Preparation of trifluoromethylated ynamines and their reactions with some electrophilic reagents

Article abstract of DOI:10.1016/j.tet.2005.11.086

N,N-Dialkyl(3,3,3-trifluoro-1-propynyl)amines were prepared by a three-step procedure starting from commercially available 2,2,3,3,3-pentafluoropropanol. The reactions of these trifluoromethylated ynamines with some electrophiles, such as aldehydes, halog

Full text of DOI:10.1016/j.tet.2005.11.086

Tetrahedron 62 (2006) 3783–3793
Preparation of trifluoromethylated ynamines and their reactions
with some electrophilic reagents
*
Takashi Ishihara, Toshiya Mantani, Tsutomu Konno and Hiroki Yamanaka
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Received 14 November 2005; accepted 26 November 2005
Available online 17 February 2006
Abstract—N,N-Dialkyl(3,3,3-trifluoro-1-propynyl)amines were prepared by a three-step procedure starting from commercially available
2,2,3,3,3-pentafluoropropanol. The reactions of these trifluoromethylated ynamines with some electrophiles, such as aldehydes, halogens or
N-halosuccinimides (NXS), were investigated. The fluorinated ynamines reacted with aldehydes in the presence of a catalytic amount of
Lewis acid to provide the corresponding a-(trifluoromethyl)-a,b-unsaturated amides in good to excellent yields with high Z-stereoselectivity.
These ynamines reacted with molecular bomine to give, after treatment with sodium hydrogen carbonate, N,N-dialkyl-2-bromo-3,3,3-
trifluoropropanamides in good yields. The reaction with an equimolecular amount of NXS in aqueous acetonitrile also gave the
corresponding 2-halo-3,3,3-trifluoropropanamides in good to excellent yields. On the other hand, the reaction of the ynamine with NXS in
anhydrous acetonitrile led to the formation of the addition products in high yields. Upon treating the addition products with an equimolecular
amount of NX0S in aqueous acetonitrile, the corresponding 2,2-dihalo(X,X0)-3,3,3-trifluoropropanamides were produced in nearly
quantitative yields.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
N,N-Disubstituted-1-alkynylamines, the common name
‘ynamines,’ are regarded as the alkynes activated through
the interaction of the amino group linked directly to a triple
bond, and thereby liable to undergoing the reactions with a
variety of electrophiles. Many kinds of ynamines have
hitherto been prepared and utilized in organic synthesis.1–5
Although fluorine-containing counterparts are expected to
be useful building blocks for preparing various organo-
fluorine compounds, there are found few or no reports on
their preparations and synthetic applications6,7 in the
literature. On the other hand, the theoretical data obtained
from the MO calculations for N,N-dimethyl-3,3,3-trifluoro-
1-propynylamine as well as N,N-dimethyl-1-propynylamine
inform us with the differences in electronic states between
these ynamines, as shown in Figure 1. These situations
prompted us to develop the method for the preparation of
trifluoromethylated ynamines, N,N-dialkyl(3,3,3-trifluoro-
1-propynyl)amines (2), by use of commercially available
2,2,3,3,3-pentafluropropanol, and to examine their reacti-
vities toward several electrophilic reagents.8–12
Fig. 1. MO calculations for nonfluorinated and fluorinated ynamines.
In this paper, we wish to describe the practical methods for the
preparation of the trifluoromethylated ynamines 2 and the
results of their reactions with several electrophiles, such as
aldehydes, halogens, and N-halosuccinimides (NXS), leading
to a-(trifluoromethyl)-a,b-unsaturated amides, 2-halo-
and 2,2-dihalo-3,3,3-trifluoropropanamides, which are
Keywords: Ynamine; Carbonyl compound; Halogen; N-Halosuccinimide;
a-Trifluoromethyl-a,b-unsaturated amide; 2-Halo-3,3,3-trifluoropropana-
mide; 2,2-Dihalo-3,3,3-trifluoropropanamide; Trifluoromethylated cyclo-
butene cyanine.
*
Corresponding author. Tel.: C81 75 724 7504/7517; fax: C81 75 724
7580; e-mail: ishihara@kit.ac.jp
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.086

3784
T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
exceedingly valuable and fundamental synthons for the
construction of trifluoromethylated carbon frameworks.13–17
Scheme 2.
2. Results and discussion
2.1. Preparation of the trifluoromethylated ynamines 2
Table 1. Preparation of 2 from the tertiary amines 1
Entry
1
Base
Additive
(2.2 equiv) (2.2 equiv) (8C)
Temperature Time
(h)
Yield of
2 (%)a
N,N-Dialkyl(2,2,3,3,3-pentafluoropropyl)amines (1) were
chosen as the precursors of the trifluoromethylated
ynamines 2. The amines 1 were prepared by the two
different procedures starting from commercially available
2,2,3,3,3-pentafluoropropanol, as shown in Scheme 1. The
polyfluoro alcohol was converted into the sulfonate esters
by the reaction with o-nitrobenzenesulfonyl chloride and
NaOH in H2O at 60 8C for 2 h (98%)18 or by the reaction
with trifluoromethanesulfonic anhydride at reflux tempe-
rature for 3 h (84%).19 o-Nitrobenzenesulfonate and
trifluoromethanesulfonate were subjected to the Hofmann-
like degradation reaction with N,N-dimethylbenzylamine20
(Method A) or polyfluoroalkylation of a secondary amine
(Method B).
1
2
1a LDA
1a LDA
None
None
0
Room
2
2
14
47
temperature
Room
3
1a LDA
None
24
66
temperature
0
Room
4
5
1a LDA
1a LDA
DMPU
DMPU
2
2
84
94 (75)
temperature
Room
temperature
Room
6
7
1a BuLi
None
None
2
5
1a t-BuOK
24
23b
temperature
0
Room
8
9
1b LDA
1c LDA
DMPU
DMPU
2
2
92
97
temperature
Room
temperature
10
1d LDA
DMPU
24
66
a Measured by 19F NMR. Value in parentheses is of isolated yield.
b N,N-Dibuty(2,3,3,3-tetrafluoro-1-propenyl)amine was given in 33%
yield.
temperature and/or for a long reaction period resulted in
increasing the yields of 2a (entries 2 and 3). The use of 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)
as an additive permitted the reaction to proceed very
efficiently (entries 4 and 5). Other bases, such as
butyllithium and potassium t-butoxide, were not so useful
for the reaction (entries 6 and 7). N,N-Dialkyl(3,3,3-
trifluoropropynyl)amines 2b–d were also prepared by the
reactions of 1b–d with LDA in THF–DMPU at 0 8C or room
temperature, as shown in entries 8–10.
Scheme 1.
The degradation between o-nitrobenzenesulfonate and
dibutylamine (Method A) provided N,N-dibutyl(2,2,3,3,3-
pentafluoropropyl)amine (1a) in a lower yield (48%),
compared with the reaction using trifluoromethanesulfonate
(Method B, 93%). This trend was observed for preparing N-
(2,2,3,3,3-pentafluoropropyl)piperidine (1c) by the
reactions of o-nitrobenzenesulfonate and trifluoromethane-
sulfonate. Such trends in the yields of 1 are attributable to
the difference in reactivity between the two sulfonate esters.
Worth remarking is that the degradation reaction between
o-nitrobenzenesulfonate and excess N,N-dimethylbenzyl-
amine (3 equiv) (Method A) is recommended for obtaining
N,N-dimethyl-(2,2,3,3,3-pentafluoropropyl)amine (1b) in
good yield.20 N,N-Diisopropyl-(2,2,3,3,3-pentafluoro-
propyl)amine (1d) was obtained in 45% yield according to
Method B.
It should be mentioned that all of these ynamines 2 are
highly susceptible to hydrolysis under acidic conditions.12
Thus, on simple treatment of 2 with a 5% HCl aqueous
solution at ambient temperature for 15 min, the correspon-
ding N,N-dialkyl-3,3,3-trifluoropropanamides 4 were pro-
duced in 65–90% yields.
2.2. Reaction of the ynamines 2 with carbonyl
compounds
The reaction of 2a with benzaldehyde was initially
investigated under various conditions, as shown in
Scheme 3, and the results are summarized in Table 2.
These fluorinated amines 1 could be converted into the
desired ynamines 2 by dehydrofluorination with a base
(Scheme 2). The results are summarized in Table 1. The
reaction of 1a with lithium diisopropylamide (LDA) in
tetrahydrofuran (THF) at 0 8C for 2 h gave the ynamine 2a
in 14% yield, together with 75% of the starting amine 1a
recovered (entry 1). The reaction conducted at room
Scheme 3.

