Synthesis of difluoromethyl-containing α-acyloxycarboxamide derivatives through a Passerini reaction and desulfonylation

Article abstract of DOI:10.1002/ejoc.201101518

A series of difluoromethyl-containing α-acyloxycarboxamide derivatives were synthesized through a Passerini reaction of acids, aldehydes, and phenylsulfanyl-protected difluorinated isocyanide followed by meta-chloroperoxybenzoic acid mediated oxidation and the removal of the phenylsulfonyl protecting group. The unexpected formation of deacylation products from the reaction between the Passerini products and Bu ₃SnH/azobis(isobutyronitrile) was also reported. A new approach to the synthesis of difluoromethyl-containing α-acyloxycarboxamide derivatives through a Passerini reaction followed by meta-chloroperoxybenzoic acid mediated oxidation and removal of thephenylsulfonyl group was developed. The formation of deacylation products from the reaction between the Passerini products and Bu₃SnH/azobis(isobutyronitrile) was also reported. Copyright

Full text of DOI:10.1002/ejoc.201101518

FULL PAPER
DOI: 10.1002/ejoc.201101518
Synthesis of Difluoromethyl-Containing α-Acyloxycarboxamide Derivatives
through a Passerini Reaction and Desulfonylation
Jingjing Wu,[a] Wenwen Zhao,[a] and Song Cao*[a]
Keywords: Multicomponent reactions / Oxidation / Protecting groups / Fluorine / Synthetic methods
A series of difluoromethyl-containing α-acyloxycarboxamide
derivatives were synthesized through a Passerini reaction of
acids, aldehydes, and phenylsulfanyl-protected difluorinated
diated oxidation and the removal of the phenylsulfonyl pro-
tecting group. The unexpected formation of deacylation
products from the reaction between the Passerini products
isocyanide followed by meta-chloroperoxybenzoic acid me- and Bu3SnH/azobis(isobutyronitrile) was also reported.
The modification of molecules by the incorporation of
fluorine-containing groups is widely used in drug discovery
Introduction
The α-acyloxycarboxamide group is a functional motif
to alter the chemical, physical, and biological properties of
which is found in many natural products and bioactive
the parent compounds.[5] A survey of the literature indicates
compounds.[1] For example, azinomycins, which are natural
that only a few examples of the synthesis of fluorinated α-
acyloxycarboxamides are reported, and furthermore, most
of these examples involve trifluoromethyl-containing com-
pounds. Gulevich used trifluoromethyl-containing carbonyl
compounds as one of the components to prepare trifluoro-
methyl α-acyloxycarboxamides through a Passerini reac-
products isolated from Streptomyces griseofuscus, can be
used as antitumor agents.[2] Compound I exhibits inhibitory
activity for the RNase H function of HIV-1 reverse tran-
scriptase,[3] and compound II is reported to have herbicidal
activity (Figure 1).[4]
tion. These trifluoromethyl-containing Passerini products
could be further transformed into trifluoromethyl depsi-
peptides for bioactivity screening.[6a] Burger synthesized the
trifluoromethyl-containing α-acyloxycarboxamides through
a Passerini reaction of acids, aldehydes, and 2-isocyano-
3,3,3-trifluoropropionate.[6b]
Recently, the introduction of the difluoromethyl group
(–CF2H) into biologically active compounds[7] has attracted
much interest because of the unique physiological proper-
ties of this group.[8] However, up until now, there has been
no investigation concerning the synthesis of difluoromethyl
α-acyloxycarboxamides. In continuation of our interest in
Figure 1. Examples of α-acyloxycarboxamide-containing drugs and
agrochemicals.
[a] Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy,
East China University of Science and Technology,
Shanghai 200237, China
Fax: +86-21-64252603
E-mail: scao@ecust.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101518.
Scheme 1. Synthesis of difluoromethyl-containing α-acyloxycarb-
oxamides through a Passerini reaction and desulfonylation.
1380
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1380–1387

Synthesis of Difluoromethyl-Containing α-Acyloxycarboxamide Derivatives
the synthesis of new difluoromethyl compounds,[9] we in- to give difluoromethylene compounds 2a–n in moderate to
tend to prepare difluoromethyl α-acyloxycarboxamides for high yields. Aldehydes with electron-withdrawing groups at-
bioactivity screening. Herein, we describe a new approach tached to the aromatic ring afforded the Passerini products
for the synthesis of difluoromethyl-containing α-acyloxy- in higher yields and were, therefore, preferable for use in the
carboxamides through a Passerini reaction followed by (m- reactions.
CPBA) meta-chloroperoxybenzoic acid mediated oxidation
and the removal of the phenylsulfonyl group (Scheme 1).
Generally, the Bu3SnH/AIBN [azobis(isobutyronitrile)]
system could be used to remove the PhS moiety from the
difluoromethylene compounds to afford the difluomethyl
compounds.[12] Hence, we carried out the desulfanylation
reaction of compound 2a in the presence of 3 equiv. of
Bu3SnH and a catalytic amount of AIBN in refluxing tolu-
ene. Much to our surprise, the unexpected deacylation
compound 5a was obtained as a major product ac-
companied by a small amount of the desired desulfanyl-
ated product 4a in a ratio of 9:1 (Scheme 2). However, in
a survey of the literature, there is no report of the deacyl-
ation of an ester with Bu3SnH. In addition, it was reported
that the ester group remained intact, when Bu3SnH was
used to remove the PhS group in a phenylsulfanyl-contain-
ing ester.[12c]
Subsequently, we selected Passerini products 2b–g to un-
dergo the deacylation reaction to further examine the influ-
ence of R1 and R2 on the formation of the deacylation com-
pounds (Table 2). The results indicate that the substituents
(R1 and R2) in Passerini products 2a–g have a profound
effect on the cleavage of the C–S or C–O bond. However,
at the present stage, the effects could not be generalized,
Results and Discussion
Recently, we reported a general synthetic methodology
for the construction of functionalized, small molecules
bearing a terminal CF2H group.[10] A new difluoromethyl-
ene-containing building block, phenylsulfanyl-protected
isocyanide 1, was designed and used in the Ugi reaction for
the synthesis of difluoromethyl-containing pseudopept-
ides.[10a] Considering the Passerini reaction involves the re-
action of aldehydes, carboxylic acids, and isocyanides and
is the most efficient method for the preparation of α-acy-
loxycarboxamides,[11] we used difluorinated isocyanide 1 as
one component in a Passerini reaction to synthesize the di-
fluoromethyl-containing α-acyloxycarboxamides. Thus, ex-
periments using several different aldehydes, acids, and iso-
cyanide 1 were carried out under solvent-free conditions
(Table 1). To our delight, the reactions proceeded smoothly
Table 1. Synthesis of α-acyloxycarboxamides 2a–n bearing a CF2
unit through a Passerini reaction.[a]
Table 2. Reaction of Passerini products 2a–g with Bu3SnH/AIBN.[a]
Entry
Compd.
R1
R2
Yield [%][b]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
Ph
CH3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
Ph
Ph
84
80
74
72
92
91
92
78
73
90
75
80
78
91
4-CH3C6H4
3,4-(CH3O)2C6H3
4-FC6H4
2,3-F2C6H3
3-F-4-CF3C6H3
PhCH2
4-CH3OC6H4
3-F-2-CH3C6H3
2-CH3C6H4
3-BrC6H4
4-CH3C6H4
4-FC6H4
Entry Compd. R1
R2
Time
[h]
Yield [%][b]
4
5
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
Ph
CH3
Ph
Ph
Ph
16
16
17
7
8
10
18
83 (5a)
67 (5a)
68 (5b)
57 (5c)
9
10
11
12
13
14
4-CH3C6H4
Ph 3,4-(CH3O)2C6H3 18
Ph
Ph
Ph
4-FC6H4
2,3-F2C6H3
3-F-4-CF3C6H3
7
8
8
81 trace (5d)
83 trace (5e)
85 trace (5f)
2g
[a] Reagents and conditions: acid (1 mmol), aldehyde (1 mmol), 1
(1 mmol), neat, room temp. [b] Isolated yield.
