Synthesis and reactivity of β-bromo-β-substituted dehydroalanines

Article abstract of DOI:10.1002/ejoc.200600094

The methyl ester of N-tert-butoxycarbonyl-(Z)-β-bromo-β-(1,2,4- triazol-1-yl)dehydroalanine was prepared by treatment of the methyl ester of N-tert-butoxycarbonyl-(E)-β-(1,2,4-triazol-1-yl)dehydroalanine with N-bromosuccinimide (NBS), followed by Et₃

Full text of DOI:10.1002/ejoc.200600094

FULL PAPER
DOI: 10.1002/ejoc.200600094
Synthesis and Reactivity of β-Bromo-β-Substituted Dehydroalanines
Paula M. T. Ferreira,*[a] and Luís S. Monteiro[a]
Keywords: Nonproteinogenic amino acids / Alanine derivatives / Glycine derivatives
The methyl ester of N-tert-butoxycarbonyl-(Z)-β-bromo-β-
the α-carbon atom also occurred when the β,β-dibromodehy-
(1,2,4-triazol-1-yl)dehydroalanine was prepared by treat- droalanine derivative was treated with primary amines, giv-
ment of the methyl ester of N-tert-butoxycarbonyl-(E)-β-
(1,2,4-triazol-1-yl)dehydroalanine with N-bromosuccinimide
(NBS), followed by Et3N. The reactivities of this compound
and of our previously synthesized methyl ester of N-tert-but-
oxycarbonyl-β,β-dibromodehydroalanine towards several
nucleophiles were studied, and it was found that these com-
pounds react with oxygen nucleophiles to give the corre-
sponding α-alkoxy-β,β-disubstituted alanines. Addition to
ing α-amino-β,β-dibromoalanines. Treatment of the β-bromo-
β-(1,2,4-triazol-1-yl)dehydroalanine derivative with amines
gave α-(alkylamino)-β-(alkylimino)alanines in high yields.
These iminoalanines afforded α-aminoglycines when treated
with silica in dichloromethane.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
primary amines, giving the corresponding α-amino-β,β-di-
bromoalanines. When the β-triazolyldehydroalanine deriva-
tive was treated with amines in methanol, α-alkylamino-β-
alkyliminoalanines were obtained in high yields. These were
then converted into the corresponding α-aminoglycines by
treatment with silica.
α-Aminoglycines have recently been used for introducing
chemical diversity into bioactive peptides and in the synthe-
sis of retro-inverso-peptides potentially more stable towards
proteolytic degradation.[5–10] The methods used for the syn-
thesis of this type of compounds are low-yielding and
multistep, and include the treatment of α-hydroxyglycines
with thiols followed by displacement of the alkylthio group
by an alkylamine through the use of mercuric salts,[11] the
displacement of sulfur from α-isopropylthioglycines with
amines in the presence of N-bromosuccinimide,[12] re-
duction of α-azidoglycines,[13] conversion of α-hydroxygly-
cines into the corresponding acetates followed by treatment
with amines[14] and the treatment of α-haloglycines with ni-
trogen nucleophiles.[15]
Introduction
Nonproteinogenic amino acids constitute an important
class of organic compounds due to their intrinsic biological
activity and their application in peptide and combinatorial
chemistry. These compounds can be used as conformation-
ally constrained components or as molecular scaffolds in
structure–activity relationship studies and in the develop-
ment of peptidomimetics,[1] so research towards efficient
methods that will allow the synthesis of this type of com-
pounds is an important area of peptide chemistry.
We have recently become interested in the synthesis of
new α- or β-substituted amino acid and dehydroamino acid
derivatives. One of our approaches towards the synthesis
of these compounds has been the reaction of β-substituted
dehydroamino acid derivatives, namely β-(1,2,4-triazol-1-yl)-
dehydroalanine, β-(1,2,4-triazol-1-yl)dehydroaminobutyric
acid, β-(1,2,4-triazol-1-yl)dehydrophenylalanine and β-(4-
tolylsulfinyl)dehydroserine, with nucleophiles.[2,3]
Here we describe the synthesis of the methyl ester of (Z)-
N-tert-butoxycarbonyl-β-bromo-β-(1,2,4-triazol-1-yl)dehy-
droalanine from the corresponding β-triazolyldehydroalan-
ine derivative by treatment with NBS, followed by Et3N.
The reactivity of this compound towards amines and oxy-
gen nucleophiles was studied, together with that of a pre-
viously synthesized β,β-dibromodehydroalanine deriva-
tive.[4] Several α-alkoxy-β-substituted alanines were pre-
pared by treating these dehydroalanine derivatives with oxy-
gen nucleophiles. The same reactivity was observed when
the β,β-dibromodehydroalanine derivative was treated with
Results and Discussion
We recently described the synthesis of β-aminodehyd-
roamino acids from β-triazolyldehydroamino acids by dis-
placement of the triazole moiety with primary amines.[3]
With these results in mind we decided to study the reactivity
towards nucleophiles of a β-bromo-β-triazolyldehydroalan-
ine derivative. The methyl ester of N-tert-butoxycarbonyl-
(Z)-β-bromo-β-(1,2,4-triazol-1-yl)-dehydroalanine was thus
synthesised in good yield by treating the methyl ester of
(E)-N-tert-butoxycarbonyl-β-(1,2,4-triazol-1-yl)dehydro-
alanine[16] with NBS followed by Et3N (Scheme 1).
[a] Departamento de Química-Universidade do Minho,
4700-320 Braga, Portugal
Fax: +35-1253678983
E-mail: pmf@quimica.uminho.pt
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Synthesis and Reactivity of β-Bromo-β-Substituted Dehydroalanines
FULL PAPER
Scheme 1.
The stereochemistry of compound 1 was determined by the α-addition product was also obtained (compound 2a,
NOE difference experiments by irradiation of the α-NH Scheme 2). Compound 2 and ethylene-1,2-diol in the pres-
and OMe protons. No NOE effect was detected when the ence of an excess of triethylamine gave the lactone resulting
α-NH was irradiated, but a NOE enhancement on 3-H and from α-addition and transesterification (compound 2b).
