Synthesis of fluorinated allylic amines: Reaction of 2-(trimethylsilyl)ethyl sulfones and sulfoxides with fluorinated imines

Article abstract of DOI:10.1016/j.jfluchem.2007.05.006

A new synthesis of fluorinated allylamines through the reaction of 2-(trimethylsilyl)ethyl sulfones and sulfoxides (as vinyl anion equivalents) with imines and imino esters has been described. The process includes a TBAF-mediated fragmentation of 2-(trime

Full text of DOI:10.1016/j.jfluchem.2007.05.006

Journal of Fluorine Chemistry 128 (2007) 1248–1254
www.elsevier.com/locate/fluor
Synthesis of fluorinated allylic amines: Reaction of
2-(trimethylsilyl)ethyl sulfones and sulfoxides with fluorinated imines
a
a
a
Santos Fustero a,b, , Sonia Flores , Ana C. Cun˜at , Diego Jimenez ,
*
´
Carlos del Pozo a, Jorge Bueno b, Juan F. Sanz-Cervera a,b
a
´ ´
Departamento de Quımica Organica, Universidad de Valencia, E-46100 Burjassot, Spain
b
´ ´
Centro de Investigacion Prıncipe Felipe, E-46013 Valencia, Spain
Received 3 April 2007; received in revised form 8 May 2007; accepted 8 May 2007
Available online 13 May 2007
Dedicated to Prof. Kenji Uneyama on the occasion of his winning of the ACS Award.
Abstract
A new synthesis of fluorinated allylamines through the reaction of 2-(trimethylsilyl)ethyl sulfones and sulfoxides (as vinyl anion equivalents)
with imines and imino esters has been described. The process includes a TBAF-mediated fragmentation of 2-(trimethylsilyl)ethyl sulfones to afford
the desired allylic amines. When the reaction is performed with the corresponding sulfoxides, the fragmentation takes place under the addition
conditions, affording the final products in a single step.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Fluorinated allylamines; Fluorinated imines; Fluorinated imino esters; 2-(Trimethylsilyl)ethyl sulfones and sulfoxides
1. Introduction
skeleton. In this context, fluorinated imines [4], fluorinated
b-enamino phosphonates [5], fluorinated allylic mesylates [6],
and fluorinated b-aminosulfones [7] have been used to prepare
these types of derivatives.
Allylamines are remarkable structural units found in several
naturally occurring compounds [1]. This, coupled with the fact
that they are also important synthetic intermediates for the
preparation of biologically active products, has led to their
popularity as starting materials for the synthesis of a range of
useful products such as amino acids, alkaloids, and carbohy-
drate derivatives [2].
Previous work by our group has demonstrated that anions of
methyl sulfones or methyl sulfoxides 2 react with imidoyl
chlorides 1 (as fluorinated building blocks) to generate the
corresponding b-enamino sulfones or sulfoxides 3. These, in
turn, can be reduced and transformed into the desired allylic
amines 4 through a methylenation-desulfonylation reaction
sequence of the corresponding b-aminosulfones in a Julia-type
process (Scheme 1) [7].
Although much has been written on allylamines and their
applications, their fluorinated analogs have received far less
attention. The methods described to date for the preparation of
fluorinated allylamines, for example, take advantage of the two
strategies commonly used for generating fluorinated com-
pounds in general, namely the direct introduction of the CF3
moiety [3] or the use of fluorinated building blocks that can
subsequently be transformed into the desired allylic amine
Furthermore, 2-(trimethylsilyl)ethyl sulfones and sulfoxides
6 have been found to be useful synthetic equivalents of vinyl
anions [8] for the preparation of different olefins and dienes
(Kocienski olefin synthesis). This is due to the fact that the
trimethylsilyl group can be easily removed upon treatment with
fluoride ions (Fig. 1).
Taking all this into account, we proposed that the use of
fluorinatediminesinsteadofimidoylchlorideswouldprovidethe
most direct strategy for obtaining the desired allylic amines.
Additionally, the use of 2-(trimethylsilyl)ethyl sulfoxides or
sulfones in a reaction with fluorinated imines 5 (in a new
´ ´
* Corresponding author at: Departamento de Quımica Organica, Facultad de
´
´
Farmacia, Universidad de Valencia, Avda. Vicente Andres Estelles s/n, 46100
Burjassot, Valencia, Spain. Tel.: +34 963544279; fax: +34 963544939.
E-mail address: santos.fustero@uv.es (S. Fustero).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.05.006

S. Fustero et al. / Journal of Fluorine Chemistry 128 (2007) 1248–1254
1249
Scheme 1.
