Highly diastereoselective synthesis of α-difluoromethyl amines from N-tert-butylsulfinyl ketimines and difluoromethyl phenyl sulfone

Article abstract of DOI:10.1002/chem.201000893

The first highly efficient and stereoselective difluoromethylation of structurally diverse N-tert-butylsulfinyl ketimines has been achieved with an in situ generated PhSO₂CF₂^- anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral α-difluoromethyl tertiary carbinamines, including α-difluoromethyl allylic amines and α-difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N-tert-butylsulfinyl aldimines, which suggests that a cyclic six-mem-bered transition state may be involved in the reaction.

Full text of DOI:10.1002/chem.201000893

FULL PAPER
DOI: 10.1002/chem.201000893
Highly Diastereoselective Synthesis of a-Difluoromethyl Amines from
N-tert-Butylsulfinyl Ketimines and Difluoromethyl Phenyl Sulfone
Jun Liu and Jinbo Hu*[a]
Abstract: The first highly efficient and
stereoselective difluoromethylation of
structurally diverse N-tert-butylsulfinyl
ketimines has been achieved with an in
fluoromethyl tertiary carbinamines, in-
cluding a-difluoromethyl allylic amines
and a-difluoromethyl propargylamines.
The stereocontrol mode of the present
diastereoselective difluoromethylation
of ketimines was found to be different
from that of other known fluoroalkyla-
tions of N-tert-butylsulfinyl aldimines,
which suggests that a cyclic six-mem-
bered transition state may be involved
in the reaction.
À
situ generated PhSO2CF2 anion, which
Keywords: amines · difluoromethy-
provides a powerful synthetic method
for the preparation of a variety of
structurally diverse homochiral a-di-
lation
· fluorine · ketimines ·
nucleophilic addition
Introduction
methodology was then extended to the synthesis of a-tri-
fluoromethyl allylic amines[4b] and a-trifluoromethylated vi-
cinal ethylenediamines.[4c] (1R,1’R)-1,1’-(Anthracene-9,10-
diyl)bis(2,2,2-trifluoroethanamine), a chiral diamine with
low basicity, was also successfully synthesized by Estivill
et al. using the same strategy.[4j] Not only did N-tert-butylsul-
finyl imines readily undergo electrophilic reactions with the
Ruppert–Prakash reagent (Me3SiCF3), but they also under-
went the addition of fluorinated Reformatsky reagents to
afford b-branched a,a-difluoro-b-amino esters.[4i]
Owing to the increasing importance of the CF2H group in
medicinal chemistry and drug discovery,[6] a-difluoromethyl
amines have attracted broad interest during the past decade.
Among the few known methods, stereoselective nucleophilic
difluoromethylation of N-tert-butylsulfinyl imines is one of
the most straightforward approaches for synthesizing a-di-
fluoromethyl amines. Previously, we found difluoromethyl
phenyl sulfone, PhSO2CF2H (1), to be a versatile nucleophil-
ic difluoromethylation reagent for the selective introduction
of highly useful difluorinated moieties such as difluorometh-
yl (CF2H), difluoromethylene (-CF2-), and difluoromethyli-
dene (=CF2).[7] We successfully synthesized chiral a-difluoro-
methyl amines[4d] and a-difluoromethyl ethylenediamines[4g]
by diastereoselective nucleophilic difluoromethylation of N-
tert-butylsulfinyl aldimines using PhSO2CF2H as a difluoro-
methylating agent. However, although significant progress
has been made in the arena of difluoromethylation of N-
tert-butylsulfinyl aldimines, the corresponding difluorome-
thylation of N-tert-butylsulfinyl ketimines has proved to be
more challenging.[4h] The difficulty of nucleophilic fluoroal-
kylation of N-tert-butylsulfinyl ketimines can be attributed
Chiral fluorinated amines are prevalent as a common motif
in the design of new biologically important compounds,
given the fact that the incorporation of a fluorine-containing
group can tune the basicity of an amine functionality and
thus enhance the bioavailability of a target drug molecule.[1]
Therefore, chiral fluorinated amines have been the focus of
numerous studies, and a number of strategies have been de-
veloped for their asymmetric synthesis, including the use of
fluorination reagents and fluorinated building blocks.[2] Re-
cently, diastereoselective nucleophilic fluoroalkylation of
imines has attracted considerable attention as a promising
method for the asymmetric synthesis of chiral fluorinated
amines.[3,4] In this context, Ellmanꢀs N-tert-butylsulfinyl
imines have been widely used in the asymmetric synthesis of
fluorinated amines.[2c,4,5]
In 2001, Prakash et al. reported the first efficient synthesis
of a-trifluoromethyl amines through diastereoselective nu-
cleophilic trifluoromethylation of N-tert-butylsulfinyl aldi-
mines, which opened up a new application of N-tert-butylsul-
finyl imines for the synthesis of fluorinated amines.[4a] This
[a] Dr. J. Liu, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai 200032 (China)
Fax : (+86)21-64166128
E-mail: jinbohu@sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000893.
Chem. Eur. J. 2010, 16, 11443 – 11454
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11443

to the relatively low electrophilicity and possible aza-enoli-
zation of ketimines, as well as the relatively low thermal sta-
bility and nucleophilicity of fluorinated carbanions RfÀ (due
to the “negative fluorine effect”).[8]
found that potassium hexamethyldisilazide (KHMDS) was
the base of choice,[9] affording the nucleophilic addition
product 5a in 70% yield (Table 1, entries 1–4). This indi-
cates that the basicity of KHMDS is appropriate for media-
In this paper, as part of our continuing effort to develop
selective difluoromethylation methodologies, we wish to dis-
close the first highly diastereoselective difluoromethylation
of structurally diverse N-tert-butylsulfinyl ketimines, which
has enabled us to efficiently synthesize a-difluoromethyl al-
lylic amines, a-difluoromethyl propargylamines, and other
a-difluoromethyl tertiary carbinamines through a simple
and reliable protocol.
Table 1. Survey of reaction conditions.[a]
Entry
Base
Solvent
Molar ratio
(3a/2/base)
Yield
[%][b]
d.r.[c]
1
nBuLi
THF
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.2
1.2:1:1.1
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1.5:1:1.2
25
12
29
70
59
59
55
84
54
77
99:1
99:1
99:1
99:1
99:1
99:1
28:72
99:1
99:1
99:1
2
3
4
5
LiHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
THF
THF
THF
THF
Results and Discussion
6
THF
Nucleophilic difluoromethylation of N-tert-butylsulfinyl ke-
timines: Previously, we discovered that pre-generation of
the (phenylsulfonyl)fluoromethyl anion paved the way for
the efficient monofluoromethylation of N-tert-butylsulfinyl
ketimines (Scheme 1a and b).[4h] However, we found that a
7[d]
8
THF/HMPA
PhCH3
PhCH3/AlMe3
PhCH3
9
10
[a] In all cases, a base was added to a mixture of 3a and 2 in a solvent at
À788C, and the reactions were usually complete in 2 h. [b] Yield of the
isolated product. [c] Diastereomeric ratio was determined by 19F NMR
spectroscopic analysis of the crude reaction mixture. [d] THF/HMPA=
6:1 (v/v).
ting this difluoromethylation reaction. Notably, in all cases
the diastereoselectivity of the nucleophilic addition was ex-
cellent (d.r.=99:1; see Table 1, entries 1–4).
Encouraged by these results, we further optimized the re-
action conditions of this nucleophilic difluoromethylation,
including the reactant ratios, solvents, and additives to fur-
ther increase the chemical yield of the addition product 5a.
It turned out that toluene was the solvent of choice
(Table 1). The optimal product yield (84%) was obtained
when the reaction proceeded at À788C in toluene with a re-
actant ratio of 3a/2/KHMDS=1:1.2:1.3 (Table 1, entry 8). It
should be noted that the opposite diastereoselectivity was
observed when hexamethylphosphoric triamide (HMPA)
was used as a co-solvent (Table 1, entry 7), indicating that
the solvation of the potassium cation by HMPA can result
in a different transition state mode of diastereoselective ad-
dition.
The optimized reaction conditions (Table 1, entry 8) were
then extended to a wide range of different N-tert-butylsul-
finyl ketimines to examine the substrate scope of the reac-
tion. As shown in Table 2, aromatic and heteroaromatic N-
tert-butylsulfinyl methyl ketimines readily underwent the nu-
cleophilic addition to provide the corresponding (phenylsul-
fonyl)difluoromethylated products in good yields with high
diastereoselectivity (Table 2, entries 1–8). In the case of iso-
propyl methyl ketimine 3i, we were still able to obtain the
addition product 5i in high yield with excellent diastereose-
lectivity (Table 2, entry 9). The nucleophilic addition to N-
tert-butylsulfinyl ketimine 3j gave only a 51% yield of prod-
uct 5j, probably due to the steric hindrance of the tert-butyl
group (Table 2, entry 10). Furthermore, phenyl butyl ket-
Scheme 1. Attempted difluoromethylation of ketimine 3a.
similar pre-generation protocol did not work for the difluor-
omethylation of ketimine 3a with the reagent PhSO2CF2H
(Scheme 1c), indicating that the lower thermal stability of
À
the PhSO2CF2 anion does not allow for its pre-generation.
Interestingly, when we attempted in situ generation of the
À
PhSO2CF2 anion, we observed the formation of addition
product 5a in 25% yield (Scheme 1d).
We envisaged that if we could find an appropriate base to
kinetically affect the deprotonation of PhSO2CF2H rather
than the unwanted aza-enolization of the ketimines at low
temperature, nucleophilic difluoromethylation of N-tert-bu-
tylsulfinyl ketimines might be successfully accomplished.
With this consideration in mind, we surveyed several bases
(such as nBuLi, LiHMDS, NaHMDS, and KHMDS) using
N-tert-butylsulfinyl ketimine 3a as a model compound, and
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Chem. Eur. J. 2010, 16, 11443 – 11454

Diastereoselective Synthesis of a-Difluoromethyl Amines
FULL PAPER
Table 2. Diastereoselective (phenylsulfonyl)difluoromethylation of N-
tert-butylsulfinyl ketimines 3.[a]
Entry
Ketimine
Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
R1 =Ph, R2 =CH3 (3a)
84
80
74
79
78
73
83
80
87
51
81
85
99:1
99:1
98:2
99:1
99:1
98:2
99:1
99:1
99:1
99:1
97:3
97:3
R1 =4-CF3C6H4, R2 =CH3 (3b)
R1 =4-CH3OC6H4, R2 =CH3 (3c)
R1 =4-CH3C6H4, R2 =CH3 (3d)
R1 =4-ClC6H4, R2 =CH3 (3e)
R1 =2-naphthyl, R2 =CH3 (3 f)
R1 =2-furyl, R2 =CH3 (3g)
R1 =2-pyridyl, R2 =CH3 (3h)
R1 =iPr, R2 =CH3 (3i)
9
10
11
12
R1 =tBu, R2 =CH3 (3j)
R1 =Ph, R2 =nBu (3k)
R1 =Ph, R2 =Et (3l)
[a] In all cases, KHMDS (1.3 equiv) was added to
a mixture of 2
(1.0 equiv) and 3 (1.2 equiv) in PhCH3 at À788C, and the reactions were
usually complete in 2 h. [b] Yield of isolated analytically pure material
with d.r.>99:1. [c] Diastereomeric ratio was determined by 19F NMR
spectroscopic analysis of the crude reaction mixture.
Figure 1. X-ray structure of product 5k (top) and proposed transition
state for chelation-controlled addition (bottom).
ACHTUNGTRENNUNGimine 3k and phenyl ethyl ketimine 3l were also successful-
ly (phenylsulfonyl)difluoromethylated in yields of 81% and
85%, respectively (Table 2, entries 11 and 12). In most
cases, the good product yields and excellent diastereoselec-
tivity of the nucleophilic addition reactions suggest that
both the rate of deprotonation of 2 with KHMDS and the
catalyzed alcoholysis (Scheme 2).[4h,10] It should be pointed
out that these deprotection procedures have proved to be
stereochemically reliable, incurring no loss of optical purity
(for additional evidence, see Scheme 4).[4d,f–h] In addition, we
À
rate of nucleophilic addition of PhSO2CF2 anion to keti-
mines 3 are significantly faster than that of the unwanted
base-mediated aza-enolization of ketimines 3.
