields, despite improving
the diastereoselectivity in the KHMDS-promoted addition
(entries 6—7). The use of more equivalents of KHMDS in-
creased the yield to 70% and the diastereoselectivity to
much higher levels (entry 8). Finally, we reduced the HFC-
23 load to just 1.1 equivalents with favorable results.
1
2
3
4
5
6
7
8
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
Table 2. Scope and limitations of the use of HFC-23 in
the synthesis of vicinal diamines.
Table 1. Optimization of the nucleophilic addition of
HFC-23 to aminoimines 1.
O
S
O
S
CF3
CF3
O
S
HCF
equiv)
3 (1.1
base
Bn2N
Bn2N
Bn2N
tBu
N
tBu
N
tBu
N
H
+
H
O
S
O
S
O
S
CF3
CF3
HCF
3 (excess)
base
R
R
R
toluene, –78 °C
12 h
Bn2N
Bn2N
Bn2N
1a
2a
2a
)-
Rs
S
)-
Rs
R
tBu
N
tBu
N
tBu
(
(
,
,
N
+
H
H
solvent, temp.
-
a
O
S
base P4 tBu
CF3
O
:
CF3
Bn2N
Bn2N
S
N
tBu
=
N
H
tBu
1a
2a
S
)-
Rs
2a
R
)-
Rs
(
,
(
,
H
entry base (equiv) temp. solvent yield
dra
>
>
= :1
99
2b:
)-
Rs
S
99:1
CF3
92%;
dr
Rs
S
2a:
dr
75%;
(
,
(
)-
,
O
S
(°C)
−78
−78
−78
−78
−78
−50
−50
−78
−78
−78
(%)
50
74
7
O
S
CF3
CF3
Bn
O
S
1
2
KHMDS (2.0)
P4-tBu (1.1)
tBuOK (2.0)
KHMDS (2.0)
P4-tBu (1.1)
KHMDS (2.0)
P4-tBu (1.1)
KHMDS (4.0)
P4-tBu (1.1)
KHMDS (4.0)
toluene
toluene
toluene
THF
16:84
>99:1
43:57
64:36
>99:1
10:90
>99:1
8:92
Bn2N
Bn2N
Ph
N
tBu
>
N
tBu
=
N
N
H
H
H
t-Bu
e:
2
)-
=
69%;
dr 89:11
>
99:1
Rs
S
2d:
58%;
dr
Rs
S
c:
2
S
)-
=
(
Rs
dr
99:1
,
94%;
(
)-
,
(
,
3
O
CF3
b
O
:
CF3
base KHMDS
4
14
44
20
22
70
75
72
Bn2N
S
Bn2N
S
N
tBu
=
N
tBu
H
5
THF
H
6
toluene
toluene
toluene
toluene
toluene
2b:
R
)-
7:93
Rs
dr
75%;
=
Rs
R
2a:
dr 8:92
(
72%;
,
(
)-
,
7
O
S
O
CF3
CF3
CF3
Bn
O
N
Bn2N
Bn2N
Ph
S
S
8
N
H
tBu
=
N
tBu
=
N
H
t-Bu
H
9b
10b
>99:1
8:92
e:
2
R
)-
=
16:84
Rs
,
dr
2d:
75%;
Rs
R
)-
dr 16:84
c:
2
R
)-
72%;
Rs
dr 13:87
(
84%;
(
,
(
,
aReaction conditions: 1 (0.2 mmol), HCF3 (1.1 equiv), P4-tBu (1.1 equiv) in
toluene (1.0 mL). b1 (0.2 mmol), HCF3 (1.1 equiv), KHMDS (4.0 equiv) in tol-
uene (0.5 mL).
a
Diastereoselectivity ((Rs, S)-2a:(Rs, R)-2a) was determined
by 19F-NMR using the crude mixture with trifluorotoluene as an
internal standard, according to the reference 16a. HPLC analy-
sis was not suitable due to the crude mixture. b1.1 equiv of
HCF3 was used.
We then explored if the resulting diamines were amena-
ble to further transformations (Scheme 2). Treatment of di-
amine (RS, S)-2a with m-CPBA afforded the sulfonyl deriva-
tive (S, S)-5 in 54% yield. The amines could also be selec-
tively deprotected: the sulfinyl group of 2d was removed
through reaction with HCl in dioxane, and the benzyl groups
were cleaved through simple hydrogenation over a Pd-cat-
alyst, furnishing free diamine (S, S)-7 in good yield.
In general, the chemical yields and diastereoselectivities
were good to excellent. In terms of the reaction promoted
by P4-tBu, the yields of (RS, S)-2 varied depending on the na-
ture of the substrate (Table 2). Aliphatic less sterically hin-
dered substrates 1b and 1c gave excellent yields, whereas
the bulkier isobutyl substituent hampered the reaction
slightly (1a), and the yield was significantly lower for aro-
matic substrate 1d. The diastereoselectivities observed
were excellent in all cases (>99:1), although the exception
Scheme 2. Further transformations with vicinal dia-
mines 2.
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The Journal of Organic Chemistry
Page 4 of 11
O
S
CF3
CF3
With these optimized conditions in hand, we then set out
Bn2N
Bn2N
SO2tBu
54 %
m
tBu
-CPBA
N
N
1
2
3
4
5
6
7
8
to explore the scope of the reaction (Table 4). The yields
were excellent for substrates bearing electron-neutral aro-
matic backbones, and moderate to good for other substrates.
However, electron-donating groups on the aromatic ring
gave much higher diastereoselectivity when compared to
electron-neutral or electron-poor aromatic substrates. An
exception to this was nitro-substituted 3h, which resulted
in complete selectivity, suggesting that the difference could
be due to the halogen nature of the other electron-with-
drawing substituents on 3f—3g, 3i. Nevertheless, we were
able to obtain a variety of the target isoindolines in good
yields and high to excellent diastereoselectivities (up to
88:12 — >99:1) using inexpensive HFC-23 as the trifluoro-
methylating agent. The stereochemistry of all the products
4 was determined through spectral data analysis using data
H
H
DCM, 0 ºC
2a
)-
:
5
S, S
)-
Rs
S
(
,
(
O
S
CF3
CF3
NH2
CF3
NH2
HCl in dioxane
Pd/C, H2
Bn2N
Ph
Bn2N
Ph
H2N
Ph
N
tBu
H
MeOH, reflux
then NaHCO3
DCM/MeOH
2d
)-
:
6
:
7
51 %
)-
Rs
S
S, S
)-
93 %
S, S
(
,
(
(
We next explored the use of HFC-23 in a complex tandem
nucleophilic addition/intramolecular aza-Michael sequence
to form enantioenriched trifluoromethylated isoindolines,
previously described by Fustero et al.16b This class of com-
pounds is particularly relevant in medicinal chemistry as ni-
trogenated heterocycles such as these are prevalent struc-
tures in pharmaceuticals and agrochemicals.17 We began by
testing conditions used for the previous reaction using an
excess of HFC-23, ethyl ester 3a and KHMDS as the base (Ta-
ble 3). Unfortunately, although resulting in a 60% yield of
the target isoindoline, the diastereoselectivity observed
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
1
from H and 19F NMR spectroscopy of literature.16b Similar
yield (4b, 1,10 g, 83%) and selectivity (dr = 96:4) were ob-
served in a gram scale reaction using 3b (cf. for 0.2 mmol
scale, 94%, dr = 93:7).
was minimal (entry 1). The use of P4-tBu and BuOK gave
t
Table 4. Scope and limitations of the use of HFC-23 in
the synthesis of isoindolines.a
similarly disappointing results, and switching the solvent to
THF also failed to increase the success of the reaction (en-
tries 2-5). During further optimization of reaction condi-
tions using ethyl ester 3a, we noticed the ethyl ester moiety
in 3a was transformed into a trifluoromethyl ketone by the
CF3
HCF
P4 tBu
O
S-tBu
(
R
3 (excess)
equiv)
(1.1
X
(
)
O
-
X
N
S-tBu
N
S
)
toluene
–78
6-16 h
R
(
)
-
CO2
tBu
CO2tBu
°C,
nucleophilic addition of CF3 to the ethyl ester (Table S1 in
3
4
Ss
)-
Ss, R, R
(
(
)-
the supporting information). We thus decided to change the
ester from ethyl 3a to the bulky tert-butyl group 3b to pre-
vent substitution of the ester, leading to dramatic improve-
ments in both the yield (94%) and the diastereoselectivity
(93:7) of the process with (Ss, R, R)-4b using P4-tBu as the
base (entry 7). However, the stereodivergent phenomena
shown in Table 1 were not observed in this transformation,
(Ss, S, S)-4b was obtained with low opposite selectivity
(40:60) (entry 6).