[a] Reagents and conditions: 2a–g (0.5 mmol), Bu3SnH (1.5 mmol),
AIBN (10 mol-%), toluene, reflux. [b] Isolated yield.
Scheme 2. Reaction of Passerini product 2a with Bu3SnH/AIBN.
Eur. J. Org. Chem. 2012, 1380–1387
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1381

J. Wu, W. Zhao, S. Cao
FULL PAPER
except that the presence of electron-withdrawing groups on some of the Passerini products. It might be a potentially
the aromatic ring (R2) were unfavorable for the deacylation new alternative for the cleavage of the C(O)–O single bond
reaction and afforded desulfanylated products 4e–g in good in an ester group.
yields. Further investigations into the deacylating capacity
of Bu3SnH with different substrates and the mechanism of
this reaction are in progress and will be reported in due
course.
Experimental Section
General Methods: All reagents were of analytic grade, obtained
from commercial suppliers, and used without further purification.
Melting points were measured in an open capillary with a Büchi
As the PhS moiety in some of the difluoromethylene
Passerini products 2 could not be efficiently removed by
Bu3SnH/AIBN to afford the corresponding difluoromethyl
compounds, we turned our efforts to find another synthetic
route to the desired compounds. Based on the literature,
difluorinated sulfones, sulfoxides, and sulfides can be used
as efficient fluoroalkylating reagents to prepare difluo-
romethyl compounds, which then undergo cleavage of the
sulfur-based functionalities.[13] Accordingly, we assumed
1
melting point B-540 apparatus. H NMR and 13C NMR spectro-
scopic data were recorded with a Bruker AM-400 spectrometer
using TMS as an internal standard. The 19F NMR spectroscopic
data were recorded with a Bruker AM-400 spectrometer, and the
19F NMR were measured with external CF3CO2H as the standard.
High-resolution mass spectra (ESI) were recorded with a Micro-
Mass LCTTM spectrometer. Column chromatography was carried
that the phenylsulfonyl group could be used as the protect- out with Merck silica gel 60 (230–400 mesh).
ing group instead of phenylsulfanyl group to obtain the di-
Preparation of (1,1-Difluoro-2-isocyanoethyl)(phenyl)sulfane (1):
fluoromethyl compounds. Generally, desulfonylation reac-
tions proceed with reducing agents such as Na/Hg amal-
gam,[14] SmI2/HMPA (hexamethylphosphoramide),[15] Mg/
HgCl2,[16] and Mg/HOAc/NaOAc.[17] Moreover, the phenyl-
sulfonyl-containing compounds can be conveniently pre-
pared by the oxidation of phenylsulfanyl-containing com-
pounds with m-chloroperbenzonic acid (m-CPBA).[18]
Hence, to overcome the drawbacks in the cleavage of some
of the above-mentioned Passerini products with Bu3SnH, we
used m-CPBA to oxidize 2a–n to phenylsulfonyl difluoro-
methylene derivatives 3a–n. Among the reducing agents
used for a desulfonylation reaction, reports show that Mg/
HOAc/NaOAc is an environmentally benign reaction sys-
tem.[17] Consequently, we removed the phenylsulfonyl group
from 3a–n by employing the reducing agent Mg/HOAc/
NaOAc. Thus, we finally obtained the difluoromethyl prod-
ucts 4a–n successfully in high to excellent yields through
this new and efficient approach (Scheme 3).
Isocyanide 1 was synthesized according to literature procedures.[10a]
General Procedure for the Synthesis of Compounds 2a–n: Isocyanide
1 (1 mmol) was added to a mixture of aldehyde (1 mmol) and car-
boxylic acid (1 mmol) at room temp. under solvent-free conditions.
The mixture was stirred for 12 to 24 h (TLC). The crude residue
was purified by chromatography to give the desired products 2a–n.
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-2-oxo-1-phenylethyl Benz-
oate (2a): White solid (359 mg, 84%); m.p. 98.0–99.4 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.13 (d, J = 7.6 Hz, 2 H), 7.66–7.34 (m, 13
H), 6.61 (s, 1 H), 6.42 (s, 1 H), 3.98–3.84 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.6, 164.9, 136.4, 135.0, 133.8, 130.3,
1
129.9, 129.3, 129.0, 128.9, 128.7, 128.5, 127.6, 127.5 (t, JC,F
=
274.9 Hz), 125.6, 75.8, 44.4 (t, JC,F = 29.1 Hz) ppm. 19F NMR
(376 MHz, CDCl3): δ = –79.1 (dt, JF,F = 214.1 Hz, JH,F = 12.4 Hz),
–79.7 (dt, JF,F = 214.2 Hz, JH,F = 12.5 Hz) ppm.
2
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-2-oxo-1-phenylethyl Acet-
1
ate (2b): White solid (292 mg, 80%); m.p. 88.7–90.0 °C. H NMR
(400 MHz, CDCl3): δ = 7.6 (d, J = 7.6 Hz, 2 H), 7.47–7.37 (m, 8
H), 6.50 (t, J = 4.4 Hz, 1 H), 6.16 (s, 1 H), 3.94–3.85 (m, 2 H), 2.23
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1, 168.5,
1
136.4, 135.0, 130.3, 129.3, 129.2, 128.9, 127.6, 127.5 (t, JC,F
=
280.0 Hz), 125.6, 75.4, 44.4 (t, JC,F = 29.0 Hz), 21.0 ppm. 19F
2
NMR (376 MHz, CDCl3): δ = –79.1 (dt, JF,F = 208.0 Hz, JH,F
12.4 Hz), –79.8 (dt, JF,F = 208.0 Hz, JH,F = 12.4 Hz) ppm.
=
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-2-oxo-1-p-tolylethyl Benz-
oate (2c): White solid (326 mg, 74%); m.p. 127.5–128.2 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 7.2 Hz, 2 H), 7.65–7.36
(m, 10 H), 7.26–7.24 (m, 2 H), 6.69 (t, J = 6.0 Hz, 1 H), 6.40 (s, 1
H), 3.98–3.85 (m, 2 H), 2.38 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.6, 165.0, 139.2, 136.4, 133.8, 132.1, 130.2, 129.9,
129.6, 129.3, 129.2, 128.7, 127.6, 127.5 (t, 1JC,F = 279.9 Hz), 125.7,
Scheme 3. Synthesis of α-acyloxycarboxamides 4a–n containing a
CF2H group from difluorinated Passerini products 2a–n.
2
75.8, 44.4 (t, JC,F = 29.1 Hz), 21.3 ppm. 19F NMR (376 MHz,
CDCl3): δ = –79.3 (t, J = 12.4 Hz) ppm.
Conclusions
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-(3,4-dimethoxyphenyl)-
2-oxoethyl Benzoate (2d): White solid (351 mg, 72%); m.p. 138.4–
In conclusion, we have reported a new and efficient ap-
proach to the synthesis of difluoromethyl-containing α-
acyloxycarboxamide derivatives through a Passerini reac-
tion followed by m-CPBA-mediated oxidation and removal
of the phenylsulfonyl group. In addition, we disclosed an
1
139.1 °C. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.7 Hz, 2
H), 7.65–6.89 (m, 11 H), 6.55 (t, J = 5.8 Hz, 1 H), 6.37 (s, 1 H),
4.04–3.81 (m, 2 H), 3.91 (s, 3 H), 3.89 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.7, 165.0, 149.9, 149.3, 136.4, 133.7,
129.8, 129.3, 129.2, 128.9, 128.7, 127.5 (t, 1JC,F = 277.6 Hz), 127.4,
2
unexpected deacylation reaction with Bu3SnH/AIBN for 125.6, 120.6, 111.2, 110.8, 75.8, 56.0, 55.9, 44.4 (t, JC,F
=
1382
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1380–1387

Synthesis of Difluoromethyl-Containing α-Acyloxycarboxamide Derivatives
3Ј
2ЈЈ
29.3 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –79.3 (t, J = 280.1 Hz), 127.3 (d,