The absolute configuration of product 5k was determined
by its single-crystal X-ray structure (Figure 1, top), and the
configurations of others were assigned by analogy. The ste-
reocontrol mode of the present diastereoselective (phenyl-
sulfonyl)difluoromethylation of ketimines can be predicted
by envisaging a cyclic six-membered transition state in
which the bulky tert-butyl group preferentially adopts an
equatorial position (Figure 1, bottom). The observed diaste-
reoselectivity mode is completely opposite to that of the nu-
cleophilic fluoroalkylation of tert-butylsulfinyl aldimines,[4]
but similar to our previous observation concerning the mon-
ofluoromethylation of N-tert-butylsulfinyl ketimines.[4h] This
transition-state model is further supported by two pieces of
experimental evidence: firstly, use of the coordinating sol-
vent HMPA, which prevents complexation of the sulfinyl
oxygen atom with the metal ion (i.e., K+, Na+, Li+), result-
ed in an opposite diastereoselectivity (Table 1, entry 7); sec-
ondly, an apolar solvent such as toluene helped to improve
the yield of the reaction (Table 1, entries 8, 10, and 11).
The obtained homochiral (phenylsulfonyl)difluoromethy-
lated products 5 (as indicated in Table 2, d.r.>99:1 after
silica gel chromatography in all cases) could be conveniently
converted into homochiral a-difluoromethyl tertiary carbin-
amines 6 in high yields by mild reductive desulfonylation
with Mg/HOAc/NaOAc in a DMF-based system and acid-
Scheme 2. Preparation of a-difluoromethyl carbinamines 6.
also extended this nucleophilic difluoromethylation to N-
tert-butylsulfinyl a-chloro ketimine 7. As shown in
Scheme 3, a-chloro ketimine 7 readily reacted with the re-
agent PhSO2CF2H in the presence of KHMDS, affording
(phenylsulfonyl)difluoromethylated aziridine 8 in good yield
Scheme 3. Synthesis of chiral fluorinated aziridine 8.
Chem. Eur. J. 2010, 16, 11443 – 11454
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11445

J. Hu and J. Liu
Table 3. Optimization of reaction conditions.[a]
and with high diastereoselectivity through an addition–de-
ACHTUNGTRENNUNGchlorinative cyclization cascade reaction.
Nucleophilic difluoromethylation of a,b-unsaturated N-tert-
butylsulfinyl ketimines: Allyllic amines are widely applied in
medicinal chemistry and drug discovery, since a variety of
synthetically and biologically important organic compounds
can be obtained through the elaboration of their double
bond.[11] However, although numerous synthetic endeavors
have been undertaken towards the efficient preparation of
nonfluorinated chiral allylic amines,[12] the synthesis of chiral
a-fluoroalkyl allylic amines has been less well explored. The
few known reports have been mostly based on the synthetic
elaboration of chiral trifluoromethylated imines or their de-
rivatives.[13] Another preparative method for chiral a-fluo-
roalkyl allylic amines is through a Julia-type methylenation–
desulfonylation reaction of fluorinated b-amino sulfones.[14]
Furthermore, the trifluoromethylation of unsaturated N-sul-
finimines or N-tosyl imines can also afford chiral a-trifluoro-
methyl allylic amines, albeit in somewhat low yields.[4b,15]
Compared with that of a-trifluoromethyl allylic amines, the
asymmetric synthesis of a-difluoromethyl allylic amines is
less well known, probably due to lower availability of di-
fluoromethylated precursors and difluoromethylation re-
agents.[16]
Entry
Base
Molar ratio
(9a/2/base)
Yield
[%][b]
d.r. (Rs,R)/ACHTUNGTRENNUNG
(Rs,S)[c]
1
2
3
4
5
6
7
8
LiHMDS
NaHMDS
KHMDS
LDA
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.1:1.2
1:1.5:1.6
1:2:2.2
23
65
82
31
trace
77
69
88
86
92:8
94:6
94:6
93:7
–
94:6
92:8
94:6
95:5
95:5
94:6
nBuLi
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
9
10
11
1.1:1:1.1
1.2:1:1.1
1.5:1:1.1
91
76
[a] In all cases, base was added to a mixture of 2 and 9a in THF at
À788C, and the reactions were usually complete in 4 h. [b] Yield of iso-
lated analytically pure material. [c] Diastereomeric ratio was determined
by 19F NMR spectroscopic analysis of the crude reaction mixture.
uene. Following initial deprotonation with lithium hexame-
thyldisilazide (LiHMDS), PhSO2CF2H reacted with 9a to
afford the 1,2-addition product 10a with good diastereose-
lectivity (d.r. 92:8), albeit in low yield (Table 3, entry 1). A
subsequent screening of bases revealed that KHMDS pro-
vided a significant increase in yield (Table 3, entry 3). It
turned out that nBuLi was not suitable for the reaction,
probably due to its high nucleophilicity toward 9a (Table 3,
entry 5). To further improve the product yield, we then care-
fully examined the effect of reactant molar ratios on the
chemical yield using KHMDS as the base. The best yield of
product 10a was obtained with a reactant molar ratio 9a/2/
KHMDS=1.2:1:1.1 (Table 3, entry 10).
Although a,b-unsaturated ketones have been widely used
in organic synthesis,[17] a,b-unsaturated ketimines remain a
relatively poorly studied class of compounds owing to their
low chemical reactivity. Known conjugate additions of a,b-
unsaturated ketimines are limited to nucleophiles such as di-
alkylzinc reagents[18a] and organocuprates.[18b] Moreover, in-
stances of nucleophilic 1,2-addition of a,b-unsaturated keti-
mines are scarce, with the only example of which we are
aware being the cyanation of a,b-unsaturated N-tosyl ket-
ACHTUNGTRENNUNG
imine catalyzed by a nucleophilic N-heterocyclic carbene.[19]
In our previous investigation, we found that because of the
high electronegativity of the fluorine atom, difluorinated
carbanions, regarded as “hard” nucleophiles, usually attack
the carbonyl group and undergo 1,2-addition reactions with
a,b-enones.[8b] Based on these results, we assumed that nu-
cleophilic 1,2-addition of the (phenylsulfonyl)difluoromethyl
Having identified the optimal reaction conditions, the
scope of this nucleophilic 1,2-addition reaction was investi-
gated with various a,b-unsaturated N-tert-butylsulfinyl ket-
AHCTUNGTREGiNNUN mines (Table 4). The reaction proved to be general and
À
À
anion (PhSO2CF2 ), generated in situ from PhSO2CF2H and
highly regioselective, with the PhSO2CF2 anion attacking
the C=N double bond of a,b-unsaturated ketimines 9 to pro-
vide a-(phenylsulfonyl)difluoromethylated allylic sulfina-
mides 10. In all cases, the a,b-unsaturated ketimines showed
high reactivity towards reagent 2, and the corresponding
(phenylsulfonyl)difluoromethylated products 10 were ob-
tained in good to excellent yields (77–97%) and with high
diastereoselectivities (d.r. 94:6–97:3). Electron-withdrawing
or -donating substituents on the aryl rings of 9 did not exert
a significant effect on the outcome of the diastereoselective
nucleophilic (phenylsulfonyl)difluoromethylation. The pres-
ent nucleophilic 1,2-addition of a,b-unsaturated ketimines 9
with 2 is remarkable, especially when compared with the
previously reported nucleophilic trifluoromethylation of a,b-
unsaturated N-tert-butylsulfinyl aldimines using TMSCF3/
TBAT or TMAF (TMS=trimethylsilyl; TBAT=tetrabutyl-
a base, to a,b-unsaturated N-tert-butylsulfinyl ketimines
would proceed smoothly to afford the desired chiral a-di-
fluoromethyl allylic amines.
Initially, we prepared a variety of a,b-unsaturated N-tert-
butylsulfinyl ketimines 9 by TiACHTNUGTRENUNG(OEt)4-mediated condensa-
tion of tert-butylsulfinamide and the requisite a,b-unsaturat-
ed ketones, according to the reported protocol[18b] (see the
Supporting Information). With these a,b-unsaturated ket-
ACHTUNGTRENNUNG
PhSO2CF2H (2). The results are summarized in Table 3. It
should be mentioned that we found that the (phenylsulfo-
nyl)difluoromethylation of 9a could be achieved with THF
as the solvent, which is more convenient to handle than tol-
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Diastereoselective Synthesis of a-Difluoromethyl Amines
Table 4. Facile synthesis of a-difluoromethyl allylic amines 11.[a]
FULL PAPER
We also attempted to react
other nucleophilic fluoroalky-
lating
agents,
such
as
Me3SiCF2SO2Ph
and
PhSO2CH2F, with a,b-unsatu-
rated N-tert-butylsulfinyl keti-
mine
9a.
Although
Entry
Substrate 9
Ar1 =Ph, Ar2 =Ph (9a)
10 [%][b]
d.r. of 10 (Rs,R)/
(Rs,S)[c]
11 [%][d]
Me3SiCF2SO2Ph generated the
PhSO2CF2 anion in the pres-
1
2
3
4
5
6
7
8
91
82
90
93
96
92
86
95
94
92
80
77
95:5
94:6
97:3
95:5
96:4
95:5
96:4
97:3
96:4
95:5
94:6
96:4
94
92
92
89
90
90
85
88
90
86
82
91
À
Ar1 =Ph, Ar2 =4-MeOC6H4 (9b)
Ar1 =4-MeOC6H4, Ar2 =Ph (9c)
Ar1 =4-CF3C6H4, Ar2 =Ph (9d)
Ar1 =4-ClC6H4, Ar2 =Ph (9e)
Ar1 =Ph, Ar2 =4-FC6H4 (9 f)
Ar1 =Ph, Ar2 =4-CF3C6H4 (9g)
Ar1 =4-FC6H4, Ar2 =Ph (9h)
Ar1 =4-CH3C6H4, Ar2 =Ph (9i)
Ar1 =Ph, Ar2 =4-CH3C6H4 (9j)
Ar1 =Ph, Ar2 =2-furyl (9k)
Ar1 =Ar2 =4-MeOC6H4 (9l)
ence of tetrabutylammonium
triphenyldifluorosilicate
(TBAT),[10] it showed lower re-
activity towards 9a, and the 1,2-
addition products were only ob-
tained in 50% yield with
9
10
11
12
modest
diastereoselectivity
(d.r.=75:25), which is inferior
to the results achieved with the
present PhSO2CF2H/KHMDS
system. In the case of
PhSO2CH2F, which readily re-
acted with a,b-unsaturated ke-
tones to afford a mixture of 1,2-
[a] In all cases, KHMDS was added to a mixture of 9 and 2 in THF at À788C, and the reactions were usually
complete in 4 h. [b] Yield of isolated analytically pure material with d.r.>99:1. [c] Diastereomeric ratio was
determined by 19F NMR spectroscopic analysis of the crude reaction mixture. [d] Yield of the isolated product
based on the amount of homochiral 10 used.
G
and 1,4-addition products,[8b] the nucleophilic monofluoro-
methylation of 9a afforded only 1,2-adducts in nearly quan-
titative yield.
ACHTUNGTRENNUNG
mined by single-crystal X-ray structure analysis (Figure 2),
and the configurations of 10b–l were assigned by analogy.
Fluorinated a-amino acids are of particular importance in
biological and peptide chemistry,[20] and have been shown to
be irreversible inhibitors of pyridoxal phosphate-dependent
enzymes.[1a] Much effort has been devoted to the synthesis
of fluorinated a-amino acids, especially in a stereocontrolled
manner.[13e,21] To demonstrate the synthetic utility of the
present highly efficient difluoromethylation reaction, a-di-
fluoromethyl allylic amine 11a was further transformed to
a-difluoromethyl a-amino acid 14 (Scheme 4). Firstly, the
Figure 2. X-ray structure of product 10a.
Scheme 4. Synthesis of N-Bz-protected a-difluoromethyl a-amino acid
14.
The sense of diastereoselective induction is consistent with a
cyclic six-membered transition state, similar to that invoked
in our previous mono- and difluoromethylation of N-tert-bu-
tylsulfinyl ketimines.[4h] Upon reductive desulfonylation with
our previously developed Mg/HOAc/NaOAc system and
acid-catalyzed alcoholysis,[4h,10] the a-(phenylsulfonyl)di-
fluoromethyl allylic sulfinamides 10 were readily converted
into the corresponding a-difluoromethyl allylic amines 11 in
excellent yields (Table 4).
amino group of 11a was protected with benzoyl chloride to
afford benzamide derivative 12 in 98% yield. Ozonolysis of
this N-Bz-protected amine in CH2Cl2 at À788C, followed by
quenching with triphenylphosphine,[13e] gave the intermedi-
ate aldehyde 13. Upon oxidation with sodium chlorite in
tert-butyl alcohol in the presence of 2-methyl-2-butene and
aqueous NaH2PO4,[22] compound 13 was converted into the
Chem. Eur. J. 2010, 16, 11443 – 11454
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11447

J. Hu and J. Liu
corresponding N-Bz-protected a-difluoromethyl a-amino
acid 14 in good yield with no loss of stereochemical purity
(with 99.8% ee). We found this two-step procedure to be
more reliable than a one-step oxidation with NaIO4/RuCl3,
which gave none of the desired product.
yield of 16a (91%) and high diastereoselectivity (d.r.=98:2)
were achieved when the reaction was allowed to proceed at
À788C for 2 h at
a reactant molar ratio of 15a/2/
NaHMDS=1.2:1:1.2 (Table 5, entry 7).
