Synthesis using Suzuki cross couplings of sulfur analogues of dehydrotryptophan with a definite stereochemistry

Article abstract of DOI:10.1002/1099-0690(200208)2002:15<2524::AID-EJOC2524>3.0.CO;2-W

Sulfur analogues of dehydrotryptophan (5-7) were prepared in moderate to good yields (40-80%) by Suzuki cross coupling [Pd(PPh₃)₄, Na₂CO₃ or NaHCO₃, DME/H₂O, 90°C] of several benzo[b]thioph

Full text of DOI:10.1002/1099-0690(200208)2002:15<2524::AID-EJOC2524>3.0.CO;2-W

FULL PAPER
Synthesis Using Suzuki Cross Couplings of Sulfur Analogues of
Dehydrotryptophan with a Definite Stereochemistry
[a]
[a]
[a]
[a]
´
´
Natalia O. Silva, Ana S. Abreu, Paula M. T. Ferreira, Luıs S. Monteiro, and
[a]
˜
Maria-Joao R. P. Queiroz*
Keywords: Amino acids / Sulfur heterocycles / Suzuki coupling / Stereoisomerism
Sulfur analogues of dehydrotryptophan (5−7) were prepared
and N-bromosuccinimide (NBS) in two steps or in a one-pot
in moderate to good yields (40−80%) by Suzuki cross coup- procedure. Both procedures were stereoselective for the E-
ling [Pd(PPh3)4, Na2CO3 or NaHCO3, DME/H2O, 90 °C] of
several benzo[b]thiophene boronic acids with the methyl
esters of N-tert-butyloxycarbonyl-β-bromodehydroalanine
isomer of Boc-∆Ala(β-Br)-OMe. However, for Boc-∆Abu(β-
Br)-OMe, different ratios of E/Z isomers were obtained in
each procedure. The stereoselectivity for the Z-isomer was
[Boc-∆Ala(β-Br)-OMe] or N-tert-butyloxycarbonyl-β-bromo- increased greatly with the one-pot procedure. Pure isomers
dehydroaminobutyric acid [Boc-∆Abu(β-Br)-OMe]. The β-
bromodehydroamino acid precursors 2 were, in turn, synthe-
were used in the coupling reactions and the stereochemistry
of the starting material was generally maintained.
sized in high yields from the corresponding N,N-diacyldehy- ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
droamino acids 1 by treatment with trifluoroacetic acid (TFA)
2002)
Introduction
tion with benzo[b]thiophene derivatives to obtain new sul-
fur analogues of dehydrotryptophan. This coupling reac-
tion was chosen because it is one of the most powerful and
versatile methods for CϪC bond formation as it: (i) toler-
ates a broad range of functionalities, (ii) can be performed
under mild conditions, and (iii) usually maintains the ste-
reochemistry of the starting material.[5]
The insertion of non-proteinogenic conformationally
constrained amino acids into bioactive peptides has proven
to be a powerful tool in the elucidation of ligand-receptor
binding interactions and in peptidomimetic design.[1] Dehy-
droamino acids are among one of the most interesting
classes of compounds that can be used for this purpose.
These compounds are also found in several peptide antibi-
otics and are important substrates for the synthesis of novel
amino acids through enantioselective catalytic hydrogena-
tion.[2] Although several methods have been described for
their preparation, dehydroamino acids remain a challenging
group of target molecules. Recently we have developed an
efficient method for the stereoselective synthesis of the Z-
isomers of N,N-diacyldehydroamino acid derivatives from
the corresponding β-hydroxyamino acids.[3] These com-
pounds have proved to be versatile substrates in Michael
addition reactions, allowing the preparation of several new
β-substituted amino acids and also β-substituted dehy-
droamino acids. By this method it was possible to obtain
several tryptophan and dehydrotryptophan analogues using
N-unprotected indoles as nucleophiles.[4]
Results and Discussion
The Z-isomers of the methyl ester of N,N-diacyldehyd-
roamino acids 1, obtained from the corresponding β-hydro-
xyamino acids,[3] were N-monodeprotected and brominated
in high yields to give β-bromo dehydroamino acids 2, using
TFA and NBS either in two separate steps or in a one-pot
procedure (Scheme 1). The latter gave slightly higher yields.
