Sonogashira cross-couplings of dehydroamino acid derivatives and phenylacetylenes

Article abstract of DOI:10.1002/ejoc.200400145

Several phenylacetylenes were coupled under Sonogashira cross-coupling conditions with the methyl esters of N-(tert-butoxycarbonyl)-(E)-β-bromo- or -β,β-dibromodehydroalanine, to give β-substituted or β,β-disubstituted dehydroalanines, respectively. The β-substituted dehydroalanines were obtained in good to high yields (60-90%) under the usual Sonogashira conditions (1 equiv. of the phenylacetylene, 1 mol % of [Pd(PPh₃)₄], 2 mol % of CuI, 18 equiv. of NEt ₃ in acetonitrile, 24 h at room temp.), with retention of stereochemistry. The β,β-disubstituted dehydroalanines were, in turn, obtained in moderate to good yields (44-63%) under modified Sonogashira conditions (4 equiv. of the phenylacetylene, 10 mol % of [PdCl ₂(PPh₃)₂], 20 mol % of CuI, 1.4 equiv. of Cs₂CO₃ in acetonitrile, 2 h at reflux). In the latter reactions, some phenylacetylene dimer and the (E) isomer of the monosubstituted coupled products were also isolated to some extent. The Sonogashira products obtained from the 4-bromophenylacetylene were allowed to react with functionalized benzo[b]thiophenes under C-C or C-N palladium-catalyzed cross-coupling conditions. Preliminary fluorescence studies were performed for mono- and disubstituted (4-aminophenyl)acetylenic dehydroamino acids and for the benzo[b]-thiophene derivatives. The results showed that some of the dehydroalanines prepared can be used as fluorescent probes. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400145

FULL PAPER
Sonogashira Cross-Couplings of Dehydroamino Acid Derivatives and
Phenylacetylenes
[a]
[a]
[a]
[b]
˜
Ana S. Abreu, Paula M. T. Ferreira, Maria-Joao R. P. Queiroz,* Emanuela Gatto,
and Mariano Venanzi[b]
Keywords: Amino acids / Phenylacetylenes / Sonogashira coupling / Palladium / Benzo[b]thiophenes / Fluorescence
Several phenylacetylenes were coupled under Sonogashira
of Cs2CO3 in acetonitrile, 2 h at reflux). In the latter reactions,
cross-coupling conditions with the methyl esters of N-(tert-
some phenylacetylene dimer and the (E) isomer of the
butoxycarbonyl)-(E)-β-bromo- or -β,β-dibromodehydroalan- monosubstituted coupled products were also isolated to some
ine, to give β-substituted or β,β-disubstituted dehydroalan- extent. The Sonogashira products obtained from the 4-brom-
ines, respectively. The β-substituted dehydroalanines were
obtained in good to high yields (60Ϫ90%) under the usual
Sonogashira conditions (1 equiv. of the phenylacetylene, 1
mol % of [Pd(PPh3)4], 2 mol % of CuI, 18 equiv. of NEt3 in
ophenylacetylene were allowed to react with functionalized
benzo[b]thiophenes under CϪC or CϪN palladium-cata-
lyzed cross-coupling conditions. Preliminary fluorescence
studies were performed for mono- and disubstituted (4-amino-
acetonitrile, 24 h at room temp.), with retention of stereo- phenyl)acetylenic dehydroamino acids and for the benzo[b]-
chemistry. The β,β-disubstituted dehydroalanines were, in
turn, obtained in moderate to good yields (44Ϫ63%) under
thiophene derivatives. The results showed that some of the
dehydroalanines prepared can be used as fluorescent probes.
modified Sonogashira conditions (4 equiv. of the phenylacet- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ylene,10 mol % of [PdCl2(PPh3)2], 20 mol % of CuI, 1.4 equiv.
Germany, 2004)
Introduction
several phenylacetylenes. Some of the coupled products were
allowed
to
react
with
functionalized
benzo-
[b]thiophenes by palladium-catalyzed (CϪC or CϪN) cross-
couplings. The acetylenic dehydroamino acids obtained may
have biological activity, and some of them may be used as
probes when inserted into peptides, due to their fluorescence
properties.