Notably, among the three types of reactions studied be-
tween PhSO2CF2H (2) and aza-enolizable ketimine 3a
(Table 1), a,b-unsaturated ketimine 9a (Table 3), and a,b-
acetylenic ketimine 15a (Table 5), an appropriate base
played a very important role. In the case of aza-enolizable
ketimine 3a, the product yield was most sensitive to the
choice of base, and the reaction with KHMDS gave a much
higher yield than those with NaHMDS or LiHMDS
(Table 1, entries 2–4). It is likely that as the strongest base
among Li-, Na-, and KHMDS, KHMDS is the best (among
the three bases) to kinetically effect the deprotonation of
PhSO2CF2H and the subsequent nucleophilic (phenylsulfo-
nyl)difluoromethylation, rather than the unwanted aza-eno-
lization of the ketimine at low temperature. Since a,b-unsa-
turated ketimine 9a and a,b-acetylenic ketimine 15a are not
aza-enolizable, it is reasonable to see that their reactions
with reagent 2 were less sensitive to the choice of base
(Table 3, entries 1–3; Table 5, entries 1–3). Indeed, the reac-
tion between a,b-acetylenic ketimine 15a and 2 gave very
similar product yields (86–90%) when LiHMDS, NaHMDS,
and KHMDS were applied (Table 5, entries 1–3).
Nucleophilic difluoromethylation of a,b-acetylenic N-tert-
butylsulfinyl ketimines: Propargylamines play an increasing-
ly significant role in organic chemistry as both synthetic in-
termediates for the preparation of polyfunctional amino de-
rivatives and biologically active compounds,[23] and their ste-
reoselective synthesis is therefore attractive to synthetic or-
ganic chemists.[24,25] Although several different methods for
the preparation of propargylamines have been disclosed in
the literature, including metal-catalyzed addition of alkynes
to enamines or imines[24] and asymmetric addition of alkynyl
metal reagents to chiral sulfinylimines,[25] little synthetic
effort has been reported so far about the synthesis of fluo-
roalkylated propargylamines, which are important building
blocks for drug design and for the synthesis of bioactive
target molecules.[26] In this context, we sought to extend our
nucleophilic difluoromethylation strategy to the diastereose-
lective synthesis of a-difluoromethyl propargylamines
through 1,2-addition of PhSO2CF2H (2) to a,b-acetylenic N-
tert-butylsulfinyl ketimines in the presence of a base.
Accordingly, a,b-acetylenic N-tert-butylsulfinyl ketimines
15 were first prepared in good yields from the commercially
available (Rs)-tert-butylsulfinamide and a,b-acetylenic ke-
tones[27] (see the Supporting Information). Firstly, a,b-acety-
lenic ketimine 15a was chosen as a model compound to op-
timize the reaction conditions for the 1,2-addition with
PhSO2CF2H. As shown in Table 5, we found that KHMDS,
NaHMDS, and LiHMDS were all suitable for mediating this
nucleophilic (phenylsulfonyl)difluoromethylation reaction
(Table 5, entries 1–3), although the reaction with NaHMDS
gave a slightly higher yield of product (Table 5, entry 2).
After further optimization of the reactant ratio, an optimal
The absolute configuration of 16a was confirmed by
single-crystal X-ray structure analysis (Figure 3), which indi-
Table 5. Optimization of reaction conditions.[a]
Entry
Base
Molar ratio
(15a/2/base)
Yield of
d.r.[c]
Figure 3. X-ray structure of product 16a.
16a [%][b]
1
2
3
4
5
6
7
LiHMDS
NaHMDS
KHMDS
LDA
NaHMDS
NaHMDS
NaHMDS
1.2:1:1.1
1.2:1:1.1
1.2:1:1.1
1.2:1:1.1
1.1:1:1.1
1:1.2:1.3
1.2:1:1.2
86
90
88
50
88
86
91
98:2
98:2
98:2
98:2
98:2
98:2
98:2
cated that the stereochemistry of this nucleophilic 1,2-addi-
tion was chelation-controlled and that the reaction proceed-
ed through a similar cyclic six-membered transition state to
that mentioned above in relation to the difluoromethylation
of ketimines.
[a] In all cases, base was added to a mixture of 2 and 15a in THF at
À788C, and the reaction was usually complete in 2 h. [b] Yield of isolated
analytically pure material with d.r.>99:1. [c] Diastereomeric ratio was
determined by 19F NMR spectroscopic analysis of the crude reaction mix-
ture. LDA=lithium diisopropylamide.
The scope of the reaction was explored with a variety of
substrates to establish the generality of the process, and the
results are summarized in Table 6. It turned out that, in the
presence of NaHMDS, the difluoromethylating agent 2
11448
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11443 – 11454

Diastereoselective Synthesis of a-Difluoromethyl Amines
Table 6. Preparation of a-difluoromethyl propargylamines 17.[a]
FULL PAPER
Conclusion
We have developed the first ef-
ficient synthesis of a-difluoro-
methyl tertiary carbinamines, a-
difluoromethyl allylic amines,
and a-difluoromethyl propar-
gylamines through diastereose-
lective nucleophilic difluorome-
thylations of N-tert-butylsulfinyl
ketimines, a,b-unsaturated N-
tert-butylsulfinyl ketimines, and
a,b-acetylenic N-tert-butylsul-
finyl ketimines with in situ gen-
Entry
Ketimines 15
R1 =R2 =Ph (15a)
16 [%][b]
d.r. of 16[c]
17 [%][d]
1
2
3
4
5
6
7
8
91
94
86
96
93
86
32
83
98:2
98:2
95:5
99:1
98:2
96:4
99:1
99:1
90:10
–
96
95
93
95
92
94
–
93
–
–
R1 =Ph, R2 =4-CH3C6H4 (15b)
R1 =4-CH3OC6H4, R2 =Ph (15c)
R1 =4-ClC6H4, R2 =Ph (15d)
R1 =Ph, R2 =4-CH3OC6H4 (15e)
R1 =4-CH3C6H4, R2 =Ph (15 f)
R1 =2-CH3OC6H4, R2 =Ph (15g)
R1 =Ph, R2 =TIPS (15h)
R1 =Ph, R2 =nBu (15i)
49
À
9
10
11
erated PhSO2CF2 anion and an
R1 =Ph, R2 =CH2CH2Ph (15j)
R1 =tBu, R2 =Ph (15k)
complex mixture
trace
appropriate base (such as
KHMDS). The kinetically pre-
ferred generation of the
–
–
[a] In all cases, NaHMDS was added to a mixture of 15 and 2 in THF at À788C, and the reactions were usually
complete in 2 h. [b] Yield of isolated analytically pure material with d.r.>99:1. [c] Diastereomeric ratios were
determined by 19F NMR spectroscopic analysis of the crude reaction mixture. [d] Yield of the isolated product
based on the amount of homochiral 16 used. TIPS=triisopropylsilyl.
À
PhSO2CF2 anion and nucleo-
philic
addition
of
the
À
PhSO2CF2 anion to ketimines
over the undesired aza-enoliza-
smoothly reacted with a,b-acetylenic N-tert-butylsulfinyl
ketimines 15 to accomplish the 1,2-addition reaction. Good
tion of ketimines are the key factors for the success of these
difluoromethylation reactions. The stereocontrol mode of
the present diastereoselective difluoromethylation of keti-
mines is opposite to that of other known fluoroalkylations
of N-tert-butylsulfinyl aldimines, but similar to that observed
in our previous report concerning the monofluoroalkylation
of ketimines, indicating a remarkable difference between
the chemistry of ketimines and aldimines. Not only do our
results represent a practically useful synthetic method for
many potential applications, but the significantly different
generation methods required for the (phenylsulfonyl)difluor-
omethyl anion (in situ generation) and the previously
known (phenylsulfonyl)monofluoromethyl anion (pre-gener-
ation), as for the addition to N-tert-butylsulfinyl ketimines,
also provide some new insights into the thermal stability
and chemical reactivity of a-fluorinated carbanions.
ACHTUNGTRENNUNG
to excellent yields and high diastereoselectivities were ob-
served with aryl rings present as both R1 and R2 (Table 6,
entries 1–6), an exception being when a methoxy group was
present at the ortho position of the aryl ring at R1, in which
case a relatively lower product yield, but still with excellent
diastereoselectivity, was obtained, probably due to steric
hindrance (Table 6, entry 7). The successful addition to a,b-
acetylenic N-tert-butylsulfinyl ketimine 15h demonstrates
the promising functional group tolerance of the reaction
(Table 6, entry 8). A moderate yield was obtained for the
a,b-acetylenic ketimine 15i, albeit with somewhat reduced
diastereoselectivity (Table 6, entry 9) due to competitive
base-assisted propargyl–allenyl isomerization.[27a] However,
in the case of a,b-acetylenic ketimine 15j, the nucleophilic
1,2-addition of PhSO2CF2H was unsuccessful (Table 6,
entry 10). Likewise, only a trace of the desired product was
observed when sterically demanding ketimine 15k was sub-
jected to our optimized reaction conditions (Table 6,
entry 11). It is clear that steric interaction significantly re-
tards the nucleophilic 1,2-addition. Moreover, the nucleo-
philic 1,2-addition products 16 can be further converted into
a-difluoromethyl propargylamines 17 in excellent yields
after deprotection of both the tert-butylsulfinyl and phenyl-
sulfonyl groups under mild conditions.[4h,10] Desilylation of
17h by treatment with tetrabutylammonium fluoride
(TBAF) in THF afforded the synthetically useful terminal
acetylene 18 in 76% yield (as demonstrated in Scheme 5).
Experimental Section
The N-tert-butylsulfinyl ketimines 3[28] were prepared from the corre-
sponding ketones according to the known condensation procedure in one
step. Difluoromethyl phenyl sulfone 2[29] was prepared according to
known procedures. Unless otherwise mentioned, all chemicals were pur-
chased from commercial sources. THF was freshly distilled over sodium.
Silica gel (300–400 mesh) was used for column chromatography, and in
most cases a petroleum ether/ethyl acetate combination was used as the
eluent. All melting points are uncorrected. 1H, 13C, and 19F NMR spectra
were recorded on 400 MHz or 300 MHz NMR spectrometers. 1H NMR
chemical shifts were determined relative to internal (CH3)4Si (TMS) at
d=0.0 or to the signal of a residual protonated solvent: CDCl3 d=7.26.
13C NMR chemical shifts were determined relative to internal TMS at
d=0.0. 19F NMR chemical shifts were determined relative to CFCl3 at
d=0.0. Chemical shifts are reported in ppm. Mass spectra were obtained
on a Aglient 1100 mass spectrometer. High-resolution mass data were re-
corded on a high-resolution mass spectrometer in EI, ESI, or MALDI
modes.
Scheme 5. Desilylation of a-difluoromethyl propargylamine 17h.
Chem. Eur. J. 2010, 16, 11443 – 11454
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11449

J. Hu and J. Liu
Typical procedure for stereoselective nucleophilic difluoromethylation of
N-tert-butylsulfinyl ketimines using difluoromethyl phenyl sulfone:
analysis calcd (%) for C19H22ClF2NO3S2: C 50.72, H 4.93, N 3.11; found:
C 50.71, H 5.06, N 2.98; MS (ESI): m/z: 450.0 [M++1].
3
Under an atmosphere of N2, KHMDS (0.5m solution in toluene; 2.6 mL,
1.3 mmol) was added dropwise to a solution of N-tert-butylsulfinyl keti-
mine 3 (1.0 mmol) and PhSO2CF2H (230 mg, 1.2 mmol) in PhCH3 (8 mL)
at À788C. The reaction mixture was stirred vigorously at À788C for 2 h,
and then saturated aqueous NaCl solution (10 mL) was added. The re-
sulting mixture was extracted with Et2O (3ꢂ10 mL), and the combined
organic phases were dried over MgSO4. After the removal of volatile sol-
vents under vacuum, the crude product was further purified by silica gel
column chromatography to give product 5.
Compound 5 f: 73% yield; white solid; m.p. 70–728C; d.r.>99:1 (after
silica gel chromatography), [a]2D8 =À99.67 (c=0.93, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.05–8.08 (m, 1H), 7.92 (d, J=7.8 Hz, 2H), 7.77–
7.87 (m, 3H), 7.64–7.72 (m, 2H), 7.48–7.57 (m, 4H), 5.33 (brs, 1H), 2.40
(s, 3H), 1.35 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=À102.3 (d,
J=235.5 Hz, 1F), À103.3 ppm (d, J=235.2 Hz, 1F); 13C NMR (100 MHz,
CDCl3): d=135.4, 133.6, 133.2, 133.1, 132.6, 130.4, 129.4, 129.2, 128.6,
127.5, 127.4, 127.1, 126.4, 126.2, 120.9 (t, J=295.6 Hz), 66.0 (dd, J=22.7,
17.6 Hz), 57.2, 24.2, 22.8 ppm; IR (KBr): n˜ =3288, 2960, 1334, 1159, 1110,
1079, 715, 593 cmÀ1; elemental analysis calcd (%) for C23H25F2NO3S2: C
59.33, H 5.41, N 3.01; found: C 59.07, H 5.59, N 2.85; MS (ESI): m/z:
466.2 [M++1].