In the case of Boc-∆Ala(β-Br)-OMe, using both methods,
only the E-isomer was obtained. Other authors have re-
ported the formation of only the Z-isomer when the amine
function is monoprotected either with acetyl[6] or with
methyloxycarbonyl[7] groups. Our result could be due to the
steric hindrance produced by the bulky Boc group. Mix-
tures of E/Z isomers were obtained in the synthesis of Boc-
∆Abu(β-Br)-OMe, with increased stereoselectivity for the
Z-isomer, when the deprotection and bromination were car-
ried out in a one-pot procedure (Scheme 1). This could re-
sult from the presence of TFA in the reaction mixture. The
ratio of E/Z isomers obtained using the two step procedure
(1:1) is in agreement with the bromination performed by
Here we report the use of our readily available N,N-di-
acyldehydroamino acid derivatives, after N-monodeprotec-
tion and β-bromination, in the Suzuki cross coupling reac-
[a]
´
Departamento de Quımica-Universidade do Minho
4700Ϫ320 Braga Portugal
Fax: (internat.) ϩ351-25/367-8983
E-mail: mjrpq@quimica.uminho.pt
2524
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0815Ϫ2524 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2524Ϫ2528

Suzuki Cross Couplings of Sulfur Analogues of Dehydrotryptophan
FULL PAPER
Hoerrner et al.[8] on the methyl ester of N-acetyldehydroam-
inobutyric acid. The isomers were separated by column
chromatography and the stereochemistry was determined
using differential NOE enhancements between the β (∆Ala)
or γ protons (∆Abu) and the αNH.
Scheme 1
Scheme 3. i) DME/H2O, Pd(PPh3)4 (10 mol %), Na2CO3 or
NaHCO3 (2 equiv.), 90 °C
The pure β-bromodehydroamino acids (E)-2a and (E)- or
(Z)-2b were prepared in order to be coupled under Suzuki
coupling conditions with the commercially available
benzo[b]thiophene 2- and 3-boronic acids and also with 7-
boronic-2,3-dimethylbenzo[b]thiophene acid (4). The latter
was prepared in order to study the reactivity of the benzene
ring of the benzo[b]thiophene system, to which less atten-
tion has been paid. Compound 4 was obtained from 7-
bromo-2,3-dimethylbenzo[b]thiophene (3) by halogen-li-
thium exchange, followed by boron transmetallation and
treatment with acid (Scheme 2). Compound 3 was synthe-
sized from 2-bromothiophenol and 3-bromobutan-2-one
using 30% NaOH in the first step and polyphosphoric acid
(PPA) in the cyclodehydration step (Scheme 2).[9]
Table 1. Yields of the coupled products
Benzo[b]thiophene ∆aa
Base, time
Product Yield (%)
3-boronic acid
2-boronic acid
4
(E)-2a Na2CO3, 4 h
(E)-2b Na2CO3, 7 h
(E)-5a
(E)-5b
72
52
62
(Z)-2b NaHCO3, 5 h (Z)-5b
(E)-2a Na2CO3, 4 h (E)-6a
(E)-2b NaHCO3, 4 h (E)-6b
(Z)-2b NaHCO3, 6 h (Z)-6b
81
61
47
(E)-2a Na2CO3, 4 h
(E)-2b NaHCO3,
7 h 30 min
(E)-7a
(E)-7b
40
61
(Z)-7b
(Z)-7b
7
70
(Z)-2b NaHCO3,
5 h 30 min
(Z)-7b were isolated in a ratio of 9:1. This could be due to
base-catalysed isomerization[10] to the thermodynamically
more stable Z-isomer, since a longer reaction time was
needed (7.5 h). With (Z)-2b as starting material, and under
the same reaction conditions, no isomerization occurred
and (Z)-7b was isolated in 70% yield after 5.5 h (Table 1). In
both cases 2,3-dimethyl-7-hydroxybenzo[b]thiophene[9] was
also isolated in 11% yield.
As in the case of the starting materials, the stereochem-
istry of the coupled products was determined by NOE ex-
periments. For dehydroaminobutyric acid derivatives the
proton chemical shifts (in CDCl3) of the methyl ester
(OMe) and of the γ protons (Me) of the Z-isomers always
appear at higher values than those of the E-isomers
(Table 2).
Scheme 2
The Suzuki coupling reactions were performed in DME/
water (4:1) using NaHCO3 (2 equiv.), or in DME and aque-
ous 2  Na2CO3 (2 equiv.).[8] In both cases Pd(PPh3)4 (10
mol %) was used as the palladium catalyst at 90 °C for be-
tween 4 and 7.5 h (Scheme 3, Table 1).
The coupled products were obtained in moderate to good
yields (Table 1); the corresponding deboronated benzo[b]-
thiophenes were also isolated in small amounts (10Ϫ15%
yield). The results show a similar reactivity of both rings of
the benzo[b]thiophene system and of both β-bromo dehy-
droamino acid derivatives.
