An efficient synthesis of N′-(fluoroalkylsulfonyl) amidines by a copper(i)-catalyzed one-pot three-component reaction

Article abstract of DOI:10.1055/s-0030-1258450

Fluoroalkylsulfonyl azides were successfully employed as an efficient reacting partner in copper(I)-catalyzed three-component couplings with terminal alkynes and amines to afford the corresponding N-(fluoroalkylsulfonyl) amidines in good yields. Possible

Full text of DOI:10.1055/s-0030-1258450

1142
PAPER
An Efficient Synthesis of N¢-(Fluoroalkylsulfonyl) Amidines by a Copper(I)-
Catalyzed One-Pot Three-Component Reaction
Wanting Xiong, Yong Xin, Jingwei Zhao, Shizheng Zhu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhusz@sioc.ac.cn
Received 5 January 2011; revised 17 January 2011
pylamine (3a, 1.2 mmol) was carried out in tetrahydrofu-
Abstract: Fluoroalkylsulfonyl azides were successfully employed
ran at room temperature in the presence of 10 mol%
as an efficient reacting partner in copper(I)-catalyzed three-compo-
nent couplings with terminal alkynes and amines to afford the cor-
responding N¢-(fluoroalkylsulfonyl) amidines in good yields.
Possible reaction pathways are proposed.
copper(I) iodide. After the mixture was stirred for 30 min-
utes, both the 19F NMR spectrum and TLC analysis
showed that the reaction had finished and only one prod-
uct was formed. General workup and purification by
column chromatography gave a white solid, N,N-diisopro-
pyl-N¢-[(nonafluorobutyl)sulfonyl]-2-phenylacetamidine
(4aaa), in 85% yield (Table 1, entry 1).
Key words: multicomponent reactions, fluoroalkylsulfonyl azides,
1-alkynes, amines, amidines
Since the introduction of sulfonyl azides by Curtius and
co-workers,1 extensive investigations on those com-
pounds have been carried out to develop synthetically im-
portant transformations such as the nitrene reaction,2
cycloaddition,3 the Schmidt reaction4 and others.5 In par-
ticular, the copper(I)-catalyzed cycloaddition of the
azides with 1-alkynes has dramatically broadened the
scope and utility of such azides.6
It was found that other copper ion sources, such as cop-
per(I) bromide and copper(I) acetate, were almost equally
effective in this reaction. Increasing the amount of cop-
per(I) iodide (up to 20 mol%) did not further increase the
product yield. Tetrahydrofuran was the best solvent
among those examined, which included dioxane, dichlo-
romethane, tetrahydrofuran and benzene. High reaction
temperature (reflux in THF) led to the formation of the
byproduct nonafluorobutane-1-sulfonamide (C4F9SO2NH2).
Under the optimized conditions, a wide range of 1-
alkynes, azides and amines smoothly reacted to afford the
corresponding amidine products 4 in good yields. These
results are summarized in Table 1. The structures of the
amidines 4 were unambiguously confirmed by spectro-
scopic methods and elemental analysis.
For the three-component coupling of a sulfonyl azide, an
alkyne and an amine, the reaction is believed to proceed
via three steps, i.e. formation of a triazole intermediate via
1,3-dipolar cycloaddition between the azide and the
alkyne, release of nitrogen to give the cuprated keten-
imine species, and subsequent addition of the amine, lead-
ing to the corresponding N-sulfonimino products.7
It is noteworthy that both aliphatic alkynes and aromatic
alkynes afforded the desired products in the same good
yields. Not only simple aliphatic alkynes but also sub-
strates bearing particular functional groups readily partic-
ipated in the reaction. In addition, alkynes directly
conjugated with a double bond or a carbonyl group were
all suitable for this reaction. Electronic variation on the
aromatic moiety caused no appreciable change in the effi-
ciency of the coupling. Other fluoroalkylsulfonyl azides
1b–d were also effectively employed and gave satisfacto-
ry results (Table 1, entries 1–10). It is noteworthy that in
the case of (trimethylsilyl)acetylene (2l), the reaction with
1a and 3a under the same reaction conditions did not give
corresponding product, rather the desilylated product 5
(Table 1, entry 20). This structure was characterized by
spectroscopic methods and further confirmed by a single-
crystal X-ray diffraction analysis; the product 5 showed
the E form of the generated C=N double bond (Figure 1).
Compared with their hydrocarbon analogues, fluoroalkyl-
sulfonyl azides (RfSO2N3) have been studied rarely. Dur-
ing the course of investigating the chemical
transformations of fluoroalkylsulfonyl azides, we have re-
ported their reactions with various compounds, including
alkenes, amines, pyridine, benzene and triphenylphos-
phine, etc.8 Recently, we also investigated the one-pot re-
action of fluoroalkylsulfonyl azides with 1-alkynes and
phosphorous amides, which gave N-(fluoroalkylsulfonyl)
phosphorus amidines. As an extension of the exploration
on the utility of fluoroalkylsulfonyl azides in organic syn-
thesis, we recently studied the copper(I)-catalyzed three-
component reaction of fluoroalkylsulfonyl azides with 1-
alkynes and amines, which afforded a series of N¢-(fluoro-
alkylsulfonyl) amidine products in good yield. Herein, we
wish to report these results.
