Synthesis of β-benzo[b]thienyldehydrophenylalanine derivatives by one-pot palladium-catalyzed borylation and suzuki coupling (BSC) and metal-assisted intramolecular cyclization - Studies of fluorescence and antimicrobial activity

Article abstract of DOI:10.1002/ejoc.200500040

Palladium-catalyzed borylation and Suzuki coupling (BSC) in a one-pot procedure was successfully applied to the synthesis of several β-substituted dehydrophenylalanines in the benzo[b]thiophene series, with the stereochemistry of the starting materials be

Full text of DOI:10.1002/ejoc.200500040

FULL PAPER
Synthesis of β-Benzo[b]thienyldehydrophenylalanine Derivatives by One-Pot
Palladium-Catalyzed Borylation and Suzuki Coupling (BSC) and Metal-
Assisted Intramolecular Cyclization – Studies of Fluorescence and
Antimicrobial Activity
Ana S. Abreu,[a] Paula M. T. Ferreira,[a] Maria-João R. P. Queiroz,*[a]
Isabel C. F. R. Ferreira,[b] Ricardo C. Calhelha,[b] and Letícia M. Estevinho[b]
Keywords: Dehydrophenylalanines / Benzothiophenes / Borylation / Suzuki coupling / Cyclization / Indoles / Fluorescence /
Antimicrobial activity
Palladium-catalyzed borylation and Suzuki coupling (BSC)
in a one-pot procedure was successfully applied to the syn-
thesis of several β-substituted dehydrophenylalanines in the
benzo[b]thiophene series, with the stereochemistry of the
starting materials being maintained. Bromobenzo[b]thio-
phenes bearing an ortho EDG (OMe or Me) were used as the
components to be borylated with pinacolborane, whilst pure
stereoisomers of β-bromodehydrophenylalanines were used
as the other Suzuki coupling components. Treatment of the
obtained methyl ester of (Z)-N-(tert-butoxycarbonyl)-β-
(2,3,5-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine
with Pd(OAc)2 and Cu(OAc)2 in DMF at 160 °C gave two in-
dole derivatives (1:3), the major product resulting from isom-
erization and cyclization and the minor product resulting
from direct cyclization (thienoindole). Carrying out the reac-
tion at 100 °C gave the same products in similar amounts.
Use of the methyl ester of (Z)-N-(tert-butoxycarbonyl)-β-
(2,3,7-trimethylbenzo[b]thien-6-yl)dehydrophenylalanine as
starting material gave only one product, resulting from isom-
erization and cyclization at 100 °C. Two of the cyclized com-
pounds were subjected to fluorescence studies; the thienoin-
dole could be useful as a fluorescent probe. Preliminary stud-
ies of antimicrobial activity were performed on the precursors
and on the cyclized products.
The authors postulated that the borylation should be per-
formed on a component bearing an ortho-EDG (electron-
donating group), with the other coupling component hav-
ing an ortho-EWG (electron-withdrawing group). The
method is also based on the use of the electron-rich steri-
cally hindered 2-(dicyclohexylphosphanyl)biphenyl as li-
gand.[4] Recently we applied this reaction to the synthesis
of 2-methyl-2Ј-nitrobiaryl compounds in the benzo[b]thio-
phene series to obtain thienocarbazoles.[5] Another applica-
tion of the BSC to the synthesis of substituted biaryl com-
pounds, with use of DPEphos as ligand and CsF as base in
the Suzuki coupling, has appeared more recently.[6]
In this work the brominated Suzuki coupling component
is not aromatic, which constitutes a novel application of the
BSC reaction as reported by us previously.[7] The C–N me-
tal-assisted cyclization[2] of differently ortho-methylated
Z-β-benzo[b]thienyldehydrophenylalanine derivatives was
studied, and a thienoindole obtained in this way was shown
to be fluorescent. Preliminary antimicrobial studies were
performed on the precursors or on the cyclized products.
Introduction
In recent years we have been interested in the linkage of
dehydroamino acid derivatives to benzo[b]thiophenes and
in the study of the fluorescence and antimicrobial activity
of the resulting products. By Suzuki coupling we were able
to synthesize either β-benzo[b]thienyl or β,β-bis(benzo[b]-
thienyl)dehydroamino acid derivatives.[1,2] The latter have
been cyclized to the corresponding dehydroprolines by me-
tal-assisted intramolecular cyclization and the fluorescence
properties of one of them have been studied.[2b]
Here we describe the application of one-pot borylation/
Suzuki coupling (BSC) to the synthesis of new benzo[b]thi-
enyldehydrophenylalanine derivatives from methylated or
methoxylated benzo[b]thiophenes and brominated dehy-
drophenylalanines. This method was first applied by Bau-
doin et al.[3] to the synthesis of 2,2Ј-disubstituted biaryl
compounds. Substituted halobenzenes were subjected to
borylation with pinacolborane, followed by in situ Suzuki
cross-coupling with a second 2-substituted halobenzene.
Results and Discussion
Synthesis
[a] Departamento de Química-Universidade do Minho,
Gualtar, 4710-057 Braga (Portugal)
Fax: +351253678983
E-mail: mjrpq@quimica.uminho.pt
[b] Escola Superior Agrária, Instituto Politécnico de Bragança,
Campus de Sta Apolónia, 5300 Bragança, Portugal
Several benzo[b]thienyldehydrophenylalanines were pre-
pared by palladium-catalyzed BSC reactions between bro-
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DOI: 10.1002/ejoc.200500040
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M.-J. R. P. Queiroz et al.
