Full text of DOI:10.1016/S0040-4020(01)01184-X

TETRAHEDRON
Pergamon
Tetrahedron 58 >2002) 989±995
The generation and reactivity of N-substituted, stabilised
a,b:g,d-unsaturated azomethine ylides
a
b
a
Miklos Nyerges, Andrea Arany, Imre Fejes, Paul W. Groundwater,b,p Weimin Zhang,b
Â
b
David Bendell, Rosaleen J. Anderson and Laszlo Toke
b
a
Â
 Í
aDepartment of Organic Chemical Technology, Research Group of the Hungarian Academy of Sciences, Technical University of Budapest,
P.O. Box 91, H-1521 Budapest, Hungary
bInstitute of Pharmacy, Chemistry and Biomedical Sciences, University of Sunderland, Wharncliffe Street, Sunderland SR1 3SD, UK
Received 20 September 2001; accepted 30 November 2001
AbstractÐThe generation of N-substituted, stabilised azomethine ylides in the presence of N-phenylmaleimide gave the bicyclo[3.3.0]
octane-3-carboxylate cycloadducts. In the absence of a dipolarophile, these azomethine ylides gave novel piperazine-6-carboxylates. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
As a continuation of these studies we have now examined
the reactivity of some a,b:g,d-unsaturated, N-substituted
stabilised azomethine ylides 3. We wish to report here the
generation of these 1,3-dipoles and their subsequent
reactions in the presence and absence of dipolarophiles.
The 1,3-dipolar cycloaddition of azomethine ylides
represents perhaps the most important example of the
variety of reaction pathways available to these dipoles.1
There are, however, many other synthetically useful
reactions of these dipoles, including the 1,5-electrocyclic
ring closure of appropriately substituted dipolar systems.2
Recently, we3 and others4 published the ®rst examples of
the 1,7-electrocyclisation of azomethine ylides with
a,b:g,d-unsaturation.5 During these studies we have found
signi®cant differences between the reactivity of a,b:g,d-
unsaturated, N-substituted, non-stabilised 1 and a,b:g,d-
unsaturated, N-unsubstituted stabilised azomethine ylides
2. The former dipoles react via a 1,7-electrocyclisation,
followed by a [1,5]-hydrogen shift to give dihydro-
benzazepines 4,3 whilst the latter give didehydroamino
acid derivatives 5 as the stable products of a novel
rearrangement >Scheme 1).6
2. Results and discussion
The condensation of various aldehydes with N-alkyl or
N-aryl a-amino esters leads to N-substituted azomethine
ylides.7 These ylides may be formed directly from the
amino-carbinol intermediate via loss of water and can be
trapped by added dipolarophiles since there are no other
reactive reagents >e.g. base, Lewis acids) present.
Upon re¯uxing a solution of b-phenylcinnamaldehyde 6a
and sarcosine ethyl ester 7b in the presence of N-phenyl-
maleimide 8, a mixture of three isomers of the cycloadducts,
Scheme 1.
Keywords: azomethine ylides; piperazines; cycloadducts.
Corresponding author. Address: Institute of Pharmacy, Chemistry, and Biomedical Sciences, University of Sunderland, Wharncliffe Street, Sunderland SR1
3SD, UK. Fax: 144-191-515-2502; e-mail: paul.groundwater@sunderland.ac.uk
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020>01)01184-X

990
M. Nyerges et al. / Tetrahedron 58 12002) 989±995
9a±c, was obtained in a 4:1:1 ratio >Scheme 2). The stereo-
chemistry of these products was elucidated by HH-COSY
and NOESY experiments. In this trapping experiment, the
dominant conformer of the conjugated azomethine ylide 3b
is the anti, leading to the adducts 9a >anti-endo) and 9b
>anti-exo). Similarly, with other N-substituted stabilised
azomethine ylides the exclusive involvement of one of the
anti conformers was observed when the electron withdraw-
ing group was an ester8 and the replacement of the ester with
a nitrile group reduced the stereoselectivity of the reaction.9
Re¯uxing a solution of b-phenylcinnamaldehyde 6a and
various sarcosine esters 7 in the absence of any dipolaro-
phile led to the formation, in all cases, of only two products.
After careful chromatographic separation these two
compounds were identi®ed as the two stereoisomers of
2-oxopiperazine-6-carboxylates, trans 10a±c and cis 11a±
c >Scheme 3, Table 1). The isomeric ratio and stereo-
Scheme 2.
1
chemistry of these products were also determined by H
Scheme 3.
Table 1. Yields and conditions for the formation of piperazines 10,11
NMR spectroscopy >nOe and NOESY), the cis isomers 11
giving a 5±6% nOe between the hydrogens at positions 5
and 6.
Entry
R
X
Time >h)
Yield >%)a
10/11 ratiob
a
b
c
d
e
CH3
CH2CH3
CH2Ph
CH2CH3
CH2CH3
H
H
H
Cl
OCH3
10
13
14
1
62
68
62
72
77
2:1
2:1
6:1
1:1
3:1
This reaction was then repeated with 40,40-substituted
b-phenylcinnamaldehydes 6b,c and sarcosine ethyl ester
7b. These substituted b-phenylcinnamaldehydes 6b,c were
prepared by the reduction of the corresponding esters 12,10
to the alcohols 13, followed by oxidation to the aldehydes
6b,c >Scheme 4). Oxidation of the chloro derivative 13a was
1
a
Combined yield of the two isomers before separation.
