Synthesis of novel amino acids and dehydroamino acids containing the benzo[b]thiophene moiety

Article abstract of DOI:10.1002/ejoc.200390212

Several novel amino acids and dehydroamino acids containing the benzo[b]thiophene moiety were prepared by Michael addition or sequential Michael addition and palladium-catalyzed C-C or C-N cross couplings. The substrates for Michael addition were the methyl esters of N,N-bis(tertbutyloxycarbonyl)dehydroalanine [Boc₂-ΔAla-OMe] and N-(4-toluenesulfonyl)-N-(tert-butyloxycarbonyl)dehydroalanine [Tos-ΔAla(N-Boc)-OMe], and the nucleophiles were aromatic thiols and 3-iodobenzylamine. The addition of mercaptobenzo[b]thiophenes directly to Tos-ΔAla(N-Boc)-OMe gave stereoselectively, in good yields, the E-isomer of the corresponding dehydrocysteine. When thiophenols and 3-iodobenzylamine were used as nucleophiles the presence of an additional function (halogen or amine) allowed a subsequent palladium-catalyzed cross-coupling reaction with functionalized benzo[b]thiophenes (boronic acids, a halogen or an amine). Using this strategy, several racemic amino acid and dehydroamino acid derivatives, which are linked to the benzo[b]thiophene moiety by an aromatic spacer, were obtained in good yields. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390212

FULL PAPER
Synthesis of Novel Amino Acids and Dehydroamino Acids Containing the
Benzo[b]thiophene Moiety
[a]
[a]
[a]
´
Ana S. Abreu, Natalia O. Silva, Paula M. T. Ferreira,* and
[a]
˜
Maria-Joao R. P. Queiroz
Keywords: Amino acids / Benzo[b]thiophenes / Cross-couplings / Michael addition / Palladium
Several novel amino acids and dehydroamino acids con-
taining the benzo[b]thiophene moiety were prepared by
corresponding dehydrocysteine. When thiophenols and 3-
iodobenzylamine were used as nucleophiles the presence of
Michael addition or sequential Michael addition and palla- an additional function (halogen or amine) allowed a sub-
dium-catalyzed C−C or C−N cross couplings. The substrates
for Michael addition were the methyl esters of N,N-bis(tert-
butyloxycarbonyl)dehydroalanine [Boc2−∆Ala−OMe] and N-
(4-toluenesulfonyl)-N-(tert-butyloxycarbonyl)dehydroala-
nine [Tos−∆Ala(N-Boc)−OMe], and the nucleophiles were
aromatic thiols and 3-iodobenzylamine. The addition of mer-
captobenzo[b]thiophenes directly to Tos−∆Ala(N-Boc)−OMe
gave stereoselectively, in good yields, the E-isomer of the
sequent palladium-catalyzed cross-coupling reaction with
functionalized benzo[b]thiophenes (boronic acids, a halogen
or an amine). Using this strategy, several racemic amino acid
and dehydroamino acid derivatives, which are linked to the
benzo[b]thiophene moiety by an aromatic spacer, were ob-
tained in good yields.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
tial Michael addition and palladium-catalyzed CϪC or
CϪN cross couplings. The final compounds have the poten-
tial for biological activity and for the use as biomarkers
because of their expected fluorescence.
Non-proteinogenic amino acids constitute an important
group of compounds in the field of peptide chemistry.
These compounds have several applications, either as bio-
logically active substrates or as individual structural com-
ponents. Among these amino acids are α,β-dehydroamino
acids[1] and β-substituted alanines.[2] When inserted into
peptides, α,β-dehydroamino acids confer conformational
constraints that are important features for studies of
structureϪactivity relationships.
We have developed a highly efficient method for the syn-
thesis of N,N-diacyldehydroamino acid derivatives from the
corresponding β-hydroxyamino acids.[3] These compounds
are versatile substrates in Michael addition reactions and
allow the preparation of several new β-substituted amino
acids as well as β-substituted dehydroamino acids.[4]
The benzo[b]thiophenes are important heterocycles,
either as biologically active molecules or as electronic or
luminescent components used in organic materials.[5] Re-
cently, we reported the synthesis of several sulfur analogues
of dehydrotryptophan using Suzuki cross-coupling of β-
bromodehydroamino acid derivatives with benzo[b]thio-
phene boronic acids.[6] Here we describe the synthesis of
novel amino acids and dehydroamino acids containing the
benzo[b]thiophene moiety by Michael addition or sequen-
Results and Discussion
Several 5- and 7-functionalized 2,3-dimethylbenzo[b]thio-
phenes were prepared from the corresponding bromo com-
pounds 1a[7] and 1b[6] (Scheme 1). The mercaptobenzo[b]-
thiophenes 2a and 2b were synthesized by halogenϪlithium
exchange followed by reaction with sulfur, and were used
as nucleophiles in Michael addition reactions (Scheme 2,
Table 1). The benzo[b]thiophene boronic acids 3a and 3b[6]
were obtained according to a procedure that we have al-
ready described.[6] The amines 4a and 4b were prepared by
palladium-catalyzed CϪN cross-coupling of compounds 1a
and 1b, respectively, with benzophenone imine, followed by
hydrolysis of the imino-coupled products.[8] It was possible
to obtain the amine 4a only by using the catalytic system
Pd2(dba)3, BINAP, and CH3ONa as base,[8a] while com-
pound 4b was obtained using the more general system,
[8b]
Pd(OAc)2, BINAP, and Cs2CO3
(Scheme 1). Both cata-
lytic systems have been applied by us, with no significant
differences, to the syntheses of methylated 6-aminobenzo-
[b]thiophenes.[8c]
[a]
´
Departamento de Quımica-Universidade do Minho
Michael addition reactions were performed using the
4700-320 Braga, Portugal
substrates Boc2Ϫ∆Ala-OMe[3]
5
and TosϪ∆Ala(N-
Fax: (internat.) ϩ 351-253678983
E-mail: pmf@quimica.uminho.pt
Boc)ϪOMe[3] 6 and the nucleophiles 4-bromothiophenol,
1537
Eur. J. Org. Chem. 2003, 1537Ϫ1544  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1537 $ 20.00ϩ.50/0

A. S. Abreu, N. O. Silva, P. M. T. Ferreira, M.-J. R. P. Queiroz
FULL PAPER
Scheme 1
philes b, 2a and 2b, the corresponding intermediates 8 were
detected during the course of the reaction by NMR spec-
troscopy, but were not isolated. The stereochemistry of the
products was determined by differential NOE enhance-
ments between the βCH and the αNH protons.
The products obtained from Michael addition reactions,
7a, 7c, 8a, and (E)-9a, were coupled with several benzo-
[b]thiophene boronic acids under Suzuki cross-coupling
conditions in good to high yields (Table 2). With
benzo[b]thiophene 3-boronic acid as starting material, a
3,3Ј-benzo[b]thiophene dimer was also isolated. Using 3a or
3b[6] as coupling components, the corresponding debo-
ronated benzo[b]thiophenes were obtained as byproducts
and, in the latter case, a small amount of 2,3-dimethyl-7-
hydroxybenzo[b]thiophene[6,9] was also isolated. After sev-
eral trial experiments, we established these conditions to be
the best for the Suzuki cross-couplings: DME/H2O (10:1)
as solvent and a 30% excess of the boronic acid. As an
example, the yield in the synthesis of (E)-15 from (E)-9a
was improved from 34% to 52% by increasing the amount
of the boronic acid (from 10% to 30% excess). The latter
yield was improved again to 85% by changing the ratio of
DME to H2O from 6:1 to 10:1.
