Three-component synthesis of (E)-α,β-unsaturated amides of the piperine family

Article abstract of DOI:10.1039/b105745f

Selective formation of (E)-α,β-unsaturated amides by intermolecular three-component reaction between aldehydes, amines (1° or 2°) and ketenylidenetriphenylphosphorane (Ph₃P=C=C=O) is described. Natural amides such as fagaramide and piperines could be prepared from immediately available educts. The method is shown to be extendable to the preparation of thioesters from thiols and aldehydes.

Full text of DOI:10.1039/b105745f

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Three-component synthesis of (E )-ꢀ,ꢁ-unsaturated amides of the
piperine family
Rainer Schobert,* Sven Siegfried and Gary J. Gordon
1
School of Chemistry, The Queen’s University of Belfast, 23 Stranmillis Road, Belfast,
BT9 5AG, Northern Ireland. E-mail: R.Schobert@qub.ac.uk
Received (in Cambridge, UK) 27th June 2001, Accepted 10th August 2001
First published as an Advance Article on the web 12th September 2001
Selective formation of (E)-α,β-unsaturated amides by intermolecular three-component reaction between aldehydes,
amines (1Њ or 2Њ) and ketenylidenetriphenylphosphorane (Ph P᎐C᎐C᎐O) is described. Natural amides such as
fagaramide and piperines could be prepared from immediately available educts. The method is shown to be extendable
3
᎐ ᎐ ᎐
to the preparation of thioesters from thiols and aldehydes.
Introduction
Efforts towards an extension and refinement of the Wittig
olefination reaction have never abated since the very early days
and less common variants such as the ‘non-classical’ reactions
between stabilized phosphorus ylides and less reactive carbonyl
1
compounds are currently experiencing a renaissance. We have
frequently used the cumulated ylide ketenylidenetriphenyl-
phosphorane 1 as a 1,2-dipolar C -building block for the syn-
2
thesis of various O-, N- and S-heterocycles from carboxylic
esters bearing OH, NHR or SH groups by an addition–
2
intramolecular Wittig olefination sequence. These XH-acidic
groups add readily across the C᎐C bond of 1 leading to
᎐
X-acylated phosphorus ylides. These can then undergo a non-
classical Wittig olefination between the stabilized ylide and the
ester terminus. Analogous intermolecular three-component
reactions between 1, an XH-acidic and a carbonyl compound
are more problematic. In the case of aldehydes and ketones, a
direct olefination reaction with the ylide 1 might compete with
1
the addition of R XH, especially for the less acidic thiols and
3
amines. For the latter, an unwanted formation of imines or
Scheme 1
enamines by reaction with the carbonyl component is a further
conceivable complication. Finally, Michael addition reactions
between stabilized ylides and unsaturated carbonyl compounds
are also well-known processes which might interfere with the
orderly progress of this ‘one-pot’ domino procedure (Scheme
4
1
). So far, only three-component reactions of mixtures of
alcohols 2 (X = O), ylide 1 and aldehydes 3 to give (E)-α,β-
unsaturated esters 5 (X = O) have been reported.
Scheme 2
5
and found to inhibit arachidonate 5-lipoxygenase and PG
7b
synthetase.
The same synthetic concept was then applied to the prepar-
Results and discussion
We have now found that (E)-α,β-unsaturated amides 7 are
8,9
α,β
ation of the pepper substances piperine ‡7g
and ∆ -
accessible likewise by three-component reaction between ylide
8,10
dihydropiperine 7h
from piperonal 3a and piperidine 6d.
1
, (alkyl, aryl or vinyl) aldehydes 3, and (1Њ or 2Њ) amines 6.
Piperine is the principal alkaloid of black pepper (piper nigrum,
piperaceae) and the substance that gives black pepper its
hot taste. It has been used extensively because of its anti-
Yields and conditions are similar to those of the preparation of
esters 5 (X = O) from alcohols. None of the above mentioned
side and follow-up reactions were observed. Table 1 lists some
typical examples. Fagaramide 7a, a natural product occurring
11
inflammatory, sedative and insecticidal properties. The
dihydro derivative 7h was isolated from piper guineense. Chain
6a
in the root cortex of fagara zanthoxylum lamaire and fagara
lengthening of 3a by a C -unit to give the required precursor
2
6b
zanthoxylum rigidifolium, was prepared from piperonal 3a,†
aldehydes 3d and 3e was achieved following a Wittig
olefination–redox sequence (Scheme 3). Olefination of 3a
isobutylamine 6a and 1. A congener of 7c lacking acetalisation
of the diol moiety was isolated from annona cherimola Mill
7a
with formylide (PH P᎐CHCHO), which should have provided
3
the shortest possible synthetic pathway to 3d, gave a mixture
†
The IUPAC name for fagaramide is N-isobutyl-3,4-(methylenedioxy)-
cinnamamide and the IUPAC name for piperonal is 3,4-(methylene-
dioxy)benzaldehyde.
‡ The IUPAC name for piperine is 5-[3,4-(methylenedioxy)phenyl]-
penta-2,4-dienylpiperidine.
DOI: 10.1039/b105745f
J. Chem. Soc., Perkin Trans. 1, 2001, 2393–2397
This journal is © The Royal Society of Chemistry 2001
2393

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Table 1 (E)-α,β-Unsaturated amides 7 from 1, aldehydes 3 and amines 6
Educt 3
Educt 6
Product 7
Yield (%)
a
5
0
b
b
6
3
3
3
3
a
a
b
45
94
c
d
d
6d
70
51
6
d
a
b
c
d
THF, 48 h. Toluene, 24 h. THF, 36 h. THF, 24 h.
hydride with concomitant hydrogenation of the C᎐C bond, and
᎐
subsequent oxidation of the intermediate alcohol with PDC. A
mixture of 1, 3e and 6d finally produced 7h upon heating in
THF.