Determined by H NMR spectroscopy of the crude mixtures.
b
1

M. Nyerges et al. / Tetrahedron 58 12002) 989±995
991
As expected, the azomethine ylide 1 is the least stable, due
to the absence of an ester group and thus lack of resonance
stabilisation of the anion. Presumably the stabilisation of the
dipoles 2 and 3 results in a greater half-life in solution, and
so a greater probability of their reaction with their pre-
cursors. In addition, however, the non-stabilised, substituted
dipole 1 can cyclise to the intermediate 15a >which again is
less stable than its analogs 15b,c) and this process is some
52 kJ mol21 more exothermic than the cyclisation of the
other dipoles 2,3 to their respective intermediates 15b,c. It
is presumably this greater exothermicity, in addition to the
decreased stability of this dipole, which accounts for the
1,7-electrocyclisation of this dipole 1, whilst the other
dipoles 2,3 do not cyclise but react with their precursors.
Scheme 4.
accomplished with aq. sodium hypochlorite but these con-
ditions proved unsuccessful for the methoxy derivative 13b,
which was eventually oxidised with activated MnO2 in
chloroform. These aldehydes were then reacted with
sarcosine ethyl ester 7b to give the corresponding substi-
tuted piperazines 10d,e and 11d,e. The use of other carbonyl
compounds, such as aromatic aldehydes, cinnamaldehyde
etc. in place of b-phenylcinnamaldehyde 6a resulted in
the formation of complex mixtures of products.
3. Experimental
3.1. General
The piperazine-6-carboxylates 10,11, which are novel
products from the reactions of azomethine ylides, are
presumably formed from an intermediate secondary amine
14, itself formed from the nucleophilic attack of the active
methylene of the sarcosine ester 7 on the azomethine ylide
3.
Mps were determined on a Gallenkamp apparatus and are
uncorrected. Elemental analyses were performed on a
Perkin±Elmer 240C or Carlo Erba 1106 Elemental
Analyser. IR spectra were recorded on a NICOLET FT-IR
instrument or Perkin±Elmer 1600 series FTIR using sodium
1
chloride plates. H NMR spectra were recorded on Bruker
250, 300 or JEOL 270 MHz spectrometers. Coupling
constants are given in Hz and all chemical shifts are relative
to an internal standard of tetramethylsilane. 13C NMR
spectra were obtained on a Jeol GFX 270 FT NMR
>68 MHz) or Bruker 250 MHz >63 MHz) spectrometer.
Low resolution electron impact mass spectra were obtained
on a Trio 2000 VG. High resolution spectra were obtained
on Bruker APEX II FTMS. Column chromatography was
In order to account for the 1,7-electrocyclisation of only the
non-stabilised, substituted dipoles 1, we have performed
energy calculations on these dipoles 1±3 and the products
of their electrocyclisations 15 >Scheme 5) using semi-
empirical >MOPAC PM3)11 methods with Insight II
>Release 2000)/MOPAC software >MSI/Biosym, CA,
USA) on a Silicon Graphics Octane workstation >Table 2).
Scheme 5.
Table 2. Heats of formation for dipoles 1±3 and intermediates 15a±c
Dipole
DHf >kJ mol21
)
Intermediate
DHf >kJ mol21
)
DDHf >kJ mol21
)
1
2
3
413.8
17.4
34.9
15a
15b
15c
248.9
280.9
277.9
2164.9
298.3
2112.8

992
M. Nyerges et al. / Tetrahedron 58 12002) 989±995
performed using Merck Kieselgel 60 70±230 mesh, TLC on
aluminium sheets coated with Kieselgel 60 F254
for 0.5 h. The organic layer was separated and the aq.
phase was extracted with diethyl ether >3£20 mL). The
combined organic phases were washed with sat. aq. sodium
hydrogen carbonate >20 mL) and dried over magnesium
sulphate. The solvent was evaporated under reduced
pressure to give a liquid, which was puri®ed by column
chromatography on silica, eluting with hexane/ethyl acetate
>90:10) to give 3,3-bis140-chlorophenyl)prop-2-enal 6b as a
yellow oil >2.02 g, 75%);6 IR >neat) 1667 >CvO), 1586
.
3.2. Materials
Ethyl 3,3-bis>40-chlorophenyl)prop-2-enoate 12a and ethyl
3,3-bis>40-methoxyphenyl)prop-2-enoate 12b were pre-
pared by the method of Collomb, Chantegrel, and
Deshayas.10
1
>CvC), 1490 >CvC) cm21; H NMR >270 MHz, CDCl3)
3.2.1. 3,3-Bis.40-chlorophenyl)prop-2-enol 13a.
A
dˆ6.55 >1H, d, Jˆ7.9 Hz, vCH), 7.22±7.46 >8H, m, ArH),
9.49 >1H, d, Jˆ7.9 Hz, CHO); 13C NMR >68 MHz, CDCl3)
dˆ127.6 >vCH), 128.7 >2£CH), 128.9 >2£CH), 129.7
>2£CH), 131.8 >2£CH), 134.5 >q), 135.8 >q), 136.7 >q),
137.6 >q), 159.0 >q), 192.3 >CvO); MS >EI): m/z 280
>M1, 8%), 278 >M1, 44), 276 >M 1, 67), 243 >49), 241
>94), 214 >23), 212 >61), 178 >77), 176 >79), 136 >100), 88
>82), and 75 >88); HRMS >EI): Found: M1, 276.0110, Calcd
for C15H10Cl2O: M1ˆ276.0109.
