Microwave-assisted synthesis of N -isobutyl-4,5-epoxy-2(E)-decenamide

Article abstract of DOI:10.1080/14786419.2012.678349

A new and efficient synthesis of a naturally occurring amide alkaloid, N-isobutyl-4,5-epoxy-2(E)-decenamide isolated from the roots of Piper nigrum has been described involving a total of nine steps. Octanal and 2-bromoacetic acid have been used as the starting materials.

Full text of DOI:10.1080/14786419.2012.678349

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Microwave-assisted synthesis of N-
isobutyl-4,5-epoxy-2(E)-decenamide
a
a
a
a
Neeraj Gupta , Manvinder Kaur , Shallu , Neeru Gupta ,
a
a
Goverdhan Lal Kad & Jasvinder Singh
a
Department of Chemistry and Centre of Advanced Studies in
Chemistry, Panjab University, Chandigarh 160014, India
Version of record first published: 26 Apr 2012.
To cite this article: Neeraj Gupta , Manvinder Kaur , Shallu , Neeru Gupta , Goverdhan Lal Kad &
Jasvinder Singh (2013): Microwave-assisted synthesis of N-isobutyl-4,5-epoxy-2(E)-decenamide,
Natural Product Research: Formerly Natural Product Letters, 27:6, 548-553
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Natural Product Research, 2013
Vol. 27, No. 6, 548–553, http://dx.doi.org/10.1080/14786419.2012.678349
Microwave-assisted synthesis of N-isobutyl-4,5-epoxy-2(E)-decenamide
Neeraj Gupta, Manvinder Kaur, Shallu, Neeru Gupta, Goverdhan Lal Kad and
Jasvinder Singh*
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University,
Chandigarh 160014, India
(
Received 8 September 2011; final version received 12 February 2012)
A new and efficient synthesis of a naturally occurring amide alkaloid, N-isobutyl-
4,5-epoxy-2(E)-decenamide isolated from the roots of Piper nigrum has been
described involving a total of nine steps. Octanal and 2-bromoacetic acid have
been used as the starting materials.
Keywords: amide alkaloid; dehydrohalogenation; modified Wittig reaction;
microwave irradiation; ionic liquid
1
. Introduction
Alkaloids are highly reactive substances with biological activity in low doses. Many plant
extract and essential oils possess larvicidal activity against various mosquito species.
Isobutyl amide moiety appears to be essential for toxicity against mosquito larvae (Ikan,
2
007). Certain plant-derived compounds were found to be highly effective against
insecticide resistant insect pests. For example, Piper nigrum fruits-derived guineensine
exhibits remarkable lethal activity against a pyrenthrin-resistant strain of Musca
domestica. The insecticidal constituents of piper fruits are N-isobutyl amide alkaloids
such as dihydropipercide, guineensine, pellitorine and pipercide. These isobutyl amides
have knock down activity against adults of Callosobruchus chinensis, M. domestica and
Periplaneta americana. Most of the already known compounds isolated from dried seeds of
P. nigrum L. exhibited toxicity against larvae of Aedes aegypti (I.-K. Park, Lee, Shin,
J.-D. Park, & Ahn, 2002).
Piper nigrum (Williamson, 2002) is a climbing perennial shrub, rooting at the stem
nodes with ovoid or globose fruits. It is widely distributed in the tropical and subtropical
regions of the world. Pepper (fruits of P. nigrum) is one of the most popular spices in the
world and has been used as a folk medicine due to its many physiological activities, e.g.
stimulation of the central nervous system, analgesic and antipyretic activities (Lee, Shin, &
Woo, 1984; Thampuran & Vijayan, 2000). It is much employed as an aromatic stimulant in
weakness following fevers, coma, etc. as a stomachic in cholera, dyspepsia, flatulence
indigestion, diarrhoea and various other gastrointestinal ailments. It has bacteriostatic,
fungistatic, anti-inflammatory and rubefacient properties.
Phytochemical investigations of the roots of P. nigrum L. resulted in the isolation of 39
amides (Wei et al., 2004). In the total synthesis of sylvamide, an N-isobutyl alkaloid
*
Corresponding author. Email: jsbrar_pu@yahoo.com
©
2013 Taylor & Francis