CF3
CF3
CF3
CF3
MeO
MeO
O
O
O
O
O
S-tBu
N
S-tBu
N
S-tBu
N
S-tBu
N
O
CO2tBu
CO2tBu
CO2tBu
CO2tBu
:
4e
40%;
=
=
:
=
:
=
4b
4c
4d
dr 98:2
94%; dr 93:7
91%; dr 94:6
53%; dr 98:2
b
=
dr 96:4)
(83%;
CF3
CF3
CF3
CF3
O2N
F3C
O
S-tBu
O
Cl
F
O
S-tBu
O
S-tBu
N
N
S-tBu
N
N
CO2
tBu
CO2
tBu
CO2tBu
CO2tBu
:
=
:
=
=
:
4i
68%; dr 92:8
=
4f
4g
4h
51%; dr 92:8
38%; dr 88:12
52%; dr >99:1
aReaction conditions: 3 (0.2 mmol), HCF3 (excess), P4-tBu (1.1 equiv) in tol-
uene (0.5 mL). b3b (1.1 g, 3.27 mmol), HCF3 (excess), P4-tBu (1.1 equiv) in
toluene (17 mL).
Table 3. Optimization of the nucleophilic addition/in-
tramolecular aza-Michael sequence.
O
S-tBu
(
CF3
CF3
R
)
S
)
HCF3
(
(
(excess)
base
O
S-tBu
O
S-tBu
In conclusion, we have succeeded in taming HFC-23 as an
inexpensive trifluoromethyl anion source for the diastere-
oselective synthesis of enantioenriched trifluoromethyl-
ated ethylenediamines and isoindolines containing two ste-
reogenic carbon centers, using conditions based on either
the phosphazine superbase P4-tBu or KHMDS. Furthermore,
we have shown that HFC-23 can be used in a simple base-
dependent stereodivergent procedure to trifluoromethyl-
ate β-aminoimines in good yields and diastereoselectivities
comparable to those previously described using the tradi-
tional trifluoromethylating reagent Me3SiCF3. While most of
the reactions were carried out using an excess amount of
HFC-23, this is just a practical reason in the laboratory, and
one equivalent of HFC-23 is enough for this transformation
as also shown. The resulting protected diamines can be
used in further transformations to synthesize trifluoro-
methylated vicinal diamines that have potential as ligands
in asymmetric catalysis.18 Although these stereoselective
reactions have been carried out previously with Me3SiCF3 in
the presence of fluoride, alternative inexpensive and cost-
effective sources for trifluoromethylation reactions have
been long desired from a green chemistry point of view. The
N
S
)
N
N
+
CO2R
solvent, –78 °C
R
)
S
( )
(
3
)-
Ss
R
(
CO2R
CO2
4a,b
Ss, S, S
)-
:
=
3a
R
Et
tBu
4a,b
Ss, R, R
)-
(
(
:
=
3b
R
entry
R
base (equiv)
solvent
yield
(%)a
drb
1
2
3
4
5
6
7
Et
Et
KHMDS (2.0) toluene
60
0
57:43
P4-tBu (1.1)
tBuOK (2.0)
KHMDS (2.0)
P4-tBu (1.1)
toluene
toluene
THF
-
-
Et
0
Et
trace
59
67
94
-
Et
THF
62:38
40:60
93:7
tBu
tBu
KHMDS (2.0) toluene
P4-tBu (1.1)
toluene
a All yields refer to isolated yields. b Diastereoselectivity ((Ss, R,
R)-4a,b:(Ss, S, S)-4a,b) was determined by 19F-NMR using the
crude mixture with trifluorotoluene as an internal standard, ac-
cording to the reference 16b. HPLC analysis was not suitable
due to the crude mixture.
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Page 5 of 11
The Journal of Organic Chemistry
stereodivergent synthesis is also additional advantage for
1257, 1155, 1080, 910, 746, 700, 579, 474, 418 cm−1; MS
(ESI, m/z) 469 [M]+. This compound has been previously
1
2
3
4
5
6
7
8
the HFC-23. Further work is ongoing in our laboratories to
exploit HFC-23 in more reactions and convert it into a cheap
and staple reactant in the organic chemist’s toolbox.
synthesized.16a
(R)-N-((2R,3S)-3-(dibenzylamino)-1,1,1-trifluoro-5-
methylhexan-2-yl)-2-methylpropane-2-sulfinamide ((RS,
R)-2a). Following the general procedure using KHMDS, the
mixture was purified by column chromatography on silica
gel (nhexane/ethyl acetate = 90/10) to give (RS, R)-2a (67.5
EXPERIMENTAL SECTION
General Information. All reactions were performed in
oven-dried glassware. Solvents were transferred via sy-
ringe. All reactions were monitored by thin-layer chroma-
tography (TLC) carried out on 0.25 mm Merck silica-gel (60-
F254). Column chromatography was carried out in a col-
umn packed with silica-gel 60N spherical neutral size 40-50
μm. The 1H-NMR (300 MHz), 19F-NMR (282 MHz), 13C-NMR
(125.8 MHz) spectra for a solution in CDCl3 were recorded
on Varian Mercury 300, Bruker Avance 500. Chemical shifts
(δ) are expressed in ppm downfield from internal TMS, or
Hexafluorobenzene. High resolution mass spectrometry
(HRMS) was recorded on a SHIMADZU GCMS-QP5050A (EI-
MS). Infrared spectra were recorded on a JASCO FT/IR-
4100 spectrometer. Melting points were recorded on a
BUCHI M-565. Commercially available chemicals were ob-
tained from Ark Pharm Inc., Aldrich Chemical Co., Nacalai
tesque, TCI, or Wako, and were used as received unless oth-
erwise stated.
25
mg, 72% yield, dr = 8 : 92) as a colorless oil. [α]D = +10.8
1
(c 0.43, CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.39–
9
7.22 (m, 10H), 3.91 (d, J = 14.4 Hz, 2H), 3.76 (d, J = 10.7 Hz,
1H), 3.66–3.49 (m, 3H), 3.35 (dd, J = 7.9, 2.6 Hz, 1H), 1.61–
1.43 (m, 2H), 1.36–1.22 (m, 1H), 1.06 (s, 9H), 0.95–0.80 (m,
6H) ppm; 13C{1H} NMR (126 MHz, Chloroform-d) δ: 138.61,
128.61, 128.45, 128.45–121.63 (m), 127.23, 60.23 (q, J =
27.4 Hz), 57.19, 55.39, 54.81, 35.41, 25.21, 23.82, 22.4,
21.53 ppm; 19F NMR (282 MHz, Chloroform-d) δ: −71.54 (d,
J = 7.7 Hz, 3F) ppm; ATR-FTIR (neat): ν = 3371, 3064, 3030,
2956, 2862, 1722, 1599, 1468, 1074, 906, 858, 746, 700,
577 cm−1; mp: 73–74 °C; HRMS (ESI, m/z) calcd. for
C25H36F3N2OS [M+H]+: 469.2500 Found: 469.2505.
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
(R)-N-((2S,3S)-3-(dibenzylamino)-1,1,1-trifluorohexan-
2-yl)-2-methylpropane-2-sulfinamide ((RS, S)-2b). Follow-
ing the general procedure using P4-tBu, the mixture was pu-
rified by column chromatography on silica gel (nhex-
ane/ethyl acetate = 90/10) to give (RS, S)-2b (83.6 mg, 92%
Substrates 1a-e were prepared according to previously
published procedures.16a
25
yield, dr = >99 : 1) as a colorless oil. [α]D = −81.3 (c 0.50,
General procedure for the synthesis of (RS, S)-2a–2e
using P4-tBu. A Schlenk tube containing 1 (0.2 mmol) in tol-
uene (1.0 mL) was charged with CF3H (4.5 mL, 1.1 equiv) by
cooling in liquid nitrogen under vacuum. P4-tBu (0.8 M in
hexane) (0.28 mL, 1.1 equiv) was added at –78 °C, and the
reaction mixture was stirred at the same temperature for 12
h. After this time, sat. NH4Cl aq. was added and the aqueous
layer was extracted with CH2Cl2. The combined organic
layer was washed with brine, dried over Na2SO4, concen-
trated under reduced pressure, and purified by column
chromatography on silica gel to give products (RS, S)- 2.
