Synthesis of vinylogous β-amino esters from N-(N,N-dialkylaminoalkyl)benzotriazoles

Article abstract of DOI:10.1081/SCC-120016308

Treatment of N-(N,N-dialkylaminoalkyl)benzotriazoles with 4- bromocrotonates in the presence of zinc provides a new route to 5-(N,N-dialkylamino)-2-alkenoate esters. This is formally the result of the γ-addition of zinc dienolate reagents to iminium catio

Full text of DOI:10.1081/SCC-120016308

This article was downloaded by: [University of Windsor]
On: 15 November 2014, At: 22:27
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Vinylogous β-Amino Esters from N -( N , N
-Dialkylaminoalkyl)benzotriazoles
José M. Aurrecoechea a , Alvaro Fernández a , José M. Gorgojo a & Rubén Suero a
a Departamento de Química Orgánica II , Facultad de Ciencias , Universidad del País Vasco ,
Bilbao, Spain
Published online: 17 Aug 2006.
To cite this article: José M. Aurrecoechea , Alvaro Fernández , José M. Gorgojo & Rubén Suero (2003) Synthesis of Vinylogous
β-Amino Esters from N -( N , N -Dialkylaminoalkyl)benzotriazoles, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:5, 693-702, DOI: 10.1081/SCC-120016308
To link to this article: http://dx.doi.org/10.1081/SCC-120016308
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 5, pp. 693–702, 2003
Synthesis of Vinylogous b-Amino Esters from
N-(N,N-Dialkylaminoalkyl)benzotriazoles
*
Jose M. Aurrecoechea, Alvaro Fernandez,
Jose M. Gorgojo, and Ruben Suero
Departamento de Quımica Organica II,
Facultad de Ciencias, Universidad del Paıs Vasco,
Bilbao, Spain
ABSTRACT
Treatment of N-(N,N-dialkylaminoalkyl)benzotriazoles with 4-
bromocrotonates in the presence of zinc provides a new route to 5-
(N,N-dialkylamino)-2-alkenoate esters. This is formally the result of
the g-addition of zinc dienolate reagents to iminium cations formed in
situ by dissociation of the aminoalkylbenzotriazoles. When N-allyl
protecting groups are incorporated into the benzotriazole substrate,
*Correspondence: Jose M. Aurrecoechea, Departamento de Quımica Organica
II, Facultad de Ciencias, Universidad del Paıs Vasco, Apartado 644, 48080
Bilbao, Spain; E-mail: gopaufem@lg.ehu.es.
693
DOI: 10.1081/SCC-120016308
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
694
Aurrecoechea et al.
deallylation of the tertiary allylamine products gives also a ready
access to the corresponding secondary amines.
INTRODUCTION
A current research project involving the synthesis of pyrrolidines
via radical cyclizations[1] required the synthesis of unsaturated amines of
general structure 3 as starting materials. A further requirement in 3 was
that the N atom should not contain any aryl- or electron-withdrawing
substituents of the carbonyl type.[1] A simple direct route to 3 would
involve the g-addition of an appropriate metallic dienolate 2 to an imine
1 (Sch. 1). While this kind of reaction has been known for some time,
significant restrictions do exist. For example, acyclic silyloxy dienes (2,
M ¼ SiR3) undergo Lewis-acid catalyzed cycloaddition with aldimines
leading to the formation of dihydropyridones.[2] Under appropriate
conditions, amines 3 are also obtained but the use of either imines
derived from aromatic aldehydes[2b,3] or very reactive dienes[2c,2d] is
generally required for good yields. The same applies for the similar
use of preformed zinc dienolates (2, M ¼ ZnX).[4] Exceptions are the
Lewis acid-promoted addition of 2-silyloxyfurans to imines that yields
g-addition products in high yields without apparent limitations,[5] and
the use of aldonitrones in the presence of TMSOTf, that also leads to
products of type 3.[6] Alternatively, methyl 4-bromocrotonate has been
utilized as precursor of in situ-generated chromium-[7] or zinc-[8]
dienolates in reactions with imines,[7,8a] N-acyl-a-methoxyamines[8b] or
a-sulfonyl amides.[8c] Limitations here include the use of less convenient
starting materials[8b,8c] and/or predominantformaiot n of
a-allylated
products 4.[7,8b] Also effective, in terms of g-selectivity, is the use
of iminium salts, both with silyloxy dienes[9] and with 4-bromocroto-
nates[10] as starting materials. However, apparently this method has
been applied only to additions to benzylic-type positions.