Natural Product Research
549
O
O
H
a
c
H
1
2
Br
b
O
O
O
O
O
Br
4
5
3
d
O
O
e
H
H
6
Scheme 1. (a) Br
NaOC
2
, CaCO
�
3
, CHCl
, DMSO, 120 C, 16 h; (d) [bmim]HSO
3
, 36 h, stir; (b) C OH, [bmim]HSO , MWI 160 W (5 min); (c)
4
2
H
5
2
H
5
, MWI, 8 min; (e) H O , pH 8–8.5, 2 h.
4 2 2
(Banerji & Pal, 1983) N-isobutyl-4,5-epoxy-2(E)-decenamide was prepared as an
intermediate.
2
. Results and discussion
In continuation of our study utilising microwave energy as a source of heat in organic
synthesis (Gupta, Sonu, Kad, & Singh, 2007; Kad, Kaur, Bansal, & Singh, 1996; Kad,
Kaur, Bhandari, Singh, & Kaur, 2003; Kad, V. Singh, Kaur, & J. Singh, 1997; Singh,
Gupta, Kad, & Kaur, 2006; Singh, Sharma, Kad, & Chhabra, 1997; Singh, Sharma, &
J. Singh, 2008, 2009), we report herein, a simple synthesis of N-isobutyl-4,5-epoxy-2(E)-
decenamide. Retrosynthetic analysis revealed the need of oct-2-enal as the starting
material for the synthesis of title compound.
Our first attempt to synthesise oct-2(E)-enal from 1,1-diethoxyhexane and ethyl vinyl
ether in the presence of K-10 clay (Fishman, Klug, & Shani, 1981) was unsuccessful as the
yield of the required product was very poor. Therefore, shifting to another route, we
decided to synthesise oct-2(E)-enal by the allylic oxidation of alkene using 2-octene and
SeO , t-BuOOH (Payne, 1960) or SeO /H O (MWI) or SeO /UHP (MWI) (Manktala,
2
2
2
2
2
Dhillon, & Chhabra, 2006), but none results in the isolation of desired product.
Finally, the oct-2(E)-enal was synthesised using protection and dehydrohalogenation
strategy starting from octanal (Scheme 1). Bromination (Heilbron, Jones, Richardson, &
Sondheimer, 1949) of octanal (1) using bromine and CaCO in CHCl3 at room
3
�
temperature (10–15 C) furnished 2-bromooctanal (2) in 94% yield. Compound (2) when
treated with [bmim]HSO and ethanol under microwave irradiation gave 2-bromo-1,
4
1-diethoxyoctane (3) in 85% yield. Dehydrohalogenation (Nelson & Mash, 1986) of 2-
�
bromo-1,1-diethoxyoctane (3) using sodium ethoxide in DMSO at 120 C furnished 1,1-
diethoxyoct-2-ene (4). Compound (4) when treated with [bmim]HSO under microwave
4
irradiation afforded oct-2(E)-enal (5) in 84% yield. Epoxidation (Payne, 1959) of oct-2(E)-
enal (5) with 30% H O at pH 8–8.5 provided 2,3-epoxyoctanal (6) in 88% yield. 2-
2
2
Bromoacetic acid (7) on heating with PCl3 gave 2-bromoethanoylchloride (8). The
formation of the product was indicated by the appearance of solid residue at the bottom
and the product formed was used as such (Scheme 2). Reacting isobutylamine with

