Sodium carbonate mediated regioselective synthesis of novel N-(hydroxyalkyl)cinnamamides Dedicated to Dr. Sunita Dhingra on her 65th birthday

Article abstract of DOI:10.1016/j.tetlet.2013.10.086

A synthetic protocol for the direct synthesis of N-(hydroxyalkyl) cinnamamides from cinnamates and aminoalcohols in the presence of sodium carbonate as the base is presented. A wide variety of N-(hydroxyalkyl) cinnamamides were isolated in up to 99% yield

Full text of DOI:10.1016/j.tetlet.2013.10.086

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sodium carbonate mediated regioselective synthesis of novel
N-(hydroxyalkyl)cinnamamides
⇑
Parul Garg, Marilyn Daisy Milton
Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic protocol for the direct synthesis of N-(hydroxyalkyl)cinnamamides from cinnamates and ami-
noalcohols in the presence of sodium carbonate as the base is presented. A wide variety of N-(hydroxy-
alkyl)cinnamamides were isolated in up to 99% yields. The reaction is highly regioselective and yields
only N-acylated products by 1,2-addition of aminoalcohols to cinnamates.
Received 30 August 2013
Revised 14 October 2013
Accepted 18 October 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated to Dr. Sunita Dhingra on her 65th
birthday
Keywords:
N-(Hydroxyalkyl)cinnamamides
Cinnamates
Aminoalcohols
Regioselective 1,2-addition
Amide functionality is present in a variety of natural products,
biologically active compounds, pharmaceutical drugs, polymeric
materials, insecticides, etc. It is also the key linkage in peptides
and proteins. Generally, the synthesis of amide bond is carried
out by amidation of an acid chloride or ester with an amine in
the presence of a base, under harsh conditions for example use
of strong base, high reaction temperature or pressure, etc.1 In the
past many new methods for the synthesis of amide bond have been
reported. However, most of these methods use expensive reagents
or catalysts for amidation.2 Recent reports on the use of inexpen-
sive catalysts like boric acid3 and activated alumina balls4 for
amide bond formation from carboxylic acids and amines are prom-
ising synthetic strategies, but these procedures require high reac-
tion temperatures.
As part of our ongoing research on the synthesis of biologically
active compounds, we were interested in the synthesis of new N-
(hydroxyalkyl)cinnamamides because this class of compounds
have shown promising anti-convulsant,5 muscle relaxant6 and
anti-depressant5b,7 activities (Fig. 1). N-(hydroxyalkyl)cinnama-
mides are also important building blocks for the preparation of
synthetically useful molecules such as oxazolines, oxazolinium
salts, benzoxazoles,8 and photoresponsive polymers.9
O
O
OH
OH
N
H
N
H
n
R1
R1 = H, OH
n = 1, 2
R
R2
R2 = OH, OMe
R = H, F
Figure 1. Examples of some biologically active N-(hydroxyalkyl)cinnamamides.
vated carboxylic acids.5,10 Thus we became interested in exploring
the possibility of using less hazardous reagents for the synthesis of
N-(hydroxyalkyl)cinnamamides. We came across reports on ami-
dation of unactivated esters by aminoalcohols under mild condi-
tions in the presence of catalytic amount of expensive
organobases.11 We reasoned that aminoalcohols, being reactive
amines, should be able to react with cinnamates in the presence
of readily available bases. Our reasoning was further supported
by a recent report on amidation of a benzoate by ethanolamine
using catalytic amount of sodium methoxide as a base, wherein a
mixture of hydroxyl amide and amino ester was obtained.12 Here-
in, we wish to report a new route to N-(hydroxyalkyl)cinnama-
mides via 1,2-addition of aminoalcohols to methyl cinnamates in
the presence of inexpensive and readily available Na2CO3 as the
base. It is noteworthy that no corresponding amino esters or 1,4-
addition products were isolated.
Generally, N-(hydroxyalkyl)cinnamamides are synthesized by
conventional methods of amidation that require hazardous chem-
icals like thionyl chloride or methylchloroformate to generate acti-
Various cinnamates were synthesized by Pd-catalyzed cross-
coupling reactions of aryl bromides with acrylates.13 We started
our work by trying amidation of methyl 4-acetylcinnamate 1a with
ethanolamine 2a in methanol in the presence of a variety of
⇑
Corresponding author.
E-mail address: mdmilton@chemistry.du.ac.in (M.D. Milton).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.086
Please cite this article in press as: Garg, P.; Milton, M. D. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.10.086