T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
Table 2. Reaction of the ynamines 2 with benzaldehyde
3785
Entry
2
Lewis
acida
Solvent
Time (h)
Yield of
3a (%)b
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
None
CH2CL2
24
1
1
1
1
1
1
1
1
24
24
24
1
3
92
28
90
80
81
84
82
82
71
65
73
40
2
BF3$OEt2 CH2CL2
BF3$OEt2 CH2CL2
ZnBr2
TiCl4
SnCl4
BF3$OEt2 Toluene
BF3$OEt2 Et2O
BF3$OEt2 THF
La(OTf)3
La(OTf)3
La(OTf)3
3c
4
CH2CL2
CH2CL2
CH2CL2
5
6
7
8
9
d
10c
11c
12c
13
CH2CL2
CH2CL2
CH2CL2
d
d
BF3$OEt2 CH2CL2
a Lewis acid (0.1 equiv) used, unless otherwise noted.
b Isolated yields.
Scheme 4.
c
˚
Without MS 4 A.
(O96% Z). Although the reaction with 2,2-dimethylpropa-
nal required 0.2 equiv of BF3$OEt2 and a longer reaction
time (2 h), the corresponding amide 3ap was given in 68%
yield as a mixture of Z/EZ56:44. A variety of ketones, such
as acetone, 3-pentanone, cyclohexanone, and acetophenone,
were also found to participate in the reaction with 2a to give
the corresponding a,b-unsaturated amides 3aq–at in
72–85% yields. All the reactions with ketones necessitated
a prolonged reaction time (2 h) for obtaining satisfactory
results. The reaction with acetophenone took place with an
appreciably low stereoselectivity to form 3at as a mixture of
Z/EZ71:29.
d La(OTf)3 (0.3 equiv) used.
The treatment of 2a with benzaldehyde in dichloromethane
˚
˚
(CH2Cl2) in the presence of molecular sieves 4 A (MS 4 A)
revealed little or no evidence of reaction. Workup of this
reaction mixture with a 5% HCl aqueous solution afforded
N,N-dibutyl-3,3,3-trifluoropropanamide (4a) and the corres-
ponding a-(trifluoromethyl)-a,b-unsaturated amide 3aa in
79 and 3% yield, respectively (entry 1). The addition of
boron trifluoride etherate (BF3$OEt2) (0.1 equiv) as a Lewis
acid promoted the reaction effectively, leading to a high
yield of the amide 3aa as an isomeric mixture of Z/EZO
˚
97:!3 (entry 2). MS 4 A was requisite to suppress the
formation of 4a, which may be based upon the acidic
hydration with a small quantity of water contaminating 2a.
The above-cited reactions of 2 with carbonyl compounds are
presumed to occur via the mechanism shown in Scheme 5,
which is essentially analogous to that proposed recently for
the reaction between alkynolates and carbonyl com-
pounds.22 Thus, the ynamine 2 may attack a carbonyl
compound activated by a Lewis acid23 to form an
intermediary oxetene. This intermediate would be subject
to a metathesis process in such a way that both the Lewis
acid part and the substituent R1 or R2 (R1OR2) exert their
repulsive interaction minimally, leading to the preferential
formation of the (Z)-isomers of 3.
19
˚
F NMR analysis of the reaction in the absence of MS 4 A
revealed the in situ formation of 4a (66%) as well as 3aa
(28%) (entry 3). Zinc bromide, titanium(IV) chloride, and
tin(IV) chloride were applicable to the reaction, giving good
yields of 3aa (entries 4–6). Toluene, diethyl ether, and THF
could be used as the solvents (entries 7–9). In addition,
lanthanum(III) triflate, known to be hard to hydrolysis,21
˚
was effective for the reaction of 2a without MS 4 A,
affording an acceptable result (entry 10). The similar
reaction of 2b or 2c with benzaldehyde in the presence of
La(OTf)3 offered the corresponding a,b-unsaturated amides
3ba and 3ca in fairly good yields with high Z-stereo-
selectivity (entries 11 and 12). The ynamine 2d reacted
reluctantly in the presence of BF3$OEt2 to give the amide
3da in 40% yield (entry 13). It is likely that the bulky
isopropyl groups on the nitrogen of 2d are responsible for
low efficiency of the reaction.
Scheme 5.
2.3. Reaction of the ynamines 2 with bromine or iodine
Next, the reactions of 2a with other aldehydes or ketones
were carried out by using BF3$OEt2 as a Lewis acid and
CH2Cl2 as a solvent (Scheme 4). Various sorts of aldehydes,
such as aromatic, heteroaromatic, a,b-unsaturated, and
aliphatic aldehydes, were made to react with 2a in the
The nonfluorinated ynamines are known to undergo the
unique reactions with bromine to give a different type of
product depending on an alkynyl substituent, as depicted in
Scheme 6. Thus, t-butylethynyl(dimethyl)amine reacts with
bromine in dioxane to afford the corresponding
allene amidinium salt,24 and the reaction of phenyl-
ethynyl(dimethyl)amine gives rise to the cyclobutene
cyanine salt.25 Such unique behaviors of the ynamines
strongly stimulated us to examine the reaction of the
fluorinated ynamines 2 with bromine.
˚
presence of 0.1 equiv of BF3$OEt2 and MS 4 A in CH2Cl2 at
room temperature for 1 h, and the usual workup provided
the corresponding a-(trifluoromethyl)-a,b-unsaturated
amides 3ab–at in 75–97% yields. Of synthetic value is
that the reactions of 2a with aldehydes, except 2,2-
dimethylpropanal, occurred in a highly stereoselective
fashion to give the (Z)-isomers of 3a predominantly

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T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
Table 3. The one-pot preparation of 6Br from 1
Entry
R
Temperature (8C)
Yield of 6Br (%)a
1
2
3
4
Bu
Me
–(CH2)5–
i-Pr
Room temperature
0
Room temperature
Room temperature
6aBr
75
64
78
37 (41)
6bBr
6cBr
6dBr
a Isolated yields. Value in parentheses stands for the recovery of 1
determined by 19F NMR.
Scheme 6.
bromo amides 6aBr–cBr in satisfactory yields, as shown
in entries 1–3, but the amine 1d having a bulky group, such
as isopropyl, gave 6dBr in a lower yield, along with the
recovery of unchanged 1d (entry 4).
As shown in Scheme 7, when the ynamine 2a was allowed
to react with bromine (1.1 equiv) in acetonitrile (MeCN) in
˚
the presence of MS 4 A at ambient temperature for 1 h, N,N-
dibutyl(1,2-dibromo-3,3,3-trifluoro-1-propenyl)amine (5a)
was formed quantitatively. Although the enamine 5a was
not so stable for isolation, its structural determination was
made by IR and 13C NMR analyses of the crude product
after filtration and concentration of the reaction mixture. 19F
NMR analysis indicated that 5a consisted of two geome-
trical isomers in a ratio of 78:22. Other solvents, such as
CH2Cl2, THF, diethyl ether, and dioxane, could also be
employed similarly. The resultant enamine 5a was readily
hydrolyzed to N,N-dibutyl-2-bromo-3,3,3-trifluoropropan-
amide (6aBr) by simple treatment with a saturated NaHCO3
aqueous solution at room temperature for 0.5 h. In order to
simplify the access to 2-bromo propanamide 6aBr, we
examined the one-pot reaction starting from 1a, the
precursor of 2a. Thus, the amine 1a was treated with LDA
(2.2 equiv) and DMPU (2.2 equiv) in THF at room
temperature for 2 h, and bromine (2.0 equiv) was succes-
sively added to the reaction mixture at 0 8C. After stirring at
room temperature for 1 h, addition of a saturated NaHCO3
aqueous solution, followed by a usual workup, led to the
amide 6aBr in 75% overall yield.
The reaction of the ynamine 2a with iodine was also
performed under the similar conditions to that with bromine.
As depicted in Scheme 9, the corresponding cyclobutene
cyanine 7a was obtained in 51% yield, no addition product
like 5a being detected in the reaction mixture. The product
7a could be isolated as a white solid and be kept for several
days at ambient temperature under argon without any
detectable changes. Interestingly, on standing for several
days in contact with air, 7a was deiodinated gradually to
form 8a. The mechanistic details of this transformation
remain obscure at the present time. Successive treatment of
the in situ formed 7a with water gave rise to 8a in 49%
overall yield.
Scheme 9.
