Synthesis of α-Alkynyl-β,β,β-trifluoroalanine Derivatives by Sonogashira Cross-Coupling Reaction

Article abstract of DOI:10.1002/ejoc.200901354

An efficient route to new a-CF₃-a-amino acid derivatives bearing an arylalkynyl moiety at the a-carbon atom has been developed. The method is based on palladium-catalyzed cross-coupling of the corresponding a-propargyl (ethynyl) a- amino esters

Full text of DOI:10.1002/ejoc.200901354

FULL PAPER
DOI: 10.1002/ejoc.200901354
Synthesis of α-Alkynyl-β,β,β-trifluoroalanine Derivatives by Sonogashira
Cross-Coupling Reaction
Grigorii T. Shchetnikov,[a] Maria A. Zotova,[a] Christian Bruneau,[b] Pierre H. Dixneuf,[b]
and Sergey N. Osipov*[a]
Keywords: Amino acids / Alkynes / Cross-coupling / Peptidomimetics / Hydrogenation
An efficient route to new α-CF3-α-amino acid derivatives
bearing an arylalkynyl moiety at the α-carbon atom has been
developed. The method is based on palladium-catalyzed
cross-coupling of the corresponding α-propargyl (ethynyl) α-
amino esters with aryl halides to afford the amino acid deriv-
atives with an internal triple bond that is suitable for further
modifications.
sitions of peptides retards their proteolytic degradation, in-
duces secondary structure motifs, and improves lipophil-
icity,[8c] which enhances absorption in vivo and thus im-
proves the permeability through certain body barriers.
Therefore, the synthesis of new members of this special
class of Cα,α-disubstituted amino acids as building blocks
for specific peptide modification and as potent inhibitors
that block biologically important enzymes, is of current
interest.[9]
We have previously described highly efficient syntheses
of various α-CF3-amino acid derivatives based on addition
of different C-nucleophiles to acylimines of 3,3,3-trifluoro-
pyruvates.[10] α-Alkynyl α-CF3-amino esters obtained by
this method were successfully applied further in metal-cata-
lyzed reactions, such as ring-closing metathesis, 1,3-dipolar
cycloaddition and cyclotrimerization, to afford new families
of the corresponding proline,[11] aza-histidine[12] and pipec-
olic acid derivatives[13] (Scheme 1).
Introduction
Non-proteinogenic α-amino acids have played a crucial
role in the development of peptides and peptidomimetics as
therapeutic agents.[1] Unsaturated α-amino acids have
turned out to be especially important building blocks for
these studies due to the diverse reactivities of the multiple
bonds and their ability to introduce biologically active func-
tionalities.[2] Thus, such compounds are useful in providing
a handle for a range of transformations, especially transi-
tion-metal-mediated functionalizations.[3] Among those,
metal-catalyzed cross-coupling and metathesis-type reac-
tions including acetylene metathesis[4] have become stan-
dard tools in organic synthesis. Moreover, with the advent
of the “click chemistry” concept,[5] interest in acetylenic
amino acids has been sharply rising. Furthermore, unsatu-
rated α-amino acids currently play an important role in
peptide chemistry due to their facile incorporation into pro-
tein structures.[3]
On top of this, the introduction of fluorine or fluoroalkyl
substituents into biologically relevant compounds has be-
come an important tool in the drug discovery process.[6]
Special attention is paid to trifluoromethyl-containing com-
pounds due to the unique properties of the trifluoromethyl
group, such as high electronegativity, steric hindrance, and
hydrophobic character[7] that can greatly improve the phar-
macokinetic properties of potential drugs. Moreover, incor-
poration of α-trifluoromethyl α-amino acids[8] into key po-
[a] A. N. Nesmeyanov Institute of Organoelement compounds,
Russian Academy of Sciences,
Scheme 1. α-Alkynyl-α-CF3-amino acids derivatives in metal-cata-
lyzed transformations.
119991 Moscow, Vavilov str. 28, Russian Federation
Fax: +7-495-135-5085
E-mail: osipov@ineos.ac.ru
[b] Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Uni-
versité de Rennes 1,
Here, we disclose an efficient synthetic approach to novel
α-CF3-amino acid derivatives bearing an aromatic moiety
at the end of an alkyne chain attached to the α-carbon
atom. The derivatives were obtained by applying the Sono-
Campus de Beaulieu, 35042 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901354.
Eur. J. Org. Chem. 2010, 1587–1592
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1587

S. N. Osipov et al.
FULL PAPER
gashira cross-coupling reaction conditions to a combina-
tion of the corresponding α-ethynyl- or α-propargyl-con-
taining α-amino esters and aryl halides (Scheme 2).
Scheme 2. Cross-coupling of α-alkynyl-α-CF3-amino esters with
aryl halides.
Scheme 4. Reaction of 2a with phenyl iodide.
Results and Discussion
Synthesis of starting α-ethynyl- and α-propargyl-β,β,β-
trifluoroalaninates 2 and 3 was accomplished by addition
of either sodium acetylenide or allenylmagnesium bromide
to electrophilic imines 1. The reactions proceeded in anhy-
drous diethyl ether or tetrahydrofuran under mild condi-
tions to give the corresponding amino esters in moderate
to good yields (Scheme 3). Some of these compounds were
previously described in short communications as mentioned
above.[11–13] Here we give some additional examples
(Table 1), and provide detailed experimental procedures for
all products and their full characterizations (see Exp. Sect.).