Conclusion
The stereochemistry of Boc-∆Ala(β-Br)-OMe and Boc-
∆Abu(β-Br)-OMe was maintained, except in the case of the
The Suzuki coupling reaction was applied successfully to
coupling of compound 4 with (E)-2b, in which (E)-7b and the synthesis of both E and Z isomers of several sulfur ana-
Eur. J. Org. Chem. 2002, 2524Ϫ2528
2525

N. O. Silva, A. S. Abreu, P. M. T. Ferreira, L. S. Monteiro, M.-J. R. P. Queiroz
FULL PAPER
Table 2. 1H NMR chemical shifts (CDCl3) of the OMe and Me
groups of coupled ∆Abu derivatives
Bromination of the Methyl Esters of N-tert-butyloxycarbonyldehyd-
roamino Acids
Synthesis of Boc-(E)-∆Ala(β-Br)-OMe [(E)-2a]: Boc-∆Ala-OMe
(1.01 g, 5 mmol) was dissolved in dichloromethane (0.1 ) and 1.2
equiv. of N-bromosuccinimide were added with vigorous stirring.
After reacting for 16 hours, triethylamine (1.5 equiv.) was added
and stirring continued for an additional hour. The solvent was then
evaporated at reduced pressure and the residue partitioned between
100 mL of dichloromethane and 50 mL of KHSO4 (1 ). The or-
ganic phase was washed with KHSO4 (1 ), NaHCO3 (1 ) and
brine (3 ϫ 30 mL each). After drying over MgSO4 the extract was
taken to dryness at reduced pressure to afford (E)-2a (1.15 g, 82%)
as a colourless oil. 1H NMR (CDCl3): δ ϭ 1.47 (s, 9 H, CH3 Boc),
3.82 (s, 3 H, OCH3), 6.19 (broad s, 1 H, αNH), 6.87 (s, 1 H, βCH)
ppm. 13C NMR (CDCl3): δ ϭ 27.78 [C(CH3)3], 52.78 (OCH3),
81.61 [OC(CH3)3], 109.17 (CH), 132.50 (C), 151.83 (CϭO), 162.70
(CϭO) ppm.
Compound
δ OMe
δ Me
(E)-5b
(Z)-5b
(E)-6b
(Z)-6b
(E)-7b
(Z)-7b
3.34
3.90
3.59
3.87
3.37
3.89
2.19
2.30
2.21
2.45
2.21
2.27
logues of dehydrotryptophan. In this study the couplings
were performed using benzo[b]thiophenes functionalized
either on the thiophene or on the benzene ring. In general
the stereochemistry of the β-bromo dehydroamino acid
derivatives was maintained.
Both stereoisomers of the coupled products obtained
could be useful in structure-activity relationship studies
aimed at elucidating the biologically active conformation of
peptides and also in the development of new molecules of
pharmaceutical interest.
Synthesis of Boc-∆Abu(β-Br)-OMe [(E)-2b and (Z)-2b]: The same
procedure as described above was followed, substituting Boc-∆Ala-
OMe for Boc-∆Abu-OMe (1.08 g, 5 mmol) to give a 1:1 mixture of
(E)-2b and (Z)-2b (1.35 g, 92%). The diastereomers were separated
by column chromatography using 30% diethyl ether/petroleum
ether as eluent.
(E)-2b: M.p. 108.0Ϫ109.0 °C (from diethyl ether/n-hexane). 1H
NMR (CDCl3): δ ϭ 1.46 (s, 9 H, CH3 Boc), 2.41 (s, 3 H, γCH3),
3.82 (s, 3 H, OCH3), 6.00 (broad s, 1 H, αNH) ppm. 13C NMR
(CDCl3): δ ϭ 25.54 (CϭCCH3), 28.02 [C(CH3)3], 52.19 (OCH3),
81.21 [OC(CH3)3], 121.95 (C), 126.23 (C), 152.63 (CϭO), 164.45
(CϭO) ppm. C10H16BrNO4 (294.1): calcd. C 40.83, H 5.44, N 4.76;
found C 40.92, H 5.43, N 4.88.
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-
(Z)-2b: M.p. 75.5Ϫ77.0 °C (from n-hexane). 1H NMR (CDCl3):
δ ϭ 1.46 (s, 9 H, CH3 Boc), 2.52 (s, 3 H, γCH3), 3.83 (s, 3 H,
OCH3), 6.23 (broad s, 1 H, αNH) ppm. 13C NMR (CDCl3): δ ϭ
24.43 (CϭCCH3), 28.00 [C(CH3)3], 52.42 (OCH3), 81.46
[OC(CH3)3], 120.40 (C), 127.33 (C), 152.31 (CϭO), 163.17 (CϭO)
ppm. C10H16BrNO4 (294.1): calcd. C 40.83, H 5.44, N 4.76; found
C 41.19, H 5.52, N 4.81.
spin decoupling techniques were used to assign the signals. The 13
C
NMR spectra were measured on the same instrument at 75.4 MHz
(using DEPT θ 45°). Elemental analyses were determined on a
LECO CHNS 932 elemental analyser.