J
= 8.9 Hz), 125.6, 124.9 (d,
J
=
C,F
C,F
4Ј
2Ј
12.4 Hz) ppm.
17.4 Hz), 123.6 (d,
J
C,F
= 3.2 Hz), 116.1 (d,
J
C,F
= 23.4 Hz),
4ЈЈ
2
3ЈЈЈ
73.1(d,
J
C,F
= 3.1 Hz), 44.4 (t, JC,F = 28.9 Hz), 10.8 (d,
J
C,F
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-(4-fluorophenyl)-2-oxo-
= 5.8 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –79.5 (q, J =
ethyl Benzoate (2e): White solid (409 mg, 92 %); m.p. 119.4–
12.1 Hz), –114.8 to –114.9 (m) ppm.
1
120.3 °C. H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 7.3 Hz, 2
H), 7.67–7.09 (m, 12 H), 6.71 (t, J = 5.7 Hz, 1 H), 6.40 (s, 1 H),
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-2-oxo-1-o-tolylethyl Benz-
4.04–3.81 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.4, oate (2k): White solid (331 mg, 75%); m.p. 86.3–87.3 °C. 1H NMR
1Ј
4Ј
164.8, 163.2 (d,
J
C,F
= 248.6 Hz), 136.4, 133.9, 131.0 (d,
J
C,F
=
(400 MHz, CDCl3): δ = 8.15 (d, J = 7.7 Hz, 2 H), 7.65–7.27 (m, 12
H), 6.74 (t, J = 6.0 Hz, 1 H), 6.69 (s, 1 H), 4.01–3.86 (m, 2 H), 2.60
3.3 Hz), 130.3, 129.8, 129.6 (d, 3ЈJC,F = 8.7 Hz), 129.3, 128.9, 128.8,
127.4 (t, 1JC,F = 279.8 Hz), 125.6, 115.9 (d,
J
C,F
= 21.9 Hz), 75.1, (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.9, 166.0,
2Ј
44.5 (t, JC,F = 29.0 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ =
137.4, 136.4, 133.8, 131.2, 130.3, 130.1, 129.9, 129.4, 129.1, 128.7,
2
1
2
1
–79.4 (td, J = 12.2 Hz, J = 3.9 Hz), –111.9 to –112.0 (m) ppm.
128.5, 128.2, 127.6 (t, JC,F = 280.1 Hz), 126.5, 125.7, 73.7, 44.5 (t,
2JC,F = 28.8 Hz), 19.6 ppm. 19F NMR (376 MHz, CDCl3): δ =
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-(2,3-difluorophenyl)-2-
–79.0 to –79.2 (m) ppm.
oxo-ethyl Benzoate (2f): White solid (421 mg, 91%); m.p. 111.8–
1
112.5 °C. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.2 Hz, 2 1-(3-Bromophenyl)-2-[2,2-difluoro-2-(phenylthio)ethylamino]-2-oxo-
H), 7.67–7.37 (m, 9 H), 7.26–7.13 (m, 2 H), 6.76 (t, J = 5.9 Hz, 1
ethyl Benzoate (2l): White solid (405 mg, 80%); m.p. 84.3–85.6 °C.
H), 6.62 (s, 1 H), 4.05–3.86 (m, 2 H) ppm. 13C NMR (100 MHz, 1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 7.6 Hz, 2 H), 7.76–
1Ј
2ЈЈ
CDCl3): δ = 167.4, 164.7, 150.6 (dd,
J
= 249.5 Hz,
J
C,F
=
7.29 (m, 12 H), 6.75 (t, J = 6.0 Hz, 1 H), 6.38 (s, 1 H), 4.00–3.82
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.1, 164.7,
C,F
1ЈЈ
2Ј
12.3 Hz), 149.0 (dd,
J
C,F
= 251.6 Hz,
J
= 13.7 Hz), 136.4,
C,F
1
134.0, 130.3, 129.9, 129.3, 128.8, 128.6, 127.4 (t, JC,F = 280.1 Hz), 137.2, 136.9, 136.4, 134.0, 132.4, 130.5, 130.4, 129.9, 129.3, 128.8,
2ЈЈЈ
125.6, 125.1, 124.9, 124.8, 118.4 (d,
J
= 17.0 Hz), 70.3, 44.5
128.7, 127.5 (t, 1JC,F = 280.6 Hz), 126.3, 125.6, 122.9, 74.9, 44.5 (t,
2JC,F = 29.2 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –78.9 (dt,
JF,F = 208.2 Hz, JH,F = 12.2 Hz), –79.5 (dt, JF,F = 208.2 Hz, JH,F
= 9.8 Hz) ppm.
C,F
(t, JC,F = 29.1 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –79.5
2
1
2
(t, J = 12.4 Hz), –136.9 to –137.0 (m), –140.7 (dt, J = 20.8 Hz, J
= 6.6 Hz) ppm.
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-[3-fluoro-4-(trifluoro-
methyl)phenyl]-2-oxoethyl Benzoate (2g): White solid (472 mg,
92%); m.p. 162.5–163.5 °C. 1H NMR (400 MHz, CDCl3): δ = 8.14
(d, J = 7.5 Hz, 2 H), 7.71–7.37 (m, 11 H), 6.71 (t, J = 5.6 Hz, 1
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-2-oxo-1-p-tolylethyl Acet-
ate (2m): White solid (295 mg, 78%); m.p. 96.4–97.6 °C. H NMR
1
(400 MHz, CDCl3): δ = 7.59 (d, J = 7.5 Hz, 2 H), 7.48–7.20 (m, 7
H), 6.53 (t, J = 6.0 Hz, 1 H), 6.13 (s, 1 H), 3.93–3.84 (m, 2 H), 2.37
H), 6.44 (s, 1 H), 4.03–3.84 (m, 2 H) ppm. 13C NMR (100 MHz, (s, 3 H), 2.20 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
3Ј
CDCl3): δ = 167.3, 164.4, 161.1, 141.6 (d,
J
C,F
= 8.5 Hz), 136.3,
169.2, 168.7, 139.2, 136.4, 132.1, 130.2, 129.5, 129.3, 127.6, 127.5
1
2
134.3, 130.4, 129.9, 129.4, 128.9, 128.3, 127.7, 127.6, 127.3, 125.4,
(t, JC,F = 282.5 Hz), 125.7, 75.3, 44.4 (t, JC,F = 29.0 Hz), 21.2,
2Ј
122.9 (d, 4ЈJC,F = 3.9 Hz), 115.8 (d,
J
C,F
= 22.1 Hz), 74.3, 44.5 (t,
21.0 ppm. 19F NMR (376 MHz, CDCl3): δ = –79.0 (dt, JF,F
208.4 Hz, JH,F = 12.3 Hz), –79.6 (dt, JF,F = 208.4 Hz, JH,F
12.3 Hz) ppm.
=
=
2JC,F = 28.9 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –61.5 (d,
J = 12.5 Hz), –79.6 (q, J = 12.7 Hz), –112.7 to –112.9 (m) ppm.
1-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-oxo-3-phenylpropan-2-yl 2-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-(4-fluorophenyl)-2-oxo-
Benzoate (2h): White solid (344 mg, 78%); m.p. 81.3–82.6 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 7.5 Hz, 2 H), 7.65–7.22
(m, 13 H), 6.36 (t, J = 5.7 Hz, 1 H), 5.72 (t, J = 5.8 Hz, 1 H),
3.89–3.79 (m, 2 H), 3.42–3.32 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 169.3, 165.1, 136.3, 135.6, 133.8, 130.2, 129.8, 129.7,
eth-yl Acetate (2n): White solid (348 mg, 91%); m.p. 72.9–74.1 °C.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.5 Hz, 2 H), 7.49–
7.05 (m, 7 H), 6.79 (t, J = 6.0 Hz, 1 H), 6.14 (s, 1 H), 3.92–3.83
(m, 2 H), 2.19 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
1Ј
4Ј
169.2, 168.6, 163.1 (d,
J
= 248.5 Hz), 136.4, 131.1 (d,
J
=
=
=
C,F
3Ј
C,F
1
129.3, 129.0, 128.7, 128.5, 127.3 (t, 1JC,F = 278.5 Hz), 127.1, 125.7, 3.2 Hz), 130.3, 129.6 (d,
J
= 8.5 Hz), 129.3, 127.4 (t, JC,F
C,F
2Ј
2
2
74.7, 44.3 (t, JC,F = 29.1 Hz), 37.7 ppm. 19F NMR (376 MHz,
CDCl3): δ = –79.1 (dt, JF,F = 208.0 Hz, JH,F = 9.5 Hz), –79.7 (dt,
JF,F = 213.6 Hz, JH,F = 9.8 Hz) ppm.