mixture of ethyl 3,3-bis>40-chlorophenyl)prop-2-enoate
12a >3.21 g, 10.0 mmol), sodium borohydride >1.52 g,
40.0 mmol), zinc chloride >2.73 g, 20.0 mmol), and triethyl-
amine >2.78 mL, 20.0 mmol) was re¯uxed, with stirring,
under nitrogen in THF >30 mL) for 2.5 h. The reaction
mixture was cooled in ice-water, and 10% aq. hydrochloric
acid >30 mL) and diethyl ether >50 mL) were added, with
stirring. The organic layer was separated, washed con-
secutively with sat. aq. sodium hydrogen carbonate solution
>20 mL), water >20 mL), sat. aq. sodium chloride solution
>20 mL), and dried over magnesium sulphate. The solvent
was evaporated under reduced pressure and the residue was
puri®ed by column chromatography on silica, eluting with
hexane/ethyl acetate >70:30) to give 3,3-bis140-chloro-
phenyl)prop-2-enol 13a as a white solid >2.47 g, 88.5%),
mp 66±688C; IR 3302 >OH), 1591 >CvC), 1491
3.2.4. 3,3-Bis.40-methoxyphenyl)prop-2-enal 6c. To a
stirred suspension of activated manganese dioxide >3.41 g,
39.22 mmol) in chloroform >30 mL) was added 3,3-bis>40-
methoxyphenyl)prop-2-enol 13b >2.65 g, 9.81 mmol). The
mixture was stirred for 48 h at room temperature then
®ltered. The ®ltrate was then evaporated under reduced
pressure, and the residue was puri®ed by column
chromatography on silica, eluting with hexane/ethyl acetate
>70:30) to give 3,3-bis140-methoxyphenyl)prop-2-enal 6c as
a light yellow oil >2.13 g, 81%); IR >neat) 1657 >CvO),
1
>CvC) cm21; H NMR >270 MHz, CDCl3) dˆ1.95 >1H,
s, OH), 4.17 >2H, d, Jˆ6.6 Hz, CH2), 6.20 >1H, t,
Jˆ6.6 Hz, vCH), 7.04±7.15 >4H, m, H-20,60), 7.21±7.35
>4H, m, H-30,50); 13C NMR >68 MHz, CDCl3) dˆ60.3
>CH2), 128.3 >vCH), 128.4 >2£CH), 128.6 >2£CH), 128.8
>2£CH), 131.0 >2£CH), 133.7 >q), 133.8 >q), 136.9 >q),
139.8 >q), 141.9 >q); MS >EI): m/z 282 >M1,4%), 280
>M1, 21), 278 >M1, 31), 262 >14), 260 >18), 245 >44), 243
>100), 237 >77), 235 >95), 141 >22), 139 >68), 127 >18), 125
>53), 103 >49), and 77 >35); Anal. Calcd for C15H12Cl2O: C,
64.5; H, 4.3%. Found: C, 64.3; H, 4.4%.
1605 >CvC), 1511 >CvC) cm21 1H NMR >270 MHz,
;
CDCl3) dˆ3.81 >3H, s, OCH3), 3.85 >3H, s, OCH3), 6.48
>1H, d, Jˆ8.1 Hz, vCH), 6.81±6.97 >4H, m, H-30,50),
7.20±7.32 >4H, m, H-20,60), 9.49 >1H, d, Jˆ8.1 Hz,
CHO); 13C NMR >68 MHz, CDCl3) dˆ55.1 >2£OCH3),
113.5 >2£CH), 113.8 >2£CH), 125.2 >vCH), 128.9 >q),
130.3 >2£CH), 132.1 >q), 132.2 >2£CH), 160.6 >q), 161.5
>q), 161.7 >q), 193.2 >CvO); MS >EI): m/z 268 >M1, 92%),
267 >76), 237 >58), 135 >84), and 132 >100); HRMS >ESI):
Found: MH1, 269.1173, Calcd for C17H17O3:
MH1ˆ269.1172.
3.2.2. 3,3-Bis.40-methoxyphenyl)prop-2-enol 13b. Ethyl
3,3-bis>40-methoxyphenyl)prop-2-enoate 12b >2.14 g,
6.86 mmol) and sodium borohydride >1.04 g, 27.4 mmol)
were reacted using the method above to give, after column
chromatography on silica eluting with hexane/ethyl acetate
>70:30), 3,3-bis140-methoxyphenyl)prop-2-enol 13b as a
colourless oil >1.61 g, 87%); IR >neat) 3458 >OH), 1607
3.3. 1,3-Dipolar cycloaddition between N-phenyl-
maleimide 8 and the azomethine ylide 3b derived from
b-phenylcinnamaldehyde 6a and sarcosine ethyl ester 7b
1
>CvC), 1511 >CvC) cm21; H NMR >270 MHz, CDCl3)
Sarcosine ethyl ester 7b >64 mg, 0.42 mmol), b-phenyl-
cinnamaldehyde 6a >86 mg, 0.42 mmol) and N-phenyl-
maleimide 8 >71 mg, 0.42 mmol) were dissolved in
toluene >5 mL), and the mixture was re¯uxed for 24 h.
After 12 h, further sarcosine ethyl ester 7b >64 mg,
0.42 mmol) was added to the reaction mixture. When the
reaction was complete, the solvent was removed in vacuo.
