Synthesis of β,γ-unsaturated primary amides from α,β-unsaturated acids and investigation of the mechanism

Article abstract of DOI:10.1016/j.tet.2011.05.096

α,β-Unsaturated acids, through their acid chlorides, react with tritylamine in the presence of triethylamine under mild conditions, to afford in high yield and high regioselectivity the corresponding β,γ- unsaturated tritylamides. Detritylation with TFA generates quantitatively β,γ-unsaturated primary amides. An investigation of this deconjugative isomerization was performed.

Full text of DOI:10.1016/j.tet.2011.05.096

Tetrahedron 67 (2011) 5630e5634
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Synthesis of
b,
g
-unsaturated primary amides from
a
,b
-unsaturated acids
and investigation of the mechanism
,
a
a
b
Vassiliki Theodorou a , Marina Gogou , Maria Philippidou , Valentine Ragoussis ,
*
Georgios Paraskevopoulos a, Konstantinos Skobridis a
a Department of Chemistry, University of Ioannina, GR-45110, Greece
b Department of Chemistry, University of Athens, Zografou, GR-15771 Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
a
,
b
-Unsaturated acids, through their acid chlorides, react with tritylamine in the presence of triethyl-
amine under mild conditions, to afford in high yield and high regioselectivity the corresponding
-unsaturated tritylamides. Detritylation with TFA generates quantitatively -unsaturated primary
amides. An investigation of this deconjugative isomerization was performed.
Received 1 March 2011
Received in revised form 5 May 2011
Accepted 23 May 2011
b
,
g
b,g
Available online 30 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tritylamine
b
b
,
,
g
-Unsaturated N-tritylamides
g-Unsaturated primary amides
3-Alkenamides
Isomerization
Detritylation
1. Introduction
as, for example, the reaction of the corresponding acyl chlorides
with ammonia3a,3c and the hydration of -unsaturated nitriles.2g,3b
b,g
The development of efficient methods for the synthesis of am-
ides remains a great challenge because of their importance in
chemistry and biology, as valuable intermediates in organic syn-
thesis and with a wide range of applications in industry.
However the above precursors are not always readily accessible.
Ragoussis et al. prepared (E)-3-alkenoic acids, in good yields, by
a modified Knoevenagel condensation.4 In addition, starting from
allylic compounds, b,g-unsaturated amides were obtained by rho-
In the course of our ongoing interest in tritylamine reactions and
their synthetic uses,1 we have designed the synthesis of primary
amines and primary amides by aminotritylation of the corre-
sponding halides or acid chlorides and subsequent detritylation
with TFA, under mild conditions. A wide range of carboxylic acids
and derivatives were successfully converted to their corresponding
primary amides.1d During this study it has been observed that the
described procedure, applied on an E-2-unsaturated acid, did not
gave the expected E-2-unsaturated amide, but a deconjugative
isomerization occurred and the corresponding 3-unsaturated am-
ide was obtained in high yield.
dium carbonyl-catalyzed azacarbonylation of allyl phosphates5
and by treatment of allylic alcohols with N,N-dimethylformamide
acetals, giving
of -dialkylphosphoryl-
unsaturated amides.7 Moreover, several palladium-catalyzed
b,g
-unsaturated N,N-dimethylamides.6 Aminolysis
b
g-lactones, provided preferentially (E)-b,g-
methods for the synthesis of important
b,g-unsaturated amides
have been reported.8
The present work was undertaken in order to establish an effi-
cient procedure to
of tritylamine with
b,
g
-unsaturated primary amides by the reaction
-unsaturated acid halides and subsequent
a,
b
detritylation by TFA, under mild conditions. Moreover, an in-
vestigation of the deconjugative isomerization of the -un-
Although the
b
,g-unsaturated primary amides are synthetically
a,b
important key intermediates and useful precursors for various im-
portant and biologically active compounds,2 there is no extensive
literature on their synthesis. In general, traditional methods are
saturated acid derivatives, during the tritylation process, was
performed in our laboratory.
suggested for the conversion of b,g-unsaturated carboxylic acids (3-
2. Results and discussion
alkenoic acids) and their derivatives to the corresponding amides,3
The reaction of
a,b-unsaturated acyl chlorides with tritylamine
* Corresponding author. E-mail address: vtheodor@cc.uoi.gr (V. Theodorou).
and the subsequent detritylation of the N-tritylamides1d was
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.096

V. Theodorou et al. / Tetrahedron 67 (2011) 5630e5634
5631
further investigated to explore the optimal reaction conditions, in
order to finally obtain the desired unsaturated primary amides. In
In a similar way, under the same reaction conditions, we treated
two different -unsaturated acyl chlorides (crotonic chloride and
a,b
a typical procedure the
a
,
b
-unsaturated acyl chlorides, derived
2-hexenoic chloride) with a series of several amines, in the pres-
ence or not of Et3N, in order to study the possible deconjugation of
the double bond in the corresponding substituted amides. The re-
sults are summarized in Table 2. The ratio of the substituted amides,
appearing in the Table 2, is deduced from the 1H NMR spectra.