Column chromatography was performed on MachereyϪNagel sil-
ica gel 230Ϫ400 mesh. Petroleum ether refers to the boiling range
40Ϫ60 °C. When a solvent gradient was used the increase of polar-
ity was done gradually from petroleum ether to mixtures of diethyl
ether/petroleum ether increasing the amount of diethyl ether by
10% until the isolation of the product.
One-Pot Procedure for Synthesis of the β-Bromo N-tert-butyloxycar-
bonyldehydroamino Acid Methyl Esters
Synthesis of Boc-(E)-∆Ala(β-Br)-OMe [(E)-2a]: Boc2-∆Ala-OMe
(1.51 g, 5 mmol) was dissolved in dichloromethane (0.1 ) and 2%
of TFA was added slowly with vigorous stirring. The reaction was
monitored by TLC and when no starting material was detected (ca.
1 hour) 1.2 equiv. of N-bromosuccinimide was added. After re-
acting for 16 hours triethylamine (3 equiv.) was added and stirring
continued for an additional hour. The solvent was then evaporated
at reduced pressure and the product (E)-2a (1.25 g, 89%) was isol-
ated as an oil, according to the procedure given above.
Preparation of the Methyl Esters of N,N-bis(tert-butyloxycarbonyl)-
dehydroamino Acids
Synthesis of Boc2-∆Ala-OMe (1a) and Boc2-∆Abu-OMe (1b): These
compounds were prepared from Boc-Ser-OMe and Boc-Thr-OMe,
respectively, using the tert-butylpyrocarbonate/dimethylaminopyri-
dine procedure described elsewhere.[3]
Monodeprotection of the Methyl Esters of N,N-bis(tert-butyloxycar-
bonyl)dehydroamino Acids
Synthesis of Boc-∆Abu(β-Br)-OMe [(E)-2b and (Z)-2b]: The same
procedure as described above was followed, substituting Boc2-
∆Ala-OMe for Boc2-∆Abu-OMe (1.58 g, 5 mmol) to give (E)-2b
and (Z)-2b (1.31 g, 89%) as a 1:9 mixture. Separation of the diaster-
eomers was carried out by column chromatography using 30% di-
ethyl ether/petroleum ether as eluent. Alternatively, (Z)-2b could be
obtained by crystallization from diethyl ether/n-hexane.
Synthesis of Boc-∆Ala-OMe and Boc-∆Abu-OMe: Compound 1a
(1.51 g, 5 mmol) or 1b (1.58 g, 5 mmol) was dissolved in dichloro-
methane (0.1 ) and 2% of TFA was added slowly with vigorous
stirring. The reaction was monitored by TLC and when no starting
material was detected (ca. 1 hour) an additional 50 mL of dichloro-
methane was added. The organic phase was then washed with
NaHCO3 (1 ) and brine (3 ϫ 30 mL each). After drying over
MgSO4 the extract was taken to dryness at reduced pressure to af-
Synthesis of 7-Boronic-2,3-dimethylbenzo[b]thiophene Acid (4)
ford Boc-∆Ala-OMe (0.98 g, 98%), as an oil,[3] or Boc-∆Abu-OMe 7-Bromo-2,3-dimethylbenzo[b]thiophene (3): A 30% aqueous NaOH
(0.96 g, 89%). Crystallization of the latter from diethyl ether/n-hex- solution (7 mL, 53 mmol) was added with stirring to 2-bromothi-
ane gave the pure Z-isomer as a white solid; m.p. 69.5Ϫ71.0 °C.
ophenol (4.90 g, 26 mmol) at 0 °C. After 30 min 3-bromobutan-2-
2526
Eur. J. Org. Chem. 2002, 2524Ϫ2528

Suzuki Cross Couplings of Sulfur Analogues of Dehydrotryptophan
FULL PAPER
one (3.70 g, 26 mmol) was added dropwise from an addition funnel
and the mixture was left stirring for 30 min at room temp. Chloro-
form (30 mL) and water (20 mL) were then added and the phases
separated. The aqueous phase was extracted with chloroform (2 ϫ
30 mL) and the combined organic phases were dried (MgSO4), fil-
tered and the solvent removed to give the corresponding ketoaryl-
graphy affording the coupled products. The corresponding de-
boronated benzo[b]thiophenes were isolated as the less polar prod-
ucts in 10Ϫ15% yield.