In recent years, dehydroamino acids have shown to be ver-
satile substrates for the synthesis of novel amino acids.[1,2]
We have been interested in the synthesis of benzo[b]thienyl-
amino acids that may have biological activity or may be used
as fluorescent probes when inserted into peptides.[3] Using
several differently functionalized benzo[b]thiophenes, we have
been able to synthesize new amino acids and dehydroamino
acids either by Suzuki coupling or by sequential Michael ad-
dition and CϪC (Suzuki) or CϪN palladium-catalyzed
cross-couplings.[4aϪ4c]
Some ethynylamino acid derivatives have been isolated
from microorganisms or prepared by various methods, and
have shown biological activities.[5] Sonogashira cross-coupling
reactions have been used in the synthesis of alkynylamino
acid derivatives having the triple bond either in the amino
acid side chain[6,7] or in its amine function.[8]
Results and Discussion
The methyl esters of N-(tert-butoxycarbonyl)-(E)-β-bromo-
[4a]
and -β,β-dibromodehydroalanine[4c] were coupled with
several phenylacetylenes under different Sonogashira con-
ditions to give the corresponding coupled products (Scheme 1
and 2).
The coupled products (E)-1aϪc were obtained in good to
high yields (60Ϫ90%) from the methyl ester of N-(tert-bu-
toxycarbonyl)-(E)-β-bromodehydroalanine, under the usual
Sonogashira coupling conditions[6,9] (Scheme 1). In this reac-
tion, NEt3 is usually used as base and solvent (ca. 18 equiv.),
but in our case, it was necessary to add a small amount of
acetonitrile, due to the low solubility of the starting materials
in NEt3.
Herein, we describe the use of Sonogashira cross-coupling
for the synthesis of dehydroamino acids, in which β-bromo-
or β,β-dibromodehydroalanine derivatives were coupled with
[a]
´
Departamento de Quımica Ϫ Universidade do Minho,
Gualtar, 4710-057 Braga, Portugal
Fax: (internat.) ϩ 351-253678983
E-mail: mjrpq@quimica.uminho.pt
Department of Chemical Sciences and Technologies, University
of Tor Vergata,
The stereochemistry of the products was determined by
NOE difference experiments, observing an enhancement of
the β-CH signal when α-NH was irradiated.
[b]
00133 Rome, Italy
Eur. J. Org. Chem. 2004, 3985Ϫ3991
DOI: 10.1002/ejoc.200400145
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3985

A. S. Abreu, P. M. T. Ferreira, M.-J. R. P. Queiroz, E. Gatto, M. Venanzi
FULL PAPER
The best conditions to obtain disubstituted coupled prod-
ucts from the β,β-dibromodehydroalanine derivative, found
after several experiments, are shown in Scheme 2. Com-
pounds 2aϪc were isolated in moderate to good yields, to-
gether with a small amount of the corresponding monosub-
stituted (E) isomer and the phenylacetylene dimers. The
change of NEt3 to Cs2CO3 was crucial for the formation of
the disubstituted coupled products. In fact, even when the
amount of NEt3 was lowered to 9 equiv. in the coupling of
phenylacetylene with the dibromo compound, only the
monosubstituted compound (E)-1a and the phenylacetylene
dimer were isolated. The use of 1.4 equiv. of Cs2CO3 gave the
best yields of the disubstituted compounds. In the coupling
of (4-aminophenyl)acetylene using 2.8 equiv. of Cs2CO3, the
disubstituted product 2b was only obtained in 10% yield, to-
gether with 20% of the monosubstituted (E)-1b and an in-
creased amount of the corresponding dimer. Higher yields of
the disubstituted products were obtained when the reactions
were carried out in refluxing acetonitrile instead of room tem-
perature, and when [PdCl2(PPh3)2] was used. Compound 2a
was obtained in only 25% yield, together with (E)-1a in 27%
yield and the corresponding acetylene dimer, using the best
conditions but stirring at room temperature for 18 h.
The differences in the reaction yields for compounds 2aϪc
(Scheme 2) are due to the different amounts of the corre-
sponding phenylacetylene dimers obtained in the reactions
(see Exp. Sect.).
Scheme 1. i) 1 equiv. of the phenylacetylene, 1 mol% of [Pd(PPh3)4],
2 mol% of CuI, 18 equiv. of NEt3 in acetonitrile, 24 h at room temp.
Compounds (E)-1c and 2c were allowed to undergo pal-
ladium-catalyzed CϪC and CϪN cross-couplings with func-
tionalized benzo[b]thiophenes. Benzo[b]thiophene-3-boronic
acid reacted under Suzuki cross-coupling conditions[4b] with
compound (E)-1c to give compound 3 in 50% yield, along
with 3,3Ј-bi(benzo[b]thienyl) (18%) (Scheme 3). Compound
2c reacted with 7-amino-2,3-dimethylbenzo[b]thiophene[4b]
under CϪN palladium-catalyzed cross-coupling con-
ditions[4b] to give compound 4 in 40% yield, together with the
starting aminobenzo[b]thiophene (40%), due to some de-
composition of the starting dehydroamino acid (Scheme 4).