Scheme 2
Using compound 8a in the coupling reaction with benzo-
[b]thiophene 3-boronic acid, elimination of the Tos group
occurred, with regeneration of the α,β double bond, giving
a mixture of the stereoisomers (E)-15 and (Z)-15 (ratio 4:1),
which were separated by column chromatography (Table 2).
The stereochemistry of each was determined by NOE
experiments in which we found, as we have observed in
other cases,[6] that the chemical shift of the OMe signal is
higher for the Z-isomer (δ ϭ 3.94 vs. 3.82 ppm) than for
the E-isomer.
4-aminothiophenol, 3-iodobenzylamine, and 7- and 5-mer-
captobenzo[b]thiophenes 2a and 2b (Scheme 2). The
Michael adducts 7a and 7c were obtained in good to high
yields as shown in Table 1. BocϪAla(N-Boc)Ϫβ-(4-
aminophenylsulfanyl)ϪOMe 7b has been described by us
previously.[4b]
When compound 6 was used as the substrate, the Michael
adducts 8 eliminate the tosyl group spontaneously giving
the E-isomers, stereoselectively, of the corresponding β-sub-
stituted α,β-dehydroamino acids 9a, 9b, 10 and 11 (Table 1).
On comparing the yields obtained in the syntheses of
With 4-bromothiophenol, we could isolate the intermediate compounds 12, 13, and 14 from compound 7a, we conclude
addition product 8a in high yield (Table 1). Using nucleo- that the benzo[b]thiophene 3-boronic acid is the most reac-
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Eur. J. Org. Chem. 2003, 1537Ϫ1544

Synthesis of Novel Amino Acids and Dehydroamino Acids
FULL PAPER
Table 1. Starting materials and yields of products in the Michael
addition reactions
Table 2. Starting materials and yields of products in the Suzuki
cross-coupling reactions; reaction conditions: Boronic acid (1.3
equiv.), Pd(PPh3)4 (10 mol %), Na2CO3 (2 equiv.), DME/H2O
(10:1), 90 °C; a) boronic acid (1.1 equiv.), DME/H2O (6:1)
we observed could be due to the lower reactivity of com-
pound 3a in the Suzuki coupling.
Compound 3a was also the least reactive boronic acid
when (E)-9a was used as the starting material, but no differ-
ence was observed between the reactivities of 3b and 3-bo-
ronic benzo[b]thiophene acid and their corresponding prod-
ucts were obtained in similar yields (Table 2).
Compound 4b was coupled with the Michael adduct 7a,
which has a bromine atom as an additional function, using
Buchwald’s CϪN cross-coupling conditions[10,11] to give the
diarylamine 20 (Table 3). The amine 4a did not react; in-
stead, it decomposes under the reaction conditions.
The same CϪN coupling reactions were performed using
tive one. Some cleavage of the β-CϪS bond was observed
during the synthesis of 13 and 14 from compound 7a, with bromobenzo[b]thiophenes 1a and 1b with Michael adducts
Boc2Ϫ∆AlaϪOMe being isolated in 23 and 45%, respec- having a free amino function, 7b[4b] and (E)-9b, giving the
tively. In the latter case, the higher percentage of cleavage diarylamines 20, 21, and 22 (Table 3). In these cases, an
Eur. J. Org. Chem. 2003, 1537Ϫ1544
1539

A. S. Abreu, N. O. Silva, P. M. T. Ferreira, M.-J. R. P. Queiroz
FULL PAPER
used as biomarkers because of their expected fluorescence
properties.
Table 3. Starting materials and product yields in the CϪN cross
couplings reactions; reaction conditions: Pd(OAc)2 (10 mol %), BI-
NAP (15 mol %), Cs2CO3 (1.4 equiv.), dry toluene, 100 °C under
Ar, 5 h. 1a or 1b (1.5 equiv.)
Experimental Section
General Remarks: Melting points were determined on a Gallenk-
amp apparatus and are uncorrected. The 1H NMR spectra were
measured on a Varian Unity Plus spectrometer at 300 MHz. Spin-
spin decoupling techniques were used to assign the signals. NOE
experiments were performed to determine the stereochemistry of
the products. The 13C NMR spectra were measured in the same
instrument at 75.4 MHz (using DEPT θ 45°). Elemental analyses
were determined on a LECO CHNS 932 elemental analyzer. Mass
spectra (EI and FAB) and HRMS were obtained by the mass spec-
trometry service of University of Vigo, Spain.
Column chromatography was performed on MachereyϪNagel sil-
ica gel (230Ϫ400 mesh). Petroleum ether refers to that of the boil-
ing range 40Ϫ60 °C. When a solvent gradient was used, the in-
crease of polarity was made gradually from neat petroleum ether
to mixtures of diethyl ether/petroleum ether, with sequential 10%
increases of the proportion of diethyl ether, until the product was
isolated.
The benzo[b]thiophenes 1a,[7] 1b,[6] 3a, and 3b[6] were prepared by
methods already described by us.[6] Amino acids 5,[3] 6,[3] and 7b[4b]
were prepared also according to methods described by us.
excess (1.5 equiv.) of the benzo[b]thiophene coupling com-
ponent was needed to obtain the products in good yields.
When compounds 7a and 7b were used as starting materi-
als, cleavage of the β-CϪS bond occurred to some extent,
yielding Boc2Ϫ∆AlaϪOMe (ഠ 30%).
General Procedure for the Synthesis of 2a and 2b: A solution of
nBuLi in hexane (2.5 , 1.24 mL, 3.10 mol) was added dropwise,
under Ar, to a solution of 1a or 1b (0.500 g, 2.07 mmol) in dry
diethyl ether (10 mL) at 0 °C. The mixture was stirred for 10 min
at 0 °C, then sulfur (0.100 g, 3.11 mmol) was added under Ar and
The CϪN coupling reaction of compound (E)-9b with 1b the mixture was stirred at room temperature for 2 h. Ice and conc.
HCl (1 mL) were added and the mixture was stirred for 15 min.
The phases were separated and the aqueous phase was extracted
with diethyl ether (2 ϫ 10 mL). The organic extracts were collected,
dried (MgSO4), and then the solvent was evaporated to give the
products as oils, which were used directly in the Michael additions
without further purification. The corresponding Michael adducts
were characterized completely.
gave a mixture (2.5:1) of stereoisomers (E)-22 and (Z)-22
(Table 3), which were separated by column chromatography.
The stereochemistry was determined by NOE experiments,
with which it was observed again that the chemical shift of
the OMe group is higher for the Z-isomer (δ ϭ 3.91 vs.
3.77 ppm) than for the E-isomer.
It was possible with this strategy to obtain diarylamines,
linked to amino acids and dehydroamino acids, that could
have interesting applications as biomaterials with electronic
properties. These diarylamines are also precursors of thien-
ocarbazoles,[11] bioisosteres of the natural antitumor pyri-
docarbazoles (ellipticines and olivacines) that intercalate in
DNA.
2,3-Dimethyl-5-mercaptobenzo[b]thiophene (2a): 0.350 g (ഠ 87%);
1H NMR (CDCl3): δ ϭ 2.26 (s, 3 H, ArCH3), 2.48 (s, 3 H, ArCH3),
3.60 (s, 1 H, SH), 7.20 (dd, J ϭ 8.4, 1.8 Hz, 1 H, 6-H), 7.54 (d,
J ϭ 1.8 Hz, 1 H, 4-H), 7.61 (d, J ϭ 8.4 Hz, 1 H, 7-H) ppm.