The 1H NMR spectrum of the crude residue gave the isomer
ratio as 4:1:1. The three isomers were separated by column
chromatography on silica, eluting with hexane/ether
>50:50).
dˆ2.40 >1H, s, OH), 3.75 >3H, s, OCH3), 3.78 >3H, s,
OCH3), 4.17 >2H, d, Jˆ6.6 Hz, CH2), 6.07 >1H, t,
Jˆ6.6 Hz, vCH), 6.75±6.87 >4H, m, H-30,50), 7.02±7.17
>4H, m, H-20,60); 13C NMR >68 MHz, CDCl3) dˆ55.1
>2£OCH3), 60.5 >CH2), 113.4 >4£CH), 125.5 >vCH),
128.7 >2£CH), 130.8 >2£CH), 131.5 >q), 134.8 >q), 143.0
>q), 158.8 >q), 159.0 >q); MS >EI): m/z 270 >M1, 53%), 252
>32), 242 >48), 227 >100), 135 >84), and 77 >36); HRMS
>ESI): Found: M1, 253.1220, Calcd for C17H17O2:
>M2OH)1ˆ253.1223.
3.2.3. 3,3-Bis.40-chlorophenyl)prop-2-enal 6b. A mixture
of 3,3-bis>40-chlorophenyl)prop-2-enol 13a >2.70 g,
9.09 mmol), ethyl acetate >50 mL), benzyltri-n-butyl-
ammonium chloride >0.1 g) and sodium hypochlorite
solution >ca. 14% available chlorine, 30 mL) was stirred
3.3.1. Ethyl 1,4-diaza-4-methyl-2,6-dioxo-1-phenyl-5-
.20,20-diphenylethenyl)bicyclo[3.3.0]octane-3-carboxyl-
ate 9a .anti-endo isomer). Colourless oil >0.074 g, 37%);
IR >nujol) 1778 >CvO), 1716 >CvO), 1596 >CvC), 1496
1
>CvC) cm21; H NMR >270 MHz, CDCl3) dˆ1.16 >3H, t,

M. Nyerges et al. / Tetrahedron 58 12002) 989±995
993
Jˆ7.0 Hz, CH3), 2.37 >3H, s, NCH3), 3.41 >1H, m, H-2a and
H-5a), 3.94 >1H, m, H-5), 4.11 >2H, m, OCH2), 4.19 >1H, s,
H-3), 5.74 >1H, d, Jˆ9.9 Hz, vCH), 7.25±7.48 >15H, m,
ArH); 13C NMR >68 MHz, CDCl3) dˆ14.7 >CH3), 35.8
>CH3), 48.5 >CH2), 49.6 >CH), 61.3 >CH), 63.6 >CH), 68.1
>CH), 125.3 >vCH), 126.3 >CH), 126.9 >2£CH), 128.0
>2£CH), 128.2 >CH), 128.6 >2£CH), 128.8 >2£CH), 129.1
>CH), 129.6 >2£CH), 129.8 >2£CH), 140.1 >q), 142.1 >q),
170.5 >q), 175.4 >2£q), 176.9 >q); MS >EI): m/z 480 >M1,
50%), 465 >28), 407 >100), 307 >12), 260 >20), 234 >68), 202
>28), 191 >88), 178 >50), 167 >57), 115 >25), 84 >45); HRMS
>EI): Found: M1, 480.2050, Calcd for C30H28N2O4:
M1ˆ480.2049.
of the residue gave the isomer ratio. The isomers were
separated by column chromatography on silica, eluting
with hexane /ether >50:50).
3.4.1. Methyl trans-1,4-dimethyl-2-oxo-5-.20,20-diphenyl-
ethenyl)piperazine-6-carboxylate 10a. White powder
>0.124 g, 34%), mp 135±1378C; IR >KBr) 1748 >CvO),
1
1655 >CvO), 1489 >CvC), 1212 >C±O) cm21; H NMR
>250 MHz, CDCl3) dˆ2.12 >3H, s, NCH3), 2.98 >3H, s,
NCH3), 3.35 >2H, s, CH2), 3.70 >3H, s, OCH3), 3.86 >1H,
d, Jˆ3.1 Hz, H-6), 3.90±3.94 >1H, m, H-5), 6.20 >1H, d,
Jˆ10.2 Hz, vCH), 7.17±7.21 >2H, m, ArH), 7.22±7.43
>5H, m, ArH), 7.34±7.47 >3H, m, ArH); 13C NMR
>63 MHz, CDCl3) dˆ34.4 >NCH3), 41.9 >NCH3), 52.7
>OCH3), 54.5 >CH2), 58.8 >CH), 66.7 >CH), 120.2 >vCH),
127.4 >2£CH), 127.8 >CH), 128.2 >CH), 128.4 >2£CH),
128.5 >2£CH), 129.6 >2£CH), 138.8 >q), 141.3 >q), 148.7
>q), 167.5 >CvO), 170.2 >CvO); Anal. Calcd for
C22H24N2O3: C 72.5; H 6.6; N 7.7%. Found: C, 73.0; H,
6.6; N, 7.5.
