The Ugi reaction with 2-substituted cyclic imines. Synthesis of substituted proline and homoproline derivatives

Article abstract of DOI:10.1016/j.tet.2006.04.021

The Ugi three-component reaction with 2-substituted five-, six-, and seven-membered cyclic imines was investigated. The reaction opens a new route to substituted proline and homoproline derivatives. It was shown that the method is efficient for the one-st

Full text of DOI:10.1016/j.tet.2006.04.021

Tetrahedron 62 (2006) 5922–5930
The Ugi reaction with 2-substituted cyclic imines. Synthesis
of substituted proline and homoproline derivatives
*
Valentine G. Nenajdenko, Anton V. Gulevich and Elizabeth S. Balenkova
Department of Chemistry, Moscow State University, Leninskije gory, 119899 Moscow, Russia
Received 2 February 2006; revised 22 March 2006; accepted 6 April 2006
Available online 5 May 2006
Abstract—The Ugi three-component reaction with 2-substituted five-, six-, and seven-membered cyclic imines was investigated. The reac-
tion opens a new route to substituted proline and homoproline derivatives. It was shown that the method is efficient for the one-step preparation
of seminatural dipeptides containing natural amino acid residues, and fragments of substituted proline or pipecolinic acid. The scope and
limitation of the approach are discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Unnatural non-proteinogenic a-amino acids are important
substances for different areas of chemistry, biology and
material science.1 They have a wide biological activity and
hence numerous medicinal applications. The replacement
of natural amino acids in peptides with non-proteinogenic
derivatives has become an important goal in synthetic
organic chemistry because their incorporation into biologi-
cally relevant peptides may influence their properties dra-
matically.2 The synthesis of proline peptidomimetics that
mimic natural dipeptides is very attractive.3 Proline is the
most conformationally restricted amino acid. The proline
residue plays an important role in protein secondary struc-
ture, and in many biological processes such as protein folding
and protein recognition.4 Proline isomerism can influence the
receptor function of neurotransmitter-gated ion channels.5
Substituted proline analogues were developed in order to
constrain and control the peptide backbone in reverse turn
motifs6 or to alter the imide cis/trans ratio.7 Pipecolinic
acid (homoproline) is abundant in many natural products
such as immunosuppressants or cyclic peptides with anti-
fungal activity.8 Pipecolinic acid residues accelerate the
rate of cis–trans imide isomerism, and observe a higher pref-
erence for cis-imide bonds on the N-terminal of pipecolinic
acid in comparison to proline residues.8 Synthesis of
2-substituted proline or homoproline derivatives and their
incorporation into natural peptides is an important goal for
peptide chemistry.
Among the methods for the multicomponent synthesis of
peptides or amino acids, the Ugi reaction is one of the
most popular.9 The Ugi reaction with non-substituted five-
and six-membered cyclic aldimines was recently reported.10
The use of 2-substituted cyclic ketimines in the Ugi MCR
can give a short and very attractive synthesis of substituted
proline derivatives and their higher six- and seven-mem-
bered analogues. This article is devoted in investigating
the possibility of 2-substituted cyclic imines participating
in the Ugi MCR (Scheme 1).
R2
HN
2
3
4
(n)
1
R1COOH R2NC
(n)
O
R
N
N
R
n=1,2
O
R1
1a-t
Scheme 1.
Starting cyclic imines with various aliphatic or aromatic sub-
stituents in the a-position can be easily prepared according
to literature procedure from cheap, commercially available
starting materials.11 This can open broad possibilities for
the syntheses of a variety of cyclic amino acid derivatives.
We decided to investigate the synthetic scope and limitations
of the approach. Influence of the acid, isocyanide, and imine
components on the yield of target cyclic amino acid was
studied for this aim. We proposed that the structure of
starting cyclic ketimines could most significantly affect the
reaction path due to the considerable difference in the
Keywords: Ugi reaction; Multicomponent reaction; Imine; Amino acid;
Isocyanide; Proline; Homoproline; Peptide.
* Corresponding author. Tel.: +7 095 939 2276; fax: +7 095 932 8846;
e-mail: nen@acylium.chem.msu.ru
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.021

V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
5923
Table 1. Influence of acid component on reaction time and yield (R¼Me and
R2¼Bn)
Table 3. Influence of imine component on reaction time and yield (R1¼CF3
and R2¼Bn)
Entry
R1
Product
pKa
Reaction
time (d)
Yield (%)
Entry
R
Product
Reaction
time (d)
Yield (%)
1
2
3
4
5
6
CH3
Ph
CH2Cl
CHCl2
CCl3
CF3
—
1a
1b
1c
1d
1e
4.75
4.20
2.85
1.48
0.7
5
5
3
3
2.5
2
0
50
80
73
78
83
11
12
13
14
15
16
17
Me
Bn
Bu
i-Pr
Cyclopentyl
t-Bu
Ph
1e
1i
1j
1k
1l
1m
1n
2
3
3
4
4
6
5
83
45
95
60
50
95
7
0.23
conformation behavior of five-, six-, and seven-membered
nitrogen heterocycles.12
formation of 1o are the lower acidity of 2-phenylpyrroline
compared to 2-alkylsubstituted pyrrolines, the lower electro-
philicity of intermediate iminium salt, and finally, the pos-
sibility of conjugation of the enamide double bond with
the phenyl ring in 1o. The isocyanide behaves very interest-
ingly in this reaction as a dehydrating agent to form trifluoro-
acetic anhydride, TFAA, from TFA.14 The final step of
this sequence is trifluoroacylation of 2-phenylpyrroline by
TFAA to give enamide 1p in 65% yield (Scheme 2). Our
attempts to perform this reaction with other acids also
gave the same results.
A model imine (2-methyl pyrroline) and benzylisocyanide
were chosen to study the influence of the acid. We found
that target amides of 2-methylproline can be prepared
generally in good yield (Scheme 1, Table 1). However,
the acidity of the carboxylic acid affects significantly the
reaction time. The best result was observed in the case of
trifluoroacetic acid TFA. In this case the reaction proceeds
in reasonable time at room temperature to give the target
amide in 83% yield. Another reason to use TFA is the
possibility of subsequent deprotection of the amino acid
nitrogen under mild conditions.13 Acetic acid did not give
any Ugi product.
R
NC CF3COOH
R
NHCHO
(CF3CO)2O
(CF3CO)2O
Ph
O
Ph
N
N
The reaction is of general type. No restrictions on the struc-
ture of the isocyanide component were found (using model
reaction with methyl pyrroline and TFA). As a rule, various
isocyanides having alkyl and aryl substituents or ester
groups gave substituted amides of 2-methylproline in high
yields (Table 2).
CF3
1o
Scheme 2.
We have demonstrated that Ugi multicomponent reaction
with 2-alkyl pyrrolines is a general approach to construct
derivatives of 2-substituted proline, with a broad variety of
such products prepared using this very simple procedure.
In the case of isocyanides prepared from protected natural
amino acids, this method opens a new route to seminatural
dipeptides containing 2-substituted proline (as the acid
building block) and a natural amino acid residue (as the
amine building block). A crucial step in this synthesis is
the preparation of a dipeptide with orthogonal protecting
groups at each end. This opens up the possibility for the
subsequent selective synthesis of tripeptides and longer
peptides.
It was found that the effect of the structure of the 2-sub-
stituted imine on the reaction path is much more important.
Using a model benzylisocyanide and trifluoroacetic acid,
we have investigated the relationship between the structure
of substituents in the 2-position of the imine and the yield
of the Ugi type product (Table 3). Imines with alkyl substit-
uent react smoothly. Even in the case of sterically hindered
2-tert-butylpyrroline the target amide can be prepared in
almost quantitative yield, however more prolonged reaction
time was necessary. A very unusual result was observed in
the case of 2-phenylpyrroline and other arylsubstituted
imines. Instead of formation of the Ugi product the reaction
is directed mainly to the trifluoroacylation of the imine.
2-Phenyl proline derivative 1n is minor product in this case.
For example, in the case of the 2-phenylpyrroline–TFA–
benzylisocyanide system, the target Ugi amide was isolated
in only 7% yield. We believe that the main reasons for the
Usually no stereoinduction is observed in the case of chiral
isocyanides in Ugi reactions in contrast to the Passerini reac-
tion.15 However, we proposed that the fixed conformation of
cyclic imines could influence the possibility of a diastereo-
selective Ugi reaction with chiral isocyanides. Chiral iso-
cyanide 2e was prepared from L-phenylalanine by a literature
procedure.16
Table 2. Influence of isocyanide component on the reaction (R¼Me and
R1¼CF3)
We demonstrated that the method works for the one-step
synthesis of some seminatural orthogonally protected di-
peptides in good yield. Unfortunately, no induction was
observed, and the reaction give a mixture of two diastereo-
mers in a 1/1 ratio in the case of chiral isocyanide 2e, and
four diastereomers in the case of racemic isocyanides 2a–
d (by H NMR spectroscopy) (Scheme 3). The results of
the reaction of model 2-methyl pyrroline and TFA with
various isocyanides 2a–e are given in Table 4.