2,3-Dimethyl-7-mercaptobenzo[b]thiophene (2b): 0.300 g (ഠ 72%);
1H NMR (CDCl3): δ ϭ 2.30 (s, 3 H, ArCH3), 2.52 (s, 3 H, ArCH3),
3.60 (s, 1 H, SH), 7.27Ϫ7.30 (m, 2 H, 2 ϫ ArH), 7.44Ϫ7.50 (m, 1
H, ArH) ppm.
Conclusion
2,3-Dimethylbenzo[b]thiophene 5-Boronic Acid (3a): From com-
pound 1a (1.50 g, 6.20 mmol), following the method described by
us for the synthesis of 3b,[6] compound 3a was obtained as a white
solid (0.650 g, 50%), m.p. 184.0Ϫ186.0 °C. 1H NMR ([D6]DMSO):
δ ϭ 2.28 (s, 3 H, ArCH3), 2.45 (s, 3 H, ArCH3), 7.67 (d, J ϭ 8.0
Hz, 1 H, 6- or 7-H), 7.77 (d, J ϭ 8.0 Hz, 1 H, 7- or 6-H), 8.05 (br
s, 2 H, 2 ϫ OH), 8.11 (s, 1 H, 4-H) ppm. 13C NMR ([D6]DMSO):
δ ϭ 11.1 (CH3), 13.5 (CH3), 121.0 (CH), 127.1 (C), 127.5 (CH),
129.2 (CH), 132.7 (C), 139.32 (C), 140.1 (C) ppm.
Saturated and unsaturated amino acids having a benzo-
[b]thiophene moiety were obtained in good to high yields
either by Michael additions or by sequential Michael ad-
dition and palladium catalyzed CϪC or CϪN cross coup-
lings. The starting materials were functionalized benzo-
[b]thiophenes (Br, B(OH)2, SH, NH2) and dehydroamino
acids or Michael adducts having an additional functionality
(Br or NH2). The final compounds might have biological
activity or, when inserted into peptides, might be useful for
5-Amino-2,3-dimethylbenzo[b]thiophene (4a): A dried Schlenk tube
was charged under Ar with dry toluene (4 mL), compound 1a
conformational studies. These compounds might also be (500 mg, 2.10 mmol), Pd2(dba)3 (9.60 mg, 0.011 mmol), BINAP
1540 Eur. J. Org. Chem. 2003, 1537Ϫ1544

Synthesis of Novel Amino Acids and Dehydroamino Acids
FULL PAPER
(13.0 mg, 0.021 mmol), CH3ONa (170 mg, 3.15 mmol), and benzo-
gradient, from petroleum ether to 30% diethyl ether/petroleum
phenone imine (0.5 mL, 2.95 mmol), and then the mixture was ether (unless stated otherwise).
stirred for 21 h at 100 °C. After cooling, diethyl ether (6 mL) was
Boc-Ala[N-Boc-β-(4-bromophenylsulfanyl)]-OMe (7a): Column
added and the mixture filtered. Removal of the solvents gave an
oily yellow solid that after washing with MeOH gave a yellow solid,
which corresponded to the imino-coupled product (560 mg), m.p.
158.5Ϫ160.2 °C. 1H NMR (CDCl3): δ ϭ 2.14 (s, 3 H, ArCH3),
2.44 (s, 3 H, ArCH3), 6.63 (dd, J ϭ 8.4, 2.1 Hz, 1 H, 6-H), 7.03
(d, J ϭ 2.1 Hz, 1 H, 4-H), 7.14Ϫ7.26 (m, 4 H, ArH), 7.39Ϫ7.51
(m, 5 H, ArH), 7.84Ϫ7.89 (m, 2 H, ArH). THF (7 mL) and HCl
(2 , 1.5 mL) were added to this solid and the mixture was then
stirred overnight. A mixture of EtOAc and hexane (1:2, 3 mL) and
HCl (0.5 , 5 mL) were added and the mixture was stirred for 1 h.
The phases were separated and the aqueous phase was basified and
then extracted with chloroform (2 ϫ 20 mL). The organic phase
was dried and the solvent evaporated to give the amine 4a as an
chromatography gave product 7a (1.06 g, 72%) as a white solid.
Recrystallization from diethyl ether/n-hexane gave colorless crys-
tals, m.p. 64.7Ϫ65.4 °C. 1H NMR (CDCl3): δ ϭ 1.47 (s, 18 H, Boc
CH3), 3.46 (dd, J ϭ 14.7, 9.9 Hz, 1 H, βCH2), 3.71 (dd, J ϭ 14.7,
4.5 Hz, 1 H, βCH2), 3.73 (s, 3 H, OCH3), 5.08 (dd, J ϭ 9.9, 4.5
Hz, 1 H, αCH), 7.25 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ ArH), 7.40 (d, J ϭ
8.4 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR (CDCl3): δ ϭ 27.9
[C(CH3)3], 34.9 (βCH2), 52.5 (OCH3), 57.7 (αCH), 83.4
[OC(CH3)3], 120.40 (C), 131.4 (CH), 132.0 (CH), 134.8 (C), 151.8
(CϭO), 170.1 (CϭO) ppm. C20H28BrNO6S (490.41): calcd. C
48.98, H 5.75, N 2.86, S 6.54; found C 49.26, H 6.06, N 2.93,
S 6.41.
1
oil (130 mg, overall yield 35%). H NMR (CDCl3): δ ϭ 2.22 (s, 3
Boc-Ala[N-Boc-β-(3-iodobenzylamino)]-OMe (7c): Column chroma-
tography gave product 7c (1.44 g, 90%) as an oil that failed all
attempts to crystallize it. 1H NMR (CDCl3): δ ϭ 1.45 (s, 18 H,
CH3 Boc), 3.40Ϫ3.50 (m, 2 H, βCH2), 3.75 (s, 3 H, OCH3),
4.27Ϫ4.49 (m, 3 H, αCH and CH2 Bn), 5.54 (d, J ϭ 6.3 Hz, 1 H,
NH), 7.07 (t, J ϭ 7.5 Hz, 1 H, 5-H), 7.18Ϫ7.21 (m, 1 H, ArH),
7.59Ϫ7.62 (m, 2 H, ArH) ppm. 13C NMR (CDCl3): δ ϭ 28.2
[C(CH3)3], 47.8 (CH2), 50.5 (CH2), 52.4 (OCH3), 52.7 (αCH), 79.7
[OC(CH3)3], 80.7 [OC(CH3)3], 126.2 (CH), 126.8 (CH), 130.2 (CH),
136.1 (C), 136.2 (CH), 140.2 (C), 155.2 (CϭO), 156.0 (CϭO), 171.0
(CϭO) ppm. HMRS: C21H31IN2O6 [M ϩ H]ϩ, found (calcd.)
535.1329 (535.1305).
H, ArCH3), 2.45 (s, 3 H, ArCH3), 3.65 (br s, 2 H, NH2), 6.71 (dd,
J ϭ 8.4, 2.4 Hz, 1 H, 6-H), 6.89 (d, J ϭ 2.4 Hz, 1 H, 4-H), 7.50
(d, J ϭ 8.4 Hz, 1 H, 7-H) ppm. 13C NMR (CDCl3): δ ϭ 11.3
(CH3), 13.8 (CH3), 106.5 (CH), 113.6 (CH), 122.5 (CH), 126.3 (C),
128.5 (C), 134.6 (C), 142.2 (C), 143.3 (C) ppm. MS (EI): m/z (%) ϭ
179 (15) [Mϩ ϩ 2], 178 (39) [Mϩ ϩ 1], 177 (100) [Mϩ], 176 [Mϩ
Ϫ 1], 162 (65) [Mϩ Ϫ 15]. HRMS: found (calcd.) for C10H11NS
[Mϩ], 177.0614 (177.0612).