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mobenzo[b]thiophenes ortho-substituted with EDG groups Table 1. Starting materials and product yields of BSC reaction.
(OMe or Me) and pure stereoisomers of the methyl esters
of N-(tert-butoxycarbonyl)-β-bromodehydrophenylalanine:
(Z)-Boc-ΔPhe-(β-Br)-OMe) [(Z)-1] and (E)-Boc-ΔPhe-(β-
Br)-OMe ((E)-1), already prepared by us.[1] The bro-
mobenzo[b]thiophenes were borylated with pinacolborane
with subsequent Suzuki coupling with (Z)-1 or (E)-1 in a
one-pot procedure (Scheme 1, Table 1).
Scheme 1. i) Pd(OAc)2 (5 mol%), 2-(dicyclohexylphosphanyl)bi-
phenyl (20 mol%), NEt3 (4 equiv.), dry dioxane, 80 °C, 1 h, Ar. ii)
Ba(OH) 2·8H2O (3 equiv.), H2O, 100 °C, 1 h 30 min.
Debrominated benzo[b]thiophenes were isolated as by-
products in all cases (25–50%). If the two components are
aromatic the component to be borylated needs an EDG and
the other Suzuki coupling component requires an EWG.[3,5]
In our case, however, the carbamate group of the dehy-
droamino acid derivative has a slight electron-donating ef-
fect and this can affect the product yields, which were mod-
erate to good (Table 1). The products maintained the ste-
reochemistry of the starting materials, as observed by NOE
difference experiments. Enhancements on the phenyl pro-
tons for the (E) isomers and on the ortho-methyl or -meth-
oxy and on the benzo[b]thienyl protons for the (Z) isomers
were observed on irradiation of the α-NH, as shown as ex-
amples in Figure 1 and 2 for compounds (Z)-3 and (E)-3.
In Figure 1 we observe an enhancement of the 7-Me (δ =
from direct cyclization of the starting material was isolated.
This could be due to the cyclization on the phenyl ring be-
ing much more favorable than on position 5 of the benzo[b]-
thiophene moiety.
2.39 ppm) and of the doublet of 5-H (δ = 7.06 ppm). In
Figure 2 the NOE enhancement is only observed for the
phenyl protons.
In order to obtain cyclic amino acids, compounds (Z)-
We believe that the mechanism of cyclization involves an
2 and (Z)-3 were subjected to our cyclization conditions[2]
electrophilic attack of PdII on the aromatic ring and a nu-
(Scheme 2 and Scheme 3). Compound (Z)-2 gave two cy-
clized products resulting either from isomerization followed
by cyclization to give indole 5 (major product), or from
direct cyclization to give thienoindole 6. The reaction was
also performed at 100 °C for 6 h, but the same compounds
were obtained in similar amounts.
cleophilic attack of nitrogen, forming a palladacycle, the
indole being formed after Pd0 extrusion. The role of the
Cu(OAc)2 may be the reoxidation of Pd0, avoiding the use
of stoichiometric amounts of Pd(OAc)2 (Scheme 4). In our
case N-deprotection also occurs depending on the reaction
conditions (temperature and/or time).
Compound (Z)-3 was also subjected to the same condi-
tions (heating at 100 °C for 2 h; Scheme 3), but a cyclized
intermediate 7, resulting from isomerization and cyclization
without N-deprotection was formed (this compound was
isolated from an independent experiment, stopping the re-
Antimicrobial Activity in vitro
action at this point). Heating at 130 °C for an additional
A screening of antibacterial activities with two Gram
hour gave the corresponding N-deprotected dehydroproline negative (Escherichia coli and Pseudomonas aeruginosa) and
derivative in high yield. In this case no product resulting two Gram positive bacteria (Bacillus subtilis and Bacillus
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Synthesis of β-Benzo[b]thienyldehydrophenylalanine Derivatives
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1
Figure 1. H NMR (CDCl3) spectrum and NOE difference experiment with irradiation of the α-NH of compound (Z)-3.
1
Figure 2. H NMR (CDCl3) spectrum and NOE difference experiment with irradiation of the αNH of compound (E)-3.
Scheme 2. i) Pd(OAc)2 (50 mol%), Cu(OAc)2·H2O (3 equiv.), DMF,
160 °C, 2 h 30 min.
Scheme 3. i) Pd(OAc)2 (50 mol%), Cu(OAc)2·H2O (3 equiv.), DMF.
2953
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M.-J. R. P. Queiroz et al.
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relative quantum yield of fluorescence in dichloromethane
Φdcm = 0.33 by the standard method[9] with 9,10-diphenyl-
anthracene in EtOH (2×10–5 m) as reference (ΦEtOH
=
0.95)[10] at λexc = 333 nm. Indole 5 showed a λem = 408 nm
and a relative quantum yield of fluorescence in dichloro-
methane Φdcm = 0.0067 by the same method and at λexc
=
296 nm. The excitation wavelengths (λexc) were chosen from
the UV spectra of the compounds (see Experimental Sec-
tion). From the results obtained it can be concluded that
thienoindole 6 may be useful as a fluorescent probe.