Entry
R2
Product
Yield (%)
7
8
Bn
4-Br–Ph
1e
1f
83
72
9
1g
85
EtOOC
Me
1
Me
COOEt
10
1h
50

5924
V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
R3
R3
fragments of some natural products. Therefore, development
of an effective synthesis of higher analogs of proline having
six- and seven-membered rings is important. Pipecolinic
acid (also known as homoproline) is a proline analogue,
which contains a six-membered ring. It is found in several
important natural products such as the immunosuppressant
FK506, rapamycin, and cyclic peptides with antifungal
activity.8
COOEt
HN
COOEt
HN
R3
COOEt
NC
CF3COOH
O
O
+
Me
N
N
N
Me
Me
O
CF3
O
CF3
1:1
1p-s
2a-d
Bn
Bn
COOMe
N
HN
COOMe
HN
Bn
COOMe
O
O
+
N
Me
NC
Me
The Ugi reaction works is very well both in the case of
2-alkyl and 2-phenylpiperideines in contrast to the reaction
with 2-aryl pyrrolines. As a result, a number of pipecolinic
acid derivatives can be prepared using the same approach.
Probably the difference in the reactivity of 2-substituted pyr-
rolines and 2-substituted piperideines in the Ugi reaction can
be explained by the conformational peculiarities of five- and
six-membered rings. In the case of pyrrolines the formation
of enamides is more preferable due to lowering of vicinal in-
teractions.17 We found that it was also possible to synthesize
orthogonally protected dipeptides containing a 2-substituted
pipecolinic acid moiety (Scheme 6). In general no restriction
for this synthesis was found and yields were generally high.
Similarly to the reaction with chiral isocyanide 2e for
2-substituted pyrrolines, the Ugi reaction with 6-ring imine
(2-phenylpiperideine) is not diastereoselective, giving both
diastereomers in a 1/1 ratio (Table 6, entry 36).
O
CF3
1:1
CF3
1t
O
2e
Scheme 3.
Table 4. Ugi reaction with isocyanide derivatives of natural amino acids
Entry
R3
Product
Yield, %
18
19
Me
Bn
1p
1q
65
55
S
20
21
1r
1s
52
56
EtOOC
The possibility of selective deprotection was shown.
Deprotection of 1e–m results in N-unsubstituted amides
3a–f (Scheme 4). The N-cleavage of trifluoroacetyl group
was carried out under mild conditions in excellent yield
(Table 5).
R2
3
N
2
4
1
CF3COOH R2NC
O
5
Bn
R
N
R
N
Bn
HN
HN
NaBH4
O
CF3
4a-l
O
O
N
H
MeOH
R
N
R
Scheme 6.
O
CF3
3a-f
1e-m
Table 6. Ugi synthesis of homoproline derivatives
Scheme 4.
Table 5. Cleavage of TFA group
Entry
R
R2
Product
Yield (%)
28
29
Bu
Ph
Bn
Bn
4a
4b
84
79
Entry
R
Product
Yield (%)
EtOOC
30
Ph
4c
67
22
23
24
25
26
27
Me
Bn
Bu
i-Pr
Cyclopentyl
t-Bu
3a
3b
3c
3d
3e
3f
80
90
82
81
83
77
Me
COOEt
Me
31
Ph
4d
71
Me
32
32
33
34
35
Bu
Ph
Ph
Ph
4e
4f
COOEt
COOEt
COOEt
Similarly, the use of aq methanol/K2CO3 solution permits
selective deprotection of the ester moiety to give the unpro-
tected carboxylic acid (Scheme 5).
Me
Bn
72
84
68
4g and 4ha
Me
Me
COOH
HN
COOEt
HN
S
K2CO3
4i
O
N
O
Me
COOEt
N
MeOH/H2O
72%
Me
O
CF3
O
CF3
EtOOC
Bn
Ph
Ph
4j
69
84
1p
3g
COOEt
Scheme 5.
36
4k and 4l
COOMe
In addition to the 20 common natural amino acids there are
a number of rare amino acids as which occur structural
a
Mixture of two pairs of diastereomers in a 1:1 ratio was isolated.

V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
5925
We found that in the case of Ugi reactions with imines con-
taining a seven-membered ring, no formation of the target
amino acid derivatives was observed. Similarly to the reac-
tion of 2-aryl pyrrolines only the formation of enamides
take place both in the case of 2-phenyl and 2-methyl imines.
Both reactions give the enamide as the only reaction product.
In the case of 2-methylazepine, unpredictable elimination to
form enamide 5b having an exocyclic double bond was ob-
served. These results confirmed that conformational pecu-
liarities of five-, six-, and seven-membered cyclic imines
are very important in the Ugi reaction. We demonstrated
that only in the case of five- and six-membered 2-substituted
imines the formation of 2-substituted proline and homopro-
line derivatives is possible (Scheme 7).
H, 6.66. C20H22N2O2 requires C, 74.51; H, 6.88%]; nmax
(Nujol) 2880, 1660, 1650 cmꢁ1; dH (400 MHz, CDCl3) 7.7
(1H, br, NH), 7.30–7.45 (5H, m, COPh), 7.20–7.35 (5H,
m, Ph), 4.5 (2H, d, J 5.7 Hz, CH2Ph), 3.40–3.55 (2H, m,
H-4), 2.67–2.77 (1H, m, H-2), 1.85–1.92 (1H, m, H-2),
1.75–1.85 (2H, m, H-3), 1.80 (3H, s, Me); dC (400 MHz,
CDCl3) 174.75, 167.35, 137.15, 136.70, 131.28, 128.65,
127.40, 126.66, 126.16, 69.40, 48.57 (m), 43.61, 38.31,
23.77, 21.06.
4.2.2. N-Benzyl-1-(chloroacetyl)-2-methylprolinamide
(1b). Yield 80%, colorless oil [Found: C, 61.36; H, 6.86.
C15H19ClN2O2 requires C, 61.12; H, 6.50%]; Rf (50%
EtOAc/hexane) 0.60; nmax (liquid film) 2870, 1660 cmꢁ1
;
dH (400 MHz, CDCl3) 8.5 (1H, br, NH), 7.20–7.35 (5H, m,
Ph), 4.41 and 4.45 (2H, both d, J 5.6 Hz, CH2Ph), 4.03
(2H, d, J 1.5 Hz, CH2Cl), 3.60–3.75 (2H, m, H-4), 2.51–
2.63 (1H, m, H-2), 1.9–2.05 (1H, m, H-2), 1.71–1.93 (2H,
m, H-3), 1.67 (3H, s, Me); dC (400 MHz, CDCl3) 172.9,
165.78, 138.19, 128.43, 127.19, 68.72, 48.81 (m), 43.48,
42.90, 38.54, 23.36, 21.82.
3
4
2
1
5
BnNC
BnNC
6
CF3COOH
68%
CF3COOH
71%
N
N
N
N
Ph
H2C
Ph
Me
O
CF3
O
CF3
5a
5b
Scheme 7.
4.2.3. N-Benzyl-1-(dichloroacetyl)-2-methylprolinamide
(1c). Yield 73%, white solid, mp 107–108 ꢀC [Found:
C, 55.01; H, 5.72. C15H18Cl2N2O2 requires C, 54.72;
H, 5.51%]; Rf (50% EtOAc/hexane) 0.65; nmax (Nujol)
2870, 1670 cmꢁ1; dH (400 MHz, CDCl3) 7.22–7.33 (5H,
m, Ph), 6.8 (1H, br, NH), 6.13 (1H, s, CHCl2), 4.43 (2H, d,
J 5.3 Hz, CH2Ph), 3.71–3.86 (2H, m, H-4), 2.50–2.63 (1H,
m, H-2), 1.95–2.05 (1H, m, H-2), 1.75–1.87 (2H, m, H-3),
1.70 (3H, s, Me); dC (400 MHz, CDCl3) 172.51, 162.47,
138.06, 128.54, 127.32, 127.23, 69.45, 66.15, 48.85 (m),
43.67, 38.38, 23.62, 21.54.
3. Conclusion
Thus, we have investigated the reaction of 2-substituted cy-
clic imines in Ugi reaction conditions. The reaction permits
preparation of substituted proline and homoproline deriva-
tives. It was shown that the method is efficient for the one-
step preparation of seminatural dipeptides containing natural
amino acid residues and fragments of substituted proline or
pipecolinic acid. The significant difference in the reactivity
of five-, six-, and seven-membered cyclic ketimines was
demonstrated.
4.2.4. N-Benzyl-2-methyl-1-(trichloroacetyl)prolinamide
(1d). Yield 78%, white solid, mp 111–112 ꢀC [Found: C,
49.40; H, 5.08. C15H17Cl3N2O2 requires C, 49.54; H,
4.71%]; Rf (50% EtOAc/hexane) 0.70; nmax (Nujol) 2900,
1670, 1650 cmꢁ1; dH (400 MHz, CDCl3) 7.20–7.35 (5H,
m, Ph), 6.6 (1H, br, NH), 4.44 (2H, d, J 5.5 Hz, CH2Ph),
3.70–3.85 (2H, m, H-4), 2.40–2.50 (1H, m, H-2), 1.93–
2.08 (2H, m, H-2 and H-3), 1.77–1.84 (1H, m, H-3), 1.70
(3H, s, Me); dC (400 MHz, CDCl3) 172.47, 158.70, 138.02,
128.62, 127.55, 127.39, 93.58, 70.37, 51.31 (m), 43.83,
38.56, 24.61, 20.88.