7-Amino-2,3-dimethylbenzo[b]thiophene (4b): A dried Schlenk tube
was charged under Ar with dry toluene (4 mL), compound 1b
(500 mg, 2.10 mmol), Pd(OAc)2 (19.0 mg, 0.0840 mmol), BINAP
(65.0 mg, 0.105 mmol), Cs2CO3 (960 mg, 2.94 mmol), and benzo-
phenone imine (0.5 mL, 2.95 mmol), and then the mixture was
stirred for 21 h at 100 °C. After cooling, diethyl ether (6 mL) was
added and the mixture filtered. Evaporation of the solvents gave
an oily yellow solid that after washing with MeOH gave a yellow
solid, which corresponded to the imino-coupled product (650 mg),
m.p. 109.3Ϫ111.6 °C. 1H NMR (CDCl3): δ ϭ 2.28 (s, 3 H, ArCH3),
2.48 (s, 3 H, ArCH3), 6.32 (dd, J ϭ 7.5, 0.9 Hz, 1 H, 6-H), 7.05 (t,
J ϭ 7.5 Hz, 1 H, 4-H), 7.14Ϫ7.26 (m, 5 H, ArH), 7.40Ϫ7.52 (m,
4 H, ArH), 7.84Ϫ7.89 (m, 2 H, Ar-H) ppm. THF (7 mL) and HCl
(2 , 1.5 mL) were added to this solid and the mixture was stirred
overnight. A mixture of EtOAc and hexane (1:2, 3 mL) and HCl
(0.5 , 5 mL) were added and the mixture was stirred for 1 h. The
phases were separated and the aqueous phase was basified and then
extracted with chloroform (2 ϫ 20 mL). The organic phase was
dried and the solvent evaporated to give the amine 4b as a white
solid (234 mg, overall yield 63%). Recrystallization from diethyl
ether/petroleum ether gave colorless crystals, m.p. 94.0Ϫ95.0 °C.
1H NMR (CDCl3): δ ϭ 2.29 (s, 3 H, ArCH3), 2.50 (s, 3 H, ArCH3),
3.80 (br s, 2 H, NH2), 6.64 (dd, J ϭ 7.5, 0.9 Hz, 1 H, 6-H), 7.11
(dd, J ϭ 7.5, 0.9 Hz, 1 H, 4-H), 7.22 (t, J ϭ 7.5 Hz, 1 H, 5-H)
ppm. 13C NMR (CDCl3): δ ϭ 11.7 (CH3), 13.9 (CH3), 109.2 (CH),
112.5 (CH), 124.5 (C), 125.3 (CH), 128.3 (C), 132.6 (C), 140.3 (C),
142.4 (C) ppm. C10H11NS (177.28): calcd. C 67.76, H 6.25, N 7.90,
S 18.09; found C 67.56, H 6.30, N 7.94, S 18.05.
Tos-Ala[N-Boc-β-(4-bromophenylsulfanyl)]-OMe (8a): The pro-
cedure described above was followed using compound
6
(1.50 mmol). Column chromatography gave product 8a (0.690 g,
85%) as a white solid. Recrystallization from petroleum ether gave
1
colorless crystals, m.p. 70.8Ϫ72.6 °C. H NMR (CDCl3): δ ϭ 1.28
(s, 9 H, Boc CH3), 2.45 (s, 3 H, Tos CH3), 3.48 (dd, J ϭ 14.7, 9.3
Hz, 1 H, βCH2), 3.75 (s, 3 H, OCH3), 3.83 (dd, J ϭ 14.7, 4.5 Hz,
1 H, βCH2), 5.22 (dd, J ϭ 9.3, 4.5 Hz, 1 H, αCH), 7.26Ϫ7.45 (m,
6 H, ArH) 7.93 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR
(CDCl3): δ ϭ 21.4 (CH3), 27.5 [C(CH3)3], 35.0 (βCH2), 52.6
(OCH3), 58.5 (αCH), 85.2 [OC(CH3)3], 120.5 (C), 128.6 (CH),
128.8 (CH), 131.8 (CH), 131.8 (CH), 134.3 (C), 136.2 (C), 144.3
(C), 149.7 (CϭO), 169.1 (CϭO) ppm. C22H26BrNO6S2 (544.49):
calcd. C 48.53, H 4.81, N 2.57, S 11.78; found C 48.86, H 4.69, N
2.65, S 11.48.
Boc-(E)-∆Ala[β-(4-bromophenylsulfanyl)]-OMe [(E)-9a]: The pro-
cedure described above was followed using compound
6
(2.58 mmol, 0.920 g). Column chromatography gave product (E)-
9a (0.750 g, 75%) as a white solid. Recrystallization from diethyl
ether/petroleum ether gave colorless crystals, m.p. 115.7Ϫ116.7 °C.
1H NMR (CDCl3): δ ϭ 1.51 (s, 9 H, Boc CH3), 3.80 (s, 3 H,
OCH3), 6.35 (br s, 1 H, αNH), 7.33 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ ArH),
7.34 (s, 1 H, βCH), 7.49 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ ArH) ppm. 13C
NMR (CDCl3):
δ ϭ 28.1 [C(CH3)3], 52.6 (OCH3), 81.2
[OC(CH3)3], 122.3 (C), 122.9 (C), 128.3 (CH), 132.4 (CH), 133.7
(C), 152.4 (CϭO), 163.5 (CϭO) ppm. C15H18BrNSO4 (388.28):
calcd. C 46.40, H 4.67, N 3.61, S 8.26; found C 46.28, H 4.77, N
3.62, S 8.28.
General Procedure for Michael Addition of Nucleophiles to Dehydro-
Amino Acid Derivatives: As described elsewhere,[4a,4b] K2CO3 (6
equiv.) was added to a solution of (unless stated otherwise) the
methyl esters of compounds 5[3] or 6[3] (3 mmol) in acetonitrile
(20 mL), and then the nucleophile (1 equiv.) was added with rapid
stirring at room temperature. The reaction was monitored by 1H
NMR spectroscopy and then, when no starting material was de-
tected, the solution was filtered and the solvents evaporated under
reduced pressure. The residue was chromatographed with a solvent
Boc-(E)-∆Ala[β-(4-aminophenylsulfanyl)]-OMe [(E)-9b]: Column
chromatography using diethyl ether gave product (E)-9b (0.924 g,
95%) as a light-yellow solid. Recrystallization from diethyl ether/
petroleum ether gave light-yellow crystals, m.p. 123.4Ϫ125.1 °C. 1H
NMR (CDCl3) : δ ϭ 1.51 (s, 9 H, CH3 Boc), 3.75 (s, 3 H, OCH3),
3.83 (br s, 2 H, NH2), 6.16 (br s, 1 H, αNH), 6.65 (d, J ϭ 8.7 Hz,
Eur. J. Org. Chem. 2003, 1537Ϫ1544
1541

A. S. Abreu, N. O. Silva, P. M. T. Ferreira, M.-J. R. P. Queiroz
FULL PAPER
2 H, 2 ϫ ArH), 7.29 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ ArH), 7.36 (s, 1 H,
Boc-Ala{N-Boc-β-[4-(2,3-dimethylbenzo[b]thien-7-yl)-
βCH) ppm. 13C NMR (CDCl3): δ ϭ 28.2 [C(CH3)3], 52.3 (OCH3), phenylsulfanyl]}-OMe (13): The procedure described above was fol-
80.9 [OC(CH3)3], 115.6 (CH), 120.68 (C), 121.2 (C), 133.9 (CH),
lowed using compound 7a (0.500 mmol, 0.250 g), with heating for
138.0 (CH), 147.2 (C), 152.5 (CϭO), 163.5 (CϭO) ppm. 5 h. Column chromatography using a solvent gradient, from neat
C15H20N2O4S (324.40): calcd. C 55.54, H 6.21, N 8.64, S 9.88;
found C 55.55, H 6.36, N 8.47, S 9.71.