Thiols such as 9 are also sufficiently acidic to add to the
central C᎐C bond of 1 in preference of reacting with aldehyde
᎐
functions. Mixtures of 1, an aldehyde and a thiol thus undergo
a domino reaction upon heating to form (E)-α,β-unsaturated
thioesters such as 10. Sulfides and thiophenes do not react
under these conditions, which is demonstrated in Scheme 4 by
Scheme 3 Reagents and conditions: i) Ph P᎐CHCO Me, PhH, 24 h,
3
2
Scheme 4
reflux, 94%; ii) DIBAL-H, THF, Ϫ10 ЊC
rt, 87%; iii) PDC, CH Cl ,
2
2
ϩ
rt, 55%; iv) [Ph PCH CH ] Br, n-BuLi, 0 ЊC
rt, 92% (mixture of
3
2
3
Z–E-isomers); v) SeO , 1,4-dioxane, 24 h, reflux, 65%; vi) 1, 6d, THF,
the selective conversion of compound 11 into the correspond-
ing ester 12.
2
2
4 h, reflux; vii) LAH (2.2 equiv.), THF, rt
reflux, then H O, 73%.
2
of cis- and trans-isomers and thus was of no benefit. An
alternative route went through the methyl (E)-3,4-(methylene-
dioxy)cinnamoate 8 as obtained by olefination of 3a with
methoxycarbonylmethylenetriphenylphosphorane. The sub-
sequent reduction of 8 with DIBAL-H firstly gave the corre-
sponding alcohol, which was then oxidized with PDC to the
aldehyde 3d. No selective direct reduction of 8 to produce 3d
could be achieved using DIBAL-H at Ϫ78 ЊC. Conversion of 3a
into 3d was also possible in only two steps. Olefination with
ethylidenetriphenylphosphorane produced cis–trans-isomeric
mixtures of 3,4-(methylenedioxy)-β-methylstyrene which were
then subjected to a trans-selective allylic oxidation with selen-
Experimental
Melting points were recorded using a Gallenkamp apparatus
and are uncorrected. IR spectra were recorded on a Bruker
FT-IR Vektor 22 as potassium bromide (KBr) disks, or films
(film). Nuclear magnetic resonance (NMR) spectra were
recorded under conditions as indicated using Bruker DPX 300
and DRX 500 spectrometers. Chemical shifts are given in parts
per million (δ) downfield from tetramethylsilane as internal
standard, and coupling constants (J) are given in Hz. Mass
spectra were recorded using a Varian MAT 311A (EI). Micro-
analyses were obtained using a Perkin–Elmer 2400 CHN
elemental analyser. Flash chromatography was effected using
12
ium dioxide to furnish the E-aldehyde 3d. The final three-
3a
component domino reaction of the latter with 1 and piperidine
Merck Kieselgel 60 (230–400 mesh). Ylide 1 was prepared by
the literature method, all other starting compounds were
purchased from ALDRICH and used as such without further
purification.
α,β
6
d yielded piperine 7g in 90%. The preparation of ∆ -
dihydropiperine 7h was analogous. The aldehyde 3e was
obtained by reducing the ester 8 with lithium aluminium
2
394
J. Chem. Soc., Perkin Trans. 1, 2001, 2393–2397

View Online
ϩ
1
General experimental procedure for the three-component
(C-3), 148.5, 149.2 (C-3Ј, C-4Ј), 165.0 (C-1); m/z (EI) 259 (M ,
ϩ
synthesis of amides 7 from ylide 1, aldehydes 3 and amines 6
27%), 206 (27%), 175 (M Ϫ C H N, 73%), 89 (100%).
5 10
A solution of 1 (2.30 g, 7.50 mmol, 1.5 equiv.), the amine 6
(
E,E )-1-(5Ј-Phenylpenta-2Ј,4Ј-dienoyl)piperidine 7e. Pale yel-
(
(
5.00 mmol) and the aldehyde 3 (5.00 mmol) in THF or toluene
50 mL) was heated under reflux for 12–48 h with exclusion of
low lamellas (0.84 g, 3.48 mmol, 70%) from piperidine 6d (0.42
g) and cinnamaldehyde 3b (0.66 g), reflux in THF for 24 h, Rf
.30 (diethyl ether–n-hexane, 4 : 1, v/v), mp 91 ЊC (from diethyl
ether) (lit. mp 91–92 ЊC); νmax(KBr)/cm 3026, 2934, 1636,
613, 1597, 1588, 1432, 1002; δH (300 MHz; CDCl ) 1.54–1.70
6 H, m, NCCH , NCCCH ), 3.43–3.48 and 3.52–3.62 (each
air and moisture. After cooling to room temperature the solvent
was removed under reduced pressure and the residue obtained
was purified by column chromatography (silica gel; solvent as
indicated).