The isomerization appeared to be dependent on the steric hin-
drance of the amine-reagent as well on the size and the basicity of
the amine present in the medium of the reaction. Thus, only in the
from the corresponding E-2-alkenoic acids, were treated with
triethylamine in dichloromethane at 0 ꢀC, followed by the addition
of tritylamine. The N-tritylamides were isolated in high yield after
work-up. Surprisingly it has been observed that, in almost all the
cases, the expected
a,b-unsaturated N-tritylamide was not
obtained, but the -unsaturated tritylamide, regioselectively and
b,g
in high yield. Detritylation of these N-tritylamides by TFA in DCM at
rt, followed by the addition of triisopropylsilane Pr3SiH, gave al-
i
case of the bulky tritylamine in the presence of Et3N, was the b,g-
most quantitatively the primary
tures of their geometrical isomers. The results are summarized in
Table 1.
b
,
g
-unsaturated amides, as mix-
unsaturated N-tritylamide the sole product. In all the other cases,
either mixtures of conjugated and deconjugated products, or only
the conjugated products were obtained. As confirmed from the 1H
Table 1
Synthesis of
b,g-unsaturated primary amides from a,b-unsaturated acyl chlorides, using tritylamine and triethylamine
Substrate
N-Tritylamidea
Amideb
Ref.
CH3CH]CHCOCl
CH3CH2CH]C(CH3)COCl
CH2]CHCH2CONHTr
CH2]CHCH2CONH2
d
3a,c
d
CH3CH]CHCH(CH3)CONHTr (22%)
þCH3CH2CH]C(CH3)CONHTr (78%)
CH3CH2CH]CHCH2CONHTr
CH3(CH2)2CH]CHCH2CONHTr
CH3(CH2)3CH]CHCH2CONHTr
CH3(CH2)4CH]CHCH2CONHTr
CH3(CH2)5CH]CHCH2CONHTr
CH3(CH2)2CH]CHCOCl
CH3(CH2)3CH]CHCOCl
CH3(CH2)4CH]CHCOCl
CH3(CH2)5CH]CHCOCl
CH3(CH2)6CH]CHCOCl
CH3CH2CH]CHCH2CONH2
CH3(CH2)2CH]CHCH2CONH2
CH3(CH2)3CH]CHCH2CONH2
CH3(CH2)4CH]CHCH2CONH2
CH3(CH2)5CH]CHCH2CONH2
2g
5
d
5
d
a
Yields, based on 2-alkenoic acids, are w80e90%.
Detritylation is almost quantitative (ꢁ85%).
b
The obtained products were easily separated or purified by
column chromatography on silica gel. Some of the final products
are already known compounds and their spectroscopic data are
consistent with the literature values. The identity of the in-
termediate N-tritylamides and of the final products was de-
termined by 1H NMR and IR spectroscopy.
The deconjugation of a carbonecarbon double bond of un-
saturated carbonyl compounds, by the use of a strong base,9 such as
LDA, t-BuOK, n-BuLi, disilazide, etc., is an interesting reaction that
Table 2
Formation of N-substituted amides from
a,b-unsaturated acyl chlorides
Substrate
Amine
(RNH2)
Base
N-Tritylamides (according to the 1
H
NMR spectra) (yield)
CH3CH]CHCOCl TrNH2
Et3N
Pyr
CH2]CHCH2CONHTr
CH3CH]CHCONHTr
CH3CH]CHCONHTr
TrNH2
BnNH2
MeNH2
BnNH2 CH3CH]CHCONHBn
Et3N CH3CH]CHCONHBn
MeNH2 CH3CH]CHCONHMe
CH2]CHCH2CONHCHPh2 (30%)þ
has been described several times in the past. The
of -unsaturated salts of carboxylic acids or esters, afforded the
corresponding -unsaturated derivatives in a mixture of Z/E iso-
mers in variable ratios.9 Deconjugation of
-unsaturated chlo-
rides has been observed during their esterification in the presence
g-deprotonation
Ph2CHNH2 Et3N
a,b
CH3CH]CHCONHCHPh2 (70%)
CH2]CHCH2CONHPh (38%)þ
CH3CH]CHCONHPh (62%)
CH2]CHCH2CONHAr (45%)þ
CH3CH]CHCONHAr (55%)
CH3 CH2CH]CHCH2CONHTr
CH3(CH2)2CH]CHCONHTr
b,g
PhNH2
Et3N
Et3N
a,b
a
ArNH2
TrNH2
of benzyl alcohol and triethylamine, affording
b,g-unsaturated
CH3(CH2)2
CH]CHCOCl
Et3N
Pyr
benzyl esters.10
n-BuNH2 n-BuNH2 CH3(CH2)2CH]CHCONHBu
Et3N CH3(CH2)2CH]CHCONHBu
Our results (Table 1) may be ascribed to the formation of an
intermediate ketene, as it is known that, when an acyl halide is
treated with a tertiary amine (Et3N), the corresponding ketene
MeNH2
BnNH2
MeNH2 CH3(CH2)2CH]CHCONHMe
BnNH2 CH3(CH2)2CH]CHCONHBn
(ReCH]C]O) is generated.11,12 The fact that
a
,b
-unsaturated acyl
Et3N
Ph2CHNH2 Et3N
CH3(CH2)2CH]CHCONHBn
chlorides disposing hydrogen atoms on the
g-carbon, in the pres-
CH3CH2CH]CH CH2CONHCHPh2 (40%)þ
CH3(CH2)2CH]CHCONHCHPh2(60%)
CH3CH2CH]CH CH2CONHPh (48%)þ
CH3(CH2)2CH]CHCONHPh (52%)
CH3CH2CH]CH CH2CONHAr (58%)þ
CH3 (CH2)2CH]CHCONHAr (42%)
ence of tertiary amines, are precursors to vinyl ketenes, strongly
indicates that a vinyl ketene is the active acylating agent. This
transformation is a base-induced elimination of hydrogen chloride
from an acid chloride.12 In the present work, the ketenes, formed
PhNH2
ArNH2
Et3N
Et3N
from the a,b-unsaturated acid chlorides (RCH]CHeCH]C]O), are
supposed to be trapped by the bulky tritylamine to afford the N-
a
Where ArNH2 is the 2-methyl-6-nitroaniline.