petroleum ether to 20% diethyl ether/petroleum ether, gave product
13 as a white solid (0.210 g, 72%). Recrystallization from petroleum
ether gave colorless crystals, m.p. 79.5Ϫ80.7 °C. 1H NMR (CDCl3):
δ ϭ 1.48 (s, 18 H, Boc CH3), 2.34 (s, 3 H, ArCH3), 2.49 (s, 3 H,
ArCH3), 3.54 (dd, J ϭ 14.6, 9.9 Hz, 1 H, βCH2), 3.76 (s, 3 H,
OCH3), 3.82 (dd, J ϭ 14.6, 4.5 Hz, 1 H, βCH2), 5.19 (dd, J ϭ 9.9,
4.5 Hz, 1 H, αCH), 7.27 (dd, J ϭ 7.4, 1.2 Hz, 1 H, 4Ј or 6Ј-H),
7.41Ϫ7.49 (m, 3 H, 2 ϫ ArH and 5Ј-H), 7.58 (dd, J ϭ 8.0, 1.2 Hz,
1 H, 6Ј or 4Ј-H), 7.64 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ ArH) ppm. 13C
NMR (CDCl3): δ ϭ 11.5 (CH3), 13.6 (CH3), 27.9 [C(CH3)3], 34.6
(βCH2), 52.4 (OCH3), 57.8 (αCH), 83.4 [OC(CH3)3], 120.2 (CH),
123.5 (CH), 124.6 (CH), 127.4 (C), 128.8 (CH), 129.5 (CH), 134.2
(C), 135.3 (C), 135.3 (C), 136.8 (C), 138.9 (C), 141.7 (C), 151.8 (Cϭ
O), 170.2 (CϭO) ppm. C30H37NO6S2 (571.76): calcd. C 63.02, H
6.52, N 2.45, S 11.21; found C 63.23, H 6.66, N 2.49, S 10.98.
Boc-∆Ala[β-(2,3-dimethylbenzo[b]thienyl-5-sulfanyl)]-OMe [(E)-10]:
The procedure described above was followed using compound 6
(0.500 mmol, 0.180 g). Column chromatography gave product (E)-
10 (0.140 g, 65%) as a white solid. Recrystallization from diethyl
ether/n-hexane gave colorless crystals, m.p. 120.9Ϫ122.5 °C. 1H
NMR (CDCl3): δ ϭ 1.53 (s, 9 H, Boc CH3), 2.29 (s, 3 H, ArCH3),
2.50 (s, 3 H, ArCH3), 3.77 (s, 3 H, OCH3), 6.27 (br s, 1 H, αNH),
7.37 (dd, J ϭ 6.9, 1.5 Hz, 1 H, 6-H), 7.47 (s, 1 H, βCH), 7.71Ϫ7.74
(m, 2 H, 4-H and 7-H) ppm. 13C NMR (CDCl3): δ ϭ 11.3 (CH3),
13.9 (CH3), 28.2 [C(CH3)3], 52.4 (OCH3), 81.0 [OC(CH3)3], 121.5
(C), 122.8 (CH), 124.7 (CH), 126.7 (CH), 126.9 (C), 129.2 (C),
135.7 (C), 136.1 (CH), 138.3 (C), 141.7 (C), 152.5 (CϭO), 163.6
(CϭO) ppm. C19H23NO4S2 (393.52): calcd. C 57.99, H 5.88, N
3.56, S 16.30; found C 58.17, H 5.97, N 3.59, S 15.90.
Boc-Ala{N-Boc-β-[4-(2,3-dimethylbenzo[b]thien-5-yl)-
phenylsulfanyl]}-OMe (14): The procedure described above was fol-
lowed using compound 7a (0.39 mmol, 0.190 g) with heating for
5 h. Column chromatography using a solvent gradient, from neat
petroleum ether to 20% diethyl ether/petroleum ether, gave product
14 as a white solid (0.110 g, 50%). Recrystallization from diethyl
ether gave colorless crystals, m.p. 175.2Ϫ177.2 °C. 1H NMR
(CDCl3): δ ϭ 1.48 (s, 18 H, Boc CH3), 2.35 (s, 3 H, ArCH3), 2.52
(s, 3 H, ArCH3), 3.48Ϫ3.53 (m, 1 H, βCH2), 3.75Ϫ3.82 (m, 4 H,
βCH2 and OCH3), 5.16 (dd, J ϭ 9.8, 4.2 Hz, 1 H, αCH), 7.45Ϫ7.50
(m, 3 H, 2 ϫ ArH and 6Ј-H), 7.59 (d, J ϭ 8.4 Hz, 2 H 2 ϫ ArH),
7.73 (d, J ϭ 1.5 Hz, 1 H, 4Ј-H), 7.79 (d, J ϭ 8.4 Hz, 1 H, 7Ј-H)
ppm. 13C NMR (CDCl3): δ ϭ 11.4 (CH3), 13.9 (CH3), 27.9
[C(CH3)3], 35.2 (βCH2), 52.5 (OCH3), 57.9 (αCH), 83.3
[OC(CH3)3], 119.4 (CH), 122.3 (CH), 122.7 (CH), 127.2 (C), 127.9
(CH), 130.4 (CH), 134.3 (C), 134.7 (C), 136.5 (C), 137.3 (C), 140.1
(C), 141.6 (C), 151.9 (CϭO), 170.3 (CϭO) ppm. C30H37NO6S2
(571.76): calcd. C 63.02, H 6.52, N 2.45, S 11.21; found C 62.71,
H 6.55, N 2.50, S 11.15.
Boc-∆Ala[β-(2,3-dimethylbenzo[b]thienyl-7-sulfanyl)]-OMe [(E)-11]:
The procedure described above was followed using compound 6
(1.20 mmol, 0.430 g). Column chromatography gave product (E)-
11 (0.360 g, 75%) as a white solid. Recrystallization from diethyl
ether/n-hexane gave colorless crystals, m.p. 103.4Ϫ104.9 °C. 1H
NMR (CDCl3): δ ϭ 1.54 (s, 9 H, Boc CH3), 2.31 (s, 3 H, ArCH3),
2.50 (s, 3 H, ArCH3), 3.74 (s, 3 H, OCH3), 6.28 (br s, 1 H, αNH),
7.36 (s, 1 H, βCH), 7.38 (t, J ϭ 7.5 Hz, 1 H, 5-H), 7.46 (dd, J ϭ
7.5, 1.2 Hz, 1 H, 4-H or 6-H), 7.60 (dd, J ϭ 7.5, 1.2 Hz, 1 H, 4-H
or 6-H) ppm. 13C NMR (CDCl3): δ ϭ 11.6 (CH3), 13.8 (CH3), 28.2
[C(CH3)3], 52.4 (OCH3), 81.1 [OC(CH3)3], 121.8 (CH), 122.8 (C),
124.8 (CH), 126.1 (C), 127.9 (C), 128.0 (CH), 133.9 (CH), 135.4
(C), 141.7 (C), 142.0 (C), 152.5 (CϭO), 163.5 (CϭO) ppm.
C19H23NS2O4 (393.52): calcd. C 57.99, H 5.88, N 3.56, S 16.30;
found C 57.97, H 6.04, N 3.58, S 15.95.