Initially, a template reaction of (nonafluorobutyl)sulfonyl
azide (1a, 1.2 mmol), phenylacetylene (2a) and diisopro-
According to several literature works and combining our
previous work on fluorinated azides, probable pathways
of the reaction are proposed (see Scheme 1).
SYNTHESIS 2011, No. 7, pp 1142–1148
x
x
.
x
x
.2
0
1
1
Advanced online publication: 01.03.2011
DOI: 10.1055/s-0030-1258450; Art ID: H09211SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Three-Component Synthesis of N¢-(Fluoroalkylsulfonyl) Amidines
1143
Table 1 Results of the Three-Component Reactiona
R2
N
R2
N
R1
R2
R2
R2
R2
or
THF, r.t.
R1
+
N
RfSO2N3
1a–d
+
H
N
N
SO2Rf
RfSO2
2a–l
3a,b
1a: Rf = C4F9
3a: R2 = i-Pr
3b: R2 = i-Bu
5 (R1 = TMS)
4
1b: Rf = C2F4OC2F4H
1c: Rf = CF2CO2Me
1d: Rf = CF2CO2i-Pr
Entry
Azide
1-Alkyne
Amine
Product
Mp (°C)
Yield (%)
1
2
3
4
1a
1b
1c
1d
4aaa
4baa
4caa
4daa
68–70
60–62
137–139
117–118
85
79
83
81
N
H
3a
3a
2a
5
6
7
1a
1b
1c
4aba
4bba
4cba
yellow oil
yellow oil
145–147
81
78
78
MeO
2b
8
9
10
1a
1b
1c
4aca
4bca
4cca
83–85
71–73
147–149
80
70
80
3a
3a
2c
OH
11
1a
4ada
117–119
88
2d
Ts
N
12
13
1a
1a
3a
3a
4aea
4afa
98–100
68
70
Boc
2e
115–117
MeO
2f
OH
14
15
16
1a
1a
1a
3a
3a
3a
4aga
4aha
4aia
135–137
81–83
73
76
72
2g
EtO2C
2h
43–45
2i
17
18
1a
1a
3a
3a
4aja
67–69
62–64
80
81
F
2j
O
4aka
2k
Synthesis 2011, No. 7, 1142–1148 © Thieme Stuttgart · New York

1144
W. Xiong et al.
PAPER
Table 1 Results of the Three-Component Reactiona (continued)
R2
N
R2
N
R1
R2
R2
R2
R2
or
THF, r.t.
R1
+
N
RfSO2N3
1a–d
+
H
N
N
SO2Rf
RfSO2
2a–l
3a,b
1a: Rf = C4F9
3a: R2 = i-Pr
3b: R2 = i-Bu
5 (R1 = TMS)
4
1b: Rf = C2F4OC2F4H
1c: Rf = CF2CO2Me
1d: Rf = CF2CO2i-Pr
Entry
19
Azide
1-Alkyne
Amine
Product
Mp (°C)
65–67
Yield (%)
79
1a
4aab
N
H
3b
3a
2a
TMS
20
1a
5
79–81
40
2l
a The reactions were carried out in the presence of 10 mol% CuI in THF at r.t., with a molar ratio 1/2/3 of 1.2:1:1.2.
and amines. The fruitful utility of the fluoroalkylsulfonyl
azides has allowed us to demonstrate the synthetic useful-
ness of such compounds, and expanding the scope of the
multicomponent reaction to prepare additional fluoro-
alkylsulfonyl-substituted compounds is now under further
investigation in our laboratory.
Figure 1 The molecular structure of product 5
Melting points were measured on a Mel-Temp apparatus and are
uncorrected. 1H (300 MHz) and 19F (282 MHz) NMR spectra were
recorded on a Bruker AM-300 UltraShield, 300-MHz, high-perfor-
mance digital FT-NMR spectrometer with TMS and CFCl3 as the
internal and external standards, respectively. FT-IR spectra were
obtained with a Nicolet AV-360 spectrophotometer. Low-resolu-
tion mass spectra (LRMS) and high-resolution mass spectra
(HRMS) were obtained on Finnigan GC-MS 4021 and MAT-8430
instruments using the electron-impact ionization technique (70 eV)
or electrospray ionization. Elemental analyses were performed by
the Shanghai Institute of Organic Chemistry. Single-crystal X-ray
structure analysis was performed on a Bruker AXS D8 instrument.
All solvents and reagents were used as obtained without further pu-
rification, unless otherwise stated.
In pathway A, a [3+2] cycloaddition proceeds in the pres-
ence of copper(I) iodide and affords a pair of resonance
components a and b, which both could form the interme-
diate c by releasing nitrogen.9 Then, nucleophilic addition
of amine 3 gives the product 4. On the other hand, path-
way B consists of [3+2] cycloaddition, cleavage and a hy-
dride shift along with nitrogen release,10 which could also
give the product 4.