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Vinylogous b-Amino Esters
RESULTS AND DISCUSSION
695
We have developed a simple procedure that, starting from aldehydes 5
and secondary amines 6, leads to tertiary amines 10 as a resultof selective
g-allylation of an intermediate benzotriazole derivative 7 with an in situ-
generated zinc dienolate derived from methyl or ethyl 4-bromocrotonates
9 (Sch. 2). The procedure takes advantage of the ability of N-(N,N-
dialkylaminoalkyl)benzotriazoles 7 to dissociate[11] to the corresponding
iminium cations 8 and benzotriazolyl anion, and to undergo nucleophilic
addition with a large variety of nucleophiles,[12] including Reformatsky
reagents,[13] silyl enol ethers,[14] and simple allylic organometallics.[15] We
have examined the reactions of some representative substrates 7 with 9 in
the presence of Zn and the results are presented in Table 1. g-Allylation
products 10 are obtained preferentially or exclusively in moderate isolated
yields, which are given in Table 1 for two steps starting from amines 6. In
some cases, the alternative a-allylation products 11 were also isolated
(Entries 1 and 6) as diastereomeric mixtures. Included in Table 1 are
examples of reactions of benzotriazole adducts derived from formal-
dehyde (Entries 1 and 2), an aromatic aldehyde (Entry 6), and aliphatic
aldehydes (Entries 3–5), both linear and branched. Therefore, the reaction
appears to be of general application for benzotriazole adducts derived
from any kind of aldehyde 5. As for the amine component, both cyclic
and acyclic aliphatic amines participate well, and some useful
functionality has been incorporated albeit with some loss of efficiency
(Entries 2, 5, 6). Particularly interesting is the incorporation of benzyl
and allyl protecting groups since removal of these would allow the
method to be applied also to the synthesis of secondary or even primary
amines. As an example, deallylation of 10e and 10f with N,N-dimethyl-
barbituric acid (NDMBA) and catalytic Pd(PPh3)4[16] led in good yields to
the corresponding secondary amines 12d and 12f, respectively (Sch. 3).
Scheme 2.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
696
Aurrecoechea et al.
Table 1. Preparation of 5-amino-2-alkenoate esters 10 from aldehydes 5 and
amines 6.
Yieldc of
10 (%)
Entry
R1
R2
R3
R
t (h)a
T (ꢀC)b
1
2
3
4
5
6
H
H
Bn
Bn
(CH2)2CN
Bn
Me
Me
Me
Et6
Et8
Et6
3
24
8
25
25
25
10a (58)d
10b (39)
10c (61)
10d (73)
10e (48)e
10f (48)
n-Pr
Bn
i-Pr
i-Pr
(CH2)4
35
n-Pr
3-pyridyl
Bn
Bn
allyl
allyl
35
35
aTime for the reaction between 7 and 9.
bTemperature of the reaction between 7 and 9.
cTwo-step yields starting from the corresponding amines 6.
dAlkene 11a was also isolated in 12% yield.
eAlkene 11e was also isolated in 19% yield.
Scheme 3.
In summary, the reaction of N-(N,N-dialkylaminoalkyl)benzotria-
zoles 7 with zinc dienolates results in exclusive or predominant g-coupling
with formation of vinylogous b-amino esters.[17] If the amine 6 precursor
of 7 contains an allyl group, deallylation of the tertiary amine product
results in a very convenient two-step synthesis of the corresponding
secondary amines.