0
1
4
Ϫ
1
1
(
3
2 2
2
H, each m, NCH ), 6.48 (1 H, d, J 14.67, 2-H), 6.85–6.89 (2 H,
2
Fagaramide 7a. White solid (0.63 g, 2.51 mmol, 50%) from
isobutylamine 6a (0.36 g) and piperonal 3a (0.75 g), reflux
m, 4-H, 5-H), 7.26–7.46 (6 H, m, 3-H, Ph-H); δ (75.6 MHz;
CDCl ) 25.6 (NCCCH ), 26.6, 27.7 (NCCH ), 44.2, 47.9
(NCH ), 121.9 (C-2), 127.9, 128.0 (Ph–C), 128.7 (C-4), 129.5
(Ph–C), 137.5 (ipso-C), 139.4, 143.3 (C-3, C-5), 166.3 (C-1); m/z
C
3
2
2
in THF for 48 h, R 0.48 (ethyl acetate–hexane, 1 : 1, v/v), mp
f
2
6b
Ϫ1
1
1
15 ЊC (lit. mp 116 ЊC); νmax(KBr)/cm 3296, 1650, 1614,
544, 1492, 1447, 1253, 1038; δ (500 MHz; CDCl ) 0.94 (6 H,
ϩ
ϩ
ϩ
H
3
(EI) 241 (M , 76%), 164 (M Ϫ C H , 6%), 157 (M Ϫ C H N,
6 5 5 10
ϩ
d, J 8.93, CHMe ), 1.79–1.88 (1 H, m, CHMe ), 3.20 (2 H, d,
2
2
100%), 128 (C H , 63%).
10 8
J 6.33, NCH ), 5.59 (2 H, s, OCH O), 6.05 (1 H, s, NH), 6.28
2
2
(
1 H, d, J 15.49, 2-H), 6.75–6.99 (3 H, m, 2Ј-H, 5Ј-H, 6Ј-H),
(E )-1-(5Ј-Phenylpent-2Ј-enoyl)piperidine 7f. Colourless vis-
cous oil (0.62 g, 2.56 mmol, 51%) from piperidine 6d (0.42 g)
and 3-phenylpropanal 3c (0.67 g), reflux in THF for 24 h, Rf
0.79 (ethyl acetate–n-hexane, 10 : 1, v/v), bp 128 ЊC/0.1 mmHg
7
2
1
1
.55 (1 H, d, J 15.49, 3-H); δ (125.7 MHz; CDCl ) 20.2 (Me),
C
3
8.7 (CMe ), 47.1 (NCH ), 101.4 (OCH O), 106.3, 108.5, 119.0,
2
2
2
23.7 (C-2, C-2Ј, C-5Ј, C-6Ј), 129.3 (C-1Ј), 140.5 (C-3), 148.2,
ϩ
14
Ϫ1
48.9 (C-4Ј, C-3Ј), 166.2 (C-1); m/z (EI) 247 (M , 37%), 190
(lit. bp 164–169 ЊC/0.2 mmHg); νmax(film)/cm 3025, 2935,
ϩ
ϩ
(
M Ϫ C H , 56%), 175 (M Ϫ C H N, 100%).
1656, 1616, 1440; δH (300 MHz; CDCl ) 1.45–1.65 (6 H, m,
4
9
4
10
3
NCCH , NCCCH ), 2.51 (2 H, m, 4-H), 2.77 (2 H, t, J 7.16,
2
2
(
E,E )-N-Allyl-5-phenylpenta-2,4-dienamide
7b.
White
5-H), 3.31–3.37 and 3.55–3.57 (each 2 H, each m, NCH
(1 H, dt, J 15.14, 1.45, 2-H), 6.81 (1 H, dt, J 15.14, 6.90, 3-H),
7.15–7.27 (5 H, m, Ph–H); δ (75.6 MHz; CDCl ) 24.5
(NCCCH ), 25.5, 26.5 (NCCH ), 34.2, 35.1 (C-4, C-5), 43.0,
46.8 (NCH ), 121.4 (C-2), 126.0, 128.3, 128.4 (Ph-C), 141.1
2
), 6.20
needles (0.79 g, 3.16 mmol, 63%) from allylamine 6b (0.28 g)
and cinnamaldehyde 3b (0.66 g), reflux in toluene for 24 h, Rf
.56 (diethyl ether–n-pentane, 4 : 1, v/v), mp 131 ЊC (from
diethyl ether) (Found: C, 78.88; H, 6.98; N, 6.51. C H NO
requires C, 78.84; H, 7.09; N, 6.57%); νmax(film)/cm 3249,
658, 1641, 1604, 1551, 1258, 1006; δ (500 MHz; CDCl ) 3.99
2 H, dt, J 5.69, J 1.42, NCH ), 5.15 (1 H, dd, J 10.20, 1.42,
CHH ), 5.22 (1 H, dd, J 17.24, 1.42, ᎐CHH ), 5.58–5.91
1 H, m, H CCH), 6.05 (1 H, d, J 14.90, 2-H), 6.12 (1 H, s, NH),
.84–6.86 (2 H, m, 4-H, 5-H), 7.27–7.43 (6 H, m, 3-H, Ph–H);
C
3
0
2
2
1
4
15
2
Ϫ1
ϩ
(ipso-C), 144.0 (C-3), 165.5 (C-1); m/z (EI) 243 (M , 83%), 217
ϩ
ϩ
ϩ
9
1
(
(58%), 159 (M Ϫ C
H
5
10N, 39%), 126 (M Ϫ C
H
9
, 72%), 91
H
3
3
4
(100%).
2
cis
trans
᎐
᎐
2
Synthesis of piperine 7g
Methyl (E )-3Ј,4Ј-(methylenedioxy)cinnamoate 8. A solution
of methoxycarbonylmethylenetriphenylphosphorane (16.70 g,
0 mmol) and piperonal 3a (7.50 g, 50 mmol) in dry benzene
100 mL) was heated under exclusion of air and moisture
(
6
2
δC (125.7 MHz; CDCl ) 42.1 (NCH ), 116.4 (H C᎐), 123.9
C-2), 126.3 (C-4), 127.0, 128.7, 128.8 (arom. CH), 134.2 (H2-
3
2
2
(
5
(
C᎐C), 133.2 (C-3), 136.2 (ipso–C), 141.2 (C-5), 166.0 (C-1); m/z
᎐
ϩ
ϩ
ϩ
(
1
EI) 213 (M , 87%), 172 (M Ϫ C H , 34%), 157 (M Ϫ C H N,
00%).