In summary, fluoroalkylsulfonyl azides can now be listed
as new and efficient reacting partners in copper(I)-cata-
lyzed three-component coupling reactions with 1-alkynes
R1
Cu
RfSO2N3
N
N
SO2Rf
R1
N
– N2
1
Cu(I)
R2
R2
a
N
N
H
path A
Cu
SO2Rf
R2
N
R1
N2
Cu
c
R1
R2
R1
N
SO2Rf
N
SO2Rf
2
b
4
R2
R2
R2
R2
R1
N
R2
R2
R1
N
N
RfSO2N3
[3+2] cycloaddition
Cu(I)
cleavage
N
H
path B
N
N
N
SO2Rf
R1
SO2Rf
N
N
R2
R2
N
d
e
f
H
3
Scheme 1 Proposed reaction pathways
Synthesis 2011, No. 7, 1142–1148 © Thieme Stuttgart · New York

PAPER
One-Pot Three-Component Synthesis of N¢-(Fluoroalkylsulfonyl) Amidines
1145
N¢-(Fluoroalkylsulfonyl) Amidines by the Copper(I)-Catalyzed
One-Pot Three-Component Reaction of Fluoroalkylsulfonyl
Azides, Terminal Alkynes and Amines; General Procedure
Under N2 atmosphere and at r.t., a terminal alkyne 2 (1.0 mmol), a
fluoroalkylsulfonyl azide 1 (1.2 mmol) and an amine 3 (1.2 mmol)
were added to a single-necked flask containing CuI (20 mg, 0.1
mmol) and anhyd THF (10 mL). The mixture was stirred until the
reaction was finished (ca. 30 min), as monitored by TLC analysis
and 19F NMR spectra. Then, the reaction was quenched with sat. aq
NH4Cl. The CuI residue was removed by filtration, and the filtrate
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
phase was washed with brine (30 mL), then dried (MgSO4). The sol-
vent was removed and the product was purified by column chroma-
tography (petroleum ether–EtOAc, 10:1 v:v).
Anal. Calcd for C17H24F2N2O4S: C, 52.29; H, 6.20; N, 7.17. Found:
C, 52.33; H, 6.12; N, 7.18.
N¢-{[Difluoro(isopropoxycarbonyl)methyl]sulfonyl}-N,N-diiso-
propyl-2-phenylacetamidine (4daa)
Yellow solid; 339 mg (81%).
IR (KBr): 2989, 2971, 1760, 1553, 1446, 1377, 1315, 1299, 1134
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.31 (m, 2 H), 7.25–7.22 (m,
3 H), 5.24 (q, J = 6.6 Hz, 1 H, OCH), 4.32 (s, 2 H, CH2), 4.09 (q,
J = 6.6 Hz, 1 H, NCH), 3.57 (br s, 1 H, NCH), 1.51 (d, J = 6.6 Hz,
6 H, 2 CH3), 1.38 (d, J = 6.0 Hz, 6 H, 2 CH3), 0.93 (d, J = 6.6 Hz, 6
H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –109.2 (s, CF2S).
MS (ESI): m/z = 419.2 [M + H]+.
N,N-Diisopropyl-N¢-[(nonafluorobutyl)sulfonyl]-2-phenylacet-
amidine (4aaa)
White solid; 425 mg (85%).
HRMS (ESI): m/z [M + H]+ calcd for C19H29F2N2O4S: 419.1811;
found: 419.1801.
IR (KBr): 2977, 2938, 1556, 1440, 1352, 1322, 1213, 1138, 1058
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.32 (m, 2 H), 7.28–7.20 (m,
3 H), 4.33 (s, 2 H, CH2), 4.14–4.10 (m, 1 H, NCH), 3.59 (br s, 1 H,
NCH), 1.50 (d, J = 6.9 Hz, 6 H, 2 CH3), 0.95 (d, J = 6.9 Hz, 6 H, 2
CH3).
19F NMR (282 MHz, CDCl3): d = –80.7 (t, J = 9.6 Hz, 3 F, CF3),
–112.6 (m, 2 F, CF2S), –120.8 (m, 2 F, CF2), –125.9 (t, J = 15.5 Hz,
2 F, CF2).
Anal. Calcd for C19H28F2N2O4S: C, 54.53; H, 6.74; N, 6.69. Found:
C, 54.80; H, 6.67; N, 6.55.
N,N-Diisopropyl-2-(4-methoxyphenyl)-N¢-[(nonafluoro-
butyl)sulfonyl]acetamidine (4aba)
Yellow oil; 430 mg (81%).
IR (KBr): 2976, 2940, 1613, 1555, 1514, 1445, 1377, 1330, 1210,
1139 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.14 (d, J = 9.0 Hz, 2 H), 6.87 (d,
J = 9.0 Hz, 2 H), 4.25 (s, 2 H, CH2), 4.13 (q, J = 6.6 Hz, 1 H, NCH),
3.79 (s, 3 H, OCH3), 3.59 (br s, 1 H, NCH), 1.49 (d, J = 6.6 Hz, 6 H,
2 CH3), 0.97 (d, J = 6.6 Hz, 6 H, 2 CH3).
MS (ESI): m/z = 501.1 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H21F9N2O2SNa:
523.1072; found: 523.1054.
19F NMR (282 MHz, CDCl3): d = –81.1 (t, J = 10.3 Hz, 3 F, CF3),
–113.1 (t, J = 13.8 Hz, 2 F, CF2S), –121.2 (m, 2 F, CF2), –126.4 (dt,
J = 5.6, 14.1 Hz, 2 F, CF2).
Anal. Calcd for C18H21F9N2O2S: C, 43.20; H, 4.23; N, 5.60. Found:
C, 43.58; H, 4.36; N, 5.43.
N,N-Diisopropyl-N¢-[(1,1,2,2,4,4,5,5-octafluoro-3-oxa-
pentyl)sulfonyl]-2-phenylacetamidine (4baa)
Yellow solid; 393 mg (79%).