Scheme 2. i)
4 equiv. of the phenylacetylene, 10 mol% of
[PdCl2(PPh3)2], 20 mol% of CuI, 1.4 equiv. of Cs2CO3, 2 h at reflux
of acetonitrile
Scheme 3
The reaction yields significantly increased when the phenyl-
acetylene was para-substituted either with a bromine atom or
an amino group.
The UV/Vis absorption and fluorescence properties of
The same reaction conditions applied to the coupling of compounds (E)-1b, 2b, (E)-3 and 4 were studied with the aim
the methyl ester of N-(tert-butoxycarbonyl)-β,β-dibromo- of using these compounds as fluorescent probes.
dehydroalanine with (4-aminophenyl)acetylene (2 equiv.) gave
The absorption spectral features of compounds (E)-1b and
only the monosubstituted derivative (E)-1b in 35% yield, 2b in dichloromethane are very different (Figure 1). The red-
along with a significant amount of the corresponding phenyl- shifted absorption of (E)-1b suggests a large delocalization of
acetylene dimer. The isolation of the (E) isomer could be due the (aminophenyl)acetylenic electron distribution over
to the fact that the first oxidative addition occurs at the less the entire molecule, lowering the FranckϪCondon energy
hindered side of the carbonϪhalogen bonds, as has been ob- gap. The linkage of
a
second (4-aminophenyl)acet-
served by other authors for the case of 1,1-dibromo-1-al- ylene strongly perturbs the spectral profile of compound
kenes.[10]
2b, shifting its lowest energy absorption band to shorter wave-
3986
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Sonogashira Cross-Couplings of Dehydroamino Acid Derivatives and Phenylacetylenes
FULL PAPER
radiative electronic states of the dehydroamino acid (internal
conversion).
Scheme 4
Figure 2. Fluorescence spectra of compounds (E)-1b and 2b in di-
chloromethane
The high fluorescence quantum yield of compound 2b sug-
gests that the linkage of a second (4-aminophenyl)acetylene
weakens the electronic coupling with the dehydroamino acid
moiety, decreasing the efficiency of non-radiative processes.
The polar character of the new emissive state is proved by
the strong solvent dependence of compound 2b emission
(Figure 3). Lower quantum yields and longer lifetimes in po-
lar solvents are typical of radiative charge-transfer states;[11]
the fluorescence properties of compound 2b in acetonitrile
show these features (Table 1). The time-resolved fluorescence
decay of the latter compound is described by a function con-
taining two exponential components in both solvents studied,
implying that at least two different electronic states contribute
to its emission.
lengths, and splitting it into two components. These findings
suggest the occurrence of a strong electronic coupling be-
tween the two phenylacetylenic groups in compound 2b. The
exciton-like character of this interaction is shown by the split-
ting of the lowest energy absorption band, while the shift to
shorter wavelengths indicates the predominant stabilization of
the chromophore ground state with respect to the electronic
excited state.
Figure 1. Absorption spectra of compounds (E)-1b and 2b in di-
chloromethane
Figure 3. Fluorescence spectra of compound 2b in dichloromethane
(DCM) and acetonitrile (MeCN)
This interaction is also responsible for the different fluor-
escence properties of compounds (E)-1b and 2b (Figure 2).
The emission of (E)-1b is hardly detectable, implying that its
The absorption spectra of compound (E)-3 is dominated
lowest energy excited state decays through very efficient non- at low energies by the π,π* transitions of the phenylacetylene
radiative relaxation processes. This is probably due to the moiety, as shown in Figure 4. The absorption profile of com-
electronic coupling of the phenylacetylene moiety with non- pound 4 shows a broader band, with respect to the spectrum
Eur. J. Org. Chem. 2004, 3985Ϫ3991
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A. S. Abreu, P. M. T. Ferreira, M.-J. R. P. Queiroz, E. Gatto, M. Venanzi
Table 1. The fluorescence lifetimes (τi), pre-exponential factors (αi) and quantum yields (φ) for compound 2b
FULL PAPER
Solvent
λem (max.) [nm]
Φ[a]
τ1 [ns]
α1
τ2 [ns]
α2
ϽτϾ [ns][b]
Dichloromethane
Acetonitrile
467
498
0.03
0.01
0.27
0.74
0.98
0.98
1.94
2.66
0.02
0.02
0.31
0.78
[a]
[b]
With respect to anthracene in ethanol (Φ ϭ 0.27 0.01). ϽτϾ ϭ α1τ1ϩ α2τ2.
of the compound (E)-3, suggesting the occurrence of a second
spectral component, associated with the aminobenzothi-
ophene group at shorter wavelengths.