Compound 5a: 84% yield; white solid; m.p. 82–838C; d.r.>99:1 (after
silica gel chromatography, as detected by 19F NMR spectroscopy), [a]2D7
=
À63.06 (c=0.98, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.93 (d, J=
7.5 Hz, 2H), 7.72 (t, J=7.5 Hz, 1H), 7.54–7.62 (m, 4H), 7.34–7.40 (m,
3H), 5.28 (brs, 1H), 2.26 (s, 3H), 1.33 ppm (s, 9H); 19F NMR (282 MHz,
CDCl3): d=À102.4 (d, J=234.9 Hz, 1F), À103.6 ppm (d, J=234.4 Hz,
1F); 13C NMR (100 MHz, CDCl3): d=135.78, 135.77, 135.4, 133.6, 130.5,
129.2, 129.1, 129.0, 128.2, 128.0, 120.7 (dd, J=298.6, 295.7 Hz), 65.8 (dd,
J=22.6, 17.5 Hz), 57.2, 23.9, 22.7 ppm (d, J=17.5 Hz); IR (KBr): n˜ =
3273, 2979, 1451, 1340, 1166, 1070, 761, 538 cmÀ1; elemental analysis
calcd (%) for C19H23F2NO3S2: C 54.92, H 5.58, N 3.37; found: C 54.64, H
5.79, N 3.24; MS (ESI): m/z: 416.2 [M++1].
Compound 5g: 83% yield; white solid; m.p. 68–708C; d.r.>99:1 (after
silica gel chromatography), [a]2D8 =À48.16 (c=0.98, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.95 (d, J=6.9 Hz, 2H), 7.74 (t, J=7.8 Hz, 1H),
7.59 (t, J=6.9 Hz, 2H), 7.47–7.49 (m, 1H), 6.57 (d, J=3.6 Hz, 1H), 6.41–
6.44 (m, 1H), 4.84 (brs, 1H), 2.14 (s, 3H), 1.26 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À103.1 ppm (s, 2F); 13C NMR (100 MHz, CDCl3):
d=148.8, 143.7, 135.4, 133.4, 130.6, 129.2, 120.4 (t, J=298.0 Hz), 111.9,
110.7, 62.4 (t, J=21.1 Hz), 56.9, 22.5, 21.6 ppm; IR (KBr): n˜ =3295, 1451,
1331, 1110, 1068, 750, 580 cmÀ1
; elemental analysis calcd (%) for
C17H21F2NO4S2: C 50.36, H 5.22, N 3.45; found: C 50.12, H 5.36, N 3.43;
Compound 5b: 80% yield; white solid; m.p. 44–468C; d.r.>99:1 (after
MS (ESI): m/z: 406.0 [M++1].
silica gel chromatography, detected by 19F NMR spectroscopy), [a]2D7
=
À52.89 (c=1.24, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.93 (d, J=
7.8 Hz, 2H), 7.71–7.78 (m, 3H), 7.55–7.66 (m, 4H), 5.35 (brs, 1H), 2.28
(s, 3H), 1.34 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=À62.0 (s, 3F),
À102.6 (d, J=232.7 Hz, 1F), À103.8 ppm (d, J=240.3 Hz, 1F); 13C NMR
(100 MHz, CDCl3): d=139.9, 135.6, 133.3, 131.2 (q, J=32.9 Hz), 130.5,
129.6, 129.3, 125.0 (q, J=9.5 Hz), 122.4, 120.3 (t, J=296.4 Hz), 65.7 (dd,
J=23.4, 18.3 Hz), 57.4, 23.9, 22.8 ppm; IR (KBr): n˜ =3292, 2964, 1451,
Compound 5h: 80% yield; white solid; m.p. 74–768C; d.r.>99:1 (after
silica gel chromatography), [a]2D8 =À63.79 (c=0.91, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.66–8.70 (m, 1H), 7.89 (d, J=6.9 Hz, 2H), 7.79
(td, J=8.1, 2.1 Hz, 1H), 7.65–7.74 (m, 2H), 7.54 (t, J=7.8 Hz, 2H), 7.32–
7.37 (m, 1H), 6.11 (brs, 1H), 2.14 (s, 3H), 1.25 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À101.0 (d, J=234.4 Hz, 1F), À102.6 ppm (d, J=
235.2 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=154.8, 148.5, 136.6, 135.2,
133.7, 130.7, 129.1, 123.8, 122.7 (d, J=2.4 Hz), 121.3 (t, J=298.6 Hz), 64.4
(t, J=19.7 Hz), 56.9, 22.6, 20.8 ppm; IR (KBr): n˜ =3296, 2962, 1592, 1450,
1334, 1154, 1076, 685, 537 cmÀ1; MS (ESI): m/z: 417.2 [M++1]; HRMS
(MALDI): m/z: calcd for C18H23N2O3F2S2 [M++H]: 417.1125; found:
417.1112.
1330, 1078, 1017, 612 cmÀ1
;
elemental analysis calcd (%) for
C20H22F5NO3S2: C 49.68, H 4.59, N 2.90; found: C 49.71, H 4.74, N 2.77;
MS (ESI): m/z: 484.2 [M++1].
Compound 5c: 74% yield; white solid; m.p. 36–388C; d.r.>99:1 (after
silica gel chromatography,), [a]2D7 =À66.33 (c=0.94, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.93 (d, J=7.8 Hz, 2H), 7.72 (t, J=7.5 Hz, 1H),
7.57 (t, J=7.5 Hz, 2H), 7.49 (d, J=6.9 Hz, 2H), 6.88 (d, J=9.3 Hz, 2H),
5.21 (brs, 1H), 3.81 (s, 3H), 2.24 (s, 3H), 1.32 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À102.7 (d, J=229.0 Hz, 1F), À103.7 ppm (d, J=
236.9 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=160.0, 135.3, 133.7, 130.5,
130.4, 129.2, 127.4, 120.8 (t, J=296.8 Hz), 113.3, 65.5 (dd, J=22.1,
17.2 Hz), 57.1, 55.2, 24.1, 22.8 ppm; IR (KBr): n˜ =3291, 2961, 1610, 1514,
1334, 1259, 1111, 1081, 597 cmÀ1; MS (ESI): m/z: 446.0 [M++1]; HRMS
(ESI): m/z: calcd for C20H26NO4F2S2 [M++H]: 446.1283; found: 446.1265.
Compound 5i: 97% yield; a liquid; d.r.>99:1 (after silica gel chromatog-
1
raphy), [a]2D7 =À48.49 (c=1.27, CHCl3); H NMR (300 MHz, CDCl3): d=
8.02 (d, J=7.8 Hz, 2H), 7.73 (t, J=6.9 Hz, 1H), 7.59 (t, J=7.8 Hz, 2H),
4.27 (brs, 1H), 2.55–2.71 (m, 1H), 1.54 (s, 3H), 1.26 (s, 9H), 1.12 ppm (t,
J=6.6 Hz, 6H); 19F NMR (282 MHz, CDCl3): d=À94.9 (d, J=239.2 Hz,
1F), À95.9 ppm (d, J=239.2 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=
135.2, 133.6, 130.7, 129.1, 122.9 (t, J=292.8 Hz), 66.0 (t, J=17.8 Hz), 57.0,
33.9, 22.7, 17.8 (dd, J=10.5, 6.3 Hz), 15.9 ppm (t, J=4.1 Hz); IR (KBr):
n˜ =3315, 2966, 1584, 1450, 1336, 1151, 1083, 905, 719, 593 cmÀ1; MS
(ESI): m/z: 382.2 [M++1]; HRMS (ESI): m/z: calcd for C16H26NO3F2S2
[M++H]: 382.1324; found: 382.1318.
Compound 5d: 79% yield; white solid; m.p. 30–328C; d.r.>99:1 (after
silica gel chromatography), [a]2D7 =À57.33 (c=0.91, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.93 (d, J=7.2 Hz, 2H), 7.72 (t, J=7.5 Hz, 1H),
7.56 (t, J=7.2 Hz, 2H), 7.46 (d, J=6.9 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H),
5.23 (brs, 1H), 2.35 (s, 3H), 2.24 (s, 3H), 1.32 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À102.4 (d, J=234.1 Hz, 1F), À103.6 ppm (d, J=
237.2 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=139.1, 135.3, 133.7,
132.73, 132.72, 130.4, 129.2, 128.98, 128.96, 128.8, 120.8 (t, J=297.2 Hz),
65.6 (dd, J=22.6, 17.5 Hz), 57.1, 23.9, 22.8, 21.1 ppm; IR (KBr): n˜ =3290,
2960, 1450, 1335, 1111, 1082, 723, 595 cmÀ1; elemental analysis calcd (%)
for C20H25F2NO3S2: C 55.92, H 5.87, N 3.26; found: C 55.84, H 6.16, N
3.13; MS (ESI): m/z: 430.2 [M++1].
Compound 5j: 51% yield; white solid; m.p. 101–1038C; d.r.>99:1 (after
silica gel chromatography), [a]2D7 =À74.10 (c=0.99, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.02 (d, J=7.8 Hz, 2H), 7.72 (t, J=7.2 Hz, 1H),
7.59 (t, J=7.8 Hz, 2H), 4.75 (brs, 1H), 1.63 (s, 3H), 1.30 (s, 9H),
1.23 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=À89.4 (d, J=
248.2 Hz, 1F), À95.7 ppm (d, J=247.9 Hz, 1F); 13C NMR (100 MHz,
CDCl3): d=135.1, 134.4, 130.8, 129.1, 122.9 (dd, J=303.7, 294.3 Hz), 70.5
(t, J=18.8 Hz), 57.1, 38.8 (d, J=3.3 Hz), 26.8, 23.0, 16.3 ppm (dd, J=5.4,
3.3 Hz); IR (KBr): n˜ =3329, 2966, 1584, 1450, 1335, 1143, 1087, 717,
595 cmÀ1; MS (ESI): m/z: 396.2 [M++1]; HRMS (ESI): m/z: calcd for
C17H28NO3F2S2 [M++H]: 396.1486; found: 396.1473.
Compound 5e: 78% yield; white solid; m.p. 119–1208C; d.r.>99:1 (after
silica gel chromatography), [a]2D7 =À61.02 (c=0.92, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.93 (d, J=7.8 Hz, 2H), 7.74 (t, J=7.2 Hz, 1H),
7.48–7.62 (m, 4H), 7.34 (d, J=8.7 Hz, 2H), 5.26 (brs, 1H), 2.24 (s, 3H),
1.32 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=À102.6 (d, J=
234.9 Hz, 1F), À103.9 ppm (d, J=235.2 Hz, 1F); 13C NMR (100 MHz,
CDCl3): d=135.5, 135.4, 134.4, 133.4, 130.5, 129.3, 129.0, 128.3, 120.4 (t,
J=297.8 Hz), 65.5 (dd, J=22.6, 17.5 Hz), 57.3, 23.9, 22.8 ppm; IR (KBr):
n˜ =3289, 2960, 1494, 1450, 1335, 1159, 1081, 721, 586 cmÀ1; elemental
Compound 5k: 81% yield; white solid; m.p. 124–1258C; d.r.>99:1 (after
silica gel chromatography), [a]2D7 =À20.86 (c=0.92, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.84 (d, J=7.2 Hz, 2H), 7.67 (t, J=7.5 Hz, 1H),
7.48–7.60 (m, 4H), 7.38–7.47 (m, 3H), 5.58 (brs, 1H), 2.48–2.60 (m, 1H),
2.29–2.43 (m, 1H), 1.42 (s, 9H), 1.11–1.36 (m, 3H), 0.80 ppm (t, J=
7.2 Hz, 4H); 19F NMR (282 MHz, CDCl3): d=À96.3 (d, J=228.4 Hz,
1F), À101.4 ppm (d, J=226.2 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=
135.3, 135.2, 135.0, 133.7, 130.5, 129.0, 128.6, 128.4, 127.5, 127.4, 121.1 (t,
J=303.3 Hz), 67.8 (dd, J=21.5, 18.8 Hz), 57.9, 30.9, 24.3, 23.2, 22.4,
11450
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11443 – 11454

Diastereoselective Synthesis of a-Difluoromethyl Amines
FULL PAPER
13.7 ppm; IR (KBr): n˜ =3312, 2955, 1449, 1335, 1145, 1079, 709, 536 cmÀ1
;
Compound 10d: 93% yield; white solid; m.p. 80–828C; d.r.>99:1 (after
silica gel chromatography), [a]2D4 =22.23 (c=1.04, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.92 (d, J=7.5 Hz, 2H), 7.71–7.78 (m, 3H), 7.51–
7.66 (m, 6H), 7.28–7.42 (m, 4H), 6.75 (d, J=16.2 Hz, 1H), 5.62 (s, 1H),
1.36 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=À63.3 (s, 3F), À101.8
(d, J=230.1 Hz, 1F), À102.8 ppm (d, J=230.1 Hz, 1F); 13C NMR
(100 MHz, CDCl3): d=137.9, 137.6, 135.8, 135.4, 133.6, 131.6 (q, J=
32.6 Hz), 130.5, 129.3, 128.72, 128.69, 127.4, 125.1 (q, J=3.7 Hz), 124.6 (d,
J=2.0 Hz), 122.4, 121.1 (t, J=304.0 Hz), 119.7, 71.1 (dd, J=21.3,
17.9 Hz), 57.6, 22.9 ppm; IR (KBr): n˜ =3315, 1620, 1450, 1328, 1172,
elemental analysis calcd (%) for C22H29F2NO3S2: C 57.74, H 6.39, N 3.06;
found: C 57.58, H 6.54, N 3.08; MS (ESI): m/z: 458.2 [M++1].