Scheme 4.
cereus) and of antifungal activity with Candida albicans as
a representative of fungi was assessed for compounds (Z)-2,
(Z)-3, 5, 6, 7, and 8. The minimal inhibitory concentrations
(MICs in μg·mL–1) were determined (Table 2) by an adapta-
tion of the agar streak dilution method based on radial dif-
fusion.[8] Under the same conditions, different concentrated
solutions of ampicillin (antibacterial) and cyclohexamide
(antifungal) were used as standards. The MIC was consid-
ered to be the lowest concentration of the tested compound
able to inhibit growth of bacteria or fungi on the plate. The
diameters of the inhibition zones corresponding to the
MICs are presented in Table 2. The compounds tested are
not active against Pseudomonas aeruginosa, starting from
DMSO solutions of 6000 μg·mL–1 of each compound.
Compounds (Z)-2 and (Z)-3 are also not active against Es-
cherichia coli, but are the only ones active against Candida
albicans, (Z)-2 (MIC = 6 μg·mL–1) being more active than
(Z)-3 (MIC = 600 μg·mL–1) and than cyclohexamide (MIC
= 12.5 μg·mL–1). Against Gram-positive bacteria (Z)-2 is
more active against B. cereus, but (Z)-3 shows a lower MIC,
even lower than ampicillin, against B. subtilis.
Figure 3. Fluorescence spectra of compounds 5 and 6 in dichloro-
methane (1.6×10–6 m).
Conclusions
Several new β-benzo[b]thienyldehydrophenylalanines
were synthesized in moderate to good yields from ortho-
substituted bromobenzo[b]thiophenes and pure stereoiso-
mers of β-brominated dehydrophenylalanines by one-pot
borylation and Suzuki coupling (BSC), with the stereo-
chemistry of the starting materials being maintained. Two
of the (Z) isomers obtained, (Z)-2 and (Z)-3, were subjected
to C–N metal-assisted cyclization to give dehydroprolines
(indoles and a thienoindole). From preliminary antimicro-
Against Escherichia coli, indoles 7 and 8 are more active
(MIC = 0.06 μg·mL–1) than thienoindole 6 (MIC =
0.6 μg·mL–1). All the cyclized products are active against
Gram-positive bacteria, presenting lower MICs than their
precursors (Z)-2, (Z)-3 and ampicillin, indole 7 being the
most active (MIC = 0.006 μg·mL–1).
Fluorescence Studies
The fluorescence of compounds 5 and 6 was studied bial studies on the precursors and on the cyclized products
(Figure 3). Thienoindole 6 showed a λem = 393 nm and a it is possible to conclude that all the compounds were active
Table 2. Antimicrobial activity of compounds (Z)-2, (Z)-3, 5, 6, 7, and 8.
Compounds
MIC in μg·mL–1 (Zone of inhibition in mm)
E. coli CECT 101[a]
B. cereus CECT148[a]
B. subtilis CECT498[a]
C. albicans CECT 1394[a]
(Z)-2
not active[b]
not active[b]
600 (11)
0.6 (7)
0.06 (8)
0.06 (11)
6.25 (15)
–
6 (10)
60 (11)
6 (8)
6 (8)
600 (9)
(Z)-3
60 (12)
0.6 (13)
0.06 (10)
0.006 (10)
0.06 (9)
3.13 (13)
–
Indole 5
Thienoindole 6
Indole 7
Indole 8
Ampicillin
Cyclohexamide
0.6 (9)
0.06 (9)
0.006 (13)
0.06 (8)
12.5 (10)
–
not active[b]
not active[b]
not active[b]
not active[b]
–
12.5 (5)
[a] CECT-Spanish type culture collection from Valencia University. [b] Not active starting from 6000 μg·mL–1.
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Synthesis of β-Benzo[b]thienyldehydrophenylalanine Derivatives
FULL PAPER
that was subjected to column chromatography with petroleum
ether.
against the Gram positive bacteria (B. cereus and B. subti-
lis), the cyclized products being more active (lower MICs).
The latter were also active against E. coli, despite presenting
very different MICs, and the precursors were in turn the
only compounds active against Candida albicans. Fluores-
cence studies on compounds 5 and 6 show that the thieno-
indole 6 may be useful as a fluorescent probe.
5-Bromo-6-methoxy-2,3-dimethylbenzo[b]thiophene: This compound
(62.0 mg, 8%) was isolated as the less polar product as a white
solid, m.p. 119–120 °C. 1H NMR (CDCl3): δ = 2.24 (s, 3 H,
ArCH3), 2.45 (s, 3 H, ArCH3), 3.95 (s, 3 H, OCH3), 7.25 (s, 1 H,
7-H), 7.74 (s, 1 H, 4-H) ppm. 13C NMR (CDCl3): δ = 11.29 (CH3),
13.65 (CH3), 56.44 (OCH3), 104.53 (CH), 109.34 (C), 125.27 (CH),
125.94 (C), 132.40 (C), 136.01 (C), 138.08 (C), 152.54 (C) ppm.
C11H11BrOS (271.17): calcd. C 48.72, H 4.09, S 11.82; found C
48.87, H 4.23, S 11.60.
Experimental Section
General Remarks: Melting points were determined on a Gallen-
kamp apparatus and are uncorrected. The H NMR spectra were
7-Bromo-6-methoxy-2,3-dimethylbenzo[b]thiophene: This compound
(484 mg, 60%) was isolated as a white solid, m.p. 120–122 °C. H
1
1
measured on a Varian Unity Plus instrument at 300 MHz. Spin–
spin decoupling techniques were used to assign the signals. NOE
difference experiments were performed to determine the stereo-
chemistries of the products. The 13C NMR spectra were measured
in the same instrument at 75.4 MHz (with DEPT θ 45°). The UV
spectra were recorded on a Schimadzu UV-250 1PC, UV/Vis re-
cording spectrophotometer.