Scheme 4.
to produce the desired allylic amines 4a–c in good yields
(Method A) after chromatographic purification (Scheme 3).
We then extended this methodology to the corresponding
sulfoxides (Scheme 4). When we performed the addition of the
fluorinated imine 5a with the lithium anion of 2-(trimethylsi-
lyl)ethyl-p-tolyl sulfoxide 6b, the crude reaction mixture
proved to be a complex one in which it was possible to identify
the final allylamine 4a. After several isolation attempts, we
discovered that when the reaction mixture was allowed to reach
room temperature and then subjected to acidic treatment, the
allylamine could be isolated in 77% yield (Method B). Under
these conditions, aldimines 5b and 5d thus afforded the
corresponding allylic amines in good to moderate yields.
It is worth noting that under these conditions it was possible
to perform the two-step, organometallic addition-trimethylsilyl
group fragmentation sequence in a single operation, giving rise
to the final allylamines 4 directly. Furthermore, when the
workup was carried out with sodium bicarbonate instead of
acidic medium, the final allylamine was obtained as the N-
trimethylsilyl derivative 8a. This finding prompted us to
propose the explanation for this tandem process as set out in
Scheme 5. Thus, once the addition to the imine takes place, the
lithium amide intermediate can attack the silicon, thereby
starting the fragmentation process. This would explain why the
trimethylsilyl group is attached to the nitrogen after the
purification process. Nevertheless, when these conditions were
applied to the sulfone in its reaction with imine 5a, it produced a
mixture of the addition product 7a and the final allylic amine 4a
in a 3:1 ratio and in 48% overall yield. Without further
investigation, it is difficult to explain why the fragmentation
Fig. 1. 2-(TMS)ethyl sulfones and sulfoxides as vinyl anions equivalents.
application of the Kocienski methodology) would be particularly
interesting as the trimethylsilyl group suffers fragmentation
under mild conditions. As an extension of our previous work, we
thus developed a new method for the creation of allylic amines 4
by reacting 2-(trimethylsilyl)ethyl sulfones 6 with fluorinated
imines 5 [either with aldimines (R1 H) or imino esters
(R1 COOR)], followed by a TBAF-mediated fragmentation
of the 2-(trimethylsilyl)ethyl derivatives (Scheme 2). It is worth
noting that when the reaction was performed with the sulfoxide
analogs, the formation of the allylamine was achieved in a single
step, with the elimination process taking place spontaneously in
situ. Our retrosynthetic analysis for the synthesis of the
fluorinated allylic amines 4 is presented in Scheme 2.
2. Results and discussion
The first step involved the reaction of the lithium anion of 2-
(trimethylsilyl)ethyl-p-tolyl sulfone 6a, which was obtained
upon treatment with 2 equiv. of LDA, with fluorinated
aldimines 5a–c. The reaction was performed at À40 8C and,
after the aqueous workup, afforded b-aminosulfones 7a–c as a
mixture of diastereoisomers in which the anti product was
predominant (dr anti/syn > 10/1). The fragmentation of the
trimethylsilyl group was carried out with TBAF at 0 8C in THF
Scheme 2.
Scheme 3.

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S. Fustero et al. / Journal of Fluorine Chemistry 128 (2007) 1248–1254
Scheme 5.
when lithium bis(trimethylsilyl)amide was used as a base.
Unfortunately, because these amines decomposed under
purification conditions, only moderate yields of the silylated
amino acids 10 were obtained as purified products (Scheme 7).
The final fluorinated quaternary a-amino acids 4e–h were
obtained in quantitative yield by removing the TMS group with
amberlyst.
Scheme 6.
3. Conclusions
process takes place easily with sulfoxides, but with more
difficulty when a sulfone is involved.
In summary, we have developed a new and simple
methodology to access fluorinated allylic amines and fluori-
nated quaternary a-amino acids through addition of 2-
(trimethylsilyl)ethyl sulfones and sulfoxides to fluorinated
imines and imino esters. The process was more efficient when
2-(trimethylsilyl)ethyl sulfoxides were used as starting
materials since a tandem protocol involving an organometallic
addition-elimination sequence occurred spontaneously under
the normal reaction conditions to afford the final allylamine
derivatives 4 and 10 in a single step. An asymmetric version of
this protocol is currently underway in our laboratories.
As an extension of this protocol, we surmised that the
application of this tandem process to fluorinated imino esters
would convert them into quaternary fluorinated a-amino acids.