Compound 5l: 85% yield; white solid; m.p. 32–338C; d.r.>99:1 (after
silica gel chromatography), [a]2D7 =À18.49 (c=1.02, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.84 (d, J=8.7 Hz, 2H), 7.67 (t, J=7.5 Hz, 1H),
7.36–7.61 (m, 7H), 5.55 (brs, 1H), 2.57–2.72 (m, 1H), 2.35–2.51 (m, 1H),
1.42 (s, 9H), 0.69 ppm (t, J=7.2 Hz, 3H); 19F NMR (282 MHz, CDCl3):
d=À96.3 (d, J=225.1 Hz, 1F), À101.3 ppm (d, J=230.7 Hz, 1F);
13C NMR (100 MHz, CDCl3): d=134.9, 134.85 (d, J=1.2 Hz), 134.8 (d,
J=1.4 Hz), 133.6, 130.4, 129.0, 128.6, 128.4, 127.6, 127.5, 121.2 (t, J=
302.3 Hz), 68.1 (dd, J=21.4, 17.8 Hz), 57.8, 24.3, 23.1, 7.0 ppm; IR (KBr):
n˜ =3312, 2982, 1450, 1336, 1147, 1082, 710, 593 cmÀ1; elemental analysis
calcd (%) for C20H25F2NO3S2: C 55.92, H 5.87, N 3.26; found: C 55.77, H
6.09, N 3.20; MS (ESI): m/z: 430.2 [M++1].
1143, 1073, 1018, 582 cmÀ1
;
elemental analysis calcd (%) for
C27H26F5NO3S2: C 56.73, H 4.58, N 2.45; found: C 56.68, H 4.73, N 2.35;
MS (ESI): m/z: 572.0 [M++1].
Compound 10e: 96% yield; white solid; m.p. 158–1608C; d.r.>99:1
(after silica gel chromatography). [a]2D4 =15.31 (c=1.02, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.92 (d, J=7.5 Hz, 2H), 7.73 (t, J=
7.2 Hz, 1H), 7.50–7.60 (m, 6H), 7.28–7.41 (m, 6H), 6.71 (d, J=15.9 Hz,
1H), 5.56 (s, 1H), 1.35 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=
À101.9 (d, J=229.2 Hz, 1F), À102.9 ppm (d, J=229.2 Hz, 1F); 13C NMR
(100 MHz, CDCl3): d=137.2, 135.9, 135.8, 135.3, 133.7, 132.3, 131.4 (d,
J=3.9 Hz), 130.5, 129.3, 128.64, 128.59, 128.5, 127.4, 124.9 (d, J=2.0 Hz),
121.3 (t, J=301.0 Hz), 71.0 (dd, J=21.3, 17.2 Hz), 57.4, 22.9 ppm; IR
(KBr): n˜ =3327, 1494, 1449, 1341, 1141, 1080, 720, 586 cmÀ1; elemental
analysis calcd (%) for C26H26ClF2NO3S2: C 58.04, H 4.87, N 2.60; found:
C 58.20, H 4.94, N 2.43; MS (ESI): m/z: 538.0 [M++1].
Typical procedure for stereoselective nucleophilic difluoromethylation of
a,b-unsaturated N-tert-butylsulfinyl ketimines
9 using difluoromethyl
phenyl sulfone: Under an atmosphere of N2, KHMDS (0.5m solution in
toluene; 1.1 mL, 0.55 mmol) was added dropwise to a solution of a,b-un-
saturated N-tert-butylsulfinyl ketimine 9a (189 mg, 0.6 mmol) and
PhSO2CF2H (96 mg, 0.5 mmol) in THF (8 mL) at À788C. The reaction
mixture was stirred vigorously at À788C for 4 h, and then saturated aque-
ous NaCl solution (5 mL) was added. The resulting mixture was extracted
with Et2O (3ꢂ10 mL), and the combined organic phases were dried over
MgSO4. After the removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column chromatography (petro-
leum ether/EtOAc=3:1 as eluent) to give product 10a (229 mg, 91%
yield).
Compound 10 f: 92% yield; white solid; m.p. 98–1008C; d.r.>99:1 (after
silica gel chromatography), [a]2D4 =21.39 (c=0.99, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.93 (d, J=7.8 Hz, 2H), 7.74 (t, J=7.5 Hz, 1H),
7.50–7.61 (m, 6H), 7.34–7.41 (m, 4H), 7.06 (t, J=8.4 Hz, 2H), 6.69 (d,
J=16.2 Hz, 1H), 5.56 (s, 1H), 1.35 ppm (s, 9H); 19F NMR (282 MHz,
CDCl3): d=À101.9 (d, J=228.7 Hz, 1F), À102.9 (d, J=226.9 Hz, 1F),
À113.6–113.7 ppm (m, 1F); 13C NMR (100 MHz, CDCl3): d=162.9 (d,
J=246.6 Hz), 135.6, 135.3, 133.8, 133.6, 132.4 (d, J=3.0 Hz), 130.5, 130.0
(d, J=3.5 Hz), 129.6, 129.3, 129.0 (d, J=8.2 Hz), 128.3, 125.3, 121.4 (t,
J=304.2 Hz), 115.5 (d, J=21.5 Hz), 71.4 (dd, J=21.3, 17.3 Hz), 57.4,
23.0 ppm; IR (KBr): n˜ =3320, 2984, 1604, 1513, 1449, 1328, 1235, 1144,
1061, 713, 572 cmÀ1; MS (ESI): m/z: 522.0 [M++1]; HRMS (MALDI):
m/z: calcd for C26H26NO3F3S2Na [M++Na]: 544.1198; found: 544.1226.
Compound 10a: 91% yield; white solid; m.p. 168–1708C; d.r.>99:1
(after silica gel chromatography), [a]2D3 =22.68 (c=0.96, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.92 (d, J=7.5 Hz, 2H), 7.72 (t, J=
7.5 Hz, 1H), 7.51–7.62 (m, 6H), 7.30–7.41 (m, 7H), 6.74 (d, J=14.7 Hz,
1H), 5.56 (s, 1H), 1.35 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=
À101.7 (d, J=226.9 Hz, 1F), À102.7 ppm (d, J=229.2 Hz, 1F); 13C NMR
(100 MHz, CDCl3): d=136.8, 136.2, 135.2, 133.9, 133.7, 130.5, 130.06 (d,
J=3.8 Hz), 129.5, 129.2, 128.6, 128.4, 128.2, 127.4, 125.4 (d, J=2.2 Hz),
121.5 (dd, J=304.0, 300.9 Hz), 71.3 (dd, J=21.2, 17.3 Hz), 57.3, 22.9 ppm;
IR (KBr): n˜ =3320, 1498, 1448, 1333, 1191, 1145, 1084, 1068, 685 cmÀ1; el-
emental analysis calcd (%) for C26H27F2NO3S2: C 62.01, H 5.40, N 2.78;
found: C 62.02, H 5.34, N 2.64; MS (ESI): m/z: 504.0 [M++1].
Compound 10g: 86% yield; white solid; m.p. 85–878C; d.r.>99:1 (after
silica gel chromatography), [a]2D4 =18.80 (c=0.93, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.94 (d, J=7.2 Hz, 2H), 7.49–7.79 (m, 10H),
7.33–7.42 (m, 3H), 6.91 (d, J=15.9 Hz, 1H), 5.59 (s, 1H), 1.36 ppm (s,
9H); 19F NMR (282 MHz, CDCl3): d=À62.9 (s, 3F), À102.2 (d, J=
229.8 Hz, 1F), À103.2 ppm (d, J=228.9 Hz, 1F); 13C NMR (100 MHz,
CDCl3): d=139.8, 135.4, 135.3, 133.6, 133.3, 130.5, 130.05, 130.02, 129.9
(q, J=32.1 Hz), 129.7, 129.3, 128.4, 127.6, 125.5 (q, J=3.7 Hz), 122.8,
121.3 (dd, J=303.6, 300.6 Hz), 71.6 (q, J=21.7, 17.5 Hz), 57.4, 22.9 ppm;
IR (KBr): n˜ =3318, 1616, 1450, 1326, 1168, 1144, 1068, 1017, 713,
600 cmÀ1; elemental analysis calcd (%) for C27H26F5NO3S2: C 56.73, H
4.58, N 2.45; found: C 56.40, H 4.69, N 2.27; MS (ESI): m/z: 572.1 [M+
+1].
Compound 10b: 82% yield; white solid; m.p. 79–818C; d.r.>99:1 (after
silica gel chromatography), [a]2D4 =12.19 (c=1.08, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.91 (d, J=7.5 Hz, 2H), 7.71 (t, J=7.8 Hz, 1H),
7.51–7.62 (m, 4H), 7.46 (d, J=8.7 Hz, 2H), 7.32–7.40 (m, 3H), 7.27 (d,
J=16.2 Hz, 1H), 6.89 (d, J=8.7 Hz, 2H), 6.57 (dd, J=16.5, 1.5 Hz, 1H),
5.55 (s, 1H), 3.83 (s, 3H), 1.35 ppm (s, 9H); 19F NMR (282 MHz, CDCl3):
d=À101.6 (d, J=228.9 Hz, 1F), À102.6 ppm (d, J=229.5 Hz, 1F);
13C NMR (100 MHz, CDCl3): d=159.9, 136.2, 135.1, 134.0, 130.5, 130.1,
130.05, 129.4, 129.2, 128.9, 128.7, 128.2, 123.07 (d, J=2.5 Hz), 121.5 (dd,
J=304.4, 301.2 Hz), 114.0, 71.3 (dd, J=21.3, 17.1 Hz), 57.3, 55.3,
23.0 ppm; IR (KBr): n˜ =3316, 2958, 1608, 1513, 1449, 1336, 1250, 1143,
1076, 713 cmÀ1; elemental analysis calcd (%) for C27H29F2NO4S2: C 60.77,
H 5.48, N 2.62; found: C 60.78, H 5.82, N 2.39; MS (ESI): m/z: 534.1
Compound 10h: 95% yield; white solid; m.p. 82–848C; d.r.>99:1 (after
silica gel chromatography), [a]2D5 =12.82 (c=0.93, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.92 (d, J=7.8 Hz, 2H), 7.73 (t, J=7.8 Hz, 1H),
7.51–7.61 (m, 6H), 7.28–7.41 (m, 4H), 7.05 (t, J=8.7 Hz, 2H), 6.73 (d,
J=16.2 Hz, 1H), 5.56 (s, 1H), 1.35 ppm (s, 9H); 19F NMR (282 MHz,
CDCl3): d=À101.9 (d, J=229.5 Hz, 1F), À102.9 (d, J=227.2 Hz, 1F),
À111.89 to À111.96 ppm (m, 1F); 13C NMR (100 MHz, CDCl3): d=163.2
(d, J=248.8 Hz), 137.1, 136.0, 135.3, 133.8, 132.1 (dd, J=8.4, 4.3 Hz),
130.5, 129.6, 129.3, 128.6, 128.5, 127.4, 125.2 (d, J=2.1 Hz), 121.3 (t, J=
301.1 Hz), 115.2 (d, J=21.4 Hz), 71.0 (q, J=21.3, 17.1 Hz), 57.4,
22.9 ppm; IR (KBr): n˜ =3317, 2961, 1604, 1509, 1450, 1336, 1143, 1075,
838, 595 cmÀ1; MS (ESI): m/z: 522.1 [M++1]; HRMS (MALDI): m/z:
calcd for C26H26NO3F3S2Na [M++Na]: 544.1198; found: 544.1196.