2.4. Reaction of the ynamine 2a with NXS in a water-
containing solvent
We next examined the reaction of the ynamine 2a with
N-bromosuccinimide (NBS), which is one of the easy-
handling brominating agents,26 as shown in Scheme 10 and
Table 4. When the ynamine 2a was allowed an exposure to
NBS (1.0 equiv) in water at room temperature for 1 h, the
amide 6aBr was given in 57% yield, together with 27%
yield of the addition product 9aBr, which was a mixture of
two geometrical isomers in a ratio of 76:24 (entry 1). A
THF–H2O (3/2 v/v) mixed solvent afforded a comparable
yield of 6aBr and an increased yield of 9aBr (entry 2). With
the reaction in acetone–H2O (3/2 v/v), the yields were
appreciably decreased (entry 3). Interestingly, the use of a
carbon tetrachloride–H2O (3/2 v/v) mixed solvent, a two
phase solvent system, resulted in the formation of 9aBr in
preference to 6aBr (entry 4). Eventually, the most
satisfactory result was obtained for the reaction using a
Scheme 7.
This one-pot reaction procedure was applicable for other
amines 1b–d, as shown in Scheme 8. The results are
summarized in Table 3. The alkyl substituents at the
nitrogen atom of 1 were observed to influence the yields of
the amides 6Br. The amines 1a–c carrying a butyl, methyl
and pentamethylene group provided the corresponding
Scheme 8.
Scheme 10.

T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
3787
Table 4. Reactions of 2a with NXS in mixed solvents
formed in the reaction of 2a under aqueous conditions
(Scheme 10), are not derived from the hydrolysis of in situ
formed 9aX but from the addition of a halonium ion to the
acetylenic b-carbon of 2a followed by attack with water.
Entry
NXS
Solvent
Yield of
6aX (%)a
Yield of
9aX (%)a
1
2
3
4
5
6
7
8
NBS
NBS
NBS
NBS
NBS
NBSb
NCS
NIS
H2O
57
54
31
42
27
44
20
51
12
10
3
THF–H2O
Acetone–H2O
CCl4–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
It was further found that these addition products 9aX
reacted readily with N-halosuccinimides (NX0S) in a
MeCN–H2O mixed solvent at room temperature, leading
to high yields of the corresponding 2,2-dihalo propanamides
10aXX0, which are extremely difficult to prepare, as shown
in Scheme 11 and Table 6.
85
27, 46c
85
80
tr
a Isolated yields.
b NBS (2.0 equiv) used.
c Isolated yields of 2,2-dibromo-3,3,3-trifluoropropanamide (10aBrBr).
MeCN–H2O mixed solvent, where 6aBr was provided in
85% yield and 9aBr in 12% yield (entry 5).
With optimum conditions (entry 5) in hand, we conducted
the halogenation reaction of 2a with other N-halosuccini-
mides (NXS), such as NCS and NIS. As shown in entries 7
and 8, the reaction of 2a with NCS or NIS proceeded
efficiently to give the corresponding 2-halo amides 6aCl and
6aI in 85 and 80% yield, respectively. In both cases, the
addition product 9aCl or 9aI was formed in less than 3%
yield. The 2-chloro amide 6aCl could also be obtained in
75% yield through the reaction of 2a with aqueous sodium
hypochloride (5 equiv) in MeCN at ambient temperature for
1 h. It is very interesting that the use of 2.0 equiv of NBS
brought about the formation of N,N-dibutyl-2,2-dibromo-
3,3,3-trifluoropropanamide (10aBrBr) as a major product,
along with the products 6aBr and 9aBr (entry 6).
Scheme 11.
Table 6. Reaction of the addition products 9aX with NX0S
X0
Yield of 10aXX0 (%)a
Entry
9aX
ClCl
ClBr
BrBr
ClI
1
2
3
9aCl
9aBr
9aCl
9aBr
9aI
Cl
Br
Br
Cl
Cl
99
0
0
35
27
0
0
99
42
0
0
99
0
21
0
0
0
0
0
0
4
5b
a Isolated yields.
b The addition product 9aCl was obtained in 5% yield.
Thus, on treating 9aCl or 9aBr with NCS or NBS
(1.1 equiv) in MeCN–H2O (3/2 v/v) at room temperature
for 24 h, the corresponding 2,2-dihalo propanamides
10aClCl and 10aBrBr were obtained, respectively, in
quantitative yields (entries 1 and 2). The treatment of 9aCl
with NBS likewise gave high yield of the amide 10aClBr
carrying two different halogens at the a carbon (entry 3).
However, the reaction of 9aBr with NCS under the same
conditions led to 10aClCl, 10aClBr, and 10aBrBr in 35,
42, and 21% yields, respectively (entry 4). The reaction of
9aI with NCS gave rise to 10aClCl and 9aCl in 27 and 55%
yields, respectively, no expected product 10aClI being
formed at all (entry 5).
2.5. Reaction of the ynamine 2a with NXS in anhydrous
MeCN
Next, the reaction between 2a and NXS was investigated
under anhydrous reaction conditions. The results of the
reactions are summarized in Table 5.
Table 5. Reaction of 2a with NXS in anhydrous MeCN
Entry
NXS
Yield of
6aX (%)a
Yield of
9aX (%)a
Isomer ratio
9aX (%)b
1
2
3
NBS
NCS
NIS
tr
tr
0
99
83
66 (87)
74:26
53:47
73:27
a Isolated yields. Value in parentheses is of yield measured by 19F NMR.
b Determined by 19F NMR.
2.6.0 Mechanistic aspects for the reaction of 9aX with
NX S
A possible mechanism for the reaction of 9aX with NX0S is
as follows. As shown in Scheme 12, the addition product
9aBr reacts with chloronium ion, generated from NCS, to
form the intermediate Int-BrCl, which undergoes hydro-
lysis with water to give the product 2-bromo-2-chloro
propanamide 10aBrCl. This intermediate Int-BrCl may
also be subject to the elimination of bromonium ion to
generate 9aCl. No elimination of chloronium ion occurs on
Int-BrCl in any extent, in view of the fact that the reaction
of 9aCl with NBS led to the exclusive formation of
10aClBr (corresponding to 10aBrCl in Scheme 12), as
shown in entry 3 of Table 6. The in situ generated 9aCl may
react with chloronium ion to give the intermediate Int-ClCl,
which is hydrolyzed with water to afford the product
When 2a was allowed to react with NXS (1.0 equiv) in
˚
anhydrous MeCN in the presence of MS 4 A at room
temperature for 1 h, the corresponding addition product 9aX
was exclusively obtained in good yield as a mixture of the
geometrical isomers. Little or no 2-halo propanamide 6aX
was produced in the reaction. The addition product 9aI was
susceptible to decomposition during isolation by silica gel
column chromatography, resulting in a remarkable decrease
in an isolated yield (entry 3). To be noted is that neither
9aBr nor 9aCl was changed even when treated with a HCl
aqueous solution in MeCN–H2O (3/2 v/v) at room
temperature for 24 h, the corresponding 2-halo propan-
amides 6aBr and 6aCl being not obtained at all. These
findings strongly suggest that the 2-halo propanamides 6aX,

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T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
manner prior to use. 2,2,3,3,3-Pentafluoropropyl o-nitro-
benzenesulfonate and trifluoromethanesulfonate were pre-
pared according to the literature method18 or slightly
modified procedure.19 All reactions were carried out under
an atmosphere of argon.
3.2. Typical procedure for the preparation of the tertiary
amines 1
Method A. A mixture of o-nitrobenzenesulfonate (50.27 g,
150 mmol) and N,N-dimethylbenzylamine (60.84 g,
450 mmol) was heated with stirring at such temperatures
(140–160 8C) that in situ formed tertiary amine 1b was
constantly distilled. The collected distillate was subjected to
fractional distillation giving the amine 1b (86% yield).
Method B. A mixture of trifluoromethanesulfonate (42.32 g,
150 mmol) and dibutylamine (58.16 g, 450 mmol) was
stirred without solvent at 60 8C for 1 h. After cooling to
room temperature, the mixture was filtered to remove
dibutylammonium salt, which was washed with diethyl
ether (ca. 50 mL). The filtrate was washed successively with
5% HCl (100 mL!2) and with water (50 mL), followed by
drying over anhydrous Na2SO4, filtration, and concen-
tration. The residual oil was distilled to afford 1a (93%
yield).
Scheme 12.
10aClCl. On the other hand, 9aBr may also react with
bromonium ion, generated in situ via elimination from Int-
BrCl, to form Int-BrBr, which is hydrolyzed to give the
product 10aBrBr.