Boc-(E)-∆Ala[β-(benzo[b]thiophen-3-yl)]-OMe [(E)-5a)]: Column
chromatography using a solvent gradient from neat petroleum ether
to 40% diethyl ether/petroleum ether gave compound (E)-5a as a
white solid (0.24 g, 72%), m.p. 158.0Ϫ159.0 °C. 1H NMR (CDCl3):
δ ϭ 1.41 (s, 9 H, CH3 Boc), 3.91 (s, 3 H, OCH3), 6.17 (s, 1 H, α-
NH), 7.40Ϫ7.47 (m, 2 H, 2 ϫ Ar-H), 7.58 (s, 1 H, 2-H), 7.86Ϫ7.92
(m, 3 H, 2 ϫ Ar-H and β-CH) ppm. 13C NMR (CDCl3): δ ϭ 28.07
[C(CH3)3], 52.65 (OCH3), 81.14 [OC(CH3)3], 121.61 (CH), 121.74
(CH), 122.72 (CH), 124.65 (CH), 124.92 (CH), 125.31(C), 128.28
(CH), 129.19 (C), 138.24 (C), 139.20 (C), 153.21 (CϭO), 165.91
(CϭO) ppm. C17H19NO4S (333.4): calcd. C 61.24, H 5.74, N 4.20,
S 9.62; found C 61.12, H 5.77, N 4.23, S 9.52.
1
sulfide as a light yellow oil (5.04 g, 75%). H NMR (CDCl3): δ ϭ
1.45 (d, J ϭ 7.0 Hz, 3 H, SCHCH3), 2.20 (s, 3 H, COCH3), 3.85
(q, J ϭ 7.0 Hz, 1 H, SCHCH3), 7.04 (broad t, J ϭ 7.5 Hz, 1 H, 4-
H), 7.20 (broad t, J ϭ 7.5 Hz, 1 H, 5-H), 7.32 (broad d, J ϭ 7.5 Hz,
1 H, 6-H), 7.22 (broad d, J ϭ 7.5 H, 1 Hz, 3-H). This compound
(5.00 g, 20 mmol) was added dropwise from an addition funnel to
PPA (10 g) which had previously been heated at 150 °C for 15 min.
The mixture was then heated for 1 h at 150 °C. After cooling,
crushed ice was added (30 g) and it was left stirring until the ice
had melted. Chloroform was added (30 mL) and the phases were
separated. The aqueous phase was extracted with chloroform (2 ϫ
50 mL) and the organic phase was dried (MgSO4), filtered and the
solvent removed to give compound 3 (4.80 g, quantitative yield),
Boc-(E)-∆Ala[β-(benzo[b]thiophen-2-yl)]-OMe [(E)-6a]: Column
chromatography using a solvent gradient from neat petroleum ether
to 40% diethyl ether/petroleum ether gave compound (E)-6a as a
white solid (0.27 g, 81%), m.p. 150.0Ϫ151.0 °C. 1H NMR (CDCl3):
δ ϭ 1.50 (s, 9 H, CH3 Boc), 3.87 (s, 3 H, OCH3), 5.98 (s, 1 H, α-
NH), 7.25Ϫ7.44 (m, 2 H, 2 ϫ Ar-H), 7.55 (s, 1 H, 3-H), 7.74 (broad
s, 1 H, β-CH), 7.77Ϫ7.86 (m, 2 H, 2 ϫ Ar-H) ppm. 13C NMR
(CDCl3): δ ϭ 28.20 [C(CH3)3], 52.53 (OCH3), 81.25 [OC(CH3)3],
122.21 (CH), 124.28 (CH), 124.69 (CH), 125.91 (CH), 128.52 (CH),
129.73 (CH), 134.99 (C), 136.67 (C), 138.29 (C), 141.83 (C), 153.60
(CϭO), 165.51 (CϭO) ppm. C17H19NO4S (333.4): calcd. C 61.24,
H 5.74, N 4.20, S 9.62; found C 61.00, H 5.74, N 4.07, S 9.31.
1
m.p. 67.0Ϫ68.5 °C (from n-hexane). H NMR (CDCl3): δ ϭ 2.29
(s, 3 H, Ar-CH3), 2.51 (s, 3 H, Ar-CH3), 7.23 (t, J ϭ 8.0 Hz, 1 H,
5-H), 7.42 (dd, J ϭ 8.0, 1.0 Hz, 1 H, 4-H), 7.54 (dd, J ϭ 8.0, 1.0 Hz,
1 H, 6-H) ppm. 13C NMR (CDCl3): δ ϭ 11.78 (CH3), 13.77 (CH3),
115.46 (C), 120.00 (CH), 125.16 (CH), 126.23 (CH), 132.88 (C),
134.99 (C), 139.61 (C), 142.02 (C) ppm. C10H9BrS (241.1): calcd.
C 49.81, H 3.76, S 13.29; found C 49.40, H 3.86, S 13.30.