5-H of the triazole ring was observed when the OMe pro- The
tons were irradiated, thus indicating that compound 1 is the (compound 1a) was also obtained when compound 1 was
(Z) isomer. treated with an excess of Et3N (10 equiv.) in methanol, al-
α-methoxy-β-bromo-β-triazolylalanine
derivative
Compound 1 was treated with sodium methoxide to give though compound 2 gave an α-methoxy dimer (compound
the α-methoxy-β-bromo-β-triazolylalanine derivative (com- 3) under the same conditions (Scheme 3). We believe that
pound 1a, Scheme 2). Two stereocenters are generated in this compound is the result of α-addition of a methoxide,
1
this reaction, but the H NMR spectrum only showed the with subsequent nucleophilic attack of the β-carbon atom
formation of one diastereomer. Previously it had been on another β,β-dibromoalanine derivative.
found that the methyl ester of N-tert-butoxycarbonyl-β-
A study of the reactivity of compounds 1 and 2 with
(1,2,4-triazol-1-yl)dehydroalanine reacted with sodium primary amines was also carried out. Compound 2 reacted
methoxide to give, after substitution of the triazole group with benzylamine to give the α-benzylamino-β,β-dibromo-
and β-addition, the β,β-dimethoxyalanine derivative.[3] The alanine derivative (compound 4, Scheme 2), thus exhibiting
different reactivity now observed for compound 1 can be similar reactivity to that shown towards oxygen nucleo-
attributed to the electron-withdrawing effect of the bro- philes.
mine, which induces α-addition. When the methyl ester of
The results presented above are all consistent with the
N-tert-butoxycarbonyl-β,β-dibromodehydroalanine[4] was addition to the α-carbon atom previously reported by us
treated with sodium methoxide (compound 2, Scheme 2) when
a β-(4-tolylsulfinyl)dehydroserine derivative was
Scheme 2.
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Scheme 3.
treated with nucleophiles.[3] This was attributed to the elec- formation of benzylformamide in the reaction of 5a to give
tron-withdrawing effect of the 4-tolylsulfinyl group. In com- 6a.
pounds 1 and 2 the β-bromine atoms produce the same ef-
fect, activating the α-carbon atom towards addition.
The use of 10 equiv. of amine in a two-step, one-pot pro-
cedure gave the corresponding amides of the α-(alkyl-
The reaction between compound 1 and benzylamine in amino)glycines (compounds 7a and 7b, Scheme 7).
methanol gave – after α-addition, β-substitution and β-eli- The possibility of using this reaction to cross-link amino
mination – the α-benzylamino-β-(benzylimino)alanine de- acids was also investigated. Thus, compound 1 was treated
rivative in good yield (compound 5a, Scheme 4). Similar with the methyl ester of glycine in a two-step, one-pot pro-
compounds were obtained with several other primary cedure, giving compound 6f in high yield (Scheme 7). The
amines (compounds 5b–5e, Scheme 4).
synthesis of this compound shows that this strategy can be
NMR assignments for compounds 5a–e were done using used to create cross-links between the α-carbon atom of gly-
HMQC and HMBC spectra. A correlation between the cine and an amino function of another amino acid deriva-
CH2 (two doublets at δ = 4.57 and 4.61 ppm) and the β tive.
carbon atom (δ =159.84 ppm) in the HMBC spectrum of
compound 5a, for example, allowed the identification of the
=NCH2 function. The stereochemistry of the β-C–N double
bond in compound 5a was studied by NOE difference ex-
Conclusions
periments, by irradiation of the β-CH and observation of
an NOE enhancement on the =NCH2 protons. This result tuted β-bromo-β-substituted alanines and α-amino-β-imi-
indicates an (E) configuration (Figure 1). noalanines – were synthesized by treatment of β-bromo-β-
Several nonproteinogenic amino acids – namely α-substi-
Compounds 5a–e were treated with silica (SiO2) in substituted dehydroalanines with oxygen and nitrogen
dichloromethane at room temperature, giving racemic α- nucleophiles. Treatment of the β-bromo-β-substituted dehy-
(alkylamino)glycines 6a–e in good to high yields droalanine derivatives with alkoxides afforded the corre-
(Scheme 5).
sponding α-alkoxy-β-bromo-β-substituted alanines in high
This reaction may involve addition of water to the imine yields. When the β,β-dibromodehydroalanine derivative was
carbon atom and elimination of an amide (Scheme 6). An treated with primary amines the corresponding α-amino-
acidic medium is necessary in order to activate the imine β,β-dibromoalanines were obtained. It thus seems that the
carbon atom towards nucleophilic attack. Support for the electron-withdrawing effect of the β-bromine atoms acti-
proposed mechanism was obtained observing by HPLC the vates the α-carbon atoms of these compounds towards ad-
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Synthesis and Reactivity of β-Bromo-β-Substituted Dehydroalanines
FULL PAPER
Scheme 4.
Scheme 5.
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Figure 1. NOE difference experiment on compound 5a on irradiation of the β-CH proton.
Scheme 6.
Scheme 7.
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Synthesis and Reactivity of β-Bromo-β-Substituted Dehydroalanines
FULL PAPER
solid, m.p. 103.5–105.0 °C. 1H NMR (CDCl3): δ = 1.46 [s, 9 H,
OC(CH3)3], 3.56 (s, 3 H, OCH3), 3.75 (s, 3 H, CH3, CO2CH3), 5.69
(s, 1 H, 2-NH), 6.88 (s, 1 H, 3-CH), 7.91 (s, 1 H, 3-H triaz.), 8.32
(s, 1 H, 5-H triaz.) ppm. 13C NMR (CDCl3): δ = 28.00 [C(CH3)3],
52.81 (OCH3), 53.43 (CO2CH3), 63.26 (βCH), 81.96 [OC(CH3)3],
86.17 (2-C), 145.39 (5-CH triaz.), 151.58 (3-CH triaz.), 153.44
(C=O Boc), 165.16 (CO2CH3) ppm. C12H19BrN4O5 (379.21): calcd.
C 38.01, H 5.05, N 14.77; found C 38.25, H 5.20, N 14.50.
dition. The reactions between primary amines and a β-
bromo-β-(1,2,4-triazol-1-yl)dehydroalanine gave iminoala-
nines that were easily converted into aminoglycines by treat-
ment with silica. The compounds synthesized could have
biological activity, since anticonvulsant activity has been re-
ported for several α-aminoglycines.[11] Furthermore, these
amino acids can be introduced into bioactive peptides to
enhance chemical diversity and to increase stability towards
proteolytic enzymes and/or can be used in structure–activity
relationship studies.