Variation of solvent (THF, Et2O, MeCN), organic base
(Et2NH, iPr2NEt), catalyst [PdCl2(MeCN)2, Pd(PPh3)4]
and reaction temperature did not significantly influence the
ratio of 4a and 6 formed in the reaction. However, we were
pleased to find that formation of the homo-coupled deriva-
tive 6 could be almost completely suppressed (Ͻ5%, 19F
NMR spectroscopic analysis) by adding a solution of alk-
yne 2a in DMF over period of one hour to the iodo-
benzene/catalyst solution in the same solvent; this pro-
cedure allowed the Sonogashira product 4a to be isolated
in a yield of 80%. The reaction was complete in three hours
at ambient temperature. These conditions proved to be suit-
able for the cross-coupling of functionalized aryl iodides
with other α-propargyl (and ethynyl)-α-amino acid deriva-
tives bearing a range of protecting groups. The nature of
the substituents on the benzene ring did not significantly
affect the outcome of the reaction (Scheme 5, Table 2).
Scheme 3. Synthesis of α-ethynyl(propargyl) trifluoroalaninates 2
and 3.
Table 1. α-Ethynyl(propargyl) trifluoroalaninates 2 and 3.
Entry
PG
Product
Yield [%]
1
2
3
4
5
6
Boc
Cbz
SO2Ph
Boc
Cbz
2a
2b
2c
3a
3b
3c
69
54
55
64
67
61
Scheme 5. Coupling of α-ethynyl(propargyl) trifluoroalaninates
with aryl halides.
SO2Ph
Investigations into the palladium-catalyzed cross-cou-
The cross-coupling of N-Boc-protected α-propargyl α-
pling of alkynyl-containing amino esters with aryl halides amino ester 2a with aryl bromide required heating at 80 °C
commenced with the reaction of Boc-protected propargyl- and went to completion within two hours to give 4e in poor
alaninate 2a with iodobenzene. Application of conventional yield (entry 6). In this case, homo-coupled compound 6 was
conditions for Sonogashira-type coupling initially gave un- isolated as the major product in 35% yield. In the case of
satisfactory results. Thus, the reaction of 2a with iodo- 5-bromopyrimidine (entry 9), none of the corresponding
benzene performed at room temperature in dichlorometh- product 4h was detected when the reaction was performed
ane, in the presence of PdCl2(PPh3)2 (5 mol-%), copper either at room temperature or under heating at 80 °C for
iodide (5 mol-%) and an excess of triethylamine (5 equiv.), eight hours.
lead to the desired product 4a in just 35% yield after col-
To demonstrate one of the possible further synthetic ap-
umn chromatography. Comparable amounts of the homo- plications of the new amino esters, we performed palla-
coupled derivative 6 (32%), presumably arising from a Gla- dium-catalyzed hydrogenation of the internal triple bond to
ser-type coupling,[14] was also isolated as a byproduct afford two homologues of α-CF3-phenylalanine (7 and 8),
(Scheme 4).
in excellent yields (Scheme 6).
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Eur. J. Org. Chem. 2010, 1587–1592

Synthesis of α-Alkynyl-β,β,β-trifluoroalanine Derivatives
with UV light or spraying with Ce(SO4)2 solution in 5% H2SO4.
Flash chromatography was carried out using Merck silica gel 60
(230–400 mesh ASTM) and ethyl acetate/petroleum ether as eluent.
NMR spectra were obtained with Bruker AV-300, AV-400, or AV-
600 spectrometers operating at 300, 400, or 600 MHz, respectively,
for 1H (TMS reference), at 75, 100, or 150 MHz for 13C, and at
288 MHz for 19F (CF3COOH reference).
Table 2. Coupling of α-ethynyl(propargyl) trifluoroalaninates 2 and
3 with aryl halides.
General Procedure for the Synthesis of 2a–c: Allenylmagnesiumbro-
mide,[15] obtained from magnesium (30 mmol) and propargyl bro-
mide (20 mmol) in the presence of HgCl2 (5 mol-%) in diethyl ether
(30 mL), was added dropwise to a stirred solution of an imine
(10.0 mmol) in dry ether (25 mL) at –78 °C. After 1 h at –70 °C the
reaction mixture was warmed to r.t. over 2 h. The reaction was
quenched with sat. NH4Cl and extracted with diethyl ether
(2ϫ25 mL). The combined organic layer was washed with brine
(25 mL), dried with Na2SO4, and filtered. The solvent was removed
under reduced pressure, and the crude product was purified by
flash chromatography (ethyl acetate/hexanes).
Methyl 2-[(tert-Butoxycarbonyl)amino]-2-(trifluoromethyl)pent-4-
ynoate (2a): Yield: 69%; m.p. 70–71 °C. 1H NMR (300.13 MHz,
CDCl3): δ = 1.51 [s, 9 H, C(CH3)3], 2.11 (t, J = 2.5 Hz, 1 H, ϵCH),
3.16 (dd, J = 16.9, J = 2.5 Hz, 1 H, CH2), 3.76 (m, 1 H, CH2), 3.95
(s, 3 H, OCH3), 5.75 (br. s, 1 H, NH) ppm. 19F NMR (282.4 MHz,
CDCl3): δ = 3.40 (s, 3 F, CF3) ppm. 13C NMR (150.93 MHz,
[a] After column chromatography on silica gel (hexanes/ethyl ace-
tate). [b] Reactions were performed at 80 °C.