EXPERIMENTAL
All reactions involving air- and moisture-sensitive materials were
performed under an atmosphere of dry Ar. THF and diethyl ether were
freshly distilled from sodium/benzophenone. CH2Cl2 was distilled from
CaH2 previous to use. Flash chromatography[18] was performed on silica
gel (230–400 mesh). 1H and 13C-NMR spectra were obtained in CDCl3 at

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Vinylogous b-Amino Esters
697
250 MHz and 62.9 MHz, respectively. IR data include only characteristic
absorptions. Mass spectra were obtained at 70 eV. Zn powder was purified
according to the literature procedure.[19] Technical methyl- and ethyl 4-
bromocrotonate were purified by flash chromatography using 20%
EtOAc in Hexanes as eluent. 3-(N-Propylamino)propanenitrile was
obtained using the literature procedure.[20]
N-Allyl-N-benzylamine
Benzyl bromide (2.00 mL, 16.5 mmol) was added dropwise to a stir-
red mixture of allylamine (6.18 mL, 80.7 mmol) and K2CO3 (2.70 g,
19.4 mmol) while keeping the mixture at room temperature. The resulting
suspension was stirred for 11 h, filtered over celite, and the solids were
washed with CH2Cl2 (60 mL). The combined filtrate and washings were
evaporated and the residue was chromatographed (10% EtOAc in
hexanes and then EtOAc) to yield 1.78 g (74%) of the title compound,
identical in spectral characteristics to the reported material.[21]
Preparation of Benzotriazole Adducts (7)
In a typical experiment, a mixture of aldehyde 5 (12.4 mmol), amine 6
(11.4 mmol), benzotriazole (11.5 mmol), and 4 A molecular sieves (5.7 g)
in dry THF (14 mL) was stirred overnight, filtered and evaporated to give
the crude adducts 7, that were used without further purification.
Reactions of Benzotriazoles 7 with
Alkyl 4-Bromocrotonates 9
In a typical experiment, a mixture of Zn powder (1.05 g, 16 mmol)
and TMSCl (0.4 mL, 3.2 mmol) in dry ether (30 mL) was stirred for
20 min under an Ar atmosphere. A solution of the benzotriazole
adduct 7 (0.9 mmol) in dry THF (10 mL) was added and the resulting
suspension was refluxed for 5 min and allowed to cool to room
temperature. Methyl or ethyl 4-bromocrotonate (0.9 mmol) was added
neat via syringe, the mixture was stirred at 25–35ꢀC for 3–24 h (Table 1)
and then poured over ice-cold ammonia (10 mL). The mixture was
extracted with ether (3 Â 100 mL). The organic extracts were washed
successively with water (10 mL), K2CO3 (10 mL), and dried (Na2SO4).

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
698
Aurrecoechea et al.
After filtration and evaporation, the crude product was purified by flash
chromatography under the conditions indicated for the individual cases.
Methyl (E )-5-(N,N-dibenzylamino)pent-2-enoate (10a) and methyl
2-[(N,N-dibenzylamino)]methylbut-3-enoate (11a): Elution with 7% EtOAc
in Hexanes yielded first 11a (12%) and then 10a (58%) as oils. Data for
10a: Colorless oil. The analytical sample was obtained after HPLC
(mPorasil 10m, 19 Â 1.5 mm, 6% EtOAc in hexanes, 4 mL/min,
tR ¼ 23 min). 1H NMR ꢀ 2.41 (t, J ¼ 7.0 Hz, 2H, H-4), 2.61 (t, J ¼ 7.0 Hz,
2H, H-5), 3.61 (s, 4H, CH2–Ph), 3.75 (s, 3H, CH3), 5.82 (d, J ¼ 15.7 Hz,
1H, H-2), 6.91 (dt, J ¼ 15.7, 7.0 Hz, 1H, H-3), 7.25–7.40 (m, 10H, Ar–H);
13C NMR ꢀ 30.0, 51.3, 51.8, 58.2, 121.6, 126.9, 128.2, 128.7, 139.3, 147.8,
166.85; IR (neat) ꢁ 1740 (C¼O), 1670 (C¼C) cmÀ1. Anal. calcd. for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.39; H, 7.37; N,
4.64. Data for 11a: Yellowish oil. The characterized sample was obtained
after HPLC (mPorasil 10m, 19 Â 1.5 mm, 6% EtOAc in hexanes,
4 mL/min, tR ¼ 15 min): 1H NMR ꢀ 2.54 (dd, J ¼ 12.6, 6.2 Hz, 1H,
C-2(CH2)), 2.92 (dd, J ¼ 12.7, 9.3 Hz, 1H, C-2(CH2)), 3.34–3.48 (m, 3H),
3.46 (d, J ¼ 13.6 Hz, 2H, CH2–Ph, included in m at3.34–3.48), 3.64 (s,
3H, CH3), 3.68 (d, J ¼ 13.6 Hz, 2H, CH2–Ph), 5.10 (s, 1H, H-4), 5.15 (d,
J ¼ 6.8 Hz, 1H, H-4), 5.64–5.78 (m, 1H, H-3), 7.21–7.31 (m, 10H);
13C NMR ꢀ 49.7, 51.7, 56.1, 58.3, 117.8, 127.0, 128.1, 128.9, 134.4,
139.0, 173.3; IR (neat) ꢁ 1740 (C¼O), 1650 (C¼C) cmÀ1; HRMS calcd.
for C20H23NO2 309.1729, found 309.1725.