5
50
N. Gupta et al.
O
f
O
Br
Br
OH
Cl
7
8
g
O
P
H CO
O
O
h
H CO
Br
3
N
N
3
H
H
1
0
9
i
O
O
N
H
11
i
N Bu, (C
�
Scheme 2. (f) PCI
(
3
, heat; (g) H
2
2 5
H )
3
N, dry DCM, 0 C, 18 h; (h) (CH
3
O) P, MWI 640 W
3
10 min); (i) 6, NaH, anhydrous Al
2
O
3
, stir for 3 h.
�
2
-bromoethanoylchloride (8) in the presence of triethylamine and dry DCM at 0 C gave
N-isobutyl-2-bromoethanamide (9) in 65% yield. Microwave irradiation of a mixture of
N-isobutyl-2-bromoethanamide (9) and trimethylphosphite at 640 W for 10 min afforded
phosphonate (10) in 75% yield. Modified Wittig reaction of phosphonate (10) (Wadsworth
& Emmons, 1961) and 2,3-epoxyoctanal (6) using NaH doped on anhydrous Al O gave
2 3
N-isobutyl-4,5-epoxy-2(E)-decenamide (11) in 47% yield.
Spectral data of the synthesised compound were compatible with that reported in
literature (Wei et al., 2004).
3
. Experimental
1
IR spectra were recorded on a Perkin Elmer model 1430 spectrometer. H-NMR spectra
were recorded using Varian EM-360 (60 MHz) spectrometer. Chemical shifts (�) are
reported in ppm with tetramethylsilane as internal standard. Microwave-assisted reactions
were carried out in LG MS-194A (800 W) domestic microwave oven.
3
.1. 2-Bromooctanal (2)
Octanal (1, 7.0 g, 54.6 mmol) in chloroform (22 mL) together with finely powdered calcium
carbonate (4.34 g) was taken in a round bottom flask. The reaction mixture was stirred at
�
room temperature (10–15 C) and a solution of bromine (8.68 g, 10.8 mmol) in CHCl
3
(8 mL) was added dropwise. After being stirred until the colour of the reaction mixture
changes from orange to white, the mixture was filtered and solvent removed under reduced
pressure to yield 2-bromooctanal (2, 10.4 g, 94%).
ꢀ
1
IR (neat)/ꢀmax cm : 2927, 2857, 1730, 610. H-NMR (CDCl , 60 MHz) �: 9.5 (d, 1H,
1
3
J ¼ 2 Hz, –CHO), 4.2 (m, 1H, –CHBr–), 1.6–1.1 (m, 10H, saturated methylene protons),
0
.9 (t, 3H, J ¼ 6 Hz, –CH ).
3
3
.2. 2-Bromo-1,1-diethoxyoctane (3)
Ionic liquid [bmim]HSO (0.1 g, 0.42 mmol) was added to a mixture of 2-bromooctanal (2,
4
0.50 g, 2.5 mmol) and ethanol (0.23 g, 5 mmol) taken in a conical flask which was covered
with a polythene film and exposed to MWI at 160 W for 5 min non-continuously with 30 s