271.1 Hz), 125.6, 115.8 (d,
J
C,F
= 21.8 Hz), 74.7, 44.5 (t, JC,F
28.8 Hz), 20.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –79.3 (td,
2
1J = 12.5 Hz, J = 4.4 Hz), –111.9 to –112.0 (m) ppm.
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-(4-methoxyphenyl)-2- General Procedure for the Synthesis of Compounds 3a–n: To a solu-
oxoethyl Benzoate (2i): White solid (334 mg, 73 %); m.p. 109.7– tion of Passerini products 2a–n (0.7 mmol) in CH2Cl2 was added
110.5 °C. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.2 Hz, 2 m-CPBA (2.1 mmol) at 0 °C. The ice bath was removed, and the
1
H), 7.65–7.36 (m, 10 H), 6.96–6.94 (m, 2 H), 6.66 (t, J = 6.0 Hz, 1
reaction mixture was stirred at room temp. for 24–48 h (TLC). A
saturated aqueous solution of Na2S2O3 was added to quench the
H), 6.38 (s, 1 H), 3.99–3.83 (m, 2 H), 3.82 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 168.6, 165.0, 160.3, 136.4, 133.7, 130.3, reaction. The layers were separated, and the aqueous phase was
129.9, 129.3, 129.2, 129.1, 128.7, 127.5 (t, 1JC,F = 279.9 Hz), 127.2, extracted with CH2Cl2. The combined organic phases were washed
2
125.6, 114.3, 75.6, 55.3, 44.4 (t, JC,F = 29.0 Hz) ppm. 19F NMR
with saturated NaHCO3 and brine, dried with Na2SO4, filtered,
and concentrated to get the crude product which was purified by
chromatography to afford products 3a–n.
1
2
(376 MHz, CDCl3): δ = –79.5 (td, J = 12.4 Hz, J = 2.0 Hz) ppm.
2-[2,2-Difluoro-2-(phenylthio)ethylamino]-1-(3-fluoro-2-methyl-
phenyl)-2-oxoethyl Benzoate (2j): White solid (413 mg, 90%); m.p.
97.9- 98.5 °C. 1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.2 Hz,
2 H), 7.67–7.37 (m, 8 H), 7.31–7.20 (m, 2 H), 7.10–7.05 (m, 1 H),
6.63 (s, 1 H), 6.59 (t, J = 5.8 Hz, 1 H), 4.04–3.83 (m, 2 H), 2.47 (d,
J = 1.9 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.3,
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-2-oxo-1-phenylethyl
Benzoate (3a): White solid (289 mg, 90%); m.p. 126.1–127.6 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.8 Hz, 2 H), 7.96–7.38
(m, 13 H), 7.08 (t, J = 5.5 Hz, 1 H), 6.43 (s, 1 H), 4.36–4.26 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.9, 164.7, 136.0,
135.1, 133.8, 131.4, 130.8, 130.0, 129.6, 129.3, 128.9, 128.7, 127.4,
1Ј
3ЈЈ
164.7, 161.4 (d,
J
= 244.8 Hz), 136.4, 136.0 (d,
4.1 Hz), 133.9, 130.3, 129.9, 129.4, 128.9, 128.8, 127.4 (t, JC,F
J
=
=
C,F
C,F
1
1
2
124.9, 120.2 (t, JC ,F = 289.7 Hz), 75.8, 38.4 (t, JC, F
=
Eur. J. Org. Chem. 2012, 1380–1387
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1383

J. Wu, W. Zhao, S. Cao
25.9 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –107.7 (t, J = 134.2, 131.3, 130.7, 130.0, 129.6, 128.9, 128.3, 127.7, 127.6, 123.0
FULL PAPER
4Ј
1
2Ј
12.4 Hz) ppm.
(d,
J
C,F
= 3.8 Hz), 120.2 (t, JC,F = 258.3 Hz), 115.7 (d,
J
C,F
=
22.0 Hz), 74.3, 38.6 (t, 2JC,F = 26.3 Hz) ppm. 19F NMR (376 MHz,
CDCl3): δ = –61.5 (d, J = 12.6 Hz), –107.1 (dt, JF,F = 235.7 Hz,
JH,F = 12.3 Hz), –107.9 (dt, JF,F = 235.7 Hz, JH,F = 12.6 Hz),
–112.7 to –112.9 (m) ppm.
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-2-oxo-1-phenylethyl
Acetate (3b): White solid (253 mg, 91%.); m.p. 107.8–108.9 °C. H
1
NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.7 Hz, 2 H), 7.84–7.39
(m, 8 H), 6.91 (t, J = 5.6 Hz, 1 H), 6.19 (s, 1 H), 4.38–4.15 (m, 2
H), 2.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1,
168.9, 135.9, 134.9, 131.6, 130.8, 129.6, 129.2, 128.8, 127.4, 120.2
1-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-oxo-3-phenylpropan-
2-yl Benzoate (3h): White solid (301 mg, 91%); m.p. 60.1–61.2 °C.
1H NMR (400 MHz, CDCl3): δ = 8.05–8.03 (m, 2 H), 7.89–7.22
(m, 13 H), 6.96 (t, J = 6.3 Hz, 1 H), 5.72 (dd, 1J = 6.6 Hz, 2J =
5.0 Hz, 1 H),4.24–4.10 (m, 2 H), 3.41–3.30 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 169.9, 165.2, 135.9, 135.7, 133.7,
131.6, 130.7, 129.8, 129.7, 129.5, 129.0, 128.6, 128.5, 127.0, 120.4
1
2
(t, JC,F = 288.7 Hz), 75.3, 38.4 (t, JC,F = 25.9 Hz), 20.9 ppm. 19F
NMR (376 MHz, CDCl3): δ = –107.0 (dt, JF,F = 235.1 Hz, JH,F
11.7 Hz), –108.2 (dt, JF,F = 235.1 Hz, JH,F = 13.2 Hz) ppm.
=
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-2-oxo-1-p-tolylethyl
1
Benzoate (3c): White solid (301 mg, 91%.); m.p. 84.8–85.6 °C. H
1
2
(t, JC,F = 289.8 Hz), 74.7, 38.1 (t, JC,F = 24.4 Hz), 37.8 ppm. 19F
NMR (376 MHz, CDCl3): δ = –79.1 (td, 1J = 13.5 Hz, 2J =
4.3 Hz) ppm.
NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.5 Hz, 2 H), 7.96–7.22
(m, 12 H), 7.07 (t, J = 6.0 Hz, 1 H), 6.40 (s, 1 H), 4.34–4.25 (m, 2
H), 2.37 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1,
164.8, 139.2, 135.9, 133.7, 132.2, 131.6, 130.7, 130.0, 129.6, 129.5,
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-(4-methoxyphenyl)-
2-oxoethyl Benzoate (3i): White solid (305 mg, 89%); m.p. 140.3–
1
2
129.1, 128.6, 127.4, 120.3 (t, JC,F = 289.9 Hz), 75.8, 38.4 (t, JC,F
1
141.5 °C. H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 7.8 Hz, 2
= 25.3 Hz), 21.3 ppm. 19F NMR (376 MHz, CDCl3): δ = –107.6
(td, J = 12.8 Hz, J = 2.2 Hz) ppm.
H), 7.95–7.47 (m, 10 H), 7.11 (t, J = 6.1 Hz, 1 H), 6.95–6.93 (m, 2
1
2
H), 6.38 (s, 1 H), 4.35–4.23 (m, 2 H), 3.81 (s, 3 H) ppm. 13C NMR
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-(3,4-dimethoxy-
(100 MHz, CDCl3): δ = 169.3, 164.9, 160.3, 135.9, 133.7, 131.6,
1
phenyl)-2-oxoethyl Benzoate (3d): White solid (327 mg, 90%); m.p.