1
CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.45–7.15 (m,
10H), 4.18–3.90 (m, 2H), 3.82 (d, J = 13.9 Hz, 2H), 3.60 (d, J
= 13.9 Hz, 2H), 3.24–3.14 (m, 1H), 1.71–1.45 (m, 2H), 1.45–
1.28 (m, 2H), 1.24 (s, 9H), 0.79 (t, J = 7.1 Hz, 3H) ppm; 19
F
NMR (282 MHz, Chloroform-d) δ: −73.23 (d, J = 8.4 Hz, 3F)
ppm; ATR-FTIR (neat): ν = 3207, 3032, 2960, 2875, 2800,
1495, 1456, 1315, 1259, 1061, 914, 849, 746, 698, 492, 459,
438 cm−1; MS (ESI, m/z) 455 [M]+. This compound has been
previously synthesized.16a
(R)-N-((2R,3S)-3-(dibenzylamino)-1,1,1-trifluorohexan-
2-yl)-2-methylpropane-2-sulfinamide ((RS, R)-2b). Follow-
ing the general procedure using KHMDS, the mixture was
purified by column chromatography on silica gel (nhex-
ane/ethyl acetate = 90/10) to give (RS, R)-2b (68.2 mg, 75%
General procedure for the synthesis of (RS, R)-2a–2e
using KHMDS. A Schlenk tube containing 1 (0.2 mmol) in
toluene (0.5 mL) was charged with CF3H (4.5 mL, 1.1 equiv)
by cooling in liquid nitrogen under vacuum. KHMDS (1.0 M
in toluene) (0.88 mL, 4.0 equiv) was added at –78 °C, and
the reaction mixture was stirred at the same temperature
for 12 h. After this time, sat. NH4Cl aq. was added and the
aqueous layer was extracted with CH2Cl2. The combined or-
ganic layer was washed with brine, dried over Na2SO4, con-
centrated under reduced pressure, and purified by column
chromatography on silica gel to give products (RS, R)- 2.
25
yield, dr = 7 : 93) as a white solid. [α]D = +21.1 (c 0.31,
1
CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.39–7.21 (m,
10H), 3.90 (d, J = 14.5 Hz, 2H), 3.81 (d, J = 10.5 Hz, 1H), 3.70–
3.49 (m, 3H), 3.35–3.27 (m, 1H), 1.57–1.42 (m, 2H), 1.37–
1.18 (m, 2H), 1.04 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H) ppm;
13C{1H} NMR (126 MHz, Chloroform-d) δ: 140.17, 129.74,
129.30, 128.04, 126.51 (q, J = 284.1 Hz), 61.18 (q, J = 27.0
Hz), 58.53, 57.69, 56.02, 29.22, 22.69, 20.99, 14.22 ppm; 19
F
(R)-N-((2S,3S)-3-(dibenzylamino)-1,1,1-trifluoro-5-
methylhexan-2-yl)-2-methylpropane-2-sulfinamide ((RS,
S)-2a). Following the general procedure using P4-tBu, the
mixture was purified by column chromatography on silica
gel (nhexane/ethyl acetate = 90/10) to give (RS, S)-2a (70.3
mg, 75% yield, dr = >99 : 1) as a colorless oil. [α]D25 = −80.8
NMR (282 MHz, Chloroform-d) δ: −71.60 (d, J = 7.7 Hz, 3F)
ppm; ATR-FTIR (KBr): ν = 3303, 3032, 2968, 2802, 1952,
1603, 1496, 1454, 1363, 1271, 1230, 1165, 1078, 993, 947,
908, 877, 746, 700, 553 cm−1; mp: 68–69 °C; HRMS (ESI,
m/z) calcd. for C24H34F3N2OS [M+H]+: 455.2344 Found:
455.2334.
1
(c 0.49, CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.40–
(R)-N-((2S,3S)-3-(dibenzylamino)-1,1,1-trifluorobutan-
2-yl)-2-methylpropane-2-sulfinamide ((RS, S)-2c). Follow-
ing the general procedure using P4-tBu, the mixture was pu-
rified by column chromatography on silica gel (nhex-
ane/ethyl acetate = 90/10) to give (RS, S)-2c (80.2 mg, 94%
7.15 (m, 10H), 4.20–4.02 (m, 1H), 3.94–3.78 (m, 3H), 3.57
(d, J = 13.8 Hz, 2H), 3.31–3.15 (m, 1H), 1.93–1.73 (m, 1H),
1.60–1.40 (m, 1H), 1.31–1.08 (m, 10H), 0.91 (d, J = 6.7 Hz,
3H), 0.51 (d, J = 6.5 Hz, 3H) ppm; 19F NMR (282 MHz, Chlo-
roform-d) δ: −73.46 (d, J = 8.6 Hz, 3F) ppm; ATR-FTIR
(neat): ν = 3379, 3030, 2952, 2870, 1603, 1495, 1454, 1367,
25
yield, dr = >99 : 1) as a colorless oil. [α]D = −29.7 (c 0.58,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
1
CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.45–7.16 (m,
10H), 3.95–3.69 (m, 4H), 3.55 (d, J = 13.8 Hz, 2H), 3.32 (dq,
J = 11.2, 6.6 Hz, 1H), 1.30–1.12 (m, 12H) ppm; 19F NMR (282
MHz, Chloroform-d) δ: −72.10 (d, J = 6.7 Hz, 3F) ppm; ATR-
FTIR (neat): ν = 3442, 3084, 2912, 2881, 1645, 1601, 1448,
1390, 1363, 1265, 1176, 1022, 918, 841, 810, 742, 702, 604,
580, 498, 469, 442, 411 cm−1; MS (ESI, m/z) 427 [M]+. This
compound has been previously synthesized.16a
purified by column chromatography on silica gel (nhex-
1
2
3
4
5
6
7
8
ane/ethyl acetate = 90/10) to give (RS, S)-2e (50.0 mg, 69%
yield, dr = 89 : 11) as a colorless oil. [α]D25 = −111.4 (c 0.29,
1
CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.45–7.22 (m,
5H), 4.29 (s, 1H), 4.15–4.02 (m, 2H), 3.14 (d, J = 12.2 Hz, 1H),
2.98–2.80 (m, 2H), 2.22 (q, J = 8.9 Hz, 1H), 1.98–1.79 (m, 2H),
1.75–1.56 (m, 2H), 1.27 (s, 9H) ppm; 19F NMR (282 MHz,
Chloroform-d) δ: −71.52 (d, J = 7.5 Hz, 3F) ppm; ATR-FTIR
(neat): ν = 3199, 2962, 2810, 1726, 1452, 1367, 1269, 1173,
1072, 918, 702, 600, 472, 444, 409 cm−1; MS (ESI, m/z) 363
[M]+. This compound has been previously synthesized.16a
(R)-N-((2R,3S)-3-(dibenzylamino)-1,1,1-trifluorobutan-
2-yl)-2-methylpropane-2-sulfinamide ((RS, R)-2c). Follow-
ing the general procedure using KHMDS, the mixture was
purified by column chromatography on silica gel (nhex-
ane/ethyl acetate = 90/10) to give (RS, R)-2c (71.7 mg, 84%
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
(R)-N-((R)-1-((S)-1-benzylpyrrolidin-2-yl)-2,2,2-trifluo-
roethyl)-2-methylpropane-2-sulfinamide ((RS, R)-2e). Fol-
lowing the general procedure using KHMDS, the mixture
was purified by column chromatography on silica gel (nhex-
ane/ethyl acetate = 90/10) to give (RS, R)-2e (54.4 mg, 75%
25
yield, dr = 13 : 87) as a white solid. [α]D = +5.01 (c 0.38,
1
CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.39–7.20 (m,
10H), 3.94–3.80 (m, 3H), 3.59–3.37 (m, 4H), 1.16 (d, J = 6.6
Hz, 3H), 1.10 (s, 9H) ppm; 13C{1H} NMR (126 MHz, Chloro-
form-d) δ: 138.55, 128.70, 128.47, 128.47–121.18 (m),
127.26, 61.02 (q, J = 27.4 Hz), 57.08, 54.66, 53.39, 22.32,
12.09 ppm; 19F NMR (282 MHz, Chloroform-d) δ: −70.87 (d,
J = 7.4 Hz, 3F) ppm; ATR-FTIR (neat): ν = 3203, 2958, 2802,
1819, 1495, 1452, 1365, 1309, 1259, 1176, 1124, 1061, 903,
746, 700, 602, 530, 513, 480, 459, 424, 403 cm−1; mp: 73.5-
74.3 °C HRMS (ESI, m/z) calcd. for C22H30F3N2OS [M+H]+:
427.2031 Found: 427.2030.
25
yield, dr = 16 : 84) as a colorless oil. [α]D = −29.4 (c 0.17,
1
CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.36–7.20 (m,
5H), 4.74 (d, J = 9.9 Hz, 1H), 4.02 (d, J = 13.1 Hz, 1H), 3.64–
3.48 (m, 1H), 3.48–3.36 (m, 2H), 2.91–2.81 (m, 1H), 2.56–
2.44 (m, 1H), 2.28–2.10 (m, 1H), 1.83–1.59 (m, 3H), 1.25 (s,
9H) ppm; 13C{1H} NMR (126 MHz, Chloroform-d) δ: 139.56,
128.50, 128.34, 127.06, 125.32 (q, J = 284.2 Hz), 61.94 (d, J
= 1.9 Hz), 60.48 (d, J = 1.9 Hz), 59.66 (q, J = 27.8 Hz), 57.14,
55.26, 31.76, 24.56, 22.53 ppm; 19F NMR (282 MHz, Chloro-
form-d) δ: −71.54 (d, J = 8.1 Hz, 3F) ppm; ATR-FTIR (KBr): ν
= 3028, 2962, 2877, 2810, 1454, 1367, 1269, 1169, 1076,
916, 752, 702, 596, 463, 409 cm−1; HRMS (ESI, m/z) calcd.
for C17H26F3N2OS [M+H]+: 363.1718 Found: 363.1714.
(R)-N-((2S,3S)-3-(dibenzylamino)-1,1,1-trifluoro-4-phe-
nylbutan-2-yl)-2-methylpro-pane-2-sulfinamide ((RS, S)-
2d). Following the general procedure using P4-tBu, the mix-
ture was purified by column chromatography on silica gel
(nhexane/ethyl acetate = 90/10) to give (RS, S)-2d (58.3 mg,
Substrates 3b–i were prepared according to previously
25
58% yield, dr = >99 : 1) as a colorless oil. [α]D = −53.9 (c
published procedures.16b
0.17, CHCl3). 1H NMR (300 MHz, Chloroform-d) δ; 7.37–7.18
(m, 13H), 7.18–7.09 (m, 2H), 3.99–3.89 (m, 2H), 3.85 (d, J =
14.1 Hz, 2H), 3.75 (d, J = 14.0 Hz, 2H), 3.70–3.58 (m, 1H),
3.04–2.87 (m, 2H), 1.16 (s, 9H) ppm; 19F NMR (282 MHz,
Chloroform-d) δ: −72.41 (d, J = 7.5 Hz, 3F) ppm; ATR-FTIR
(neat): ν = 3334, 3064, 3024, 2958, 2929, 1599, 1491, 1454,
1367, 1261, 908, 739, 694, 552, 409 cm−1; MS (ESI, m/z) 503
[M]+. This compound has been previously synthesized.16a
General procedure for the synthesis of Substrates 3b–
i. A solution of the corresponding aldehyde (4.0 mmol, 1.0
equiv) and Ti(OEt)4 (2.0 equiv) in dichloromethane (0.1 M)
was stirred for 5 minutes. To the resulting solution (S)-N-
(tert-butanesulfinyl)amine was added and was stirred at
room temperature for 20 hours. At this time, saturated
aqueous NaHCO3 was added until the white titanium salts
precipitated. The suspension was filtered through a short
pad of Celite, washing with small portions of ethyl acetate.
The filtrate was extracted with ethyl acetate and the com-
bined organic layers were washed with brine, dried over an-
hydrous Na2SO4, concentrated under vacuum, and purified
by means of flash chromatography on silica gel employing
mixtures of n-hexane: ethyl acetate as eluents.
(R)-N-((2R,3S)-3-(dibenzylamino)-1,1,1-trifluoro-4-phe-
nylbutan-2-yl)-2-methylpro-pane-2-sulfinamide ((RS, R)-
2d). Following the general procedure using KHMDS, the
mixture was purified by column chromatography on silica
gel (nhexane/ethyl acetate = 90/10) to give (RS, R)-2d (72.4
mg, 72% yield, dr = 16 : 84) as a white solid. [α]D25 = +14.8
1
(c 0.19, CHCl3). H NMR (300 MHz, Chloroform-d) δ: 7.54–
tert-Butyl
(E)-3-(2-((E)-(((S)-tert-butylsulfi-
7.13 (m, 13H), 7.04 (d, J = 7.2 Hz, 2H), 4.06 (d, J = 14.6 Hz,
2H), 3.89 (d, J = 10.8 Hz, 1H), 3.76 (d, J = 14.6 Hz, 2H), 3.68–
3.41 (m, 2H), 2.91–2.65 (m, 2H), 1.11 (s, 9H) ppm; 13C{1H}
NMR (126 MHz, Chloroform-d) δ: 138.24, 138.17, 129.14,
128.97, 128.65, 128.54, 127.43, 126.84, 124.85 (q, J = 284.5
Hz), 59.34, 58.73 (q, J = 27.5 Hz), 57.30, 55.40, 33.14, 22.56
ppm; 19F NMR (282 MHz, Chloroform-d) δ: −71.68 (d, J = 7.6
Hz, 3F) ppm; ATR-FTIR (KBr): ν = 3323, 3024, 2810, 1603,
1495, 1454, 1367, 1267, 1167, 1138, 1084, 1028, 930, 746,
698, 611, 544 cm−1; mp: 156–157 °C; HRMS (ESI, m/z) calcd.
for C28H34F3N2OS [M+H]+: 503.2344 Found: 503.2348.
nyl)imino)methyl)phenyl)acrylate (3b). Following the gen-
eral procedure, the mixture was purified by column chro-
matography on silica gel (nhexane/ethyl acetate = 90/10) to
1
give 3b (1.24 g, 92% yield) as a white solid. H NMR (300
MHz, Chloroform-d) δ: 8.82 (s, 1H), 8.34 (d, J = 15.8 Hz, 1H),
7.89–7.79 (m, 1H), 7.62–7.55 (m, 1H), 7.54–7.43 (m, 2H),
6.25 (d, J = 15.8 Hz, 1H), 1.53 (s, 9H), 1.29 (s, 9H); 13C{1H}
NMR (126 MHz, Chloroform-d) δ: 165.52, 161.76, 141.29,
136.31, 132.02, 132.00, 131.50, 129.54, 128.20, 124.16,
80.72, 57.78, 28.14, 22.60 ppm; ATR-FTIR (neat): ν = 2985,
1705, 1637, 1583, 1477, 1365, 1329, 1277, 1207, 1161,
1086, 995, 870, 777, 760, 715, 580, 445 cm−1; mp: 85.1-
86.1 °C; HRMS (ESI, m/z) calcd. for C18H25NNaO3S [M+Na]+:
358.1453 Found: 358.1452.
(R)-N-((S)-1-((S)-1-benzylpyrrolidin-2-yl)-2,2,2-trifluo-
roethyl)-2-methylpropane-2-sulfinamide ((RS, S)-2e). Fol-
lowing the general procedure using P4-tBu, the mixture was
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The Journal of Organic Chemistry
(E)-3-(2-((E)-(((S)-tert-butylsulfi- tert-Butyl
tert-Butyl
(E)-3-(2-((E)-(((S)-tert-butylsulfi-
1
nyl)imino)methyl)-4-methylphenyl)acrylate (3c). Follow-
ing the general procedure, the mixture was purified by col-
umn chromatography on silica gel (nhexane/ethyl acetate =
90/10) to give 3c (1.10 g, 79% yield) as a white solid.1H
NMR (300 MHz, Chloroform-d) δ: 8.80 (s, 1H), 8.31 (d, J =
15.8 Hz, 1H), 7.66 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.31 (d, J =
8.8 Hz, 1H), 6.23 (d, J = 15.8 Hz, 1H), 2.42 (s, 3H), 1.52 (s,
9H), 1.29 (s, 9H) ppm; 13C{1H} NMR (126 MHz, Chloroform-
d) δ: 165.70, 161.86, 141.01, 139.87, 133.51, 132.89, 131.90,
131.84, 128.09, 123.33, 80.61, 57.76, 28.16, 22.62, 21.20
ppm; ATR-FTIR (neat): ν = 2981, 1711, 1635, 1585, 1475,
1392, 1365, 1325, 1279, 1155, 1086, 972, 868, 818, 777,
586, 471, 413 cm−1; mp: 92.8-93.5 °C; HRMS (ESI, m/z) calcd.