Figure 5. Fluorescence spectra of compounds (E)-3 and 4 in MeCN
(λexc 334 nm)
Figure 4. Absorption spectra of compounds (E)-3 and 4 in aceto-
nitrile (MeCN)
by the second time component (Table 2) found in the time-
resolved fluorescence measurement. This interaction has been
found in other aminobenzothiophene-based compounds, and
is currently under investigation in our laboratory.
These preliminary results suggest that compounds 2b and
(E)-3 can be used as fluorescent probes when inserted into
peptides. A proper selection of the chromophores and the
fine-tuning of the interactions that involve the aromatic moi-
eties could be usefully exploited to modulate the fluorescence
properties of the newly designed compounds.
The fluorescence time decay of compound (E)-3 is de-
scribed by a single exponential function (Table 2) and its em-
ission quantum yield is notably higher than that one of com-
pound 4, as shown in Figure 5. These findings suggest that
the excited state electronic distribution of (E)-3 is localized
on the phenylacetylene moiety.
Table 2. Fluorescence data of compounds (E)-3 and 4 in acetonitrile
Compound λem (max) [nm] Φ[a]
τ1 [ns] α1
τ2 [ns] α2
(E)-3
4
471
471
0.14
0.006 0.8
1.2
1.0
0.96 2.5
Ϫ
Ϫ
0.04
[a]
Conclusions
With respect to anthracene in ethanol (Φ ϭ 0.27 0.01).
The emission quantum yield of compound 4 is very low,
and its time decay is described by two time components
(Table 2). Due to extensive overlap between the wavelengths
of aminobenzothiophene fluorescence emission and the phe-
nylacetylene absorption, a complete intramolecular energy
transfer process occurs, leading to emission only from the
phenylacetylene moiety. The presence in compound 4 of an
amino group (a strong electron donor) bridging the electron
distributions of the benzothiophene and the phenylacetylene
groups favors the formation of an intramolecular charge
transfer (ICT) state. ICT states are characterized by very low
quantum yield and relatively slow decay times,[11] as revealed
Several new acetylenic α,β-dehydroamino acids were pre-
pared using Sonogashira cross-coupling reactions. Different
conditions were established to obtain either eneyne or ‘‘ene-
diyne’’ amino acids. The dehydroamino acids having a bro-
mine atom in their side chains, (E)-1c and 2c, were coupled
with benzo[b]thiophenes by CϪC (Suzuki) or CϪN pal-
ladium-catalyzed cross-couplings to give the benzo[b]thienyl
amino acids (E)-3 and 4.
The photophysical properties of four of the compounds
obtained were studied. The results suggest that two of them
can be used as fluorescent markers.
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Sonogashira Cross-Couplings of Dehydroamino Acid Derivatives and Phenylacetylenes
FULL PAPER
(CH), 129.01 (CH), 131.65 (CH), 134.86 (C), 151.71 (CϭO), 164.36
(CϭO) ppm. C17H19NO4 (301.34): calcd. C 67.76, H 6.35, N 4.65;
found C 67.50, H 6.34, N 4.75.
Experimental Section
General Remarks: Melting points were determined with a Gallenk-
amp apparatus and are uncorrected. The 1H NMR spectra were
measured with a Varian Unity Plus at 300 MHz. Spin-spin decoup-
ling techniques were used to assign the signals. NOE experiments
were performed to determine the stereochemistry of the products.
