A facile and efficient synthesis of 2,2,2-trifluoroethyl 2-[(E)-N-phenylcinnamamido]-2-phenylacetates in trifluoroethanol via sequential Ugi four-component reaction/esterification

Article abstract of DOI:10.1016/j.tetlet.2012.08.096

We describe an efficient approach for the synthesis of N-substituted 2-alkenylamides in trifluoroethanol via an Ugi 4-component reaction in short reaction times. The use of a catalytic amount of sulfuric acid in trifluoroethanol gave the desired trifluoroethyl derivatives in good to high yields.

Full text of DOI:10.1016/j.tetlet.2012.08.096

Tetrahedron Letters 53 (2012) 6177–6181
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Tetrahedron Letters
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A facile and efficient synthesis of 2,2,2-trifluoroethyl
2-[(E)-N-phenylcinnamamido]-2-phenylacetates in trifluoroethanol
via sequential Ugi four-component reaction/esterification
Saeed Balalaie a, , Hassan Motaghedi a, Daryoush Tahmassebi b, , Morteza Bararjanian a,
⇑
⇑
Hamid Reza Bijanzadeh a,c
a Peptide Chemistry Research Center, K.N. Toosi University of Technology, PO Box 15875-4416, Tehran, Iran
b Chemistry Department, Indiana University–Purdue University Fort Wayne, Fort Wayne, IN 46805, USA
c Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2012
Revised 6 August 2012
Accepted 24 August 2012
Available online 3 September 2012
We describe an efficient approach for the synthesis of N-substituted 2-alkenylamides in trifluoroethanol
via an Ugi 4-component reaction in short reaction times. The use of a catalytic amount of sulfuric acid in
trifluoroethanol gave the desired trifluoroethyl derivatives in good to high yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Majid M. Heravi on
the occasion of his 60th birthday
Keywords:
Ugi-4CR
Trifluoroethanol
Sequential Ugi-4CR/trifluoroethyl
esterification
Multicomponent reactions (MCRs) have attracted considerable
interest owing to their exceptional synthetic efficiency.1,2 MCRs
have a high attendant bond forming efficiency and easily install
molecular complexity and diversity.3 The wide variation in starting
materials available for MCRs opens up versatile opportunities for
the synthesis of compound libraries. Reactions that result in the
formation of carbon–carbon, carbon–nitrogen, and other carbon–
heteroatom bonds at the same time, and that introduce hetero-
atom-containing functionality into structural frameworks are
especially attractive for the rapid construction of organic
molecules.4
Isocyanide-based MCRs (IMCRs) allow the synthesis of a large
number of different scaffolds. The significant potential of isocya-
nides for the development of multicomponent reactions is a result
of their ability to take part in diverse bond formation processes,
their functional group tolerance, and the high levels of chemo-, re-
gio-, and stereoselectivity often observed.5 Therefore, the design of
novel IMCRs, has attracted attention in areas such as drug
discovery, organic synthesis, combinatorial chemistry, and materi-
als science.6
Highly fluorinated alcohols exhibit very good hydrogen bonding
donor ability, low nucleophilicity, high ionizing power, and ability
for hydrogen bonding with water. Reactions in fluorinated alcohols
are generally selective and do not result in by-product formation.
Also, isolation of the products is simple and fluorinated alcohols
can be easily recovered by distillation.7
Among several fluorinated alcohols, the most commonly used
and the cheapest are trifluoroethanol (TFE) and hexafluoroisopro-
panol (HFIP).8 Due to their activity, these solvents have been used
for various reactions, such as the activation of orthoesters,9 synthe-
sis of heterocycles,10 and condensation reactions.11
The Ugi 4-component reaction (Ugi-4CR) is one of the corner-
stones of multicomponent processes, and many efforts have been
devoted to the exploration of the potential of this transformation.12
According to the literature, pseudopeptides have been prepared
via the Ugi-4CR of an appropriate primary amine, carbaldehyde,
isocyanide, and carboxylic acid derivative in an organic solvent.
This reaction normally takes about 24 h, and in some cases with
substituted amines or carboxylic acids up to seven days. Hence,
there is a strong demand for a highly efficient and environmentally
benign method to prepare functionalized pseudopeptides. In
⇑
Corresponding authors.
E-mail addresses: balalaie@kntu.ac.ir (S. Balalaie), tahmassd@ipfw.edu (D.
Tahmassebi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.096