3 5 3 6
for 24 h. After cooling to room temperature the solvent was
evaporated on a rotary evaporator and the crude product
thus obtained was recrystallized from ethanol to yield 8 (9.77 g,
(
E )-N-Phenethyl-3Ј,4Ј-(methylenedioxy)cinnamamide
White solid (0.63 g, 2.29 mmol, 45%) from 2-phenylethylamine
c (0.61 g) and piperonal 3a (0.75 g), reflux in toluene for 24 h,
R 0.83 (ethyl acetate), mp 117 ЊC (Found: C, 73.34; H, 5.84;
7c.
15
4
7.30 mmol, 94%) as white needles, mp 69 ЊC (lit. mp 68 ЊC);
Ϫ1
νmax(KBr)/cm 2996, 1702, 1625, 1599, 1254; δH (300 MHz;
6
CDCl ) 3.79 (3 H, s, Me), 6.00 (2 H, s, OCH ), 6.23 (1 H, d,
3
2
f
J 19.86, 2-H), 6.75–7.02 (3 H, m, arom. H), 7.53 (1 H,
d, J 19.86, 3-H); δC (75.6 MHz; CDCl ) 52.0 (CH ), 101.9
N, 4.71. C H NO requires C, 73.20; H, 5.80; N, 4.74%);
νmax(KBr)/cm 3291, 1650, 1617, 1544, 1249; δH (300 MHz;
CDCl ) 2.79 (2 H, t, J 6.62, NCCH ), 3.64 (2 H, m, NCH ), 5.86
2 H, s, OCH O), 5.94 (1 H, s, NH), 6.17 (1 H, d, J 15.49, 2-H),
.66 (1 H, d, J 8.46, 5Ј-H), 6.85 (1 H, d, J 8.46, 6Ј-H), 7.10–7.25
6 H, m, Ph–H, 2Ј-H), 7.44 (1 H, d, J 15.49, 3-H); δ (75.6 MHz;
CDCl ) 34.7 (NCCH ), 39.8 (NCH ), 100.4 (OCO), 105.3,
07.1 (C-2Ј, C-5Ј), 117.8 (C-2), 122.8 (C-6Ј), 125.8 (C-1Ј), 127.3,
27.6, 129.0 (Ph–CH), 137.9 (ipso–C), 139.6 (C-3), 147.0
18
17
Ϫ1
3
3
3
(OCH ), 106.8, 108.9, 116.1, 124.8 (arom. CH), 129.2 (C-1Ј),
2
3
2
2
144.9 (C-3), 148.7, 150.0 (C-3Ј, C-4Ј), 168.0 (C-1); m/z (EI) 206
(
ϩ
ϩ
2
(M , 100%), 175 (M Ϫ CH O, 92%), 145 (70%), 117 (44%), 89
3
6
(
83%).
(E )-3,4-(Methylenedioxy)cinnamyl alcohol. To a stirred solu-
(
C
3
2
2
1
1
(
tion of 8 (1.0 g, 5.0 mmol) in dry THF (75 mL), a solution of
diisobutylaluminium hydride (DIBAL-H; 15.0 mL of a 1.0 M
solution in hexane, 15 mmol) was added dropwise over a period
of 30 min at Ϫ10 ЊC. The mixture was stirred at this temper-
ature for 2 h and then at room temperature for a further 4 h. It
was then quenched by slowly adding water (20 mL). The pre-
cipitate of aluminium salts was treated with 1 M aqueous HCl
solution, the organic layer was separated, the aqueous phase
extracted four times with diethyl ether and the combined
ϩ
C-3Ј), 148.0 (C-4Ј), 165.2 (C-1); m/z (EI) 296 (MH , 9%),
95 (M , 38%), 190 (M Ϫ C H , 42%), 175 (M Ϫ C H N,
ϩ
ϩ
ϩ
2
8 9 8 10
1
00%).