These types of derivatives are of interest because when they are
introduced into peptidic chains, they impose conformational
restrictions on the parent peptide. This introduction has thus
become a commonly used strategy to improve the biological
properties of bioactive peptides. In our work, starting imino
esters 9 were synthesized in accordance with Uneyama’s
methodology [9] by carrying out a palladium catalyzed
alcoxycarbonylation reaction with the corresponding imidoyl
iodide (which had previously been prepared through reaction of
imidoyl chloride 1 with sodium iodide), in the presence of
carbon monoxide and the corresponding alcohol (Scheme 6).
The imino esters 9 thus obtained were then were subjected to
the tandem protocol through reaction with the lithium sulfinyl
anion of 6b. In light of our previous experience, we
subsequently allowed the reaction to reach room temperature;
this gave rise to a complex reaction mixture, probably due to the
addition of both the iminic and ester functionalities. In order to
perform the chemoselective addition to the iminic function of 9,
the reaction conditions were optimized. When the reaction
temperature was kept between À50 and À30 8C, the reaction
took place in a chemoselective fashion to afford the
corresponding amino acids 10a–d with the trimethylsilyl
group attached to the nitrogen; the best results were obtained
4. Experimental
4.1. General experimental procedures
All reactions were performed with magnetic stirring in
flame-dried glassware under an argon atmosphere with dry,
distilled solvents. Tetrahydrofuran (THF) was distilled over
Na–K alloy. All other commercially obtained solvents or
reagents were used as received. All reactions were monitored
with thin layer chromatography (TLC) in which precoated 250
micron softlayer silica gel GF uniplates (Merck) were used.
TLC plates were visualized with UV light (254 nm), vanillin, or
cerium molybdate stains. Flash chromatography was performed
with the indicated solvent system on normal phase silica gel
(230–400 mesh, particle size 0.040–0.063 mm). In several
cases, all of which are clearly identified in the text, the silica gel
Scheme 7.

S. Fustero et al. / Journal of Fluorine Chemistry 128 (2007) 1248–1254
1251
for column chromatography was deactivated prior to the actual
separation through overnight treatment with a 2% solution of
triethylamine in hexane, followed by equilibration with the
solvent mixture finally employed. Yields refer to chromato-
graphically and spectroscopically pure compounds. All new
compounds were determined to be at least 95% pure by means
of NMR. All melting points were determined with an open
capillary. Chemical shifts were reported in d values relative to
6.57 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 7.18 (d,
J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H). 13C NMR
(75.5 MHz, CDCl3) d (ppm): À0.0, 11.8, 21.5, 53.4–54.5,
1
2
55.5, 61.05, 115.1, 114.4 (tq, JCF = 259 Hz, JCF = 36 Hz),
1
2
118.8 (qt, JCF = 285 Hz, JCF = 35 Hz), 128.5, 129.6, 135.5,
138.9, 145.1, 153.4. 19F NMR (282.4 MHz, CDCl3) d (ppm):
À123.27 (d, J = 270 Hz, 1F), À117.8 (d, J = 270 Hz, 1F),
À123.27 (s, 3F), HRMS Calc. for C22H28F5NO3SSi:
509.1479. Found: 509.1471.
1
either tetramethylsilane for H NMR, fluorotrichloromethane
for 19F NMR, or the solvent peak for 13C NMR. The units for
coupling constants are Hertz (Hz).
4.1.4. N-(4-Methoxyphenyl)-1-difluoro(phenyl)methyl-3-
trimethylsilyl-2-p-tolylsulfonyl-1-propanamine (7c)
The preparation of 5a, b, d [10], 5c [11], and 9c, d [9] has
been described previously.
By means of the general procedure described above, 7c was
obtained from 6a (100 mg) as a yellow oil (177 mg) in 88%
yield after flash chromatography with hexanes:ethyl acetate
4.1.1. General procedure for the condensation of 2-
(trimethylsilyl)ethyl-p-tolylsulfone 6a with fluorinated
aldimines (5a–c): synthesis of b-aminosulfones (7a–c)
A solution of 2-(trimethylsilyl)ethyl-p-tolylsulfone (6a)
(1 mmol) in 2 mL of dry THF was added dropwise to a stirred
solution of LDA (2.1 mmol) in dry THF (8 mL) under
nitrogen at 0 8C. After 15 min at the same temperature, the
yellow solution was cooled to À40 8C. A solution of N-PMP
(fluoroalkyl)imine 5 (2 mmol) in 2 mL of dry THF was then
added. After 1 h of stirring at À40 8C, the reaction was
quenched with aqueous NH4Cl and extracted with ethyl
acetate; the combined organic phases were washed with brine
and dried over anhydrous sodium sulfate. The residue
obtained after solvent evaporation was purified by means
of column chromatography with hexanes:ethyl acetate as
eluent to afford the desired N-PMP a-fluoroalkyl-b-sulfony-
lamines 7.