MS (ESI): m/z = 531.0 [M + H]+.
Anal. Calcd for C19H23F9N2O3S: C, 43.02; H, 4.37; N, 5.28. Found:
C, 43.08; H, 4.55; N, 5.21.
IR (KBr): 2977, 2389, 1558, 1447, 1379, 1316, 1209, 1135, 1053
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.31 (m, 2 H), 7.28–7.21 (m,
3 H), 5.86 (tt, J = 3.6, 52.5 Hz, 1 H, HCF2), 4.32 (s, 2 H, CH2), 4.11
(q, J = 6.6 Hz, 1 H, NCH), 3.60 (br s, 1 H, NCH), 1.51 (d, J = 6.6
Hz, 6 H, 2 CH3), 0.95 (d, J = 6.6 Hz, 6 H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –80.6 (t, J = 12.5 Hz, 2 F, CF2O),
–88.8 (m, 2 F, OCF2), –116.3 (s, 2 F, CF2S), –137.4 (td, J = 5.5, 52.2
Hz, 2 F, CF2H).
N,N-Diisopropyl-2-(4-methoxyphenyl)-N¢-[(1,1,2,2,4,4,5,5-
octafluoro-3-oxapentyl)sulfonyl]acetamidine (4bba)
Yellow oil; 412 mg (78%).
IR (KBr): 2977, 2940, 2841, 1614, 1557, 1515, 1486, 1377, 1326,
1252 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.14 (d, J = 8.4 Hz, 2 H), 6.87 (d,
J = 8.4 Hz, 2 H), 5.86 (tt, J = 3.6, 52.8 Hz, 1 H, HCF2), 4.23 (s, 2 H,
CH2), 4.12 (q, J = 6.6 Hz, 1 H, NCH), 3.79 (s, 3 H, OCH3), 3.59 (br
s, 1 H, NCH), 1.49 (d, J = 6.9 Hz, 6 H, 2 CH3), 0.96 (d, J = 6.9 Hz,
6 H, 2 CH3).
MS (ESI): m/z = 499.2 [M + H]+, 521.1 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H23F8N2O3S: 499.1296;
19F NMR (282 MHz, CDCl3): d = –81.1 (t, J = 12.4 Hz, 2 F, CF2O),
–89.2 (m, 2 F, OCF2), –116.8 (s, 2 F, CF2S), –137.8 (td, J = 5.9, 53.3
Hz, 2 F, CF2H).
found: 499.1305.
Anal. Calcd for C18H22F8N2O3S: C, 43.37; H, 4.45; N, 5.62. Found:
C, 43.53; H, 4.56; N, 5.44.
MS (ESI): m/z = 529.0 [M + H]+.
N¢-{[Difluoro(methoxycarbonyl)methyl]sulfonyl}-N,N-diiso-
propyl-2-phenylacetamidine (4caa)
White solid; 323 mg (83%).
Anal. Calcd for C19H24F8N2O4S: C, 43.18; H, 4.58; N, 5.30. Found:
C, 42.99; H, 4.82; N, 5.36.
IR (KBr): 3031, 2977, 1766, 1586, 1478, 1277, 1207 cm–1.
N¢-{[Difluoro(methoxycarbonyl)methyl]sulfonyl}-N,N-diiso-
propyl-2-(4-methoxyphenyl)acetamidine (4cba)
White solid; 328 mg (78%).
1H NMR (300 MHz, CDCl3): d = 7.39–7.33 (m, 2 H), 7.29–7.24 (m,
3 H), 4.34 (s, 2 H, CH2), 4.11 (q, J = 6.6 Hz, 1 H, NCH), 4.00 (s, 3
H, OCH3), 3.59 (br s, 1 H, NCH), 1.51 (d, J = 6.9 Hz, 6 H, 2 CH3),
0.95 (d, J = 6.9 Hz, 6 H, 2 CH3).
IR (KBr): 2976, 1764, 1557, 1516, 1448, 1375, 1316, 1175, 1145,
1059 cm–1.
19F NMR (282 MHz, CDCl3): d = –109.2 (s, CF2S).
MS (ESI): m/z = 390.9 [M + H]+, 412.9 [M + Na]+.
1H NMR (300 MHz, CDCl3): d = 7.15 (d, J = 8.7 Hz, 2 H), 6.86 (d,
J = 8.7 Hz, 2 H), 4.24 (s, 2 H, CH2), 4.10 (q, J = 6.6 Hz, 1 H, NCH),
Synthesis 2011, No. 7, 1142–1148 © Thieme Stuttgart · New York

1146
W. Xiong et al.
PAPER
3.98 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 3.56 (br s, 1 H, NCH),
1.47 (d, J = 6.6 Hz, 6 H, 2 CH3), 0.94 (d, J = 6.6 Hz, 6 H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –109.8 (s, CF2S).
MS (ESI): m/z = 421.2 [M + H]+.
H, NCH), 3.35 (dd, J = 3.9, 14.4 Hz, 1 H, CH), 3.25–3.17 (m, 1 H,
CH), 2.54 (br s, 1 H, OH), 1.48 (t, J = 8.1 Hz, 6 H, 2 CH3), 1.32 (d,
J = 5.7 Hz, 3 H, CH3), 1.18 (br s, 3 H, CH3).