3.2.1. N,N-Dibutyl(2,2,3,3,3-pentafluoropropyl)amine
(1a). Bp 75.0–76.0 8C/20 mmHg; IR (neat) 2960, 1190,
1110 (cmK1); 1H NMR d 0.91 (t, JZ7.1 Hz, 6H), 1.22–1.49
(m, 8H), 2.57 (t, JZ7.1 Hz, 4H), 3.03 (tq, JZ15.8, 1.1 Hz,
2H); 13C NMR d 13.9, 20.2, 29.4, 53.6 (t, JZ21.8 Hz), 55.2,
115.0 (tq, JZ253.9, 35.6 Hz), 119.2 (tq, JZ35.6,
286.7 Hz); 19F NMR d K117.8 (t, JZ15.8 Hz, 2F),
K82.2 (t, JZ1.1 Hz, 3F); MS (EI) m/z (rel intensity) 261
(MC, 6), 218 (100); HRMS (EI) calcd for C11H20F5N (MC):
261.1516, found 261.1515. Anal. Calcd for C11H20F5N: C
50.57, H 7.72, N 5.36. Found: C 49.94, H 7.62, N 5.41.
It is also possible to explain the formation of 10aClCl and
9aCl in the reaction of 9aI with NCS according to this
mechanism.
3. Experimental
3.1. Measurements and materials
Infrared spectra (IR) were measured in a liquid film or KBr
disk method with a Shimadzu FTIR-8200PC spectro-
1
photometer. H and 13C NMR spectra were obtained with
GEQE-300 (300 MHz for1H and75 MHz for 13C)andBruker
3.2.2. N,N-Dimethyl(2,2,3,3,3-pentafluoropropyl)amine
1
(1b). Bp 58.0 8C; IR (neat) 2960, 1200, 1105 (cmK1); H
1
DRX-500 (500 MHz for H and 125 MHz for 13C) spec-
NMR d 2.41 (s, 6H), 2.93 (tq, JZ15.6, 1.1 Hz, 2H); 13C
NMR d 46.5, 57.8 (t, JZ22.3 Hz), 115.0 (tq, JZ254.1,
35.8 Hz), 119.1 (tq, JZ35.8, 285.6 Hz); 19F NMR d
K117.3 (t, JZ15.6 Hz, 2F), K82.2 (t, JZ1.1 Hz, 3F);
MS (EI) m/z (rel intensity) 177 (MC, 100); HRMS (EI)
calcd for C5H8F5N (MC): 177.0577, found 177.0573.
trometers in a chloroform-d (CDCl3) solution with tetra-
methylsilane as an internal reference. A JEOL JNM EX90A
(84.1 MHz) spectrometer was used to measure 19F NMR
spectra in CDCl3 using trichlorofluoromethane as an internal
standard. Mass (MS) and high resolution mass spectra
(HRMS) were taken on a Hitachi M-80B and JEOL JMS-
700 mass spectrometer by electron impact (EI) or chemical
ionization (CI) method. Melting points were obtained on a
ShimadzuMM-2micromeltingpointdeterminationapparatus
and are uncorrected. The elemental analyses of products were
carried out with a Yanaco CHN CORDER MT-5 instrument.
3.2.3. N-(2,2,3,3,3-Pentafluoropropyl)piperidine (1c). Bp
1
122.0–123.0 8C; IR (neat) 2941, 1198, 1134 (cmK1); H
NMR d 1.38–1.46 (m, 2H), 1.55–1.463 (m, 4H), 2.58 (t, JZ
5.3 Hz, 4H), 2.91 (tq, JZ15.6, 1.2 Hz, 2H); 13C NMR d
23.7, 26.0, 55.7, 57.4 (t, JZ22.0 Hz), 114.9 (tq, JZ290.1,
35.6 Hz), 119.1 (tq, JZ35.6, 286.2 Hz); 19F NMR d
K119.5 (t, JZ15.6 Hz, 2F), K84.5 (t, JZ1.2 Hz, 3F);
MS (EI) m/z (rel intensity) 217 (MC, 19), 98 (100); HRMS
(EI) calcd for C8H12F5N (MC): 217.0870, found 217.0894.
THF and diethyl ether were freshly distilled from sodium
benzophenone ketyl under argon. MeCN was distilled from
calcium hydride and stored under argon. Other solvents
were dried according to the conventional methods prior to
use. Butyllithium (a 1.6 M hexane solution) was commer-
cially available from Aldrich or Kanto Chemical Co.
Aldehydes and ketones were distilled (or vacuum distilled)
over calcium hydride or recrystallized from appropriate
solvents, and were stored under argon. All chemicals were
of reagent grade and, if necessary, were purified in the usual
3.2.4. N,N-Diisopropyl(2,2,3,3,3-pentafluoropropyl)-
amine (1d). Bp 136.0–136.5 8C; IR (neat) 2972, 1194,
1
1153 (cmK1); H NMR d 1.02 (d, JZ6.5 Hz, 12H), 2.99–
3.11 (m, 4H); 13C NMR d 20.8, 45.4 (t, JZ22.3 Hz), 49.5,
114.7 (tq, JZ252.1, 35.5 Hz), 119.6 (tq, JZ35.5,

T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
3789
286.5 Hz); 19F NMR d K120.4 (t, JZ15.6 Hz, 2F), K84.4
(s, 3F); MS (EI) m/z (rel intensity) 233 (MC, 2), 176 (100);
HRMS (EI) calcd for C9H16F5N (MC): 233.2102, found
233.1207.
product 3aa (92% yield), together with a small amount of
4a.
3.4.1. N,N-Dibutyl-(Z)-3-phenyl-2-(trifluoromethyl)-2-
1
propenamide (3aa). IR (neat) 1640 (cmK1); H NMR d
3.3. Typical procedure for the preparation
of the ynamines 2
0.94 (t, JZ7.1 Hz, 3H), 0.96 (t, JZ7.1 Hz, 3H), 1.23–1.46
(m, 4H), 1.53–1.68 (m, 4H), 3.39 (t, JZ7.9 Hz, 2H), 3.44 (t,
JZ7.6 Hz, 2H), 6.94 (s, 1H), 7.35–7.44 (m, 5H); 13C
NMR d 13.7, 13.8, 19.9, 20.1, 29.2, 30.5, 44.4, 48.5, 121.8
(q, JZ274.7 Hz), 127.5 (q, JZ32.6 Hz), 128.4, 128.9 (q,
JZ2.0 Hz), 129.4, 132.5, 137.9 (q, JZ4.1 Hz), 165.5 (q,
JZ2.1 Hz); 19F NMR d K54.7 (s, 3F); MS (EI) m/z (rel
intensity) 327 (MC, 7), 199 (100); HRMS (EI) calcd for
C18H24F3NO (MC): 327.1810, found 327.1807. Anal. Calcd
for C18H24F3NO: C 66.04, H 7.39, N 4.28. Found: C 66.48,
H 7.45, N 4.07.
To a solution of LDA (2.2 mmol) in THF (3.0 mL) was
gradually added a solution of 1a (0.262 g, 1.0 mmol) in THF
(1.0 mL) and DMPU (0.282 g, 2.2 mmol) at 0 8C under
argon. The mixture was stirred at room temperature for 2 h.
After being quenched with water, the resulting mixture was
extracted with diethyl ether (20 mL!3) and the combined
ethereal extracts were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure to leave
crude 2a, of which the yield was determined by 19F NMR
using a,a,a-trifluorotoluene as the reference. The ynamine
2a was subjected to the following reactions without any
purifications.
3.4.2. N,N-Dimethyl-(Z)-3-phenyl-2-(trifluoromethyl)-2-
propenamide (3ba). Mp 71–72 8C; IR (KBr) 1628 (cmK1);
1H NMR d 3.05 (s, 3H), 3.12 (s, 3H), 6.98 (s, 1H), 7.36–7.45
(m, 5H); 13C NMR d 34.9, 38.6, 121.7 (q, JZ274.7 Hz),
126.8 (q, JZ32.7 Hz), 128.4, 129.0, 129.6, 132.3, 138.8 (q,
JZ4.0 Hz), 165.6 (q, JZ2.3 Hz); 19F NMR d K57.7 (s,
3F); MS (EI) m/z (rel intensity) 243 (MC, 31), 199 (100);
HRMS (EI) calcd for C12H12F3NO (MC): 243.0871, found
243.0871. Anal. Calcd for C12H12F3NO: C 59.26, H 4.97, N
5.76. Found: C 59.54, H 5.03, N 5.34.
3.3.1. N,N-Dibutyl(3,3,3-trifluoro-1-propynyl)amine
(2a). Bp 36 8C/15 mmHg; IR (neat) 2361 (cmK1); 1H
NMR d 0.94 (t, JZ7.2 Hz, 6H), 1.31–1.43 (m, 4H), 1.55–
1.65 (m, 4H), 2.98 (t, JZ7.2 Hz, 4H); 13C NMR d 13.5,
19.7, 29.7, 52.6, 55.8 (q, JZ52.08 Hz), 100.5 (q, JZ
7.12 Hz), 118.3 (q, JZ255.01 Hz); 19F NMR d K46.2 (s,
3F); MS (EI) m/z (rel intensity) 221 (MC, 19), 128 (100);
HRMS (EI) calcd for C11H18F3N (MC): 221.1391, found
221.1378.