2
P. Garg, M. D. Milton / Tetrahedron Letters xxx (2013) xxx–xxx
organic (Et3N, DBU, NaOAc) as well as inorganic (KOH, K2CO3, Na2-
CO3) bases. With these bases, (E)-N-(2-hydroxyethyl)-4-acetylc-
innamamide 3a was obtained in moderate to excellent yields
(Table 1, entries 1–6). Na2CO3 turned out to be the best base, the
amidation of 1a was accomplished at 80 °C within 1.25 h to give
3a in 99% isolated yield (Table 1, entry 6). Next, we tried the ami-
dation with catalytic amount of Na2CO3 (20 mol %), however, the
yield of 3a reduced to 82% (Table 1, entry 7). Also, the product yield
reduced drastically to 44% on attempting the amidation with ethyl
4-acetylcinnamate 1j (Table 1, entry 8). Interestingly, when etha-
nol was used as the solvent, the yield of 3a reduced to 60% (Table 1,
entry 9). Other solvents like DMF, NMP, or toluene also reduced the
yield of 3a (Table 1, entries 10–12). The concentration of ethanol-
amine 2a (5.0 mmol) was also crucial for the success of this reac-
R1
R1
H
N
Na2CO3
OMe H N
+
2
OH
OH
MeOH, 80 °C
O
O
1.25-2 h
1b-1h
2a
3b-3h
COMe
H
N
O2N
H
N
OH
O
OH
O
3c, p-NO2; 90% (2 h)
3b, 92% (2 h)
3d
, m-NO2; 85% (2 h)
3e, o-NO2; 91% (2 h)
O
R1
H
N
H
N
OH
OH
O
O
1
3g
, R = Me; 91 % (2 h)
3f
, 89% (2 h)
tion as
a decrease in the concentration of 2a from 5.0 to
3h, R1= H; 87% (2 h)
2.5 mmol, decreased the yield of 3a to 54% (Table 1, entry 13).
The amidation of ester 1a can also be carried out at room temper-
ature, however, only 77% yield of 3a was isolated even after per-
forming the reaction for 7 h (Table 1, entry 14). In addition, this
transformation was also feasible in the absence of any base, but
the reaction was sluggish giving only 46% of 3a in 2 h (Table 1, en-
try 15). Furthermore, this transformation was not air and moisture
sensitive, and therefore all the reactions were performed in air,
without drying methanol prior to use.
Next we examined the amidation of a variety of cinnamates
(1b–1h) with 2a in the presence of Na2CO3 (Scheme 1). All the es-
ters bearing electron withdrawing or electron donating groups on
the aromatic ring afforded the corresponding cinnamamides 3b–
3h in excellent yields (85–92%). It is noteworthy that these reac-
tions showed high regioselectivity as the amidation proceeded
exclusively via 1,2-addition of 2a to the ester carbonyl group of
Scheme 1. Scope of amidation for esters.
NC
O
OMe
Na2CO3
MeOH, 80 °C
NC
N
H
N
H
N
O
1i
OH
+
OH
+
O
O
H2N
5a
4a
OH
(i) 1 h; 4a (65%), 5a (6%)
(ii) 6 h; 4a (49%), 5a (32%)
2a
(5.0 mmol)
Scheme 2. Amidation of ester 1i with ethanolamine 2a.
R1
R2
R
3R4
OH
R1
the
a,b-unsaturated esters 1a–1h followed by the elimination of
Na2CO3
H
N
O R2
OMe + H2N
OH
the methoxide anion to afford the corresponding cinnamamides
n
MeOH, 80 °C
3.5-8 h
n
R3
O
R4
n = 0,1
3a–3h. No products arising out of 1,4-addition to a,b-unsaturated
esters14 were observed and only clean N-acylated products were
4b-4f
1a, 1f
R1
2b-2f
5b-5f
isolated.
R1
H
N
H
N
OH
OH
O
O
4b, R1= COMe; 66% (3.5 h)
5b, R1= COPh; 81% (3.5 h)
4c, R1= COMe; 92% (6 h)
Table 1
5c, R1= COPh; 85% (7 h)
Optimization of reaction conditionsa
R1
R1
O
O
H
H
N
N
OH
OH
OH
H
N
base
solvent, 80 °C
OMe + H2N
O
O
OH
OH
1a
2a
3a
4d, R1= COMe; 88% (7 h)
4e, R1= COMe; 92% (7 h)
O
O
5d, R1= COPh; 95% (8 h)
5e, R1= COPh; 99% (7 h)
Yieldb (%)
R1
Entry
Base
Solvent
Time (h)
OH
H
N
1
2
3
4
5
Et3N
DBU
NaOAc
KOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
DMF
NMP
Toluene
MeOH
MeOH
MeOH
2
1
2
0.5
1.25
1.25
1.25
1.25
2
2
2
2
1.25
7
56
88
66
87
93
99
82
44
60
41
63
40
54
77
46
O
4f, R1= COMe; 57% (7 h)
5f, R1= COPh; 72% (8 h)
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
—
6
Scheme 3. Scope of amidation for aminoalcohols.
7c
8d
9
Interestingly, on performing amidation of methyl 4-cyanocin-
namate 1i with 2a in the presence of Na2CO3 for 1 h, 65% of desired
cinnamamide 4a was isolated along with 6% of oxazoline 5a, and
some unidentified product (Scheme 2). When we tried to increase
the yield of 4a by carrying out the same reaction for a longer dura-
tion (6 h), the yield of 4a dropped to 49% with an increase in the
isolated yield of oxazoline 5a to 32%. Thus, we concluded that
oxazoline 5a was being formed due to the reaction of nitrile group
with an excess of ethanolamine. To the best of our knowledge, this
is the first example of direct oxazoline formation from nitrile and
ethanolamine under mild reaction conditions without the use of