NMR (CDCl3): δ = 2.26 (s, 3 H, ArCH3), 2.46 (s, 3 H, ArCH3),
3.97 (s, 3 H, OCH3), 7.00 (d, J = 8.4 Hz, 1 H, 5-H), 7.48 (d, J =
8.4 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3): δ = 11.60 (CH3), 13.67
(CH3), 57.05 (OCH3), 103.97 (C), 109.73 (CH), 120.39 (CH),
127.39 (C), 132.55 (C), 135.85 (C), 141.55 (C), 152.74 (C) ppm.
C11H11BrOS (271.17): calcd. C 48.72, H 4.09, S 11.82; found C
49.00, H 4.27, S 11.74.
General Procedure for One-pot BSC Reactions: A dried Schlenk
tube was charged under Ar with dry dioxane (2 mL), the ortho-
methylated or -methoxylated bromobenzo[b]thiophene (0.5 mmol)
was added, and the mixture was heated for 5 min at 80 °C. Triethyl-
amine (4 equiv.), Pd(OAc)2 (5 mol%), 2-(dicyclohexylphosphanyl)
biphenyl (20 mol%), and pinacolborane (3 equiv.) were added, and
the mixture was left rapidly stirring at 80 °C for 1 h. After cooling,
a pure stereoisomer of β-bromodehydrophenylalanine derivative
(1 equiv.) and Ba(OH)2·8H2O (3 equiv.) were added, and the mix-
ture was heated at 100 °C for 1 h 30 min. Water and ethyl acetate
were added, the phases were separated, and the aqueous phase was
then extracted with more ethyl acetate. The organic phases were
collected, dried (MgSO4), and filtered, and the solvent was then
evaporated at reduced pressure to give a brown solid, which was
subjected to column chromatography.
Elemental analyses were determined on a LECO CHNS 932 ele-
mental analyser. Mass spectra (EI) and HRMS were measured by
the mass spectrometry service of the University of Vigo, Spain.
Column chromatography was performed on Macherey–Nagel silica
gel (230–400 mesh). “Petroleum ether” had a boiling range of 40–
60 °C. “Ether” refers to diethyl ether. When a solvent gradient was
used the increase of polarity was done gradually from neat petro-
leum ether to mixtures of ether/petroleum ether, increasing by 10%
of ether until the isolation of the product.
For the determination of in vitro antimicrobial activity, suspensions
of the microorganism were prepared to contain approximately
108 cfu·mL–1 and the plates were inoculated. Stock solutions of the
synthesized compound (6000 μg·mL–1) in DMSO were prepared
and graded dilutions (10×) of the tested compounds were incorpo-
rated in a cavity (depth 3 mm, diameter 4 mm) made in the center
of the Petri dish (nutrient agar for antibacterial activity and sabou-
raud dextrose agar medium for antifungal activity). The plates were
incubated in duplicate at 37 °C (for bacteria) and at 30 °C (for
fungi) for 24 h. Positive control using only inoculation and negative
control using only DMSO in the cavity were carried out.
(Z)-Boc-ΔPhe[β-(2,3,5-trimethylbenzo[b]thien-6-yl)]-OMe
(Z)-2:
The procedure described above was followed, with 6-bromo-2,3,5-
trimethylbenzo[b]thiophene (0.500 mmol, 128 mg) and (Z)-Boc-
ΔPhe(β-Br)-OMe (0.410 mmol, 147 mg), but with addition of water
(200 μL) in the second step. Column chromatography with a sol-
vent gradient from neat petroleum ether to 30% diethyl ether/petro-
leum ether gave product (Z)-2 (112 mg, 61%) as an oil. Crystalli-
zation from diethyl ether/n-hexane gave a light yellow solid, m.p.
The fluorescence studies were performed on a spectrofluorimeter
Spex Fluorolog 1680 Double Spectrometer.
1
154–156 °C. H NMR (CDCl3): δ = 1.44 (s, 9 H, CH3 Boc), 2.31
Samples quantum yields are given by Φs = [(ArFsns2)/(AsFrnr2)]Φr ,
where A is the absorbance at the excitation wavelength, F the inte-
grated emission area and n the refraction index of the solvents used.
Subscripts refer to the reference (r) or sample (s) compound.
(s, 3 H, 5-CH3), 2.35 (s, 3 H, ArCH3), 2.49 (s, 3 H, ArCH3), 3.64
(s, 3 H, OCH3), 5.80 (s, 1 H, NH), 7.13–7.16 (m, 2 H, ArH), 7.24–
7.29 (m, 3 H, ArH), 7.48 (broad s, 1 H, ArH), 7.51 (s, 1 H,
ArH) ppm. 13C NMR (CDCl3): δ = 11.25 (CH3), 13.76 (CH3),
19.57 (CH3), 27.99 (C(CH3)3), 52.03 (OCH3), 81.22 (OC(CH3)3),
122.87 (CH), 123.20 (CH), 126.50 (C), 126.73 (C), 127.56 (CH),
128.00 (CH), 128.41 (CH), 132.28 (C), 133.32 (C), 135.21 (C),
135.91 (C), 139.17 (C), 141.22 (C), 152.48 (C=O), 166.30
(C=O) ppm. MS: m/z (%) = 451 (22) [M]+, 351 (100) [M – Boc]+,
291 (34) [(M – Boc – CO2CH3]+. HRMS: calcd. for C26H29NO4S
[M]+ 451.1817; found 451.1801.