2
CDCl3): δ = 20.84, 28.12, 54.24, 64.59 (q, JC–F = 28.8 Hz), 72.13,
1
76.34, 80.97, 123.38 (q, JC–F = 288.6 Hz), 153.23, 166.33 ppm.
C12H16F3NO4 (295.26): calcd. C 48.82, H 5.46, N 4.74; found C
48.74, H 5.47, N 4.68.
Methyl
2-[(Benzyloxycarbonyl)amino]-2-(trifluoromethyl)pent-4-
1
ynoate (2b): Yield: 54%; oil. H NMR (300.13 MHz, CDCl3): δ =
2.09 (t, J = 2.5 Hz, 1 H, ϵCH), 3.18 (dd, J = 16.2, J = 2.5 Hz, 1
H, CH2), 3.85 (m, 1 H, CH2), 3.95 (s, 3 H, OCH3), 5.18 (dAB, J =
12.2 Hz, 1 H, OCH2), 5.24 (dAB, J = 12.2 Hz, 1 H, OCH2), 6.12
(br. s, 1 H, NH), 7.42 (m, 5 H, ArH) ppm. 19F NMR (282.4 MHz,
CDCl3): δ = 3.38 (s, 3 F, CF3) ppm. 13C NMR (150.93 MHz,
2
CDCl3): δ = 20.69, 54.45, 64.87 (q, JC–F = 28.8 Hz), 67.29, 72.45,
76.03, 123.30 (q, 1JC–F = 288.6 Hz), 128.14, 128.34, 128.57, 135.85,
153.91, 166.04 ppm. C15H14F3NO4 (329.28): calcd. C 54.71, H 4.29,
N 4.25; found C 55.12, H 4.68, N 4.24.
Scheme 6. Hydrogenation of 4a and 5c.
Conclusions
Methyl 2-[(Phenylsulfonyl)amino]-2-(trifluoromethyl)pent-4-ynoate
(2c): Yield: 55%; m.p. 94–95 °C. H NMR (300.13 MHz, CDCl3):
1
In summary, we have developed an efficient method with
which to synthesize new α-CF3-α-amino acid derivatives
comprising an arylalkynyl moiety at the α-carbon atom
through palladium-catalyzed Sonogashira cross-coupling of
the corresponding α-propargyl (ethynyl) α-amino esters
with aryl halides. Various N-protected amino esters, which
are potentially applicable in a number of pharmaceutical
and biochemical areas, were conveniently obtained in mod-
erate to excellent yields. Their synthetic application in ru-
thenium-catalyzed cyclotrimerization to produce previously
unknown bicyclic amino acid derivatives is under current
investigation.
δ = 2.05 (t, J = 2.3 Hz, 1 H, ϵCH), 3.18 (dd, J = 17.0, J = 2.3 Hz,
1 H, CH2), 3.59 (dd, J = 17.0, J = 2.3 Hz, 1 H, CH2), 3.94 (s, 3 H,
OCH3), 6.0 (s, 1 H, NH), 7.53–7.66 (m, 3 H, ArH), 7.97 (d, J =
7.8 Hz, 2 H, ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ = 4.38
(s, 3 F, CF3) ppm. 13C NMR (150.93 MHz, CDCl3): δ = 22.02,
2
1
54.72, 67.20 (q, JC–F = 28.8 Hz), 73.10, 75.67, 122.49 (q, JC–F
=
288.6 Hz), 126.97, 128.80, 132.86, 141.55, 165.54 ppm.
C13H12F3NO4S (335.30): calcd. C 46.57, H 3.61, N 4.18; found C
46.51, H 3.54, N 4.11.
General Procedure for the Synthesis of 3a–c: Sodium acetylide
(17.5 mmol, 18% solution in xylol) was added dropwise to a solu-
tion of CF3-imine (17.0 mmol) in anhydrous THF (60 mL) at
–78 °C. The reaction mixture was warmed to r.t. over a period of
2 h, treated with 1  HCl (50 mL) and extracted with diethyl ether
(2ϫ30 mL). The combined organic layer was washed with brine
(50 mL) and dried with MgSO4. The solvent was removed under
reduced pressure and the crude product was purified by column
chromatography on silica gel (hexanes/ethyl acetate).
Experimental Section
General: All solvents used in reactions were freshly distilled from
appropriate drying agents before use. All other reagents were
recrystallized or distilled as necessary. Reactions were performed
under an atmosphere of dry argon. Analytical TLC was performed
with Merck silica gel 60 F254 plates; visualization was accomplished
Methyl
2-[(tert-Butoxycarbonyl)amino]-2-(trifluoromethyl)but-3-
1
ynoate (3a): Yield: 64%; oil. H NMR (300.13 MHz, CDCl3): δ =
Eur. J. Org. Chem. 2010, 1587–1592
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S. N. Osipov et al.