The 13C NMR spectra were measured with the same instrument at
75.4 MHz (using DEPT, θ ϭ 45°). Elemental analyses were deter-
mined with a LECO CHNS 932 elemental analyser. Mass spectra (EI
and FAB) and HRMS data were recorded by the mass spectrometry
service of University of Vigo-Spain. Steady-state fluorescence spectra
were recorded with a Fluoromax spectrofluorimeter (JobinϪYvon,
France), operating in SPC (Single Photon Counting) mode. Quantum
yields were obtained by using anthracene in ethanol as reference:
Φr ϭ 0.27 0.01. The quantum yields of the samples are given by
Φs ϭ [(ArFsn2s)/(AsFrn2r)]Φr, where A is the absorbance at the exci-
tation wavelength, F the integrated emission area and n the refraction
index of the solvent used. Subscripts refer to the reference (r) or
sample (s) compound. Nanosecond time decays were measured by a
CD-900 (Edinburgh Instruments, Edinburgh, U.K.) lifetime appar-
atus with SPC detection. Excitation in the UV region was achieved
by a flashlamp filled with ultrapure hydrogen (300 Torr), working at
a repetition rate of 30 kHz. Under these conditions, the full width at
half maximum (FWHM) of the excitation profile was 1.2 ns. Exper-
imental decay curves were fitted by a non-linear least-squares analysis
to exponential functions or time distributions through an iterative
deconvolution method, using standard software licensed by Edin-
burgh Instruments. All fluorescence experiments were carried out in
quartz cells, using solutions previously bubbled with ultrapure nitro-
gen for 20 min. All solutions for fluorescence measurements were
freshly prepared at micromolar concentrations [absorbances Ͻ 0.1
(l ϭ 1 cm) to avoid inner filter effects]. Excitation wavelengths used
were as follows. (E)-1b: λexc ϭ 360 nm; 2b: λexc ϭ 321 nm; (E)-3:
λexc ϭ 334 nm; 4: λexc ϭ 334 nm. Column chromatography was per-
formed on MachereyϪNagel silica gel 230Ϫ400 mesh. Petroleum
ether refers to the boiling range 40Ϫ60 °C. Ether refers to diethyl
ether. When a solvent gradient was used, the polarity was gradually
increased from neat petroleum ether to mixtures of ether/petroleum
ether by 10% increments of ether until the product could be isolated.
Boc-(E)-∆Ala{β-[2-(4-aminophenyl)ethynyl]}؊OMe [(E)-1b]: Column
chromatography using ether as solvent gave product (E)-1b (284 mg,
90%) as a yellow solid. Recrystallization from ether gave yellow crys-
tals, m.p. 107.8Ϫ108.8 °C. 1H NMR (CDCl3): δ ϭ 1.50 (s, 9 H, CH3
Boc), 3.83 (s, 3 H, OCH3), 3.91 (br. s, 2 H, NH2), 6.30 (s, 1 H, βCH),
6.45 (br. s, 1 H, NH), 6.62 (d, J ϭ 8.4 Hz, 2 H, ArH ortho to NH2),
7.29 (d, J ϭ 8.4 Hz, 2 H, ArH meta to NH2) ppm. 13C NMR
(CDCl3): δ ϭ 28.04 [C(CH3)3], 52.49 (OCH3), 81.18 [OC(CH3)3],
82.50 (C), 104.35 (C), 107.49 (CH), 111.32 (C), 114.53 (CH), 133.27
(CH), 133.35 (C), 147.58 (C), 151.97 (CϭO), 164.56 (CϭO) ppm.
C17H20N2O4 (316.36): calcd. C 64.54, H 6.37, N 8.86; found C 64.27,
H 6.09, N 8.84.
Boc-(E)-∆Ala{β-[2-(4-bromophenyl)ethynyl]}؊OMe [(E)-1c]: Column
chromatography using a solvent gradient from neat petroleum ether
to 40% ether/petroleum ether gave product (E)-1c (304 mg, 80%) as
a solid. Recrystallization from ether/petroleum ether gave colourless
1
crystals, m.p. 123.1Ϫ124.1 °C. H NMR (CDCl3): δ ϭ 1.49 (s, 9 H,
CH3 Boc), 3.84 (s, 3 H, OCH3), 6.27 (s, 1 H, βCH), 6.59 (br. s, 1 H,
NH), 7.32 (d, J ϭ 8.4 Hz, 2 H, ArH meta to Br), 7.47 (d, J ϭ 8.4 Hz,
2 H, ArH ortho to Br) ppm. 13C NMR (CDCl3): δ ϭ 28.04
[C(CH3)3], 52.75 (OCH3), 81.46 [OC(CH3)3], 85.22 (C), 101.34 (C),
105.41 (CH), 121.45 (C), 123.37 (C), 131.65 (CH), 133.03 (CH),
134.88 (C), 151.48 (CϭO), 164.29 (CϭO) ppm. C17H18BrNO4
(380.24): calcd. C 53.70, H 4.77, N 3.68; found C 53.85, H 4.89,
N 3.72.