5.2. Methyl 3,3-Dibromo-2-(tert-butoxycarbonylamino)-2-methoxy-
propanoate: Boc-Ala(3-Br,3-Br,2-methoxy)-OMe (2a): Sodium
methoxide (1.10 equiv.) was added with rapid stirring to a solution
of Boc-∆Ala(3-Br, 3-Br)-OMe (180 mg, 0.500 mmol) in methanol
(0.100 mol·dm–3). After the mixture had been kept for 3 h at room
temperature, ethyl acetate (100 cm3) was added and the solution
was washed with water and brine (3×30 cm3 each). The organic
layer was dried with MgSO4 and the solvent was evaporated at
reduced pressure to give 2a (186 mg, 95%) as an oil. 1H NMR
(CDCl3): δ = 1.44 [s, 9 H, OC(CH3)3], 3.49 (s, 3 H, OCH3), 3.86
(s, 3 H, CO2CH3), 5.62 (s, 1 H, 2-NH), 6.11 (s, 1 H, 3-CH) ppm.
13C NMR (CDCl3): δ = 27.99 [C(CH3)3], 52.93 (OCH3), 53.37
(CO2CH3), 45.87 (3-CH), 81.60 [OC(CH3)3], 87.07 (2-C), 153.02
(C=O Boc), 165.99 (CO2CH3) ppm. HRMS (FAB) [M + H]+ found
389.9562; calcd. for C10H18Br2NO5 389.9552.
Experimental Section
1. General Remarks: Melting points (°C) were determined in a Gal-
lenkamp apparatus and are uncorrected. 1H and 13C NMR spectra
were recorded on a Varian Unity Plus instrument at 300 and
75.4 MHz, respectively. Chemical shifts are given in ppm and coup-
ling constants in Hz. MS and HRMS data were recorded by the
mass spectrometry service of the University of Vigo, Spain. Ele-
mental analysis was performed on a LECO CHNS 932 elemental
analyser.
The reactions were monitored by thin-layer chromatography
(TLC). Column chromatography was performed on Macherey–Na-
gel silica gel (230–400 mesh). Petroleum ether refers to the boiling
range 40–60 °C.
5.3. tert-Butyl 2-(Dibromomethyl)-(3-oxo-1,4-dioxan-2-yl)carbamate
(2b): Et3N (10.0 equiv.) was added with rapid stirring to a solution
of Boc-∆Ala(3-Br,3-Br)-OMe (90.0 mg, 0.250 mmol) in ethane-1,2-
diol (0.100 mol·dm–3). After the mixture had been kept for 18 h at
room temperature, diethyl ether (100 cm3) was added and the solu-
tion was washed with water and brine (3×30 cm3 each). The or-
ganic layer was dried with MgSO4 and the solvent was evaporated
2. Boc-∆Ala[3-(1,2,4-triazol-1-yl)]-OMe: The synthesis of this com-
pound was described elsewhere.[16]
3. Methyl (Z)-3-Bromo-2-(tert-butoxycarbonylamino)-3-(1H-1,2,4-
triazol-1-yl)acrylate, Boc-(Z)-∆Ala[3-Br,3-(1,2,4-triazol-1-yl)]-OMe
(1): NBS (1.10 equiv.) was added with rapid stirring to a solution
of (E)-Boc-∆Ala[3-(1,2,4-triazol-1-yl)]-OMe (268 mg, 1.00 mmol)
in dichloromethane (0.100 mol·dm–3). After the mixture had been
kept for 18 h at room temperature, Et3N (2.00 equiv.) was added
and the solution was left stirring for another hour. Dichlorometh-
ane (90 cm3) was then added and the solution was washed with
water and brine (3×30 cm3 each). The organic layer was dried with
MgSO4 and the solvent was evaporated at reduced pressure to give
a yellow oil. Column chromatography (diethyl ether in petroleum
ether, 30%) afforded compound 1 (250 mg, 72%) as a white solid,
m.p. 119.0–120.0 °C. 1H NMR (CDCl3): δ = 1.49 [s, 9 H, OC-
(CH3)3], 3.64 (s, 3 H, CO2CH3), 6.61 (s, 1 H, αNH), 8.03 (s, 1 H,
3-H or 5-H triaz.), 8.32 (s, 1 H, 3-H or 5-H triaz.) ppm. 13C NMR
(CDCl3): δ = 27.95 [C(CH3)3], 53.25 (OCH3), 83.40 [OC(CH3)3],
103.02 (C), 132.61 (C), 145.94 (CH), 151.07 (C=O Boc), 152.73
(CH), 160.90 (CO2CH3) ppm. C11H15BrN4O4 (347.17): calcd. C
38.06, H 4.35, N 16.14; found C 38.27, H 4.50, N 15.91.
1
at reduced pressure to give 2b (71.0 mg, 72%) as an oil. H NMR
(CDCl3): δ = 1.46 [s, 9 H, OC(CH3)3], 4.12–4.18 (m, 1 H, CH2),
4.51–4.67 (m, 2 H, CH2), 4.75–4.83 (m, 1 H, CH2), 5.65 (s, 1 H, 2-
NH), 5.98 (s, 1 H, CH) ppm. 13C NMR (CDCl3): δ = 28.08
[C(CH3)3], 47.67 (CH), 60.89 (5-CH2), 68.60 (6-CH2), 82.41
[C(CH3)3], 84.76 (3-C), 153.93 (C=O Boc), 162.71 (2-C=O) ppm.
C10H15Br2NO5 (389.04): calcd. C 30.87, H 3.89, N 3.60; found C
31.26, H 3.92, N 3.65.
5.4. Compound 3: Et3N (10.0 equiv.) was added with rapid stirring
to a solution of Boc-∆Ala(3-Br,3-Br)-OMe (90.0 mg, 0.250 mmol)
in methanol (0.100 mol·dm–3). After the mixture had been kept for
4 h at room temperature, diethyl ether (100 cm3) was added and
the solution was washed with water and brine (3×30 cm3 each).