Methyl (E )-5-[(N-2-cyanoethyl)-N-propylamino]pent-2-enoate (10b):
1
Eluted with 30% EtOAc in hexanes. Yellowish oil: H NMR ꢀ 0.88 (t,
J ¼ 7.3 Hz, 3H, CH3), 1.40–1.49 (m, 2H), 2.30–2.45 (m, 6H), 2.61 (t,
J ¼ 7.3 Hz, 2H), 2.79 (t, J ¼ 7.0 Hz, 2H), 3.71 (s, 3H, CO2–CH3), 5.86
(dd, J ¼ 14.4, 1.3 Hz, 1H, H-2), 6.93 (dt, J ¼ 7.0, 1.3 Hz, 1H, H-3);
13C NMR ꢀ 11.6, 16.4, 20.4, 30.4, 49.6, 51.4, 52.3, 55.5, 118.9,
122.1, 146.9, 166.8; IR (neat) ꢁ 2200 (CꢁN), 1700 (C¼O), 1635
(C¼C) cmÀ1; HRMS calcd. for C10H18NO2 (M–CH2CN) 184.1337,
found 184.1338.
Methyl (E )-5-(N,N-dibenzylamino)-6-methylhept-2-enoate (10c):
1
Eluted with 2% EtOAc in hexanes. Colorless oil: H NMR ꢀ 0.92 (d,
J ¼ 6.6 Hz, 3H, CH3–CH), 1.06 (d, J ¼ 6.6 Hz, 3H, CH3–CH),
1.92–2.02 (m, 1H, CH–CH3), 2.30–2.69 (m, 3H), 3.57 (d, J ¼ 13.7 Hz,
2H, CH2–Ph), 3.82 (d, 13.7 Hz, CH2–Ph), and 3.80 (s, CO2CH3) (total
5H), 5.93 (d, J ¼ 15.7 Hz, 1H, H-2), 7.11 (dt, J ¼ 15.6, 7.4 Hz, 1H, H-3),
7.25–7.44 (m, 10H, Ar–H); 13C NMR ꢀ 20.5, 21.2, 30.1, 30.4, 51.2, 54.2,
62.8, 121.4, 126.7, 128.1, 128.8, 139.8, 149.7, 166.8; IR (neat) ꢁ 1730
(C¼O), 1650 (C¼C) cmÀ1. Anal. calcd. for C23H29NO2: C, 78.59; H,
8.32; N, 3.98. Found: C, 78.47; H, 8.27; N, 4.16.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Vinylogous b-Amino Esters
699
Ethyl (E )-6-methyl-5-(pyrrolidin-1-yl)hept-2-enoate (10d): Eluted with
90:8:2 hexanes/EtOAc/Et3N using silica gel saturated with Et3N:
1H NMR
ꢀ
0.83–0.88 (m, 6H, CH3), 1.23 (t, J ¼ 7.1 Hz, 3H,
OCH2CH3), 1.68 (brs, 4H, CH2–N), 1.74–1.97 (m, 1H), 2.18 (dd,
J ¼ 9.7, 4.8 Hz, 1H), 2.29–2.38 (m, 2H), 2.50 (br s, 4H, CH2–CH2N),
4.13 (q, J ¼ 7.1 Hz, 2H, CO2CH2), 5.78 (d, J ¼ 15.7 Hz, 1H, H-2),
6.95–7.07 (m, 1H, H-3); 13C NMR ꢀ 14.2, 17.3, 20.2, 23.3, 30.9, 31.6,
51.2, 60.0, 68.0, 121.3, 149.8, 166.6; IR (neat) ꢁ 1735 (C¼O), 1650
(C¼C) cmÀ1; HRMS calcd. for C14H25NO2 239.1885, found 239.1876.