E )-1-[3Ј,4Ј-(Methylenedioxy)cinnamoyl]piperidine 7d. White
(
solid (1.22 g, 4.71 mmol, 94%) from piperidine 6d (0.42 g) and
piperonal 3a (0.75 g), reflux in THF for 36 h, R 0.53 (ethyl
acetate–n-hexane, 2 : 1, v/v), mp 83 ЊC (lit. mp 85–87 ЊC);
νmax(KBr)/cm 3067, 2939, 1645, 1590, 1492, 1443, 1250;
f
13
organic extracts were finally dried over MgSO . After filtration
4
Ϫ1
and evaporation of the solvent the residue was purified by col-
δ (300 MHz; CDCl ) 1.59–1.72 (6 H, m, NCCH , NCCCH ),
umn chromatography, R 0.42 (diethyl ether–n-hexane, 2 : 1, v/v)
H
3
2
2
f
3
.74 (4 H, m, NCH ), 5.98 (2 H, s, OCH O), 6.74 (1 H, d,
yielding (E)-3Ј,4Ј-(methylenedioxy)cinnamyl alcohol (0.78 g,
2
2
16
J 15.49, 2-H), 6.77–7.03 (3 H, m, 2Ј-H, 5Ј-H, 6Ј-H), 7.56 (1 H,
d, J 15.49, 3-H); δC (75.6 MHz; CDCl ) 25.0, 26.1, 27.1
4.35 mmol, 87%) as a white solid, mp 71 ЊC (lit. mp 72–73 ЊC);
Ϫ1
νmax(KBr)/cm 3398, 2894, 1651, 1503, 1445, 1036; δH (300
3
(
NCCH , NCCCH ), 43.7, 47.3 (NCH ), 101.8 (OCO), 106.7,
MHz; CDCl ) 1.70 (1 H, s, OH), 4.27 (2 H, dd, J 5.85, 1.30,
2
2
2
3
1
08.8, 116.0, 123.9 (C-2Ј, C-5Ј, C-6Ј, C-2), 130.3 (C-1Ј), 142.3
1-H), 5.94 (2 H, s, OCH O), 6.18 (1 H, dt, J 15.80, 5.85, 2-H),
2
J. Chem. Soc., Perkin Trans. 1, 2001, 2393–2397
2395

View Online
6
.51 (1 H, dd, J 15.80, 1.30, 3-H), 6.37–6.91 (3 H, m, arom. H);
obtained from piperidine 6d (0.42 g, 5.00 mmol), (E)-3,4-
δ (75.6 MHz; CDCl ) 64.1 (C-1), 101.5 (OCO), 106.2, 108.7,
(methylenedioxy)cinnamaldehyde 3d (0.88 g, 5.00 mmol) and
ylide 1 (2.30 g, 7.50 mmol), THF, reflux, 24 h, pale yellow solid,
C
3
1
1
1
21.6, 127.1, 131.4 (C-2, C-3, arom. CH), 131.5 (ipso-C), 147.7,
qu
ϩ
ϩ
9
Ϫ1
48.4 (arom. C ); m/z (EI) 178 (M , 100%), 147 (M Ϫ CH O,
mp 126–127 ЊC (lit. mp 125–126 ЊC); νmax(KBr)/cm 2938,
1636, 1620, 1598, 1490, 1443, 1244, 1029; δ (500 MHz; CDCl )
3
1%), 135 (93%), 122 (42%), 103 (18%).
H
3
1
.65–1.69 (6 H, m, NCCH , NCCCH ), 3.52–3.59 (4 H, m,
2 2
3
,4-(Methylenedioxy)-ꢁ-methylstyrene. To
a
well stirred
NCH ), 5.97 (2 H, s, OCH ), 6.43 (1 H, d, J 14.86, 2-H), 6.72–
2
2
suspension of ethyltriphenylphosphonium bromide (7.5 g, 20.2
mmol) in dry THF (100 mL), a solution of n-butyllithium (12.6
mL of a 1.6 M solution in hexane, 20.2 mmol) was added drop-
wise over a period of 30 min at 0 ЊC. The mixture was warmed
to room temperature and stirred for 60 min. A solution of
piperonal 3a (3.0 g, 20.0 mmol) in THF (25 mL) was then
slowly added and the resulting mixture left stirring for a further
6.97 (5 H, m, 4-H, 5-H, arom. CH), 7.40 (1 H, ddd, J 14.86,
8.79, 1.42, 3-H); δ (125.7 MHz; CDCl ) 24.7 (NCCCH ), 26.2,
C
3
2
26.5 (NCCH ), 43.4, 46.8 (NCH ), 101.3 (OCO), 105.7, 108.5,
2
2
120.1, 122.1, 125.4 (C-2, C-4, arom. CH), 131.2 (ipso-C), 138.2,
qu
142.5 (C-3, C-5), 148.1, 148.2 (arom. C ), 165.4 (C-1); m/z (EI)
ϩ
ϩ
285 (M , 86%), 201 (M Ϫ C H N, 100%), 173 (33%), 115
5
10
(74%).
6
h. Water (100 mL) was added, the organic layer was separ-
ꢀ
,ꢁ
ated, the aqueous phase extracted twice with diethyl ether and
the combined organic phases were finally dried over MgSO4.
After filtration and evaporation of the solvents the residue was
eluted from silica gel with CH Cl to remove phosphine oxide
3
Synthesis of ꢂ -dihydropiperine 7h
3
Ј,4Ј-(Methylenedioxy)dihydrocinnamyl alcohol. To a well
stirred slurry of lithium aluminium hydride (1.70 g, 44.80
mmol) in dry THF (150 mL), methyl 3Ј,4Ј-(methylenedioxy)-
cinnamoate 8 (4.12 g, 20.00 mmol) was added in small portions
over a period of 60 min at 0 ЊC. The reaction mixture was then
warmed to room temperature, stirred for another 60 min and
finally heated for 2 h. It was then cooled in an ice-bath to 0 ЊC
and quenched by the careful addition of water until no further
hydrogen gas evolved. The precipitate of aluminium salts was
treated with 1 M aqueous HCl solution and the organic phase
was separated. The aqueous layer was extracted four times with
diethyl ether (100 mL), the combined organic phases were
washed with brine and dried over MgSO . After filtration, the
solvent was removed and the product was purified by column
chromatography, R 0.46 (diethyl ether–n-pentane, 2 : 1, v/v)
and distillation, bp 109 ЊC/0.1 Torr, to yield 3Ј,4Ј-(methylene-
dioxy)dihydrocinnamyl alcohol (2.63 g, 14.63 mmol, 73%) as a
colourless oil (Found: C, 66.74; H, 6.74. C H O requires C,
6.65; H, 6.71%); νmax(film)/cm 3349, 2939, 1503, 1489, 1441,
246, 1038; δ (300 MHz; CDCl ) 1.67 (1 H, s, OH), 1.83 (2 H,
2
2
and the residue was purified by distillation, bp 121 ЊC/15 Torr
17
(
lit. bp 123 ЊC/11.5 Torr), 3.0 g (18.5 mmol, 92%) as a colour-
less oil, mixture of Z- and E-isomers (Z–E = 1 : 10); νmax(film)/
cm 3022, 2994, 1501, 1490, 1444, 1249, 1040; δH (300 MHz;
CDCl ) mixture of Z- and E-isomer: 1.84 and 1.87 (3 H, each
dd, J 6.57/7.20 and J 1.62/1.86, CH ), 5.64 and 5.70 (2 H, each
s, OCH ), 5.92–6.57 (1 H, m, MeCH), 6.26–6.33 (1 H, m,
MeCCH), 6.72–6.87 (3 H, arom. CH); δ (75.6 MHz; CDCl ),
major isomer: 18.3 (Me), 100.8 (OCO), 105.3, 109.0, 120.0,
Ϫ1
3
3
4
3
2
C
3
1
1
1
23.9, 130.5 (MeC, MeCC, arom. CH), 132.4 (ipso-C), 146.4,
qu
4
47.8 (arom. C ); minor isomer: 14.7 (Me), 101.0 (OCO), 108.0,
09.0, 122.5, 125.5, 129.4 (MeC, MeCC, arom. CH), 131.7
qu
f
(
ipso-C), 145.4, 146.7 (arom. C ).