tritylamides, which are, later, detritylated with TFA (Fig. 1).
O
O
O
TrNH2
TFA
Et3N
R
R
C C O
Cl
CH2Cl2, 0oC
R
NHTr
R
NH2
Fig. 1. Synthesis of
b,
g
-unsaturated primary amides from
a,
b-unsaturated acid chlorides.

5632
V. Theodorou et al. / Tetrahedron 67 (2011) 5630e5634
NMR spectra, highly reactive and unhindered amines (n-butyl-
amine, benzylamine and methylamine) produced the conjugated
products, with or without Et3N in the medium. When the steric
effects become more significant and the nucleophilicity is weaker
(diphenylmethylamine, aniline or 2-methyl-6-nitroaniline), poor
selectivity was obtained and mixtures of the above two isomers
were formed. It is noteworthy that, in the synthesis of tritylamides,
when pyridine was used in the place of Et3N, or when tritylamine
was used in excess without Et3N, the sole product was the conju-
gated isomer in all the cases.
Taking into account the fact of the formation of an intermediate
ketene, when an acyl halide is treated with a tertiary amine,11 we
can reasonably assume, now, that the above described isomeriza-
tion takes place during the amidation of the acyl halide by a weak
and bulky amine, as follows (Fig. 2, A).
proton abstraction and the double bond migration step, and could
be explained starting from different conformations of the RCH2
group of the acyl chloride (Fig. 2, A). The Z and E isomers could be
separated by column chromatography or preparative TLC, accord-
ing to the literature.9e
Under the same reaction conditions, as mentioned above, the
weaker tertiary base pyridine can not abstract the
proton and cause the double bond migration. In this case a nucle-
ophilic acyl substitution takes place by the amine and pure a,b-
g-methylene
unsaturated products are isolated. The conjugated amides arise, in
any case, via the direct acylation of the amine with the acid chlo-
ride, as the nucleophile reacts rapidly attacking the carbonyl group,
before the generation of a ketene (Fig. 2, B).
It should also be noted that a steric effect on the reaction of
an
CH3CH2CH]C(CH3)COCl (E-2-methyl-2-pentenoyl chloride), the
main reaction product, 78%, was the E- -unsaturated tritylamide
CH3CH2CH]C(CH3)CONHTr and only 22% of the Z- -unsaturated
a-substituted acid halide was observed. In the case of the
a,b
A
O
b,g
H
C
Cl
H
R
H
C
R
H
H
C
product CH3CH]CHCH(CH3)CONHTr was obtained. The above ratio
of the two substituted amides, appearing in the Table 1, is deduced
from the 1H NMR spectrum of the isolated product. Obviously, the
replacement of hydrogen by a methyl group produces significant
C
C
C
C
H
C
C
H
H
+
-Et3NH Cl
H
C
O
C O
or
H
R
RNH2
RNH2
(I)
steric hindrance10 in the abstraction of a
Et3N to form the corresponding ketene.
g-hydrogen by the bulky
Et3N
H
H
R
H
C
C
C C
+
As an alternative synthetic method, in order to better elucidate the
proposed mechanism, we triedto couple crotonic acidwith tritylamine
by the use of bromotripyrrolidinophosphonium hexafluorophosphate
(PyBroP), an effective peptide coupling reagent suggested for sterically
hindered reactants, in the presence of Et3N,1d,13 through the prepara-
tion of an active ester (Scheme 1). In this case, the isomerized
R
CH2CONHR
H
CH2CONHR
B
O
H
C
Cl
RNH2
H
CONHR
Pyr or Et3N
C
C
+ Pyr.HCl or Et3NH Cl
C
C
RCH2
H
RCH2
H
b
,
g
-unsaturated compound was obtained as the mainproduct (w75%).