7-Boronic-2,3-dimethylbenzo[b]thiophene acid (4): A solution 1.6 
of nBuLi in hexane (5.1 mL, 8.1 mmol) was added dropwise to a
solution of bromo compound 3 (1.50 g, 6.2 mmol) in dry ether
(35 mL) at 0 °C, under argon. A white precipitate was formed and
the mixture was left stirring for 20 min at 0 °C. The temperature
was lowered to Ϫ20 °C, tributyl borate was added (2.2 mL,
8.1 mmol), and the mixture was stirred at this temperature for 10
min, becoming a limpid solution that was left stirring for 2 h at
room temp. The mixture was then cooled to 0 °C and acidified to
pH 1Ϫ2 with 1  HCl. More ether was added and the mixture
stirred for 15 min. The phases were separated, and a 20% aqueous
solution of NaOH (50 mL) was added to the organic phase to form
a white precipitate. The two phases were filtered under vacuum and
a white solid was separated. This solid was completely dissolved
with 1  HCl (20 mL) and the mixture was extracted with ether (3
ϫ 20 mL). The combined organic phases were dried (MgSO4), fil-
tered and solvent removal gave compound 4 as a white solid (0.60 g,
Boc-(E)-∆Ala[β-(2,3-dimethylbenzo[b]thiophen-7-yl)]-OMe [(E)-7a]:
Column chromatography using a solvent gradient from neat petro-
leum ether to 40% diethyl ether/petroleum ether gave the product
as a white solid (0.14 g, 40%), m.p. 125.0Ϫ126.0 °C. 1H NMR
(CDCl3): δ ϭ 1.34 (s, 9 H, CH3 Boc), 2.31 (s, 3 H, Ar-CH3), 2.50
(s, 3 H, Ar-CH3), 3.90 (s, 3 H, OCH3), 6.25 (s, 1 H, α-NH),
7.33Ϫ7.39 (m, 2 H, β-CH and 5-H), 7.50Ϫ7.60 (m, 2 H, 4- and 6-
H) ppm. 13C NMR (CDCl3): δ ϭ 11.45 (CH3), 13.74 (CH3), 27.99
[C(CH3)3], 52.67 (OCH3), 80.99 [OC(CH3)3], 121.71 (CH), 123.47
(CH), 124.00 (CH), 125.28 (CH), 126.23 (C), 127.43 (C), 128.19
(C), 133.79 (C), 138.47 (C), 141.49 (C), 152.45 (CϭO), 165.77 (Cϭ
O) ppm. C19H23NO4S (361.5): calcd. C 63.14, H 6.41, N 3.88, S
8.87; found C 63.39, H 6.57, N 3.88, S 8.68.
Boc-(Z)-∆Abu[β-(benzo[b]thiophen-2-yl)]-OMe [(E)-6b]: Column
chromatography using a solvent gradient from neat petroleum ether
to 30% diethyl ether/petroleum ether gave product (E)-6b (0.21 g,
61%). Crystallization from diethyl ether/n-hexane gave white crys-
tals, m.p. 116.0Ϫ118.0 °C. 1H NMR (CDCl3): δ ϭ 1.49 (s, 9 H,
CH3 Boc), 2.21 (s, 3 H, γ-CH3), 3.59 (s, 3 H, OCH3), 6.14 (s, 1 H,
α-NH), 7.14 (s, 1 H, 3-H), 7.30Ϫ7.41 (m, 2 H, 2 ϫ Ar-H),
7.68Ϫ7.82 (m, 2 H, 2 ϫ Ar-H) ppm. 13C NMR (CDCl3): δ ϭ 21.00
(CϭCCH3), 28.14 [C(CH3)3], 52.26 (OCH3), 81.38 [OC(CH3)3],
122.07 (CH), 122.53 (CH), 123.54 (CH), 124.35 (CH), 124.43 (CH),
125.50 (C), 126.55 (C), 139.46 (C), 139.96 (C), 142.62 (C), 152.67
(CϭO), 165.95 (CϭO) ppm. C18H21NO4S (347.4): calcd. C 62.23,
H 6.09, N 4.03, S 9.23; found C 62.29, H 6.10, N 4.00, S 8.99.
1
47%), m.p. 288.0Ϫ290.0 °C. H NMR ([D6]DMSO): δ ϭ 2.24 (s, 3
H, Ar-CH3), 2.42 (s, 3 H, Ar-CH3), 7.31 (apparent t, J ϭ 7.0 Hz,
1 H, 5-H), 7.65 (broad d, J ϭ 7.0 Hz, 1 H, 4 or 6-H), 7.65 (broad
d, J ϭ 7.0 Hz, 1 H, 4 or 6-H), 8.30 (broad s, 2 H, 2 ϫ OH) ppm.
13C NMR ([D6]DMSO): δ ϭ 11.07 (CH3), 13.33 (CH3), 109.30 (C),
123.04 (CH), 123.14 (CH), 125.61 (C), 130.15 (CH), 134.33 (C),
140.23 (C), 143.16 (C) ppm.