3.4.3. N,N-Pentamethylene-(Z)-3-phenyl-2-(trifluoro-
methyl)-2-propenamide (3ca). IR (neat) 1639 (cmK1);
1H NMR d 1.57–1.66 (m, 6H), 3.53–3.63 (m, 4H), 6.94 (s,
1H), 7.31–7.44 (m, 5H); 13C NMR d 24.2, 25.2, 26.0, 42.8,
48.2, 121.7 (q, JZ274.9 Hz), 126.7 (q, JZ32.6 Hz), 128.3,
128.9, 128.9, 129.4, 132.3, 138.0 (q, JZ3.2 Hz), 163.8 (q,
JZ2.4 Hz); 19F NMR d K57.7 (s, 3F); MS (EI) m/z (rel
intensity) 283 (MC, 24), 199 (100); HRMS (EI) calcd for
C15H16F3NO (MC): 283.1184, found 283.1176.
3.3.2. N,N-Dimethyl(3,3,3-trifluoro-1-propynyl)amine
(2b). IR (THF soln) 2218 (cmK1); 19F NMR (THF) d
K46.2 (s, 3F). Other spectral data could not be obtained due
to contamination with the solvent.
3.3.3. N-(3,3,3-Trifluoro-1-propynyl)piperidine (2c). IR
1
(neat) 2203 (cmK1); H NMR d 1.22 (d, JZ6.5 Hz, 12H),
3.19 (sept, JZ6.5 Hz, 4H); 13C NMR d 21.2, 52.3, 60.7 (q,
JZ51.7 Hz), 98.7 (q, JZ5.5 Hz), 118.7 (q, JZ255.1 Hz);
19F NMR d K44.8 (s, 3F).
3.4.4. N,N-Diisopropyl-(Z)-3-phenyl-2-(trifluoromethyl)-
1
2-propenamide (3da). IR (neat) 1639 (cmK1); H NMR d
1.24 (d, JZ6.4 Hz, 6H), 1.50 (d, JZ6.2 Hz, 6H), 3.41–3.60
(m, 1H), 4.11–4.30 (m, 1H), 6.86 (s, 1H), 7.35–7.46 (m, 5H);
13C NMR d 20.0, 20.2, 45.9, 51.1, 121.9 (q, JZ274.8 Hz),
128.3, 128.6 (q, JZ31.8 Hz), 128.9 (q, JZ1.9 Hz), 129.2,
132.5, 136.2 (q, JZ3.4 Hz), 164.4 (q, JZ2.2 Hz); 19F NMR d
K57.7 (s, 3F); MS (EI) m/z (rel intensity) 299 (MC, 11), 199
(100); HRMS (EI) calcd for C16H20F3NO (MC): 299.1498,
found 299.1500.
3.3.4. N,N-Diisopropyl(3,3,3-trifluoro-1-propynyl)amine
(2d). IR (neat) 2203 (cmK1); 1H NMR d 1.22 (d, JZ6.5 Hz,
12H), 3.19 (sept, JZ6.5 Hz, 4H); 13C NMR d 21.2, 52.3,
60.7 (q, JZ51.7 Hz), 98.7 (q, JZ5.5 Hz), 118.7 (q, JZ
255.1 Hz); 19F NMR d K44.8 (s, 3F).
3.4. Typical procedure for the reaction of the ynamines 2
with carbonyl compounds
3.5. Reaction of the ynamine 2a with bromine
˚
To a mixture of the ynamine 2a (1.0 mmol) and MS 4 A
To a solution of 2a (1.0 mmol) in CH2Cl2 (3.0 mL)
˚
containing MS 4 A (1.0 g) were dropwise added succes-
(1.0 g) in anhydrous MeCN was gradually added bromine
(0.320 g, 2.0 mmol) at 0 8C. After stirring at room
temperature for 1 h, a saturated NaHCO3 aqueous solution
(20 mL) was added to the mixture at room temperature and
then the resultant mixture was stirred for 0.5 h. Water
(10 mL) and diethyl ether (30 mL) were added to the
mixture. The organic layer was separated and the aqueous
layer was extracted with diethyl ether (20 mL!4). The
combined ethereal layers were washed with brine (20 mL)
and dried over anhydrous Na2SO4. After evaporating the
solvents, the residue was chromatographed on silica gel
sively benzaldehyde (1.1 mmol) and BF3$OEt2 (0.1 mmol)
at 0 8C under an argon atmosphere. After stirring at room
temperature for 1 h, the mixture was filtered to remove MS
˚
4 A. The filtrate was poured into 3% HCl (10 mL) and the
resulting mixture was extracted with CH2Cl2 (10 mL!3).
The combined organic layers were washed with brine
(20 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo to leave a residual oil, which was submitted to 19F
NMR analysis. The residual oil was chromatographed on a
silica gel column with benzene to provide analytically pure

3790
T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
with hexane–benzene (1/1) to give N,N-dibutyl-2-bromo-
3,3,3-trifluoropropanamide (6aBr) (87% yield).
3.6.2. N,N-Pentamethylene-2-bromo-3,3,3-trifluoroprop-
anamide (6cBr). Yield 78%; IR (neat) 3001, 2986, 2947,
2858, 1643, 1462, 1369, 1323, 1373, 1157, 1123, 1015, 964,
872, 853, 806, 783, 691, 656 (cmK1); 1H NMR d 1.53–1.68
(m, 6H), 3.34–3.67 (m, 4H), 4.84 (q, JZ6.2 Hz, 1H); 13C
NMR d 24.0, 25.1, 25.9, 37.2 (q, JZ32.6 Hz), 43.4, 47.6,
122.3 (q, JZ277.7 Hz), 160.3; 19F NMR d K70.7 (d, JZ
6.2 Hz, 3F).
On the other hand, after treating 2a with bromine at 0 8C for
1 h as described above, the reaction mixture was concen-
trated under reduced pressure. Hexane was added to the
resulting residue to precipitate a crude solid, which was too
labile to be purified. However, spectral analyses of this
crude solid made it possible to determine successfully the
structure of the product 5a.
3.6.3. N,N-Diisopropyl-2-bromo-3,3,3-trifluoropropan-
amide (6dBr). Yield 37%; IR (neat) 2974, 2939, 2882,
1655, 1477, 1450, 1377, 1362, 1335, 1273, 1200, 1150,
1126, 1045, 876, 799, 691, 640 (cmK1); 1H NMR d 1.29 (d,
JZ6.5 Hz, 3H), 1.27 (d, JZ7.0 Hz, 3H), 1.38 (d, JZ
6.5 Hz, 3H), 1.39 (d, JZ6.5 Hz, 3H), 3.54 (br s, 1H), 3.86
(sept, JZ6.5 Hz, 1H), 4.68 (q, JZ6.0 Hz, 1H); 13C NMR d
19.6, 20.2, 20.4, 21.1, 38.8 (q, JZ31.8 Hz), 46.9, 49.9,
122.4 (q, JZ277.8 Hz), 160.7; 19F NMR d K68.6 (d, JZ
6.0 Hz, 3F).
3.5.1. N,N-Dibutyl-2-bromo-3,3,3-trifluoropropanamide
(6aBr). Yield 87%; IR (neat) 2963, 2936, 2874, 1663, 1458,
1346, 1277, 1161, 1119, 876, 698, 671 (cmK1); 1H NMR d
0.93 (t, JZ7.5 Hz, 3H), 0.98 (t, JZ7.5 Hz, 3H) 1.26–1.73
(m, 8H), 3.19–3.54 (m, 4H), 4.77 (q, JZ6.0 Hz, 1H); 13C
NMR d 13.4, 13.5, 19.7, 19.7, 28.9, 31.1, 37.1 (q, JZ
33.1 Hz), 46.3, 48.2, 122.2 (q, JZ278.1 Hz), 161.6; 19F
NMR d K69.0 (d, JZ6.0 Hz, 3F); MS (CI) m/z (rel
intensity) 320 (MCHC2, 100), 318 (MCH, 100), 274 (38),
238 (100), 231 (52), 196 (50), 156 (55); HRMS (CI) calcd
for C11H20BrF3NO: 318.0680, found 318.0643. Anal. Calcd
for C11H19BrF3NO: C 41.52, H 6.02, N 4.40. Found: C
41.72, H 5.82, N 4.21.