3.3.2. Ethyl 1,4-diaza-4-methyl-2,6-dioxo-1-phenyl-5-
.20,20-diphenylethenyl)bicyclo[3.3.0]octane-3-carboxyl-
ate 9b .anti-exo isomer). White crystalline solid >0.020 g,
10%), mp 1288C; IR >nujol) 1712 >CvO), 1496
1
>CvC) cm21; H NMR >270 MHz, CDCl3) dˆ1.33 >3H, t,
Jˆ7.0 Hz, CH3), 2.30 >3H, s, NCH3), 3.15 >1H, d, Jˆ7.9 Hz,
H-3), 3.19 >1H, d, Jˆ9.9 Hz, H-5), 3.25 >1H, t, Jˆ7.9 Hz,
H-2a), 3.51 >1H, d, Jˆ7.9 Hz, H-5a), 4.28 >2H, m, OCH2),
6.11 >1H, d, Jˆ9.9 Hz, vCH), 7.18±7.48 >15H, m, ArH);
13C NMR >68 MHz, CDCl3) dˆ14.1 >CH3), 38.8 >CH3),
46.4 >CH2), 48.0 >CH), 61.4 >CH), 66.7 >CH), 69.8 >CH),
125.0 >vCH), 126.5 >2£CH), 127.4 >2£CH), 127.5 >CH),
127.7 >CH), 128.2 >2£CH), 128.5 >2£CH), 128.6 >CH),
129.0 >2£CH), 129.4 >2£CH), 139.8 >q), 141.2 >q), 146.6
>q), 169.0 >q), 169.1 >q), 174.0 >q); MS >EI): m/z 480 >M1,
27%), 407 >100), 260 >25), 234 >45), 215 >12), 191 >30), 115
>16), 84 >13); HRMS >EI): Found: M1, 480.2050, Calcd for
C30H28N2O4: M1ˆ480.2049.
3.4.2. Methyl cis-1,4-dimethyl-2-oxo-5-.20,20-diphenyl-
ethenyl)piperazine-6-carboxylate 11a. Colourless oil
>0.055 g, 15%); IR >neat) 1744 >CvO), 1652 >CvO),
1486 >CvC), 1203 >C±O) cm21 1H NMR >250 MHz,
;
CDCl3) dˆ2.26 >3H, s, NCH3), 2.83 >3H, s, NCH3), 2.84
>1H, d, Jˆ16.8 Hz, H-3a), 3.39 >1H, d, Jˆ10.0 and 4.0 Hz,
H-5), 3.60 >1H, d, Jˆ17.1 Hz, H-3b), 3.82 >1H, d,
Jˆ4.0 Hz, H-6), 3.84 >3H, s, OCH3), 5.98 >1H, d,
Jˆ10.0 Hz, vCH), 7.16±7.22 >2H, m, ArH), 7.23±7.35
>5H, m, ArH), 7.35±7.46 >3H, m, ArH); 13C NMR
>63 MHz, CDCl3) dˆ33.6 >NCH3), 42.7 >NCH3), 58.4
>CH2), 61.1 >CH), 65.6 >CH), 123.9 >vCH), 127.2
>2£CH), 127.7 >CH), 128.0 >CH), 128.3 >2£CH), 128.7
>2£CH), 129.3 >2£CH), 139.1 >q), 141.1 >q), 146.2 >q),
167.6 >CvO), 169.6 >CvO); Anal. Calcd for
C22H24N2O3: C, 72.5; H, 6.6; N, 7.7%. Found: C, 72.6; H,
6.6; N, 7.5.
3.3.3. Ethyl 1,4-diaza-4-methyl-2,6-dioxo-1-phenyl-5-
.20,20-diphenylethenyl)bicyclo[3.3.0]octane-3-carboxyl-
ate 9c .syn-endo isomer). Pale yellow oil >0.025 g, 12%);
IR >nujol) 1712 >CvO), 1596 >CvC), 1496 >CvC) cm21
;
1H NMR >270 MHz, CDCl3) dˆ1.15 >3H, t, Jˆ7.0 Hz,
CH3), 2.25 >3H, s, NMe), 3.44 >1H, dd, Jˆ9.2 and 4.5 Hz,
H-5a), 3.82 >1H, t, Jˆ9.0 Hz), 4.12 >2H, m), 4.18 >1H, d,
Jˆ9.0, H-3), 4.25 >1H, dd, Jˆ10.2 and 4.5 Hz, H-5), 5.99
>1H, d, Jˆ10.2 Hz, vCH), 7.22±7.48 >15H, m, ArH); 13C
NMR >68 MHz, CDCl3) dˆ14.1 >CH3), 35.9 >NCH3), 47.1
>OCH2), 50.9 >CH), 61.2 >CH), 63.6 >CH), 67.2 >CH), 125.1
>vCH), 126.5 >2£CH), 127.5 >2£CH), 127.6 >2£CH),
128.0 >CH), 128.3 >CH), 128.6 >CH), 129.1 >2£CH),
130.0 >2£CH), 132.5 >q), 138.5 >q), 142.9 >q), 164.5
>CvO), 175.5 >2£CvO); MS >EI): m/z 480 >M1, 25%),
407 >100), 260 >40), 234 >69), 215 >25), 191 >65), 167
>23), 115 >28), 91 >38), 84 >52); HRMS >EI): Found: M1,
480.2049, Calcd for C30H28N2O4: M1ˆ480.2049.