FULL PAPER
1.51 [s, 9 H, C(CH3)3], 2.71 (s, 1 H, ϵCH), 3.97 (s, 3 H, OCH3), Methyl
2-[(Benzyloxycarbonyl)amino]-5-(2-methylphenyl)-2-(tri-
5.51 (br. s, 1 H, NH) ppm. 19F NMR (282.4 MHz, CDCl3): δ =
2.65 (s, 3 F, CF3) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 28.05,
fluoromethyl)pent-4-ynoate (4c): Yield: 88%; oil. 1H NMR
(600.22 MHz, CDCl3): δ = 2.33 (s, 3 H, CH3), 3.40 (dAB, J =
16.4 Hz, 1 H, CH2), 3.94 (s, 3 H, OCH3), 4.12 (dAB, J = 16.4 Hz,
1 H, CH2), 5.13 (dAB, J = 12.1 Hz, 1 H, OCH2), 5.20 (dAB, J =
12.1 Hz, 1 H, OCH2), 6.12 (br. s, 1 H, NH), 7.12 (t, J = 7.6 Hz, 1
H, ArH), 7.19 (d, J = 7.6 Hz, 1 H, ArH), 7.23 (t, J = 7.6 Hz, 1 H,
ArH), 7.28–7.36 (m, 6 H, ArH) ppm. 19F NMR (282.4 MHz,
CDCl3): δ = 3.61 (s, 3 F, CF3) ppm. 13C NMR (150.93 MHz,
CDCl3): δ = 20.56, 21.72, 54.53, 65.18 (q, JC–F = 28.8 Hz), 67.22,
83.18, 85.08, 122.41, 123.41 (q, JC–F = 287.5 Hz), 125.51, 128.10,
128.31, 128.37, 128.56, 129.4, 132.1, 135.81, 140.27, 153.9, 166.38
ppm. C22H20F3NO4 (419.40): calcd. C 63.00, H 4.81, N 3.34; found
C 63.07, H 4.74, N 3.33.
2
54.45, 59.98 (q, JC–F = 28.7 Hz), 73.56, 75.87, 82.11, 121.93 (q,
1JC–F = 287.5 Hz), 152.96, 163.32 ppm. C11H14F3NO4 (281.23):
calcd. C 46.98, H 5.02, N 4.98; found C 46.68, H 5.00, N 4.62.
Methyl
2-[(Benzyloxycarbonyl)amino]-2-(trifluoromethyl)but-3-
ynoate (3b):[16] Yield: 67%; oil. H NMR (300.13 MHz, CDCl3): δ
= 2.75 (s, 1 H, ϵCH), 3.95 (s, 3 H, OCH3), 5.19 (dAB, J = 12.0 Hz,
1 H, OCH2), 5.23 (dAB, J = 12.0 Hz, 1 H, OCH2), 5.88 (br. s, 1 H,
NH), 7.42 (m, 5 H, ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ
= 2.77 (s, 3 F, CF3) ppm. 13C NMR (150.93 MHz, CDCl3): δ =
1
2
1
2
54.71, 59.98 (q, JC–F = 32.07 Hz), 67.90, 72.99, 76.45, 121.87 (q,
1JC–F = 287.0 Hz), 128.37, 128.53, 128.62, 135.36, 153.7, 163.07
ppm. C14H12F3NO4 (315.25): calcd. C 53.34, H 3.84, N 4.44; found
C 53.31, H 3.88, N 4.37.
Methyl 2-[(tert-Butoxycarbonyl)amino]-5-(2-methoxyphenyl)-2-(tri-
fluoromethyl)pent-4-ynoate (4d): Yield: 71%; solid; m.p. 97–98 °C.
1H NMR (600.22 MHz, CDCl3): δ = 1.47 [s, 9 H, C(CH3)3], 3.41
(dAB, J = 17.2 Hz, 1 H, CH2), 3.83 (m, 1 H, CH2), 3.92 (s, 3 H,
OCH3), 3.95 (s, 3 H, OCH3), 5.90 (br. s, 1 H, NH), 6.88 (d, J =
8.2 Hz, 1 H, ArH), 6.90 (t, J = 7.6 Hz, 1 H, ArH), 7.30 (dt, J =
8.47, J = 1.61 Hz, 1 H, ArH), 7.4 (dd, J = 7.6, J = 1.4 Hz, 1 H,
ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ = 3.89 (s, 3 F, CF3)
ppm. 13C NMR (150.93 MHz, CDCl3): δ = 22.70, 28.15, 53.96,
Methyl 2-[(Phenylsulfonyl)amino]-2-(trifluoromethyl)but-3-ynoate
(3c): Yield: 61%; solid; m.p. 117–118 °C. H NMR (400.13 MHz,
1
CDCl3): δ = 2.56 (s, 1 H, ϵCH), 3.87 (s, 3 H, OCH3), 5.88 (br. s,
1 H, NH), 7.47–7.60 (m, 3 H, ArH), 7.92 (d, J = 7.6 Hz, 2 H, ArH)
ppm. 19F NMR (282.4 MHz, CDCl3): δ = 2.00 (s, 3 F, CF3) ppm.
13C NMR (150.92 MHz, CDCl3): δ = 55.32, 61.02 (q, JC–F
=
2
33.2 Hz), 69.87, 80.09, 121.26 (q, 1JC–F = 287.5 Hz), 127.82, 128.84,
133.33, 140.12, 163.94 ppm. C12H10F3NO4S (321.27): calcd. C
44.86, H 3.14, N 4.36; found C 44.61, H 2.97, N 4.17.
2
55.71, 64.45 (q, JC–F = 27.6 Hz), 77.11, 80.81, 85.58, 110.63,
111.97, 120.36, 123.63 (q, JC–F = 287.5 Hz), 129.72, 133.41,
1
153.44, 160.26, 166.59 ppm. C19H22F3NO5 (401.38): calcd. C 56.86,
H 5.52, N 3.49; found C 56.89, H 5.41, N 3.52.