130.7, 129.9, 129.6, 129.1, 129.0, 128.6, 127.3, 120.4 (t, JC,F
=
1
289.8 Hz), 114.3, 75.6, 55.3, 38.4 (t, JC,F = 25.1 Hz) ppm. 19F
2
121.3–122.3 °C. H NMR (400 MHz, CDCl3): δ = 8.17–8.15 (m, 2
H), 7.95–7.09 (m, 10 H), 7.05 (t, J = 6.2 Hz, 1 H), 6.90–6.88 (m, 1
H), 6.37 (s, 1 H), 4.42–4.19 (m, 2 H), 3.91 (s, 3 H), 3.89 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1, 164.9, 149.9,
149.3, 136.0, 133.7, 131.6, 130.7, 129.9, 129.6, 129.1, 128.6, 127.5,
NMR (376 MHz, CDCl3): δ = –107.2 (dt, JF,F = 233.8 Hz, JH,F
12.3 Hz), –107.9 (dt, JF,F = 227.8 Hz, JH,F = 12.9 Hz) ppm.
=
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-(3-fluoro-2-methyl-
phenyl)-2-oxoethyl Benzoate (3j): White solid (309 mg, 90%); m.p.
1
120.5, 120.3 (t, JC,F = 290.4 Hz), 111.2, 110.7, 75.7, 56.0, 55.9,
1
142.5–143.8 °C. H NMR (400 MHz, CDCl3): δ = 8.18–8.15 (m, 2
2
38.5 (t, JC,F = 25.7 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ =
H), 7.97–7.19 (m, 10 H), 7.13 (t, J = 6.1 Hz, 1 H), 7.08–7.04 (m, 1
H), 6.65 (s, 1 H), 4.39–4.24 (m, 2 H), 2.48 (d, J = 1.9 Hz, 3 H) ppm.
–107.1 (dt, JF,F = 235.5 Hz, JH,F = 12.4 Hz), –107.8 (dt, JF,F
235.5 Hz, JH,F = 12.5 Hz) ppm.
=
1Ј
13C NMR (100 MHz, CDCl3): δ = 168.7, 164.7, 161.4 (d,
J
C,F
=
3ЈЈ
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-(4-fluorophenyl)-2-
244.5 Hz), 136.2 (d,
J
= 4.2 Hz), 136.0, 133.9, 131.5, 130.7,
C,F
3Ј
oxoethyl Benzoate (3e): White solid (307 mg, 92 %); m.p. 125.1–
129.9, 129.6, 128.8, 128.7, 127.3 (d,
J
= 8.9 Hz), 124.9 (d,
C,F
1
2ЈЈ
4Ј
1
126.6 °C. H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 7.5 Hz, 2
J
= 17.6 Hz), 123.4 (d,
J
= 3.4 Hz), 120.3 (t, JC,F =
C,F
C,F
2Ј
4ЈЈ
H), 7.96–7.49 (m, 10 H), 7.13–709 (m, 3 H), 6.41 (s, 1 H), 4.36–
4.25(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.8, 164.7,
163.2 (d, 1ЈJC,F = 248.5 Hz), 136.0, 133.9, 131.5, 131.1, 130.7, 129.9,
290.6 Hz), 116.0 (d,
38.4 (t, 2JC,F = 25.5 Hz), 10.7 (d,
(376 MHz, CDCl3): δ = –107.0 (dt, JF,F = 234.8 Hz, JH,F
J
C,F
= 23.4 Hz), 73.0 (d,
J
C,F
= 2.9 Hz),
3ЈЈЈ
J
= 5.7 Hz) ppm. 19F NMR
C,F
=
3Ј
1
129.6, 129.4 (d,
J
C,F
= 8.5 Hz), 128.8, 128.7, 120.3 (t, JC,F
=
=
12.1 Hz), –108.0 (dt, JF,F = 234.7 Hz, JH,F = 12.7 Hz), –115.0 to
–115.1 (m) ppm.
2Ј
2
289.8 Hz), 115.9 (d,
J
= 21.8 Hz), 75.1, 38.5 (t, JC,F
C,F
25.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –107.2 (dt, JF,F
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-2-oxo-1-o-tolylethyl
Benzoate (3k): White solid (295 mg, 89%); m.p. 143.8–144.7 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 7.6 Hz, 2 H), 7.97–7.25
(m, 12 H), 7.04 (t, J = 5.9 Hz, 1 H), 6.66 (s, 1 H), 4.38–4.24 (m, 2
H), 2.59 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.2,
164.8, 137.3, 136.0, 133.8, 133.7, 131.6, 131.1, 130.8, 129.9, 129.6,
= 235.3 Hz, JH,F = 12.4 Hz), –107.9 (dt, JF,F = 235.2 Hz, JH,F
=
12.4 Hz), –112.0 to –112.1 (m) ppm.
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-(2,3-difluorophenyl)-
2-oxoethyl Benzoate (3f): White solid (315 mg, 91%); m.p. 137.7–
1
139.0 °C. H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 7.2 Hz, 2
1
129.3, 129.0, 128.7, 127.7, 126.4, 120.3 (t, JC,F = 290.1 Hz), 73.4,
H), 7.99–7.49 (m, 8 H), 7.35 (t, J = 7.0 Hz, 1 H), 7.25–7.12 (m, 3
2
38.4 (t, JC,F = 25.3 Hz), 19.6 ppm. 19F NMR (376 MHz, CDCl3):
H), 6.63 (s, 1 H), 4.45–4.22 (m, 2 H) ppm. 13C NMR (100 MHz,
1Ј
2ЈЈ
δ = –107.1 (dt, JF,F = 235.6 Hz, JH,F = 12.7 Hz), –107.9 (dt, JF,F
235.3 Hz, JH,F = 12.4 Hz) ppm.
=
CDCl3): δ = 167.8, 164.6, 150.6 (dd,
J
= 249.4 Hz,
J
=
C,F
C,F
1ЈЈ
2Ј
12.4 Hz), 149.1 (dd,
J
C,F
= 251.4 Hz,
J
= 13.0 Hz), 136.0,
C,F
3Ј
134.0, 131.6, 130.8, 130.0, 129.6, 128.7, 128.6, 125.1 (d,
J
=
=
C,F
1-(3-Bromophenyl)-2-[2,2-difluoro-2-(phenylsulfonyl)ethylamino]-2-
10.5 Hz), 124.8, 124.5, 120.2 (t, 1JC,F = 291.0 Hz), 118.4 (d, 2ЈJC,F
oxoethyl Benzoate (3l): White solid (339 mg, 90 %); m.p. 136.2–
17.1 Hz), 70.4, 38.5 (t, 2JC,F = 25.6 Hz) ppm. 19F NMR (376 MHz,
CDCl3): δ = –107.1 (dt, JF,F = 234.9 Hz, JH,F = 12.8 Hz), –108.0
(dt, JF,F = 234.6 Hz, JH,F = 12.9 Hz), –136.9 to –137.0 (m), –140.6
(d, J = 20.7 Hz) ppm.