Compounds (Z)-1 and (E)-1 were already described by us.[1] The
6-bromotrimethylbenzo[b]thiophenes were prepared by a procedure
described by others[11a] and previously used by us.[11b]
7-Bromo-6-methoxy-2,3-dimethylbenzo[b]thiophene and 5-Bromo-6-
methoxy-2,3-dimethylbenzo[b]thiophene: Br2 (3.00 mmol, 0.154 mL,
1 equiv.) and a small amount of Fe were added to a cooled solution
(0 °C) of 6-methoxy-2,3-dimethylbenzo[b]thiophene[12] (3.00 mmol,
0.500 g) in dry ether (30 mL), protected against light. The reaction
(E)-Boc-ΔPhe[β-(2,3,5-trimethylbenzo[b]thien-6-yl)]-OMe
(E)-2:
1
was followed by H NMR and was left stirring for 1 h. Iced water
The procedure described above was followed, with 6-bromo-2,3,5-
trimethylbenzo[b]thiophene (0.460 mmol, 117 mg) and (E)-Boc-
ΔPhe(β-Br)-OMe (0.380 mmol, 136 mg), but with addition of water
(200 μL) in the second step. Column chromatography with a sol-
vent gradient from neat petroleum ether to 30% diethyl ether/petro-
leum ether gave product (E)-2 (51.0 mg, 30%) as an oil. Crystalli-
(10 mL) was added, and the mixture was stirred for 10 min. The
phases were separated and the aqueous phase was extracted with
more ether (2×30 mL). The organic phases were collected, washed
with a 5% solution of sodium sulfite and a 10% solution of sodium
carbonate, and dried (MgSO4). Removal of the solvent gave a solid
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M.-J. R. P. Queiroz et al.
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zation from petroleum ether gave white crystals, m.p. 156–157 °C.
1H NMR (CDCl3): δ = 1.48 (s, 9 H, CH3 Boc), 2.13 (s, 3 H,
ArCH3), 2.26 (s, 3 H, ArCH3), 2.48 (s, 3 H, ArCH3), 3.39 (s, 3 H,
OCH3), 6.26 (s, 1 H, NH), 7.24–7.34 (m, 6 H, ArH), 7.51 (s, 1 H,
28.03 (C(CH3)3), 52.08 (OCH3), 56.48 (OCH3), 80.86 (OC(CH3)3),
109.79 (CH), 119.50 (C), 121.93 (CH), 126.38 (C), 127.48 (CH),
127.77 (CH), 127.82 (C), 128.39 (CH), 132.46 (C), 135.62 (C),
138.18 (C), 139.75 (C), 152.70 (C), 153.77 (C=O), 166.25
ArH) ppm. 13C NMR (CDCl3): δ = 11.35 (CH3), 13.82 (CH3), (C=O) ppm. C26H29NO5S (467.58): calcd. C 66.79, H 6.25, N 3.00,
20.25 (CH3), 28.18 (C(CH3)3), 52.00 (OCH3), 81.21 (OC(CH3)3),
122.45 (CH), 122.54 (CH), 126.40 (C), 126.67 (C), 128.09 (CH),
128.63 (CH), 129.38 (CH), 132.98 (C), 134.29 (C), 135.06 (C),
137.52 (C), 140.98 (C), 152.99 (C=O), 166.24 (C=O) ppm.
C26H29NO4S (451.58): calcd. C 69.15, H 6.47, N 3.10, S 7.10; found
C 68.90, H 6.54, N 3.14, S 7.03.
S 6.86; found C 66.93, H 6.62, N 2.96, S 6.63.
(E)-Boc-ΔPhe[β-(6-methoxy-2,3-dimethylbenzo[b]thien-7-yl)]-OMe
(E)-4: The procedure described above was followed, with 7-bromo-
6-methoxy-2,3-dimethylbenzo[b]thiophene (0.340 mmol, 92.0 mg)
and (E)-Boc-ΔPhe(β-Br)-OMe (0.340 mmol, 119 mg), but with ad-
dition of water (134 μL) in the second step. Column chromatog-
raphy with a solvent gradient from neat petroleum ether to 40%
diethyl ether/petroleum ether gave product (E)-4 (63.0 mg, 40%) as
a yellow solid. Recrystallization from petroleum ether gave yellow
crystals, m.p. 135–136 °C. 1H NMR (CDCl3): δ = 1.46 (s, 9 H, CH3
Boc), 2.22 (s, 3 H, ArCH3), 2.36 (s, 3 H, ArCH3), 3.44 (s, 3 H,
OCH3), 3.78 (s, 3 H, OCH3), 6.22 (s, 1 H, NH), 6.99 (d, J = 8.7 Hz,
1 H, ArH), 7.26–7.37 (m, 5 H, ArH), 7.45 (d, J = 8.7 Hz, 1 H,
ArH) ppm. 13C NMR (CDCl3): δ = 11.34 (CH3), 13.66 (CH3),
28.15 (C(CH3)3), 51.79 (OCH3), 56.64 (OCH3), 80.92 (OC(CH3)3),
109.56 (CH), 121.12 (CH), 122.29 (C), 126.26 (C), 127.68 (C),
127.80 (C) 128.07 (C), 128.48 (CH), 129.22 (CH), 132.04 (CH),
135.37 (C), 137.26 (C), 140.02 (C), 152.96 (C), 153.57 (C=O),
165.33 (C=O) ppm. C26H29NO5S (467.58): calcd. C 66.79, H 6.25,
N 3.00, S 6.86; found C 66.54, H 6.33, N 3.07, S 6.91.