With aniline, the isomerized amide was only 8%, while with benzyl-
amine the product was exclusively the -unsaturated amide.
Fig. 2. (A) Plausible mechanism for the bulky amine RNH2/Et3N acylation and isom-
erization; (B) Mechanism for the bulky amine RNH2/Pyr acylation, or for the un-
hindered amine RNH2/Et3N acylation.
a,b
Similar results were obtained with the coupling of 2-hexenoic acid
(w80% isomerization with TrNH2 and w10% with PhNH2).
CH3CH=CHCOOH/Et3N + PyBroP+ TrNH2
CH2=CHCH2CONHTr + CH3CH=CHCONHTr
Scheme 1.
It seems that the isomerized products arise from the in-
termediate -unsaturated ketene, which reacts with tritylamine,
a weak nucleophile. The strong tertiary base triethylamine ab-
stracts the -methylene proton (RCH2CH]CHCOCl) and causes the
carbonecarbon double bond migration. Subsequent reaction of the
tritylamine with the intermediate ketene produced variable ratios
It is not evident that the intermediate activated ester liberates
the unsaturated ketene, directly or after a speculated in situ
formation13b of the acyl bromide, which may react in accord to
the same above described mechanism. At least, it seems rea-
sonable that the intermediate activated species undergoes ami-
nolysis by two paths, depending on the bulkiness and the
nucleophilicity of the amine. A possible proposed mechanism is
as follows (Fig. 3).
b,g
g
of Z and E isomers of b,g- products, the Z-configuration slightly
predominating. The observed Z/E distributions must arise in the
O
P
N
PF6
3
O
H
C
O
H
C
OH
PyBroP/Et3N
C
C
H
C
C
H
R
H
R
H
H
H
H
RNH2
A
H
C
C
C C
+
H
R
via ketene
H
R
CH2CONHR
CH2CONHR
intrmediate??
Et3N
direct nucleophile
substitution
N
O
C
P
B
PF6
3
H
CONHR
H
H
C
H
O
C
C
C
H
RCH2
RNH2
H
R
Fig. 3. Proposed possible mechanism for the coupling of 2-alkenoic acids with RNH2 by the use of PyBroP/Et3N.

V. Theodorou et al. / Tetrahedron 67 (2011) 5630e5634
5633
Inspection of the 1H NMR spectra of all the
amides reveals a useful feature, which is in accordance with the
literature:5,6,9e the
-protons of the Z- and E- -unsaturated am-
ides are observed as two very characteristic-diagnostic doublets at
b,
g-unsaturated
and Z, except of N-trityl-3-butenamide, as revealed from their 1H
NMR spectra. Yield: 80e90%.
a
b,g
4.2.1. N-Trityl-3-butenamide. 1H NMR:
5.26e5.28(m,2H,CH2]),6.01(m,1H,]CH)6.88(s,1H,NH),7.20e7.40
(m,15H, ArH); IR (KBr) 3241, 3026, 2855,1654,1633, 970 cmꢂ1
d
3.01 (d, 2H, J¼7.20 Hz, CH2),
d
¼w3.0 ppm (]CHCH2COe), with different integrals (Z,E). The
signal of the Z isomer (J¼w7 Hz) is located at slightly lower field
(w0.04e0.09 ppm) than the E isomer (J¼w6 Hz), as expected.3d,5,9e
The IR spectra of N-tritylamides revealed the NeH absorbance at
3260 cmꢂ1, which was replaced, after TFA deprotection and con-
version to primary amides, by two NeH absorptions at 3360 and
.
4.2.2. N-Trityl-2-methyl-2-pentenamide (E, 78%). 1H NMR:
d 1.11 (t,
3H, J¼7.50 Hz, CH3), 1.95 (s, 3H, CH3), 2.24 (q, 2H, J¼7.25 Hz, CH2),
6.40 (dt, 1H, J¼7.25, 1.25 Hz, CH]), 6.97 (s, 1H, NH), 7.20e7.60 (m,
15H, ArH), and N-Trityl-2-methyl-3-pentenamide (Z, 22%); 1H NMR:
3185 cmꢂ1
The structures of
.
a,b-unsaturated amides, obtained, e.g., in the
d
1.31 (d, 3H, J¼7.00 Hz, CH3), 1.80 (d, J¼7.00 Hz, 3H, CH3), 3.08 (q,
presence of pyridine or otherwise, are readily deduced from their
1H, J¼7.00 Hz, CH(CH3)), 5.65e5.75 (m, 2H, CH]CH), 6.93 (s, 1H,
NH), 7.20e7.60 (m, 15H, ArH).