General Procedure for Sonogashira Cross-Coupling Using the Methyl
Ester of N-(tert-Butoxycarbonyl)-β,β-dibromodehydroalanine and Phe-
nylacetylenes: CuI (20 mol %, 20.0 mg), PdCl2(PPh3)2 (10 mol %,
36.0 mg) and Cs2CO3 (1.4 equiv., 228 mg) were added to a solution
of compound Boc-∆Ala(β,β-Br)ϪOMe (0.5 mmol, 180 mg) in aceto-
nitrile (5 mL), and then the alkyne (4 equiv.) was added. The reaction
mixture was stirred rapidly at 85 °C under argon for 1 h 30 min. The
acetonitrile was removed under reduced pressure and the residue was
dissolved in 15 mL of ethyl acetate. The organic phase was then
washed with water and brine (2 ϫ 15 mL each), dried with MgSO4
and the solvents were evaporated at reduced pressure giving an oil
which was submitted to column chromatography on silica.
General Procedure for Sonogashira Cross-Coupling Using the Methyl
Ester of N-(tert-Butoxycarbonyl)-(E)-β-bromodehydroalanine and Phe-
nylacetylenes: CuI (2 mol %, 4.00 mg) and [Pd(PPh3)4] (1 mol %,
11.0 mg) were added to a solution of Boc-(E)-∆Ala(β-Br)ϪOMe
(1 mmol, 280 mg) in triethylamine (18 equiv.), with rapid stirring un-
der argon at room temperature, and then a solution of the alkyne (1
equiv.) in acetonitrile (0.5 mL) was added. The reaction mixture was
left stirring for 24 h. The acetonitrile was removed under reduced
pressure and the residue was dissolved in 30 mL of ethyl acetate. The
organic phase was then washed with water and brine (2 ϫ 15 mL
each), dried with MgSO4, and the solvents were evaporated at re-
duced pressure giving an oil which was submitted to column chroma-
tography.
Boc-∆Ala{β,β-bis[2-(phenyl)ethynyl]}؊OMe (2a): Column chroma-
tography using a solvent gradient from neat petroleum ether to 80%
ether/petroleum ether, gave, as a less polar product, the dimer of the
phenylacetylene (22.0 mg) as a white solid, m.p. 85Ϫ87 °C. 1H NMR
(CDCl3): δ ϭ 7.35Ϫ7.38 (m, 6 H, ArH), 7.53Ϫ7.56 (m, 4 H, ArH)
ppm, followed by compound 2a (104 mg, 52%) as an oil. Recrystalli-
zation from ether/petroleum ether gave colourless crystals, m.p.
113.7Ϫ114.0 °C. 1H NMR (CDCl3): δ ϭ 1.50 (s, 9 H, CH3 Boc),
3.95 (s, 3 H, OCH3), 6.96 (br. s, 1 H, NH), 7.32Ϫ7.34 (m, 3 H, ArH),
7.38Ϫ7.40 (m, 3 H, ArH), 7.46Ϫ7.49 (m, 2 H, ArH), 7.53Ϫ7.56 (m,
2 H, ArH) ppm. 13C NMR (CDCl3): δ ϭ 28.00 [C(CH3)3], 52.68
(OCH3), 81.97 [OC(CH3)3], 82.69 (C), 83.19 (C), 92.64 (C), 98.35 (C),
121.84 (C), 122.61 (C), 128.26 (CH), 128.45 (CH), 128.56 (CH),
129.23 (CH), 131.53 (CH), 131.72 (CH), 140.53 (C), 150.74 (CϭO),
163.33 (CϭO) ppm. C25H23NO4 (401.46): calcd. C 74.80, H 5.77, N
3.49; found C 74.69, H 5.87, N 3.53. Compound (E)-1a (22.0 mg,
14%) was isolated as a more polar product.
Boc-(E)-∆Ala{β-[2-(phenyl)ethynyl]}؊OMe [(E)-1a]: Column chroma-
tography using a solvent gradient from neat petroleum ether to 50%
ether/petroleum ether gave product (E)-1a (178 mg, 60%) as an oil.