(Z)-Boc-ΔPhe[β-(2,3,7-trimethylbenzo[b]thien-6-yl)]-OMe
(Z)-3:
The procedure described above was followed, with 6-bromo-2,3,7-
trimethylbenzo[b]thiophene (0.500 mmol, 128 mg) and (Z)-Boc-
ΔPhe(β-Br)-OMe (0.500 mmol, 178 mg), but with addition of water
(200 μL) in the second step. Column chromatography with a sol-
vent gradient from neat petroleum ether to 30% diethyl ether/petro-
leum ether gave product (Z)-3 (122 mg, 52%) as an oil. Crystalli-
zation from petroleum ether gave white crystals, m.p. 149–150 °C.
1H NMR (CDCl3): δ = 1.42 (s, 9 H, CH3 Boc), 2.31 (s, 3 H,
ArCH3), 2.39 (s, 3 H, 7-CH3), 2.53 (s, 3 H, ArCH3), 3.62 (s, 3 H,
OCH3), 5.80 (s, 1 H, NH), 7.06 (d, J = 8.4 Hz, 1 H, 5-H), 7.09–
7.13 (m, 2 H, ArH), 7.22–7.28 (m, 3 H, ArH), 7.45 (d, J = 8.4 Hz,
1 H, 4-H) ppm. 13C NMR (CDCl3): δ = 11.42 (CH3), 13.84 (CH3),
17.59 (CH3), 28.08 (C(CH3)3), 52.07 (OCH3), 81.33 (OC(CH3)3),
119.44 (CH), 126.53 (C), 126.93 (CH), 127.60 (CH), 127.90 (C),
128.06 (CH), 128.52 (CH), 130.04 (C), 133.02 (C), 134.78 (C),
139.45 (C), 139.55 (C), 140.63 (C), 152.57 (C=O), 166.38
(C=O) ppm. C26H29NO5S (467.58): calcd. C 69.12, H 6.47, N 3.10,
S 7.10; found C 69.15, H 6.63, N 3.11, S 6.91.
General Procedure for the Synthesis of Dehydroprolines: Pd(OAc)2
(50 mol%) and Cu(OAc)2·H2O (3 equiv.) were added to a solution
of the (Z)-benzo[b]thienyldehydrophenylalanines (0.1 m) in DMF,
and the mixture was heated at 100 °C, 130 °C or 160 °C, the reac-
tion being monitored by TLC. Ethyl acetate (50 mL) was then
added and the organic layer was washed with water and brine
(2×25 mL) and dried with MgSO4, and the solvents were evapo-
rated at reduce pressure to give an oil that was subjected to column
chromatography.
(E)-Boc-ΔPhe[β-(2,3,7-trimethylbenzo[b]thien-6-yl)]-OMe
(E)-3:
The procedure described above was followed, with 6-bromo-2,3,7-
trimethylbenzo[b]thiophene (0.310 mmol, 79.0 mg) and (E)-Boc-
ΔPhe(β-Br)-OMe (0.310 mmol, 111 mg), but with addition of water
(125 μL) in the second step. Column chromatography with a sol-
vent gradient from neat petroleum ether to 30% diethyl ether/petro-
leum ether gave product (E)-3 (41 mg, 43%) as an oil. Crystalli-
zation from petroleum ether gave light yellow crystals, m.p. 172–
Methyl 2,3,5-Trimethyl-6-phenyl-8H-thieno[3,2-g]indole-7-carboxyl-
ate (6) and Methyl 3-(2,3,5-Trimethylbenzo[b]thien-6-yl)indole-2-
carboxylate (5): The procedure described above was applied with
compound (Z)-2 (0.177 mmol, 80.0 mg) and heating for 2 h 30 min
at 160 °C. Column chromatography with a solvent gradient from
neat petroleum ether to 30% diethyl ether/petroleum ether gave
product 6 (12.0 mg, 20%) as a white solid, m.p. 215–217 °C, as the
1
173 °C. H NMR (CDCl3): δ = 1.47 (s, 9 H, CH3 Boc), 2.24 (s, 3
H, ArCH3), 2.29 (s, 3 H, ArCH3), 2.48 (s, 3 H, ArCH3), 3.40 (s, 3
H, OCH3), 6.24 (s, 1 H, NH), 7.15 (d, J = 8.1 Hz, 1 H, ArH), 7.23–
7.33 (m, 5 H, ArH), 7.40 (d, J = 8.1 Hz, 1 H, ArH) ppm. 13C
NMR (CDCl3): δ = 11.48 (CH3), 13.84 (CH3), 18.16 (CH3), 28.17
(C(CH3)3), 52.01 (OCH3), 81.21 (OC(CH3)3), 118.31 (CH), 126.43
(CH), 126.59 (C), 127.81 (C), 128.04 (CH), 128.52 (C), 128.65
(CH), 129.28 (CH), 130.18 (C), 133.76 (C), 133.94 (C), 138.17 (C),
139.17 (C), 140.52 (C), 152.97 (C=O), 166.27 (C=O) ppm.
C26H29NO4S (451.58): calcd. C 69.15, H 6.47, N 3.10, S 7.10; found
C 69.19, H 6.60, N 3.14, S 7.11.