1
(5:1) as eluent. Major isomer: H NMR (300 MHz, CDCl3) d
(ppm): 0.05 (s, 9H), 0.8 (dd, J = 15.3 and 3.9 Hz), 0.97 (dd,
J = 15.3 and 9.0 Hz), 2.34 (s, 3H), 3.51 (ddd, J = 9.0, 3.9 and
1 Hz, 1H), 3.64 (s, 3H), 4.41–4.52 (m, 1H), 6.34 (d, J = 9.0 Hz,
2H), 6.61 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.30–
7.40 (m, 5H), 7.45 (d, J = 8.4 Hz, 2H). 13C NMR (75.5 MHz,
CDCl3) d (ppm): À0.3, 10.0, 21.2, 59.1 (q, 2JCF = 28 Hz), 55.6,
1
61.4, 114.3, 115.7, 121.9 (t, JCF = 250 Hz), 125.7, 129.4,
2
129.7, 128.3, 129.5, 133.8, 134.1 (q, JCF = 26 Hz), 140.8,
144.6, 152.7. 19F NMR (282.4 MHz, CDCl3) d (ppm): À103.3
(dd, JFF = 245 Hz, JFH = 14 Hz, 1F), À101.7 (d, JFF = 245 Hz,
1F). HRMS Calc. for C27H33F2NO3SSi: 517.1918. Found:
517.1916.
4.2. General procedures for the synthesis of allylamines
4a–d
4.1.2. N-(4-Methoxyphenyl)-1-trifluoromethyl-3-
trimethylsilyl-2-p-tolylsulfonyl-1-propanamine (7a)
4.2.1. Method A: treatment of b-aminosulfones 7a–c with
TBAF
By means of the general procedure described above, 7a
was obtained from 6a (128 mg) as a yellow oil (211 mg) in
92% yield after flash chromatography with hexanes:ethyl
At room temperature, 1.5 equiv. of n-tetrabutylammonium
fluoride (TBAF) was added to a solution of 0.3 mmol of b-
aminosulfone in anhydrous THF (3 mL) under nitrogen. The
resulting mixture was stirred for 40 min until the starting
material had been totally consumed, as indicated by TLC
monitoring. The mixture was then concentrated and the residue
was subjected to flash chromatography using hexanes:isopropyl
ether (4:1) as eluent.
1
acetate (5:1) as eluent. Major isomer: H NMR (300 MHz,
CDCl3) d (ppm): 0.12 (s, 9H), 1.05 (dd, J = 15.6 and 4.2 Hz,
1H), 1.19 (dd, J = 15.6 and 7.8 Hz, 1H), 2.40 (s, 3H), 3.56–
3.60 (m, 1H), 3.63 (d, J = 9 Hz, 1H), 4.34–4.44 (m, 1H), 6.58
(d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 7.18 (d,
J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H). 13C NMR
(75.5 MHz, CDCl3) d (ppm): À1.0, 9.7, 21.6, 56.6, (q,
4.2.2. Method B: condensation of the 2-
(trimethylsilyl)ethyl-p-tolylsulfoxide 6b with fluorinated
aldimines 5a, 5b and 5d
1
2JCF = 29 Hz), 60.8, 114.7, 115.6, 128.5 (q, JCF = 204 Hz),
129.35, 129.7, 133.3, 139.4, 145.2, 153.4. 19F NMR
(282.4 MHz, CDCl3) d (ppm): À59.2 (s, 3F). HRMS Calc.
for C21H28F3NO3SSi: 459.1511. Found: 459.1509.