3.4.3. Ethyl trans-1,4-dimethyl-2-oxo-5-.20,20-diphenyl-
ethenyl)piperazine-6-carboxylate 10b. White powder
>0.140 g, 37%), mp 1438C; IR >KBr) 1742 >CvO), 1654
>CvO), 1488 >CvC), 1206 >C±O) cm21
;
1H NMR
>250 MHz, CDCl3) dˆ1.18 >3H, t, Jˆ7.2 Hz, CH3), 2.11
>3H, s, NCH3), 2.98 >3H, s, NCH3), 3.35 >2H, s, CH2),
3.86±3.92 >2H, m, H-5 and H-6), 4.04±4.25 >2H, m,
OCH2), 6.21 >1H, d, Jˆ10.6 Hz, vCH), 7.15±7.22 >2H,
m, ArH), 7.22±7.35 >5H, m, ArH), 7.35±7.45 >3H, m,
ArH); 13C NMR >63 MHz, CDCl3) dˆ14.0 >CH3), 34.3
>NCH3), 41.8 >NCH3), 54.5 >CH2), 58.9 >CH), 61.5 >CH2),
66.7 >CH), 120.5 >vCH), 127.4 >2£CH), 127.8 >CH), 128.2
>CH), 128.4 >2 £ CH), 128.5 >2£CH), 129.6 >2£CH), 138.9
>q), 141.3 >q), 148.7 >q), 167.5 >CvO), 169.7 >CvO); MS
>CI): m/z 379 >MH1, 61%), 308 >10), 234 >100), 192 >13),
158 >47); Anal. Calcd for C23H26N2O3: C, 73.0; H, 6.9; N,
7.4%. Found: C, 73.0; H, 7.0; N, 7.5.
3.4. Reaction of b-phenylcinnamaldehyde 6a with
sarcosine esters 7a±c in the presence of triethylamineÐ
general procedure
The N-substituted glycine ester 7a±c >2 mmol), b-phenyl-
cinnamaldehyde 6a >210 mg, 1 mmol) and triethylamine
>0.14 mL, 100 mg, 2 mmol) were dissolved in toluene
>10 mL), and the solution was re¯uxed for 10±14 h under
an argon atmosphere. When the reaction was complete, the
precipitate was ®ltered off and the solvent was removed
evaporated under reduced pressure. The 1H NMR spectrum
3.4.4. Ethyl cis-1,4-dimethyl-2-oxo-5-.20,20-diphenyl-
ethenyl)piperazine-6-carboxylate 11b. Colourless oil
>0.068 g, 18%); IR >neat) 1741 >CvO), 1655 >CvO),
1490 >CvC), 1209 >C±O) cm21 1H NMR >250 MHz,
;
CDCl3) dˆ1.28 >3H, t, Jˆ7.0 Hz, CH3), 2.26 >3H, s,
NCH3), 2.83 >1H, d, Jˆ16.9 Hz, H-3a), 2.84 >3H, s,

994
M. Nyerges et al. / Tetrahedron 58 12002) 989±995
NCH3), 3.39 >1H, dd, Jˆ10.0 and 4.0 Hz, H-5), 3.60 >1H, d,
Jˆ17.0 Hz, H-3b), 3.81 >1H, d, Jˆ4.0 Hz, H-6), 4.23±4.37
>2H, m, OCH2), 6.00 >1H, d, Jˆ10.0 Hz, vCH), 7.15±7.35
>4H, m, ArH), 7.35±7.48 >6H, m, ArH); 13C NMR >63 MHz,
CDCl3) dˆ14.2 >CH3), 33.5 >NCH3), 42.6 >NCH3), 58.3
>CH2), 61.0 >CH), 61.7 >CH2), 66.0 >CH), 124.1 >vCH),
127.3 >2£CH), 127.7 >CH), 128.0 >CH), 128.3 >2£CH),
128.7 >2£CH), 129.3 >2£CH), 139.1 >q), 141.2 >q), 146.2
>q), 167.7 >CvO), 170.0 >CvO); Anal. Calcd for
C23H26N2O3: C, 73.0; H, 6.9; N, 7.4%. Found: C, 73.2; H,
6.8; N, 7.4.
spectroscopy). The oil was further puri®ed by column chro-
matography on silica eluting with hexane/ether >50:50).
3.5.1. Ethyl trans-5-[20,20-bis.400-chlorophenyl)ethenyl]-
1,4-dimethyl-2-oxopiperazine-6-carboxylate 10d. White
solid >0.19 g, 31%), mp 132±1348C >from ethanol); IR
1
>KBr) 1733 >CvO), 1670 >CvO), 1250 >C±O) cm21; H
NMR >270 MHz, CDCl3) dˆ1.21 >3H, t, Jˆ6.9 Hz, CH3),
2.11 >3H, s, NCH3), 2.98 >3H, s, NCH3), 3.30 >1H, d,
Jˆ17.2 Hz, H-3a), 3.38 >1H, d, Jˆ17.2, H-3b), 3.81±3.86
>2H, m, H-5 and H-6), 4.07±4.28 >2H, m, OCH2), 6.19 >1H,
d, Jˆ9.9 Hz, vCH), 7.10±7.18 >4H, m, H-20,60), 7.25±7.43
>4H, m, H-30,50); 13C NMR >68 MHz, CDCl3) dˆ14.0
>CH3), 34.4 >NCH3), 41.8 >NCH3), 54.3 >CH2-3), 58.8
>CH), 61.7 >OCH2), 66.5 >CH), 121.6 >vCH), 128.6
>4£CH), 128.9 >2£CH), 130.9 >2£CH), 134.1 >q), 134.4
>q), 136.8 >q), 139.3 >q), 146.4 >q), 167.3 >CvO), 169.5
>CvO); MS >ESI): m/z 451 >MH1, 8%), 449 >MH1, 60),
447 >MH1, 100); Anal. Calcd for C23H24Cl2N2O3: C, 61.75;
H, 5.4; N, 6.3%. Found: C, 61.4; H, 5.3; N, 6.0%; HRMS
>ESI): Found: MH1, 447.1237. Calc. for C23H25Cl2N2O3:
MH1ˆ447.1237.