for C19H27NNaO3S [M+Na]+: 372.1609 Found: 372.1610.
nyl)imino)methyl)-4-fluorophenyl)acrylate (3g). Following
the general procedure, the mixture was purified by column
chromatography on silica gel (nhexane/ethyl acetate =
2
3
4
5
6
7
8
9
1
90/10) to give 3g (1.19 g, 84% yield) as a white solid. H
NMR (300 MHz, Chloroform-d) δ: 8.82 (d, J = 1.3 Hz, 1H),
8.20 (d, J = 15.7 Hz, 1H), 7.64–7.53 (m, 2H), 7.21 (td, J = 8.2,
2.8 Hz, 1H), 6.23 (d, J = 15.8 Hz, 1H), 1.53 (s, 9H), 1.29 (s,
9H) ppm; 13C{1H} NMR (126 MHz, Chloroform-d) δ: 165.29,
163.11 (d, J = 251.1 Hz), 160.05 (d, J = 2.4 Hz), 139.31,
133.93 (d, J = 7.3 Hz), 132.48 (d, J = 3.3 Hz), 130.15 (d, J =
8.1 Hz), 124.46 (d, J = 1.6 Hz), 119.34 (d, J = 22.1 Hz), 116.64
(d, J = 22.8 Hz), 80.92, 58.11, 28.13, 22.64 ppm; 19F NMR
(282 MHz, Chloroform-d) δ: −110.88–−111.04 (m, 1F) ppm;
ATR-FTIR (neat): ν = 2976, 1705, 1639, 1608, 1483, 1367,
1333, 1279, 1209, 1167, 1088, 991, 889, 866, 823, 779, 740,
710, 596, 550, 444 cm−1; mp: 119.4-120.0 °C; HRMS (ESI,
m/z) calcd. for C18H24FNNaO3S [M+Na]+: 376.1359 Found:
376.1352.
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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
tert-Butyl
(E)-3-(2-((E)-(((S)-tert-butylsulfi-
(3d).
nyl)imino)methyl)-4,5-dimethoxyphenyl)acrylate
Following the general procedure, the mixture was purified
by column chromatography on silica gel (nhexane/ethyl ac-
etate = 90/10) to give 3d (1.28 g, 81% yield) as a white solid.
1H NMR (300 MHz, Chloroform-d) δ: 8.82 (s, 1H), 8.31 (d, J
= 15.7 Hz, 1H), 7.43 (s, 1H), 7.05 (s, 1H), 6.24 (d, J = 15.7 Hz,
1H), 3.98 (s, 3H), 3.96 (s, 3H), 1.54 (s, 9H), 1.29 (s, 9H) ppm;
13C{1H} NMR (126 MHz, Chloroform-d) δ: 165.58, 160.01,
152.04, 150.13, 139.79, 130.22, 125.67, 122.74, 111.79,
109.32, 80.70, 57.71, 56.08, 55.98, 28.13, 22.58 ppm; ATR-
FTIR (neat): ν = 2968, 1695, 1599, 1556, 1523, 1454, 1400,
1362, 1300, 1269, 1151, 1126, 1080, 991, 895, 849, 814,
582, 530, 471, 445 cm−1; mp: 101.2-102.0 °C; HRMS (ESI,
m/z) calcd. for C20H29NNaO5S [M+Na]+: 418.1664 Found:
418.1661.
tert-Butyl
(E)-3-(2-((E)-(((S)-tert-butylsulfi-
nyl)imino)methyl)-4-nitrophenyl)acrylate (3h). Following
the general procedure, the mixture was purified by column
chromatography on silica gel (nhexane/ethyl acetate =
90/10) to give 3h (1.25 g, 82% yield) as an yellow solid. 1H
NMR (300 MHz, Chloroform-d) δ: 8.89 (s, 1H), 8.75 (d, J =
2.4 Hz, 1H), 8.33 (dd, J = 8.6, 2.5 Hz, 1H), 8.24 (d, J = 15.8 Hz,
1H), 7.75 (d, J = 8.6 Hz, 1H), 6.38 (d, J = 15.8 Hz, 1H), 1.54 (s,
9H), 1.31 (s, 9H) ppm; 13C{1H} NMR (126 MHz, Chloroform-
d) δ: 164.55, 159.40, 148.20, 141.91, 138.38, 133.02, 129.40,
127.72, 126.01, 125.36, 81.54, 58.41, 28.07, 22.67 ppm;
ATR-FTIR (neat): ν = 3087, 2976, 1705, 1637, 1595, 1522,
1475, 1329, 1286, 1211, 1161, 1088, 985, 862, 833, 771,
748, 471, 449 cm−1; mp: 114.2-115.0 °C; HRMS (ESI, m/z)
calcd. for C18H24N2NaO5S [M+Na]+: 403.1304 Found:
403.1305.
tert-Butyl
(E)-3-(6-((E)-(((S)-tert-butylsulfi-
nyl)imino)methyl)benzo[d][1,3]dioxol-5-yl)acrylate (3e).
Following the general procedure, the mixture was purified
by column chromatography on silica gel (nhexane/ethyl ac-
etate = 90/10) to give 3e (1.32 g, 87% yield) as a white solid.
1H NMR (300 MHz, Chloroform-d) δ: 8.82 (s, 1H), 8.20 (d, J
= 15.6 Hz, 1H), 7.43 (s, 1H), 7.04 (s, 1H), 6.20 (d, J = 15.6 Hz,
1H), 6.08 (s, 2H), 1.53 (s, 9H), 1.27 (s, 9H). ppm; 13C{1H}
NMR (126 MHz, Chloroform-d) δ: 165.47, 159.41, 151.13,
149.21, 139.21, 132.30, 127.53, 123.29, 108.54, 106.76,
102.16, 80.78, 57.81, 28.13, 22.60 ppm; ATR-FTIR (neat): ν
= 2968, 1707, 1635, 1604, 1574, 1506, 1481, 1365, 1311,
1288, 1261, 1157, 1084, 1036, 972, 930, 862, 802, 739, 447,
413 cm−1; mp: 127.5-128.3 °C; HRMS (ESI, m/z) calcd. for
C19H25NNaO5S [M+Na]+: 402.1351 Found: 402.1343.
tert-Butyl
(E)-3-(2-((E)-(((S)-tert-butylsulfi-
nyl)imino)methyl)-4(trifluoromethyl)phenyl)acrylate (3i).
Following the general procedure, the mixture was purified
by column chromatography on silica gel (nhexane/ethyl ac-
etate = 90/10) to give 3i (1.42 g, 88% yield) as a white solid.
1H NMR (300 MHz, Chloroform-d) δ: 8.86 (s, 1H), 8.27 (d, J
= 15.8 Hz, 1H), 8.14 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.69 (d,
J = 8.3 Hz, 1H), 6.31 (d, J = 15.8 Hz, 1H), 1.54 (s, 9H), 1.30 (s,
9H) ppm; 13C{1H} NMR (126 MHz, Chloroform-d) δ: 164.93,
160.25, 139.51, 139.44, 132.38, 131.61 (q, J = 33.2 Hz),
128.84, 128.30 (q, J = 3.6 Hz), 127.62 (q, J = 3.8 Hz), 126.37,
123.41 (q, J = 272.4 Hz), 81.25, 58.17, 28.11, 22.65 ppm; 19F
NMR (282 MHz, Chloroform-d) δ: −63.53 (s, 3F) ppm; ATR-
FTIR (KBr): ν = 2978, 1709, 1599, 1412, 1367, 1333, 1279,
1215, 1169, 1130, 1082, 924, 849, 785, 729, 540, 472, 420
cm−1; mp: 81.9-82.7 °C; HRMS (ESI, m/z) calcd. for
C19H24F3NNaO3S [M+Na]+: 426.1327 Found: 426.1316.