ACHTUNGTRENNUNG
[M++1].
Compound 10c: 90% yield; white solid; m.p. 88–908C; d.r.>99:1 (after
silica gel chromatography), [a]2D4 =13.37 (c=0.92, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.92 (d, J=7.8 Hz, 2H), 7.72 (t, J=7.8 Hz, 1H),
7.46–7.59 (m, 6H), 7.27–7.43 (m, 4H), 6.86 (d, J=9.0 Hz, 2H), 6.73 (d,
J=17.4 Hz, 1H), 5.51 (s, 1H), 3.81 (s, 3H), 1.35 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À101.8 (d, J=227.8 Hz, 1F), À102.9 ppm (d, J=
227.8 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=160.3, 136.5, 136.3, 135.1,
134.0, 131.5 (d, J=3.8 Hz), 130.5, 129.2, 128.6, 128.3, 127.4, 125.7 (d, J=
2.6 Hz), 125.5, 121.6 (t, J=303.2 Hz), 113.5, 71.1 (dd, J=21.4, 17.2 Hz),
57.2, 55.2, 23.0 ppm; IR (KBr): n˜ =3317, 2959, 1608, 1512, 1449, 1335,
Compound 10i: 94% yield; white solid; m.p. 173–1748C; d.r.>99:1
(after silica gel chromatography), [a]2D5 =18.00 (c=0.94, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.92 (d, J=7.5 Hz, 2H), 7.71 (t, J=
7.5 Hz, 1H), 7.43–7.58 (m, 6H), 7.27–7.30 (m, 4H), 7.16 (d, J=8.1 Hz,
1259, 1143, 1073, 834, 597 cmÀ1
; elemental analysis calcd (%) for
C27H29F2NO4S2: C 60.77, H 5.48, N 2.62; found: C 60.58, H 5.74, N 2.55;
MS (ESI): m/z: 534.1 [M++1].
Chem. Eur. J. 2010, 16, 11443 – 11454
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11451

J. Hu and J. Liu
2H), 6.73 (d, J=18.9 Hz, 1H), 5.53 (s, 1H), 2.35 (s, 3H), 1.35 ppm (s,
9H); 19F NMR (282 MHz, CDCl3): d=À101.7 (d, J=227.2 Hz, 1F),
À102.8 ppm (d, J=228.7 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=
139.5, 136.5, 136.2, 135.1, 133.9, 130.6, 130.5, 129.9 (d, J=3.8 Hz), 129.2,
128.9, 128.5, 128.3, 127.4, 125.6 (d, J=2.7 Hz), 121.3 (t, J=303.6 Hz), 71.2
(q, J=21.3, 16.9 Hz), 57.3, 23.0, 21.1 ppm; IR (KBr): n˜ =3325, 2975, 1449,
1339, 1141, 1075, 725, 595 cmÀ1; MS (ESI): m/z: 518.0 [M++1]; HRMS
(MALDI): m/z: calcd for C27H29NO3F2S2Na [M++Na]: 540.1449; found:
540.1441.
130.6, 129.8, 129.7, 129.1, 128.1, 128.0, 121.5, 119.0 (dd, J=302.2,
298.5 Hz), 92.8, 82.9 (d, J=5.2 Hz), 64.2 (t, J=22.4 Hz), 57.5, 22.8 ppm;
IR (KBr): n˜ =3303, 2980, 2227, 1490, 1449, 1331, 1146, 1083, 715,
582 cmÀ1; elemental analysis calcd (%) for C26H25F2NO3S2: C 62.26, H
5.02, N 2.79; found: C 62.12, H 4.98, N 2.82; MS (ESI): m/z: 502.2
AHCTUNGTRENNUNG
[M++1].
Compound 16b: 94% yield; white solid; m.p. 130–1328C; d.r.>99:1
(after silica gel chromatography), [a]2D5 =À119.81 (c=1.03, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.00 (d, J=7.5 Hz, 2H), 7.81–7.87 (m,
2H), 7.66 (d, J=7.2 Hz, 1H), 7.38–7.55 (m, 7H), 7.13 (d, J=8.4 Hz, 2H),
5.61 (s, 1H), 2.36 (s, 3H), 1.33 ppm (s, 9H); 19F NMR (282 MHz, CDCl3):
d=À99.9 (d, J=229.8 Hz, 1F), À104.4 ppm (d, J=229.8 Hz, 1F);
13C NMR (100 MHz, CDCl3): d=140.2, 136.1, 134.9, 133.9, 132.8, 131.4,
130.7, 130.5, 129.9, 129.7, 128.9, 119.9 (dd, J=302.2, 297.7 Hz), 119.2,
93.9, 83.1 (d, J=5.2 Hz), 65.1 (t, J=21.6 Hz), 58.3, 23.6, 22.4 ppm; IR
Compound 10j: 92% yield; white solid; m.p. 83–858C; d.r.>99:1 (after
silica gel chromatography), [a]2D5 =15.53 (c=1.01, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.91 (d, J=7.8 Hz, 2H), 7.71 (t, J=7.5 Hz, 1H),
7.51–7.62 (m, 4H), 7.26–7.45 (m, 6H), 7.17 (d, J=8.1 Hz, 2H), 6.68 (d,
J=16.2 Hz, 1H), 5.55 (s, 1H), 2.37 (s, 3H), 1.35 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À101.5 (d, J=229.8 Hz, 1F), À102.6 ppm (d, J=
228.9 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=138.4, 136.7, 135.2,
133.97, 133.92, 133.3, 130.5, 130.0 (d, J=3.8 Hz), 129.4, 129.3, 129.2,
128.2, 127.3, 124.3 (d, J=2.1 Hz), 121.5 (t, J=304.1 Hz), 71.3 (q, J=21.2,
17.3 Hz), 57.3, 22.9, 21.2 ppm; IR (KBr): n˜ =3315, 2959, 1514, 1449, 1336,
(KBr): n˜ =3306, 2980, 2230, 1510, 1450, 1331, 1146, 1087, 715, 579 cmÀ1
;
elemental analysis calcd (%) for C27H27F2NO3S2: C 62.89, H 5.28, N 2.72;
found: C 62.83, H 5.37, N 3.03; MS (ESI): m/z: 516.1 [M++1].
Compound 16c: 86% yield; white solid; m.p. 166–1678C; d.r.>99:1
(after silica gel chromatography), [a]2D5 =À107.22 (c=0.94, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.00 (d, J=8.1 Hz, 2H), 7.74 (d, J=
7.5 Hz, 2H), 7.48–7.69 (m, 5H), 7.28–7.38 (m, 3H), 6.91 (d, J=9.3 Hz,
2H), 5.58 (s, 1H), 3.82 (s, 3H), 1.33 ppm (s, 9H); 19F NMR (282 MHz,
CDCl3): d=À100.1 (d, J=226.7 Hz, 1F), À104.5 ppm (d, J=227.8 Hz,
1F); 13C NMR (100 MHz, CDCl3): d=160.6, 135.3, 134.1, 132.0, 131.3,
130.6, 129.1, 128.1, 124.6, 121.5, 119.2 (t, J=297.7 Hz), 113.4, 92.5, 83.3
(d, J=5.2 Hz), 63.8 (t, J=22.6 Hz), 57.4, 55.2, 22.8 ppm; IR (KBr): n˜ =
3275, 2232, 1607, 1511, 1338, 1259, 1145, 1083, 839, 598 cmÀ1; elemental
analysis calcd (%) for C27H27F2NO4S2: C 61.00, H 5.12, N 2.63; found: C
60.72, H 5.26, N 2.50; MS (ESI): m/z: 532.0 [M++1].
1143, 1077, 713, 572 cmÀ1 MS (ESI): m/z: 518.0 [M++1]; HRMS
;
(MALDI): m/z: calcd for C27H29NO3F2S2Na [M++Na]: 540.1449; found:
540.1452.
Compound 10k: 80% yield; white solid; m.p. 167–1698C, d.r.>99:1
(after silica gel chromatography), [a]2D5 =À33.93 (c=0.94, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.89 (d, J=8.1 Hz, 2H), 7.71 (t, J=
8.1 Hz, 1H), 7.56–7.61 (m, 2H), 7.50 (t, J=7.8 Hz, 2H), 7.33–7.40 (m,
4H), 7.21 (d, J=15.6 Hz, 1H), 6.59 (d, J=16.2 Hz, 1H), 6.41–6.47 (m,
2H), 5.57 (s, 1H), 1.35 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=
À101.8 (d, J=227.5 Hz, 1F), À103.6 ppm (d, J=229.5 Hz, 1F); 13C NMR
(100 MHz, CDCl3): d=151.7, 142.7, 134.9, 133.9, 133.7, 130.5, 130.1 (d,
J=4.1 Hz), 129.5, 129.1, 128.2, 124.8 (d, J=1.5 Hz), 123.4 (d, J=3.8 Hz),
121.4 (dd, J=304.6, 300.8 Hz), 111.6, 110.8, 71.1 (dd, J=21.8, 17.1 Hz),
57.4, 22.9 ppm; IR (KBr): n˜ =3341, 1449, 1340, 1145, 1071, 770, 604,
539 cmÀ1; elemental analysis calcd (%) for C24H25F2NO4S2: C 58.40, H
5.11, N 2.84; found: C 58.41, H 5.36, N 2.75; MS (ESI): m/z: 494.0
Compound 16d: 96% yield; white solid; m.p. 69–708C; d.r.>99:1 (after
silica gel chromatography), [a]2D5 =À105.87 (c=0.97, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.99 (d, J=7.8 Hz, 2H), 7.77 (d, J=9.0 Hz, 2H),
7.67 (t, J=6.9 Hz, 1H), 7.50–7.61 (m, 4H), 7.29–7.41 (m, 5H), 5.62 (s,
1H), 1.33 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=À100.1 (d, J=
224.5 Hz, 1F), À104.5 ppm (d, J=230.4 Hz, 1F); 13C NMR (100 MHz,
CDCl3): d=136.1, 135.4, 133.8, 132.1, 131.6, 131.3, 130.6, 129.3, 129.2,
128.3, 128.2, 121.2, 118.9 (dd, J=302.2, 298.5 Hz), 93.1, 82.5 (d, J=
5.2 Hz), 63.9 (t, J=224.5 Hz), 57.6, 22.8 ppm; IR (KBr): n˜ =3273, 2234,
1491, 1340, 1146, 1089, 757, 586, 539 cmÀ1; elemental analysis calcd (%)
for C26H24ClF2NO3S2: C 58.26, H 4.51, N 2.61; found: C 57.99, H 4.67, N
2.49; MS (ESI): m/z: 536.0 [M++1].
ACHTUNGTRENNUNG
[M++1].
Compound 10l: 77% yield; white solid; m.p. 84–878C; d.r.>99:1 (after
silica gel chromatography), [a]2D5 =4.09 (c=1.08, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.91 (d, J=7.5 Hz, 2H), 7.71 (t, J=7.8 Hz, 1H),
7.44–7.58 (m, 6H), 7.29 (d, J=16.5 Hz, 1H), 6.83–6.93 (m, 4H), 6.55 (d,
J=15.9 Hz, 1H), 5.50 (s, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 1.34 ppm (s,
9H); 19F NMR (282 MHz, CDCl3): d=À101.8 (d, J=227.8 Hz, 1F),
À102.8 ppm (d, J=227.8 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=
160.2, 159.8, 135.9, 135.1, 134.1, 131.4 (d, J=3.9 Hz), 130.4, 129.1, 128.9,
128.6, 125.7, 123.3 (d, J=2.6 Hz), 121.6 (t, J=300.1 Hz), 113.9, 113.5, 71.0
(dd, J=21.5, 17.2 Hz), 57.2, 55.2, 55.1, 22.9 ppm; IR (KBr): n˜ =3317,
Compound 16e: 93% yield; white solid; m.p. 142–1438C; d.r.>99:1
(after silica gel chromatography), [a]2D7 =À129.62 (c=1.09, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.00 (d, J=7.5 Hz, 2H), 7.80–7.87 (m,
2H), 7.66 (t, J=7.8 Hz, 1H), 7.48–7.55 (m, 4H), 7.38–7.43 (m, 3H), 6.85
(d, J=9.0 Hz, 2H), 5.62 (s, 1H), 3.82 (s, 3H), 1.33 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À99.8 (d, J=225.0 Hz, 1F), À104.3 ppm (d, J=
229.3 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=160.3, 135.3, 134.1, 133.6,
133.2, 130.6, 129.9, 129.7, 129.1, 128.1, 119.1 (t, J=302.2 Hz), 113.8, 113.6,
93.0, 81.7 (d, J=5.2 Hz), 64.3 (t, J=22.3 Hz), 57.5, 55.3, 22.8 ppm; IR
(KBr): n˜ =3273, 2978, 2233, 1608, 1512, 1450, 1333, 1145, 1095, 1025, 714,
580 cmÀ1; elemental analysis calcd (%) for C27H27F2NO4S2: C 61.00, H
5.12, N 2.63; found: C 60.95, H 5.03, N 2.49; MS (ESI): m/z: 532.1
2959, 1608, 1513, 1449, 1335, 1255, 1176, 1143, 1074, 828, 686, 597 cmÀ1
;
MS (ESI): m/z: 564.1 [M++1]; HRMS (MALDI): m/z: calcd for
C28H31NO5F2S2Na [M++Na]: 586.1504; found: 586.1506.