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S. Balalaie et al. / Tetrahedron Letters 53 (2012) 6177–6181
continuation of our interest in multicomponent reactions, we re-
port the Ugi-4CR in trifluoroethanol for the synthesis of novel N-
substituted alkenylamides 5a–g and sequential trifluoroethyl
esterification in trifluoroethanol to afford 2,2,2-trifluoroethyl es-
ters 6a–g using catalytic sulfuric acid. Initially, the four-component
reaction of benzaldehyde 1, primary amines 2, unsaturated carbox-
ylic acids 3, and isocyanide 4, in TFE at room temperature leads to
N-substituted alkenylamides 5 (Scheme 1). The products 5 could
be converted into the trifluoroethyl esters 6 in the presence of a
catalytic amount of sulfuric acid (Scheme 1).
(TFA), silica sulfuric acid (SSA), and the Lewis acids cuprous iodide
and zinc chloride were used. In the case of methanesulfonic acid, a
mixture of products was obtained, and in the other cases, trifluoro-
ethyl ester 6a was not formed. The results are summarized in
Table 1.
When cuprous iodide or zinc chloride was used, the obtained
products were separated and identified as
a-amino amide 7 and
unsaturated ester 8 (Scheme 3).
It would appear that the formation of a complex with the metal
increases the electrophilicity of the ,b-unsaturated amide group
a
2,2,2-Trifluoroethanol exhibits high ionization ability and can
promote reactions with polar intermediates.13–15 It is well known
that the Ugi-4CR involves an initial condensation between a pri-
mary amine and a carbonyl compound to form an imine, followed
by protonation of the imine by a carboxylic acid. The resulting
iminium ion reacts with the isocyanide and the carboxylate. It is
clear that formation of the intermediate iminium ion could be
accelerated in trifluoroethanol. To examine this idea, the four-com-
ponent reaction of benzaldehyde, aniline, cinnamic acid, and t-bu-
tyl isocyanide was selected as a model system. The reaction was
studied in methanol as the usual solvent for the Ugi-4CR and also
in TFE. TLC analysis showed that the reaction in TFE was complete
after 11 h, while 24 h were required in methanol. The yield of the
5a was 75% in MeOH and 85% in TFE. The spectroscopic data of
product 5a were identical to those of an authentic sample. In an-
other reaction, the Ugi product was not isolated and two drops of
concentrated sulfuric acid were added to the mixture. Following
work-up, spectroscopic data revealed that the product was trifluo-
roethyl ester 6a. We assume that the expected Ugi product 5a, ini-
tially formed under the reaction conditions, subsequently
undergoes spontaneous irreversible amide acidic esterification to
form the trifluoroethyl ester 6a (Scheme 2).
and enhances nucleophilic acyl substitution by TFE (Scheme 4).
These results encouraged us to explore the optimized reaction
conditions with different carboxylic acids and primary amines.
The results are summarized in Table 2.
The structures of the products 6a–g were characterized using
spectroscopic data. In 6b there was a doublet of quartets for the
CH2–CF3 and a signal in the region d 6.15–6.30 due to the –
C(sp3)–H hydrogen atom, but in some cases methylene was ob-
served as a multiplet. The E-configuration of the double bond
was identified by the magnitude of the coupling constant between
the two alkene protons (ca. 15.5 Hz). The atypical chemical shift for
the alkene protons is due to the conjugation of double bond with
the adjacent carbonyl moiety. A notable signal in 13C NMR spectra
of the products is that of the –OCH2 group which occurs as a quar-
tet at d 60.9 as a result of the coupling with the trifluoromethyl
moiety. The carbonyl group resonances in the 13C NMR spectra of
compound 6a appeared at d 166.6–169.1 ppm. The mass spectra
of these compounds displayed molecular ion peaks at the expected
m/z values.
To investigate in more detail this sequential Ugi/esterification
method, we performed the reaction in two separate steps. The first
step was an Ugi-4CR between the aromatic aldehyde, aniline deriv-
ative, cinnamic acid, and t-butyl isocyanide to form the Ugi-
pseudopeptides 5a–g. Next, these products were hydrolyzed and
To investigate the effect of acid on this reaction, different
Brønsted acids such as methanesulfonic acid, trifluoroacetic acid
O
OH
R2
R2
R2
R1
R1
CHO
3
CF3CH2OH
O
H
N
H2SO4
N
N
O
O
C
N
CF3CH2OH
CF3
4
NH2
O
O
1
6a-g
5a-g
R1
2
Scheme 1.
O
OH
CHO
H2SO4
CF3CH2OH
N
O
O
CF3CH2OH
O
H
N
N
C
N
CF3
NH2
O
O
5a
6a
Scheme 2. Synthesis of 2,2,2-trifluoroethyl 2-[(E)-N-phenylcinnamamido]-2-phenylacetate 6a as a model compound.