A solution of 2-(trimethylsilyl)ethyl-p-tolylsulfoxide (6b)
(1 mmol) in 1 mL of dry THF was added dropwise to a stirred
solution of LDA (2.5 mmol) in dry THF (6 mL) under nitrogen
at 0 8C. After 15 min at the same temperature, the yellow
solution was cooled to À78 8C. A solution of N-PMP
(fluoroalkyl)imine 5 (1.5 mmol) in 1 mL of dry THF was then
added. After three hours, the reaction was warmed to room
temperature, quenched with HCl (3 M), and extracted with
ethyl acetate. The combined organic extracts were washed with
Na2CO3 and brine and then dried over Na2SO4. Solvent
evaporation afforded a yellow oil which was subjected to flash
4.1.3. N-(4-Methoxyphenyl)-1-(1,1,2,2,2-pentafluoroethyl)-
3-trimethylsilyl-2-p-tolylsulfonyl-1-propanamine (7b)
By means of the general procedure described above, 7b
was obtained from 6a (110 mg) as a yellow oil (185 mg) in
85% yield after flash chromatography with hexanes:ethyl
1
acetate (5:1) as eluent. Major isomer: H NMR (300 MHz,
CDCl3) d (ppm): 0.03 (s, 9H), 1.31-1.07 (m, 2H), 2.37 (s,
3H), 3.58–3.61 (m, 1H), 3. 73 (s, 3H), 4.61–4.73 (m, 1H),

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S. Fustero et al. / Journal of Fluorine Chemistry 128 (2007) 1248–1254
chromatography to afford the desired a-fluoroalkyl allylic
amines 4.
CDCl3) d (ppm): 3.82 (s, 3H), 4.67 (d, J = 6.0 Hz, 2H), 5.24 (d,
J = 10.2 Hz, 1H), 5.25 (d, J = 17.3 Hz, 1H), 5.75 (tdd, J = 17.3,
10.2 and 6.0 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.01 (d,
J = 9.0 Hz, 2H). 13C NMR (75.5 MHz, CDCl3) d (ppm): 55.4,
4.2.3. 4-Methoxyphenyl[1-trifluoromethylallyl]amine (4a)
Following the general procedures described above, 4a was
obtained as an oil in 85% yield from 7a (Method A) and in 77%
yield from 5a (Method B).
1
66.9, 114.3, 118.4 (q, JCF = 276 Hz), 120.2, 122.2, 130.0,
2
138.9, 146.2 (q, JCF = 37 Hz), 159.5, 160.0. 19F NMR
(282.4 MHz, CDCl3) d (ppm): À69.9 (s, 3F). HRMS Calc.
for C13H12F3NO3: 287.0769. Found: 287.0755.
4.2.4. 4-Methoxyphenyl[1-(1,1,2,2,2-pentafluoroethyl)
allyl]amine (4b)
Following the general procedures described above, 4b was
obtained as an oil in 81% yield from 7b (Method A) and in 60%
yield from 5b (Method B).
4.2.10. General procedure for the synthesis of the allyl
aminoesters 10a–d
LHMDS (5 mmol) in hexanes 1 M was added dropwise to
a stirred solution of 2-(trimethylsilyl)ethyl-p-tolylsulfoxide
(6b) (1 mmol) in 6 mL dry THF cooled to À10 8C. After
20 min at the same temperature, the yellow solution
was cooled to À50 8C. A solution of N-PMP(fluoroalk-
yl)iminoesters 10 (1 mmol) in 6 mL of dry THF was then
added. After three hours, the reaction (which had reached
À30 8C) was quenched with aqueous NH4Cl and worked up
in the routine fashion. Flash chromatography of the oily
residue with mixtures of hexane:ethyl ether as eluent
afforded the desired N-PMP N-trimethylsilyl fluoroalkyl
allylamino esters 10.
4.2.5. 4-Methoxyphenyl[1-
difluoro(phenyl)methylallyl]amine (4c)
Following the general procedure described above, 4c was
obtained as an oil in 76% yield from 7c (Method A).
4.2.6. 4-Methoxyphenyl[1-chlorodifluoromethylallyl]amine
(4d)
Following the general procedure described above, 4d was
obtained as an oil in 30% yield from 5d (Method B).
4.2.7. (4-Methoxyphenyl)(trimethylsilyl)[1-
trifluoromethylallyl]amine (8a)
4.2.11. 2-(Trimethylsilyl)ethyl 2-[(4-
methoxyphenyl)(trimethylsilyl)amino]-2-(trifluoromethyl)-
3-butenoate (10a)
N-Trimethylsilylamine 8a was isolated with a slightly
modified procedure of Method B. Instead of receiving acidic
treatment, the reaction was quenched with sodium bicarbonate.