19F NMR (282 MHz, CDCl3): d = –81.1 (t, J = 9.9 Hz, 3 F, CF3),
–113.0 (s, 2 F, CF2S), –121.3 (s, 2 F, CF2), –126.4 (t, J = 11.8 Hz, 2
F, CF2).
Anal. Calcd for C18H26F2N2O5S: C, 51.42; H, 6.23; N, 6.66. Found:
C, 51.24; H, 6.24; N, 6.62.
MS (ESI): m/z = 531.2 [M + H]+.
N,N-Diisopropyl-N¢-[(nonafluorobutyl)sulfonyl]-2-(4-tol-
yl)acetamidine (4aca)
Anal. Calcd for C19H23F9N2O3S: C, 43.02; H, 4.37; N, 5.28. Found:
C, 42.91; H, 4.45; N, 5.35.
White solid; 411 mg (80%).
4-[(tert-Butoxycarbonyl)(tosyl)amino]-N,N-diisopropyl-N¢-
[(nonafluorobutyl)sulfonyl]butanamidine (4aea)
Yellow solid; 490 mg (68%).
IR (KBr): 2981, 1724, 1554, 1375, 1235, 1138 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.78 (d, J = 8.7 Hz, 2 H), 7.31 (d,
J = 8.7 Hz, 2 H), 4.21 (br s, 1 H, NCH), 3.94 (t, J = 6.6 Hz, 2 H,
NCH2), 3.61 (br s, 1 H, NCH), 2.92 (t, J = 8.3 Hz, 2 H, CH2), 2.44
(s, 3 H, ArCH3), 2.17–2.12 (m, 2 H, CH2), 1.44 (m, 6 H, 2 CH3),
1.36–1.33 (m, 15 H, 5 CH3).
19F NMR (282 MHz, CDCl3): d = –81.2 (t, J = 9.9 Hz, 3 F, CF3),
–113.3 (m, 2 F, CF2S), –121.3 (m, 2 F, CF2), –126.5 (t, J = 12.8 Hz,
2 F, CF2).
IR (KBr): 2978, 2938, 1626, 1553, 1446, 1377, 1331, 1211, 1139,
1056 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.15 (d, J = 8.1 Hz, 2 H), 7.10 (d,
J = 8.1 Hz, 2 H), 4.29 (s, 2 H, CH2), 4.14 (q, J = 6.6 Hz, 1 H, NCH),
3.61 (br s, 1 H, NCH), 2.33 (s, 3 H, ArCH3), 1.51 (d, J = 6.6 Hz, 6
H, 2 CH3), 0.98 (d, J = 6.6 Hz, 6 H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –80.7 (t, J = 9.9 Hz, 3 F, CF3),
–112.7 (t, J = 13.1 Hz, 2 F, CF2S), –120.8 (m, 2 F, CF2), –126.0 (m,
2 F, CF2).
MS (ESI): m/z = 515.0 [M + H]+, 537.0 [M + Na]+.
Anal. Calcd for C19H23F9N2O2S: C, 44.36; H, 4.51; N, 5.45. Found:
C, 44.53; H, 4.63; N, 5.42.
MS (EI): m/z (%) = 452 (48) [M – TsNBoc + 1]+, 424 (47) [M –
C4F9SO2N]+, 325 (35) [M – N(i-Pr)2 – C4F9SO2N – H]+, 297 (100)
[C4F9SO2N+].
N,N-Diisopropyl-N¢-[(1,1,2,2,4,4,5,5-octafluoro-3-oxa-
pentyl)sulfonyl]-2-(4-tolyl)acetamidine (4bca)
White solid; 358 mg (70%).
Anal. Calcd for C26H36F9N3O6S2: C, 43.27; H, 5.03; N, 5.82. Found:
C, 43.12; H, 4.90; N, 5.84.
IR (KBr): 2981, 2939, 1627, 1561, 1450, 1381, 1315, 1120, 1054
cm–1.
N,N-Diisopropyl-2-(6-methoxy-2-naphthyl)-N¢-[(nonafluoro-
butyl)sulfonyl]acetamidine (4afa)
White solid; 406 mg (70%).
1H NMR (300 MHz, CDCl3): d = 7.15 (d, J = 7.5 Hz, 2 H), 7.10 (d,
J = 7.5 Hz, 2 H), 5.86 (t, J = 52.5 Hz, 1 H, HCF2), 4.27 (s, 2 H,
CH2), 4.10 (q, J = 6.6 Hz, 1 H, NCH), 3.60 (br s, 1 H, NCH), 2.32
(s, 3 H, ArCH3), 1.50 (d, J = 6.0 Hz, 6 H, 2 CH3), 0.97 (d, J = 6.0
Hz, 6 H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –80.6 (t, J = 12.0 Hz, 2 F, CF2O),
–88.8 (m, 2 F, OCF2), –116.3 (s, 2 F, CF2S), –137.4 (td, J = 5.6, 52.5
Hz, 2 F, CF2H).