General Procedure for Palladium-Catalysed Cross Couplings of
Benzo[b]thiophene Boronic Acids with β-Bromo Dehydroamino Acid
Derivatives: Compounds (E)-2a, (E)-2b or (Z)-2b (1 mmol) were
coupled with benzo[b]thiophene boronic acids (1.1 equiv.) in a mix-
ture of either DME/water (4 mL/1 mL) and NaHCO3 (2 equiv.) or Boc-(Z)-∆Abu-[β-(benzo[b]thiophen-2-yl)]-OMe [(Z)-6b]: Column
DME (5 mL) and aqueous 2  Na2CO3 (2 equiv.), and Pd(PPh3)4 chromatography using a solvent gradient from neat petroleum ether
(10 mol %). The reactions were followed by TLC which determined
the different reaction times (Table 1). After cooling, diethyl ether
and water were added and the phases were separated. The aqueous
phase was washed with diethyl ether (3 ϫ 50 mL). The combined
organic phases were dried (MgSO4), filtered and solvent removal
gave a brown residue which was submitted to column chromato-
to 40% diethyl ether/petroleum ether gave (Z)-6b as a white solid
(0.16 g, 47%). Crystallization from diethyl ether/n-hexane gave
white crystals m.p.108.0Ϫ110.0 °C. 1H NMR (CDCl3): δ ϭ 1.48 (s,
9 H, CH3 Boc), 2.45 (s, 3 H, γ-CH3), 3.87 (s, 3 H, OCH3), 6.20 (s,
1 H, α-NH), 7.32Ϫ7.42 (m, 2 H, 2 ϫ Ar-H), 7.49 (s, 1 H, 3-H),
7.76Ϫ7.86 (m, 2 H, 2 ϫ Ar-H) ppm. 13C NMR (CDCl3): δ ϭ 19.37
Eur. J. Org. Chem. 2002, 2524Ϫ2528
2527

N. O. Silva, A. S. Abreu, P. M. T. Ferreira, L. S. Monteiro, M.-J. R. P. Queiroz
FULL PAPER
(CϭCCH3), 28.19 [C(CH3)3], 52.21 (OCH3), 81.21 [OC(CH3)3],
Boc-(E)-∆Abu-[β-(2,3-dimethylbenzo[b]thiophen-7-yl)]-OMe
[(E)-
121.97 (CH), 123.94 (CH), 124.57 (CH), 125.28 (CH), 129.06 (C),
7b]: Column chromatography using a solvent gradient from neat
138.79 (C), 140.53 (C), 140.98 (C), 153.38 (CϭO), 165.90 (CϭO) petroleum ether to 30% diethyl ether/petroleum ether gave (Z)-7b
ppm. C18H21NO4S (347.4): calcd. C 62.23, H 6.09, N 4.03, S 9.23;
found C 62.29, H 6.10, N 4.00, S 8.99.
as a white solid (0.03 g, 7%), followed by (E)-7b, also as a white
solid (0.23 g, 61%) m.p. 116.0Ϫ118.0 °C. H NMR (CDCl3): δ ϭ
1
1.51 (s, 9 H, CH3 Boc), 2.21 (s, 3 H, γ-CH3), 2.29 (s, 3 H, Ar-CH3),
2.46 (s, 3 H, Ar-CH3), 3.37 (s, 3 H, OCH3), 6.12 (s, 1 H, α-NH),
7.03 (broad d, J ϭ 7.3 Hz, 1 H, 6-H), 7.33 (apparent t, J ϭ 7.9,
7.3 Hz, 1 H, 5-H), 7.50 (dd, J ϭ 7.9, 0.9 Hz, 1 H, 4-H) ppm. 13C
NMR (CDCl3): δ ϭ 11.48 (CH3), 13.71 (CH3), 20.50 (CϭCCH3),
28.21 [C(CH3)3], 51.77 (OCH3), 80.79 [OC(CH3)3], 120.10 (CH),
122.01 (CH), 123.93 (CH), 125.12 (C), 127.22 (C), 133.66 (C),
135.51 (C), 136.15 (C), 139.01 (C), 141.12 (C), 153.09 (CϭO),
164.95 (CϭO) ppm. C20H25NO4S (375.5): calcd. C 63.98, H 6.71,
N 3.73, S 8.54; found C 63.87, H 6.79, N 3.76, S 8.47.
Boc-(E)-∆Abu[β-(benzo[b]thiophen-3-yl)]-OMe [(E)-5b]: Column
chromatography using a solvent gradient from neat petroleum ether
to 20% diethyl ether/petroleum ether gave the product as a white
1
solid (0.18 g, 52%), m.p. 120.0Ϫ122.0 °C. H NMR (CDCl3): δ ϭ
1.51 (s, 9 H, CH3 Boc), 2.19 (s, 3 H, γ-CH3), 3.34 (s, 3 H, OCH3),
6.17 (s, 1 H, α-NH), 7.19 (s, 1 H, 2-H), 7.30Ϫ7.40 (m, 2 H, 2 ϫ
Ar-H), 7.62Ϫ7.70 (m, 1 H, Ar-H) 7.82Ϫ7.88 (m, 1 H, Ar-H) ppm.