3.7. Reaction of the ynamine 2a with iodine
˚
To a mixture of the ynamine 2a (1.0 mmol) and MS 4 A
(1.0 g) in anhydrous MeCN (3.0 mL) was gradually added
iodine (0.254 g, 1.0 mmol) at room temperature under argon
and the mixture was stirred for 1 h. A saturated NaHCO3
aqueous solution (20 mL) was added to the mixture at room
temperature, and the whole mixture was stirred for 0.5 h.
The solvent was removed in vacuo to leave the crude
product, whi0ch 0was recrystallized from diethyl ether to give
pure N,N,N ,N -tetrabutyl-4-iodo-2,4-bis(trifluoromethyl)-
1-cyclobutene cyanine iodide (7a) (51% yield). On standing
in contact with the atmosphere or treatin0g with water, this
salt was readily converted into N,N,N N0-tetrabutyl-2,4-
bis(trifluoromethyl)-2-cyclobutene cyanine iodide (8a).
3.5.2. N,N-Dibutyl(1,2-dibromo-3,3,3-trifluoropropenyl)-
amine (5a). Yield 99%; IR (neat) 3506, 2963, 2936, 2874,
1651, 1601, 1578, 1466, 1346, 1250, 1192, 1119, 876 (cmK1);
1H NMR d 0.90 (t, JZ7.0 Hz, 6H), 1.25–1.35 (m, 4H), 1.41–
1.51 (m, 4H), 2.68 (t, JZ7.8 Hz, 4H) for the major isomer,
2.91 (t, JZ7.3 Hz, 4H) for the minor isomer; 13C NMR d 13.6,
20.2, 29.0, 55.4, 111.1 (q, JZ35.0 Hz), 120.6 (q, JZ
273.9 Hz), 151.1 for the major isomer; 13.6, 20.2, 29.4,
53.7, 97.0 (q, JZ37.6 Hz), 121.0 (q, JZ272.1 Hz), 139.3 (q,
JZ3.8 Hz) for the minor isomer; 19F NMR d K57.5 (s, 3F) for
the major isomer, K55.3 (s, 3F) for the minor isomer.
3.7.1. N,N,N0,N0-Tetrabutyl-4-iodo-2,4-bis(trifluoro-
methyl)-2-cyclobutene cyanine iodide (7a). Yield 51%;
mp 133–1350 8C; IR (KBr) 2963, 2905, 2878, 1589, 1462,
3.6. Typical procedure for the one-pot synthesis of N,N-
dialkyl-2-bromo-3,3,3-trifluoropropanamides (6aBr–
dBr) from the tertiary amines 1
1
1315, 1250, 1153, 1126, 1080, 1061, 941, 737 (cmK1); H
NMR d 0.96 (t, JZ7.5 Hz, 6H), 0.99 (t, JZ7.5 Hz, 6H),
1.33–1.45 (m, 8H), 1.49–1.89 (m, 8H), 3.43–3.58 (m, 4H),
3.63–3.69 (m, 2H), 3.77–3.83 (m, 2H); 13C NMR d 13.3,
13.6, 19.4, 19.5, 28.6, 29.5, 43.1 (q, JZ31.2 Hz), 52.0 (q,
JZ4.1 Hz), 53.3 (q, JZ2.0 Hz), 95.7 (q, JZ41.8 Hz), 117.9
(q, JZ268.6 Hz), 121.8 (q, JZ279.2 Hz), 160.4; 19F NMR
d K52.2 (s, 3F), K63.5 (s, 3F); MS (FAB) m/z (rel
intensity) 1265 (2MKI, 100); HRMS (FAB) calcd for
C44H72F12I3N4 (2MKI): 1265.2699, found 1265.2708.
To a solution of LDA (2.2 mmol) in anhydrous THF
(2.0 mL) was dropwise added a solution of 1a (0.261 g,
1.0 mmol) in THF (1.0 mL) and DMPU (0.282 g, 2.2 mmol)
at 0 8C and the mixture was stirred at room temperature for
2 h. After addition of bromine (0.320 g, 2.0 mmol) at 0 8C,
the mixture was stirred at room temperature for 1 h. A
saturated NaHCO3 aqueous solution (30 mL) was then
added to the reaction mixture at room temperature and the
mixture was stirred for 0.5 h. This mixture was treated in the
same manner as described above to give 6aBr (75% yield).
3.7.2. N,N,N0,N0-Tetrabutyl-2,4-bis(trifluoromethyl)-2-
cyclobutene cyanine iodide (8a). Yield 49%; mp 136.5–
137.0 8C; IR (KBr) 2963, 2936, 2874, 1728, 1620, 1466,
1373, 1331, 1258, 1234, 1215, 1173, 1119, 1080, 1053, 983,
The similar reactions of other amines 1b–d provided the
corresponding 2-bromo propanamides 6bBr–dBr.
1
937, 864, 733, 652 (cmK1); H NMR d 0.93 (t, JZ7.0 Hz,
6H), 0.94 (t, JZ6.5 Hz, 6H), 1.31–1.43 (m, 8H), 1.49–1.58
(m, 2H), 1.68–1.84 (m, 4H), 1.88–1.97 (m, 2H), 3.44–3.66
(m, 8H), 6.72–6.74 (m, 1H); 13C NMR d 13.3, 13.5, 19.7,
19.7, 28.9, 29.7, 51.5 (q, JZ3.9 Hz), 54.7, 58.0 (q, JZ
30.2 Hz), 100.3 (q, JZ42.0 Hz), 117.8 (q, JZ267.7 Hz),
122.4 (q, JZ282.0 Hz), 155.8; 19F NMR d K54.5 (s, 3F),
K65.4 (d, JZ4.4 Hz, 3F); MS (FAB) m/z (rel intensity)
1013 (2MKI, 100); HRMS (FAB) calcd for C44H74F12IN4
3.6.1. N,N-Dimethyl-2-bromo-3,3,3-trifluoropropan-
amide (6bBr). Yield 64%; IR (neat) 2993, 1659, 1501,
1458, 1420, 1358, 1281, 1258, 1204, 1165, 1115, 1065, 876,
841, 691, 656 (cmK1); 1H NMR d 2.97 (s, 3H), 3.08 (s, 3H),
4.82 (q, JZ6.0 Hz, 1H); 13C NMR d 36.2, 37.2 (q, JZ
32.9 Hz), 37.7, 122.2 (q, JZ277.7 Hz), 162.1; 19F NMR d
K69.0 (d, JZ6.0 Hz, 3F).

T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
3791
(2MKI): 1013.4766, found 1013.4760. Anal. Calcd for
C22H37F6IN2: C 46.32, H 6.54, N 4.91. Found: C 45.97, H
6.23, N 4.55.
3.9.1. N-[2-Bromo-1-(N0,N0-dibutylamino)-3,3,3-tri-
fluoro-1-propenyl]succinimide (9aBr). Yield 99%; mp
55–57 8C; IR (KBr) 2962, 2936, 2874, 1732, 1605, 1462,
1381, 1346, 1273, 1169, 1115, 1053, 1003, 941, 679 (cmK1);
1H NMR d 0.91 (t, JZ7.2 Hz, 3H), 0.92 (t, JZ7.2 Hz, 3H),
1.23–1.58 (m, 8H), 2.81 (s, 4H) for the major isomer, 2.82 (s,
4H) for the minor isomer, 3.03 (t, JZ7.5 Hz, 2H), 3.07 (t, JZ
7.5 Hz, 2H); 19F NMR d K59.4 (s, 3F) for the major isomer,
K59.9 (s, 3F) for the minor isomer; MS (EI) m/z (rel intensity)
400 (MC2, 11), 398 (MC, 11), 319 (100), 299 (9), 221 (12),
220 (11), 164 (61); HRMS (EI) calcd for C15H22BrF3N2O2:
398.0817, found 398.0822. Anal. Calcd for C15H22BrF3N2O2:
C 45.13, H 5.55, N 7.02. Found: C 44.66, H 5.38, N, 6.74.