The organic layer was dried with MgSO4 and the solvent was evap-
1
orated at reduced pressure to give 3 (87.0 mg, 93%) as an oil. H
NMR (CDCl3): δ = 1.46 [s, 9 H, OC(CH3)3], 1.47 [s, 9 H, OC-
(CH3)3], 3.51 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 3.88 (s, 3 H,
OCH3), 5.63 (s, 1 H, NH), 6.18 (s, 1 H, CH), 6.37 (s, 1 H,
NH) ppm. 13C NMR (CDCl3): δ = 27.99 [C(CH3)3], 28.05 [C-
(CH3)3CO], 45.91 (CH), 52.99 (CO2CH3), 53.43 (CO2CH3), 81.67
[C(CH3)3], 82.69 (C), 87.14 (OCH3), 150.88 (C=O Boc), 153.07
(C=O Boc), 162.53 (CO2CH3), 166.07 (CO2CH3) ppm.
C19H30Br4N2O9 (750.07): calcd. C 30.43, H 4.03, N 3.73; found C
31.08, H 4.15, N 3.77.
4. Methyl 3,3-Dibromo-2-(tert-butoxycarbonylamino)acrylate, Boc-
∆Ala(3-Br,3-Br)-OMe (2): The synthesis of this compound was de-
scribed elsewhere.[4]
5.1. Methyl 3-Bromo-2-(tert-butoxycarbonylamino)-2-methoxy-3-
(1H-1,2,4-triazol-1-yl)propanoate, Boc-Ala[3-Br,2-methoxy,3-(1,2,4-
triazol-1-yl)]-OMe (1a): Sodium methoxide (1.10 equiv.) was added
with rapid stirring to a solution of (Z)-Boc-∆Ala[3-Br, 3-(1,2,4- 6.1. Methyl 2-(Benzylamino)-3,3-dibromo-2-(tert-butoxycarbonyl-
triazol-1-yl)]-OMe (174 mg, 0.500 mmol) in methanol amino)propanoate, Boc-Ala(2-benzylamino,3-Br,3-Br)-OMe (4):
(0.100 mol·dm–3). After the mixture had been kept for 3 h at room
temperature, ethyl acetate (100 cm3) was added and the solution
was washed with water and brine (3×30 cm3 each). The organic
layer was dried with MgSO4 and the solvent was evaporated at
reduced pressure to give an oil. Crystallization from diethyl ether/
petroleum ether afforded compound 1a (176 mg, 93%) as a white
Benzylamine (2.50 equiv.) was added with rapid stirring to a solu-
tion of Boc-∆Ala(3-Br, 3-Br)-OMe (179 mg, 0.500 mmol) in meth-
anol (0.100 mol·dm–3). After the mixture had been kept for 18 h at
room temperature, diethyl ether (100 cm3) was added and the solu-
tion was washed with water and brine (3×30 cm3 each). The or-
ganic layer was dried with MgSO4 and the solvent was evaporated
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P. M. T. Ferreira, L. S. Monteiro
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at reduced pressure to give compound 4 (229 mg, 98%) as an oil.
(10.0 equiv.) were added with rapid stirring to a solution of Boc-
Recrystallization from n-hexane gave white crystals, m.p. 86.0–
(Z)-∆Ala[3-Br, 3-(1,2,4-triazol-1-yl)]-OMe (174 mg, 0.500 mmol) in
1
86.5 °C. H NMR (CDCl3): δ = 1.48 [s, 9 H, OC(CH3)3], 3.22 (s, 1 methanol (0.100 mol·dm–3). After the mixture had been kept for 18
H, NH), 3.65 (d, J = 12.6 Hz, 1 H, CH2), 3.82 (s, 3 H, CO2CH3), h at room temperature, ethyl acetate (45 cm3) was added and the
3.86 (d, J = 12.6 Hz, 1 H, CH2), 5.87 (s, 1 H, 2-NH), 6.24 (s, 1 H,
solution was washed with water and brine (3×15 cm3 each). The
organic layer was dried with MgSO4 and the solvent was evapo-
3-CH), 7.25–7.40 (m, 5 H, ArH) ppm. 13C NMR (CDCl3): δ =
28.18 [C(CH3)3], 46.16 (CH2), 48.64 (βCH), 53.63 (OCH3), 78.16 rated at reduced pressure to give compounds 5a–e.
(2-C), 80.84 [C(CH3)3], 127.20 (CH), 128.32 (CH), 128.36 (CH),
8.1. Methyl (E)-2-(Benzylamino)-3-(benzylimino)-2-(tert-butoxycar-
139.07 (C), 153.53 (C=O Boc), 168.29 (CO2CH3) ppm.
bonylamino)propanoate, Boc-Ala[2-benzylamino,3-(E)-benzylimino]-
C16H22Br2N2O4 (466.16): calcd. C 41.22, H 4.76, N 6.01; found C
OMe (5a): The general procedure described above was used with
41.21, H 4.77, N 6.00.
benzylamine. Crystallization from diethyl ether/n-hexane afforded
7.1. 2-[Ethyl(4-tolylsulfonyl)amino]ethylammonium Trifluoroacetate
compound 5a (151 mg, 74%) as a white solid, m.p. 88.5–89.5 °C.
1H NMR (CDCl3): δ = 1.49 [s, 9 H, OC(CH3)3], 3.51 (d, J =
12.9 Hz, 1 H, CH2), 3.72 (d, J = 12.9 Hz, 1 H, CH2), 3.77 (s, 3 H,
CO2CH3), 4.57 (d, J = 14.1 Hz, 1 H, =NCH2), 4.61 (d, J = 14.1 Hz,
1 H, =NCH2), 6.72 (s, 1 H, NH), 7.19–7.37 (m, 11 H, ArH + NH),
(d): This compound was obtained by treatment of N-(tert-butoxy-
carbonyl)-2-[ethyl(4-tolylsulfonyl)amino]ethylamine[17]
(685 mg,
2.00 mmol) with TFA (10 cm3) to give a white solid (683 mg, 96%).
Recrystallization from methanol/diethyl ether gave white crystals,
1
1 δ = 28.20
H, 3-CH) ppm. 13C NMR (CDCl3):
m.p. 115.5–116.5 °C. H NMR (CDCl3): δ = 1.04 (t, J = 7.2 Hz, 3
7.56 (s,
H, CH3), 2.41 (s, 3 H, Tos CH3), 3.19–3.26 (m, 4 H, 2×CH2), 3.34–
3.38 (m, 2 H, CH2), 7.29 (d, J = 8.1 Hz, 2 H, ArH), 7.68 (d, J =
8.1 Hz, 2 H, ArH), 8.21 (br. s, 3 H, NH3) ppm. 13C NMR (CDCl3):
δ = 13.20 (CH3CH2), 21.46 (CH3 Tos), 39.30 (CH2), 44.50 (CH2),
44.92 (CH2), 127.25 (2×CH), 129.94 (2×CH), 135.17 (C), 143.95
(C) ppm. C13H19F3N2O4S (356.36): calcd. C 43.83, H 5.40, N 7.85,
S 9.25; found C 43.82, H 5.37, N 7.86, S 9.00.