4. Experimental
4.1. General
1H and 13C NMR spectra were determined in deuterated sol-
vents on a Bruker VRX-400 spectrometer. Chemical shifts
are reported in parts per million (ppm) downfield from
TMS. Deuterated solvent peaks were used as internal refer-
ences: deutero-chloroform at 2.25 and 77.00 ppm and
deutero-DMSO at 2.50 and 39.50 ppm. The IR spectra were
measured using a UR-20 spectrometer. TLC was performed
using 25 DC-Alufolien Kieselgel 60 F254 (Merck). Fluka
Silica gel 60 (0.063–0.200 mm) was used for column chro-
matography. Commercial reagents and solvents were gener-
ally used as received.
4.2.5. N-Benzyl-2-methyl-1-(trifluoroacetyl)prolinamide
(1e). Yield 83%, white solid, mp 94–95 ꢀC [Found: C,
57.27; H, 5.72. C15H17F3N2O2 requires C, 57.32; H,
5.45%]; Rf (50% EtOAc/hexane) 0.65; nmax (Nujol) 2880,
1680, 1650 cmꢁ1; dH (400 MHz, CDCl3) 7.20–7.35 (5H,
m, Ph), 6.65 (1H, br, NH), 4.42 (2H, d, J 5.5 Hz, CH2Ph),
3.70–3.85 (2H, m, H-4), 2.40–2.50 (1H, m, H-2), 1.93–
2.08 (2H, m, H-2 and H-3), 1.77–1.84 (1H, m, H-3), 1.66
(3H, s, Me); dC (400 MHz, CDCl3) 171.95, 155.65 (q,
J 36.6), 137.99, 128.59, 127.34, 116.0 (q, J 288.4), 69.46,
48.57 (m), 43.71, 38.31, 23.87, 21.06.
4.2. General procedure for the Ugi reaction
The appropriate imine (1.1 mmol) and carboxylic acid
(1 mmol) were dissolved in abs CH2Cl2 (2 ml). The iso-
cyanide (1.0 mmol) was added and the solution was stirred
fortheappropriatetimeatroomtemperature. Thesolventwas
removed in vacuo and the resulting crude product was puri-
fied by column chromatography (hexane/ethyl-acetate, 1:1).
4.2.6. N-(4-Bromophenyl)-2-methyl-1-(trifluoroacetyl)-
prolinamide (1f). Yield 72%, white solid, mp 119–120 ꢀC
[Found: C, 44.50; H, 3.47. C14H14BrF3N2O2 requires C,
44.35; H, 3.72%]; Rf (50% EtOAc/hexane) 0.75; nmax
(Nujol) 2900, 1670, 1650 cmꢁ1; dH (400 MHz, CDCl3)
4.2.1. 1-Benzoyl-N-benzyl-2-methylprolinamide (1a).
Yield 50%, white solid, mp 87–88 ꢀC [Found: C, 74.62;

5926
V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
8.3 (1H, br, NH), 7.48 (2H, d, J 8.6 Hz, m-Ph), 6.95 (2H, d,
J 8.6 Hz, o-Ph), 3.32–3.38 (2H, m, H-4), 2.53–2.60 (2H, m,
H-2), 1.83–1.89 (2H, m, H-3), 1.73 (3H, s, Me); dC
(400 MHz, CDCl3) 166.72, 154.54 (q, J 36.8), 135.71,
130.63, 125.42, 124.05, 116.2 (q, J 288.3), 77.62, 49.21
(m), 38.99, 23.96, 21.50.
4.2.11. N-Benzyl-2-isopropyl-1-(trifluoroacetyl)prolin-
amide (1k). Yield 60%, colorless oil [Found: C, 59.85; H,
6.40. C17H21F3N2O2 requires C, 59.64; H, 6.18%]; Rf (50%
EtOAc/hexane) 0.70; nmax (liquid film) 2950, 1680 cmꢁ1; dH
(400 MHz, CDCl3) 8.3 (1H, br, NH), 7.22–7.35 (5H, m, Ph),
4.53–4.60 (1H, m, CH2Ph), 4.32–4.40 (1H, m, CH2Ph),
3.87–3.95 (1H, m, H-4), 3.50–3.58 (1H, m, H-4), 3.13–
3.23 (1H, m, H-2), 2.77–2.83 (1H, m, H-2), 1.86–2.03
(2H, m, H-3), 1.65–1.73 (1H, m, CH), 0.87 (3H, d, J 7 Hz,
Me), 0.83 (3H, d, J 7 Hz, Me); dC (400 MHz, CDCl3)
171.32, 157.65 (q, J 36.6), 138.37, 128.54, 127.21, 127.18,
116.53 (q, J 288.4), 79.85, 49.99 (m), 43.64, 29.23, 27.38,
23.47, 17.63, 16.18.
4.2.7. Ethyl 4-{[2-methyl-1-(trifluoroacetyl)prolyl]amino}-
butanoate (1g). Yield 85%, colorless oil [Found: C, 49.39;
H, 6.20. C14H21F3N2O4 requires C, 49.70; H, 6.26%]; Rf
(50% EtOAc/hexane) 0.55; nmax (liquid film) 2950, 1720,
1690, 1670 cmꢁ1; dH (400 MHz, CDCl3) 6.7 (1H, br, NH),
4.07 (2H, q, J 7 Hz, COOCH2Me), 3.67–3.85 (2H, m,
H-4), 3.26 (2H, q, J 5.6 Hz, CH2CH2CH2COOCH2CH3),
2.30–2.42 (3H, m, H-2 and CH2CH2CH2COOCH2Me),
1.90–2.07 (2H, m, H-2 and H-3), 1.73–1.85 (3H, m, H-3
and CH2CH2CH2COOCH2Me), 1.63 (3H, s, Me), 1.20
(3H, t, J 7.1 Hz, CH2Me); dC (400 MHz, CDCl3) 173.69,
172.12, 155.52 (q, J 36.6), 115.2 (q, J 288.6), 69.44,
60.44, 48.52 (m), 39.47, 38.40, 31.76, 24.98, 23.83, 20.96,
14.04.
4.2.12. N-Benzyl-2-cyclopentyl-1-(trifluoroacetyl)prolin-
amide (1l). Yield 50%, white solid, mp 88–89 ꢀC [Found:
C, 62.12; H, 6.44.C19H23F3N2O2 requires C, 61.95; H,
6.29%]; Rf (50% EtOAc/hexane) 0.65; nmax (Nujol) 2920,
1690, 1630 cmꢁ1; dH (400 MHz, CDCl3) 7.9 (1H, br, NH),
7.22–7.35 (5H, m, Ph), 4.53–4.60 (1H, m, CH2Ph), 4.32–
4.40 (1H, m, CH2Ph), 3.87–3.95 (1H, m, H-4), 3.50–3.58
(1H, m, H-4), 3.30–3.58 (1H, m, H-2), 2.82–2.87 (1H, m,
H-2), 1.90–2.00 (2H, m, H-3), 1.52–1.75 (7H, m, cpt),
1.20–1.35 (2H, m, cpt); dC (400 MHz, CDCl3) 171.88,
157.06 (q, J 36.6), 138.35, 128.54, 127.16, 116.3 (q,
J 288.4), 78.32, 49.92 (m), 43.63, 41.40, 29.14, 28.71,
27.06, 26.55, 25.37, 23.38.
4.2.8. Ethyl 2-methyl-1-(trifluoroacetyl)prolyl-2-methyl-
alaninate (1h). Yield 50%, white solid, mp 65–66 ꢀC
[Found: C, 50.01; H, 6.30. C14H21F3N2O4 requires C,
49.70; H, 6.26%]; Rf (50% EtOAc/hexane) 0.55; nmax
(Nujol) 2930, 1750, 1690, 1680 cmꢁ1; dH (400 MHz,
CDCl3) 6.9 (1H, br, NH), 4.15 (2H, q, J 7.1 Hz,
COOCH2Me), 3.67–3.85 (2H, m, H-4), 2.4–2.48 (1H, m,
H-2), 1.91–2.12 (2H, m, H-2 and H-3), 1.70–1.80 (1H, m,
H-3), 1.65 (3H, s, Me), 1.44 (6H, s, CMe2), 1.22 (3H, t,
J 7.1 Hz, COOCH2Me); dC (400 MHz, CDCl3) 174.51,
170.99, 155.66 (q, J 36.7), 115.2 (q, J 288.3), 69.70,
61.46, 56.68, 48.62 (m), 38.12, 24.38, 24.18, 23.81, 21.11,
13.94.