Ethyl (E )-5-(N-allyl-N-benzylamino)oct-2-enoate (10e) and ethyl
2-[1-(N-allyl-N-benzylamino)butyl]but-3-enoate (11e): Elution with 99:1
hexanes/Et3N using silica gel saturated with Et3N yielded first 11e
1
(19%) and then 10e (48%) as oils. Data for 10e: H NMR ꢀ 0.85 (t,
J ¼ 7.0 Hz, 3H, H-8), 1.20–1.56 (m, 7H), 1.30 (t, J ¼ 7.1 Hz, OCH2CH3,
included in m at1.20–1.56), 2.06–2.18 (m, 1H), 2.42–2.53 (m, 1H),
2.72–2.83 (m, 1H), 3.01 (dd, J ¼ 14.2, 6.7 Hz, 1H), 3.12 (dd, J ¼ 14.2,
5.7 Hz, 1H), 3.50 (d, J ¼ 14.0 Hz, 1H), 3.67 (d, J ¼ 14.0 Hz, 1H), 4.20
(q, J ¼ 7.1 Hz, 2H, OCH2), 5.05–5.21 (m, 2H), 5.71–5.87 (m, 2H), 6.95
(dt, J ¼ 15.5, 7.5 Hz, 1H, H-3), 7.19–7.35 (m, 5H, Ar); 13C NMR ꢀ 13.9,
14.0, 19.8, 32.5, 32.7, 52.0, 53.0, 57.1, 59.8, 116.3, 121.9, 126.5, 127.9,
128.4, 137.1, 140.0, 148.1, 166.1; IR (neat) ꢁ 1725 (C¼O), 1650 (C¼C)
cmÀ1; HRMS calcd. for C20H29NO2 315.2198, found 315.2186. Data for
1
11e (63:37 diastereomeric mixture): H NMR ꢀ 0.84–0.90 (m, 3H, H-6),
1.20–1.64 (m, 7H, OCH2CH3, H-4, H-5), 2.98–3.32 (m, 4H, H-2, H-3,
NCH2CH¼CH2), 3.52 and 3.79 (AB system, J ¼ 13.9 Hz, PhCH2, 2H of
major isomer), 3.63 and 3.75 (AB system, J ¼ 14.1 Hz, PhCH2, 2H of
minor isomer), 4.02–4.24 (m, 2H, OCH2), 5.02–5.21 (m, 4H), 5.65–6.06
(m, 2H), 7.19–7.35 (m, 5H, Ar); 13C NMR ꢀ 13.9, 14.1, 14.2, 20.5, 21.3,
30.5, 31.2, 53.3, 53.5, 53.9, 54.4, 55.9, 60.0, 60.2, 60.3, 116.3, 116.4, 117.2,
118.1, 126.5, 127.8, 127.9, 128.5, 128.7, 135.1, 135.7, 137.3, 137.4, 140.0,
140.3, 173.0; IR (neat) ꢁ 1735 (C¼O), 1640 (C¼C) cmÀ1; HRMS calcd.
for C20H29NO2 315.2198, found 315.2185.
Ethyl (E )-6-aza-6-benzyl-5-( pyridin-3-yl)non-2,8-dienoate (10f ):
Eluted with 90:8:2 hexanes/EtOAc/Et3N using silica gel saturated with
Et3N: 1H NMR ꢀ 1.27 (t, J ¼ 7.1 Hz, 3H, CH3), 2.67 (dt, J ¼ 14.9, 6.9 Hz,
1H), 2.77 (dd, J ¼ 14.3, 7.3 Hz, 1H), 2.87–2.98 (m, 1H), 3.22 (d,
J ¼ 13.9 Hz, PhCH, overlapped with signal from other proton, total
2H), 3.77 (d, J ¼ 13.9 Hz, 1H, PhCH), 3.99 (t, J ¼ 7.6 Hz, 1H), 4.16 (q,
J ¼ 7.1 Hz, 2H, CH3CH2), 5.14–5.23 (m, 2H, H-9), 5.82 (d, J ¼ 15.9 Hz,
H-2, overlapped with signal from H-8, total 2H), 6.92 (dt, J ¼ 15.7,
7.1 Hz, 1H, H-3), 7.23–7.32 (m, 6H), 7.56–7.59 (m, 1H), 8.51–8.54 (m,
2H); 13C NMR ꢀ 14.1, 33.2, 52.2, 53.3, 59.2, 60.1, 117.7, 123.0, 123.1,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
700
Aurrecoechea et al.
127.0, 128.3, 128.4, 133.7, 135.6, 136.0, 139.2, 145.8, 148.7, 150.0, 166.1;
IR (neat) ꢂ 1725 (C¼O), 1660 (C¼C) cmÀ1; HRMS calcd. for
C22H26N2O2 350.1994, found 350.1994.