[C(CH3)3], 45.99 (CH2), 53.25 (OCH3), 62.88 (=NCH2), 75.01 (2-
C), 80.10 [C(CH3)3], 127.00 (CH), 127.28 (CH), 127.91 (CH),
128.15 (CH), 128.35 (CH), 128.54 (CH), 137.73 (C), 139.62 (C),
154.28 (C=O Boc), 159.84 (3-CH), 169.08 (CO2CH3) ppm.
C23H29N3O4 (411.50): calcd. C 67.13, H 7.10, N 10.21; found C
67.20, H 6.95, N 9.96.
8.2. Methyl (E)-2-(tert-Butoxycarbonylamino)-2-(phenethylamino)-
3-(phenethylimino)propanoate, Boc-Ala[2-(2-phenyl)ethylamino,3-
(E)-(2-phenyl)ethylimino]-OMe (5b): The general procedure de-
scribed above was used with 2-(phenyl)ethylamine, giving com-
7.2. 2-[Ethyl(4-nitrobenzyloxycarbonyl)amino]ethylammonium Tri-
fluoroacetate (e): N-(tert-Butoxycarbonyl)-2-[ethyl(4-nitrobenzyl-
oxycarbonyl)amino]ethylamine was obtained from N-(tert-but-
oxycarbonyl)-2-(ethylamino)ethylamine[18] (940 mg, 5.00 mmol) by
addition of 4-nitrobenzyloxycarbonyl chloroformate (1.00 equiv.)
in dioxane/NaOH (2.00 mol·dm–3) (5:1) in an ice bath. After the
mixture had been stirred overnight the dioxane was removed and
the residue was partitioned between ethyl acetate (150 cm3) and
KHSO4 (1 mol·dm–3, 50 cm3). The organic layer was washed with
KHSO4 (1 mol·dm–3), NaHCO3 (1 mol·dm–3) and brine (3×30 cm3
each). The organic layer was dried with MgSO4 and the solvent was
evaporated at reduced pressure to give N-(tert-butoxycarbonyl)-2-
[ethyl(4-nitrobenzyloxycarbonyl)amino]ethylamine (1.70 g, 92%) as
an oil. Crystallization from ethyl acetate/n-hexane gave a white so-
1
pound 5b (192 mg, 87%) as an oil. H NMR (CDCl3): δ = 1.44 [s,
9 H, OC(CH3)3], 2.63–2.87 (m, 4 H, 2CH2), 2.96–3.05 (m, 2 H,
CH2), 3.59–3.84 (m, 5 H, =NCH2 + CO2CH3), 6.51 (s, 1 H, NH),
7.05–7.36 (m, 12 H, ArH + 3-CH + NH) ppm. 13C NMR (CDCl3):
δ = 28.20 [C(CH3)3], 36.02 (CH2), 36.44 (CH2), 45.87 (CH2), 52.68
(OCH3), 60.65 (2-C), 65.77 (=NCH2), 80.10 [C(CH3)3], 126.22
(CH), 128.34 (CH), 128.43 (CH), 128.62 (CH), 128.80 (CH), 138.96
(C), 139.40 (3-CH), 139.59 (C), 155.07 (C=O Boc), 170.63
(CO2CH3) ppm. HRMS (FAB) found 440.2565 [M + H]+, calcd.
for C25H34N3O4 440.2471.
1
8.3. Methyl (E)-2-(tert-Butoxycarbonylamino)-2-(4-methoxyben-
lid, m.p. 83.5–84.0 °C. H NMR (CDCl3): δ = 1.16 (t, J = 7.2 Hz,
zylamino)-3-(4-methoxybenzylimino)propanoate,
methoxybenzylamino),3-[(E)-4-methoxybenzylimino]}-OMe
Boc-Ala{2-(4-
(5c):
3 H, CH3), [s, 9 H, OC(CH3)3], 3.29–3.42 (comp. signal, 6 H,
3×CH2), 4.67, 4.90 (2×brs, 1 H, NH), 5.24 [s, 2 H, Z(NO2) CH2],
7.52 (br. d, J = 7.8 Hz, 2 H, ArH), 8.23 (d, J = 8.4 Hz, 2 H,
ArH) ppm. 13C NMR (CDCl3): δ = 13.94 (CH3CH2), 28.35
[C(CH3)3], 39.35 (CH2), 42.66 (CH2), 46.89 (CH2), 65.67 [CH2
Z(NO2)], 79.59 [C(CH3)3], 123.79 (2×CH), 127.96 (2×CH), 144.13
(C), 147.55 (C), 155.39 (C=O Boc), 156.14 [C=O Z(NO2)] ppm.
C17H25N3O6 (367.40): calcd. C 55.54, H 6.98, N 11.37; found C
55.58, H 6.86, N 11.44.
The general procedure described above was used with 4-methoxy-
benzylamine, giving compound 5c (151 mg, 93%) as an oil.
Crystallization from diethyl ether/n-hexane gave compound 5c as
white solid, m.p. 99.0–99.5 °C. 1H NMR (CDCl3): δ = 1.45 [s, 9 H,
OC(CH3)3], 3.44 (d, J = 12.6 Hz, 1 H, CH2), 3.63 (d, J = 12.6 Hz,
1 H, CH2), 3.77 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.81 (s, 3 H,
OCH3), 4.51 (d, J = 13.8 Hz, 1 H, =NCH2), 4.60 (d, J = 13.8 Hz,
1 H, =NCH2), 6.69 (s, 1 H, NH), 6.18–6.88 (m, 5 H, ArH), 7.11
(d, J = 8.7 Hz, 2 H, ArH), 7.22 (d, J = 8.4 Hz, 2 H, ArH), 7.51 (s,
1 H, 3-CH) ppm. 13C NMR (CDCl3): δ = 28.23 [C(CH3)3], 45.41
(CH2), 53.25 (OCH3), 55.26 (2×OCH3), 62.35 (=NCH2), 74.99 (2-
C), 80.08 [C(CH3)3], 113.73 (CH), 113.96 (CH), 129.21 (CH),
129.58 (CH), 129.83 (C), 131.75 (C), 154.33 (C=O Boc), 158.66
(C), 158.86 (C), 159.48 (3-CH), 169.16 (CO2CH3) ppm.