1
137.5 °C. H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.3 Hz, 2
H), 7.97–7.19 (m, 12 H), 7.18 (t, J = 6.1 Hz, 1 H), 6.38 (s, 1 H),
4.35–4.22 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.4,
164.6, 137.3, 136.0, 134.0, 132.4, 131.5, 130.8, 130.4, 130.3, 130.0,
1
129.6, 128.8, 128.7, 126.2, 122.8, 120.2 (t, JC,F = 290.1 Hz), 75.0,
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-[3-fluoro-4-(trifluoro-
methyl)phenyl]-2-oxoethyl Benzoate (3g): White solid (339 mg,
89%); m.p. 117.6–118.5 °C. 1H NMR (400 MHz, CDCl3): δ = 8.20
(d, J = 7.6 Hz, 2 H), 7.97–7.45 (m, 11 H), 7.24 (t, J = 5.9 Hz, 1
2
38.5 (t, JC,F = 25.8 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ =
–107.2 (dt, JF,F = 235.6 Hz, JH,F = 12.4 Hz), –107.9 (dt, JF,F
235.7 Hz, JH,F = 12.4 Hz) ppm.
=
H), 6.44 (s, 1 H), 4.42–4.22 (m, 2 H) ppm. 13C NMR (100 MHz, 2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-2-oxo-1-p-tolylethyl
3Ј
1
CDCl3): δ = 167.7, 164.4, 161.1, 141.7 (d,
J
C,F
= 7.0 Hz), 136.1,
Acetate (3m): White solid (259 mg, 90%); m.p. 130.3–131.0 °C. H
1384
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1380–1387

Synthesis of Difluoromethyl-Containing α-Acyloxycarboxamide Derivatives
NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.9 Hz, 2 H), 7.84–7.20
(m, 7 H), 6.90 (t, J = 5.8 Hz, 1 H), 6.15 (s, 1 H), 4.33–4.18 (m, 2
(m, 6 H), 6.51 (t, J = 5.8 Hz, 1 H), 6.32 (s, 1 H), 5.89 (tt, 1J =
2
55.9 Hz, J = 3.5 Hz, 1 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.84–3.62
H), 2.37 (s, 3 H), 2.23 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.4, 165.1,
δ = 169.2, 169.1, 139.2, 136.0, 132.0, 131.6, 130.8, 129.6, 129.5,
149.9, 149.3, 133.8, 129.8, 129.1, 128.7, 127.4, 120.3, 113.3 (t, 1JC,F
1
2
2
127.4, 120.3 (t, JC,F = 281.1 Hz), 75.2, 38.4 (t, JC,F = 25.3 Hz),
= 241.5 Hz), 111.2, 110.7, 75.7, 56.0, 55.9, 41.6 (t, JC,F
=
21.2, 20.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –107.1 (dt, JF,F
26.3 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –123.0 (dtd, 1J =
55.9 Hz, J = 12.5 Hz, J = 4.5 Hz) ppm. HRMS (ESI): calcd. for
2
2
= 234.9 Hz, JH,F = 12.3 Hz), –107.9 (dt, JF,F = 234.7 Hz, JH,F
=
12.2 Hz) ppm.
C19H18F2NO5 [M – H]+ 378.1153; found 378.1152.
2-(2,2-Difluoroethylamino)-1-(4-fluorophenyl)-2-oxoethyl Benzoate
(4e): White solid (150 mg, 89%); m.p. 141.2–142.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.10 (d, J = 7.3 Hz, 2 H), 7.67–7.09 (m, 7
2-[2,2-Difluoro-2-(phenylsulfonyl)ethylamino]-1-(4-fluorophenyl)-2-
oxoethyl Acetate (3n): White solid (242 mg, 91%); m.p. 100.1–
1
101.3 °C. H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.8 Hz, 2
1
H), 6.59 (t, J = 5.7 Hz, 1 H), 6.36 (s, 1 H), 5.89 (tt, J = 55.8 Hz,
H), 7.84–7.06 (m, 7 H), 7.00 (t, J = 5.8 Hz, 1 H), 6.16 (s, 1 H), 4.33–
2J = 3.9 Hz, 1 H), 3.79–3.64 (m, 2 H) ppm. 13C NMR (100 MHz,
4.18 (m, 2 H), 2.24 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
1Ј
1Ј
CDCl3): δ = 169.1, 164.9, 163.2 (d,
J
= 248.6 Hz), 134.0, 130.9
= 8.3 Hz), 128.8, 128.7,
C,F
= 169.1, 168.8, 163.1 (d,
J
= 248.3 Hz), 136.0, 131.5, 130.9 (d,
C,F
3Ј
C,F
4Ј
4Ј
3Ј
(d,
116.0 (d,
J
= 3.0 Hz), 129.8, 129.4 (d,
J
J
C,F
= 3.1 Hz), 130.7, 129.6, 129.4 (d,
J
= 8.6 Hz), 120.2 (t,
C,F
C,F
2Ј
1
1JC,F = 289.7 Hz), 115.8 (d,
J
= 21.8 Hz), 74.6, 38.4 (t, JC,F =
2Ј
2
J
C,F
= 21.9 Hz), 113.2 (t, JC,F = 241.5 Hz), 75.1, 41.6
C,F
(t, 2JC,F = 26.5 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –111.8
to –111.9 (m), –123.0 (dtd, 1J = 55.8 Hz, 2J = 13.2 Hz, 2J =
3.0 Hz) ppm. HRMS (ESI): calcd. for C17H13F3NO3 [M – H]+
336.0848; found 336.0845.
25.6 Hz), 20.9 ppm. 19F NMR (376 MHz, CDCl3): δ = –107.1 (dt,
JF,F = 234.5 Hz, JH,F = 12.3 Hz), –108.0 (dt, JF,F = 235.1 Hz, JH,F
= 12.6 Hz) ppm.
General Procedure for the Synthesis of Compounds 4a–n: A buffer
solution (8 m) of HOAc/NaOAc (1:1, 4 mL) was added to sulfone
compounds 3a–n (0.5 mmol) in DMF (dimethylformamide) at
room temp. Magnesium turnings (7.5 mmol) were added in por-
tions. The reaction mixture was stirred for 3–6 h (TLC), and then
water was added. The solution was extracted with Et2O, and the
combined organic phases were washed with a saturated solution of
NaHCO3 and brine and then dried with Na2SO4. After the removal
of solvent, the crude product was purified by silica gel column
chromatography to give products 4a–n.
2-(2,2-Difluoroethylamino)-1-(3,4-difluorophenyl)-2-oxoethyl Benzo-
ate (4f): White solid (161 mg, 91%); m.p. 109.6–111.3 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.11–8.08 (m, 2 H), 7.67–7.13 (m, 6 H),
1
2
6.70 (t, J = 5.9 Hz, 1 H), 6.58 (s, 1 H), 5.91 (tt, J = 55.9 Hz, J =
4.1 Hz, 1 H), 3.83–3.65 (m, 2 H) ppm. 13C NMR (100 MHz,
1Ј
2ЈЈ
CDCl3): δ = 168.0, 164.7, 150.6 (dd,
J
= 250.1 Hz,
J
C,F
=
C,F
1ЈЈ
2Ј
13.0 Hz), 149.1 (dd,
J
= 251.2 Hz,
J
= 13.8 Hz), 134.0,
C,F
C,F
3ЈЈ
129.9, 128.8, 128.6, 125.0 (d,
J
C,F
= 10.3 Hz), 124.8, 124.6 (dd,
3Ј
2Ј
J
C,F
= 6.7 Hz, 4ЈЈJC,F = 4.7 Hz), 118.5 (d,
J
C,F
= 17.1 Hz), 113.2
(t, 1JC,F = 241.5 Hz), 70.4, 41.7 (t, 2JC,F = 29.1 Hz) ppm. 19F NMR
2-(2,2-Difluoroethylamino)-2-oxo-1-phenylethyl Benzoate (4a):
White solid (145 mg, 91 %); m.p. 118.0–119.2 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.12 (d, J = 7.8 Hz, 2 H), 7.66–7.39 (m, 8
1
2
(376 MHz, CDCl3): δ = –123.1 (ddd, J = 55.9 Hz, J = 26.5 Hz,
3J = 14.4 Hz), –136.9 to –137.0 (m), –141.0 (dt, 1J = 20.7 Hz, 2J
= 6.6 Hz) ppm. HRMS (ESI): calcd. for C17H12F4NO3 [M – H]+
354.0753; found 354.0749.
1
H), 6.51 (t, J = 6.0 Hz, 1 H), 6.39 (s, 1 H), 5.88 (tt, J = 55.9 Hz,
2J = 3.8 Hz, 1 H), 3.78–3.64 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 164.4, 160.2, 130.3, 129.0, 125.1, 124.5, 124.3, 124.2,
2-(2,2-Difluoroethylamino)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-2-
oxoethyl Benzoate (4g): White solid (180 mg, 89%); m.p. 165.9–
1
2
123.9, 122.6, 108.5 (t, JC,F = 241.5 Hz), 71.1, 36.9 (t, JC,F
=
1
167.8 °C. H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.4 Hz, 2
26.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –123.1 (dt, J =
55.9 Hz, 2J = 14.7 Hz) ppm. HRMS (ESI): calcd. for C17H14F2NO3
[M – H]+ 318.0942; found 318.0943.