General Procedure for the Suzuki Reaction: Compounds 7a, 7c, 8a,
and (E)-9a were coupled with several boronic acids (Table 2) (1.3
equiv.) using Pd(PPh3)4 (10 mol %) and Na2CO3 (2 equiv.) in
DME/water (10:1) at 90 °C. The reactions were monitored by TLC,
which determined the different reaction times. After cooling, water
and ethyl acetate were added and then the phases were separated.
The organic phase was washed with brine, dried (MgSO4), filtered,
and the solvent was evaporated to give a brown oil that was sub-
jected to column chromatography.
Boc-(E)-∆Ala{β-[4-(benzo[b]thien-3-yl)phenylsulfanyl]}-OMe [(E)-
15]: The procedure described above was followed using compound
(E)-9a (0.390 mmol, 0.150 g) with heating for 4 h. Column chroma-
tography using a solvent gradient, from neat petroleum ether to
20% diethyl ether/petroleum ether, gave product (E)-15 (0.150 g,
85%) as a white solid. Recrystallization from diethyl ether/n-hexane
gave colorless crystals, m.p. 98.9Ϫ100.0 °C. 1H NMR (CDCl3): δ ϭ
1.54 (s, 9 H, Boc CH3), 3.82 (s, 3 H, OCH3), 6.36 (br s, 1 H, αNH),
7.40Ϫ7.44 (m, 3 H, ArH), 7.51 (s, 1 H, βCH), 7.60 (br s, 4 H,
ArH) 7.89Ϫ7.96 (m, 2 H, ArH) ppm. 13C NMR (CDCl3): δ ϭ 28.2
[C(CH3)3], 52.5 (OCH3), 81.1 [OC(CH3)3], 122.6 (CH), 123.0 (CH),
124.0 (CH), 124.5 (CH), 124.5 (CH), 129.4 (CH), 131.2 (CH), 133.6
(C), 135.8 (C), 136.8 (C), 137.5 (C), 140.7 (C), 152.4 (CϭO), 163.6
(CϭO) ppm. C23H23NO4S2 (441.58): calcd. C 62.56, H 5.25, N
3.17, S 14.52; found C 62.20, H 5.35, N 3.07, S 14.57.
Boc-Ala{N-Boc-β-[4-(benzo[b]thien-3-yl)phenylsulfanyl]}-OMe (12):
The procedure described above was followed using compound 7a
(0.500 mmol, 0.250 g) and heating for 2 h 30 min. Column chroma-
tography using a solvent gradient, from neat petroleum ether to
20% diethyl ether/petroleum ether, gave product 12 as a white solid
(0.260 g, 95%). Recrystallization from diethyl ether/n-hexane gave
colorless crystals, m.p. 110.0Ϫ110.8 °C. 1H NMR (CDCl3): δ ϭ
1.48 (s, 18 H, Boc CH3), 3.54 (dd, J ϭ 14.4, 9.9 Hz, 1 H, βCH2),
3.76 (s, 3 H, OCH3), 3.82 (dd, J ϭ 14.4, 4.5 Hz, 1 H, βCH2), 5.18 Boc-(E)-∆Ala{β-[4-(benzo[b]thien-3-yl)phenylsulfanyl]}-OMe [(E)-
(dd, J ϭ 9.9, 4.5 Hz, 1 H, αCH), 7.38Ϫ7.42 (m, 3 H, ArH), 15] and Boc-(Z)-∆Ala{β-[4-(benzo[b]thien-3-yl)phenylsulfanyl]}-
7.48Ϫ7.55 (m, 4 H, ArH), 7.87Ϫ7.95 (m, 2 H, ArH) ppm. 13C OMe [(Z)-15]: The procedure described above was followed using
NMR (CDCl3): δ ϭ 27.9 [C(CH3)3], 34.8 (βCH2), 52.5 (OCH3), compound 8a (0.500 mmol, 0.270 g) and benzo[b]thiophene 3-bo-
57.8 (αCH), 83.4 [OC(CH3)3], 122.8 (CH), 122.9 (CH), 123.4 (CH), ronic acid (1.1 equiv.) in DME/H2O (6:1), with heating for 5 h.
124.4 (CH), 124.4 (CH), 129.2 (CH), 130.0 (CH), 134.2 (C), 135.0 Column chromatography using a solvent gradient, from neat petro-
(C), 137.3 (C), 137.7 (C), 140.6 (C), 151.8 (CϭO), 170.2 (CϭO) leum ether to 10% diethyl ether/petroleum ether, gave compound
ppm. C28H33NO6S2 (543.71): calcd. C 61.83, H 6.12, N 2.58, S
11.79; found C 62.11, H 6.27, N 2.57, S 11.72.
(Z)-15 (0.0260 g, 12%), as an oil, as the less-polar product {1H
NMR (CDCl3): δ ϭ 1.49 (s, 9 H, Boc CH3), 3.94 (s, 3 H, OCH3),
1542
Eur. J. Org. Chem. 2003, 1537Ϫ1544

Synthesis of Novel Amino Acids and Dehydroamino Acids
FULL PAPER
1
6.80 (br s, 1 H, αNH), 7.40Ϫ7.43 (m, 3 H, ArH), 7.59 (d, J ϭ 8.7 as a light-yellow oil, which failed all attempts to crystallize it. H
Hz, 2 H, 2 ϫ ArH), 7.64 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ ArH), 7.90Ϫ7.97 NMR (CDCl3): δ ϭ 1.44 (s, 18 H, ArCH3, Boc), 2.34 (s, 3 H,
(m, 2 H, ArH), 8.07 (br s, 1 H, βCH) ppm} followed by (E)-15 as
a white solid (0.110 g, 48%) with spectroscopic data identical to
those described above.
ArCH3), 2.48 (s, 3 H, ArCH3), 3.40Ϫ3.58 (m, 2 H, βCH2), 3.73 (s,
3 H, OCH3), 4.38Ϫ4.76 (m, 3 H, αCH and CH2), 5.64 (br d, 1 H,
J ϭ 6.6 Hz, NH), 7.22Ϫ7.34 (m, 2 H, ArH), 7.41Ϫ7.49 (m, 2 H,
ArH), 7.55Ϫ7.65 (m, 3 H, ArH) ppm. 13C NMR (CDCl3): δ ϭ
11.5 (CH3), 13.6 (CH3), 28.3 [C(CH3)3], 47.5 (CH2), 51.0 (CH2),
52.5 (OCH3), 52.9 (αCH), 80.6 [OC(CH3)3], 120.2 (CH), 123.6
(CH), 124.6 (CH), 126.6 (CH), 126.9 (CH), 127.2 (CH), 128.9
(CH), 134.1 (C), 135.1 (C), 135.7 (C), 136.8 (C), 138.3 (C), 141.2
(C), 141.7 (C), 155.4 (CϭO), 171.5 (CϭO) ppm. C31H40N2O6S
HMRS (FAB) [M ϩ H]ϩ found (calcd.) 569.2677 (569.2685).