IR (KBr): 2982, 2936, 1606, 1556, 1445, 1378, 1323, 1209, 1137
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.74–7.67 (m, 2 H), 7.56 (s, 1 H),
7.31 (dd, J = 1.8, 8.4 Hz, 1 H), 7.15 (dd, J = 1.8, 8.4 Hz, 1 H), 7.11
(s, 1 H), 4.45 (s, 2 H, CH2), 4.21 (q, J = 6.6 Hz, 1 H, NCH), 3.91 (s,
3 H, OCH3), 3.60 (br s, 1 H, NCH), 1.53 (d, J = 6.6 Hz, 6 H, 2 CH3),
0.92 (d, J = 6.6 Hz, 6 H, 2 CH3).
MS (ESI): m/z = 513.0 [M + H]+, 535.0 [M + Na]+.
19F NMR (282 MHz, CDCl3): d = –81.1 (t, J = 9.6 Hz, 3 F, CF3),
–113.1 (t, J = 14.1 Hz, 2 F, CF2S), –121.3 (s, 2 F, CF2), –126.4 (m,
2 F, CF2).
Anal. Calcd for C19H24F8N2O3S: C, 44.53; H, 4.72; N, 5.47. Found:
C, 44.72; H, 5.02; N, 5.43.
N¢-{[Difluoro(methoxycarbonyl)methyl]sulfonyl}-N,N-diiso-
propyl-2-(4-tolyl)acetamidine (4cca)
MS (ESI): m/z = 581.2 [M + H]+.
White solid; 323 mg (80%).
IR (KBr): 2976, 1766, 1558, 1448, 1376, 1301, 1146, 1059 cm–1.
Anal. Calcd for C23H25F9N2O3S: C, 47.59; H, 4.34; N, 4.83. Found:
C, 47.45; H, 4.28; N, 4.96.
1H NMR (300 MHz, CDCl3): d = 7.11 (br s, 4 H), 4.26 (s, 2 H, CH2),
4.10 (q, J = 6.3 Hz, 1 H, NCH), 3.98 (s, 3 H, OCH3), 3.57 (br s, 1 H,
NCH), 2.31 (s, 3 H, ArCH3), 1.48 (d, J = 6.3 Hz, 6 H, 2 CH3), 0.94
(d, J = 6.3 Hz, 6 H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –109.8 (s, CF2S).
MS (ESI): m/z = 405.2 [M + H]+.
2-(1-Hydroxycyclohexyl)-N,N-diisopropyl-N¢-[(nonafluoro-
butyl)sulfonyl]acetamidine (4aga)
White solid; 381 mg (73%).
IR (KBr): 3528, 2935, 1562, 1426, 1313, 1115 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.64 (q, J = 6.6 Hz, 1 H, NCH),
3.74 (br s, 1 H, NCH), 3.15 (br s, 2 H, CH2), 2.39 (br s, 1 H, OH),
1.67–1.59 (m, 10 H, 5 CH2), 1.48 (d, J = 6.6 Hz, 6 H, 2 CH3), 1.27
(d, J = 6.6 Hz, 6 H, 2 CH3).
Anal. Calcd for C18H26F2N2O4S: C, 53.45; H, 6.48; N, 6.93. Found:
C, 53.11; H, 6.45; N, 6.79.
19F NMR (282 MHz, CDCl3): d = –81.2 (t, J = 9.9 Hz, 3 F, CF3),
–112.9 (m, 2 F, CF2S), –121.4 (t, J = 5.2 Hz, 2 F, CF2), –126.4 (m,
2 F, CF2).
3-Hydroxy-N,N-diisopropyl-N¢-[(nonafluorobutyl)sulfonyl]-3-
phenylpropanamidine (4ada)
White solid; 466 mg (88%).
IR (KBr): 3502, 2983, 1558, 1435, 1301, 1236, 1145, 1116 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.50–7.47 (m, 2 H), 7.41–7.31 (m,
3 H), 5.38–5.36 (m, 1 H, OCH), 4.49 (br s, 1 H, NCH), 3.73 (br s, 1
MS (ESI): m/z = 523.2 [M + H]+.
Anal. Calcd for C18H27F9N2O3S: C, 41.38; H, 5.21; N, 5.36. Found:
C, 41.34; H, 5.36; N, 5.43.
Synthesis 2011, No. 7, 1142–1148 © Thieme Stuttgart · New York

PAPER
One-Pot Three-Component Synthesis of N¢-(Fluoroalkylsulfonyl) Amidines
1147
2-(Ethoxycarbonyl)-N,N-diisopropyl-N¢-[(nonafluorobutyl)sul-
fonyl]acetamidine (4aha)
White solid; 377 mg (76%).
N,N-Diisobutyl-N¢-[(nonafluorobutyl)sulfonyl]-2-phenylacet-
amidine (4aab)
White solid; 417 mg (79%).
IR (KBr): 2988, 1740, 1568, 1318, 1236, 1210, 1137 cm–1.
IR (KBr): 2973, 2940, 1555, 1443, 1314, 1200, 1139 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.23 (q, J = 6.9 Hz, 2 H, OCH2),
4.07–4.02 (m, 3 H), 3.75 (br s, 1 H, NCH), 1.49 (d, J = 6.3 Hz, 6 H,
2 CH3), 1.32–1.29 (m, 9 H, 3 CH3).
19F NMR (282 MHz, CDCl3): d = –81.2 (t, J = 9.4 Hz, 3 F, CF3),
–113.3 (m, 2 F, CF2S), –121.5 (t, J = 4.8 Hz, 2 F, CF2), –126.5 (m,
2 F, CF2).
1H NMR (300 MHz, CDCl3): d = 7.37–7.32 (m, 2 H), 7.28–7.23 (m,
3 H), 4.48–4.39 (m, 1 H), 4.26–4.18 (m, 1 H), 3.84 (q, J = 6.6 Hz, 1
H), 3.15 (br s, 1 H), 2.36–2.26 (m, 1 H), 1.74–1.65 (m, 1 H), 1.47
(d, J = 6.6 Hz, 3 H, CH3), 1.41–1.24 (m, 2 H), 0.91–0.85 (m, 6 H, 2
CH3), 0.73–0.67 (m, 3 H, CH3).