1
H), 7.71–7.38 (m, 6 H), 6.63 (t, J = 5.6 Hz, 1 H), 6.41 (s, 1 H), 5.90
1
2
(tt, J = 55.9 Hz, J = 4.0 Hz, 1 H), 3.79–3.65 (m, 2 H) ppm. 13C
1Ј
NMR (100 MHz, CDCl3): δ = 167.9, 164.5, 159.8 (d,
257.3 Hz), 141.5, 134.3, 129.9, 128.9, 128.3, 127.8, 122.8 (d,
J
=
C,F
4Ј
2-(2,2-Difluoroethylamino)-2-oxo-1-phenylethyl Acetate (4b): White
J
C,F
1
2Ј
1
solid (115 mg, 90 %); m.p. 102.6–104.0 °C. H NMR (400 MHz,
= 3.6 Hz), 115.7 (d,
J
C,F
= 22.2 Hz), 113.1 (t, JC,F = 241.7 Hz),
74.3, 41.7 (t, JC,F = 26.1 Hz) ppm. 19F NMR (376 MHz, CDCl3):
2
CDCl3): δ = 7.46–7.39 (m, 5 H), 6.52 (t, J = 6.0 Hz, 1 H), 6.12 (s,
2
1 H), 5.88 (tt, 1J = 55.9 Hz, J = 4.0 Hz, 1 H), 3.72–3.63 (m, 2 H),
1
δ = –61.6 (d, J = 12.5 Hz), –112.6 to –112.8 (m), –123.2 (dt, J =
2.21 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1, 169.0,
55.7 Hz, 2J = 14.8 Hz) ppm. HRMS (ESI): calcd. for C18H12F6NO3
1
[M – H]+ 404.0721; found 404.0720.
135.0, 129.3, 128.9, 127.4, 113.3 (t, JC,F = 241.4 Hz), 75.4, 41.5 (t,
2JC,F = 26.5 Hz), 20.9 ppm. 19F NMR (376 MHz, CDCl3): δ =
1-(2,2-Difluoroethylamino)-1-oxo-3-phenylpropan-2-yl Benzoate
(4h): White solid (150 mg, 90%); m.p. 134.0–135.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.01 (d, J = 7.7 Hz, 2 H), 7.64–7.24 (m, 8
1
2
–123.1 (dt, J = 56.0 Hz, J = 14.6 Hz) ppm. HRMS (ESI): calcd.
for C12H12F2NO3 [M – H]+ 256.0785; found 256.0787.
1
2
2-(2,2-Difluoroethylamino)-2-oxo-1-p-tolylethyl Benzoate (4c):
White solid (150 mg, 90 %); m.p. 118.8–120.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.11 (d, J = 7.8 Hz, 2 H), 7.65–7.23 (m, 7
H), 6.18 (t, J = 6.3 Hz, 1 H), 5.71 (tt, J = 55.6 Hz, J = 4.2 Hz, 1
H), 5.69 (t, J = 5.5 Hz, 1 H), 3.68–3.51 (m, 2 H), 3.34 (d, J =
5.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8, 165.1,
135.4, 133.8, 129.8, 129.6, 128.9, 128.7, 128.5, 127.2, 113.3 (t, 1JC,F
1
H), 6.53 (t, J = 6.0 Hz, 1 H), 6.34 (s, 1 H), 5.87 (tt, J = 56.0 Hz,
2J = 4.0 Hz, 1 H), 3.77–3.59 (m, 2 H), 2.38 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.4, 165.0, 139.3, 133.8, 132.1, 129.9,
2
= 241.8 Hz), 74.6, 41.4 (t, JC,F = 26.7 Hz), 37.8 ppm. 19F NMR
(376 MHz, CDCl3): δ = –121.9 to –123.7 (m) ppm. HRMS (ESI):
1
calcd. for C18H16F2NO3 [M – H]+ 332.1098; found 332.1096.
129.7, 129.1, 128.7, 127.4, 113.3 (t, JC,F = 241.7 Hz), 75.7, 41.6 (t,
2JC,F = 26.7 Hz), 21.2 ppm. 19F NMR (376 MHz, CDCl3): δ =
2-(2,2-Difluoroethylamino)-1-(4-methoxyphenyl)-2-oxoethyl Benzo-
ate (4i): White solid (161 mg, 92%); m.p. 129.6–130.9 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.10 (d, J = 8.0 Hz, 2 H), 7.65–6.93 (m, 7
1
2
–123.0 (dt, J = 56.0 Hz, J = 14.6 Hz) ppm. HRMS (ESI): calcd.
for C18H16F2NO3 [M – H]+ 332.1098; found 332.1095.
1
2-(2,2-Difluoroethylamino)-1-(3,4-dimethoxyphenyl)-2-oxoethyl
Benzoate (4d): White solid (169 mg, 89%); m.p. 151.8–152.8 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 7.7 Hz, 2 H), 7.65–6.88
H), 6.55 (t, J = 5.5 Hz, 1 H), 6.33 (s, 1 H), 5.88 (tt, J = 55.9 Hz,
2J = 4.0 Hz, 1 H), 3.83 (s, 3 H), 3.78–3.62 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.5, 165.1, 160.3, 133.7, 129.8, 129.1,
Eur. J. Org. Chem. 2012, 1380–1387
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1385

J. Wu, W. Zhao, S. Cao
129.0, 128.7, 127.1, 114.4, 113.3 (t, JC,F = 241.5 Hz), 75.6, 55.3, was continued for 5 min. AIBN (8 mg, 0.05 mmol) was added, and
FULL PAPER
1
2
41.6 (t, JC,F = 26.6 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ =
the solution was heated at reflux for 24 h (TLC). The mixture was
concentrated under reduced pressure, and the residue was dissolved
in EtOAc (5 mL). The solution was stirred overnight in the pres-
ence of KF/H2O (15 mg/0.15 mL) and then extracted with EtOAc.
The organic phase was washed successively with water and brine
and then dried with anhydrous Na2SO4. After solvent removal, the
crude products were purified by chromatography to give deacyl-
ation compounds 5a–c.
1
2
–123.0 (dt, J = 56.3 Hz, J = 15.0 Hz) ppm. HRMS (ESI): calcd.
for C18H16F2NO4 [M – H]+ 348.1047; found 348.1044.
2-(2,2-difluoroethylamino)-1-(3-fluoro-2-methylphenyl)-2-oxoethyl
Benzoate (4j): White solid (158 mg, 90%); m.p. 79.4–81.2 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.10–8.08 (m, 2 H), 7.65–7.05 (m, 6
1
H), 6.75 (t, J = 5.9 Hz, 1 H), 6.61 (s, 1 H), 5.89 (tt, J = 55.9 Hz,
2J = 4.0 Hz, 1 H), 3.76–3.60 (m, 2 H), 2.44 (d, J = 2.1 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1, 164.9, 161.4 (d,
N-[2,2-Difluoro-2-(phenylthio)ethyl]-2-hydroxy-2-phenylacetamide
(5a): White solid (108 mg, 67 %); m.p. 74.1–75.5 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.57 (d, J = 7.2 Hz, 2 H), 7.45–7.34 (m, 8
H), 6.94 (t, J = 5.6 Hz, 1 H), 5.04 (s, 1 H), 3.91–3.71 (m, 2 H), 3.61
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.3, 138.9,
136.4, 130.2, 129.3, 128.9, 128.8, 127.4 (t, 1JC,F = 279.9 Hz), 127.0,
1Ј
5Ј
J
= 244.9 Hz), 136.0 (d,
J
= 4.2 Hz), 133.9, 129.8, 128.7,
C,F
C,F
128.4, 127.3 (d, 3ЈJC,F = 8.8 Hz), 124.8 (d,
J
= 17.4 Hz), 123.5
2ЈЈ
C,F
4Ј
2Ј
1
(d,
J
= 3.2 Hz), 116.1 (d,
J
= 23.4 Hz), 113.3 (t, JC,F =
C,F
C,F
4ЈЈ
2
241.5 Hz), 73.0 (d,
J
C,F
= 2.9 Hz), 41.6 (t, JC,F = 26.4 Hz), 10.7
(d, 3ЈЈJC,F = 5.8 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –114.8
to –114.9 (m), –123.0 (dt, J1 = 55.9 Hz, J2 = 14.8 Hz) ppm. HRMS
(ESI): calcd. for C18H15F3NO3 [M – H]+ 350.1004; found 350.1002.