Typical procedure for stereoselective nucleophilic difluoromethylation of
a,b-acetylenic N-tert-butylsulfinyl ketimines 15 using difluoromethyl
phenyl sulfone: Under an atmosphere of N2, NaHMDS (2m solution in
THF; 0.3 mL, 0.6 mmol) was added dropwise to a solution of a,b-unsatu-
rated N-tert-butylsulfinyl ketimine 15a (186 mg, 0.6 mmol) and
PhSO2CF2H (96 mg, 0.5 mmol) in THF (8 mL) at À788C. The reaction
mixture was stirred vigorously at À788C for 2 h, and then saturated aque-
ous NaCl solution (5 mL) was added. The resulting mixture was extracted
with Et2O (3ꢂ10 mL), and the combined organic phases were dried over
MgSO4. After the removal of volatile solvents under vacuum, the crude
product was further purified by silica gel column chromatography (petro-
leum ether/EtOAc=4:1 as eluent) to give product 16a (228 mg, 91%
yield).
AHCTUNGTRENNUNG
[M++1].
Compound 16 f: 86% yield; white solid; m.p. 67–698C; d.r.>99:1 (after
silica gel chromatography), [a]2D7 =À107.13 (c=1.03, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.00 (d, J=7.8 Hz, 2H), 7.47–7.74 (m, 7H), 7.29–
7.39 (m, 3H), 7.21 (d, J=8.1 Hz, 2H), 5.60 (s, 1H), 2.37 (s, 3H),
1.33 ppm (s, 9H); 19F NMR (282 MHz, CDCl3): d=À99.9 (d, J=
230.7 Hz, 1F), À104.4 ppm (d, J=225.0 Hz, 1F); 13C NMR (100 MHz,
CDCl3): d=139.9, 135.3, 134.1, 132.1, 130.6, 129.9, 129.8, 129.1, 128.9,
128.2, 121.6, 119.2 (dd, J=301.7, 297.2 Hz), 92.6, 83.2 (d, J=5.2 Hz), 64.1
(t, J=24.5 Hz), 57.5, 22.8, 21.1 ppm; IR (KBr): n˜ =3277, 2233, 1449, 1341,
Compound 16a: 91% yield; white solid; m.p. 150–1518C; d.r.>99:1
(after silica gel chromatography), [a]2D5 =À122.60 (c=0.98, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.00 (d, J=8.1 Hz, 2H), 7.81–7.87 (m,
2H), 7.29–7.71 (m, 11H), 5.65 (s, 1H), 1.34 ppm (s, 9H); 19F NMR
(282 MHz, CDCl3): d=À101.0 (d, J=229.2 Hz, 1F), À105.5 ppm (d, J=
228.9 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=135.3, 134.0, 132.9, 132.0,
1145, 1088, 758, 595, 539 cmÀ1
; elemental analysis calcd (%) for
C27H27F2NO3S2: C 62.89, H 5.28, N 2.72; found: C 62.60, H 5.40, N 2.48;
MS (ESI): m/z: 516.2 [M++1].
11452
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11443 – 11454

Diastereoselective Synthesis of a-Difluoromethyl Amines
FULL PAPER
Compound 16g: 32% yield; white solid; m.p. 170–1728C; d.r.>99:1
(after silica gel chromatography), [a]2D6 =13.66 (c=1.02, CHCl3);
1H NMR (300 MHz, CDCl3): d=8.21 (d, J=9.6 Hz, 1H), 7.88 (d, J=
8.1 Hz, 2H), 7.58–7.69 (m, 3H), 7.35–7.54 (m, 6H), 7.11 (t, J=7.8 Hz,
1H), 6.99 (d, J=8.4 Hz, 1H), 6.51 (s, 1H), 3.92 (s, 3H), 1.22 ppm (s,
9H); 19F NMR (282 MHz, CDCl3): d=À94.7 (d, J=229.0 Hz, 1F),
À101.5 ppm (d, J=231.2 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=
158.3, 135.1, 134.5, 132.6, 132.1, 131.6, 130.9, 129.6, 129.2, 128.6, 121.8,
121.7, 121.4, 120.5 (t, J=304.5 Hz), 112.9, 93.7, 82.5 (d, J=5.2 Hz), 66.5
(dd, J=26.4, 21.4 Hz), 57.2, 56.4, 22.9 ppm; IR (KBr): n˜ =3339, 2953,
2224, 1584, 1493, 1342, 1245, 1138, 1084, 977, 757, 585 cmÀ1; MS (ESI):
m/z: 532.0 [M++1]; HRMS (MALDI): m/z: calcd for C27H27NO4F2S2Na
[M++Na]: 554.1242; found: 554.1243.
J. L. Castro, J. Med. Chem. 1999, 42, 2087–2104; b) M. Rowley, D. J.
Hallett, S. Goodacre, C. Moyes, J. Crawforth, T. J. Sparey, S. Patel,
R. Marwood, S. Patel, S. Thomas, L. Hitzel, D. OꢀConnor, N. Szeto,
J. L. Castro, P. H. Hutson, A. M. MacLeod, J. Med. Chem. 2001, 44,
1603–1614; c) J. Liu, J. Hu, Future Med. Chem. 2009, 1, 875–888;
d) S. Fustero, J. F. Sanz-Cervera, J. L. AceÇa, M. Sꢅnchez-Rosellꢆ,
Synlett 2009, 525–549.
[3] a) V. A. Soloshonok, H. Ohkura, A. Sorochinsky, N. Voloshin, A.
Markovsky, M. Belik, T. Yamazaki, Tetrahedron Lett. 2002, 43,
5445–5448; b) G. Rçschenthaler, V. Kukhar, J. Barten, N. Gvozdov-
ska, M. Belik, A. Sorochinsky, Tetrahedron Lett. 2004, 45, 6665–
6667; c) G. Rçschenthaler, V. P. Kukhar, M. Yu. Belik, K. I. Mazur-
enko, A. E. Sorochinsky, Tetrahedron 2006, 62, 9902–9910; d) Y.
Kawano, T. Mukaiyama, Chem. Lett. 2005, 34, 894–895; e) W. Xu,
W. R. Dolbier, Jr., J. Org. Chem. 2005, 70, 4741–4745.
[4] a) G. K. S. Prakash, M. Mandal, G. A. Olah, Angew. Chem. 2001,
113, 609–610; Angew. Chem. Int. Ed. 2001, 40, 589–590; b) G. K. S.
Prakash, M. Mandal, G. A. Olah, Org. Lett. 2001, 3, 2847–2850;
c) G. K. S. Prakash, M. Mandal, J. Am. Chem. Soc. 2002, 124, 6538–
6539; d) Y. Li, J. Hu, Angew. Chem. 2005, 117, 6032–6036; Angew.
Chem. Int. Ed. 2005, 44, 5882–5886; e) Y. Li, J. Hu, Angew. Chem.
2007, 119, 2541–2544; Angew. Chem. Int. Ed. 2007, 46, 2489–2492;
f) Y. Li, C. Ni, J. Liu, L. Zhang, J. Zheng, L. Zhu, J. Hu, Org. Lett.
2006, 8, 1693–1696; g) J. Liu, Y. Li, J. Hu, J. Org. Chem. 2007, 72,
3119–3121; h) J. Liu, L. Zhang, J. Hu, Org. Lett. 2008, 10, 5377–
5380; i) D. D. Staas, K. L. Savage, C. F. Homnick, N. N. Tsou, R. G.
Ball, J. Org. Chem. 2002, 67, 8276–8279; j) C. Estivill, J. Mendiza-
bal, A. Virgili, E. Monteagudo, T. Flor, F. Sꢅnchez-Ferrando, A. Al-
varez-Larena, J. F. Piniella, Tetrahedron 2009, 65, 171–176.
Compound 16h: 83% yield; gummy liquid; d.r.>99:1 (after silica gel
chromatography), [a]2D7 =À30.32 (c=0.92, CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.90 (d, J=7.8 Hz, 2H), 7.79–7.86 (m, 2H), 7.70 (t, J=
7.5 Hz, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.38–7.45 (m, 3H), 1.30 (s, 9H),
1.09–1.27 ppm (m, 21H); 19F NMR (282 MHz, CDCl3): d=À98.8 (d, J=
224.2 Hz, 1F), À100.3 ppm (d, J=228.4 Hz, 1F); 13C NMR (100 MHz,
CDCl3): d=135.5, 134.1, 133.5, 130.7, 129.8, 129.44, 129.40, 128.3, 119.4
(t, J=301.5 Hz), 99.2, 96.5, 64.8 (t, J=23.0 Hz), 57.5, 23.0, 18.8, 11.4,
11.1 ppm; IR (KBr): n˜ =3287, 2945, 2867, 1450, 1345, 1146, 883, 714,
578 cmÀ1; MS (ESI): m/z: 582.2 [M++1]; HRMS (MALDI): m/z: calcd
for C29H41NO3F2SiS2Na [M++Na]: 604.2157; found: 604.2169.
Compound 16i: 49% yield; white solid; m.p. 88–908C; d.r.>99:1 (after
silica gel chromatography), [a]2D5 =À70.79 (c=0.92, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.97 (d, J=8.1 Hz, 2H), 7.69–7.81 (m, 3H), 7.58
(t, J=7.5 Hz, 2H), 7.35–7.42 (m, 3H), 5.47 (s, 1H), 2.31–2.38 (m, 2H),
1.55–1.65 (m, 2H), 1.42–1.51 (m, 2H), 1.31 (s, 9H), 0.93 ppm (t, J=
7.5 Hz, 3H); 19F NMR (282 MHz, CDCl3): d=À100.3 (d, J=227.6 Hz,
1F), À103.5 ppm (d, J=228.7 Hz, 1F); 13C NMR (100 MHz, CDCl3): d=
136.1, 135.1, 134.2, 131.3, 130.6, 130.4, 129.9, 128.7, 120.0 (t, J=301.5 Hz),
95.6, 74.8 (d, J=5.2 Hz), 64.7 (t, J=21.6 Hz), 58.1, 30.7, 23.6, 22.8, 19.6,
14.3 ppm; IR (KBr): n˜ =3277, 2962, 2239, 1449, 1340, 1137, 1087, 713,
582 cmÀ1; elemental analysis calcd (%) for C24H29F2NO3S2: C 59.85, H
6.07, N 2.91; found: C 60.29, H 6.12, N 3.18; MS (ESI): m/z: 582.2
[5] a) M. T. Robak, M. A. Herbage, J. A. Ellman, Chem. Rev. 2010, 110,
3600–3740; b) J. A. Ellman, T. D. Owens, T. P. Tang, Acc. Chem.
Res. 2002, 35, 984–985; c) F. Ferreira, C. Botuha, F. Chemla, A.
Pꢃrez-Luna, Chem. Soc. Rev. 2009, 38, 1162–1186; d) J. Liu, J. Hu,
Future Med. Chem. 2009, 1, 875–888.
[6] J. Hu, W. Zhang, F. Wang, Chem. Commun. 2009, 7465–7478.
[7] See reviews: a) G. K. S. Prakash, J. Hu, Acc. Chem. Res. 2007, 40,
921–930; b) J. Hu, J. Fluorine Chem. 2009, 130, 1130–1139.
ACHTUNGTRENNUNG
[M++1].
[8] a) C. Ni, Y. Li, J. Hu, J. Org. Chem. 2006, 71, 6829–6833; b) C. Ni,
L. Zhang, J. Hu, J. Org. Chem. 2008, 73, 5699–5713; c) C. Ni, J. Liu,
L. Zhang, J. Hu, Angew. Chem. 2007, 119, 800–803; Angew. Chem.
Int. Ed. 2007, 46, 786–789.
[9] It should be noted that when KHMDS was used as the base, the re-
action between the in situ generated anion PhSO2CHFÀ and keti-
mine 3a gave product 4 in low yield.
X-ray crystallographic analysis: CCDC-756004 (5k), 781706 (10a), and
781707 (16a) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
The X-ray crystallographic analysis was perfomed by using a Rigaku
FCR diffractometer.
[10] C. Ni, J. Hu, Tetrahedron Lett. 2005, 46, 8273–8277.
[11] a) S. Lauzon, F. Tremblay, D. Gagnon, C. Godbout, C. Chabot, C.