3.4.5. Benzyl trans-1,4-dimethyl-2-oxo-5-.20,20-diphenyl-
ethenyl)piperazine-6-carboxylate 10c. Colourless oil
>0.207 g, 47%); IR >neat) 1744 >CvO), 1659 >CvO),
1501 >CvC), 1226 >C±O) cm21 1H NMR >250 MHz,
;
CDCl3) dˆ2.06 >3H, s, NCH3), 2.99 >3H, s, NCH3), 3.36
>2H, s, N±CH2), 3.92±3.97 >2H, m, H-5 and H-6), 5.05 >1H,
d, Jˆ12.4 Hz, Ph±CHa), 5.20 >1H, d, Jˆ12.4 Hz, Ph±
CHb), 6.22 >1H, d, Jˆ11.0 Hz, vCH), 7.12±7.34 >15H,
m, Ar-H); 13C NMR >63 MHz, CDCl3) dˆ34.5 >NCH3),
41.8 >NCH3), 54.2 >CH2-3), 58.6 >CH), 66.7 >CH), 67.1
>PhCH2), 119.8 >vCH), 127.4 >2£CH), 127.7 >CH), 127.8
>q1CH), 128.2 >CH), 128.3 >2£CH), 128.4 >2£CH), 128.5
>4£CH), 129.5 >2£CH), 138.8 >q), 141.1 >q), 148.8 >q),
167.5 >CvO), 169.5 >CvO); Anal. Calcd for
C28H28N2O3: C, 76.3; H, 6.4; N, 6.4%. Found: C, 76.2; H,
6.6; N, 6.4.
3.5.2. Ethyl cis-5-[20,20-bis.400-chlorophenyl)ethenyl]-1,4-
dimethyl-2-oxopiperazine-6-carboxylate 11d. Light
yellow oil >0.15 g, 25%); IR >neat) 1740 >CvO), 1682
1
>CvO), 1258 >C±O) cm21; H NMR >270 MHz, CDCl3)
dˆ1.27 >3H, t, Jˆ6.9 Hz, CH3), 2.24 >3H, s, NCH3), 2.85
>3H, s, NCH3), 2.86 >1H, d, Jˆ17.2 Hz, H-3a), 3.37 >1H, dd,
Jˆ10.6, 4.0 Hz, H-5), 3.59 >1H, d, Jˆ17.2 Hz, H-3b), 3.78
>1H, d, Jˆ4.0 Hz, H-6), 4.24±4.31 >2H, m, OCH2), 5.99
>1H, d, Jˆ10.6 Hz, vCH), 7.09±7.16 >4H, m, ArH),
7.24±7.29 >2H, m, ArH), 7.40±7.43 >2H, m, ArH); 13C
NMR >68 MHz, CDCl3) d 14.3 >CH3), 33.6 >NCH3), 42.6
>NCH3), 58.1 >CH2-3), 60.8 >CH), 61.8 >OCH2), 65.5 >CH),
125.3 >vCH), 128.4 >2£CH), 128.6 >2£CH), 129.2
>2£CH), 130.7 >2£CH), 134.1 >q), 134.2 >q), 137.0 >q),
139.3 >q), 143.9 >q), 167.5 >CvO), 168.9 >CvO); m/z
>ESI) 451 >MH1, 8%), 449 >MH1, 59), 447 >MH1, 100);
HRMS >ESI): Found: MH1, 447.1236. Calc for
C23H25Cl2N2O3: MH1ˆ447.1237.
3.4.6. Benzyl cis-1,4-dimethyl-2-oxo-5-.20,20-diphenyl-
ethenyl)piperazine-6-carboxylate 11c. Colourless oil
>0.028 g, 6.5%); IR >neat) 1745 >CvO), 1655 >CvO),
1500 >CvC), 1222 >CÐO) cm21 1H NMR >250 MHz,
;
CDCl3) dˆ2.24 >3H, s, NCH3), 2.82 >3H, s, NCH3), 2.83
>1H, d, Jˆ17.0 Hz, H-3a), 3.35±3.41 >1H, m, H-5), 3.60
>1H, d, Jˆ17.0 Hz, H-3b), 3.85 >1H, d, Jˆ3.8 Hz, H-6),
5.08 >1H, d, Jˆ12.0 Hz, Ph±CHa), 5.33 >1H, d,
Jˆ12.0 Hz, Ph±CHb), 5.93 >1H, d, Jˆ10.0 Hz, vCH),
7.07±7.35 >15H, m, ArH); 13C NMR >63 MHz, CDCl3)
dˆ33.6 >NCH3), 42.5 >NCH3), 58.5 >CH2), 61.2 >CH),
65.7 >CH), 67.5 >Ph±CH2), 123.9 >vCH), 126.3 >CH),
127.2 >3£CH), 127.9 >CH), 128.1 >q), 128.4 >2£CH),
128.5 >2£CH), 128.6 >2£CH), 128.7 >2£CH), 129.3
>2£CH), 139.0 >q), 140.9 >q), 146.3 >q), 167.6 >CvO),
169.1 >CvO); Anal. Calcd for C28H28N2O3: C, 76.3; H,
6.4; N, 6.4%. Found: C, 76.3; H, 6.6; N, 6.5.