19F NMR (282 MHz, CDCl3): d = –81.1 (t, J = 9.9 Hz, 3 F, CF3),
–113.1 (t, J = 14.1 Hz, 2 F, CF2S), –121.3 (m, 2 F, CF2), –126.4 (m,
2 F, CF2).
MS (ESI): m/z = 497.0 [M + H]+.
Anal. Calcd for C15H21F9N2O4S: C, 36.29; H, 4.26; N, 5.64. Found:
C, 36.32; H, 4.32; N, 5.80.
MS (ESI): m/z = 529.2 [M + H]+.
Anal. Calcd for C20H25F9N2O2S: C, 45.45; H, 4.77; N, 5.30. Found:
C, 45.54; H, 4.86; N, 5.39.
2-(1-Cyclohexen-1-yl)-N,N-diisopropyl-N¢-[(nonafluoro-
butyl)sulfonyl]acetamidine (4aia)
White solid; 363 mg (72%).
IR (KBr): 2976, 2938, 1556, 1446, 1377, 1349, 1120 cm–1.
(E)-N,N-Diisopropyl-N¢-[(nonafluorobutyl)sulfonyl]acet-
amidine (5)
White solid; 170 mg (40%).
IR (KBr): 2978, 2941, 2346, 1560, 1430, 1326, 1237, 1138 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.12 (br s, 2 H), 2.58 (s, 3 H, CH3),
1.39 (d, J = 6.3 Hz, 6 H, 2 CH3), 1.33 (d, J = 6.3 Hz, 6 H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –80.1 (t, J = 11.7 Hz, 3 F, CF3),
–112.5 (br s, 2 F, CF2S), –120.4 (s, 2 F, CF2), –125.4 (t, J = 14.1 Hz,
2 F, CF2).
1H NMR (300 MHz, CDCl3): d = 5.44 (s, 1 H, =CH), 4.09 (q,
J = 6.6 Hz, 1 H, NCH), 3.65 (br s, 1 H, NCH), 3.53 (s, 2 H, CH2),
2.02–2.00 (m, 4 H, 2 CH2), 1.67–1.64 (m, 2 H, CH2), 1.57–1.54 (m,
2 H, CH2), 1.48 (d, J = 6.6 Hz, 6 H, 2 CH3), 1.23 (d, J = 6.6 Hz, 6
H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –81.2 (t, J = 10.2 Hz, 3 F, CF3),
–113.3 (s, 2 F, CF2S), –121.4 (m, 2 F, CF2), –126.5 (dt, J = 5.9, 13.8
Hz, 2 F, CF2).
MS (ESI): m/z = 425.2 [M + H]+, 447.0 [M + Na]+.
MS (ESI): m/z = 505.2 [M + H]+.
Anal. Calcd for C12H17F9N2O2S: C, 33.97; H, 4.04; N, 6.60. Found:
C, 34.16; H, 3.93; N, 6.38.
Anal. Calcd for C18H25F9N2O2S: C, 42.86; H, 5.00; N, 5.55. Found:
C, 42.44; H, 4.76; N, 5.67.
X-ray Crystallography of Compound 5
2-(4-Fluorophenyl)-N,N-diisopropyl-N¢-[(nonafluorobutyl)sul-
fonyl]acetamidine (4aja)
White solid; 414 mg (80%).
IR (KBr): 2982, 1560, 1514, 1449, 1378, 1117 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.23–7.19 (m, 2 H), 7.05 (t,
J = 8.4 Hz, 2 H), 4.29 (s, 2 H, CH2), 4.08 (q, J = 6.6 Hz, 1 H, NCH),
3.61 (br s, 1 H, NCH), 1.50 (d, J = 6.9 Hz, 6 H, 2 CH3), 0.99 (d,
J = 6.9 Hz, 6 H, 2 CH3).
19F NMR (282 MHz, CDCl3): d = –81.1 (t, J = 10.0 Hz, 3 F, CF3),
–113.2 (m, 2 F, CF2S), –115.0 (s, 1 F, ArF), –121.3 (t, J = 4.7 Hz, 2
F, CF2), –126.5 (m, 2 F, CF2).
Crystal data for C12H17F9N2O2S: M = 424.34, monoclinic, space
group P2(1)/c, a = 14.1721(5) Å, b = 10.5562(3) Å, c = 12.4206(4)
Å, b = 94.666(2)°, V = 1852.01(10) Å3, Z = 4, Dc = 1.522 mg/m3,
F(000) = 864, crystal dimension 0.32 × 0.28 × 0.22 mm, Mo Ka ra-
diation (l = 0.711 Å), 4.82 £ 2q £ 51.00; intensity data were collect-
ed at 298 K with a Bruker AXS D8 diffractometer, employing the
w/2q scanning technique, in the range of 17 £ h £ 16, 12 £ k £ 12,
14 £ l £ 15. The structure was solved by a direct method; all non-
hydrogen atoms were positioned and anisotropic thermal parame-
ters refined from 3442 observed reflections with Rint = 0.0288 by a
full-matrix least-squares technique converged to R = 0.0925 and
Rw = 0.1972. Full crystallographic parameters have been deposited
with the Cambridge Crystallographic Data Centre under the
reference number CCDC 802157. These data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
MS (ESI): m/z = 519.0 [M + H]+.