1H NMR spectra. The chemical shifts of all the conjugated amides
are consistent with the expected ones for the a,b-unsaturated iso-
mers, with the entire absence of the characteristic, for the
b,g-
4.2.3. N-Trityl-3-hexenamide. 1H NMR:
d 1.08 (two overlapping t,
isomer, doublet at
d
¼w3.0 ppm.9e,14
3H, CH3), 2.10e2.30 (m, 2H, CH2), 3.08 and 3.18 (two d, 2H,
J¼6.25 Hz, CH2 for (E) w35% and J¼7.00 Hz, CH2 for (Z) w65%),
5.60e5.90 (m, 2H, CH]CH), 7.02 (br s, 1H, NH), 7.20e7.46 (m, 15H,
3. Conclusions
ArH); IR (KBr) 3261, 3022, 2962, 2933, 2873, 1651, 967 cmꢂ1
.
We report in this paper a novel, easy and efficient method for
the conversion of linear -unsaturated carboxylic acids to the
a
,b
b,g-
4.2.4. N-Trityl-3-heptenamide. 1H NMR:
d
0.98 (t, 3H, J¼7.50 Hz,
unsaturated primary amides, in good yields and high regiose-
lectivity, by tritylation of the corresponding acid chlorides with
tritylamine and subsequent detritylation in mild conditions. It is
reasonably assumed that the deconjugated tritylamides arise by the
acylation of the amine through the intermediate ketene and not via
direct acylation of the amine with the acid chloride. The experi-
mental process and the reagents are readily available.
CH3),1.38e1.54 (m, 2H, CH2), 2.11 (m, 2H, CH2), 3.08 and 3.16 (two d,
2H, J¼6.25 Hz, CH2 for (E) w45% and J¼7.00 Hz, CH2 for (Z) w55%),
5.65e5.86 (m, 2H, CH]CH), 6.96 and 6.98 (two s, 1H, NH, for (E)
45% and for (Z) 55%), 7.15e7.42 (m, 15H, ArH); IR (KBr) 3260, 3023,
2959, 2928, 2871, 1650, 967 cmꢂ1
.
4.2.5. N-Trityl-3-octenamide. 1H NMR:
d
0.82 (two overlapping t,
4. Experimental
4.1. General
3H, CH3), 1.18e1.30 (m, 4H, (CH2)2), 2.05 (m, 2H, CH2), 2.97 and 3.05
(two d, 2H, J¼6.00 Hz, CH2 for (E) w48% and J¼7.00 Hz, CH2 for (Z)
w52%), 5.55e5.74 (m, 2H, CH]CH), 6.85 and 6.87 (two s, 1H, NH,
for (E) and for (Z)), 7.10e7.35 (m, 15H, ArH); IR (KBr) 3260, 3022,
1H NMR spectra were obtained at 250 MHz using a Bruker AMX-
250 spectrometer, in CDCl3 solutions. Chemical shifts are given in
2956, 2856, 1650, 968 cmꢂ1
.
d
units parts per million (ppm) relative to TMS as internal standard.
4.2.6. N-Trityl-3-nonenamide. 1H NMR:
d
0.97 (t, 3H, J¼7.50 Hz,
Infrared spectra were obtained on a PerkineElmer GX FT spectrom-
eter, using KBr disks (4000e400 cmꢂ1). Column chromatography
was carried out over silica gel 60 (70e200 mesh). Thin layer chro-
matography (TLC) was performed using Merck Silica gel 60 F254
plates. Commercially available reagents were used without further
purification. Tritylamine was prepared according to the literature.1a
All solvents were dried by standard methods and distilled before use.
CH3), 1.25e1.54 (m, 6H, (CH2)3), 2.17 (m, 2H, CH2), 3.09 and 3.18
(two d, 2H, J¼6.00 Hz, CH2 for (E) w43% and J¼6.75 Hz, CH2 for (Z)
w57%), 5.76 (m, 2H, CH]CH), 7.01e7.03 (two overlapping s, 1H, NH
for (Z) and for (E)), 7.20e7.44 (m, 15H, ArH); IR (KBr) 3260, 3020,
2924, 2855, 1651, 970 cmꢂ1
.
4.2.7. N-Trityl-3-decenamide. 1H NMR:
d
0.89 (t, 3H, J¼7.50 Hz,
4.2. Typical procedure for the preparation of N-trityl-3-
alkenamides from a,b-unsaturated acids
CH3), 1.18e1.42 (m, 8H, (CH2)4), 2.08 (m, 2H, CH2), 3.01 and 3.09
(two d, 2H, J¼6.50 Hz, CH2 for (E) w47% and J¼7.25 Hz, CH2 for (Z)
w53%), 5.56e5.84 (m, 2H, CH]CH), 6.89 and 6.92 (two s, 1H, NH,
for (E) and for (Z)), 7.15e7.35 (m, 15H, ArH); IR (KBr) 3259, 3029,
(a) To a solution of the 2-alkenoic acid (1 mmol) in dry
dichloromethane (DCM, 3 mL), oxalyl chloride (COCl)2 (3.5 mmol,
0.3 mL) and two drops of DMF were added at 0 ꢀC. The mixture was
allowed to stir for 15 min at 0 ꢀC and then for w2 h at rt, until no gas
was observed. The solvent and the excess of oxalyl chloride were
distilled off to dryness. The obtained acyl chloride was used in the
next step without further purification.