3.8. Typical procedure for the reaction of the ynamine 2a
with NXS in a water-containing solvent
To a solution of 2a (1.0 mmol) in MeCN–water (3/2 v/v,
5 mL) was added NBS (0.180 g, 1.0 mmol) at room
temperature. After stirring at room temperature for 1 h,
the mixture was extracted with diethyl ether (20 mL!4).
The combined extracts were washed with brine (20 mL),
followed by drying over anhydrous Na2SO4, filtration and
concentration in vacuo. The crude residue was purified by
column chromatography on silica gel with hexane–benzene
(1/2) to afford N,N-dibutyl-2-bromo-3,3,3-trifluoropropan-
amide (6aBr) (85% yield) and N-[2-bromo-1-(N,N-dibutyl-
amino)-3,3,3-trifluoro-1-propenyl]succinimide (9aBr)
(12% yield).
3.9.2. N-[2-Chloro-1-(N0,N0-dibutylamino)-3,3,3-tri-
fluoro-1-propenyl]succinimide (9aCl). Yield 83%; mp
44.0–45.5 8C; IR (KBr) 2963, 2936 (s), 2878, 1732, 1670,
1620, 1462, 1427, 1350, 1281, 1234, 1119, 1057, 968, 945,
683 (cmK1); 1H NMR d 0.92 (t, JZ7.5 Hz, 6H) for the major
isomer, 1.25–1.34 (m, 4H), 1.49–1.56 (m, 4H), 2.81 (br s, 4H),
3.06 (t, JZ7.5 Hz, 4H), 0.90 (t, JZ7.5 Hz, 6H) for the minor
isomer, 1.25–1.34 (m, 4H), 1.49–1.56 (m, 4H), 2.83 (br s, 4H),
3.02 (t, JZ7.5 Hz, 4H); 13C NMR d 13.8, 19.9, 28.2, 30.2,
50.1, 97.3 (q, JZ36.7 Hz), 121.9 (q, JZ269.9 Hz), 137.2,
174.7forthemajorisomer, 13.7, 19.9, 28.3, 29.9, 51.1, 97.4(q,
JZ36.7 Hz), 121.9 (q, JZ269.9 Hz), 140.0 (q, JZ2.4 Hz),
174.2 for the minor isomer; 19F NMR d K62.7 (s, 3F) for the
major isomer,K63.3(s, 3F) for theminor isomer; MS(EI)m/z
(rel intensity) 356 (MC2, 7), 354 (MC, 22), 319 (100), 313
(19), 311 (55), 277 (46), 263 (22), 229 (12), 164 (34), 162 (12),
151 (11), 57 (13); HRMS (EI) calcd for C15H22ClF3N2O2:
354.1321, found 354.1316. Anal. Calcd for C15H22ClF3N2O2:
C 50.78, H 6.25, N 7.90. Found: C 51.00, H 6.12, N 7.71.
Other 2-bromo propanamides 6aX were synthesized in a
similar manner.
3.8.1. N,N-Dibutyl-2-chloro-3,3,3-trifluoropropanamide
(6aCl). Yield 85%; IR (neat) 2963, 2936, 2874, 1670, 1458,
1350, 1281, 1165, 1119, 934, 887, 733, 687, 644 (cmK1); 1H
NMR d 0.93 (t, JZ7.2 Hz, 3H), 0.97 (t, JZ7.2 Hz, 3H),
1.26–1.43 (m, 4H), 1.50–1.61 (m, 4H), 3.25–3.47 (m, 4H),
4.85 (q, JZ6.6 Hz, 1H); 13C NMR d 13.6, 13.6, 19.8, 19.9,
29.2, 31.3, 46.5, 48.1, 49.9 (q, JZ33.4 Hz), 122.2 (q, JZ
279.6 Hz), 161.3; 19F NMR d K71.4 (d, JZ6.6 Hz, 3F); MS
(EI) m/z (rel intensity) 275 (MC2, 1), 273 (MC, 3), 238
(47), 232 (9), 230 (26), 190 (33), 188 (100), 174 (14), 156
(14); HRMS (EI) calcd for C11H19ClF3NO: 273.1107, found
273.1082. Anal. Calcd for C11H19ClF3NO: C 48.27, H 7.00,
N 5.12. Found: C 48.12, H 6.67, N, 5.12.
3.9.3. N-[2-Iodo-1-(N0,N0-dibutylamino)-3,3,3-trifluoro-
1-propenyl]succinimide (9aI). Yield 66%; mp 66–69 8C;
IR (KBr) 2963, 2939, 2874, 1728, 1639, 1585, 1462, 1339,
1250, 1165, 1096, 930, 706 (cmK1); 1H NMR d 0.90 (t, JZ
7.3 Hz, 6H), 1.21–1.34 (m, 4H), 1.47–1.55 (m, 4H), 2.76–
2.86 (m, 4H), 3.07 (t, JZ7.8 Hz, 4H); 13C NMR d 13.7,
19.9, 28.5, 29.9, 51.3, 59.9 (q, JZ37.3 Hz), 122.3 (q, JZ
268.9 Hz), 144.7 (q, JZ2.8 Hz), 174.2 for the major isomer,
13.8, 20.0, 28.2, 30.0, 51.1, 59.9 (q, JZ37.3 Hz), 122.3 (q,
JZ268.9 Hz), 144.7 (q, JZ2.8 Hz), 174.2 for the minor
isomer; 19F NMR d K54.0 (s, 3F) for the major isomer,K
56.0 (s, 3F) for the minor isomer; MS (EI) m/z (rel intensity)
446 (MC, 28), 403 (37), 347 (11), 319 (100), 278 (16), 277
(99), 238 (42), 236 (20), 235 (22), 221 (22), 196 (25), 165
(40), 164 (81), 86 (60), 84 (13), 57 (38); HRMS (EI) calcd
for C15H22F3IN2O2: 446.0678, found 446.0687.
3.8.2. N,N-Dibutyl-2-iodo-3,3,3-trifluoropropanamide
(6aI). Yield 80%; IR (neat) 2963, 2936, 2874, 1659, 1458,
1342, 1265, 1157, 1145, 1092, 664, 617 (cmK1); 1H NMR d
0.93 (t, JZ7.2 Hz, 3H), 0.98 (t, JZ7.2 Hz, 3H), 1.26–1.43
(m, 4H), 1.48–1.77 (m, 4H), 3.10–3.59 (m, 4H), 4.84 (q, JZ
6.6 Hz, 1H); 19F NMR d K66.0 (d, JZ6.6 Hz, 3F); MS (EI)
m/z (rel intensity) 365 (MC, 1), 322 (51), 280 (66), 238
(100), 209 (12), 196 (47), 156 (16), 86 (84); HRMS (EI)
calcd for C11H19F3INO: 365.0465, found 365.0463.
3.9. Typical procedure for the reaction of the ynamine 2a
with NXS in anhydrous MeCN
˚
To a mixture of 2a (1.0 mmol) and MS 4 A (1.0 g) in MeCN
3.10. Typical procedure for the reaction of 9aX with
NXS or NX0S in a MeCN–water mixed solvent
(3.0 mL) was gradually added NBS (0.180 g, 1.0 mmol) at
ambient temperature under an argon atmosphere. After
stirring for 1 h, the mixture was filtered to remove the
resulting solids and the filtrate was concentrated in vacuo.
The residue was chromatographed on silica gel using
benzene as an eluent to provide a mixture of the E and Z
isomers of N-[2-bromo-1-(N,N-dibutylamino)-3,3,3-tri-
fluoro-1-propenyl]succinimide (9aBr) (99% yield).
To a solution of 9aBr (0.399 g, 1.0 mmol) in MeCN–water
(3/2 v/v, 5 mL) was gradually added NBS (0.196 g,
1.1 mmol) and then the mixture was stirred at ambient
temperature for 24 h. After addition of water (20 mL),
the mixture was extracted with diethyl ether (10 mL!5).
The combined ethereal extracts were washed with
brine (20 mL) and dried over anhydrous Na2SO4. After
evaporating the solvents, the resulting residue was
chromatographed on silica gel with hexane–benzene
Other addition products 9aX were prepared in a similar
manner.

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T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
(1/1) to give N,N-dibutyl-2,2-dibromo-3,3,3-trifluoro-
propanamide (10aBrBr) (99% yield).
the aqueous layer was extracted with diethyl ether (20 mL!