C25H33N3O6 (324.37): calcd. C 63.68, H 7.05, N 8.91; found C
63.66, H 7.06, N 8.96.
Treatment of N-(tert-butoxycarbonyl)-2-[ethyl(4-nitrobenzyloxy-
carbonyl)amino]ethylamine (1.42 g, 3.90 mmol) with TFA
(12.0 cm3) gave compound e (1.30 g, 87%). Crystallization from
1
methanol/diethyl ether gave a white solid, m.p. 130.0–131.0 °C. H
NMR (DMSO): δ = 1.07 (t, J = 6.6 Hz, 3 H, CH3), 2.96 (t, J =
6.6 Hz, 2 H, CH2CH3), 3.29–3.46 (complex signal, 4 H, 2×CH2),
5.22 [s, 2 H, Z(NO2) CH2], 7.63 (d, J = 8.7 Hz, 2 H, ArH), 7.95
(br. s, 3 H, NH3), 8.23 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13C NMR
(CDCl3): δ = 13.54 (CH3CH2), 37.34 (CH2), 41.78 (CH2), 44.16
(CH2), 65.25 [CH2 Z(NO2)], 123.58 (2×CH), 128.13 (2×CH),
144.76 (C), 146.98 (C), 155.44 [C=O Z(NO2)] ppm. C14H18F3N3O6
(381.31): calcd. C 44.05, H 4.73, N 10.99; found C 44.10, H 4.76,
N 11.02.
8.4. Boc-Ala{2-[2-ethyl,2-(4-tolylsulfonylamino)ethylamino],3-(E)-
[2-ethyl,2-(4-tolylsulfonylamino)ethylimino]}-OMe (5d): The general
procedure described above was used with 2-[ethyl(4-tolylsulfonyl)-
amino]ethylamine trifluoroacetate, giving compound 5d (313 mg,
92%) as an oil. 1H NMR (CDCl3): δ = 1.04–1.11 (m, 6 H, 2×CH3),
1.42 [s, 9 H, OC(CH3)3], 2.40 (s, 6 H, 2×Tos CH3), 2.48–2.76 (m,
8. General Procedure for the Synthesis of α-(Alkylamino)-β-(alk-
ylimino)alanines 5a–e: The amine (2.20 equiv.) and Et3N
3232
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3226–3234

Synthesis and Reactivity of β-Bromo-β-Substituted Dehydroalanines
FULL PAPER
2 H, CH2), 3.12–3.25 (m, 7 H, 3×CH2 + NH), 3.34–3.39 (m, 2 H, (d, J = 8.7 Hz, 2 H, ArH), 7.24 (d, J = 8.7 Hz, 2 H, ArH) ppm.
CH2), 3.68–3.72 (m, 2 H, =NCH2), 3.76 (s, 3 H, CO2CH3), 6.51 (s, 13C NMR (CDCl3): δ = 28.25 [C(CH3)3], 48.20 (CH2), 52.64
1 H, BocNH), 7.25–7.29 (m, 4 H, ArH), 7.44 (m, 1 H, 3-H), 7.65– (OCH3), 52.22 (OCH3), 65.61 (CH), 80.15 [C(CH3)3], 113.79 (CH),
7.70 (m, 4 H, ArH) ppm. 13C NMR (CDCl3): δ = 13.83 (CH3CH2), 129.46 (CH), 131.25 (C), 155.04 (C=O Boc), 158.76 (C), 170.68
13.90 (CH3CH2), 21.38 (2×CH3, Ar–CH3), 28.10 [C(CH3)3], 43.81
(CH2), 43.91 (CH2), 47.54 (CH2 N=CH2CH2), 48.05 (CH2), 53.27
(OMe), 58.79 (N=CH2), 74.57 (2-C), 80.09 [C(CH3)3], 127.00
(2×CH), 127.06 (2×CH), 129.55 (2×CH), 129.62 (2×CH), 136.53
(C), 136.68 (C), 143.05 (C), 143.18 (C), 154.21 (C=O Boc), 160.08
(3-CH), 168.78 (CO2CH3) ppm. HRMS (FAB) [M + H]+ found
682.2935; calcd. for C31H49N5O8S2 682.2944.
(CO2CH3) ppm. MS (FAB) m/z (%): 325.12 (100) [M + H]+, 265.11
(19) [M – CO2Me]+. C16H24N2O5 (324.37): calcd. C 59.24, H 7.46,
N 8.64; found C 59.05, H 7.31, N 8.64.
9.4. Boc-Gly{2-[2-[ethyl(4-tolylsulfonyl)amino]ethylamino]}-OMe
(6d): The same procedure as described above was used, with substi-
tution of compound 5a by compound 5d, giving compound 6d
(117 mg, 91%) as an oil. 1H NMR (CDCl3): δ = 1.12 (t, J = 7.2 Hz,
3 H, CH3), 1.46 [s, 9 H, OC(CH3)3], 2.43 (s, 3 H, Tos CH3), 2.84–
2.90 (m, 2 H, CH2), 3.20–3.24 (m, 4 H, 2×CH2), 3.80 (s, 3 H,
CO2CH3), 5.02 (d, J = 8.4 Hz, 1 H, BocNH or CH2NH), 5.34
(comp. signal, 1 H, BocNH or CH2NH), 7.30 (d, J = 8.1 Hz, 2 H,
ArH), 7.70 (d, J = 8.1 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3): δ
= 14.08 (CH3CH2), 21.42 (CH3 Tos), 28.21 [C(CH3)3], 43.78 (CH2),
43.91 (CH2), 47.62 (CH2), 52.72 (OCH3), 65.65 (αCH), 80.22
[C(CH3)3], 127.11 (2×CH), 129.61 (2×CH), 136.53 (C), 143.17 (C),
155.15 (C=O Boc), 170.29 (CO2CH3) ppm. HRMS (FAB)
[M + H]+ found 430.2021, calcd. for C19H32N3O6S 430.2012.
8.5.