(b) The above obtained chloride was dissolved in dry DCM
(5 mL) under argon and cooled at 0 ꢀC. Et3N (5 mmol) was added,
followed by addition of TrNH2 or other RNH2 (1 mmol) in DCM
(3 mL) at 0 ꢀC under stirring for 5 min. The resulting mixture was
allowed to stir at rt until complete conversion, as indicated by TLC.
The solvent was removed, the residue was redissolved in DCM,
washed with water, an aqueous solution of 5% potassium hydrogen
sulfate (KHSO4) and brine, dried over anhydrous Na2SO4, concen-
trated in vacuo and purified by column chromatography on silica
gel (methanol/dichloromethane, 1:20). The products, N-trityl-3-
alkenamides, are white solids, mixtures of geometrical isomers E
2957, 2924, 2853, 1650 cmꢂ1
.
4.3. Typical procedure for the preparation of (E)-N-trityl-2-
alkenamides from -unsaturated acids
a,b
These compounds were prepared and purified according to the
general procedure described above for the synthesis of N-trityl-3-
alkenamides, using pyridine instead of triethylamine. The pure
products were identified only by their 1H NMR spectra.
1
4.3.1. N-Trityl-2-butenamide (E). A white solid, mp 190e191 ꢀC; H
NMR:
d
1.84(dd,3H, J¼8.00,2.00Hz,CH3),5.94(dd,1H, J¼15.50, 2.00 Hz,
CH]), 6.56 (s,1H, NH), 6.81 (m,1H, CH]), 7.15e7.43 (m,15H, ArH).
4.3.2. N-Trityl-2-hexenamide (E). A white solid, mp 199e201 ꢀC; 1H
NMR:
d
0.98 (t, 3H, J¼7.25 Hz, CH3), 1.48 (m, 2H, J¼7.25 Hz, CH2),

5634
V. Theodorou et al. / Tetrahedron 67 (2011) 5630e5634
2.25 (m, 2H, CH2), 5.98 (d, 1H, J¼15.25 Hz, CH]), 6.63 (s, 1H, NH),
6.89 (dt, 1H, J¼15.25, 7.25 Hz, CH]), 7.20e7.42 (m, 15H, ArH).
J¼7.25 Hz, CH2 for (Z) w50%), 5.40e5.75 (m, 2H, CH]CH), 5.82 and
6.34 (two br s, 2H, NH2); IR (KBr) 3360, 3195, 2938, 2927, 2850,
1653 cmꢂ1
.
4.3.3. N-Trityl-2-octenamide (E). A white solid, mp 203e205 ꢀC;
1H NMR:
d
0.91 (t, 3H, J¼7.00 Hz, CH3), 1.20e1.45 (m, 6H,
4.5.5. 3-Nonenamide. A white solid; [Found: C, 69.89; H, 10.83; N,
9.24. C9H17NO requires C, 69.63; H, 11.04; N, 9.02%]; 1H NMR:
0.86
(CH2)3), 2.18 (m, 2H, CH2), 5.77 (d, 1H, J¼15.50 Hz, CH]), 6.68
(s, 1H, NH), 6.90 (dt, 1H, J¼15.50, 7.00 Hz, CH]), 7.08e7.40
(m, 15H, ArH).
d
(t, 3H, J¼7.5 Hz, CH3), 1.15e1.40 (m, 6H, (CH2)3), 2.02 (m, 2H, CH2),
2.93 and 3.00 (two d, 2H, J¼6.50 Hz, CH2 for (E) w44% and
J¼7.25 Hz, CH2 for (Z) w56%), 5.45e5.70 (m, 2H, CH]CH),
5.70e6.10 (br d, 2H, NH2); IR (KBr) 3364, 3185, 2958, 2924, 2856,
4.4. Typical procedure for the preparation of N-tritylamides
from
a
,b-unsaturated acids with PyBroP as coupling reagent
1651, 969 cmꢂ1
.
To a solution of the carboxylic acid (1 mmol) in dry DCM
(3 mL), TrNH2 (1 mmol), PyBroP (1 mmol) and Et3N (3 mmol) in
DCM (2 mL) were added and the mixture was allowed to stir at
4.5.6. 3-Decenamide. A white solid; [Found: C, 70.69; H, 11.48; N,
8.51. C10H19NO requires C, 70.96; H, 11.31; N, 8.28%]; 1H NMR:
0.82
d
(t, 3H, J¼7.5 Hz, CH3), 1.12e1.36 (m, 8H, (CH2)4), 2.00 (m, 2H, CH2),
2.88 and 2.95 (two d, 2H, J¼6.50 Hz, CH2 for (E) w46% and
J¼7.25 Hz, CH2 for (Z) w54%), 5.40e5.70 (m, 2H, CH]CH), 5.90 and
6.50 (two br s, 2H, NH2); IR (KBr) 3354, 3186, 2926, 2856, 1667,
0
ꢀC for 5 min and at rt overnight, until completion of the re-
action. The mixture was then diluted with AcOEt (25 mL),
washed with water, 5% KHSO4, dried over anhydrous Na2SO4,
concentrated in vacuo and purified by column chromatography
on silica gel. The obtained N-tritylamides were mixtures of
969 cmꢂ1
.
a,b- and b,g
-unsaturated compounds, as identified by 1H NMR
Acknowledgements
spectroscopy.