4.2.13. N-Benzyl-2-tert-butyl-1-(trifluoroacetyl)prolin-
amide (1m). Yield 95%, white solid, mp 85–86 ꢀC [Found:
C, 60.40; H, 6.72. C18H23F3N2O2 requires C, 60.66; H,
6.50%]; Rf (50% EtOAc/hexane) 0.75; nmax (Nujol) 2910,
1680, 1660 cmꢁ1; dH (400 MHz, CDCl3) 7.8 (1H, br, NH),
7.20–7.33 (5H, m, Ph), 4.43–4.51 (2H, m, CH2Ph), 3.87–
3.95 (1H, m, H-4), 3.45–3.55 (1H, m, H-4), 2.87–2.95
(1H, m, H-2), 1.83–1.93 (2H, m, H-2 and H-3), 1.53–1.65
(1H, m, H-3), 1.13 (9H, s, t-Bu); dC (400 MHz, CDCl3)
171.56, 158.66 (q, J 36.9), 138.09, 128.59, 127.53, 127.27,
116.7 (q, J 288.1), 84.32, 50.99 (m), 43.98, 38.39, 34.88,
27.84, 23.27.
4.2.9. N,2-Dibenzyl-1-(trifluoroacetyl)prolinamide (1i).
Yield 45%, white solid, mp 89–90 ꢀC [Found: C, 64.59;
H, 5.42. C21H21F3N2O2 requires C, 64.61; H, 5.42%]; Rf
(50% EtOAc/hexane) 0.65; nmax (Nujol) 2910, 1680,
1650 cmꢁ1; dH (400 MHz, CDCl3) 7.23–7.38 (8H, m, Ph
and Ph), 7.07 (2H, dd, J 2.2, J 5.7 Hz, o-Ph), 6.9 (1H, br,
NH), 4.42–4.55 (2H, m, NHCH2Ph), 3.65–3.75 (2H, m, H-
4), 3.10–3.20 (2H, m, CH2Ph), 2.35–2.47 (1H, m, H-2),
2.03–2.10 (1H, m, H-2), 1.70–1.85 (1H, m, H-3), 1.32–1.44
(1H, m, H-3); dC (400 MHz, CDCl3) 172.03, 155.65 (q,
J 36.6), 138.60, 137.99, 130.33, 128.59, 127.50, 127.34,
126.88, 116.0 (q, J 288.4), 70.55, 48.57 (m), 43.70, 39.07,
23.95.
4.2.14. N-Benzyl-2-phenyl-1-(trifluoroacetyl)prolin-
amide (1n). Yield 7%, white solid, mp 100–101 ꢀC [Found:
C, 63.43; H, 5.09. C20H19F3N2O2 requires C, 63.82; H,
5.09%]; Rf (50% EtOAc/hexane) 0.75; nmax (Nujol) 3000,
1690, 1660 cmꢁ1; dH (400 MHz, CDCl3) 7.18–7.33 (8H,
m, Ph and Ph), 7.07–7.12 (2H, m, Ph), 4.50–4.57 (2H, m,
CH2Ph), 4.35–4.43 (1H, m, CH2Ph), 3.97–4.05 (1H, m,
H-4), 3.87–3.97 (1H, m, H-4), 3.10–3.20 (1H, m, H-2),
1.86–2.05 (3H, m, H-2 and H-3); dC (400 MHz, CDCl3)
170.34, 156.56 (q, J 36.3), 138.06, 137.89, 128.75, 128.57,
127.93, 127.45, 127.29, 125.50, 116.0 (q, J 288.6), 77.11,
49.37 (m), 44.11, 40.75, 24.28.
4.2.10. N-Benzyl-2-butyl-1-(trifluoroacetyl)prolinamide
(1j). Yield 95%, white solid, mp 84–85 ꢀC [Found: C,
60.34; H, 6.62. C18H23F3N2O2 requires C, 60.66; H,
6.50%]; Rf (50% EtOAc/hexane) 0.70; nmax (Nujol) 2890,
1670, 1650 cmꢁ1; dH (400 MHz, CDCl3) 7.20–7.40 (5H,
m, Ph), 4.33–4.57 (2H, m, CH2Ph), 3.85–3.93 (1H, m,
H-4), 3.57–3.62 (1H, m, H-4), 2.65–2.73 (1H, m, H-2),
2.10–2.25 (2H, m, CH2CH2CH2CH3), 1.91–2.02 (2H, m,
H-2 and H-3), 1.75–1.85 (1H, m, H-3), 1.05–1.35 (4H, m,
CH2CH2CH2CH3), 0.86 (3H, t, CH2CH2CH2Me); dC
(400 MHz, CDCl3) 171.79, 156.53 (q, J 36.6), 138.20,
128.58, 127.27, 116.0 (q, J 288.4), 74.21, 48.57 (m),
43.66, 34.53, 33.46, 26.10, 23.69, 22.63, 13.80.
4.2.15. Ethyl 2-methyl-1-(trifluoroacetyl)prolylalaninate
(1p), mixture of diastereomers, ratio 1:1. Yield 65%,
white solid, mp 69–70 ꢀC [Found: C, 47.83; H, 6.12.
C13H19F3N2O4 requires C, 48.15; H, 5.91%]; Rf (50%
EtOAc/hexane) 0.55; nmax (Nujol) 2920, 1740, 1700,
1670 cmꢁ1; dH (400 MHz, CDCl3) 6.7, 6.8 (1H, br, NH),
4.48 (1H, m, CH), 4.17–4.25 (2H, m, COOCH2CH3),
3.70–3.87 (2H, m, H-4), 2.37–2.48 (1H, m, H-2), 1.91–
2.10 (2H, m, H-2 and H-3), 1.76–1.85 (1H, m, H-3), 1.68,

V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
5927
1.59 (3H, s, Me), 1.38 (3H, m, CHMe), 1.25–1.27 (3H, m,
COOCH2Me); dC (400 MHz, CDCl3) 172.81, 172.76,
171.55, 171.42, 155.97 (q, J 36.7), 116.0 (q, J 288.3),
69.58, 69.16, 61.49, 61.46, 53.40, 53.24, 48.63 (m), 38.33,
38.24, 23.94, 23.78, 21.10, 20.94, 14.02, 14.00.
(2H, m, CH2Ph), 2.27–2.42 (1H, m, H-2), 1.85–2.00 (2H,
m, H-2 and H-3), 1.72–1.83 (1H, m, H-3), 1.65, 1.63 (3H,
s, Me); dC (400 MHz, CDCl3) 171.82, 171.73, 171.55,
155.97 (q, J 36.7), 135.79, 135.64, 129.37, 129.26, 128.58,
129.52, 127.18, 126.11, 116.0 (q, J 288.3), 69.49, 69.43,
53.38, 53.19, 48.54 (m, C-4), 38.44, 38.16, 37.78, 37.65,
23.74, 21.09, 20.90.
4.2.16. Ethyl 2-methyl-1-(trifluoroacetyl)prolylphenyl-
alaninate (1q), mixture of diastereomers, ratio 1:1. Yield
55%, white solid, mp 66–67 ꢀC [Found: C, 56.64; H, 5.45.
C19H23F3N2O4 requires C, 56.99; H, 5.79%]; Rf (50%
EtOAc/hexane) 0.55; nmax (Nujol) 2940, 1740, 1710,
1680 cmꢁ1; dH (400 MHz, CDCl3) 7.07–7.30 (5H, m, Ph),
6.6, 6.5 (1H, br, NH), 4.83 (1H, m, CH), 4.17 (2H, q,
J 7.1 Hz, COOCH2CH3), 3.65–3.80 (2H, m, H-4), 3.05–
3.20 (2H, m, CH2Ph), 2.30–2.40 (1H, m, H-2), 1.83–2.01
(2H, m, H-2 and H-3), 1.72–1.83 (1H, m, H-3), 1.65, 1.62
(3H, s, Me), 1.25 (t, J 7.1 Hz, COOCH2Me); dC (400 MHz,
CDCl3) 171.46, 171.43, 171.26, 171.19, 155.97 (q, J 36.7),
135.88, 135.72, 129.37, 129.29, 128.46, 129.39, 127.05,
126.99, 116.0 (q, J 288.3), 69.52, 69.46, 61.47, 53.40,
53.24, 48.49 (m), 38.41, 38.15, 37.76, 37.66, 23.67, 21.06,
20.91, 13.99.
4.3. General procedure for deprotection 1e–m
The appropriate amides 1e–m (0.5 mmol) were dissolved in
abs MeOH (5 ml). The NaBH4 (0.25 mmol) was added and
the solution was stirred for the appropriate time at room tem-
perature. The solvent was removed in vacuo and the result-
ing crude residue was treated with 2 ml of 2 M aq K2CO3.
Product was extracted with ethyl-acetate (3ꢂ10 ml), dried
over K2CO3, and evaporate in vacuo.
4.3.1. N-Benzyl-2-methylprolinamide (3a). Yield 80%,
yellow oil [Found: C, 71.20; H, 8.48. C13H18N2O requires
C, 71.53; H, 8.31%]; Rf (2% NH3(aq)/CH3CN) 0.6; nmax (liq-
uid film) 2960, 1680 cmꢁ1; dH (400 MHz, CDCl3) 8.3 (1H,
br, CONH), 7.22–7.35 (5H, m, Ph), 4.40 (2H, t, J 5.9 Hz,
CH2Ph), 3.03–3.10 (1H, m, H-4), 2.77–2.83 (1H, m, H-4),
2.25–2.37 (1H, m, H-2), 1.60–1.80 (3H, m, H-2 and H-3),
1.43 (3H, s, Me); dC (400 MHz, CDCl3) 177.24, 138.84,
128.47, 127.32, 127.06, 66.50, 47.03, 42.96, 37.61, 26.47,
25.94.