4). The combined extracts were washed with brine (20 mL)
and dried over anhydrous Na2SO4. After evaporating the
solvents, the resultant residue was chromatographed on
silica gel with hexane–benzene (1/1) to give 6aCl (75%
yield).
The reactions between 9aX and various NXS or NX0S were
carried out in the same manner.
3.10.1. N,N-Dibutyl-2,2-dibromo-3,3,3-trifluoroprop-
anamide (10aBrBr). Yield 99%; IR (neat) 2963, 2936,
2874, 1663, 1466, 1427, 1292, 1238, 1200, 1173, 895, 814,
1
710, 664 (cmK1); H NMR d 0.87 (t, JZ7.2 Hz, 3H), 0.92
(t, JZ7.2 Hz, 3H), 1.19–1.71 (m, 8H), 3.28 (t, JZ7.5 Hz,
2H), 3.63 (t, JZ8.0 Hz, 2H); 13C NMR d 13.6, 13.7, 19.9,
20.0, 28.5, 29.4, 46.5, 49.7, 50.9 (q, JZ29.2 Hz), 121.2 (q,
JZ279.9 Hz), 159.7; 19F NMR d K70.5 (s, 3F); MS (EI)
m/z (rel intensity) 399 (MC4, 1), 397 (MC2, 2), 395 (MC, 1),
356 (52), 354 (100), 352 (55), 310 (81), 300 (17), 298 (35),
296 (17), 276 (13), 274 (14), 256 (11), 214 (15), 212 (16);
HRMS (EI) calcd for C11H18Br2F3N: 394.9707, found
394.9718. Anal. Calcd for C11H18Br2F3N: C 33.27, H 4.57,
N 3.53. Found: C 33.01, H 4.40, N 3.30.
References and notes
1. Collard-Motte, J.; Janousek, Z. Top. Curr. Chem. 1986,
130, 89.
2. Ficini, J. Tetrahedron 1976, 32, 1449.
3. Viehe, H. G. In Ynamines; Viehe, H. G., Ed.; Chemistry of
Acetylenes; Mercel Dekker: New York, 1968; Chapter 12,
pp 861–912.
4. Katrizky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63,
1455.
5. For the hetero Diels–Alder reactions, see: Ficini, J.; Krief, A.
Tetrahedron Lett. 1969, 10, 1427. Ficini, J.; Krief, A.
Tetrahedron Lett. 1970, 11, 885. Ficini, J.; Besseyre, J.;
Krief, A. Bull. Soc. Chim. Fr. 1976, 987. Myers, P. L.; Lewis,
J. W. J. Heterocycl. Chem. 1973, 10, 165. Steinhagen, H.;
Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928. For other
cycloaddition reactions, see: Nesi, R.; Giomi, D.; Papaleo, S.;
Bracci, S. J. Org. Chem. 1989, 54, 706. Nesi, R.; Giomi, D.;
Papaleo, S.; Turchi, S. Tetrahedron Lett. 1991, 32, 6223.
Sakai, N.; Funabashi, M.; Hamada, T.; Minakata, S.; Kamatsu,
M. Tetrahedron 1999, 55, 13703. Nesi, R.; Turchi, S.; Giomi,
D.; Danesi, A. Tetrahedron 1999, 55, 13809. Balsells, J.;
Vazquez, J.; Mayano, A.; Pericas, M. A.; Riera, A. J. Org.
Chem. 2000, 65, 7291. For the reactions with carbonyl
compounds, see: Guillaume, M.; Janousek, Z.; Viehe, H. G.
Synthesis 1995, 920. Wentrup, C.; Rao, V. V. R.; Frank, W.;
Fulloon, B. E.; Moloney, D. W. J.; Mosandl, T. J. Org. Chem.
1999, 64, 3608. Rainier, J. D.; Imbriglio, J. E. J. Org. Chem.
2000, 65, 7272. For the reactions with allylic alcohols or acids,
see: Wolf, V.; Kowitz, F. Justus Liebigs Ann. Chem. 1960,
638, 33. Ficini, J.; Barbara, C. Tetrahedron Lett. 1966, 7, 6425.
Ficini, J.; Lumbroso-Bader, N.; Pouliquen, J. Tetrahedron
Lett. 1968, 9, 4139.
3.10.2. N,N-Dibutyl-2-bromo-2-chloro-3,3,3-trifluoro-
propanamide (10aClBr). Yield 99%; IR (neat) 2963,
2936, 2874, 1670, 1466, 1377, 1292, 1242, 1207, 1177, 910,
1
833, 679 (cmK1); H NMR d 0.94 (t, JZ7.5 Hz, 3H), 0.99
(t, JZ7.5 Hz, 3H), 1.31–1.43 (m, 2H), 1.54–1.60 (m, 2H),
1.68–1.76 (m, 2H), 3.26–3.42 (m, 4H), 3.54–3.60 (m, 2H),
3.75–3.81 (m, 2H); 13C NMR d 13.8, 19.0, 20.0, 28.6, 29.7,
46.7, 49.2, 64.6 (q, JZ30.1 Hz), 121.3 (q, JZ281.2 Hz),
159.7; 19F NMR d K72.6 (s, 3F); MS (CI) m/z (rel intensity)
356 (MCHC4, 79), 355 (MC4, 22), 354 (MCHC2, 35),
353 (MC2, 19), 352 (MCH, 55), 310 (20), 308 (15), 274
(20), 272 (49), 238 (16), 156 (39); HRMS (CI) calcd for
C11H19BrClF3NO (MCH): 352.0291, found 352.0254.
Anal. Calcd for C11H18BrClF3NO: C 37.47, H 5.15, N
3.97. Found: C 37.51, H 5.10, N 3.91.
3.10.3. N,N-Dibutyl-2,2-dichloro-3,3,3-trifluoropropan-
amide (10aClCl). Yield 99%; IR (neat) 2963, 2878,
1674, 1466, 1431, 1381, 1250, 1215, 1180, 922, 860,
718, 691 (cmK1); 1H NMR d 0.93 (t, JZ7.5 Hz, 3H),
0.97 (t, JZ7.5 Hz, 3H), 1.32 (tq, JZ7.5, 7.5 Hz, 2H),
1.37 (tq, JZ7.5, 7.5 Hz, 2H), 1.56 (tt, JZ7.5, 7.5 Hz,
2H), 1.68 (tt, JZ7.5, 7.5 Hz, 2H), 3.32 (t, JZ7.5 Hz,
2H), 3.62 (t, JZ7.5 Hz, 2H); 13C NMR d 13.7, 19.9,
20.1, 28.7, 29.9, 46.8, 48.8, 76.9 (q, JZ30.7 Hz), 121.3
(q, JZ282.2 Hz), 159.5; 19F NMR d K75.5 (s, 3F); MS
(EI) m/z (rel intensity) 311 (MC4, 1), 309 (MC2, 2),
307 (MC, 2), 274 (31), 272 (77), 268 (18), 266 (80), 264
(90), 230 (21), 226 (45), 224 (94), 222 (100), 210 (55),
208 (70), 156 (68), 84 (18), 57 (81); HRMS (EI) calcd
for C11H18Cl2F3NO: 307.0717, found 307.0719. Anal.
Calcd for C11H18Cl2F3NO: C 42.87, H, 5.89, N 4.55.
Found: C 42.00, H 5.65, N 4.01.
6. Freear, J.; Tipping, A. E. J. Chem. Soc. C 1968, 1096.
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3.11. Reaction of the ynamine 2a with sodium
hypochloride
13. Shi, G.-Q.; Cao, Z.-Y.; Zhang, X.-B. J. Org. Chem. 1995, 60,
6608.
To a solution of the ynamine 2a (1.0 mmol) in MeCN
(2.0 mL) was gradually added aqueous sodium hypo-
chloride (5.0 mmol) at 0 8C. After stirring at room
temperature for 1 h, water (10 mL) and diethyl ether
(30 mL) were added. The organic layer was separated and
14. Yokozawa, T.; Ishikawa, N.; Nakai, T. Chem. Lett. 1987,
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T. Ishihara et al. / Tetrahedron 62 (2006) 3783–3793
3793
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23. The Lewis acid can be anticipated to coordinate
effectively with a carbonyl compound in preference to
the ynamine 2, since the basicity of 2 is definitely
18. Yamanaka, H.; Kuwabara, M.; Komori, M.; Otani, M.; Kase, K.;
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reduced by the highly electronegative nature of the
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24. Viehe, H. G. Angew. Chem., Int. Ed. Engl. 1967, 6, 767.
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