1
less polar product. H NMR (CDCl3): δ = 2.10 (s, 3 H, Ar–CH3),
2.32 (s, 3 H, Ar–CH3), 2.54 (s, 3 H, Ar–CH3), 3.74 (s, 3 H, OCH3),
7.07 (s, 1 H, ArH), 7.41 (s, 5 H, ArH), 9.07 (broad s, 1 H,
NH) ppm. 13C NMR (CDCl3): δ = 11.80 (CH3), 13.84 (CH3), 20.62
(CH3), 51.64 (OCH3), 116.40 (CH), 118.53 (C), 121.87 (C), 123.47
(C), 126.82 (C), 127.14 (CH), 127.28 (CH), 128.41 (C), 129.83 (C),
130.50 (CH), 132.09 (C), 135.88 (C), 139.94 (C), 162.23 (C=O).
UV(CH2Cl2): λmax (ε mol–1·dm3·cm–1)
= 333 (14750), 266
(30938) nm. MS: m/z (%) = 349 (85) [M]+, 318 (26) [M – OCH3]+,
317 (100), 288 (28). HRMS: calcd. for C21H19NO2S [M]+ 349.1137;
found 349.1130.
(Z)-Boc-ΔPhe[β-(6-methoxy-2,3-dimethylbenzo[b]thien-7-yl)]-OMe
(Z)-4: The procedure described above was followed, with 7-bromo-
6-methoxy-2,3-dimethylbenzo[b]thiophene (0.400 mmol, 108 mg)
and (Z)-Boc-ΔPhe(β-Br)-OMe (0.400 mmol, 142 mg), but with ad-
dition of water (160 μL) in the second step. Column chromatog-
raphy with a solvent gradient from neat petroleum ether to 40%
diethyl ether/petroleum ether gave product (Z)-4 (100 mg, 54%) as
a yellow solid. Recrystallization from petroleum ether gave yellow
Product 5: This compound was eluted next, with 40% diethyl ether/
petroleum ether and was isolated as a white solid (37.0 mg, 60%),
m.p. 267–269 °C. 1H NMR (CDCl3): δ = 2.23 (s, 3 H, Ar–CH3),
2.35 (s, 3 H, Ar–CH3), 2.52 (s, 3 H, Ar–CH3), 3.75 (s, 3 H, OCH3),
7.12 (ap.t, 1 H, ArH), 7.33–7.49 (m, 3 H, ArH), 7.54 (s, 1 H, ArH),
crystals, m.p. 104–106 °C. 1H NMR (CDCl3): δ = 1.41 (s, 9 H, CH3 7.63 (s, 1 H, ArH), 9.04 (broad s, 1 H, NH) ppm. 13C NMR
Boc), 2.26 (s, 3 H, ArCH3), 2.37 (s, 3 H, ArCH3), 3.59 (s, 3 H, (CDCl3): δ = 11.43 (CH3), 13.84 (CH3), 20.40 (CH3), 51.84
OCH3), 3.74 (s, 3 H, 6-OCH3), 5.86 (s, 1 H, NH), 7.04 (d, J = (OCH3), 111.64 (CH), 120.72 (CH), 121.78 (CH), 121.93 (CH),
8.4 Hz, 1 H, ArH), 7.20–7.24 (m, 5 H, ArH), 7.53 (d, J = 8.4 Hz,
123.43 (C), 123.71 (CH), 123.78 (C), 125.78 (CH), 126.69 (C),
128.54 (C), 129.33 (C), 133.38 (C), 133.84 (C), 135.07 (C), 135.70
1 H, ArH) ppm. 13C NMR (CDCl3): δ = 11.33 (CH3), 13.57 (CH3),
2956
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2951–2957

Synthesis of β-Benzo[b]thienyldehydrophenylalanine Derivatives
FULL PAPER
(C), 140.80 (C), 162.46 (C=O). UV (CH2Cl2): λmax (ε
mol–1·dm3·cm–1) = 296 (20875) 240 (48125) nm. MS: m/z (%) = 349
(100) [M]+, 318 (15) [M – OCH3]+, 317 (41). HRMS: calcd. for
C21H19NO2S [M]+: 349.1137; found 349.1126.
Acknowledgments
Financial support by the Foundation for Science and Technology
(Portugal) is acknowledged (project POCTI/99/QUI/32689).
A. S. A. thanks for a Ph.D. stipend (SFRH/BD/4709/2001).
Methyl N-(tert-Butoxycarbonyl)-3-(2,3,7-trimethylbenzo[b]thien-6-
yl)indole-2-carboxylate (7): The procedure described above was ap-
plied with compound (Z)-3 (0.310 mmol, 140 mg) and heating for
2 h at 100 °C. Column chromatography with a solvent gradient
from neat petroleum ether to 10% diethyl ether/petroleum ether
[1] A. S. Abreu, P. M. T. Ferreira, L. S. Monteiro, M.-J. R. P. Quei-
roz, I. C. F. R. Ferreira, R. Calhelha, L. M. Estevinho, Tetrahe-
dron 2004, 11821–11828.
[2] a) A. S. Abreu, N. O. Silva, P. M. T. Ferreira, M.-J. R. P. Quei-
roz, Tetrahedron Lett. 2003, 44, 3377–3379; b) A. S. Abreu,
N. O. Silva, P. M. T. Ferreira, M.-J. R. P. Queiroz, M. Venanzi,
Eur. J. Org. Chem. 2003, 4792–4796.
[3] a) O. Baudoin, D. Guénard, F. Guéritte, J. Org. Chem. 2000,
65, 9268–9271; b) O. Baudoin, M. Cesario, D. Guénard, F. Gu-
éritte, J. Org. Chem. 2002, 67, 1199–1207.