4.2.17. Ethyl 2-methyl-1-(trifluoroacetyl)prolylmethioni-
nate (1r), mixture of diastereomers, ratio 1:1. Yield 52%,
yellow oil [Found: C, 46.83; H, 6.15. C15H23F3N2O4S re-
quires C, 46.87; H, 6.03%]; Rf (50% EtOAc/hexane) 0.50;
nmax (liquid film) 2980, 1730, 1680 cmꢁ1; dH (400 MHz,
CDCl3) 6.9, 7.0 (1H, br, NH), 4.63 (1H, m, CH), 4.17 (2H,
m, CH2CH3), 3.70–3.90 (2H, m, H-4), 2.35–2.60 (3H, m,
H-2, CH2CH2SCH3), 2.12–2.20 (1H, m, H-2), 2.09, 2.08
(3H, s, SCH3), 1.94–2.06 (3H, m, H-3, CH2CH2SMe),
1.80–1.88 (1H, m, H-3), 1.68, 1.69 (3H, s, Me), 1.27–1.35
(3H, m, CH2Me); dC (400 MHz, CDCl3) 171.71, 171.69,
171.58, 155.60 (q, J 36.7), 116.5 (q, J 288.5), 69.45,
69.99, 61.54, 52.06, 51.95, 48.44 (m), 38.37, 38.16, 31.04,
30.76, 29.78, 29.75, 23.87, 23.70, 20.79, 20.71, 15.24, 13.93.
4.3.2. N,2-Dibenzylprolinamide (3b). Yield 90%, yellow
oil [Found: C, 77.77; H, 7.23. C19H22N2O requires C,
77.52; H, 7.53%]; Rf (2% NH3(aq)/CH3CN) 0.6; nmax (liquid
film) 2960, 1690 cmꢁ1; dH (400 MHz, CDCl3) 8.0 (1H,
br, CONH), 7.05–7.35 (10H, m, Ph and Ph), 4.27–4.45
(2H, m, PhCH2NH), 3.67 (1H, d, J 13.3 Hz, CH2Ph),
2.97–3.05 (1H, m, H-4), 2.82–2.88 (1H, m, H-4), 2.70 (1H,
d, J 13.3 Hz, PhCH2), 2.23–2.30 (1H, m, H-2), 1.83–1.92
(2H, m, H-2 and H-3), 1.67–1.80 (1H, m, H-3); dC
(400 MHz, CDCl3) 176.12, 138.55, 137.08, 127.79, 128.41,
127.44, 127.03, 126.70, 70.01, 46.53, 43.49, 43.03, 37.11,
25.61.
4.2.18. Diethyl 2-methyl-1-(trifluoroacetyl)prolylgluta-
mate (1s), mixture of diastereomers, ratio 1:1. Yield
56%, yellow oil [Found: C, 49.48; H, 6.04. C17H25F3N2O6 re-
quires C, 49.75; H, 6.14%]; Rf (50% EtOAc/hexane) 0.45;
nmax (liquid film) 2990, 1730, 1690 cmꢁ1; dH (400 MHz,
CDCl3) 6.9, 7.1 (1H, br, NH), 4.50 (1H, m, CH), 4.07–4.22
(4H, m, COOCH2CH3 and COOCH2CH3), 3.70–3.92
(2H, m, H-4), 2.32–2.46 (3H, m, H-2, CH2CH2COOEt),
2.12–2.25 (1H, m, H-2), 1.93–2.10 (3H, m, H-3 and
CH2CH2COOEt), 1.80–1.90 (1H, m, H-3), 1.68, 1.67 (3H,
s, Me), 1.20–1.27 (6H, m, COOCH2Me and COOCH2Me);
dC (400 MHz, CDCl3) 173.43, 173.37, 172.07, 172.01,
171.60, 157.5 (q, J 36.5), 116.0 (q, J 288.6), 69.52, 68.99,
61.54, 60.71, 52.45, 52.32, 48.50 (m, C-4), 38.60, 38.37,
30.21, 30.18, 26.33, 26.50, 23.95, 23.76, 20.86, 20.79,
14.05, 14.03.
4.3.3. N-Benzyl-2-butylprolinamide (3c). Yield 82%, yel-
low oil [Found: C, 73.62; H, 8.95. C16H24N2O requires C,
73.81; H, 9.29%]; Rf (2% NH3(aq)/CH3CN) 0.65; nmax (liq-
uid film) 2980, 1690 cmꢁ1; dH (400 MHz, CDCl3) 8.4 (1H,
br, CONH), 7.22–7.35 (5H, m, Ph), 4.40 (2H, d, J 6 Hz,
CH2Ph), 2.96–3.05 (1H, m, H-4), 2.75–2.82 (1H, m, H-4),
2.20–2.27 (1H, m, H-2), 1.96–2.04 (1H, m, H-2), 1.60–
1.73 (3H, m, H-3 and CH2CH2CH2Me), 1.43–1.50 (1H, m,
CH2CH2CH2Me), 1.15–1.30 (4H, m, CH2CH2CH2Me),
0.85 (3H, t, J 7 Hz, Me); dC (400 MHz, CDCl3) 176.59,
138.89, 128.46, 127.44, 127.08, 69.94, 47.04, 43.04,
38.99, 36.92, 27.06, 26.09, 22.96, 13.88.
4.2.19. Methyl 2-methyl-1-(trifluoroacetyl)prolyl-L-phe-
nylalaninate (1t), mixture of diastereomers, ratio 1:1.
Yield 55%, colorless oil, crystallizes on standing [Found:
C, 55.90; H, 5.60. C18H21F3N2O4 requires C, 55.96; H,
5.48%]; Rf (50% EtOAc/hexane) 0.55; nmax (liquid film)
2940, 1740, 1700, 1670 cmꢁ1; dH (400 MHz, CDCl3)
7.07–7.30 (5H, m, Ph), 6.6, 6.5 (1H, br, NH), 4.83–4.88
(1H, m, CH), 3.65–3.80 (5H, m, H-4, COOMe), 3.05–3.20
4.3.4. N-Benzyl-2-isopropylprolinamide (3d). Yield 81%,
yellow oil [Found: C, 73.13; H, 8.95. C15H22N2O requires
C, 73.13; H, 9.00%]; Rf (2% NH3(aq)/CH3CN) 0.65; nmax
(liquid film) 2950, 1680 cmꢁ1; dH (400 MHz, CDCl3) 8.3
(1H, br, CONH), 7.22–7.35 (5H, m, Ph), 4.40 (2H, d,
J 5.9 Hz, CH2Ph), 2.94–3.03 (1H, m, H-4), 2.73–2.80 (1H,
m, H-4), 2.13–2.27 (2H, m, H-2 and CH), 1.60–1.76 (3H,
m, H-2 and H-3), 0.89 (6H, m, Me and Me); dC (400 MHz,

5928
V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
CDCl3) 176.33, 138.82, 128.55, 127.39, 126.96, 73.09,
47.21, 42.89, 34.64, 34.59, 26.33, 18.69, 16.99.
[Found: C, 64.65; H, 5.42. C21H21F3N2O2 requires C,
64.61; H, 5.42%]; Rf (50% EtOAc/hexane) 0.60; nmax
(Nujol) 2960, 1700, 1670 cmꢁ1; dH (400 MHz, CDCl3)
7.05–7.35 (10H, m, Ph and Ph), 5.8 (1H, br, NH), 4.37–
4.45 (1H, m, PhCH2), 4.22–4.27 (1H, m, PhCH2), 3.73–
3.83 (1H, m, H-5), 3.23–3.30 (1H, m, H-5), 2.55–2.64
(1H, m, H-2), 2.23–2.32 (1H, m, H-2), 1.67–1.83 (2H, m,
H-3), 1.52–1.63 (1H, m, H-4), 1.26–1.40 (1H, m, H-4); dC
(400 MHz, CDCl3) 171.16, 158.13 (q, J 36.6), 138.31,
133.66, 129.66, 128.81, 128.72, 127.60, 127.51, 127.40,
117.0 (q, J 288.6), 70.40, 44.29, 43.65 (m), 34.68, 23.53,
18.66.
4.3.5. N-Benzyl-2-cyclopentylprolinamide (3e). Yield 83%,
yellow oil [Found: C, 75.13; H, 8.98. C17H24N2O requires C,
74.96; H, 8.88%]; Rf (2% NH3(aq)/CH3CN) 0.7; nmax (liquid
film) 2980, 2780 cmꢁ1; dH (400 MHz, CDCl3) 8.3 (1H,
br, CONH), 7.23–7.38 (5H, m, Ph), 4.30–4.40 (2H, m,
CH2Ph), 2.92–3.01 (1H, m, H-4), 2.75–2.81 (1H, m, H-4),
2.42–2.51 (1H, m, H-2), 2.20–2.30 (1H, m, H-2), 1.45–1.76
(9H, m, CH, H-3 and cpt), 1.15–1.35 (2H, m, cpt);
dC (400 MHz, CDCl3) 176.56, 138.77, 128.43, 127.55,
126.88, 71.56, 47.17, 45.74, 42.76, 34.78, 26.37, 27.06,
26.52, 25.40.