General Procedure for the Cross-Coupling Reaction: A mixture of
PdCl2(PPh3)2 (0.017 mmol), CuI (0.034 mmol), Et3N (0.25 mL),
and aryl halide (0.4 mmol) was stirred in degassed DMF (4 mL)
Methyl 2-[(tert-Butoxycarbonyl)amino]-5-(4-methoxyphenyl)-2-(tri-
fluoromethyl)pent-4-ynoate (4e): Yield: 76%; oil. 1H NMR
(300.13 MHz, CDCl3): δ = 1.46 [s, 9 H, C(CH3)3], 3.29 (dAB, J =
16.9 Hz, 1 H, CH2), 3.80 (s, 3 H, OCH3), 3.81 (m, 1 H, CH2), 3.91
(s, 3 H, OCH3), 5.74 (br. s, 1 H, NH), 6.82 (d, J = 8.6 Hz, 2 H,
ArH), 7.30 (d, J = 8.6 Hz, 2 H, ArH) ppm. 19F NMR (282.4 MHz,
CDCl3): δ = 4.09 (s, 3 F, CF3) ppm. 13C NMR (100.61 MHz,
for 30 min.
A solution of alkynyl-containing amino ester
(0.34 mmol) in the same solvent (2 mL) was added over a period
of 1 h to the above catalyst/aryl halide solution, and the resulting
mixture was stirred at r.t. until the starting alkyne had completely
disappeared (ca. 3 h, detection by TLC analysis). Methylene chlo-
ride (30 mL) was added and the mixture was treated with 5%
NaHCO3 (20 mL). The organic layer was washed with water
(2ϫ10 mL), separated and dried with MgSO4. After removing sol-
vent under reduced pressure the crude product was purified by col-
umn chromatography on silica gel with ethyl acetate/hexanes as
eluent.
2
CDCl3): δ = 21.97, 28.02, 53.97, 55.13, 64.64 (q, JC–F = 28.7 Hz),
1
79.77, 80.82, 83.98, 113.74, 114.76, 123.43 (q, JC–F = 287.6 Hz),
133.01, 153.21, 159.49, 166.46 ppm. C19H22F3NO5 (401.38): calcd.
C 56.86, H 5.52, N 3.49; found C 56.64, H 5.61, N 3.78.
Methyl
2-[(tert-Butoxycarbonyl)amino]-5-(2-nitrophenyl)-2-(tri-
Methyl 2-[(tert-Butoxycarbonyl)amino]-5-phenyl-2-(trifluoromethyl)-
pent-4-ynoate (4a): Yield: 80%; oil. 1H NMR (300.13 MHz,
CDCl3): δ = 1.52 [s, 9 H, C(CH3)3], 3.37 (dAB, J = 16.8 Hz, 1 H,
CH2), 3.92 (m, 1 H, CH2), 3.97 (s, 3 H, OCH3), 5.80 (br. s, 1 H,
NH), 7.32–7.38 (m, 3 H, ArH), 7.40–7.45 (m, 2 H, ArH) ppm. 19F
fluoromethyl)pent-4-ynoate (4f): Yield: 72%; oil. 1H NMR
(300.13 MHz, CDCl3): δ = 1.49 [s, 9 H, C(CH3)3], 3.48 (dAB, J =
17.2 Hz, 1 H, CH2), 3.92 (m, 1 H, CH2), 4.00 (s, 3 H, OCH3), 3.91
(s, 3 H, OCH3), 5.90 (br. s, 1 H, NH), 7.50 (m, 1 H, ArH), 7.61 (d,
J = 4.4 Hz, 2 H, ArH), 8.07 (d, J = 8.1 Hz, 1 H, ArH) ppm. 19F
NMR (282.4 MHz, CDCl3): δ = 3.61 (s, 3 F, CF3) ppm. 13C NMR
NMR (282.4 MHz, CDCl3): δ = 3.38 (s, 3 F, CF3) ppm. 13C NMR
(75.46 MHz, CDCl3): δ = 22.28, 28.10, 54.38, 64.67 (q, JC–F
2
(100.61 MHz, CDCl3): δ = 22.04, 28.15, 54.16, 64.80 (q, JC–F
=
2
=
28.7 Hz), 81.00, 81.56, 84.25, 122.79, 123.52 (q, 1JC–F = 288.5 Hz),
128.24, 128.30, 131.73, 153.34, 166.54 ppm. C18H20F3NO4
(371.36): calcd. C 58.22, H 5.43, N 3.77; found C 58.65, H 5.44, N
3.68.
28.7 Hz), 79.18, 80.98, 90.42, 118.09, 123.41 (q, 1JC–F = 288.2 Hz),
124.55, 128.76, 132.77, 134.94, 150.00, 153.41, 166.16 ppm.
C18H19F3N2O6 (416.35): calcd. C 51.93, H 4.60, N 6.73; found C
52.10, H 4.81, N 6.67.