Mercier-Shanks, S. Perreault, H. DeSꢇve, C. Spino, J. Org. Chem.
2008, 73, 6239–6250; b) S. Krishnan, J. T. Bagdanoff, D. C. Ebner,
Y. K. Ramtohul, U. K. Tambar, B. M. Stoltz, J. Am. Chem. Soc.
2008, 130, 13745–13754; c) C. E. Jakobsche, P. Gorka, S. J. Miller,
Angew. Chem. 2008, 120, 6809–6813; Angew. Chem. Int. Ed. 2008,
47, 6707–6711; d) T. L. Suyama, W. H. Gerwick, Org. Lett. 2008, 10,
4449–4452; e) A. D. Brosius, L. E. Overman, L. Schwink, J. Am.
Chem. Soc. 1999, 121, 700–709; f) for a review on the application of
allylamines, see: S. Otsuka, K. Tani, Synthesis 1991, 665–680; g) H.
Nagashima, Y. Isono, S. Iwamatsu, J. Org. Chem. 2001, 66, 315–319;
h) S. Robin, G. Rousseau, Eur. J. Org. Chem. 2000, 3007–3011;
i) B. M. Trost, Angew. Chem. 1989, 101, 1199–1219; Angew. Chem.
Int. Ed. Engl. 1989, 28, 1173–1192; j) J. P. Monk, R. N. Brogden,
Drugs 1991, 42, 659; k) J. A. Balfour, D. Faulds, Drugs 1992, 43, 259.
[12] Selected examples of the asymmetric synthesis of allylic amines:
a) K. Brak, J. A. Ellman, J. Am. Chem. Soc. 2009, 131, 3850–3851;
b) T. Nagano, S. Kobayashi, J. Am. Chem. Soc. 2009, 131, 4200–
4201; c) M. J. Pouy, L. M. Stanley, J. F. Hartwig, J. Am. Chem. Soc.
2009, 131, 11312–11313; d) T. Nishikata, B. H. Lipshutz, Org. Lett.
2009, 11, 2377–2379; e) S. Shekhar, B. Trantow, A. Leitner, J. F.
Hartwig, J. Am. Chem. Soc. 2006, 128, 11770–11771; f) E. Skucas,
M. Ngai, V. Komanduri, M. J. Krische, Acc. Chem. Res. 2007, 40,
1394–1401; g) L. R. Reddy, B. Hu, M. Prashad, K. Prasad, Org. Lett.
Acknowledgements
Support of our work by the NSF of China (20825209, 20772144,
20832008) and the Chinese Academy of Sciences (Hundreds-Talent Pro-
gram and Knowledge Innovation Program) is gratefully acknowledged.
[1] a) J. T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991; b) I. Ojima, J. R. McCarthy, J. T. Welch
(Eds.), Biomedical Frontiers of Fluorine Chemistry, ACS, Washing-
ton, 1996; c) J.-P. Bꢃguꢃ, D. Bonnet-Delpon, Bioorganic and Medici-
nal Chemistry of Fluorine, Wiley, New York, 2008; d) W. K. Hag-
mann, J. Med. Chem. 2008, 51, 4359–4369; e) K. Mꢄller, C. Faeh, F.
Diederich, Science 2007, 317, 1881–1886; f) M. Molteni, M. C. Bel-
lucci, S. Bigotti, S. Mazzini, A. Volonterio, M. Zanda, Org. Biomol.
Chem. 2009, 7, 2286–2296; g) I. Ojima (Ed.), Fluorine in Medicinal
Chemistry and Medicinal Biology, Wiley-Blackwell, West Sussex,
2009.
[2] a) M. B. van Niel, I. Collins, M. S. Beer, H. B. Broughton, S. K. F.
Cheng, S. C. Goodacre, A. Heald, K. L. Locker, A. M. MacLeod, D.
Morrison, C. R. Moyes, D. OꢀConnor, A. Pike, M. Rowley, M. G. N.
Russell, B. Sohal, J. A. Stanton, S. Thomas, H. Verrier, A. P. Watt,
Chem. Eur. J. 2010, 16, 11443 – 11454
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11453

J. Hu and J. Liu
2008, 10, 3109–3112; h) M. Johannsen, K. A. Jøgensen, Chem. Rev.
1998, 98, 1689–1708.
60, 6711–6745; i) K. Ogu, S. Matsumoto, M. Akazome, K. Ogura,
Org. Lett. 2005, 7, 589–592; j) H. Wang, X. Zhao, Y. Li, L. Lu, Org.
Lett. 2006, 8, 1379–1381.
[13] a) N. T. N. Tam, G. Magueur, M. Ourevitch, B. Crousse, J.-P. Bꢃguꢃ,
D. Bonnet-Delpon, J. Org. Chem. 2005, 70, 699–702; b) S. D.
Kuduk, C. N. D. Marco, S. M. Pitzenberger, N. Tsou, Tetrahedron
Lett. 2006, 47, 2377–2381; c) S. Fries, J. Pytkowicz, T. Brigaud, Tetra-
hedron Lett. 2005, 46, 4761–4764; d) Z.-J. Liu, J.-T. Liu, Chem.
Commun. 2008, 5233–5235; e) F. Palacios, A. M. Ochoa de Retana,
S. Pascual, J. Oyarzabal, J. Org. Chem. 2004, 69, 8767–8774; f) G.
Magueur, B. Crousse, D. Bonnet-Delpon, Eur. J. Org. Chem. 2008,
1527–1534.
[14] S. Fustero, J. Garcia Soler, A. Bartolome, M. Sanchez Rosello, Org.
Lett. 2003, 5, 2707–2710.
[15] a) I. Kumadaki, S. Jonoshita, A. Harada, M. Omote, A. Ando, J.
Fluorine Chem. 1999, 97, 61–63; b) D. W. Nelson, J. Owens, D. Hir-
aldo, J. Org. Chem. 2001, 66, 2572–2582.
[16] a) K. Uneyama, Organofluorine Chemistry, Blackwell, New Delhi,
2006; b) R. D. Chambers, Fluorine in Organic Chemistry, Blackwell
and CRC, Oxford, 2004; c) P. Kirsch, Modern Fluoroorganic
Chemistry, Wiley-VCH, Weinheim, 2004; d) T. Hiyama (Ed.), Orga-
nofluorine Compounds: Chemistry and Applications, Springer, New
York, 2000.
[17] a) S. Patai, Z. Rappoport (Eds.), The Chemistry of Enones (Chemis-
try of Functional Groups), Wiley, New York, 1989; b) M. B. Smith, J.
March, Marchꢀs Advanced Organic Chemistry: Reactions, Mecha-
nisms, and Structure, 6th ed., Wiley, New York, 2007.
[22] a) C. Spino, C. Gobdout, J. Am. Chem. Soc. 2003, 125, 12106–12107;
b) P. V. Ramachandran, T. E. Burghardt, R. M. V. Reddy, J. Org.
Chem. 2005, 70, 2329–2331.
[23] For selected examples, see: a) A. Brik, J. Alexandratos, Y.-C. Lin,
J. H. Elder, A. J. Olson, A. Wlodawer, D. S. Goodsell, C.-H. Wong,
ChemBioChem 2005, 6, 1167–1169; b) B. M. Trost, C. K. Chung,
A. B. Pinkerton, Angew. Chem. 2004, 116, 4427–4429; Angew.
Chem. Int. Ed. 2004, 43, 4327–4329; c) M. H. Davidson, F. E.
McDonald, Org. Lett. 2004, 6, 1601–1603; d) C. J. Brennan, G. Pat-
tenden, G. Rescourio, Tetrahedron Lett. 2003, 44, 8757–8760;
e) J. W. Corbett, S. S. Ko, J. D. Rodgers, L. A. Gearhart, N. A.
Magnus, L. T. Bacheler, S. Diamond, S. Jeffrey, R. M. Klabe, B. C.
Cordova, S. Garber, K. Logue, G. L. Trainor, P. S. Anderson, S. K.
Erickson-Viitanen, J. Med. Chem. 2000, 43, 2019–2030; f) for a
review, see: P. Aschwanden, E. M. Carreira, F. Diederich, P. J. Stang,
R. R. Tykwinski (Eds.), Acetylene Chemistry: Chemistry, Biology,
and Material Science, Wiley-VCH, Weinheim, 2005.
[24] a) C. Koradin, K. Polborn, P. Knochel, Angew. Chem. 2002, 114,
2651–2654; Angew. Chem. Int. Ed. 2002, 41, 2535–2538; b) N. Gom-
mermann, C. Koradin, K. Polborn, P. Knochel, Angew. Chem. 2003,
115, 5941–5944; Angew. Chem. Int. Ed. 2003, 42, 5763–5766; c) N.
Gommermann, P. Knochel, Chem. Commun. 2004, 2324–2325; d) J.
Liu, B. Liu, X. Jia, X. Li, A. S. C. Chan, Tetrahedron: Asymmetry
2007, 18, 396–399; e) V. K.-Y. Lo, Y. Liu, M.-K. Wong, C.-M. Che,
Org. Lett. 2006, 8, 1529–1532; f) A. Bisai, V. K. Singh, Org. Lett.
2006, 8, 2405–2408.
[18] a) J. Esquivias, R. G. Arrayꢅs, J. C. Carretero, J. Org. Chem. 2005,
70, 7451–7454; b) J. P. McMahon, J. A. Ellman, Org. Lett. 2005, 7,
5393–5396.
[19] Y. Fukuda, K. Kondo, T. Aoyama, Synthesis 2006, 2649–2652.
[20] a) V. A. Soloshonok (Ed.), Enantiocontrolled Synthesis of Fluoro-
Organic Compounds: Stereochemical Challenges and Biomedical
Targets, Wiley, New York, 1999; b) V. P. Kukhar, V. A. Soloshonok
(Eds.), Fluorine-Containing Amino Acids: Synthesis and Applica-
tions, Wiley, New York, 1995; c) R. Smits, C. D. Cadicamo, K.
Burger, B. Koksch, Chem. Soc. Rev. 2008, 37, 1727–1739.
[21] a) P. Bravo, M. Crucianelli, B. Vergani, M. Zanda, Tetrahedron Lett.
1998, 39, 7771–7774; b) F. A. Davis, V. Srirajan, D. D. Titus, J. Org.
Chem. 1999, 64, 6931–6934; c) M. Crucianelli, P. Bravo, A. Arnone,
E. Corradi, V. S. Meille, M. Zanda, J. Org. Chem. 2000, 65, 2965–
2971; d) H. Amii, Y. Kishikawa, K. Kageyama, K. Uneyama, J. Org.
Chem. 2000, 65, 3404–3408; e) H. Abe, H. Amii, K. Uneyama, Org.
Lett. 2001, 3, 313–315; f) S. Fustero, A. Navarro, B. Pina, J. G. Soler,
A. Bartolome, A. Asensio, A. Simꢆn, P. Bravo, G. Fronza, A. Volon-
terio, M. Zanda, Org. Lett. 2001, 3, 2621–2624; g) A. Asensio, P.
Bravo, M. Crucianelli, A. Farina, S. Fustero, J. G. Soler, S. V. Meille,
W. Panzeri, F. Viani, A. Volonterio, M. Zanda, Eur. J. Org. Chem.
2001, 1449–1458; h) X. Qiu, W. Meng, F. Qing, Tetrahedron 2004,
[25] a) C.-H. Ding, D.-D. Chen, Z.-B. Luo, L.-X. Dai, X.-L. Hou, Synlett
2006, 1272–1274; b) S. Turcaud, F. Berhal, J. Royer, J. Org. Chem.
2007, 72, 7893–7897; c) A. W. Shaw, J. S. de Solms, Tetrahedron Lett.
2001, 42, 7173–7176; d) A. W. Patterson, J. A. Ellman, J. Org.
Chem. 2006, 71, 7110–7112.
[26] a) B. Jiang, Y.-G. Si, Angew. Chem. 2003, 115, 218–220; Angew.
Chem. Int. Ed. 2004, 43, 216–218; b) M. Crucianelli, F. De Angelis,
F. Lazzaro, L. Malpezzi, A. Volonterio, M. Zanda, J. Fluorine Chem.
2004, 125, 573–577; c) G. Magueur, B. Crousse, D. Bonnet-Delpon,
Tetrahedron Lett. 2005, 46, 2219–2221.
[27] a) K. Y. Lee, M. J. Lee, J. N. Kim, Tetrahedron 2005, 61, 8705–8710;
b) L. P. Feng, D. Kumar, S. M. Kerwin, J. Org. Chem. 2003, 68,
2234–2242.
[28] G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang, J. A. Ellman, J. Org.
Chem. 1999, 64, 1278–1284.
[29] J. Hine, J. J. Porter, J. Am. Chem. Soc. 1960, 82, 6178–6181.
Received: April 9, 2010
Published online: August 19, 2010
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