S. Balalaie et al. / Tetrahedron Letters 53 (2012) 6177–6181
6179
Table 1
Identification of suitable reaction conditions for the synthesis of compound 6a
Table 2
Synthesis of trifluoroethyl ester via sequential Ugi-4CR/esterification reactions
Catalyst
Temperature
Products
Yield (%)
R1 R2 Product
R1 R2 Product
CF3SO3H
TFA
SSA
CuI
ZnCl2
H2SO4
rt
Several products
0
0
0
0
0
Reflux or rt
Reflux or rt
Reflux or rt
Reflux or rt
rt
NR
NR
NR
NR
6a
Cl
55
N
O
O
N
O
O
H
H
Cl
H
CF3
CF3
NR = no reaction.
O
O
6a
6e
55%, 11 h
55%, 11 h
Cl
Cl
NH
H
CuI or ZnCl2
CF3CH2OH
O
N
N
H
N
O
Cl
F3C
O
O
O
N
O
O
N
O
O
8
7
5a
H
Cl
Cl
Cl
CF3
CF3
Scheme 3.
O
O
6f
6b
50%, 12 h
52%, 12 h
CF3CH2-OH
Cl
NH
H
N
Et
N
O
O
Cu+
Br
F3C
O
O
O
N
O
O
HN
CF3
N
O
O
8
Br Cl
Et
H
7
CF3
O
Scheme 4. Formation of amino amide 7 in the presence of CuI or ZnCl2.
O
6g
6c
60%, 10 h
51%, 12 h
esterified as a domino process to form esters 6a–g in 50–60%
yields. The proposed mechanism is shown in Scheme 5. It seems
reasonable to propose that the high polarity via stabilization of
the iminium salts and the hydrogen bonding interaction of TFE
may be responsible for promoting the reaction.
Br
In conclusion, we have described TFE as an efficient medium for
the synthesis of N-substituted alkenylamides in good isolated
yields. In contrast to the existing methods which require between
24 and 36 h for the completion of the Ugi reaction, the present
method offers the following competitive advantages: (i) shorter
reaction times, (ii) higher yields compared to the reported meth-
ods. The corresponding trifluoroethyl ester derivatives 6a–g were
formed via the addition of a catalytic amount of sulfuric acid to
form the trifluoroethyl esters in good yields.
N
O
O
CF3
Br
H
O
6d
57%, 11 h
organic layers were dried with sodium sulfate, and concentrated
to dryness in vacuum. The final purification was done by silica
gel column chromatography eluted by an EtOAc/hexane (1:3) mix-
ture, to afford the corresponding pure 6a–g with 50–60%.
General procedure for the synthesis of 2,2,2-trifluoroethyl 2-
[(E)-N-phenylcinnamamido]-2-phenylacetates 6a–g
Aniline derivative (1 mmol), aldehyde (1 mmol), and TFE (5 mL)
were stirred for 30 min. Then, cinnamic acid (148 mg, 1 mmol) and,
after 15 min, t-butyl isocyanide (83 mg, 1 mmol) were added and
the mixture was stirred for 10–11 h. The progress of the reaction
was monitored by TLC (eluent hexane/ethyl acetate 5:1). Sulfuric
acid (98%, 2 drops) was added to the solution of Ugi adduct in
TFE. The mixture was stirred at room temperature for 10 min.
The progress of the reaction was monitored by TLC (eluent hex-
ane/ethyl acetate 3:1).
Selected data for compounds 6a–g: 2,2,2-trifluoroethyl 2-[(E)-N-
phenylcinnamamido]-2-phenylacetate (6a)
IR (NaCl, cmÀ1):
t
1647, 1684, 3303; 1H NMR (CDCl3, 300 MHz)
d (ppm) 4.55–4.77 (m, 2H, OCH2), 6.24 (s, 1H, CH), 6.26 (d,
J = 15.4 Hz, 1H, C@CH), 7.14–7.33 (m, 15H, H-Ar), 7.79 (d,
J = 15.5 Hz, 1H, C@CH); 13C NMR (CDCl3, 75 MHz) d (ppm) 60.9
(q, J = 36.5 Hz, OCH2), 64.0, 117.7, 120.9, 124.6, 128.0, 128.3,
128.6, 128.7, 128.9, 129.2, 130.0, 132.0, 132.5, 134.4, 134.7,
After this time, the reaction mixture was evaporated and after
washing with H2O was extracted with EtOAc. The combined