tert-Butyl
(E)-3-(2-((E)-(((S)-tert-butylsulfi-
nyl)imino)methyl)-4-chlorophenyl)acrylate (3f). Following
the general procedure, the mixture was purified by column
chromatography on silica gel (nhexane/ethyl acetate =
1
90/10) to give 3f (1.33 g, 90% yield) as a white solid. H
NMR (300 MHz, Chloroform-d) δ: 8.80 (s, 1H), 8.21 (d, J =
15.8 Hz, 1H), 7.90–7.84 (m, 1H), 7.57–7.43 (m, 2H), 6.26 (d,
J = 15.8 Hz, 1H), 1.53 (s, 9H), 1.29 (s, 9H) ppm; 13C{1H} NMR
(126 MHz, Chloroform-d) δ: 165.15, 160.05, 139.33, 135.68,
134.56, 133.26, 131.94, 130.23, 129.39, 124.84, 80.93,
58.06, 28.08, 22.61 ppm; ATR-FTIR (neat): ν = 3057, 2976,
1709, 1633, 1587, 1475, 1367, 1321, 1151, 1080, 980, 912,
862, 822, 769, 633, 588, 474, 417 cm−1; mp: 105.3-106.2 °C;
HRMS (ESI, m/z) calcd. for C18H24ClNNaO3S [M+Na]+:
392.1063 Found: 392.1056.
General procedure for the synthesis of 4b–i using P4-
tBu. A Schlenk tube containing 3 (0.2 mmol) in toluene (0.5
mL) was charged with CF3H (excess) by cooling in liquid ni-
trogen under vacuum. P4-tBu (0.8 M in hexane) (0.28 mL, 1.1
equiv) was added at –78 °C, and the reaction mixture was
stirred at the same temperature until TLC revealed the dis-
appearance of the starting material. SiO2 (spatula tip) and 1
N HCl aq. (2 drops) were then added at 0 ºC, and the reaction
was stirred for a further 1 h. Sat. NH4Cl aq. was added at
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
same temperature, and the aqueous layer was extracted
tert-Butyl
2-((5R,7R)-6-((S)-tert-butylsulfinyl)-7-(tri-
1
2
3
4
with CH2Cl2, and the combined organic layer was washed
with brine, and dried over Na2SO4. The resulting mixture
was concentrated under reduced pressure and purified by
column chromatography on silica gel to give products (Ss, R,
R)-4.
fluoromethyl)-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindol-
5-yl)acetate ((Ss, R, R)-4e). Following the general procedure,
the mixture was purified by column chromatography on sil-
ica gel (nhexane/ethyl acetate = 90/10) to give (Ss, R, R)-4e
25
(36.0 mg, 40% yield, dr = 98 : 2) as a colorless oil. [α]D
=
5
+26.3 (c 0.078, CHCl3). 1H NMR (300 MHz, Chloroform-d) δ:
6.80–6.71 (m, 2H), 6.02–5.95 (m, 2H), 5.55–5.46 (m, 1H),
5.09 (q, J = 7.4 Hz, 1H), 2.90 (dd, J = 16.3, 2.2 Hz, 1H), 2.56
(dd, J = 16.3, 11.0 Hz, 1H), 1.50 (s, 9H), 1.32 (s, 9H) ppm;
13C{1H} NMR (126 MHz, Chloroform-d) δ: 169.92, 149.35,
148.10, 138.75, 124.38 (q, J = 280.7 Hz), 124.35, 103.87,
103.45, 101.82, 81.45, 72.71 (q, J = 32.0 Hz), 58.60, 54.07,
44.28, 28.10, 23.53 ppm; 19F NMR (282 MHz, Chloroform-d)
δ: −75.62 (d, J = 7.4 Hz, 3F) ppm; ATR-FTIR (neat): ν = 2976,
2918, 1726, 1479, 1367, 1336, 1271, 1215, 1167, 1124,
1074, 1039, 980, 935, 841, 764, 671, 577, 461 cm−1; HRMS
(ESI, m/z) calcd. for C20H25F3NO5S [M]+: 448.1406 Found:
448.1407.
6
7
8
9
tert-Butyl
2-((1R,3R)-2-((S)-tert-butylsulfinyl)-3-(tri-
fluoromethyl)isoindolin-1-yl)acetate ((Ss, R, R)-4b). Follow-
ing the general procedure, the mixture was purified by col-
umn chromatography on silica gel (nhexane/ethyl acetate =
90/10) to give (Ss, R, R)-4b (76.0 mg, 94% yield, dr = 93 : 7)
as a colorless oil.[α]D25 = +23.7 (c 0.20, CHCl3). 1H NMR (300
MHz, Chloroform-d) δ: 7.44–7.27 (m, 4H), 5.71–5.58 (m, 1H),
5.22 (q, J = 7.6 Hz, 1H), 2.94 (dd, J = 16.2, 2.2 Hz, 1H), 2.58
(dd, J = 16.2, 11.1 Hz, 1H), 1.50 (s, 9H), 1.34 (s, 9H) ppm;
13C{1H} NMR (126 MHz, Chloroform-d) δ: 169.79, 144.99,
131.74, 129.66, 127.99, 124.44 (q, J = 280.5 Hz), 123.84,
122.96, 81.39, 72.81 (q, J = 32.0 Hz), 58.63, 54.25, 44.22,
28.09, 23.55 ppm; 19F NMR (282 MHz, Chloroform-d) δ:
−75.37 (d, J = 7.7 Hz, 3F) ppm; ATR-FTIR (KBr): ν = 2978,
2929, 1726, 1462, 1367, 1277, 1161, 1128, 984, 943, 841,
766, 690, 638, 611, 550, 472, 420 cm−1; HRMS (ESI, m/z)
calcd. for C19H26F3NNaO3S [M+Na]+ 428.1483 Found:
428.1479.
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
tert-Butyl 2-((1R,3R)-2-((S)-tert-butylsulfinyl)-5-chloro-
3-(trifluoromethyl) isoindolin-1-yl)acetate ((Ss, R, R)-4f).
Following the general procedure, the mixture was purified
by column chromatography on silica gel (nhexane/ethyl ac-
etate = 90/10) to give (Ss, R, R)-4f (44.9 mg, 51% yield, dr =
92 : 8) as a white solid. [α]D25 = +48.9 (c 0.15, CHCl3). 1H NMR
(300 MHz, Chloroform-d) δ: 7.38–7.24 (m, 3H), 5.65–5.55
(m, 1H), 5.18 (q, J = 7.5 Hz, 1H), 2.92 (dd, J = 16.4, 2.3 Hz,
1H), 2.56 (dd, J = 16.4, 11.2 Hz, 1H), 1.49 (s, 9H), 1.33 (s, 9H)
ppm; 13C{1H} NMR (126 MHz, Chloroform-d) δ: 169.67,
143.59, 134.03, 133.75, 130.02, 124.27, 124.15 (q, J = 280.6
Hz), 124.08, 81.58, 72.49 (q, J = 32.3 Hz), 58.77, 53.85, 43.95,
28.07, 23.47; 19F NMR (282 MHz, Chloroform-d) δ: −75.24
(d, J = 7.5 Hz, 6F) ppm; ATR-FTIR (KBr): ν = 2991, 1724,
1477, 1421, 1367, 1294, 1171, 1130, 1088, 982, 945, 914,
881, 833, 766, 679, 644, 590, 557, 519, 444 cm−1; mp: 119–
120 °C; HRMS (ESI, m/z) calcd. for C19H25ClF3NNaO3S
[M+Na]+: 462.1093 Found: 462.1092.
tert-Butyl 2-((1R,3R)-2-((S)-tert-butylsulfinyl)-5-methyl-
3-(trifluoromethyl)isoindo-lin-1-yl)acetate ((Ss, R, R)-4c).
Following the general procedure, the mixture was purified
by column chromatography on silica gel (nhexane/ethyl ac-
etate = 90/10) to give (Ss, R, R)-4c (76.4 mg, 91% yield, dr =
94 : 6) as a white solid. [α]D25 = +43.4 (c 0.17, CHCl3). 1H NMR
(300 MHz, Chloroform-d) δ: 7.24–7.06 (m, 3H), 5.59 (d, J =
10.9 Hz, 1H), 5.16 (q, J = 7.6 Hz, 1H), 2.92 (dd, J = 16.1, 2.3
Hz, 1H), 2.55 (dd, J = 16.1, 11.1 Hz, 1H), 2.36 (s, 3H), 1.49 (s,
9H), 1.34 (s, 9H) ppm; 13C{1H} NMR (126 MHz, Chloroform-
d) δ: 169.83, 142.15, 137.93, 131.92, 130.55, 124.48 (q, J =
280.5 Hz) 124.23, 122.64, 81.30, 72.71 (q, J = 32.0 Hz), 58.59,
54.11, 44.29, 28.09, 23.58, 21.22 ppm; 19F NMR (282 MHz,
Chloroform-d) δ: −75.30 (d, J = 7.5 Hz, 3F) ppm; ATR-FTIR
(neat): ν = 2987, 1724, 1458, 1367, 1296, 1275, 1244, 1165,
1130, 1088, 984, 953, 924, 829, 652, 592, 544, 467 cm−1;
mp: 120–121 °C; HRMS (ESI, m/z) calcd. for C20H28F3NNaO3S
[M+H]+: 442.1640 Found: 442.1638.
tert-Butyl 2-((1R,3R)-2-((S)-tert-butylsulfinyl)-5-fluoro-
3-(trifluoromethyl)isoindolin-1-yl)acetate ((Ss, R, R)-4g).