Recrystallization from ether/petroleum ether gave yellow crystals,
m.p. 108.8Ϫ109.5 °C. 1H NMR (CDCl3): δ ϭ 1.49 (s, 9 H, CH3
Boc), 3.84 (s, 3 H, OCH3), 6.28 (s, 1 H, βCH), 6.60 (broad s, 1 H, Boc-∆Ala{β,β-bis[2-(4-aminophenyl)ethynyl]}؊OMe (2b): Column
NH), 7.33Ϫ7.35 (m, 3 H, ArH), 7.46Ϫ7.49 (m, 2 H, ArH) ppm. 13
NMR (CDCl3): 28.02 [C(CH3)3], 52.63 (OCH3), 81.40
C
chromatography using a solvent gradient from neat petroleum ether
to 80% ether/petroleum ether, gave, as a less polar product, com-
δ
ϭ
[OC(CH3)3], 83.93 (C), 102.49 (C), 105.85 (CH), 122.41 (C), 128.33 pound (E)-1b (16 mg, 10%), followed by the dimer of (4-aminopheny-
Eur. J. Org. Chem. 2004, 3985Ϫ3991
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A. S. Abreu, P. M. T. Ferreira, M.-J. R. P. Queiroz, E. Gatto, M. Venanzi
FULL PAPER
l)acetylene as a solid (50.0 mg), m.p. 220Ϫ222 °C. 1H NMR (CDCl3): C؊N Cross-Coupling
δ ϭ 3.88 (br. s, 4 H, 2 ϫ NH2), 6.60 (d, J ϭ 9 Hz, 4 H, 2 ϫ ArH
Synthesis
of
Boc-∆Ala(β,β-bis{2-[4-amino(2,3-dimethylbenzo[b]-
ortho to NH2) 7.32 (d, J ϭ 9 Hz, 4 H, 2 ϫ ArH meta to NH2) ppm.
C16H12N2 (232.28): calcd. C 82.73, H 5.21, N 12.06; found C 82.47,
H 5.49, N 12.05. As a more polar product, compound 2b was isolated
as an oil (93.0 mg, 44%). Recrystallization from diethyl ether/n-hex-
ane gave a yellow solid, m.p. 129.6Ϫ131.8 °C. 1H NMR (CDCl3):
δ ϭ 1.43 (s, 9 H, CH3 Boc), 3.84 (br. s, 4 H, NH2), 3.93 (s, 3 H,
OCH3), 6.26 (s, 1 H, NH), 6.63 (d, J ϭ 8.7 Hz, 2 H, ArH ortho to
NH2), 6.68 (d, J ϭ 8.7 Hz, 2 H, ArH ortho to NH2), 7.23 (d, J ϭ
8.7 Hz, 2 H, ArH meta to NH2), 7.34 (d, J ϭ 8.7 Hz, 2 H, ArH
meta to NH2) ppm. 13C NMR (CDCl3): δ ϭ 27.19 [C(CH3)3], 51.72
(OCH3), 80.88 [OC(CH3)3], 85.37 (C), 94.23 (C), 112.70 (C), 113.84
(C), 114.35 (CH), 114.65 (CH), 120.81 (C), 124.34 (C), 130.15 (CH),
132.93 (CH), 139.05 (C), 146.66 (C), 146.91 (C), 149.26 (C), 160.51
thien-7-yl)phenyl]ethynyl})؊OMe (4): A dried Schlenk tube was
charged under Ar with dry toluene (1.5 mL) and compound 2c
(0.150 mmol, 84.0 mg), and the mixture was heated at 80 °C for
10 min. Pd(OAc)2 (0.0300 mmol, 6.73 mg), BINAP (0.0450 mmol,
28.0 mg) and Cs2CO3 (0.420 mmol, 137 mg) were added and the mix-
ture was heated at 80 °C for another 10 min. 7-Amino-2,3-dimeth-
ylbenzo[b]thiophene (0.300 mmol, 53 mg) was added in dry toluene
(1.5 mL), and the mixture was heated with stirring at 100 °C under
Ar for ca. 1 h 30 min. After cooling, water and diethyl ether were
added, the phases were separated, and then the aqueous phase was
washed with diethyl ether (3 ϫ 10 mL). The organic phase was col-
lected, dried with MgSO4, filtered, and then the solvent was evapo-
rated at reduced pressure giving a brown oil, which was subjected to
column chromatography after traces of toluene were evaporated using
MeOH. A solvent gradient from neat petroleum ether to 50% diethyl
ether/petroleum ether was used, giving product 4 (44 mg, 40%) as a
(CϭO),
170.71
(CϭO)
ppm.
MS:
m/z (%) ϭ 431 (20) [Mϩ], 331 (100) [Mϩ Ϫ Boc], 299 (49), 270 (42).
HRMS: calcd. for C25H25N3O4 [Mϩ] 431.1844; found 431.1845.
1
Boc-∆Ala{β,β-bis[2-(4-bromophenyl)ethynyl]}؊OMe (2c): Column
chromatography using a solvent gradient from neat petroleum ether
to 20% ether/petroleum ether, gave, as a less polar product, the dimer
of (4-bromophenyl)acetylene as a solid (10 mg), m.p. 257Ϫ258 °C.