6180
S. Balalaie et al. / Tetrahedron Letters 53 (2012) 6177–6181
H
N
R2
O
O
R1
O
HO
R1
H
H
N
H
N
H
R2
R3CO2H
R3
R3
O
R2
R1
R1
R2 NH2
H
C
N
R4
R4
R4
H
O
N
N
R2
R1
H
N
O
N
O
H2SO4
HOCH2CF3
R3
O
R4
NH
R2
O
R1
R1
R3
N
R2
R3
O
R3
R3
R2
R1
R2
R1
O
O
N
H
N
R2
R1
H
HOCH2CF3
Proton exchange
Proton exchange
N
O
O
NH3
R4
OCH2CF3
R4
N
CF3
NH2
R4
HO
O
Scheme 5. Proposed mechanism for the sequential Ugi/trifluoroethyl esterification.
143.7, 166.6, 169.1; HR-MS (ESI) Calcd for C25H21F3NO3 [M+1]+
440.14678. Found 440.14680, Calcd for C25H20F3NNaO3 [M+Na]+
462.12875. Found 462.12875.
2,2,2-Trifluoroethyl 2-[(E)-N-(4-ethylphenyl)cinnamamido]-2-
phenylacetate (6g)
IR (KBr, cmÀ1): 1655, 1767; 1H NMR (CDCl3, 300 MHz) d (ppm)
t
4.50–4.74 (m, 2H, OCH2), 6.16 (s, 1H, CH), 6.26 (d, J = 15.6 Hz, 1H,
2,2,2-Trifluoroethyl 2-[(E)-3-(4-chlorophenyl]-N-
phenylacrylamido)-2-phenylacetate (6b)
C@CH), 7.06–7.32 (m, 13H, H-Ar), 7.75 (d, J = 15.6 Hz, 1H, C@CH);
13C NMR (CDCl3, 75 MHz):
d (ppm) = 15.3, 28.4, 60.9 (q,
J = 36.5 Hz, OCH2), 64.7, 118.3, 121.0, 124.7, 127.7, 128.0, 128.4,
128.5, 128.6, 128.7, 129.6, 129.7, 130.0, 130.1, 133.1, 135.0,
136.7, 143.0, 144.6, 166.8, 169.1; HR-MS (ESI) Calcd for
C
C
IR (NaCl, cmÀ1):
t
1655, 1767.1654, 1767; 1H NMR (CDCl3,
300 MHz) d (ppm) 4.49–4.74 (dq, 2H, J = 12.6, 8.4 Hz, OCH2), 6.17
(d, J = 15.5 Hz, 1H, C@CH), 6.19 (s, 1H, CH), 7.08–7.26 (m, 14H, H-
Ar), 7.69 (d, J = 15.5 Hz, 1H, C@CH); 13C NMR (CDCl3, 75 MHz) d
(ppm) 60.9 (q, J = 36.5 Hz, OCH2), 64.5, 118.6, 120.9124.6, 128.4,
128.7, 128.9, 129.0, 129.1, 130.0, 130.4, 132.8, 133.4, 135.6,
138.9, 141.7, 166.4, 169.0; HR-MS (ESI) Calcd for C25H20Cl F3NO3
[M+1]+ 474.10782. Found 474.10783, Calcd for C25H19ClF3NNaO3
[M+Na]+ 496.08975. Found 496.08978.
27H25F3NO3 [M+1]+ 468.17791. Found 468.17810, Calcd for
27H24F3NNaO3 [M+Na]+ 490.15998. Found 490.16005.
Acknowledgments
S.B. gratefully acknowledges the Alexander von Humboldt foun-
dation for research fellowship. We are also grateful to Professor
T.J.J. Mueller for fruitful and helpful discussions.
2,2,2-Trifluoroethyl 2-[(E)-N-(4-chlorophenyl)cinnamamido]-2-
phenylacetate (6e)
Supplementary data
IR (NaCl, cmÀ1):
(ppm) 4.49–4.75 (m, 2H, OCH2), 6.18 (d, J = 15.5 Hz, 1H, C@CH),
t
1653, 1767; 1H NMR (CDCl3, 300 MHz) d
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
08.096.
6.28 (s, 1H, CH), 7.06–7.31 (m, 13H, H-Ar), 7.76 (d, J = 15.5 Hz,
1H, C@CH); 13C NMR (CDCl3, 75 MHz)
d (ppm) 60.9 (q,
J = 36.5 Hz, OCH2), 64.0, 117.7, 120.9, 124.6, 128.0, 128.3, 128.6,
References and notes
128.7, 128.9, 129.2, 130.0, 132.0, 132.5, 134.4, 134.7, 143.7,
166.6, 169.1; HR-MS (ESI) Calcd for
C
25H20ClF3NO3 [M+1]+
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2-phenylacetate (6f)
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t
1647, 1684, 3303; 1H NMR (CDCl3, 300 MHz)
d (ppm) 4.48–4.74 (m, 2H, OCH2), 6.14 (d, J = 15.5 Hz, 1H, C@CH),
6.27 (s, 1H, CH), 7.04–7.28 (m, 13H, H-Ar), 7.69 (d, J = 15.5 Hz,
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133.1, 134.5, 135.9, 137.2, 142.3, 166.3, 169.1; HR-MS (ESI) Calcd
for C25H19Cl2F3NO3 [M+1]+ 508.06883. Found 508.06886, Calcd
for C25H18Cl2F3NNaO3 [M+Na]+ 530.05077. Found 530.05080.

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