Methyl 2-[(Benzyloxycarbonyl)amino]-5-phenyl-2-(trifluoromethyl)-
pent-4-ynoate (4b): Yield: 75%; oil. 1H NMR (300.13 MHz, Methyl
2-[(Benzyloxycarbonyl)amino]-5-pyridin-2-yl-(trifluoro-
CDCl3): δ = 3.40 (dAB, J = 16.9 Hz, 1 H, CH2), 3.95 (s, 3 H, methyl)pent-4-ynoate (4g): Yield: 83%; oil. 1H NMR (300.13 MHz,
OCH3), 4.08 (dAB, J = 16.9 Hz, 1 H, CH2), 5.15 (dAB, J = 12.2 Hz, CDCl3): δ = 3.40 (dAB, J = 17.0 Hz, 1 H, CH2), 3.91 (s, 3 H,
1 H, OCH2), 5.27 (dAB, J = 12.2 Hz, 1 H, OCH2), 6.22 (br. s, 1 H, OCH3), 4.00 (dAB, J = 17.0 Hz, 1 H, CH2), 5.11 (dAB, J = 12.3 Hz,
NH), 7.31–7.41 (m, 10 H, ArH) ppm. 19F NMR (282.4 MHz,
1 H, OCH2), 5.21 (dAB, J = 12.3 Hz, 1 H, OCH2), 6.18 (br. s, 1 H,
NH), 7.19–7.38 (m, 7 H, ArH), 7.58 (dt, J = 7.8, J = 1.8 Hz, 1 H,
CDCl3): δ = 3.63 (s, 3 F, CF3) ppm. 13C NMR (150.93 MHz,
2
CDCl3): δ = 21.79, 54.42, 64.15 (q, JC–F = 28.8 Hz), 67.22, 81.30, ArH), 8.54 (d, J = 4.3 Hz, 1 H, ArH) ppm. 19F NMR (282.4 MHz,
84.48, 122.65, 123.51, (q, 1JC–F = 288.6 Hz), 128.09, 128.30, 128.42,
CDCl3): δ = 4.07 (s, 3 F, CF3) ppm. 13C NMR (150.93 MHz,
2
128.59, 131.82, 135.98, 154.07, 166.32 ppm. C21H18F3NO4 CDCl3): δ = 21.71, 54.58, 64.83 (q, JC–F = 28.8 Hz), 67.25, 81.78,
(405.37): calcd. C 62.22, H 4.48, N 3.46; found C 62.34, H 4.41, N
3.36.
83.72, 123.03, 123.32, (q, 1JC–F = 287.5 Hz), 127.44, 128.17, 128.28,
128.56, 135.87, 136.14, 142.66, 149.88, 154.03, 166.07 ppm.
1590
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Eur. J. Org. Chem. 2010, 1587–1592

Synthesis of α-Alkynyl-β,β,β-trifluoroalanine Derivatives
C20H17F3N2O4 (406.36): calcd. C 59.11, H 4.22, N 6.89; found C
59.29, H 4.15, N 6.96.
H, OCH3), 3.90 (s, 3 H, OCH3), 5.51 (br. s, 1 H, NH), 6.85 (d, J
= 8.4 Hz, 1 H, ArH), 6.89 (t, J = 7.5 Hz, 1 H, ArH), 7.32 (dt, J =
9.0, J = 1.8 Hz, 1 H, ArH), 7.41 (dd, J = 7.5, J = 1.5 Hz, 1 H,
ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ = 2.85 (s, 3 F, CF3)
ppm. 13C NMR (150.92 MHz, CDCl3): δ = 28.05, 54.01, 55.83,
Methyl 2-[(tert-Butoxycarbonyl)amino]-4-phenyl-2-(trifluoromethyl)-
but-3-ynoate (5a): Yield: 77%; m.p. 112–113 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 1.52 [s, 9 H, C(CH3)3], 3.98 (s, 3 H,
OCH3), 5.56 (br. s, 1 H, NH) 7.35–7.46 (m, 3 H, ArH), 7.53–7.56
(m, 2 H, ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ = 2.82 (s,
3 F, CF3) ppm. 13C NMR (75.47 MHz, CDCl3): δ = 28.07, 54.21,
2
60.54 (q, JC–F = 31.0 Hz), 81.77, 82.44, 83.90, 110.01, 110.92,
1
120.37, 122.41 (q, JC–F = 287.5 Hz), 131.13, 134.01, 152.98,
160.86, 163.72 ppm. C18H20F3NO5 (387.36): calcd. C 55.81, H 5.20,
N 3.62; found C 55.74, H 5.17, N 3.64.
2
1
60.50 (q, JC–F = 31.8 Hz), 78.71, 81.90, 87.03, 122.30 (q, JC–F
=
287.0 Hz), 128.37, 129.58, 132.15, 152.98, 163.71 ppm.
C17H18F3NO4 (357.33): calcd. C 57.14, H 5.08, N 3.92; found C
57.04, H 5.05, N 3.90.
Methyl 2-[(Benzyloxy)carbonyl]amino-4-(2-nitrophenyl)-2-(trifluoro-
methyl)but-3-ynoate (5g): Yield: 89%; oil. H NMR (300.13 MHz,
1
CDCl3): δ = 3.98 (s, 3 H, OCH3), 5.20 (dAB, J = 12.1 Hz, 1 H,
OCH2), 5.25 (dAB, J = 12.1 Hz, 1 H, OCH2), 6.14 (s, 1 H, NH),
7.41 (br. s, 5 H, ArH), 7.56–7.72 (m, 3 H, ArH), 8.15 (dd, J = 7.3,
J = 0.7 Hz, 1 H, ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ =
3.33 (s, 3 F, CF3) ppm. 13C NMR (75.47 MHz, [D6]DMSO): δ =
Methyl
2-[(tert-Butoxycarbonyl)amino]-4-(2-methylphenyl)-2-(tri-
fluoromethyl)but-3-ynoate (5b): Yield: 76%; m.p. 74–75 °C. 1H
NMR (300.13 MHz, CDCl3): δ = 1.53 [s, 9 H, C(CH3)3], 2.49 (s, 3
H, CH3), 3.98 (s, 3 H, OCH3), 5.55 (br. s, 1 H, NH), 7.18–7.28 (m,
2 H, ArH), 7.31–7.36 (m, 1 H, ArH), 7.5 (dd, J = 7.7, J = 1.1 Hz,
1 H, ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ = 2.82 (s, 3 F,
CF3) ppm. 13C NMR (150.92 MHz, CDCl3): δ = 20.35, 28.06,
2
54.48, 60.87 (q, JC–F = 31.3 Hz), 67.04, 86.28, 115.10, 122.62 (q,
1JC–F = 286.8 Hz), 125.45, 128.45, 128.88, 131.71, 134.42, 135.58,
136.56, 149.82, 155.05, 163.23 ppm. C20H15F3N2O6 (436.34): calcd.