4.3.10. Ethyl 4-({[2-phenyl-1-(trifluoroacetyl)piperidin-
2-yl]carbonyl}amino)butanoate (4c). Yield 67%, colorless
oil [Found: C, 57.60; H, 6.16. C20H25F3N2O4 requires
C, 57.96; H, 6.08%]; Rf (50% EtOAc/hexane) 0.45; nmax
(liquid film) 2990, 1720, 1690, 1670 cmꢁ1; dH (400 MHz,
CDCl3) 7.33–7.47 (3H, m, Ph), 7.22–7.27 (2H, m, Ph),
5.6 (1H, br, NH), 4.05 (2H, q, J 7.1 Hz, COOCH2CH3),
3.78–3.88 (1H, m, H-5), 3.23–3.32 (1H, m, H-5), 3.16–
3.23 (2H, q, J 6.3 Hz, CH2CH2CH2COOEt), 2.58–2.67
(1H, m, H-2), 2.27–2.34 (1H, m, H-2), 2.24 (2H, t,
J 7.1, CH2CH2CH2COOEt), 1.55–1.85 (5H, m, H-3 and
CH2CH2CH2COOEt and H-4), 1.21–1.45 (1H, m, H-4),
1.19 (3H, t, J 7.1 Hz, COOCH2Me); dC (400 MHz, CDCl3)
172.84, 170.66, 157.38 (q, J 35.9), 136.06, 129.12, 128.14,
126.95,115.6 (q, J 289.1), 69.81, 60.03, 43.03 (m), 39.08,
33.85, 31.17, 23.92, 23.00, 18.09, 13.84.
4.3.6. N-Benzyl-2-tert-butylprolinamide (3f). Yield 77%,
yellow oil [Found: C, 73.62; H, 8.95. C16H24N2O requires
C, 73.81; H, 9.29%]; Rf (2% NH3(aq)/CH3CN) 0.65; nmax
(liquid film) 2960, 1690 cmꢁ1; dH (400 MHz, CDCl3) 8.5
(1H, br, CONH), 7.22–7.35 (5H, m, Ph), 4.40 (2H, m,
CH2Ph), 2.94–3.0 (1H, m, H-4), 2.75–2.85 (1H, m, H-4),
2.24–2.33 (1H, m, H-2), 1.60–1.80 (3H, m, H-2 and H-3),
1.04 (9H, s, t-Bu); dC (400 MHz, CDCl3) 175.74, 138.95,
128.44, 127.56, 127.03, 75.73, 47.05, 43.16, 35.87, 31.19,
26.43, 26.28.
4.3.7. 2-Methyl-1-(trifluoroacetyl)prolylalanine (3g),
mixture of isomers. To a stirred solution of amide 1p
157 mg (0.5 mmol) in a mixture of MeOH/H2O (1:1,
5 ml), 69 mg (0.25 mmol) K2CO3 was added and the solu-
tion was stirred for 24 h at room temperature. The solvent
was removed in vacuo and the resulting crude residue was
treated with 0.2 ml of 50% aq CF3COOH and product was
extracted with ethyl-acetate (3ꢂ5 ml) and evaporated in
vacuo to yield 72% 3g as yellow oil [Found: C, 44.65; H,
5.12. C11H15F3N2O4 requires C, 44.60; H, 5.10%]; Rf (5%
4.3.11. Ethyl 2-methyl-N-{[2-phenyl-1-(trifluoroacetyl)-
piperidin-2-yl]carbonyl}alaninate (4d). Yield 71%, color-
less oil [Found: C, 57.77; H, 6.15. C20H25F3N2O4 requires C,
57.96; H, 6.08%]; Rf (50% EtOAc/hexane) 0.6; nmax (liquid
film) 2980, 1710, 1700, 1680 cmꢁ1; dH (400 MHz, CDCl3)
7.22–7.43 (5H, m, Ph), 6.4 (1H, br, NH), 4.07–4.19 (2H,
m, COOCH2CH3), 3.72–3.85 (1H, m, H-5), 3.37–3.45
(1H, m, H-5), 2.51–2.60 (1H, m, H-2), 1.17–2.24 (1H, m,
H-2), 1.74–1.88 (2H, m, H-3), 1.58–1.7 (2H, m, H-4), 1.50
(3H, s, CMeMe), 1.42 (3H, s, CMeMe), 1.22 (3H, t,
J 7.1 Hz, COOCH2Me); dC (400 MHz, CDCl3) 174.20,
169.52, 157.85 (q, J 35.9), 134.14, 129.11, 128.11, 126.73,
117.7 (q, J 289.1), 70.08, 61.31, 56.59, 43.36, 34.77,
24.50, 23.75, 23.14, 18.32, 13.98.
MeOH/CH3CN) 0.7; nmax (liquid film) 2950, 1690 cmꢁ1
;
dH (400 MHz, DMSO-d6) 7.90, 7.85 (1H, s, NH), 4.15–
4.25 (1H, m, CH), 3.65–3.85 (2H, m, H-4), 2.03–2.15 (1H,
m, H-2), 1.81–2.00 (3H, m, H-2 and H-3), 1.59, 1.48 (3H,
s, Me), 1.20–2.30 (3H, m, MeCH); dC (400 MHz, DMSO-
d6) 174.18, 174.13, 171.37, 171.25, 153.95 (q, J 36.4),
116.12 (q, J 288.4), 68.89, 68.77, 48.21, 47.85, 38.07,
38.01, 23.37, 20.29, 19.99, 17.03, 16.67.
4.3.8. N-Benzyl-2-butyl-1-(trifluoroacetyl)piperidine-2-
carboxamide (4a). Yield 84%, white solid, mp 91–29 ꢀC
[Found: C, 62.00; H, 6.90. C19H25F3N2O2 requires C,
61.61; H, 6.80%]; Rf (50% EtOAc/hexane) 0.50; nmax
(Nujol) 2970, 1690, 1670 cmꢁ1; dH (400 MHz, CDCl3)
7.22–7.37 (5H, m, Ph), 6.10 (1H, br, NH), 4.46 (2H, d, J
5.5 Hz, CH2Ph), 3.60–3.70 (1H, m, H-5), 3.39–3.49 (1H,
m, H-5), 2.42–2.52 (1H, m, H-2), 1.95–2.06 (1H, m, H-2),
1.60–1.90 (6H, m, H-3 and CH2CH2CH2CH3 and
CH2CH2CH2CH3), 1.22–1.39 (3H, m, CH2CH2CH2CH3
and H-4), 1.09–1.20 (1H, m, H-4), 0.87 (3H, t, J 7.0 Hz,
CH2CH2CH2Me); dC (400 MHz, CDCl3) 171.98, 155.75
(q, J 36.4), 138.25, 128.71, 127.60, 127.45, 116.0 (q, J
288.6), 66.65, 43.82, 42.71 (m), 34.35, 30.48 (C-2), 25.99,
22.85, 21.97, 16.55, 13.94.
4.3.12. Ethyl N-{[2-butyl-1-(trifluoroacetyl)piperidin-2-
yl]carbonyl}alaninate (4e), mixture of diastereomers,
ratio 1:1. Yield 78%, white solid, mp 83–84 ꢀC [Found: C,
53.50; H, 7.16. C17H27F3N2O4 requires C, 53.68; H,
7.15%]; Rf (50% EtOAc/hexane) 0.60; nmax (Nujol) 2980,
1740, 1690, 1680 cmꢁ1; dH (400 MHz, CDCl3) 6.47, 6.33
(1H, br, NH), 4.46–4.57 (1H, m, CH), 4.12–4.25 (2H, m,
COOCH2CH3), 3.65–3.75 (1H, m, H-5), 3.33–3.47 (1H, m,
H-5), 2.33–2.50 (1H, m, H-2), 1.95–2.10 (1H, m, H-2),
1.60–1.90 (7H, m, H-3, H-2, CH2CH2CH2Me and
CH2CH2CH2Me), 1.35–1.45 (3H, m, Me), 1.30–1.35
(2H, m, CH2CH2CH2Me), 1.27–1.30 (3H, t, J 7.6 Hz,
COOCH2Me), 1.05–1.17 (1H, m, H-4), 0.85–0.93 (3H, m,
CH2CH2CH2Me); dC (400 MHz, CDCl3) 173.11, 171.50,
171.37, 157.38 (q, J 35.9), 115.7 (q, J 289.1), 66.69, 66.04,
61.53, 48.47, 48.28, 42.68, 42.32, 33.87, 33.67, 30.32,
30.10, 25.88, 22.86, 22.01, 21.69, 18.30, 18.27, 16.52,
16.16, 14.07, 13.98.