We are grateful to Dr. Nikitas Ragoussis, VIORYL S.A. (Greece) for
providing us with samples of 2-alkenoic acids. We thank the NMR
center of the University of Ioannina for having obtained the 1H NMR
spectra.
4.5. Typical procedure for the detritylation of the N-trityl-3-
alkenamides
To a solution of the tritylamide (1 mmol) in DCM (2 mL), TFA
(6 mL) was added and the reaction mixture was allowed to stand at
rt for 0.5e3 h, until completion of the reaction. Triisopropylsilane
(w3 mmol) was added and the produced bright yellow colour of
the solution was disappeared in a few minutes. After 30 min the
colourless solution was diluted with CCl4 and evaporated to dry-
ness. The residue was redissolved in diethyl ether (2 mL) and
hexane was added for the precipitation of the deprotected amide as
white amorphous solid. The resulting triphenylmethane remains
soluble in hexane. If necessary, the amide was purified by column
chromatography on silica gel (methanol/dichloromethane, 1:20 to
1:4). The obtained 3-alkenamides were, as expected, mixtures of E
and Z isomers, except of 3-butenamide, and the yield was ꢁ85%.
References and notes
1. (a) Theodorou, V.; Ragoussis, V.; Strongilos, A.; Zelepos, E.; Eleftheriou, A.;
Dimitriou, M. Tetrahedron Lett. 2005, 46, 1357; (b) Theodorou, V.; Skobridis, K.
Tetrahedron Lett. 2005, 46, 5021; (c) Theodorou, V.; Skobridis, K.; Karkatsoulis,
A. Tetrahedron 2007, 63, 4284; (d) Theodorou, V.; Karkatsoulis, A.; Kinigopou-
lou, M.; Ragoussis, V.; Skobridis, K. Arkivoc 2009, xi, 277.
2. (a) Valcavi, U.; Caponi, R.; Martelli, P.; Minoja, F. Eur. J. Drug Metab. Pharma-
cokinet. 1979, 4, 231; (b) Ojima, I.; Korda, A. Tetrahedron Lett. 1989, 30, 6283; (c)
Marson, C.; Fallah, A. Tetrahedron Lett. 1994, 35, 293; (d) Tang, Y.; Li, C. Tetra-
hedron Lett. 2006, 47, 3823; (e) Marson, C.; Grabowska, U.; Walsgrove, T.;
Eggleston, D.; Baures, P. J. Org. Chem. 1991, 56, 2603; (f) Marson, C.; Grabowska,
U.; Walsgrove, T. J. Org. Chem. 1992, 57, 5045; (g) Marson, C.; Grabowska, U.;
Walsgrove, T.; Eggleston, D.; Baures, P. J. Org. Chem. 1994, 59, 284; (h) Marson,
C.; Grabowska, U.; Fallah, A.; Walsgrove, T.; Eggleston, D.; Baures, P. J. Org. Chem.
1994, 59, 291.
3. (a) Ragazzini, M.; Vandi, A.; Campadelli, F. Eur. Polym. J. 1970, 6, 1331; (b) Cacchi,
S.; Misiti, D.; La Torre, F. Synthesis 1980, 243; (c) Knapp, S.; Levorse, A. J. Org.
Chem. 1988, 53, 4006; (d) Bajrachara, G. B.; Koranne, P. S.; Nadaf, R. N.; Gabr, R.
K. M.; Takenaka, K.; Takizawa, S.; Sasai, H. Chem. Commun. 2010, 9064.
4. (a) Ragoussis, N. Tetrahedron Lett. 1987, 28, 93; (b) Ragoussis, N.; Ragoussis, V. J.
Chem. Soc., Perkin Trans. 1 1998, 3529.
5. Imada, Y.; Shibata, O.; Murahashi, S. I. J. Organomet. Chem. 1993, 451, 183.
6. Buchi, G.; Cushman, M.; Wuest, H. J. Am. Chem. Soc. 1974, 96, 5563.
7. (a) Janecki, T.; Bodalski, R. Tetrahedron Lett. 1991, 32, 6231; (b) Janecki, T.;
Bodalski, R.; Wieczorek, M.; Buzacz, G. Tetrahedron 1995, 51, 1721.
8. (a) Murahashi, S. I.; Imada, Y.; Nishimura, K. J. Chem. Soc., Chem. Commun. 1988,
1578; (b) Larock, R.; Ding, S. Tetrahedron Lett. 1989, 30, 1897; (c) Larock, R.; Ding,
S. Tetrahedron Lett. 1993, 34, 979; (d) Larock, R.; Ding, S. J. Org. Chem. 1993, 58,
2081; (e) Loh, T. P.; Cao, G. Q.; Yin, Z. Tetrahedron Lett. 1999, 40, 2649; (f) Luo, F.