C 55.05, H 3.46, N 6.42; found C 55.34, H 3.18, N 6.48.
2
54.17, 60.68 (q, JC–F = 31.0 Hz), 81.84, 82.55, 86.21, 120.62,
1
122.34 (q, JC–F = 287.5 Hz), 125.55, 129.54, 129.57, 132.29,
Methyl
4-(2-Aminophenyl)-2-[(benzyloxy)carbonyl]amino-2-(tri-
141.35, 152.96, 163.82 ppm. C18H20F3NO4 (371.36): calcd. C 58.22,
H 5.43, N 3.77; found C 58.14, H 5.51, N 3.74.
fluoromethyl)but-3-ynoate (5h): Yield: 68%; oil. 1H NMR
(300.13 MHz, CDCl3): δ = 4.01 (s, 3 H, OCH3), 4.60 (br. s, 2 H,
NH2), 5.22 (br. s, 2 H, OCH2), 6.07 (br. s, 1 H, NH), 6.67–6.74 (m,
2 H, ArH), 7.22 (m, 1 H, ArH), 7.32 (s, 1 H, ArH), 7.43 (br. s, 5
H, ArH) ppm. 19F NMR (282.4 MHz, CDCl3): δ = 2.71 (s, 3 F,
CF3) ppm. 13C NMR (150.93 MHz, CDCl3): δ = 54.93, 60.69 (q,
2JC–F = 33.2 Hz), 67.76, 82.51, 85.78, 104.7, 114.3, 117.2, 122.18 (q,
1JC–F = 287.5 Hz), 128.32, 128.48, 128.64, 131.04, 132.19, 135.52,
149.88, 153.76, 163.98 ppm. C20H17F3N2O4 (406.36): calcd. C
59.11, H 4.22, N 6.89; found C 58.99, H 4.20, N 6.75.
Methyl 4-Phenyl-2-[(phenylsulfonyl)amino]-2-(trifluoromethyl)but-3-
1
ynoate (5c): Yield: 84%; m.p. 118–120 °C. H NMR (300.13 MHz,
CDCl3): δ = 3.97 (s, 3 H, OCH3), 6.06 (br. s, 1 H, NH), 7.30–7.38
(m, 4 H, ArH), 7.45 (t, J = 9.0 Hz, 3 H, ArH), 7.58 (t, J = 7.4 Hz,
1 H, ArH), 7.98 (d, J = 7.3 Hz, 2 H, ArH) ppm. 19F NMR
(282.4 MHz, CDCl3): δ = 1.97 (s, 3 F, CF3) ppm. 13C NMR
(150.92 MHz, CDCl3): δ = 55.30, 61.74 (q, 2JC–F = 33.2 Hz), 74.97,
91.18, 120.23, 121.53 (q, 1JC–F = 287.5 Hz), 127.72, 128.29, 128.83,
129.89, 132.16, 133.00, 140.39, 164.65 ppm. C18H14F3NO4S Dimethyl
(397.37): calcd. C 54.41, H 3.55, N 3.52; found C 54.49, H 3.50, N
3.53.
2,9-Bis[(tert-butoxycarbonyl)amino]-2,9-bis(trifluoro-
methyl)deca-4,6-diynedioate (6): Yield: 32%; m.p. 150–152 °C. 1H
NMR (300.13 MHz, CDCl3): δ = 1.51 [s, 18 H, 2ϫC(CH3)3], 3.26
(dAB, J = 16.5 Hz, 2 H, 2ϫCH2), 3.82 (m, 2 H, 2ϫCH2), 3.94 (s,
3 H, 6ϫOCH3), 5.71 (br. s, 2 H, 2ϫNH) ppm. 19F NMR
Methyl 4-(2-Methylphenyl)-2-[(phenylsulfonyl)amino]-2-(trifluoro-
methyl)but-3-ynoate (5d): Yield: 72%; m.p. 104–106 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 3.98 (s, 3 H, OCH3),
6.08 (br. s, 1 H, NH), 7.17–7.25 (m, 3 H, ArH), 7.31–7.34 (m, 1 H,
ArH), 7.42 (t, J = 7.9 Hz, 2 H, ArH), 7.56 (t, J = 7.3 Hz, 1 H,
ArH), 7.96 (d, J = 7.3 Hz, 2 H, ArH) ppm. 19F NMR (282.4 MHz,
(282.4 MHz, CDCl3): δ = 3.27 (s, 6 F, 2ϫCF3) ppm. 13C NMR
2
(75.47 MHz, CDCl3): δ = 21.80, 28.08, 54.36, 64.48 (q, JC–F
=
29.3 Hz), 68.17, 70.31, 81.23, 123.19 (q, 1JC–F = 287.9 Hz), 153.24,
166.02 ppm. C24H30F6N2O8 (588.50): calcd. C 48.98, H 5.14, N
4.76; found C 49.01, H 5.27, N 4.58.