2
125.7, 74.4, 44.5 (t, JC,F = 29.0 Hz) ppm. 19F NMR (376 MHz,
CDCl3): δ = –79.0 (dt, JF,F = 213.0 Hz, JH,F = 12.4 Hz), –79.6 (dt,
JF,F = 213.5 Hz, JH,F = 12.5 Hz) ppm. HRMS (ESI): calcd. for
C16H15F2NO2SNa [M + Na]+ 346.0689; found 346.0689.
2-(2,2-Difluoroethylamino)-2-oxo-1-o-tolylethyl Benzoate (4k):
White solid (150 mg, 90 %); m.p. 99.1–100.8 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.10 (d, J = 7.3 Hz, 2 H), 7.65–7.26 (m, 7
N-[2,2-Difluoro-2-(phenylthio)ethyl]-2-hydroxy-2-p-tolylacetamide
(5b): White solid (114 mg, 68 %); m.p. 98.0–99.4 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.59 (d, J = 7.6 Hz, 2 H), 7.48–7.18 (m, 7
H), 6.99 (t, J = 5.7 Hz, 1 H), 5.00 (s, 1 H), 3.92–3.70 (m, 2 H), 3.88
(s, 1 H), 2.37 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
172.8, 138.6, 136.4, 136.1, 130.2, 129.5, 129.3, 128.2, 127.5 (t, 1JC,F
1
H), 6.63 (s, 1 H), 6.50 (t, J = 6.0 Hz, 1 H), 5.89 (tt, J = 55.9 Hz,
2J = 4.0 Hz, 1 H), 3.78–3.63 (m, 2 H), 2.55 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 169.4, 165.0, 137.3, 133.8, 133.6, 131.2,
1
129.9, 129.4, 129.0, 128.7, 127.8, 126.5, 113.3 (t, JC,F = 241.4 Hz),
73.5, 41.6 (t, JC,F = 26.6 Hz), 19.5 ppm. 19F NMR (376 MHz,
2
2
= 279.9 Hz), 126.9, 74.2, 44.5 (t, JC,F = 28.9 Hz), 21.2 ppm. 19F
1
2
CDCl3): δ = –123.0 (dt, J = 55.9 Hz, J = 14.8 Hz) ppm. HRMS
(ESI): calcd. for C18H16F2NO3 [M – H]+ 332.1098; found 332.1099.
NMR (376 MHz, CDCl3): δ = –78.8 (dt, JF,F = 212.7 Hz, JH,F
=
12.4 Hz), –79.5 (dt, JF,F = 212.7 Hz, JH,F = 12.6 Hz) ppm. HRMS
(ESI): calcd. for C17H17F2NO2SNa [M + Na]+ 360.0846; found
360.0844.
1-(3-Bromophenyl)-2-(2,2-difluoroethylamino)-2-oxoethyl Benzoate
(4l): White solid (177 mg, 89 %); m.p. 92.7–93.8 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.11 (d, J = 7.6 Hz, 2 H), 7.70–7.28 (m, 7
1
N-[2,2-Difluoro-2-(phenylthio)ethyl]-2-(3,4-dimethoxyphenyl)-2-hy-
droxyacetamide (5c): White solid (138 mg, 57%); m.p. 120.5–
H), 6.68 (t, J = 6.0 Hz, 1 H), 6.32 (s, 1 H), 5.87 (tt, J = 55.8 Hz,
2J = 3.4 Hz, 1 H), 3.76–3.60 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 168.7, 164.8, 137.1, 134.0, 132.4, 130.5, 130.3, 129.9,
1
121.7 °C. H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 7.6 Hz, 2
1
H), 7.47–6.85 (m, 6 H), 6.74 (t, J = 6.0 Hz, 1 H), 5.05 (s, 1 H),
3.99–3.73 (m, 2 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 3.48 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 172.5, 149.5, 149.4, 136.3, 131.4,
128.8, 127.4, 126.1, 122.9, 113.2 (t, JC,F = 241.6 Hz), 74.9, 41.6 (t,
2JC,F = 26.4 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –123.0
(dt, 1J = 55.8 Hz, 2J = 14.7 Hz) ppm. HRMS (ESI): calcd. for
C17H13BrF2NO3 [M – H]+ 396.0047; found 396.0048.
130.2, 129.3, 127.4 (t, 1JC,F = 279.9 Hz), 125.7, 119.8, 111.2, 109.7,
2
74.2, 56.0, 55.9, 44.5 (t, JC,F
=
28.9 Hz) ppm. 19F NMR
2-(2,2-Difluoroethylamino)-2-oxo-1-p-tolylethyl Acetate (4m): White
solid (122 mg, 90 %); m.p. 97.1–98.5 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.34–7.20 (m, 4 H), 6.46 (t, J = 5.8 Hz, 1 H), 6.09 (s,
(376 MHz, CDCl3): δ = –79.1 (dt, JF,F = 213.0 Hz, JH,F = 12.3 Hz),
–79.7 (dt, JF,F = 213.2 Hz, JH,F = 12.6 Hz) ppm. HRMS (ESI):
calcd. for C18H19F2NO4SNa [M + Na]+ 406.0901; found 406.0899.
1
2
1 H), 5.85 (tt, J = 55.9 Hz, J = 4.1 Hz, 1 H), 3.73–3.62 (m, 2 H),
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR, 13C NMR, 19F NMR spectra and
high-resolution mass spectra.
2.37 (s, 3 H), 2.20 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 169.3, 169.2, 139.3, 132.1, 129.6, 127.4, 113.3 (t, JC,F
1
=
241.4 Hz), 75.3, 41.6 (t, 2JC,F = 26.6 Hz), 21.2, 20.9 ppm. 19F NMR
(376 MHz, CDCl3 ): δ = –123.0 (dt, 1 J = 55.9 Hz, 2 J =
14.7 Hz) ppm. HRMS (ESI): calcd. for C13H14F2NO3 [M – H]+
270.0942; found 270.0940.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21072057), the National
Basic Research Program of China (973 Program, 2010CB126101),
and the Key Project in the National Science & Technology Pillar
Program of China in the twelfth five-year plan period
(2011BAE06B05).
2-(2,2-Difluoroethylamino)-1-(4-fluorophenyl)-2-oxoethyl Acetate
(4n): White solid (126 mg, 92%); m.p. 116.8–118.0 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.44–7.05 (m, 4 H), 6.63 (t, J = 5.8 Hz, 1
1
2
H), 6.09 (s, 1 H), 5.85 (tt, J = 55.8 Hz, J = 3.9 Hz, 1 H), 3.73–
3.61 (m, 2 H), 2.20 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
1Ј
4Ј
= 169.1, 169.0, 163.1 (d,
J
= 248.5 Hz), 131.0 (d,
J
=
C,F
C,F
3.4 Hz), 129.4 (d, 3ЈJC,F = 8.5 Hz), 115.9 (d, 2ЈJC,F = 21.9 Hz), 113.3
(t, JC,F = 241.4 Hz), 74.6, 41.5 (t, JC,F = 26.2 Hz), 20.9 ppm. 19F
1
2
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Chem. Int. Ed. 2000, 39, 3168–3210.
1
NMR (376 MHz, CDCl3): δ = –111.9 to –112.0 (m), –123.1 (dt, J
= 55.8 Hz, 2 J = 14.9 Hz) ppm. HRMS (ESI): calcd. for
[2] a) K. Nagaoka, M. Matsumoto, J. Oono, K. Yokoi, S. Ishizeki,
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General Procedure for the Synthesis of Compounds 5a–c: To a solu-
tion of 2a–d (0.5 mmol) in dry toluene (1 mL) was added Bu3SnH
(870 mg, 1.5 mmol) under an argon atmosphere. Deoxygenation
1386
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1380–1387

Synthesis of Difluoromethyl-Containing α-Acyloxycarboxamide Derivatives
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Received: October 18, 2011
Published Online: January 23, 2012
Eur. J. Org. Chem. 2012, 1380–1387
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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