Starting from 5a (141 mg), N-trimethylsilylamine 8a was
obtained as a pale yellow oil (150 mg) in 72% yield.1H NMR
(300 MHz, CDCl3) d (ppm): 0.08 (s, 9H), 3.79 (s, 3H), 4.08
(quint, J = 8.4 Hz, 1H), 5.33 (d, J = 9.6 Hz, 1H), 5.37 (d,
J = 16.8 Hz, 1H), 5.75 (dd, J = 16.8 and 9.6 Hz, 1H), 6.79 (d,
J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H). 13C NMR (75.5 MHz,
According to the general procedure described above,
86.6 mg of N-PMP (fluoroalkyl)iminoester 9a (0.25 mmol)
afforded 36 mg of N-PMP N-trimethylsilyl aminoester 10a as a
yellow oil in 32% yield. 1H NMR (300 MHz, CDCl3) d (ppm):
0.03 (s, 9H), 0.08 (s, 9H), 1.05–1.16 (m, 2H), 3.79 (s, 3H),
4.21–4.38 (m, 2H), 5.18 (d, J = 17.4 Hz, 1H), 5.22 (d,
J = 10.8 Hz, 1H), 5.47 (dd, J = 17.4 and 10.8 Hz, 1H), 6.75
(d, J = 9.3 Hz, 2H), 7.07 (d, J = 9.3 Hz, 2H). 13C NMR
(75.5 MHz, CDCl3) d (ppm): À1.6, 1.5, 17.3, 55.2, 64.4, 73.9
2
CDCl3) d (ppm): 0.22, 55.2, 62.8 (q, JCF = 28 Hz), 113.4,
120.54, 125.8 (q, 1JCF = 285 Hz), 131.8, 133.6, 135.76, 157.5.
19F NMR (282.4 MHz, CDCl3) d (ppm): À71.9 (d, 3JHF = 8 Hz,
3F). HRMS Calc. for C14H20F3NO3Si: 303.1266. Found:
303.1266.
(q, JCF = 27.7 Hz), 112.5–113.7 (m), 119.1, 124.8 (q,
2
1JCF = 285 Hz), 132.3, 134.3–132.9 (m), 136.2, 157.6, 169.4
(s). 19F NMR (282.4 MHz, CDCl3) d (ppm): À71.2 (s, 3F).
HRMS Calc. for C20H32F3NO3Si2: 447.1873. Found:
447.1860.
4.2.8. 2-(Trimethylsilyl)ethyl 3,3,3-trifluoro-2-(4-
methoxyphenylimino)propanoate (9a)
Iminoester 9a was prepared from N-PMP trifluoroimidoyl
4.2.12. Allyl 2-[(4-methoxyphenyl)(trimethylsilyl)amino]-
2-(trifluoromethyl)-3-butenoate (10b)
1
chloride 1 as a yellow oil in 66% yield. H NMR (300 MHz,
According to the general procedure described above,
71.5 mg of N-PMP (fluoroalkyl)iminoester 9b (0.25 mmol)
afforded 19.3 mg of N-PMP N-trimethylsilyl aminoester 10b
CDCl3) d (ppm): 0.00 (s, 9H), 0.87–0.93 (m, 2H), 3.81 (s, 3H),
4.25–4.30 (m, 2H), 6.89 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz,
2H). 13C NMR (75.5 MHz, CDCl3) d (ppm): À1.7, 17.1, 55.4,
1
as a yellow oil in 20% yield. H NMR (300 MHz, CDCl3) d
1
65.4, 114.3, 118.4 (q, JCF = 276 Hz), 122.4, 139.0, 146.8 (q,
(ppm): 0.03 (9H, s), 3.79 (s, 3H), 4.65–4.80 (m, 2H), 5.17 (d,
J = 17.4 Hz, 1H), 5.22 (d, J = 10.8 Hz, 1H), 5.33 (dd,
J = 10.5, 1.2 Hz, 1H), 5.44 (dd, J = 17.1, and 1.2 Hz, 1H),
5.47 (dd, J = 17.4 and 10.8 Hz, 1H), 5.99 (tdd, J = 17.1, 10.5
and 5.7 Hz, 1H), 6.76 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz,
2H). 13C NMR (75.5 MHz, CDCl3) d (ppm): 1.4, 55.3, 66.4,
2JCF = 36 Hz), 159.4, 160.5. 19F NMR (282.4 MHz, CDCl3) d
(ppm): À70.1 (s, 3F). HRMS Calc. for C15H21F3NO3Si
(M + 1): 348.1243. Found: 348.1190.
4.2.9. Allyl 3,3,3-trifluoro-2-(4-
methoxyphenylimino)propanoate (9b)
Iminoester 9b was prepared from N-PMP trifluoroimidoyl
1
chloride 1 as a yellow oil in 50% yield. H NMR (300 MHz,
2
73.1 (q, JCF = 26.2 Hz), 112.6–113.9 (m), 119.5, 120.0,
1
124.8 (q, JCF = 286 Hz), 131.0, 132.1, 132.9–134.0 (m),
136.1, 157.6, 169.0. 19F NMR (282.4 MHz, CDCl3) d (ppm):

S. Fustero et al. / Journal of Fluorine Chemistry 128 (2007) 1248–1254
1253
À71.4 (s, 3F). HRMS Calc. for C18H24NO3F3Si: 387.1478.