Following the general procedure, the mixture was purified
by column chromatography on silica gel (nhexane/ethyl ac-
etate = 90/10) to give (Ss, R, R)-4g (32.2 mg, 38% yield, dr =
25
1
88 : 12) as a white solid. [α]D = +30.2 (c 0.14, CHCl3). H
NMR (300 MHz, Chloroform-d) δ: 7.36–7.24 (m, 1H), 7.10–
6.99 (m, 2H), 5.60 (d, J = 11.1 Hz, 1H), 5.18 (q, J = 7.5 Hz, 1H),
2.93 (d, J = 16.3 Hz, 1H), 2.56 (dd, J = 16.3, 11.1 Hz, 1H), 1.49
(s, 9H), 1.33 (s, 9H) ppm; 13C{1H} NMR (126 MHz, Chloro-
form-d) δ: 169.75, 162.59 (d, J = 246.8 Hz), 140.70, 133.81
(d, J = 8.8 Hz), 124.48 (d, J = 9.0 Hz), 124.18 (q, J = 280.6 Hz),
117.06 (d, J = 22.8 Hz), 111.09 (d, J = 24.2 Hz), 81.54, 72.58
(qd, J = 32.2, 2.2 Hz), 58.75, 53.74, 44.14, 28.08, 23.50 ppm;
19F NMR (282 MHz, Chloroform-d) δ: −75.30 (d, J = 7.4 Hz,
3F), −114.49–−114.72 (m, 1F) ppm; ATR-FTIR (neat): ν =
2974, 1726, 1612, 1493, 1365, 1279, 1219, 1165, 1126,
1095, 987, 933, 850, 837, 768, 692, 652, 598, 538, 409 cm−1;
mp: 102–103 °C; HRMS (ESI, m/z) calcd. for C19H25F4NNaO3S
[M+Na]+: 446.1389 Found: 446.1383.
tert-Butyl
2-((1R,3R)-2-((S)-tert-butylsulfinyl)-5,6-di-
methoxy-3-(trifluoromethyl)isoindolin-1-yl)acetate ((Ss, R,
R)-4d). Following the general procedure, the mixture was
purified by column chromatography on silica gel (nhex-
ane/ethyl acetate = 90/10) to give (Ss, R, R)-4d (49.3 mg,
53% yield, dr = 98 : 2) as a white solid.[α]D25 = +27.3 (c 0.31,
CHCl3). 1H NMR (300 MHz, Chloroform-d) δ: 6.85 (s, 1H),
6.81 (s, 1H), 5.61–5.52 (m, 1H), 5.15 (q, J = 7.4 Hz, 1H), 3.87
(s, 3H), 3.83 (s, 3H), 2.94 (dd, J = 16.5, 2.3 Hz, 1H), 2.58 (dd,
J = 16.4, 11.2 Hz, 1H), 1.50 (s, 9H), 1.33 (s, 9H) ppm; 13C{1H}
NMR (126 MHz, Chloroform-d) δ: 170.07, 150.53, 149.31,
137.36, 123.17, 124.50 (q, J = 280.7 Hz), 106.07, 105.47,
81.24, 72.97 (q, J = 32.0 Hz), 58.56, 56.13, 55.87, 54.32,
44.15, 28.07, 23.57 ppm; 19F NMR (282 MHz, Chloroform-d)
δ: −75.49 (d, J = 7.4 Hz, 3F) ppm; ATR-FTIR (KBr): ν = 2979,
2841, 2616, 1606, 1466, 1415, 1392, 1344, 1275, 1225,
1159, 1090, 1028, 999, 972, 928, 839, 704, 671, 617, 511,
463 cm−1; mp: 100–101 °C; HRMS (ESI, m/z) calcd. for
C21H30F3NNaO5S [M+Na]+: 488.1694 Found: 488.1697.
tert-Butyl 2-((1R,3R)-2-((S)-tert-butylsulfinyl)-5-nitro-3-
(trifluoromethyl)isoindolin-1-yl)acetate ((Ss, R, R)-4h). Fol-
lowing the general procedure, the mixture was purified by
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column chromatography on silica gel (nhexane/ethyl ace-
tate = 90/10) to give (Ss, R, R)-4h (46.8 mg, 52% yield, dr =
concentrated under reduced pressure to give the crude
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product, which was purified by flash column chromatog-
raphy on silica gel (nhexane/ethyl acetate = 80/20) to give
(S, S)-5 (52.3 mg, 54% yield) as a colorless oil. [α]D25 = +8.08
25
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>99 : 1) as a white solid. [α]D = +35.7 (c 0.10, CHCl3). H
NMR (300 MHz, Chloroform-d) δ: 8.35–8.17 (m, 2H), 7.58 (d,
J = 8.3 Hz, 1H), 5.78–5.65 (m, 1H), 5.30 (q, J = 7.4 Hz, 1H),
2.97 (dd, J = 16.8, 2.2 Hz, 1H), 2.61 (dd, J = 16.7, 11.3 Hz, 1H),
1.50 (s, 9H), 1.34 (s, 9H) ppm; 13C{1H} NMR (126 MHz, Chlo-
roform-d) δ: 169.46, 151.89, 148.19, 133.87, 125.47, 123.93
(q, J = 280.6 Hz), 124.24, 119.52, 82.01, 72.37 (q, J = 32.7 Hz),
58.99, 53.91, 43.58, 28.06, 23.38 ppm; 19F NMR (282 MHz,
Chloroform-d) δ: −75.17 (d, J = 7.4 Hz, 3F) ppm; ATR-FTIR
(neat): ν = 2987, 1724, 1537, 1475, 1358, 1284, 1176, 1130,
1074, 984, 955, 926, 856, 839, 768, 748, 688, 642, 523, 451,
415 cm−1; mp: 117–118 °C; HRMS (ESI, m/z) calcd. for
C19H25F3N2NaO5S [M+Na]+: 473.1334 Found: 473.1333.
1
(c 0.79, CHCl3). H NMR (300 MHz, Acetonitrile-d3) δ 7.36–
7.14 (m, 10H), 5.15 (d, J = 10.0 Hz, 1H), 4.57–4.40 (m, 1H),
3.77 (d, J = 13.9 Hz, 2H), 3.55 (d, J = 13.9 Hz, 2H), 3.15–3.02
(m, 1H), 1.94–1.77 (m, 1H), 1.77–1.61 (m, 1H), 1.34 (s, 9H),
1.21–1.09 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H), 0.48 (d, J = 6.4 Hz,
3H) ppm; 13C{1H} NMR (126 MHz, Chloroform-d) δ: 138.80,
129.13, 128.32, 127.19, 125.31 (q, J = 283.0 Hz), 61.05,
56.79, 54.10, 53.70 (q, J = 28.2 Hz), 35.64, 24.64, 24.23,
22.57, 22.25 ppm; 19F NMR (282 MHz, Chloroform-d) δ:
−70.58 (d, J = 8.4 Hz, 3F) ppm; ATR-FTIR (neat): ν = 3394,
3303, 3064, 3032, 2958, 2312, 1954, 1722, 1599, 1308,
1124, 918, 739, 434 cm−1; HRMS (ESI, m/z) calcd. for
C25H36F3N2O2S [M+H]+: 485.2450 Found: 485.2451.
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tert-Butyl
2-((1R,3R)-2-((S)-tert-butylsulfinyl)-3,5-
bis(trifluoromethyl)isoindolin-1-yl)acetate ((Ss, R, R)-4i).