T.; Lu, T. Y.; Xue, C. Tetrahedron Lett. 2003, 44, 7249.
9. (a) Majewski, M.; Mpango, G. B.; Thomas, M. T.; Wu, A.; Snieckus, V. J. Org. Chem.
1981, 46, 2029; (b) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H. Tetrahedron 1987, 43,
743; (c) Aurell, M.; Domingo, L.; Mestres, R.; Munoz, E.; Zaragoza, R. Tetrahedron
1999, 55, 815; (d) Cardillo, G.; Fabbroni, S.; Gentilucci, L.; Perciaccante, R.; Tolo-
melli, A. Tetrahedron: Asymmetry 2004, 15, 593; (e) Guha, S.; Shibayama, A.; Abe,
D.; Sakaguchi, M.; Ukaji, Y.; Inomata, K. Bull. Chem. Soc. Jpn. 2004, 77, 2147; (f)
Green, J.; Majewski, M.; Snieckus, V. Can. J. Chem. 2006, 84, 1397.
10. Cardillo, G.; De Simone, A.; Mingardi, A.; Tomasini, C. Synlett 1995, 1131.
11. (a) Luknitskii, F.; Vovsi, B. Russ. Chem. Rev. 1969, 38, 487; (b) Lynch, J.; Riseman,
S.; Laswell, W.; Tschaen, D.; Volante, R.; Smith, G.; Shinkai, I. J. Org. Chem. 1989,
54, 3792.
12. Murphy, J.; Hadden, M.; Stevenson, P. Tetrahedron 1997, 53, 11827.
13. (a) Artuso, F.; Sindona, G.; Athanassopoulos, C.; Stavropoulos, G.; Papaioannou,
D. Tetrahedron Lett. 1995, 36, 9309; (b) Montalbetti, C.; Falque, V. Tetrahedron
2005, 61, 10827.
14. (a) Geog, G.; Durst, T. J. Org. Chem. 1983, 48, 2092; (b) Oates, L.; Jacson, R.; Block,
M. Org. Biomol. Chem. 2003, 1, 140; (c) Concellon, J. M.; Rodriguez-Solla, H.;
Concellon, C.; Simal, C.; Alvaredo, N. J. Org. Chem. 2010, 75, 3451.
15. Goldschmith, S.; Dachs, K. Chem. Ber. 1955, 88, 583.
4.5.1. 3-Butenamide. A white solid, mp 71e72 ꢀC (lit.3a 74e75 ꢀC;
lit.15 72 ꢀC); [Found: C, 56.70; H, 8.13; N, 16.52. C4H7NO requires C,
56.45; H, 8.29; N, 16.46%]; 1H NMR:
d
2.98 (d, 2H, J¼7.20 Hz, CH2),
5.40e5.75 (m, 2H, ]CH2), 6.00 (br m, 2H: 1H, ]CH and 1H, NH,
NH2); 6.20 (br s, 1H, NH, NH2); IR (KBr): 3353, 3186, 2815, 1671,
962 cmꢂ1
.
4.5.2. 3-Hexenamide. A white solid; [Found: C, 63.81; H, 9.73; N,
12.51. C6H11NO requires C, 63.68; H, 9.80; N, 12.38%]; 1H NMR:
d
0.95 (two overlapping t, 3H, CH3), 2.03 (m, 2H, CH2), 2.90 and
2.95 (two d, 2H, J¼6.25 Hz, CH2 for (E) w35% and J¼7.00 Hz,
CH2 for (Z) w65%), 5.40e5.75 (m, 2H, CH]CH), 5.82 and 6.35
(two br s, 2H, NH2); IR (KBr) 3354, 3191, 2964, 2870, 1667,
969 cmꢂ1
.
4.5.3. 3-Heptenamide. A white solid; [Found: C, 66.01; H, 10.43; N,
11.24. C7H13NO requires C, 66.10; H, 10.30; N, 11.01%]; 1H NMR:
d
0.89 (m, 3H, CH3), 1.27e1.54 (m, 2H, CH2), 2.02 (m, 2H, CH2), 2.93
and 3.01 (two d, 2H, J¼6.00 Hz, CH2 for (E) w40% and J¼6.75 Hz,
CH2 for (Z) w60%), 5.40e5.90 (br m, 4H: 2H, CH]CH and 2H, NH2);
IR (KBr) 3353, 3200, 2961, 2872, 1665, 970 cmꢂ1
.
4.5.4. 3-Octenamide. A white solid; [Found: C, 67.91; H, 10.93; N,
10.14. C8H15NO requires C, 68.04; H, 10.71; N, 9.92%]; 1H NMR:
d
0.84 (m, 3H, CH3), 1.20e1.40 (m, 4H, (CH2)2), 2.01 (m, 2H, CH2),
2.92 and 3.00 (two d, 2H, J¼6.25 Hz, CH2 for (E) w50% and