Ethyl (E )-6-aza-7-phenyl-5-(pyridin-3-yl)hept-2-enoate (12f): A solu-
tion of 10f (1.17 g, 3.35 mmol), Pd(PPh3)4 (0.039 g, 0.03 mmol), and N,N-
dimethylbarbituric acid (NDMBA) (1.57 g, 10.0 mmol) in dry CH2Cl2
(10 mL) was stirred for 24 h under Ar. After removal of the solvent, the
residue was redissolved in EtOAc (60 mL) and the solution was washed
with sat. K2CO3 (3 Â 20 mL) and brine (15 mL), and dried (Na2SO4). The
residue after evaporation was purified by flash chromatography (silica gel
saturated with Et3N, 80:15:5 hexanes/EtOAc/Et3N and then 65:30:5
1
hexanes/EtOAc/Et3N) to afford 12f (928 mg, 90%) as an oil: H NMR
ꢀ 1.18 (t, J ¼ 7.1 Hz, 3H, CH3), 1.73 (br s, 1H, NH), 2.48 (t, J ¼ 7.0 Hz,
2H), 3.45 and 3.57 (AB system, J ¼ 13.3 Hz, 2H, PhCH2), 3.76 (t,
J ¼ 6.7 Hz, 1H, H-5), 4.07 (q, J ¼ 7.1 Hz, 2H, CH2O), 5.74 (d,
J ¼ 15.7 Hz, 1H, H-2), 6.72–6.84 (m, 1H, H-3), 7.12–7.25 (m, 6H), 7.63
(d, J ¼ 7.7 Hz, H-40), 8.45 (dd, J ¼ 4.8, 1.4 Hz, 1H, H-60), 8.50 (d,
J ¼ 1.8 Hz, 1H, H-20); 13C NMR ꢀ 13.8, 40.5, 50.9, 58.3, 59.9, 123.2,
123.8, 126.7, 127.7, 128.0, 134.3, 137.8, 139.4, 144.0, 148.6, 148.9, 165.5;
IR (neat) ꢁ 3400–3300 (br, N–H), 1725 (C¼O), 1660 (C¼C) cmÀ1
;
HRMS calcd. for C19H23N2O2 (M þ 1) 311.1759, found 311.1767.
Ethyl (E )-5-(N-Benzylamino)oct-2-enoate (12e): Following the pre-
vious procedure, 12e was obtained from 10e as an oil in 75% yield
after flash chromatography (20% EtOAc in hexanes, then 50% EtOAc
1
in hexanes): H NMR ꢀ 0.90 (distorted t, J ꢂ 7.0 Hz, 3H, H-8), 1.29 (t,
J ¼ 7.1 Hz, OCH2CH3 included in m at1.26–1.48), 1.26–1.48 (m, H-6,
H-7, N–H, total 8H), 2.32–2.39 (m, 2H, H-4), 2.69–2.76 (m, 1H, H-5),
3.76 and 3.80 (AB system, J ¼ 13.0 Hz, 2H, PhCH2), 4.19 (q, J ¼ 7.1 Hz,
2H, OCH2), 5.87 (dt, J ¼ 15.5, 1.5 Hz, 1H, H-2), 6.97 (dt, J ¼ 15.6, 7.5 Hz,
1H, H-3), 7.22–7.32 (m, 5H, Ar); 13C NMR ꢀ 14.1, 14.2, 18.8, 36.3, 36.7,
51.0, 55.7, 60.1, 123.2, 126.8, 128.0, 128.3, 140.4, 146.4, 166.2; IR (neat) ꢁ
3320 (N–H), 1720 (C¼O), 1650 (C¼C) cmÀ1; HRMS calcd. for
C17H25NO2 275.1885, found 275.1830.
ACKNOWLEDGMENTS
Financial supportwas provided by Universidad del Paı s Vasco (UPV
170.310-EC201/94), Ministerio de Ciencia y Tecnologıa (DGI BQU2000-
01354), and Janssen-Cilag. A fellowship to A.F. (Gobierno Vasco) is also
gratefully acknowledged.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
Vinylogous b-Amino Esters
701
REFERENCES
1. Aurrecoechea, J.M.; Fernandez, A.; Gorgojo, J.M.; Saornil, C.
Tetrahedron 1999, 55, 7345–7362.