any metal catalysts and/or high temperatures.15
10
11
12
13e
14f
15
2
a
Unless otherwise noted, reaction was carried out with ester 1a (1.0 mmol),
ethanolamine 2a (5.0 mmol), base (1.0 mmol), solvent (1.0 mL) at 80 °C.
b
Isolated yields.
Using 20 mol % of Na2CO3.
Using ester 1j.
Using 2.5 mmol of 2a.
c
d
e
f
At room temperature.
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P. Garg, M. D. Milton / Tetrahedron Letters xxx (2013) xxx–xxx
3
Figure 2. ORTEP view of (E)-N-((2R)-1-hydroxypropan-2-yl)-4-benzoylcinnamamide 5c. Thermal ellipsoids are drawn at 50% probability level for non-hydrogen atoms.
Next we explored the scope and limitations of various aminoal-
cohols in the amidation reaction (Scheme 3). All the aminoalcohols
reacted regioselectively to give the corresponding cinnamamides
(4b–4f; 5b–5f) in good to excellent yields (57–99%). Increasing
the chain length from ethyl to propyl in aminoalcohol moiety, re-
duced the yields of cinnamamides 4b (66%) and 5b (81%). The
influence of steric factors was quite apparent, the reactions involv-
ing sterically hindered aminoalcohols 2c–2f required a longer reac-
tion time (6–8 h) to produce the corresponding cinnamamides in
high yields. However, in all the cases, exclusively N-acylated prod-
decreased rate of ester conversion could be due to increased aggre-
gation of the active centers as the reaction mixture became very
viscous after 20 min.
The literature reports suggest that the conversion of unactivat-
ed esters into amidoalcohols proceed via transesterification fol-
lowed by subsequent N,O-acyl rearrangement11c,17 to give the
corresponding amidoalcohols. However, despite our numerous ef-
forts we could not isolate any amino ester. So, at this stage it is dif-
ficult to comment on the involvement of N,O-acyl rearrangement
under our reaction conditions.
ucts were obtained by 1,2-addition to
a
,b-unsaturated esters.
In conclusion, we have reported a direct and efficient synthetic
protocol for the synthesis of N-(hydroxyalkyl)cinnamamides from
cinnamates and aminoalcohols in the presence of inexpensive,
non-toxic, and readily available Na2CO3 as the base. This reaction
is highly regioselective as the addition of aminoalcohols to cinna-
mates follows 1,2-addition pathway exclusively to give N-
(hydroxyalkyl)cinnamamides. Further studies on the biological
activities of the newly synthesized N-(hydroxyalkyl)cinnamamides
and the mechanistic aspects of the transformation are currently
underway in our laboratory.
The reaction with chiral aminoalcohols 2c and 2f proceeded
with complete retention of configuration. The single crystal X-ray
analysis confirmed the absolute configuration of 5c and 5f to be
R which is the same as the starting chiral aminoalcohols 2c and
2f (Fig. 2; see Fig. S2–S6 and Table S1 in SI). Also, the crystal struc-
tures showed the trans-configuration of the amide bond as well as
the olefinic bond.16
Amidation of ester 1a with n-butylamine afforded only 33% of
(E)-N-butyl-4-acetylcinnamamide 6 in 7 h (Scheme 4). Thus these
reaction conditions are more suitable for reactive amines such as
aminoalcohols.
Acknowledgment
To gain an insight into this Na2CO3 mediated transformation of
cinnamates into cinnamamides with respect to time, the progress
of the reaction of ester 1a with aminoalcohol 2a was monitored
by 1H NMR. The reaction profile shown in Figure 3 provides infor-
mation regarding the change in % of ester conversion as a function
of time. Within the first 20 min, 83% of the ester 1a was converted
into cinnamamide 3a. Interestingly, the rate of ester conversion
slowed down afterward and reached >99% at 75 min. The
We gratefully acknowledge financial support from the Univer-
sity of Delhi, India and the Department of Science and Technology,
India. P.G. also acknowledges the Council for Scientific and Indus-
trial Research, India for Junior and Senior Research Fellowships.
The authors are grateful to USIC-CIF, University of Delhi for NMR
spectral data and single crystal XRD data.
Supplementary data
O
O
Supplementary (1H, 13C{1H} NMR spectroscopic and HRMS)
data associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2013.10.086. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
Na2CO3
H
N
OMe + H2N
MeOH, 80 °C
O
O
7 h
1a
6 (33%)
Scheme 4. Amidation of ester 1a with n-butylamine.
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