Natural Product Research
551
heating and cooling time. The reaction mixture was extracted with diethyl ether
(2 � 15 mL). Unreacted aldehyde was removed by shaking with alkaline hydrogen
peroxide solution and finally washed with water. The resulting solution was dried over
anhydrous sodium sulphate. Evaporation of the solvent in vacuo provided pure 2-bromo-
1
,1-diethoxyoctane (3, 0.663 g, 85%).
ꢀ
cm : 2925, 2856, 1110, 624. H-NMR (CDCl , 60 MHz) ꢀ: 4.4 [d, 1H,
3
1
1
IR (CCl )/�
4
max
J ¼ 6 Hz, –CHBr–CH(OC H ) ], 3.4–3.1 [m, 5H, 2 � –OCH and –CHBr], 1.3–0.9 (m,
2
5 2
2
1
9H, saturated methylene and methyl protons).
3
.3. 1,1-Diethoxyoct-2-ene (4)
To a well-stirred solution of 2-bromo-1,1-diethoxyoctane (3, 2.0 g, 7.11 mmol) in DMSO
ꢁ
(
12 mL) at 120 C was added sodium ethoxide (1.50 g, 22 mmol) and the progress of the
reaction was monitored by thin layer chromatography. The reaction mixture was poured
into saturated NaCl solution (50 mL) after 16 h and extracted with diethyl ether
(
3 � 25 mL). The combined organic extracts were dried over anhydrous sodium sulphate,
filtered and concentrated in vacuo. Chromatography of the crude product on silica gel
eluted with 10% ethyl acetate in hexane gave the desired product 1,1 diethoxyoct-2-ene (4,
0
.639 g, 45% yield).
ꢀ
cm : 3012, 2924, 2856, 1653, 1108. H-NMR (CDCl , 60 MHz) ꢀ: 5.2
3
1
1
IR (CCl )/�
4
max
[
d, 1H, J ¼ 6 Hz, –CH(OCH CH ) ], 4.8 (dd, 1H, J ¼ 4 Hz, J ¼ 12 Hz, –CH –CH¼CH–),
2
3 2
2
4
and methyl protons).
.2–3.7 (m, 5H, 2 � –OCH and CH –CH¼CH–), 1.5–0.9 (m, 17H, saturated methylene
2
2
3
.4. Oct-2(E)-enal (5)
Equimolar mixture of 1,1 diethoxyoct-2-ene (4, 2.0 g, 10 mmol), [bmim]HSO (1.39 g,
4
1
0 mmol) and water (0.18 g, 10 mmol) were taken in a conical (50 mL) and exposed to
microwave radiations (160 W) for 8 min non-continuously (30 þ 30s þ ꢂ ꢂ ꢂ). The resulting
mixture was allowed to cool and extracted with diethyl ether. Organic layer was washed
with brine and finally dried over anhydrous sodium sulphate. Evaporation of the solvent
under reduced pressure afforded crude aldehyde that was purified by column chroma-
tography using ethyl acetate and hexane (0.5:9.5) as eluent to afford pure aldehyde
(
5, 1.07 g, 84%).
IR (neat)/�max cm : 2960, 2734, 1690, 1643. H-NMR (CDCl , 60 MHz) ꢀ: 9.4 (d, 1H,
ꢀ1
1
3
J ¼ 4 Hz, –CHO), 6.8 (dd, 1H, J ¼ 4 Hz, J ¼ 12 Hz, –CH¼CH–CHO), 6.2–5.9 (m, 1H, –
CH¼CH–CHO), 1.8–1.1 (m, 8H, saturated methylene protons), 0.9 (t, 3H, J ¼ 6 Hz, CH ).
3
3
.5. 2,3-Epoxyoctanal (6)
Totally, 30% H O (1.70 g, 0.05 mol) and distilled water (12 mL) were taken in a three-
2
2
necked round-bottom flask equipped with two additional funnels and standard electrode
connected to a digital pH meter. The pH was adjusted between 8 and 8.5 by the addition of
0
.2N NaOH and then oct-2(E)-enal (5, 1.0 g, 9.80 mmol) was added dropwise. The pH was
maintained at 8–8.5 by the addition of alkali. After the complete addition of oct-2(E)-enal,
the reaction mixture was stirred for an additional hour, saturated with sodium chloride
and finally extracted with DCM (4 � 15 mL). Combined organic extracts were dried and
evaporated in vacuo to give pure 2,3-epoxyoctanal (6, 1.22 g, 88%).
ꢀ1
1
IR (neat)/�max cm : 2959, 2848, 1728, 1252. H-NMR (CDCl , 60 MHz) ꢀ: 9.1 (d, 1H,
3
O
O
J ¼ 8 Hz, –CHO), 3.4 (t, 1H, J ¼ 6.4 Hz,
H, saturated methylene protons), 0.9 (t, 3H, J ¼ 6 Hz, CH3).
CHO), 3.1 (m, 1H,
CHO), 1.3–1.1 (m,
H
H
H
H
8