Boc-Ala{2-[2-ethyl,2-(4-nitrobenzyloxycarbonylamino)ethyl-
amino],3-(E)-[2-ethyl,2-(4-nitrobenzyloxycarbonylamino)ethyl-
imino]}-OMe (5e): The general procedure described above was used
with 2-[ethyl(4-nitrobenzyloxycarbonyl)amino]ethylamine trifluo-
1
roacetate, giving compound 5e (347 mg, 95%) as an oil. H NMR
(CDCl3): δ = 1.11–1.20 (m, 6 H, CH3 Et), 1.43 [s, 9 H, OC-
(CH3)3], 2.76–2.84 (m, 1 H, CH2), 3.30–3.47 (m, 11 H, 6×CH2),
3.76 (s, 3 H, CO2CH3), 5.02 (s, 1 H, NH), 5.21 [s, 2 H, Z(NO2)-
CH2], 5.23 [s, 2 H, Z(NO2) CH2], 6.40 (s, 1 H, NH), 7.48–7.52 (m,
4 H, ArH), 8.13–8.24 (m, 5 H, ArH + 3-CH) ppm. 13C NMR
(CDCl3): δ = 13.11 (CH2CH3), 13.84 (CH2CH3), 28.19 [C(CH3)3],
37.68 (=NCH2), 42.56 (CH2), 43.07 (CH2), 43.14 (CH2), 46.10
(CH2), 47.18 (CH2), 65.52 [CH2 Z(NO2)], 65.82 [CH2 Z(NO2)],
79.59 (2-C), 80.33 [C(CH3)3], 123.72 (CH), 123.77 (CH), 127.88
(2×CH), 143.85 (C), 144.26 (C), 147.44 (C), 147.55 (C), 155.12
(C=O Boc), 161.56 (CO2CH3), 170.46 (3-CH) ppm. HRMS (FAB)
found 732.3207 [M + H]+, calcd.for C33H46N7O12 732.3204.
9.5. Boc-Gly{2-[2-[ethyl(4-nitrobenzyloxycarbonyl)amino]-
ethylamino]}-OMe (6e): The same procedure as described above
was used, with substitution of compound 5a by compound 5e, giv-
1
ing compound 6e (119 mg, 87%) as an oil. H NMR (CDCl3): δ =
1.14 (t, J = 7.5 Hz, 3 H, CH3), 1.45 [s, 9 H, OC(CH3)3], 2.83 (br.
d, J = 5.4 Hz, 2 H, CH2), 3.31–3.41 (m, 4 H, 2×CH2), 3.73 (s, 3
H, CO2CH3), 5.01 (comp. signal, 1 H, αCH), 5.22 [s, 2 H, Z(NO2),
CH2], 5.35 (br. s, 1 H, CONH), 7.51 (d, J = 8.1 Hz, 2 H, ArH),
8.22 (d, J = 9.0 Hz, 2 H, ArH) ppm. 13C NMR (CDCl3): δ = 13.90
(CH3CH2), 28.23 [C(CH3)3], 42.45 (CH2), 43.11 (CH2), 46.43
(CH2), 47.22 (CH2), 52.76 (OCH3), 65.54 (αCH), 80.40 [C(CH3)3],
123.76 (2×CH), 127.97 (2×CH), 144.29 (C), 147.50 (C), 155.15
(C=O Boc), 164.68 [CO Z(NO2)], 170.47 (CO2CH3) ppm. HRMS
(FAB) [M + H]+ found 455.2132, calcd. for C20H31N4O8 455.2142.
9. Synthesis of α-Alkylaminoglycines
9.1. Methyl 2-(Benzylamino)-2-(tert-butoxycarbonylamino)acetate,
Boc-Gly(2-benzylamino)-OMe (6a): Treatment of Boc-Ala[2-ben-
zylamino,3-(E)-benzylimino]-OMe (5a) (104 mg, 0.300 mmol) with
silica (1.00 g) in dichloromethane (5.00 cm3) for 1 h afforded com-
pound 6a (80.0 mg, 83%) as a white solid, m.p. 69.0–70.0 °C. 1H
NMR (CDCl3): δ = 1.47 [s, 9 H, OC(CH3)3], 3.75 (s, 3 H,
CO2CH3), 3.83 (s, 2 H, CH2), 5.07 (d, J = 6.3 Hz, 1 H, 2-CH), 5.37
(s, 1 H, NH), 7.26–7.35 (m, 6 H, ArH + NH) ppm. 13C NMR
(CDCl3): δ = 28.27 [C(CH3)3], 48.83 (CH2), 52.69 (OCH3), 65.77
(CH), 80.26 [C(CH3)3], 127.20 (CH), 128.24 (CH), 128.44 (CH),
139.20 (C), 155.24 (C=O Boc), 170.63 (CO2CH3) ppm. MS (FAB)
m/z (%): 295.16 (100) [M + H]+, 235.15 (27.5) [M – CO2Me]+.
C15H22N2O4 (294.35): calcd. C 61.22, H 7.48, N, 9.52; found C
61.08, H 7.39, N 9.52.
10.1. Methyl 2-(tert-Butoxycarbonylamino)-2-(2-methoxy-2-oxo-
ethylamino)acetate,Boc-Gly[2-(methoxycarbonylmethylamino)]-
OMe (6f): H-Gly-OMe (2.20 equiv.) was added with rapid stirring
to a solution of (Z)-Boc-∆Ala[3-Br, 3-(1,2,4-triazol-1-yl)-OMe
(174 mg, 0.500 mmol) in methanol (0.100 mol·dm–3). After the
mixture had been kept for 18 h at room temperature, diethyl ether
(45 cm3) was added and the solution was washed with water and
brine (3×15 cm3 each). The organic layer was dried with MgSO4,
and the solvent was evaporated at reduced pressure to give an oil,
which was subjected to column chromatography with diethyl ether/
petroleum ether (2:1) to give compound 6f (79.0 mg, 92%) as an
9.2. Methyl 2-(tert-Butoxycarbonylamino)-2-(phenethylamino)ace-
tate,Boc-Gly[2-(2-phenyl)ethylamino]-OMe (6b): The same pro-
cedure as described above was used, with substitution of compound
5a by compound 5b, giving compound 6b (71.0 mg, 76%) as an oil.