(
E )-3Ј,4Ј-(Methylenedioxy)cinnamaldehyde 3d. a) Oxidation
1
0
12
3
of 3Ј,4Ј-(methylenedioxy)cinnamyl alcohol with pyridinium
dichromate (PDC). To a vigorously stirred suspension of pyrid-
inium dichromate (2.36 g, 7.00 mmol) in CH Cl (20 mL) a
Ϫ1
6
1
H
3
2
2
tt, J 7.65, 6.40, 2-H), 2.62 (2 H, t, J 7.65, 3-H), 3.64 (2 H, t,
J 6.40, 1-H), 5.94 (2 H, s, OCH O), 6.61–6.79 (3 H, arom. H);
δ (75.6 MHz; CDCl ) 34.4, 37.0 (C-2, C-3), 64.6 (C-1), 103.3
OCO), 110.7, 111.4, 123.7 (arom. CH), 138.2 (ipso-C), 148.2,
50.2 (arom. C ); m/z (EI) 180 (M , 74%), 162 (M Ϫ H O,
7%), 149 (27%), 135 (100%).
solution of 3Ј,4Ј-(methylenedioxy)cinnamyl alcohol (0.89 g,
.00 mmol) in CH Cl (10 mL) was added dropwise over a
2
5
2
2
C
3
period of 20 min. The mixture was then allowed to stir over-
night at room temperature. While being stirred, the mixture was
finally diluted with diethyl ether (100 mL), the resulting precipi-
tation of chromium oxide was removed by filtration, and the
filtrate thus obtained was washed twice with small portions of
(
1
2
qu
ϩ
ϩ
2
3
Ј,4Ј-(Methylenedioxy)dihydrocinnamaldehyde 3e. Following
water and then dried over MgSO . After evaporation of the
solvent the residue was purified by column chromatography, Rf
4
the procedure described above for the preparation of 3d,
aldehyde 3e (0.49 g, 2.76 mmol, 55%) was obtained from
PDC (2.63 g, 7.00 mmol) and 3Ј,4Ј-(methylenedioxy)dihydro-
cinnamyl alcohol (0.90 g, 5.00 mmol) as a colourless oil, R 0.95
diethyl ether–n-pentane, 2 : 1, v/v) (Found: C, 67.44; H, 5.74.
C H O requires C, 67.41; H, 5.66%); νmax(film)/cm 3070,
895, 1724, 1504, 1489, 1445, 1248, 1036; δ (300 MHz; CDCl )
.61–2.67 (2 H, m, 2-H), 2.80 (2 H, t, J 7.17, 3-H), 5.83 (2 H, s,
OCH O), 6.49–6.68 (3 H, m, arom. CH), 9.72 (1 H, d, J 4.75,
-H); δC (75.4 MHz; CDCl ) 26.0 (C-3), 43.6 (C-2), 99.0
OCO), 106.4, 106.9, 119.2 (arom. CH), 132.2 (ipso-C), 144.1,
45.7 (arom. C ), 199.5 (C-1); m/z (EI) 178 (M , 83%), 150
M Ϫ CO, 36%), 135 (100%).
0
.57 (diethyl ether–n-hexane, 1 : 1, v/v) to leave pure 3d (0.49 g,
18a
2
.78 mmol, 55%) as a white solid, mp 77 ЊC (lit. mp 77–79 ЊC,
18b
lit. : mp 83–84 ЊC).
f
(
b) Oxidation of 3,4-(methylenedioxy)-β-methylstyrene with
selenium dioxide. A suspension of selenium dioxide (0.40 g, 3.00
mmol) in dry 1,4-dioxane (20 mL) was treated with 3,4-
Ϫ1
10 10
3
2
2
H
3
(
methylenedioxy)-β-methylstyrene (0.53 g, 3.00 mmol) and then
heated under reflux with the exclusion of air and moisture for
6 h. After cooling to room temperature the precipitate of
2
1
(
1
(
1
3
selenium was removed by filtration over a pad of Celite and the
product was eluted with 1,4-dioxane (50 mL). The solvent was
evaporated under reduced pressure and the residue was purified
qu
ϩ
ϩ
by column chromatography as described above to give pure 3d
Ϫ1
ꢀ,ꢁ
(
0.36 g, 1.96 mmol, 65%); νmax(KBr)/cm 2916, 1655, 1623,
ꢂ -Dihydropiperine 7h. Following the general procedure for
α,β
1
6
502, 1449, 1259; δH (300 MHz; CDCl ) 6.11 (2 H, s, OCH ),
.56 (1 H, dd, J 15.81, 7.74, 2-H), 6.51–7.08 (3 H, m, arom.