Following the general procedure, the mixture was purified
by column chromatography on silica gel (nhexane/ethyl ac-
etate = 90/10) to give (Ss, R, R)-4i (64.4 mg, 68% yield, dr =
92 : 8) as a white solid. [α]D25 = +15.2 (c 0.30, CHCl3). 1H NMR
(300 MHz, Chloroform-d) δ: 7.71–7.57 (m, 2H), 7.50 (d, J =
8.4 Hz, 1H), 5.70 (d, J = 11.1 Hz, 1H), 5.26 (q, J = 7.4 Hz, 1H),
2.95 (dd, J = 16.5, 2.3 Hz, 1H), 2.59 (dd, J = 16.5, 11.2 Hz, 1H),
1.50 (s, 9H), 1.34 (s, 9H) ppm; 13C{1H} NMR (126 MHz, Chlo-
roform-d) δ: 169.58, 148.94, 132.87, 130.79 (q, J = 32.7 Hz),
127.06 (q, J = 3.6 Hz), 124.10 (q, J = 280.5 Hz), 123.77,
123.73 (q, J = 272.4 Hz), 121.54–120.37 (m), 81.76, 72.58 (q,
J = 32.4 Hz), 58.85, 54.03, 43.78, 28.06, 23.44 ppm; 19F NMR
(282 MHz, Chloroform-d) δ: −62.79 (s, 3F), −75.25 (d, J = 7.6
Hz, 3F) ppm; ATR-FTIR (neat): ν = 2979, 1726, 1624, 1473,
1369, 1333, 1298, 1207, 1163, 1126, 1078, 984, 951, 918,
768, 661, 642, 465, 413 cm−1; mp: 82–83 °C; HRMS (ESI,
m/z) calcd. for C20H25F6NNaO3S [M+Na]+: 496.1357 Found:
496.1355.
(2S,3S)-N3,N3-dibenzyl-1,1,1-trifluoro-4-phenylbutane-
2,3-diamine ((S, S)-6). To a stirred solution of (RS, S)-2d
(251.3 mg, 0.5 mmol, 1.0 equiv) in dry MeOH (5.0 mL) was
added 1 M HCl in dioxane (5 mL, 5.0 mmol, 10 equiv). Reac-
tion mixture was stirred reflux for 2 h, sat. NaHCO3 aq. was
added to the mixture and the mixture was extracted with
CH2Cl2. The combined organic layer was washed with brine,
dried over Na2SO4 and concentrated under reduced pres-
sure to give the crude product, which was purified by flash
column chromatography on silica gel (nhexane/ethyl ace-
tate = 8/2) to give (S, S)-6 (185.3 mg, 93% yield) as a white
1
solid. H NMR (300 MHz, Chloroform-d) δ: 7.36–6.96 (m,
15H), 3.94 (d, J = 14.3 Hz, 2H), 3.61 (q, J = 8.9 Hz, 1H), 3.48
(d, J = 14.1 Hz, 2H), 3.34–3.21 (m, 1H), 3.09–2.96 (m, 1H),
2.75 (dd, J = 13.8, 4.3 Hz, 1H), 1.46 (brs, 2H) ppm; 19F NMR
(282 MHz, Chloroform-d) δ: −76.52 (d, J = 8.9 Hz, 3F) ppm;
ATR-FTIR (neat): ν = 3425, 3356, 3062, 3030, 2925, 2800,
1954, 1603, 1495, 1452, 1365, 1257, 1217, 1161, 1028, 860,
804, 746, 698, 494, 430 cm−1; MS (ESI, m/z) 399 [M]+. This
compound has been previously synthesized.16a
Gram scale of tert-Butyl 2-((1R,3R)-2-((S)-tert-butylsulfi-
nyl)-3-(trifluoromethyl)isoindolin-1-yl)acetate ((Ss, R, R)-
4b). Following the general procedure, a 100 mL flask con-
taining 3b (1.1 g, 3.27 mmol) in toluene (17 mL) was
charged with CF3H (excess) by cooling in liquid nitrogen un-
der vacuum. P4-tBu (0.8 M in hexane) (4.5 mL, 1.1 equiv)
was added at –78 °C, and the reaction mixture was stirred
at the same temperature until TLC revealed the disappear-
ance of the starting material. SiO2 (three times of spatula
tip) and 1 N HCl aq. (5 mL) were then added at 0 °C, and the
reaction was stirred for a further 1 h. Sat. NH4Cl aq. was
added at same temperature, and the aqueous layer was ex-
tracted with CH2Cl2, and the combined organic layer was
washed with brine, and dried over Na2SO4. The resulting
mixture was concentrated under reduced pressure. The
mixture was purified by column chromatography on silica
gel (nhexane/ethyl acetate = 90/10) to give (Ss, R, R)-4b
(1.10 g, 83% yield, dr = 96 : 4) as a colorless oil.
(2S,3S)-1,1,1-trifluoro-4-phenylbutane-2,3-diamine ((S,
S)-7). To a stirred solution of (S, S)-6 (119.5 mg, 0.3 mmol,
1.0 equiv) and Pd/C in dry CH2Cl2/MeOH (3.0 mL) was
added H2 gas. Reaction mixture was stirred at room temper-
ature for 3 h, the crude mixture was filtrated with pad of
Celite, concentrated under reduced pressure to give the
pure product (S, S)-7 (33.4 mg, 51% yield) as a white solid.
[α]D25 = −19.4 (c 0.12, CHCl3). 1H NMR (300 MHz, Methanol-
d4) δ: 7.46–7.24 (m, 5H), 3.87–3.67 (m, 2H), 3.11 (dd, J =
14.7, 3.7 Hz, 1H), 2.90 (dd, J = 14.7, 10.8 Hz, 1H) ppm; 19F
NMR (282 MHz, Chloroform-d) δ: −71.64 (d, J = 8.0 Hz, 3F)
ppm; MS (ESI, m/z) 219 [M]+. This compound has been pre-
viously synthesized.16a
ASSOCIATED CONTENT
Supporting Information
N-((2S,3S)-3-(dibenzylamino)-1,1,1-trifluoro-5-
methylhexan-2-yl)-2-methylpropane-2-sulfonamide ((S, S)-
5). To a stirred solution of (RS, S)-2a (93.7 mg, 0.2 mmol, 1.0
equiv) in dry CH2Cl2 (3.3 mL) was added mCPBA (51.8 mg,
0.3 mmol, 1.5 equiv) at 0 °C. Reaction mixture was stirred at
rt overnight, sat. Na2SO3 aq. was added to the mixture and
the mixture was extracted with CH2Cl2. The combined or-
ganic layer was washed with brine, dried over Na2SO4 and
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental procedures, characterization of all new com-
pounds, and their corresponding NMR spectra (PDF).
AUTHOR INFORMATION
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The Journal of Organic Chemistry
Page 10 of 11
F.; Saint-Jalmes, L. Fluoroform: an efficient precursor for the tri-
Corresponding Author
fluoromethylation of aldehydes. Tetrahedron Lett. 1998, 19, 2973-
2976. (d) Russell, J.; Roques, N. Effective nucleophilic trifluoro-
methylation with fluoroform and common base. Tetrahedron 1998,
54, 13771-13782. (e) Mispelaere, C.; Roques, N. Hemiaminals of tri-
fluoroacetaldehyde, as trifluoromethylating agents. Tetrahedron
Lett. 1999, 40 6411-6414. (f) Folléas, B.; Marek, I.; Normant, J.-F.;
Saint-Jalmes, L. Fluoroform: an Efficient Precursor for the Trifluo-
romethylation of Aldehydes. Tetrahedron 2000, 56, 275-283. (g)
Large, S.; Roques, N.; Langlois, B. R. Nucleophilic Trifluoromethyla-
tion of Carbonyl Compounds and Disulfides with Trifluoromethane
and Silicon-Containing Bases. J. Org. Chem. 2000, 65, 8848-8856.
(h) Billard, T.; Bruns, S.; Langlois, B. R. New Stable Reagents for the
Nucleophilic Trifluoromethylation. 1. Trifluoromethylation of Car-
bonyl Compounds with N-Formylmorpholine Derivatives. Org. Lett.
2000, 2, 2101-2103.
(9) Tomashenko, O. A.; Escudero-Adán, E. C.; Martínez Belmonte,
M.; Grushin, V. V. Simple, Stable, and Easily Accessible Well-Defined
CuCF3 Aromatic Trifluoromethylating Agents. Angew. Chem. Int. Ed.
2011, 50, 7655-7659.
(10) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.;
Grushin, V. V. Direct Cupration of Fluoroform, J. Am. Chem. Soc.
2011, 133, 20901-20913
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* E-mail: nozshiba@nitech.ac.jp
ORCID
Norio Shibata: 0000-0002-3742-4064
Santos Fustero: 0000-0002-7575-9439
Daniel M. Sedgwick: 0000-0003-3902-6171
Author Contributions
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
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ACKNOWLEDGMENT
This work was supported by the Asahi Glass Foundation as well
as by JSPS KAKENHI grants JP18H02553 (KIBAN B) and
JP18H04401 (Middle Molecular Strategy). We also would like
to thank Tosoh Finechem Corporation for their support.
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