4.3.9. N-Benzyl-2-phenyl-1-(trifluoroacetyl)piperidine-2-
carboxamide (4b). Yield 79%, white solid, mp 99–100 ꢀC

V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
5929
4.3.13. Ethyl N-{[2-phenyl-1-(trifluoroacetyl)piperidin-
2-yl]carbonyl}alaninate (4f), mixture of diastereomers,
ratio 1:1. Yield 72%, white solid, mp 96–97 ꢀC [Found: C,
57.05; H, 5.51. C19H23F3N2O4 requires C, 56.99; H,
5.79%]; Rf (50% EtOAc/hexane) 0.55; nmax (Nujol) 2960,
1730, 1700, 1690 cmꢁ1; dH (400 MHz, CDCl3) 7.20–7.50
(5H, m, Ph), 5.9, 6.4 (1H, br, NH), 4.41–4.52 (1H, m, CH),
4.10 (2H, q, J 7.1 Hz, COOCH2Me), 3.75–3.90 (1H, m, H-
5), 3.21–3.42 (1H, m, H-5), 2.52–2.64 (1H, m, H-2), 2.20–
2.40 (1H, m, H-2), 1.72–1.87 (2H, m, H-3), 1.55–1.69 (1H,
m, H-4), 1.38–1.52 (1H, m, H-4), 1.15–1.4 (6H, m, Me,
COOCH2Me); dC (400 MHz, CDCl3) 172.76, 172.43,
170.32, 169.98, 157.8 (q, J 36.0), 136.79, 135.68, 129.45,
129.20, 128.37, 128.28, 127.31, 127.78, 116.8 (q, J 289.2),
69.86, 61.38, 61.26, 48.74, 48.67, 43.61, 43.18 (m), 34.52,
34.07, 23.43, 23.14, 18.66, 18.18, 18.06, 17.59, 14.04, 13.94.
1.95–2.03 (3H, s, CH2CH2SMe), 1.67–1.83 (2H, m, H-3),
1.52–1.63 (1H, m, H-4), 1.26–1.40 (1H, m, H-4), 1.15–
1.25 (3H, m, COOCH2Me); dC (400 MHz, CDCl3) 174.20,
169.52, 158.00 (q, J 35.9), 137.14, 129.11, 128.11, 126.73,
116.5 (q, J 289.3), 70.08, 61.31, 56.89, 42.36 (m), 34.77,
24.50, 23.75, 23.14, 22.88, 18.32 (C-3), 13.98.
4.3.16. Diethyl N-{[2-phenyl-1-(trifluoroacetyl)piperidin-
2-yl]carbonyl}glutamate (4j), mixture of diastereomers,
ratio 1:1. Yield 69%, yellow oil [Found: C, 56.50; H, 6.05.
C23H29F3N2O6 requires C, 56.78; H, 6.01%]; Rf (50%
EtOAc/hexane) 0.50; nmax (liquid film) 2990, 1720, 1690,
1680 cmꢁ1; dH (400 MHz, CDCl3) 7.23–7.50 (5H, m, Ph),
6.4, 6.1 (1H, br, NH), 4.47–4.56 (1H, m, CH), 4.00–4.17
(4H, m, COOCH2CH3 and COOCH2CH3), 3.77–3.90 (1H,
m, H-5), 3.24–3.40 (1H, m, H-5), 2.50–2.60 (1H, m, H-2),
2.20–2.44 (3H, m, H-2 and CH2CH2COOEt), 2.13–2.18
(2H, m, CH2CH2COOEt), 1.73–1.90 (2H, m, H-3), 1.56–
1.67 (1H, m, H-4), 1.34–1.50 (1H, m, H-4), 1.15–1.28 (6H,
m, CH2CH2COOCH2Me and COOCH2Me); dC (400 MHz,
CDCl3) 172.30, 172.49, 171.53, 171.13, 170.62, 170.28,
157.53 (q, J 35.9), 136.40, 135.58, 129.33, 129.18, 128.45,
128.30, 127.23, 126.80, 116.3 (q, J 289.7), 69.77, 69.73,
61.46, 61.32, 60.43, 60.28, 52.14, 50.00, 43.47, 43.02 (m),
34.35, 34.00, 29.93, 27.03, 26.63, 23.35, 23.02, 18.50,
18.03, 13.94.
4.3.14. Ethyl N-{[2-phenyl-1-(trifluoroacetyl)piperidin-
2-yl]carbonyl}phenylalaninate (4g and 4h). Yield 84%,
ratio of the diastereomers 1:1.
Diastereomer 1: white solid, mp 96–97 ꢀC [Found: C,
63.05; H, 5.61. C25H27F3N2O4 requires C, 63.02; H,
5.71%]; Rf (50% EtOAc/hexane) 0.55; nmax (Nujol) 2960,
1730, 1700, 1690 cmꢁ1; dH (400 MHz, CDCl3) 7.20–7.41
(6H, m, Ph and Ph), 6.78–7.01 (4H, m, Ph), 6.2 (1H, br,
NH), 4.68–4.75 (1H, m, CH), 4.00 (2H, q, J 7.1 Hz,
COOCH2CH3), 3.63–3.75 (1H, m, H-5), 3.25–3.35 (1H, m,
H-5), 3.15–3.23 (1H, m, CH2Ph), 2.73–2.85 (1H, m,
CH2Ph), 2.33–2.45 (1H, m, H-2), 2.03–2.12 (1H, m, H-2),
1.60–1.75 (2H, m, H-3), 1.45–1.60 (1H, m, H-4), 1.23–1.38
(1H, m, H-4), 1.19 (3H, t, J 7.1 Hz, COOCH2Me); dC
(400 MHz, CDCl3) 170.98, 170.13, 156.5 (q, J 35.9),
136.41, 136.17, 129.30, 129.10, 128.28, 128.15, 126.73,
126.66, 116.5 (q, J 289.2), 69.87, 61.42, 53.57, 43.53 (m),
37.55, 34.52, 23.44, 18.65, 13.94.
4.3.17. Methyl N-{[2-phenyl-1-(trifluoroacetyl)piperidin-
2-yl]carbonyl}-L-phenylalaninate (4k and 4l). Yield 84%,
ratio of the diastereomers 1:1.
Diastereomer 1: colorless oil, crystallizes on standing
[Found: C, 62.35; H, 5.45. C24H25F3N2O4 requires C,
62.33; H, 5.45%]; Rf (50% EtOAc/hexane) 0.55; nmax (liquid
film) 2960, 1730, 1700, 1690 cmꢁ1; dH (400 MHz, CDCl3)
7.2–7.34 (6H, m, Ph and Ph), 6.98–7.05 (4H, m, Ph), 6.2
(1H, br, NH), 4.78–4.85 (1H, m, CH), 3.72–3.82 (1H, m,
H-5), 3.65 (3H, s, COOMe), 3.3–3.4 (1H, m, H-5), 3.15–
3.23 (1H, m, CH2Ph), 2.9–2.97 (1H, m, CH2Ph), 2.42–2.53
(1H, m, H-2), 2.08–2.18 (1H, m, H-2), 1.70–1.85 (2H, m,
H-3), 1.58–1.69 (1H, m, H-4), 1.34–1.44 (1H, m, H-4); dC
(400 MHz, CDCl3) 171.50, 170.19, 156.5 (q, J 35.9),
136.36, 136.03, 129.17, 129.08, 128.33, 128.13, 126.85,
126.66, 116.4 (q, J 289.1), 69.80, 53.44, 52.22, 43.50 (m),
37.44, 34.48, 23.38, 18.58.
Diastereomer 2: white solid, mp 112–113 ꢀC [Found: C,
63.12; H, 5.67. C25H27F3N2O4 requires C, 63.02; H,
5.71%]; Rf (50% EtOAc/hexane) 0.45; nmax (Nujol) 2960,
1730, 1700, 1690 cmꢁ1; dH (400 MHz, CDCl3) 7.20–7.35
(3H, m, Ph), 7.15–7.20 (2H, m, Ph), 6.91–7.05 (3H, m,
Ph), 6.76–6.83 (2H, Ph), 5.90 (1H, br, NH), 4.70–4.80
(1H, m, CH), 4.01 (2H, q, J 7.1 Hz, COOCH2Me), 3.63–
3.74 (1H, m, H-5), 3.12–3.21 (1H, m, H-5), 2.70–2.97
(2H, m, CH2Ph), 2.40–2.50 (1H, m, H-2), 2.20–2.38
(1H, m, H-2), 1.62–1.75 (2H, m, H-3), 1.43–1.57 (1H, m,
H-4), 1.23–1.35 (1H, m, H-4), 1.1 (3H, t, J 7.1 Hz,
COOCH2Me); dC (400 MHz, CDCl3) 171.03, 170.22,
156.6 (q, J 35.9), 136.50, 136.21, 129.33, 129.09, 128.28,
128.13, 126.68, 126.65, 116.4 (q, J 289.2), 69.89, 61.43,
53.61, 43.49 (m), 37.56, 34.52, 23.47, 18.44, 13.97.
Diastereomer 2: colorless oil, crystallizes on standing
[Found: C, 62.30; H, 5.48. C24H25F3N2O4 requires C,
62.33; H, 5.45%]; Rf (50% EtOAc/hexane) 0.45; nmax (liquid
film) 2960, 1730, 1700, 1690 cmꢁ1; dH (400 MHz, CDCl3)
7.30–7.42 (3H, m, Ph), 7.21–7.27 (2H, m, Ph), 7.05–7.14
(3H, m, Ph), 6.84–6.90 (2H, m, Ph), 6.0 (1H, br, NH),
4.82–4.89 (1H, m, CH), 3.71–3.80 (1H, m, H-5), 3.65 (3H,
s, Me), 3.2–3.29 (1H, m, H-5), 2.95–3.08 (2H, m, CH2Ph),
2.46–2.56 (1H, m, H-2), 2.28–2.35 (1H, m, H-2), 1.65–
1.82 (2H, m, H-3), 1.54–1.65 (1H, m, H-4), 1.31–1.42
(1H, m, H-4); dC (400 MHz, CDCl3) 171.54, 169.90,
157.00 (q, J 36.0), 135.76, 135.43, 129.30, 128.91, 128.39,
127.05, 126.71, 116.5 (q, J 289.1), 69.84, 53.01, 51.99,
43.50 (m), 37.19, 34.13, 23.15, 18.34.