the preparation of amides 7, ∆ -dihydropiperine 7h (0.41 g,
1.41 mmol, 70%) was obtained from piperidine 6d (0.17 g, 2.00
mmol), (E)-3Ј,4Ј-(methylenedioxy)dihydrocinnamaldehyde 3e
(0.36 g, 2.00 mmol) and ylide 1 (0.91 g, 3.00 mmol), THF,
reflux, 24 h, as a white solid, mp 78 ЊC (lit. mp 74 ЊC, lit. mp
79–80 ЊC); νmax(KBr)/cm 3000, 2935, 1657, 1612, 1503, 1489,
3
2
CH), 7.38 (1 H, d, J 15.81, 3-H), 9.92 (1 H, d, J 7.74, 1-H);
δ (75.6 MHz; CDCl ) 102.2 (OCO), 107.1, 109.1, 125.6, 127.2
C
3
qu
10a
10b
(
(
C-2, arom. CH), 128.9 (ipso-C), 149.0, 150.9 (arom. C ), 152.9
C-3), 192.9 (C-1); m/z (EI) 176 (M , 100%), 147 (M Ϫ CHO,
ϩ
ϩ
Ϫ1
3
2%), 135 (6%), 122 (17%), 118 (27%).
1442, 1247, 1038; δH (500 MHz; CDCl ) 1.54–1.66 (6 H, m,
3
NCCH , NCCCH ), 2.46 (2 H, tdd, J 7.30, 6.95, 1.52, 4-H),
2
2
Piperine 7g. Following the general procedure for the prepar-
ation of amides 7, piperine 7g (1.28 g, 4.48 mmol, 90%) was
2.69 (2 H, t, J 7.30, 5-H), 3.46–3.57 (4 H, m, NCH ), 5.90 (2 H,
2
s, OCH ), 6.21 (1 H, dt, J 15.14, 1.52, 2-H), 6.61–6.72 (3 H, m,
2
2
396 J. Chem. Soc., Perkin Trans. 1, 2001, 2393–2397

View Online
arom. CH), 6.79 (1 H, dt, J 15.14, 6.95, 3-H); δ (125.7 MHz;
Fonds der Chemischen Industrie and the Deutsche
C
CDCl ) 24.6, 25.5, 26.6 (NCCCH , NCCH ), 34.5, 34.6
Forschungsgemeinschaft is gratefully acknowledged.
3
2
2
(
C-4, C-5), 43.0, 46.0 (NCH ), 100.8 (OCO), 108.2, 108.8,
2
1
1
2
21.2, 122.4 (C-2, arom. CH), 131.2 (ipso-C), 144.0 (C-3),
qu ϩ
References
45.7, 147.6 (arom. C ), 165.5 (C-1); m/z (EI) 287 (M , 58%),
ϩ
02 (M Ϫ C H N, 16%), 174 (21%), 135 (100%).
1 (a) P. J. Murphy and J. Brennan, J. Chem. Soc. Rev., 1988, 17, 1;
5
11
(
b) P. J. Murphy and S. E. Lee, J. Chem. Soc., Perkin Trans. 1, 1999,
3
049.
(a) J. Löffler and R. Schobert, J. Chem. Soc., Perkin Trans. 1, 1996,
028; (b) J. Löffler and R. Schobert, Liebigs Ann. Chem., 1997, 217;
4
Synthesis of thioester 10 and ester 12 (according to the
2
3
general procedure for the preparation of amides 7)
1
Furan-2Ј-ylmethyl (E )-5-phenylpent-2-enethioate 10. Colour-
less oil (1.26 g, 4.63 mmol, 93%) from 2-furylmethanethiol 9
(c) J. Löffler and R. Schobert, Synlett, 1997, 283.
(a) H. J. Bestmann and D. Sandmeier, Angew. Chem., Int. Ed. Engl.,
975, 14, 634; (b) G. H. Birum and C. N. Matthews, J. Am. Chem.
1
(
0.57 g, 5.00 mmol), 3-phenylpropanal 3c (0.67 g, 5.00 mmol),
Soc., 1968, 90, 3842.
and ylide 1 (2.30 g, 7.50 mmol), THF, reflux for 24 h, R 0.74
f
4 H. J. Bestmann and A. Groβ, Tetrahedron Lett., 1997, 38, 4765.
5 H. J. Bestmann and R. Schobert, Angew. Chem., Int. Ed. Engl., 1985,
24, 790.
(
diethyl ether–hexane, 1 : 1, v/v), bp 116 ЊC/1 Torr (Found:
C, 70.65; H, 5.91. C H O S requires C, 70.56; H, 5.92%);
1
6
16
2
Ϫ1
νmax(film)/cm 3026, 2927, 1719, 1675, 1497, 1010; δH (300
6
(a) S. Terada, T. Motomiya, K. Yoshioka, T. Narita, S. Yasu and
M. Takase, Chem. Pharm. Bull., 1987, 35, 2437; (b) S. K. Adesina,
D. D. Olugbade, D. D. Akinwusi and D. Bergenthal, Pharmazie,
MHz; CDCl ) 2.48–2.55 (2 H, m, 4-H), 2.78 (2 H, t, J 7.26,
3
5
6
3
2
1
-H), 4.20 (2 H, s, SCH ), 6.12 (1 H, dt, J 15.56, 1.40, 2-H),
.21–6.29 (2 H, m, 3Ј-H, 4Ј-H), 6.95 (1 H, dt, J 15.56, 6.95,
-H), 7.18–7.64 (6 H, m, arom CH); δC (75.6 MHz; CDCl3)
2
1
997, 52, 720.