2. (a) Danishefsky, S.J.; Vogel, C. J. Org. Chem. 1986, 51, 3915–3916;
(b) Brandmaster, S.M.; Ojima, I. Tetrahedron Lett. 1987, 28, 613;
(c) Midland, M.M.; McLoughlin, J.I. Tetrahedron Lett. 1988, 29,
4653–4656; (d) Waldmann, H.; Braun, M.; Drager, M. Tetrahedron:
¨
Asymmetry 1991, 2, 1231–1246.
3. (a) Mladenova, M.; Bellassoued, M. Synth. Commun. 1993, 23,
725–736; (b) Bellassoued, M.; Ennigrou, R.; Gil, R.; Lensen, N.
Synth. Commun. 1998, 28, 3955–3964.
4. Van Maanen, H.L.; Kleijn, H.; Jastrzebski, J.T.B.H.; Lakin, M.T.;
Spek, A.L.; van Koten, G. J. Org. Chem. 1994, 59, 7839–7848.
5. Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Synlett 1999,
1333–1350.
6. Camiletti, C.; Dhavale, D.D.; Donati, F.; Trombini, C. Tetrahedron
Lett. 1995, 36, 7293–7296.
7. Giammaruco, M.; Taddei, M.; Ulivi, P. Tetrahedron Lett. 1993, 34,
3635–3638.
8. (a) El Borgi, A.; Bellassoued, M.; Moreau, J.L. C. R. Acad. Sci. II
1988, 307, 1805–1807; (b) Kise, N.; Yamazaki, H.; Mabuchi, T.;
Shono, T. Tetrahedron Lett. 1994, 35, 1561–1564; (c) Mecozzi, T.;
Petrini, M. Tetrahedron Lett. 2000, 41, 2709–2712.
9. Martin, S.F.; Chen, K.X.; Eary, C.T. Org. Lett. 1999, 1, 79–81, and
references cited therein.
10. (a) Shono, T.; Hamaguchi, H.; Sasaki, M.; Fujita, S.; Nagami, K.
J. Org. Chem. 1983, 48, 1621–1628; (b) Hirai, Y.; Terada, T.;
Hagiwara, A.; Yamazaki, T. Chem. Pharm. Bull. 1988, 36,
1343–1350.
11. Katritzky, A.R.; Yannakapoulou, K.; Kuzmierkiewicz, W.;
Aurrecoechea, J.M.; Palenik, G.J.; Koziol, A.E.; Szczesniak, M.;
Skarjune, R. J. Chem. Soc., Perkin Trans. 1 1987, 2673–2679.
12. Recent reviews: (a) Katritzky, A.R.; Lan, X.F.; Yang, J.Z.;
Denisko, O.V. Chem. Rev. 1998, 98, 409–548; (b) Katritzky, A.R.
J. Heterocycl. Chem. 1999, 36, 1501–1522; (c) Katritzky, A.R.;
Belyakov, S.A. Aldrichim. Acta 1998, 31, 35–45.
13. (a) Katritzky, A.R.; Yannakopoulou, K. Synthesis 1989, 747–751;
(b) Katritzky, A.R.; Hong, Q.M.; Yang, Z.J. J. Org. Chem. 1995,
60, 3405–3408.
14. Kobayashi, S.; Ishitani, H.; Komiyama, S.; Oniciu, D.C.;
Katritzky, A.R. Tetrahedron Lett. 1996, 37, 3731–3734.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
702
Aurrecoechea et al.
15. (a) Wang, J.; Zhou, J.; Zhang, Y. Synth. Commun. 1996, 26,
3395–3399; (b) Bao, W.; Zhang, Y. Synth. Commun. 1997,
27,615–620;(c)Churlaud,C.;Pornet,J.;Oniciu,D.C.;Katritzky,A.R.
Organometallics 1999, 18, 4270–4274.
16. Garrohelion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58,
6109–6113.
17. A recent paper that highlights the importance of b-amino acids:
Ma, D.W.; Sun, H.Y. J. Org. Chem. 2000, 65, 6009–6016.
18. Still, W.C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925.
19. Perrin, D.D.; Armarego, W.F.L. Purification of Laboratory
Chemicals, 3rd Ed.; Pergamon Press: Oxford, 1988.
20. Tarbe, D.S.; Shakespeare, N.; Claus, C.J.; Bunnett, J.F. J. Am.
Chem. Soc. 1946, 68, 1217–1219.
21. Nakanishi, S.; Okamoto, K.; Yamaguchi, H.; Takata, T. Synthesis
1998, 1735–1741.
Received in the Netherlands February 18, 2002