1H NMR (CDCl3): δ = 1.45 [s, 9 H, OC(CH3)3], 2.76–2.97 (m, 4
H, CH2), 3.80 (s, 3 H, CO2CH3), 5.06 (d, J = 7.2 Hz, 1 H, CH),
5.30 (s, 1 H, NH), 7.04–7.29 (m, 6 H, ArH + NH) ppm. 13C NMR
(CDCl3): δ = 28.20 [C(CH3)3], 36.02 (CH2), 45.87 (CH2), 52.67
(OCH3), 65.77 (CH), 80.10 [C(CH3)3], 126.22 (CH), 128.43 (CH),
1 28. 6 2 (C H) , 1 3 9 . 40 ( C ) , 1 5 5 . 0 7 ( C = O B o c ) , 1 7 0 . 6 3
(CO2 CH3 ) ppm. HRMS (EI) found 308.1741, calcd. for
C16H24N2O4 [M]+ 308.1736.
1
oil. H NMR (CDCl3): δ = 1.44 [s, 9 H, OC(CH3)3], 3.48 (d, J =
3.3 Hz, 2 H, CH2), 3.73 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 5.05
(d, J = 8.4 Hz, 1 H, 2-CH), 5.36 (br. d, J = 8.4 Hz, 1 H, NH) ppm.
13C NMR (CDCl3): δ = 28.20 [C(CH3)3], 46.27 (CH2), 52.00
(OCH3), 52.83 (OCH3), 65.53 (2-CH), 80.35 [C(CH3)3], 155.12
(C=O Boc), 170.04 (CO2CH3), 172.42 (CO2CH3) ppm. HRMS
(FAB) found 277.1410 [M + H]+, calcd. for C11H21N2O6 277.1400.
10.2. tert-Butyl 1,2-Bis(benzylamino)-2-oxoethylcarbamate, Boc-
Gly(2-benzylamino)-NHBn (7a): The same procedure as described
above was used, with substitution of H-Gly-OMe (2.20 equiv.) by
benzylamine (10.0 equiv.) to give compound 7a (103 mg, 93%).
Crystallization from diethyl ether/n-hexane afforded a white solid,
m.p. 134.0–135.5 °C. 1H NMR (CDCl3): δ = 1.48 [s, 9 H, OC-
(CH3)3], 3.54 (d, J = 13.2 Hz, 1 H, CH2), 3.80 (d, J = 13.2 Hz, 1
9.3. Methyl 2-(tert-Butoxycarbonylamino)-2-(4-methoxyben-
zylamino)acetate, Boc-Gly[2-(4-methoxybenzylamino)]-OMe (6c):
The same procedure as described above was used, with substitution
of compound 5a by compound 5c, giving compound 6c (61.0 mg,
1
63%) as a white solid, m.p. 47.0–48.0 °C. H NMR (CDCl3): δ =
1.47 [s, 9 H, OC(CH3)3], 3.74 (s, 3 H, OCH3), 3.75 (s, 2 H, CH2), H, CH2), 4.44 (d, J = 5.7 Hz, 2 H, CH2), 4.95 (d, J = 4.8 Hz, 1 H,
3.79 (s, 3 H, OCH3), 5.03 (br. s, 1 H, CH), 5.40 (s, 1 H, NH), 6.85 CH), 5.89 (s, 1 H, NH), 7.25–7.42 (m, 12 H, ArH + 2NH) ppm.
Eur. J. Org. Chem. 2006, 3226–3234
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3233

P. M. T. Ferreira, L. S. Monteiro
FULL PAPER
13C NMR (CDCl3): δ = 28.29 [C(CH3)3], 43.65 (CH2), 47.32 (CH2),
66.49 (CH), 80.01 [C(CH3)3], 127.14 (CH), 127.58 (CH), 127.65
(CH), 127.82 (CH), 128.09 (CH), 128.47 (CH), 128.71 (CH), 137.77
(C), 139.31 (C), 155.94 (C=O Boc), 169.28 (CO2CH3) ppm.
C21H27N3O3 (369.46): calcd. C 68.27, H 7.37, N 11.37; found C
68.07, H 7.25, N 10.98.
[3] P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro, Eur. J. Org.
Chem. 2003, 2635–2644.
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Tetrahedron Lett. 2003, 44, 3377–3379.
[5] J. E. Rivier, G. Jiang, S. C. Koerber, J. Porter, L. Simon, A. G.
Craig, C. A. Hoeger, Proc. Natl. Acad. Sci. USA 1996, 93,
2031–2036.
[6] G. Jiang, C. Miller, S. C. Koerber, J. Porter, A. G. Craig, S.
Bhattacharjee, P. Kraft, T. P. Burris, C. A. Campen, C. L. Riv-
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10.3. tert-Butyl 2-Oxo-1,2-bis(phenethylamino)ethylcarbamate, Boc-
Gly[2-(2-phenyl)ethylamino]-NHCH2CH2Ph (7b): The same pro-
cedure as described above was used, with substitution of H-Gly-
OMe (2.20 equiv.) by phenylethylamine (10.0 equiv.), giving com-
pound 7b (104 mg, 87%) as an oil. Crystallization from diethyl
ether/n-hexane afforded a white solid, m.p. 121.0–123.0 °C. 1H
NMR (CDCl3): δ = 1.44 [s, 9 H, OC(CH3)3], 2.37–2.46 (m, 1 H,
CH2), 2.60–2.71 (m, 4 H, CH2), 2.88–3.00 (m, 1 H, CH2), 3.28–
3.49 (m, 2 H, CH2), 4.78 (d, J = 3.9 Hz, 3 H, 2-CH), 5.72 (s, 1 H,
NH), 6.83 (s, 1 H, NH), 7.10–7.33 (m, 11 H, ArH + NH) ppm. 13
C
NMR (CDCl3): δ = 28.24 [C(CH3)3], 35.40 (CH2), 36.31 (CH2),
40.56 (CH2), 43.99 (CH2), 66.39 (CH), 79.72 [C(CH3)3], 126.18
(CH), 126.48 (CH), 128.35 (CH), 128.55 (CH), 128.59 (CH), 128.77
(CH), 138.54 (C), 139.91 (C), 155.89 (C=O Boc), 169.15
(CO2CH3) ppm. C23H31N3O3 (397.51): calcd. C 69.49, H 7.86, N
10.57; found C 69.40, H 7.89, N 10.66.
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Chem. 2002, 67, 5408–5411.
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Acknowledgments
Thanks are due to the Fundação para a Ciência e Tecnologia (Por-
tugal) and FEDER for funding Centro de Química-Universidade
do Minho and for financial support through project POCI/QUI/
59407/2004.
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Received: February 3, 2006
Published Online: May 18, 2006
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