Boc-(E)-∆Ala{β-[4-(2,3-dimethylbenzo[b]thien-7-yl)phenylsulfanyl]}-
OMe [(E)-16]: The procedure described above was followed using
compound (E)-9a (0.390 mmol, 0.150 g) with heating for 4 h. Col-
umn chromatography using a solvent gradient, from neat petroleum
ether to 30% diethyl ether/petroleum ether, gave product (E)-16 as
a white solid (0.160 g, 86%). Recrystallization from diethyl ether/
petroleum ether gave colorless crystals, m.p. 133.7Ϫ134.4 °C. 1H
NMR (CDCl3): δ ϭ 1.54 (s, 9 H, Boc CH3), 2.35 (s, 3 H, ArCH3), General Procedure for C؊N Coupling: A dried Schlenk tube was
2.50 (s, 3 H, ArCH3), 3.82 (s, 3 H, OCH3), 6.31 (br s, 1 H, αNH), charged under Ar with dry toluene (2 mL), the bromo compound
7.30 (dd, J ϭ 7.5, 0.9 Hz, 1 H, 4Ј-H or 6Ј-H), 7.46 (t, J ϭ 7.5 Hz, was added and the mixture heated for 10 min at 80 °C. Pd(OAc)2
1 H, 5Ј-H), 7.53 (s, 1 H, βCH), 7.57Ϫ7.62 (m, 3 H, 2 ϫ ArH and
(10 mol %), BINAP (15 mol %), and Cs2CO3 (1.4 equiv.) were ad-
ded and the mixture was heated for another 10 min at 80 °C. The
6Ј-H or 4Ј-H), 7.72 (d, J ϭ 8.1 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR
(CDCl3): δ ϭ 11.5 (CH3), 13.7 (CH3), 28.2 [C(CH3)3], 52.5 (OCH3), amine was added in dry toluene (2 mL) and the mixture was heated
81.1 [OC(CH3)3], 120.5 (CH), 123.6 (CH), 124.7 (CH), 127.5 (C), with stirring at 100 °C under Ar for ca. 5 h (Table 3). The reactions
129.0 (CH), 131.1 (CH), 133.7 (CH), 134.3 (C), 134.9 (C), 136.7
were monitored by TLC and stopped when no amino acid seemed
(C), 140.7 (C), 141.8 (C), 152.5 (CϭO), 163.6 (CϭO) ppm. to be present. Water and diethyl ether were added, the phases were
C25H27NO4S2 (469.63): calcd. C 63.94, H 5.79, N 2.98, S 13.65;
found C 63.78, H 5.87, N 3.06, S 13.45.
separated, and then the aqueous phase was washed with diethyl
ether (3 ϫ 10 mL). The organic phase was collected, dried
(MgSO4), filtered, and then the solvent was evaporated to give a
brown oil, which was subjected to column chromatography after
traces of toluene were evaporated using MeOH. Solvent gradient
was used from neat petroleum to 30% diethyl ether/petroleum ether.
Boc-(E)-∆Ala{β-[4-(2,3-dimethylbenzo[b]thien-5-yl)phenylsulfanyl]}-
OMe [(E)-17]: The procedure described above was followed using
compound (E)-9a (0.390 mmol, 0.150 g), with heating for 7 h. Col-
umn chromatography using a solvent gradient, from neat petroleum
ether to 30% diethyl ether/petroleum ether, gave product (E)-17
(0.100 g, 55%) as a white solid. Recrystallization from diethyl ether/
petroleum ether gave colorless crystals, m.p. 75.0Ϫ76.2 °C. 1H
Boc-Ala{N-Boc-β-[4-amino-(2,3-dimethylbenzo[b]thien-7-yl)-
phenylsulfanyl]}-OMe (20): The procedure described above was fol-
lowed using compound 7a (0.400 mmol, 0.200 g) and amine 4b (1
NMR (CDCl3): δ ϭ 1.53 (s, 9 H, Boc CH3), 2.35 (s, 3 H, ArCH3), equiv.). Column chromatography gave product 20 as a light-yellow
2.52 (s, 3 H, ArCH3), 3.81 (s, 3 H, OCH3), 6.32 (br s, 1 H, αNH),
solid (0.140 g, 60%). Recrystallization from diethyl ether/petroleum
7.49 (dd, J ϭ 8.1, 1.2 Hz, 1 H, 6Ј-H), 7.50 (s, 1 H, βCH), 7.57 (d, ether gave light-yellow crystals, m.p. 97.8Ϫ99.7 °C. 1H NMR
J ϭ 8.4 Hz, 2 H, 2 ϫ ArH), 7.67 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ ArH), (CDCl3): δ ϭ 1.49 (s, 18 H, Boc CH3), 2.31 (s, 3 H, ArCH3), 2.49
7.76 (d, J ϭ 1.2 Hz, 1 H, 4Ј-H), 7.81 (dd, J ϭ 8.1, 1.2 Hz, 1 H, 7Ј-
H) ppm. 13C NMR (CDCl3): δ ϭ 11.4 (CH3), 13.9 (CH3), 28.2 J ϭ 14.4, 4.5 Hz, 1 H, βCH2), 3.72 (s, 3 H, OCH3), 5.09 (dd, J ϭ
[C(CH3)3], 52.5 (OCH3), 81.1 [OC(CH3)3], 119.5 (CH), 122.3 (CH), 9.9, 4.5 Hz, 1 H, αCH), 5.61 (br s, 1 H, NH), 6.95 (d, J ϭ 8.7 Hz,
122.7 (CH), 127.2 (C), 128.2 (CH), 131.4 (CH), 132.9 (C), 134.2 2 H, 2 ϫ ArH), 7.14Ϫ7.18 (m, 1 H, 6Ј-H), 7.29Ϫ7.32 (m, 2 H, 4Ј
(CH), 134.8 (C), 136.0 (C), 137.6 (C), 141.5 (C), 141.6 (C), 152.5
and 5Ј-H), 7.36 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR
(CϭO), 163.6 (CϭO) ppm. C25H27NO4S2 (469.63): calcd. C 63.94, (CDCl3): δ ϭ 11.6 (CH3), 13.8 (CH3), 27.9 [C(CH3)3], 37.1 (βCH2),
(s, 3 H, ArCH3), 3.38 (dd, J ϭ 14.4, 9.9 Hz, 1 H, βCH2), 3.63 (dd,
H 5.79, N 2.98, S 13.65; found C 63.56, H 5.90, N 3.04, S 13.68.
52.3 (OCH3), 57.9 (αCH), 83.2 [OC(CH3)3], 113.5 (CH), 115.9
(CH), 117.8 (CH), 124.9 (CH), 125.4 (C), 128.1 (C), 130.2 (C),
133.1 (C), 133.5 (CH), 136.4 (C), 142.7 (C), 142.9 (C), 151.9 (Cϭ
O), 170.3 (CϭO) ppm. C30H38N2O6S2 (586.78): calcd. C 61.41, H
6.53, N 4.77, S 10.93; found C 61.35, H 6.51, N 4.72, S 10.40.
Boc-Ala{N-Boc-β-[3-(benzo[b]thien-3-yl)benzylamino]}-OMe (18):
The procedure described above was followed using compound 7c
(0.280 mmol, 0.150 g) with heating for 7 h. Column chromatogra-
phy using a solvent gradient, from neat petroleum ether to 30%
diethyl ether/petroleum ether, gave product 18 (0.110 g, 71%) as an
Compound 20 was also obtained following the same procedure by
oil, which failed all attempts to crystallize it. 1H NMR (CDCl3): using compound 7b (0.380 mmol, 0.160 g) and 1b (1.5 equiv.). Col-
δ ϭ 1.44 (s, 18 H, Boc CH3), 3.42Ϫ3.56 (m, 2 H, βCH2), 3.73 (s, umn chromatography gave product 20 as a light-yellow solid
3 H, OCH3), 4.40Ϫ4.72 (m, 3 H, αCH and CH2), 5.61 (br s, 1 H, (0.120 g, 52%) which displayed identical spectroscopic data to those
NH), 7.36Ϫ7.54 (m, 7 H, ArH), 7.86Ϫ7.97 (m, 2 H, ArH) ppm.