HRMS Calc. for C17H24F3NO3Si1: 375.1476. Found:
375.1475.
Found: 387.1476.
4.2.13. Ethyl 2-[(4-methoxyphenyl)(trimethylsilyl)amino]-
2-(trifluoromethyl)but-3-enoate (10c)
4.2.17. Allyl 2-[(4-methoxyphenyl)amino]-2-
(trifluoromethyl)-3-butenoate (4f)
1H NMR (400 MHz, CDCl3) d (ppm): 3.73 (s, 3H), 4.67 (d,
J = 5.6 Hz 2H), 5.22 (dd, J = 10.4, and 1.2 Hz, 1H), 5.27 (d,
J = 17.2, and 1.2 Hz, 1H), 5.59 (d, J = 11 Hz, 1H), 5.63 (d,
J = 17 Hz, 1H), 5.78 (tdd, J = 17.2, 10.4, and 5.6 Hz), 6.25 (dd,
J = 17 Hz, J = 10 Hz, 1H), 6.64 (d, J = 9.2 Hz, 2H), 6.72 (d,
J = 9.2 Hz. 2H).13C NMR (100.5 MHz, CDCl3) d (ppm): 55.5,
67.3, 69.1 (q, 2JCF = 27 Hz), 114.2, 118.7, 119.3, 122.8, 123.7
(q, 1JCF = 285 Hz), 128.4, 130.7, 136.8, 153.8, 167.3. 19F NMR
(282.4 MHz, CDCl3) d (ppm): À74.15 (s, 3F). HRMS Calc. for
C15H16F3NO3: 315.1082. Found: 315.1073.
According to the general procedure described above,
68.5 mg of N-PMP (fluoroalkyl)iminoester 9c (0.25 mmol)
afforded 28.5 mg of N-PMP N-trimethylsilyl aminoester 10c as
a yellow oil in 30% yield. 1H NMR (300 MHz, CDCl3) d (ppm):
0.03 (s, 9H), 1.38 (t, J = 7.2 Hz, 3H), 3.79 (s, 3H), 4.205–4.38
(m, 2H), 5.16 (d, J = 17.7 Hz, 1H), 5.22 (d, J = 10.8 Hz, 1H),
5.46 (dd, J = 17.7 Hz and 10.8 Hz, 1H), 6.76 (d, J = 9.0 Hz,
2H), 7.07 (d, J = 9.0 Hz 2H). 13C NMR (75.5 MHz, CDCl3) d
(ppm): 1.4, 13.9, 55.2, 61.9, 73.1 (q, JCF = 25.5 Hz), 112.3–
1
113.6, 119.9, 124.8 (q, JCF = 285 Hz), 132.2, 132.9–134.2,
136.2, 157.6, 169.2. 19F NMR (282.4 MHz, CDCl3) d (ppm):
À71.7 (s, 3F). HRMS Calc. for C17H24F3NO3Si: 375.1477.
Found: 375.1493.
2
4.2.18. Ethyl 2-[(4-methoxyphenyl)amino]-2-
(trifluoromethyl)-3-butenoate (4g)
1H NMR (300 MHz, CDCl3) d (ppm): 1.19 (t, J = 7.0 Hz,
3H), 3.73 (s, 3H), 3.79 (s, 1H), 4.19–4.30 (m, 2H), 5.58 (d,
J = 10.5 Hz, 1H), 5.62 (d, J = 17.4 Hz, 1H), 6.25 (dd, J = 17.4
and 10.5 Hz, 1H), 6.64 (d, J = 9.3 Hz, 2H), 6.73 (d, J = 9.3 Hz.
2H). 13C NMR (100.5 MHz, CDCl3) d (ppm): 13.7, 55.1, 63.0,
4.2.14. Benzyl 2-[(4-
methoxyphenyl)(trimethylsilyl)amino]-2-(trifluoromethyl)-
3-butenoate (10d)
According to the general procedure described above, 84 mg
of N-PMP (fluoroalkyl)iminoester 9c (0.25 mmol) afforded
35 mg of N-PMP N-trimethylsilyl aminoester 10c as a yellow
2
68.9 (q, JCF = 27 Hz), 114.1, 118.6, 122.6, 123.7 (q,
1JCF = 285 Hz), 128.5, 137.0, 153.7, 167.6. 19F NMR
(282.4 MHz, CDCl3) d (ppm): À71.6 (s, 3F). HRMS Calc.
for C14H16F3NO3: 303.1082. Found: 310.1089.