Anal. Calcd for C18H20F10N2O2S: C, 41.70; H, 3.89; N, 5.40. Found:
C, 41.52; H, 3.90; N, 5.48.
3-(Benzyloxy)-N,N-diisopropyl-N¢-[(nonafluorobutyl)sulfo-
nyl]propanamidine (4aka)
White solid; 441 mg (81%).
Acknowledgment
IR (KBr): 2975, 2939, 2875, 1556, 1446, 1376, 1205, 1117 cm–1.
This work was financially supported by the National Nature Foun-
dation of China (Nos. 20972178 and 21032006).
1H NMR (300 MHz, CDCl3): d = 7.36–7.27 (m, 5 H), 4.49–4.43 (m,
3 H), 3.91 (t, J = 6.3 Hz, 2 H, OCH2), 3.65 (br s, 1 H, NCH), 3.21
(t, J = 6.3 Hz, 2 H, CH2), 1.43 (d, J = 6.3 Hz, 6 H, 2 CH3), 1.14 (d,
J = 5.4 Hz, 6 H, 2 CH3).
References
19F NMR (282 MHz, CDCl3): d = –81.1 (t, J = 10.9 Hz, 3 F, CF3),
(1) Curtius, T.; Rissom, J.; Kraemer, G.; Vorbach, C.; Meier, H.;
Bottler, H.; Hasse, G.; Raudenbusch, W.; Tüxen, R.; Derlon,
H. J. Prakt. Chem. 1930, 125, 303.
(2) Horner, L.; Christmann, A. Angew. Chem., Int. Ed. Engl.
1963, 2, 599.
–113.2 (s, 2 F, CF2S), –121.4 (s, 2 F, CF2), –126.5 (m, 2 F, CF2).
MS (EI): m/z (%) = 544 (0.6) [M+], 261 (24) [M+ – RfSO2], 100 (99)
+
+
[N(i-Pr)2 ], 91 (100) [PhCH2 ].
(3) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
(4) Aube, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965.
Anal. Calcd for C20H25F9N2O3S: C, 44.12; H, 4.63; N, 5.15. Found:
C, 44.02; H, 4.45; N, 5.24.
Synthesis 2011, No. 7, 1142–1148 © Thieme Stuttgart · New York

1148
W. Xiong et al.
PAPER
Tetrahedron 2001, 57, 3909. (d) Xu, Y.; Zhu, S. Z.
Synthesis 2001, 690. (e) Xu, Y.; Zhu, S. Z. Tetrahedron
1999, 48, 13725. (f) Zhu, S. Z.; He, P. Tetrahedron 2005,
61, 5679. (g) Zhu, S. Z. J. Chem. Soc., Perkin Trans. 1 1994,
2077.
(5) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem. Int. Ed. 2005, 44, 5188.
(6) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127,
2038. (b) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am.
Chem. Soc. 2005, 127, 16046. (c) Cui, S. L.; Lin, X. F.;
Wang, Y. G. Org. Lett. 2006, 8, 4517. (d) Tornøe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
(e) Jin, Y.; Fu, H.; Yin, Y. W.; Jiang, Y. Y.; Zhao, Y. F.
Synlett 2007, 901. (f) Ji, Y. K.; Seok, H. K.; Chang, S.
Tetrahedron Lett. 2008, 49, 1745.
(7) (a) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem.
Int. Ed. 2006, 45, 3154. (b) Yoo, E. J.; Ahlquist, M.; Kim, S.
H.; Bae, I.; Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew.
Chem. Int. Ed. 2007, 46, 1730.
(9) Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
(10) (a) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104.
(b) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem.
Int. Ed. 2004, 43, 3368. (c) Hong, S.; Marks, T. J. Acc.
Chem. Res. 2004, 37, 673. (d) Alonso, F.; Beletskaya, I. P.;
Yus, M. Chem. Rev. 2004, 104, 3079. (e) Odom, A. L.
Dalton Trans. 2005, 225. (f) Croce, P. D.; Stradi, R.
Tetrahedron 1977, 33, 865. (g) Fioravanti, S.; Pellacani, L.;
Ricci, D.; Tardella, P. A. Tetrahedron: Asymmetry 1997, 8,
2261. (h) Xu, Y.; Wang, Y.; Zhu, S. Synthesis 2000, 513.
(i) Xu, Y.; Zhu, S. Tetrahedron 2001, 57, 4337.
(8) (a) Xu, Y.; Xu, G. L.; Zhu, S. Z.; Zhu, G. Y.; Jia, Y. S.;
Huang, Q. C. J. Fluorine Chem. 1999, 96, 79. (b) Xu, Y.;
Zhu, S. Z. Tetrahedron 2001, 57, 669. (c) Xu, Y.; Zhu, S. Z.
Synthesis 2011, No. 7, 1142–1148 © Thieme Stuttgart · New York