13C NMR (CDCl3): δ ϭ 20.93 (CϭCCH3), 28.19 [C(CH3)3], 51.84
(OCH3), 80.95 [OC(CH3)3], 122.45 (CH), 122.64 (CH), 124.19
(CH), 124.31 (CH), 126.23 (C), 132.40 (C), 136.50 (C), 137.81 (C),
139.67 (C), 153.06 (CϭO), 165.44 (CϭO) ppm. C18H21NO4S
(347.4): calcd. C 62.23, H 6.09, N 4.03, S 9.23; found C 62.34, H
6.19, N 4.07, S 9.17.
7-Hydroxy-2,3-dimethylbenzo[b]thiophene[9] (0.02 g, 11%) was also
isolated, eluting from the column after the deboronated compound
and before the coupled products.
Boc-(Z)-∆Abu[β-(benzo[b]thiophen-3-yl)]-OMe [(Z)-5b]: Column Acknowledgments
chromatography using a solvent gradient from neat petroleum ether
The Foundation for Science and Technology (Portugal) is thanked
to 30% diethyl ether/petroleum ether gave the product as a white
for financial support through IBQF-Univ. Minho, POCTI/99/QUI/
32689 project (also financial support of N.O. Silva) and through
SFRH/BD/4709/2001 (PhD financial support of A.S. Abreu).
1
solid (0.22 g, 62%) m.p. 122.0Ϫ124.0 °C. H NMR (CDCl3): δ ϭ
1.39 (s, 9 H, CH3 Boc), 2.30 (s, 3 H, γ-CH3), 3.90 (s, 3 H, OCH3),
5.65 (s, 1 H, α-NH), 7.32Ϫ7.43 (m, 3 H, 3 ϫ Ar-H), 7.58Ϫ7.65 (m,
1 H, Ar-H) 7.86Ϫ7.93 (m, 1 H, Ar-H) ppm. 13C NMR (CDCl3):
δ ϭ 20.74 (CϭCCH3), 27.99 [C(CH3)3], 52.03 (OCH3), 80.67
[OC(CH3)3], 122.74 (CH), 124.50 (CH), 124.72 (CH), 125.85 (C),
127.87 (C), 135.37 (C), 136.17 (C), 140.03 (C), 153.02 (CϭO),
165.45 (CϭO) ppm. C18H21NO4S (347.4): calcd. C 62.23, H 6.09,
N 4.03, S 9.23; found C 62.05, H 6.21, N 4.00, S 9.08.
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[(Z)-
7b]: Column chromatography using a solvent gradient from neat
petroleum ether to 30% diethyl ether/petroleum ether gave the
product as a white solid (0.26 g, 70%), m.p. 116.0Ϫ118.0 °C. 1H
NMR (CDCl3): δ ϭ 1.35 (s, 9 H, CH3 Boc), 2.27 (s, 3 H, γ-CH3),
2.32 (s, 3 H, Ar-CH3) 2.47 (s, 3 H, Ar-CH3), 3.89 (s, 3 H, OCH3),
5.70 (s, 1 H, α-NH), 7.10 (broad signal, 1 H, 6-H), 7.39 (apparent
t, J ϭ 7.6 Hz, 1 H, 5-H) 7.56 (broad d, J ϭ 7.9 Hz, 1 H, 4-H)
ppm. 13C NMR (CDCl3): δ ϭ 11.49 (CH3), 13.71 (CH3), 19.63 (Cϭ
CCH3), 28.04 [C(CH3)3], 52.08 (OCH3), 80.60 [OC(CH3)3], 120.74
(CH), 122.53 (CH), 124.52 (CH), 125.24 (C), 127.49 (C), 131.41
(C), 133.62 (C), 134.35 (C), 135.82 (C), 141.57 (C), 153.03 (CϭO),
165.56 (CϭO) ppm. C20H25NO4S (375.5): calcd. C 63.98, H 6.71,
N 3.73, S 8.54; found C 63.65, H 6.78, N 3.84, S 8.44.
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P. M. T. Ferreira, H. Maia, L. S. Monteiro, J. Sacramento,
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7-Hydroxy-2,3-dimethylbenzo[b]thiophene[9] (0.02 g, 11%) was also
isolated, eluting from the column after the deboronated compound
and before the coupled product.
hedron 2001, 57, 6071Ϫ6077.
Received March 6, 2002
[O02119]
2528
Eur. J. Org. Chem. 2002, 2524Ϫ2528