CDCl3): δ = 1.94 (s, 3 F, CF3) ppm. 13C NMR (100.61 MHz,
2
CDCl3): δ = 20.11, 55.19, 61.71 (q, JC–F = 33.0 Hz), 78.66, 90.54, Hydrogenation of the Triple Bond: Alkynyl-containing amino ester
1
120.09, 121.58 (q, JC–F = 287.6 Hz), 125.45, 127.76, 128.73,
129.56, 129.87, 132.34, 132.93, 140.36, 141.66 164.74 ppm.
C19H16F3NO4S (411.40): calcd. C 55.47, H 3.92, N 3.40; found C
55.61, H 3.85, N 3.23.
(0.26 mmol) was dissolved in methanol (10 mL), and palladium on
carbon (0.016 mmol, 10%) was added to the solution. The resulting
suspension was degassed twice and then stirred under a hydrogen
atmosphere for 3 h. The catalyst was filtered off through a Celite
plug, and the solvent was removed under reduced pressure to give
the pure product.
Methyl 4-(4-Methylphenyl)-2-[(phenylsulfonyl)amino]-2-(trifluoro-
methyl)but-3-ynoate (5e): Yield: 91%; m.p. 125–127 °C. 1H NMR
(300.13 MHz, CDCl3): δ = 2.42 (s, 3 H, CH3), 3.97 (s, 3 H, OCH3), Methyl N-(tert-Butoxycarbonyl)-6-phenyl-2-(trifluoromethyl)norleu-
6.04 (br. s, 1 H, NH), 7.17–7.25 (m, 3 H, ArH), 7.19 (q, J = cinate (7): Yield: 98%; oil. 1H NMR (300.13 MHz, CDCl3): δ =
8.23 Hz, 4 H, ArH), 7.45 (t, J = 7.7 Hz, 2 H, ArH), 7.58 (t, J =
7.3 Hz, 1 H, ArH), 7.97 (d, J = 7.5 Hz, 2 H, ArH) ppm. 19F NMR
(282.4 MHz, CDCl3): δ = 1.93 (s, 3 F, CF3) ppm. 13C NMR
(150.93 MHz, CDCl3): δ = 21.62, 55.24, 61.76 (q, 2JC–F = 33.2 Hz),
1.43 (m, 1 H, CH2), 1.46 [s, 9 H, C(CH3)3], 1.63–1.75 (m, 1 H,
CH2), 2.13 (dt, J = 13.3, J = 4.1 Hz, 1 H, CH2), 2.58–2.68 (m, 2
H, CH2), 2.70 (m, 1 H, CH2), 3.81 (s, 3 H, OCH3), 5.51 (br. s, 1
H, NH), 7.15–7.32 (m, 5 H, ArH) ppm. 19F NMR (282.4 MHz,
1
74.3, 91.49, 117.17, 121.54 (q, JC–F = 287.5 Hz), 127.74, 128.80,
CDCl3): δ = 3.20 (s, 3 F, CF3) ppm. 13C NMR (75.47 MHz,
2
129.03, 132.07, 132.94, 140.27, 140.42 164.75 ppm. C19H16F3NO4S
(411.40): calcd. C 55.47, H 3.92, N 3.40; found C 55.59, H 3.79, N
3.41.
CDCl3): δ = 25.24, 28.01, 28.48, 35.24, 53.64, 65.72 (q, JC–F
=
1
28.5 Hz), 80.47, 123.95 (q, JC–F = 287.9 Hz), 125.93, 128.18,
128.30, 141.23, 153.05, 167.40 ppm. C18H24F3NO4 (375.39): calcd.
C 57.59, H 6.44, N 3.73; found C 57.81, H 6.64, N 3.74.
Methyl 2-[(tert-Butoxycarbonyl)amino]-4-(2-methoxyphenyl)-2-(tri-
fluoromethyl)but-3-ynoate (5f): Yield: 77%; m.p. 94–96 °C. 1H
NMR (600.22 MHz, CDCl3): δ = 1.45 [s, 9 H, C(CH3)3], 3.84 (s, 3 (8): Yield: 99%; oil. H NMR (300.13 MHz, CDCl3): δ = 2.53 (m,
Methyl 5-Phenyl-N-(phenylsulfonyl)-2-(trifluoromethyl)norvalinate
1
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1591

S. N. Osipov et al.
FULL PAPER
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2 H, CH2), 2.96 (m, 1 H, CH2), 3.11 (m, 1 H, CH2), 3.86 (s, 3 H,
OCH3), 6.13 (br. s, 1 H, NH), 7.27–7.41 (m, 5 H, ArH), 7.53–7.66
(m, 3 H, ArH), 7.99 (d, J = 8.2 Hz, 2 H, ArH) ppm. 19F NMR
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(282.4 MHz, CDCl3): δ = 4.78 (br. s, 3 F, CF3) ppm. 13C NMR
2
(150.92 MHz, CDCl3): δ = 29.84, 31.97, 54.50, 68.52 (q, JC–F
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1
28.8 Hz), 123.05 (q, JC–F = 287.5 Hz), 126.51, 126.76, 128.59,
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Acknowledgments
This work was financially supported by the Russian Foundation of
Basic Research (07-03-00593, 07-03-92171) and a GDRE-project
between France and Russia.
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Received: November 24, 2009
Published Online: January 27, 2010
1592
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Eur. J. Org. Chem. 2010, 1587–1592