1
oil in 32% yield. H NMR (300 MHz, CDCl3) d (ppm): 0.00
(9H, s), 3.78 (s, 3H), 5.05 (d, J = 17.7 Hz, 1H), 5.16 (d,
J = 11.1 Hz, 1H), 5.23 (d, J = 12.3 Hz, 1H), 5.30 (d,
J = 12.3 Hz, 1H), 5.46 (dd, J = 17.7 Hz and 11.1 Hz, 1H),
6.73 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.39–7.41 (m,
5H). 13C NMR (100.5 MHz, CDCl3) d (ppm): 1.5, 55.2, 67.6,
4.2.19. Benzyl 2-[(4-methoxyphenyl)amino]-2-
(trifluoromethyl)-3-butenoate (4h)
1H NMR (400 MHz, CDCl3) d (ppm): 3.73 (s, 3H), 5.17 (d,
J = 12.0 Hz, 1H), 5.21 (d, J = 12.0 Hz, 1H), 5.58 (d,
J = 10.8 Hz, 1H), 5. 63 (d, J = 17.2 Hz, 1H), 6.43 (dd,
J = 17.2 and 10.8 Hz, 1H), 6.59 (d, J = 9.2 Hz, 2H), 6.68 (d,
J = 9.2 Hz, 2H), 7.15–7.18 (m, 2H), 7.28–7.32 (m, 3H). 13C
NMR (100.5 MHz, CDCl3) d (ppm): 55.5, 68.5, 69.1 (q,
2
73.2 (q, JCF = 25 Hz), 112.8- 113.8 (m), 120.1, 124.8 (q,
1JCF = 285 Hz), 128.5, 128.6, 128.6, 132.0, 133.1–133.7 (m),
134.7, 136.2, 157.6, 169.1. 19F NMR (282.4 MHz, CDCl3) d
(ppm): À71.7 (s, 3F). HRMS Calc. for C22H27F3NO3Si
(M + 1): 438.1712. Found: 438.1723.
1
2JCF = 27 Hz), 114.2, 118. 4, 122.8, 123.6 (q, JCF = 285 Hz),
4.2.15. Hydrolysis of silyl aminoesteres 10a–c: typical
procedure for the synthesis of allylaminoesters 4e–h
A solution of 0.1 mmol of N-PMP N-trimethylsilyl
fluoroalkyl allylamino esters 10 in 2 mL of anhydrous THF
was treated with Amberlyst for 15 min at room temperature.
After filtration and evaporation of the solvent, N-PMP
fluoroalkyl allylamino esters 4 were isolated in quantitative
yield.
128.2, 128,4, 128,5, 128.5, 134.5, 136.9, 153.7, 167.5. 19F
NMR (282.4 MHz, CDCl3) d (ppm): À74.3 (s, 3F). HRMS
Calc. for C19H18F3NO3: 365.1239. Found: 365.1243.
Acknowledgements
´
The authors wish to thank the Ministerio de Educacion y
Ciencia (BQU2003-01610) and the Generalitat Valenciana of
Spain (GR03-193 and GV05/079) for financial support. S.F.,
´
D.J., and C.P. thank the Ministerio de Educacion y Ciencia and
the Generalitat Valenciana of Spain for predoctoral fellowships
4.2.16. 2-(Trimethylsilyl)ethyl 2-[(4-
methoxyphenyl)amino]-2-(trifluoromethyl)-3-butenoate
(4e)
1H NMR (400 MHz, CDCl3) d (ppm): 0.02 (s, 9H), 0.92–
0.97 (m, 2H), 3.73 (s, 3H), 4.49 (brs, 1H), 4.25–4.29 (m, 2H),
5.57 (d, J = 10.8 Hz, 1H), 5.61 (d, J = 17.2 Hz, 1H), 6.24 (dd,
J = 17.2 and 10.8 Hz, 1H), 6.64 (d, J = 9.2 Hz, 2H), 6.73 (d,
J = 9.2 Hz, 2H). 13C NMR (100.5 MHz, CDCl3) d (ppm):
À1.65, 17.0, 55.5, 65.7, 68.6 (q, 2JCF = 27 Hz), 114.1, 118.6,
´
and a Ramon y Cajal contract.
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