[4] a) J. P. Wolfe, S. L. Buchwald, Angew. Chem. Int. Ed. 1999, 38,
2413–2416; b) J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buch-
wald, J. Am. Chem. Soc. 1999, 121, 9550–9561.
1
gave the compound (70.0 mg, 50%) as an oil. H NMR (CDCl3):
δ = 1.70 (s, 9 H, CH3 Boc), 2.37 (s, 3 H, Ar–CH3), 2.38 (s, 3 H,
Ar–CH3), 2.56 (s, 3 H, Ar–CH3), 3.72 (s, 3 H, OCH3), 7.25–7.27
(m, 2 H, ArH), 7.32 (d, J = 8.1 Hz, 1 H, ArH), 7.42–7.49 (m, 1 H,
ArH), 7.53 (d, J = 8.1 Hz, 1 H, ArH), 8.23 (d, J = 8.4 Hz, 1 H,
ArH) ppm. 13C NMR (CDCl3): δ = 11.47 (CH3), 13.82 (CH3),
18.38 (CH3), 27.91 (C(CH3)3), 52.19 (OCH3), 84.67 (OC(CH3)3),
115.10 (CH), 118.40 (CH), 121.31 (CH), 123.33 (CH), 125.72 (C),
125.84 (C), 126.53 (CH), 127.03 (CH), 127.54 (C), 127.89 (C),
129.25 (C), 130.78 (C), 134.00 (C), 135.93 (C), 138.91 (C), 140.72
(C), 149.30 (C=O), 163.03 (C=O) ppm. MS: m/z (%) = 449 (22)
[5] I. C. F. R. Ferreira, M.-J. R. P. Queiroz, G. Kirsch, Tetrahedron
Lett. 2003, 44, 4327–4329.
ˇ
[6] P.-E. Broutin, I. Cernˇa, M. Campaniello, F. Leroux, F. Colob-
[M]+, 349 (100) [M
–
Boc]+, 317 (43). HRMS: calcd. for
ert, Org. Lett. 2004, 6, 4419–4422.
[7] A. S. Abreu, N. O. Silva, P. M. T. Ferreira, M.-J. R. P. Queiroz,
Tetrahedron Lett. 2003, 44, 6007–6009.
C26H27NO4S [M]+ 449.1650; found 449.1661.
Methyl 3-(2,3,7-Trimethylbenzo[b]thien-6-yl)indole-2-carboxylate
[8] a) P. M. Hawkey, D. A. Lewis, “Medical Bacteriology – A Prac-
tical Approach”, Oxford University Press, U.K., 1994, pp. 181–
194; b) N. Rameshkumar, M. Ashokkumar, E. H. Subraman-
ian, R. Ilavarasan, S. K. Sridhar, Eur. J. Med. Chem. 2003, 38,
1001–1004; c) M.-J. R. P. Queiroz, A. Begouin, I. C. F. R. Fer-
reira, G. Kirsch, R. Calhelha, S. Barbosa, L. M. Estevinho,
Eur. J. Org. Chem. 2004, 3679–3685.
[9] a) J. N. Demas, G. A. Crosby, J. Phys. Chem. 1971, 75, 991–
1024; b) S. Fery-Forges, D. Lavabre, J. Chem. Ed. 1999, 76,
1260–1264.
(8): The procedure described above was applied with compound
(Z)-3 (0.137 mmol, 62.0 mg) and heating for 1 h at 130 °C. Column
chromatography with a solvent gradient from neat petroleum ether
to 20% diethyl ether/petroleum ether, gave compound 8 (41.0 mg,
1
85%) as a yellow solid, m.p. 230 –232 °C. H NMR (CDCl3): δ =
2.34 (s, 3 H, Ar–CH3), 2.38 (s, 3 H, Ar–CH3), 2.56 (s, 3 H, Ar–
CH3), 3.77 (s, 3 H, OCH3), 7.14 (broad t, J = 6.9 Hz, 1 H, ArH),
7.33–7.41 (m, 3 H, ArH), 7.48 (d, J = 9.0 Hz, 1 H, ArH), 7.54 (d,
J = 8.1 Hz, 1 H, ArH), 9.21 (s largo, 1 H, NH) ppm. 13C NMR
(CDCl3): δ = 11.52 (CH3), 13.84 (CH3), 18.33 (CH3), 51.84
(OCH3), 111.70 (CH), 118.09 (CH), 120.70 (CH), 122.04 (CH),
123.50 (C), 125.73 (CH), 127.55 (CH), 127.90 (C), 128.62 (C),
130.54 (C), 133.49 (C), 135.70 (C), 138.75 (C), 140.20 (C),
162.56 (C=O) ppm. MS: m/z (%) = 349 (100) [M]+, 318 (17)
[M – OCH3]+, 317 (46), 288 (22). HRMS: calcd. for C21H19NO2S
[M]+ 349.1137; found 349.1142.
[10] J. V. Morris, M. A. Mahaney, J. R. Huber, J. Phys. Chem. 1976,
80, 969–974.
[11] a) P. Cagniant, P. Faller, D. Cagniant, Bull. Soc. Chim. France
1966, 3055–3065; b) I. C. F. R. Ferreira, M.-J. R. P. Queiroz, G.
Kirsch, J. Heterocycl. Chem. 2001, 38, 749–754.
[12] M.-J. R. P. Queiroz, R. Dubest, J. Aubard, R. Faure, R. Gugli-
elmetti, Dyes Pigments 2000, 47, 219–229.
Received: January 17, 2005
Eur. J. Org. Chem. 2005, 2951–2957
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2957