4.3.15. Ethyl N-{[2-phenyl-1-(trifluoroacetyl)piperidin-
2-yl]carbonyl}methioninate (4i), mixture of diastereo-
mers, ratio 1:1. Yield 68%, yellow oil [Found: C, 54.50;
H, 5.55. C21H27F3N2O4S requires C, 54.77; H, 5.91%]; Rf
(50% EtOAc/hexane) 0.50; nmax (liquid film) 2990, 1730,
1690 cmꢁ1; dH (400 MHz, CDCl3) 7.20–7.50 (5H, m, Ph),
6.4, 6.2 (1H, br, NH), 4.52–4.67 (1H, m, CH), 4.07–4.15
(2H, m, COOCH2Me), 3.75–3.90 (1H, m, H-5), 3.21–3.40
(1H, m, H-5), 2.50–2.60 (1H, m, H-2), 2.32–2.48 (3H, m,
H-2 and CH2CH2SCH3), 2.15–2.29 (2H, m, CH2CH2SMe),
4.3.18. 7-Phenyl-1-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-
azepine (5a). Yield 68%, yellow oil [Found: C, 62.33; H,

5930
V. G. Nenajdenko et al. / Tetrahedron 62 (2006) 5922–5930
7. (a) Dumy, P.; Keller, M.; Ryan, D. E.; Rohwedder, B.; Wohr, T.;
Mutter, M. J. Am. Chem. Soc. 1997, 119, 918–925; (b)
Beausoleil, E.; Sharma, R.; Michnick, S. W.; Lubell, W. D.
J. Org. Chem. 1998, 63, 6572–6578; (c) Beausoleil, E.;
Lubell, W. D. J. Am. Chem. Soc. 1996, 118, 12902–12908;
(d) Delaney, N. G.; Madison, V. J. Am. Chem. Soc. 1982, 104,
6635–6641; (e) Chalmers, D. K.; Marshall, G. R. J. Am. Chem.
Soc. 1995, 117, 5927–5937; (f) Grathwohl, C.; Wuthrich, K.
Biopolymers 1981, 20, 2623–2633.
5.34. C14H14F3NO requires C, 62.54; H, 5.24%]; Rf (30%
EtOAc/hexane) 0.70; nmax (liquid film) 1690, 1640 cmꢁ1
;
dH (400 MHz, CDCl3) 7.25–7.40 (5H, m, Ph), 6.45 (1H, m,
CH), 4.4–4.7 (2H, m, H-6), 2.3–2.4 (2H, m, H-3), 1.80–
2.13 (3H, m, H-4, H-5), 1.31–1.45 (1H, m, H-5); dC
(400 MHz, CDCl3) 154.5 (q, J 36.1), 142.51, 136.50,
128.67, 128.33, 127.30, 124.09, 115.9 (q, J 289.1), 48.80,
28.66, 26.59, 23.72.
8. Wu, W. J.; Raleigh, D. R. J. Org. Chem. 1998, 63, 6689–6698.
9. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–
4.3.19. 2-Methylene-1-(trifluoroacetyl)azepane (5b).
Yield 71%, yellow oil [Found: C, 52.23; H, 5.74.
C9H12F3NO requires C, 52.17; H, 5.84%]; nmax (liquid
film) 1690, 1650 cmꢁ1; dH (400 MHz, CDCl3) 5.15 (1H, s,
HHC]C), 5.03 (1H, s, HHC]C), 3.57–3.68 (2H, m, H-
6), 2.40–2.50 (2H, m, H-2), 1.71–1.81 (2H, m, H-3), 1.55–
1.69 (4H, m, H-4 and H-5); dC (400 MHz, CDCl3) 155.6
(q, J 36.3), 138.15, 116.90 (q, J 289.1), 109.82, 48.56,
34.29, 28.13, 26.08, 23.65.
¨
3210; (b) Domling, A. Chem. Rev. 2006, 106, 17–89.
¨
10. (a) Flanagan, D. M.; Joullie, M. M. Synth. Commun. 1989,
19, 1–12; (b) Bowers, M. M.; Carroll, P.; Joullie, M. M.
J. Chem. Soc., Perkin Trans. 1 1989, 857–865; (c) Hatam,
M.; Tehranfar, D.; Martens, J. Synthesis 1994, 619–623; (d)
Groger, H.; Hatam, M.; Martens, J. Tetrahedron 1995, 51,
7173–7180; (e) Zychlinski, A.; Ugi, I. Heterocycles 1998, 49,
29–32; (f) Maison, W.; Lutzen, A.; Kosten, M.; Schlemminger,
I.; Westerho, O.; Martens, J. J. Chem. Soc., Perkin Trans. 1
1999, 3515–3525; (g) Maison, W.; Lutzen, A.; Kosten, M.;
Schlemminger, I.; Westerho, O.; Saak, W.; Martens, J.
J. Chem. Soc., Perkin Trans. 1 2000, 1867–1871; (h) Schlem-
minger, I.; Janknecht, H. H.; Maison, W.; Saak, W.; Martens, J.
Tetrahedron Lett. 2000, 41, 7289–7292; (i) Banfi, L.; Basso,
A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2004, 45, 6637–
6640; (j) Chapman, T. M.; Davies, L. G.; Gu, B.; Block,
T. M.; Scopes, D. C.; Hay, P. A.; Courtney, S. M.; McNeill,
L. M.; Schofield, C. J.; Davis, B. G. J. Am. Chem. Soc. 2005,
127, 506–507; (k) Timmer, M.; Risseeuw, M.; Verdoes, M.;
Filippov, D.; Plaisier, J.; Van der Marel, G.; Overkleeft, H.;
Van Boom, J. Tetrahedron: Asymmetry 2005, 16, 177–185.
11. (a) Hua, D.; Miao, S.; Bharathi, N.; Katsuhira, T.; Bravo, A.
J. Org. Chem. 1990, 55, 3682–3684; (b) Haslego, M.;
Maryanoff, C.; Scott, L.; Sorgi, K. Heterocycles 1993, 35,
643–647.
Acknowledgements
Financial support from Russian Science Support Foundation
is gratefully acknowledged.
References and notes
1. Rutjes, F. P. J. T.; Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc.,
Perkin Trans. 1 2000, 4197–4212.
2. (a) Willims, M.; Kowaluk, E. A.; Arneric, S. P. J. Med. Chem.
1999, 42, 1481–1500; (b) Dutta, A. S. Drugs Future 1988, 13,
43–44; (c) Dutta, A. S. Drugs Future 1988, 13, 761–762; (d)
Patane, M. A.; DiPardo, R. M.; Price, R. A. P.; Chang,
R. S. L.; Ransom, R. W.; O’Malley, S. S.; Di Salvo, J.;
Block, M. G. Bioorg. Med. Chem. Lett. 1998, 8, 2495–2500;
(e) Freidinger, R. M. J. Med. Chem. 2003, 46, 5553–5566; (f)
Huruby, V. J. Acc. Chem. Res. 2001, 34, 389–397; (g) Roy,
R. S.; Balarm, P. J. Pept. Res. 2004, 63, 279–289.
12. (a) Juaristi, E. Conformational Behavior of Six-membered
Rings; VCH: New York, NY, 1995; pp 159–196; (b) Glass, R.
Conformational Analysis of Medium-sized Heterocycles;
VCH: New York, NY, 1988; pp 98–106.
3. Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789–12854.
13. Kocienski, P. Protecting Groups; Georg Thieme: Stuttgard:
New York, NY, 1994; pp 190–191.
4. Voet, D.; Voet, J.; Pratt, C. Fundamentals of Biochemistry;
Wiley: New York, NY, 1999; pp 127–128.
14. Ugi, I. Isonitrile Chemistry; Academic: New York, NY, and
London, 1971; 73–74.
5. Lummis, S. C. R.; Beene, D. L.; Lee, L. W.; Lester, H. A.;
Brodhurst, R. W.; Dougherty, D. A. Nature 2005, 248–
252.
6. (a) Soth, M.; Nowick, J. S. J. Org. Chem. 1999, 64, 276–281;
(b) Hanessian, S.; Blanco, M. J.; Paleo, M. R.; Penide, C.;
Sardina, F. J. J. Org. Chem. 1999, 64, 8786–8793.
15. Zhu, J.; Bienayme, H. Multicomponent Reaction; Wiley-VCH:
Weinheim, 2005; pp 1–33.
16. Giesemann, G.; Von Hinrichs, E.; Ugi, I. J. Chem. Res.
1982, 79.
17. Eliel, E.; Wilen, S.; Mander, L. Stereochemistry of Organic
Compounds; Wiley: New York, NY, 1994; 758–759.