3.6. The reaction of 3,3-bis.40-methoxyphenyl)propenal
6c with sarcosine ethyl ester 7b
The reaction of 3,3-bis>40-methoxyphenyl)propenal 6c
>0.51 g, 1.90 g mmol) and sarcosine ethyl ester hydrochlo-
ride 7b >0.59 g, 3.84 mmol) as described earlier, gave a
mixture which was puri®ed by column chromatography on
silica eluting with ethyl acetate to give a brown oil >0.64 g,
77%) containing trans-10e and cis-ethyl 5-[20,20-bis>400-
methoxylphenyl)ethenyl]-1,4-dimethyl-2-oxopiperazine-6-
carboxylate 11e >isomeric ratio 3:1, determined by 1H NMR
spectroscopy). This brown oil was separated by column
chromatography on silica, eluting with hexane/diethyl
ether >20:80).
3.5. The reaction of 3,3-bis.40-chlorophenyl)propenal 6b
with sarcosine ethyl ester 7b
A mixture of 3,3-bis>40-chlorophenyl)propenal 6b >0.38 g,
1.37 mmol), sarcosine ethyl ester hydrochloride 7c >0.42 g,
2.74 mmol) and dry triethylamine >0.38 mL, 2.74 mmol) in
anhydrous toluene >25 mL) was re¯uxed for 1 h under
nitrogen. After cooling to room temperature, the triethyl-
amine hydrochloride was removed by ®ltration and the
®ltrate was then evaporated under reduced pressure. The
residue was puri®ed by column chromatography on silica,
eluting with diethyl ether to give a brown oil >0.44 g, 72%)
containing trans- 10d and cis-ethyl 5-[20,20-bis>400-chloro-
phenyl)ethenyl]-1,4-dimethyl-2-oxopiperazine-6-carboxyl-
ate 11d >isomeric ratio 1:1, determined by 1H NMR
3.6.1. Ethyl trans-5-[20,20-bis.400-methoxyphenyl)ethenyl]-
1,4-dimethyl-2-oxopiperazine-6-carboxylate 10e. White
solid >0.38 g, 46%), mp 143±1458C >from ethanol); IR
>KBr) 1735 >CvO), 1666 >CvO), 1606 >CvC), 1510
1
>CvC), 1247 >C±O) cm21; H NMR >270 MHz, CDCl3)
dˆ1.21 >3H, t, Jˆ7.3 Hz, CH3), 2.10 >3H, s, NCH3), 2.98

M. Nyerges et al. / Tetrahedron 58 12002) 989±995
995
>3H, s, NCH3), 3.33 >2H, s, CH2), 3.80 >3H, s, OCH3), 3.85
>3H, s, OCH3), 3.89±3.94 >2H, m, H-5 and H-6), 4.09±4.23
>2H, m, OCH2), 6.05 >1H, d, Jˆ9.9 Hz, vCH), 6.80±6.95
>4H, m, H-30,50), 7.06±7.18 >4H, m, H-20,60); 13C NMR
>68 MHz, CDCl3) dˆ13.9 >CH3), 34.1 >NCH3), 41.6
>NCH3), 54.3 >OCH3), 55.0 >OCH3), 55.1 >CH2-3), 58.7
>CH), 61.4 >OCH2), 66.6 >CH), 113.5 >2£CH), 113.6
>2£CH), 118.0 >vCH), 128.6 >2£CH), 130.7 >2£CH),
131.2 >q), 134.1 >q), 147.6 >q), 158.9 >q), 159.5 >q), 167.4
>CvO), 169.7 >CvO); Anal. Calcd for C25H30N2O5: C,
68.5; H, 6.9; N, 6.4%. Found: C, 68.8; H, 6.9; N, 6.2.
Society. N. M. thanks the Hungarian Academy of Sciences
for a Bolyai J. Fellowship.
References
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3.6.2. Ethyl cis-5-[20,20-bis.400-methoxyphenyl)ethenyl]-
1,4-dimethyl-2-oxopiperazine-6-carboxylate 11e. Light
yellow oil >0.11 g, 13%); IR >neat) 1741 >CvO), 1665
>CvO), 1606 >CvC), 1511 >CvC), 1245 >C±O) cm21
;
1H NMR >270 MHz, CDCl3) dˆ1.27 >3H, t, Jˆ7.3 Hz,
CH3), 2.24 >3H, s, NCH3), 2.84 >3H, s, NCH3), 2.85 >1H,
d, Jˆ17.2 Hz, H-3a), 3.41 >1H, dd, Jˆ9.9, 4.0 Hz, H-5),
3.59 >1H, d, Jˆ17.2 Hz, H-3b), 3.80 >3H, s, OCH3), 3.81
>1H, d, Jˆ4.0 Hz, H-6), 3.86 >3H, s, OCH3), 4.22±4.34 >2H,
m, OCH2), 5.86 >1H, d, Jˆ9.9 Hz, vCH), 6.79±6.96 >4H,
m, H-30,50), 7.06±7.26 >4H, m, H-20,60); 13C NMR
>68 MHz, CDCl3) dˆ14.2 >CH3), 33.5 >NCH3), 42.6
>NCH3), 55.2 >OCH3), 55.3 >OCH3), 58.2 >CH2-3), 61.0
>CH), 61.6 >OCH2), 65.6 >CH), 113.6 >2£CH), 114.0
>2£CH), 121.9 >vCH), 128.4 >2£CH), 130.5 >2£CH),
131.4 >q), 134.2 >q), 145.3 >q), 159.0 >q), 159.4 >q), 167.7
>CvO), 169.2 >CvO); MS >ESI): m/z 440 >28%), 439
>MH1, 100); HRMS >ESI): Found: MH1, 439.2225. Calc
for C25H31N2O5: MH1ˆ439.2227.
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This work was ®nancially supported by the National
Foundation for Science and Research, Hungary >OTKA
Project No. F 029198 and T 032221) and NATO/Royal