5
52
N. Gupta et al.
3
.6. N-Isobutyl-2-bromoethanamide (9)
2
-Bromoethanoic acid (7, 6.12 g, 43.8 mmol) and distilled phosphorous trichloride (PCl3)
2.0 g, 14.6 mmol) were heated in a round bottom flask till the evolution of HCl gas ceases.
(
The acid chloride (8) thus prepared was decanted, dissolved in dry DCM (20 mL) and
added dropwise to ice-cold mixture of triethylamine (4.0 g, 34.0 mmol) and isobutylamine
(2.58 g, 35.0 mmol) in dry DCM (40 mL) taken in another round bottom flask. The
reaction mixture was allowed to stir overnight. The product was then extracted with DCM
(
3 � 20 mL), washed with water (3 � 10 mL), brine and dried over anhydrous sodium
sulphate. The solvent was evaporated under vacuum to afford N-isobutyl-2-bromoetha-
namide (9, 4.41 g, 65%).
ꢀ
cm : 3340, 2960, 2850, 1663, 604. H-NMR (CDCl , 60 MHz) ꢀ:
3
1
1
IR (CDCl )/�
3
max
5
1
.6 (bs, 1H, –CONH–), 4.0 (s, 2H, BrCH –), 3.1 (d, 2H, J ¼ 6 Hz, –NHCH –), 2.3–2.0 [m,
2
2
H, –CH CH(CH ) ], 0.9 [d, 6H, J ¼ 8 Hz, –CH(CH ) ].
2
3 2
3 2
3
.7. Isobutyl carbamoylmethyl phosphoric acid dimethyester (10)
A mixture of trimethylphosphite (0.32 g, 2.56 mmol) and N-isobutyl-2-bromoethanamide
9, 0.5 g, 2.56 mmol) was taken in a conical flask covered with a polythene film and
(
irradiated with microwaves at 640 W for 10 min (30 þ 30s þ ꢁ ꢁ ꢁ) to afford isobutyl
carbamoylmethyl phosphoric acid dimethyl ester (10, 0.426 g, 75%).
ꢀ
1
IR (nujol)/�max cm : 3343, 2956, 2847, 1645, 1264, 1106. H-NMR (CDCl , 60 MHz)
1
3
ꢀ
: 5.4 (bs, 1H, –CONH–), 4.9 (s, 2H, –POCH CO–), 3.9 (s, 6H, 2 � –OCH ), 3.1 (d, 2H,
2
3
J ¼ 6 Hz, –NHCH –), 2.2–1.9 [m, 1H, –CH(CH ) ], 0.9 [d, 6H, J ¼ 6 Hz, –CH(CH ) ].
2
3 2
3 2
3
.8. N-Isobutyl-4,5-epoxy-2(E)-decenamide (11)
NaH (0.83 g, 34.58 mmol) was ground with basic alumina and phosphonate (10, 3.06 g,
6.16 mmol) till the evolution of the gas ceased. The reaction mixture was cooled and 2,3-
1
epoxyoctane (6, 2.0 g, 13.8 mmol) was added dropwise to it. After the addition was
complete, the reaction mixture was ground for another 2 h and left overnight. It was then
extracted with diethyl ether (4 � 25 mL) and solvent evaporation followed by silica gel
column chromatography with pet ether: ethyl acetate (4:1) as eluent afforded N-Isobutyl-
4
,5-epoxy-2(E)-decenamide (11, 1.65 g, 47%).
ꢀ
1
IR (nujol)/�max cm : 3348, 2960, 2840, 1652, 1624, 1260, 1240. NMR (CDCl3,
0 MHz) ꢀ: 6.8 (d, 1H, J ¼ 14 Hz, –CH¼CH–CO–), 6.4 (dd, 1H, J ¼ 14 Hz, J ¼ 6 Hz, –
6
CH¼CH–CO–), 5.9 (bs, 1H, –OCNH–), 3.3 (t, 1H, J ¼ 6.4 Hz, –OCHCH¼), 3.1–2.9 (m,
1
H, –CHO–), 2.8 (d, 2H, –NHCH –), 2.2–1.9 [m, 1H, –CH(CH ) ], 1.5–1.2 (m, 8H,
2 3 2
saturated methylene protons), 1.1–0.9 (m, 9H, 3 � CH3).
4
. Conclusion
In conclusion, we have achieved a new and efficient synthesis of a naturally occurring
amide alkaloid, N-isobutyl-4,5-epoxy-2(E)-decenamide isolated from the roots of
P. nigrum, starting from octanal (1) and 2-bromoacetic acid (7). The key steps in the
synthesis involved the microwave induced acetalisation of 2-bromooctanal (2) in ionic
liquid [bmim]HSO , deprotection of 1,1-diethoxyoct-2-ene (4) using microwave energy and
4
ionic liquid [bmim]HSO and solid supported modified Wittig reaction of (6) and (10) to
4
afford the title compound.
Acknowledgements
The authors are thankful to CSIR and UGC-New Delhi (India) for providing financial assistance.

Natural Product Research
553
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