7
8
(a) C. Chen, F. Chang and Y. Wu, J. Chin. Chem. Soc. (Taipei),
1997, 44, 313; (b) C. Tseng, S. Iwakami, A. Mikajiri, M. Shibuya and
F. Hanaoka, Chem. Pharm. Bull., 1992, 40, 396.
5.8 (C-4), 34.3, 34.7 (C-5, SCH ), 108.3, 111.0 (C-3Ј, C-4Ј),
2
(a) W. Karrer, Konstitution und Vorkommen der organischen
Pflanzenstoffe, Birkhäuser, Basel, 1958, p. 405; (b) J. W. Loder,
A. Moorhouse and G. B. Russell, J. Aust. Chem., 1969, 22,
26.7, 128.7, 129.0 (arom. CH), 140.9 (ipso-C), 142.6, 145.5
(
2
C-2, C-5Ј), 149.8 (C-2Ј), 150.9 (C-3), 189.0 (C-1); m/z (EI)
ϩ
ϩ
72 (M , 42%), 191 (M Ϫ C H OS, 29%), 131 (80%), 91
5 5
1
531.
(
100%).
9
R. Ikan, Natural Products, Israel University Press, Tel Aviv, 1969,
p. 182.
Thiophen-2Ј-ylmethyl (E )-5-phenylpent-2-enoate 12. Colour-
10 (a) I. Addae-Menah, F. G. Torto, I. V. Oppong, I. Baxter and
J. M. Sanders, Phytochemistry, 1977, 16, 483; (b) J. I. Okogun,
B. L. Sondergam and S. F. Kumbu, Phytochemistry, 1977, 16,
less oil (1.09 g, 4.03 mmol, 80%) from 2-hydroxymethylthio-
phene 11 (0.57 g, 5.00 mmol), 3-phenylpropanal 3c (0.67 g, 5.00
mmol), and ylide 1 (2.30 g, 7.50 mmol), THF, reflux for 24 h, Rf
1
295.
1
1 (a) V. S. Parmar, S. C. Jain, K. S. Bisht, R. Jain, P. Taneja, A. Jha,
O. D. Tyagi, A. K. Prasad, J. Wengler, C. E. Olsen and P. M. Boll,
Phytochemistry, 1997, 46, 597; (b) V. Badmaer, M. Majeed and
L. Prakash, J. Nutr. Biochem., 2000, 11, 109.
2 (a) D. Arigoni, A. Vasella, K. B. Sharpless and H. P. Jensen, J. Am.
Chem. Soc., 1973, 95, 7917; (b) K. B. Sharpless, A. Y. Teranishi and
J.-E. Bäckvall, J. Am. Chem. Soc., 1977, 99, 2130; (c) H. J. Bestmann
and R. Schobert, Angew. Chem., Int. Ed. Engl., 1985, 24, 791.
0
.66 (diethyl ether–hexane, 1 : 4, v/v) (Found: C, 70.49; H, 6.01.
Ϫ1
C H O S requires C, 70.56; H, 5.92%); νmax(film)/cm 3062,
1
6
16
2
2
942, 1720, 1653, 1258, 1188; δ (300 MHz; CDCl ) 2.50 (2 H,
H
3
m, 4-H), 2.75 (2 H, t, J 7.24, 5-H), 5.30 (2 H, s, OCH ), 5.86
1
2
(
5
(
(
(
1
1 H, dt, J 15.64, 1.49, 2-H), 6.97–7.31 (9 H, m, 3-H, 3Ј-H, 4Ј-H,
Ј-H, PhH); δ (75.6 MHz; CDCl ) 33.6, 33.9 (C-4, C-5), 60.3
C
3
OCH ), 121.3 (C-2), 126.2, 126.8, 128.1, 128.3, 128.4, 128.5
2
13 Y. Shen and Y. Zhou, Synth. Commun., 1992, 22, 567.
14 H. Staudinger and C. Schneider, Chem. Ber., 1922, 56, 705.
15 C.-J. Feuerstein and A. Heimann, Chem. Ber., 1901, 34, 1469.
C-3Ј, C-4Ј, C-5Ј, arom. CH), 138.1, 140.7 (C-2Ј, ipso-C), 149.0
ϩ
ϩ
C-3), 166.1 (C-1); m/z (EI) 272 (M , 19%), 175 (M Ϫ C H S,
5 5
1
6 J. L. Belletiere and N. O. Mahmoodi, Tetrahedron Lett., 1989, 30,
363.
7 R. Hoering and G. Baum, Chem. Ber., 1909, 42, 3080.
5%), 159 (33%), 97 (100%).
4
1
Acknowledgements
18 (a) T. Takeya, T. Ara and S. Tobinaga, Chem. Pharm. Bull., 1995, 43,
970; (b) I. C. Parson, A. I. Gray, T. G. Hartley and P. G.
1
Financial support from EPSRC (Grant GR/M97961), the
Watermann, Phytochemistry, 1992, 33, 479.
J. Chem. Soc., Perkin Trans. 1, 2001, 2393–2397
2397