13C NMR (CDCl3): δ ϭ 28.2 [C(CH3)3], 47.5 (CH2), 51.0 (CH2),
52.4 (OCH3), 52.8 (αCH), 80.6 [OC(CH3)3], 122.7 (CH), 122.8
(CH), 123.5 (CH), 124.3 (CH), 124.4 (CH), 126.3 (CH), 127.7
(CH), 129.0 (CH), 136.2 (C), 137.6 (C), 138.0 (C), 138.4 (C), 140.6
(C), 155.3 (CϭO), 171.4 (CϭO) ppm. C29H36N2O6S HMRS (FAB)
[M ϩ H]ϩ found (calcd.) 541.2386 (541.2372).
described above.
Boc-Ala{N-Boc-β-[4-amino-(2,3-dimethylbenzo[b]thien-5-yl)-
phenylsulfanyl]}-OMe (21): The procedure described above was fol-
lowed using compound 7b (0.500 mmol, 0.210 g) and 1a (1.5
equiv.). Column chromatography gave product 21 as a light-brown
solid (0.160 g, 55%). Recrystallization from diethyl ether/petroleum
1
ether gave beige crystals, m.p. 98.8Ϫ100.5 °C. H NMR (CDCl3):
Boc-Ala{N-Boc-β-[3-(2,3-dimethylbenzo[b]thien-7-yl)benzylamino]}-
OMe (19): The procedure described above was followed using com-
pound 7c (0.300 mmol, 0.160 g) with heating for 7 h. Column chro-
δ ϭ 1.50 (s, 18 H, Boc CH3), 2.24 (s, 3 H, ArCH3), 2.48 (s, 3 H,
ArCH3), 3.37 (dd, J ϭ 14.4, 9.9 Hz, 1 H, βCH2), 3.61 (dd, J ϭ
14.4, 4.5 Hz, 1 H, βCH2), 3.71 (s, 3 H, OCH3), 5.08 (dd, J ϭ 9.9,
matography using a solvent gradient, from neat petroleum ether to 4.5 Hz, 1 H, αCH), 5.78 (br s, 1 H, NH), 6.96 (d, J ϭ 8.7 Hz, 2
30% diethyl ether/petroleum ether, gave product 19 (0.090 g, 50%)
Eur. J. Org. Chem. 2003, 1537Ϫ1544
H, 2 ϫ ArH), 7.05 (dd, J ϭ 8.4, 1.8 Hz, 1 H, 6Ј-H), 7.32 (d, J ϭ
1543

A. S. Abreu, N. O. Silva, P. M. T. Ferreira, M.-J. R. P. Queiroz
FULL PAPER
1.8 Hz, 1 H, 4Ј-H), 7.35 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ ArH), 7.63 (d,
J ϭ 8.4 Hz, 1 H, 7Ј-H) ppm. 13C NMR (CDCl3): δ ϭ 11.4 (CH3),
13.9 (CH3), 27.9 [C(CH3)3], 37.3 (βCH2), 52.4 (OCH3), 57.9 (αCH),
83.2 [OC(CH3)3], 111.8 (CH), 116.6 (CH), 117.5 (CH), 122.6 (CH),
124.4 (C), 126.7 (C), 132.0 (C), 133.9 (CH), 135.0 (C), 138.7 (C),
142.1 (C), 144.2 (C), 152.0 (CϭO), 170.4 (CϭO) ppm.
C30H38N2O6S2 (586.78): calcd. C 61.41, H 6.53, N 4.77, S 10.93;
found C 61.57, H 6.69, N 4.84, S 10.58.
Acknowledgments
We thank the Foundation for Science and Technology (Portugal)
for financial support to IBQF-Univ. Minho, project POCTI/99/
QUI/32689 (also financial support to N. O. S.) and to SFRH/BD/
4709/2001 for financial support of the PhD of A. S. Abreu.
[1] [1a]
U. Schmidt, A. Lieberknecht, J. Wild, Synthesis 1988,
[1b]
159Ϫ171.
G. Jung, Angew. Chem. 1991, 103, 1067Ϫ1084;
Boc-(E)-∆Ala{β-[4-amino(2,3-dimethylbenzo[b]thien-7-yl)-
phenylsulfanyl]}-OMe [(E)-22] and Boc-(Z)-∆Ala{β[-4-amino(2,3-di-
methylbenzo[b]thien-7-yl)phenylsulfanyl]}-OMe [(Z)-22]: The pro-
cedure described above was followed using compound (E)-9b
(0.310 mmol, 0.100 g) and 1b (1.5 equiv.). Column chromatography
gave (Z)-22 as a light-yellow solid (0.200 g, 14%) as the less-polar
product. Recrystallization from diethyl ether/petroleum ether gave
light-yellow crystals, m.p. 133.4Ϫ134.4 °C. 1H NMR (CDCl3): δ ϭ
1.47 (s, 9 H, Boc CH3), 2.32 (s, 3 H, ArCH3), 2.50 (s, 3 H, ArCH3),
3.91 (s, 3 H, OCH3), 5.71 (br s, 1 H, NH), 6.68 (br s, 1 H, αNH),
6.98 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ ArH), 7.19Ϫ7.23 (m, 1 H, 6Ј-H),
7.30Ϫ7.38 (m, 2 H, 5Ј and 4Ј-H), 6.98 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ
ArH), 7.41 (d, J ϭ 8.7 Hz, 2 H, 2 ϫ ArH), 7.87 (br s, 1 H, βCH)
ppm. 13C NMR (CDCl3): δ ϭ 11.7 (CH3), 13.9 (CH3), 28.3
[C(CH3)3], 52.4 (OCH3), 80.5 [OC(CH3)3], 114.3 (CH), 116.3 (CH),
117.6 (CH), 118.6 (C), 125.0 (CH), 126.4 (C), 128.2 (C), 132.9
(CH), 133.3 (C), 136.1 (C), 142.8 (C), 143.7 (C), 152.9 (CϭO),
163.6 (CϭO) ppm. C25H28N2O4S2 (484.65): calcd. C 61.96, H 5.82,
N 5.78, S 13.23; found C 61.90, H 6.12, N 5.64, S 12.81. Product
(E)-22 eluted next and was isolated as a white solid (0.500 g, 35%).
Recrystallization from ethyl acetate/diethyl ether gave colorless
crystals, m.p. 192.8Ϫ194.3 °C. 1H NMR (CDCl3): δ ϭ 1.52 (s, 9
H, Boc CH3), 2.32 (s, 3 H, ArCH3), 2.50 (s, 3 H, ArCH3), 3.77 (s,
3 H, OCH3), 5.71 (br s, 1 H, NH), 6.20 (br s, 1 H, αNH), 6.96 (d,
J ϭ 8.7 Hz, 2 H, 2 ϫ ArH), 7.20 (dd, J ϭ 6.9, 1.8 Hz, 1 H, 6Ј-H),
7.30Ϫ7.40 (m, 5 H, βCH, 2 ϫ ArH, 4Ј and 5Ј-H) ppm. 13C NMR
(CDCl3): δ ϭ 11.6 (CH3), 13.8 (CH3), 28.1 [C(CH3)3], 52.3 (OCH3),
80.9 [OC(CH3)3], 114.8 (CH), 116.6 (CH), 117.2 (CH), 121.0 (C),
123.6 (C), 124.9 (CH), 128.1 (C), 131.1 (C), 133.4 (CH), 135.7 (C),
137.2 (CH), 142.8 (C), 144.2 (C), 152.5 (CϭO), 163.6 (CϭO) ppm.
C25H28N2O4S2 (484.65): calcd. C 61.96, H 5.82, N 5.78, S 13.23;
found C 61.70, H 5.81, N 5.71, S 12.76.
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Received October 23, 2002
[O02591]
1544
Eur. J. Org. Chem. 2003, 1537Ϫ1544