1H NMR (CDCl3): δ ϭ 7.39 (d, J ϭ 8.7 Hz, 4 H, 2 ϫ ArH meta to
Br) 7.49 (d, J ϭ 8.7 Hz, 4 H, 2 ϫ ArH ortho to Br) ppm; C16H8Br2
(360.05): calcd. C 53.37, H 2.24; found C 53.28, H 2.27, followed by
compound 2c, which was isolated as a white solid (177 mg, 63%).
Recrystallization from ether/petroleum ether gave white crystals, m.p.
175.6Ϫ176.1 °C. 1H NMR (CDCl3): δ ϭ 1.50 (s, 9 H, CH3 Boc),
3.93 (s, 3 H, OCH3), 6.93 (br. s, 1 H, NH), 7.32 (d, J ϭ 8.4 Hz, 2 H,
ArH meta to Br), 7.39 (d, J ϭ 8.4 Hz, 2 H, ArH meta to Br), 7.46
(d, J ϭ 8.4 Hz, 2 H, ArH ortho to Br), 7.52 (d, J ϭ 8.4 Hz, 2 H,
ArH ortho to Br) ppm. 13C NMR (CDCl3): δ ϭ 28.01 [C(CH3)3],
52.79 (OCH3), 82.83 (C), 82.98 (C), 84.12 (C), 91.66 (C), 97.35 (C),
120.78 (C), 121.50 (C), 122.95 (C), 123.74 (C), 131.60 (CH), 131.80
(CH), 132.94 (CH), 133.11 (CH), 141.09 (C), 150.60 (C), 163.17 (Cϭ
O), 170.76 (CϭO) ppm. C25H21Br2NO4 (559.25): calcd. C 53.69, H
3.78, N 2.50; found C 53.68, H 4.01, N 2.60. As a more polar prod-
uct, compound (E)-1c (31 mg, 16%) was isolated.
brown oil. H NMR (CDCl3): δ ϭ 1.47 (s, 9 H, CH3 Boc), 2.33 (s,
6 H, 2 ϫ CH3), 2.50 (s, 6 H, 2 ϫ CH3), 3.95 (s, 3 H, OCH3), 5.73
(br. s, 2 H, 2 ϫ NH), 6.33 (s, 1 H, NH), 6.97 (d, J ϭ 8.7 Hz, 2 H,
ArH), 7.02 (d, J ϭ 8.7 Hz, 2 H, ArH), 7.23 (br. dd, J ϭ 6.3, 2.4 Hz,
2 H, ArH), 7.34 (m, 6 H, ArH), 7.43 (d, J ϭ 8.7 Hz, 2 H, ArH) ppm.
13C NMR (CDCl3): δ ϭ 11.65 (CH3), 13.84 (CH3), 27.28 [C(CH3)3],
51.79 (OCH3), 81.59 [OC(CH3)3], 85.55 (C), 94.02 (C), 113.53 (CH),
113.67 (C), 114.13 (CH), 114.48 (CH), 114.78 (C), 116.25 (CH),
116.29 (CH), 116.40 (CH), 116.45 (CH), 122.81 (C), 124.76 (C),
124.95 (CH), 128.12 (C), 128.15 (C), 130.04 (CH), 130.53 (C), 130.74
(C), 132.82 (CH), 133.26 (C), 133.34 (C), 135.83 (C), 136.08 (C),
138.71 (C), 142.78 (C), 143.54 (C), 143.81 (C), 149.20 (CϭO), 160.50
(CϭO) ppm. MS (FAB): m/z (%) ϭ 752 (26) [Mϩ ϩ H], 751 (26)
[Mϩ] 652 (36) [Mϩ ϩ H Ϫ Boc] 651 (53) [Mϩ Ϫ Boc]. HRMS: calcd.
for C45H42N3O4S2 [Mϩ ϩ H]ϩ 752.2617; found 752.2635.
Acknowledgments
Foundation for the Science and Technology (Portugal) for financial
support to: CQ-Univ. Minho, POCTI/99/QUI/32689 project and to
SFRH/BD/4709/2001 PhD financial support of A. S. A.
Suzuki Coupling
Synthesis
of
Boc-(E)-∆Ala(β-{2-[4-(benzo[b]thien-3-yl)phenyl]-
ethynyl})؊OMe [(E)-3]: Compound (E)-1c (0.300 mmol, 114 mg) was
coupled with benzo[b]thiophene-3-boronic acid (0.330 mmol,
59.0 mg), using Pd(PPh3)4 (0.0300 mmol, 35.0 mg) and Na2CO3
(0.600 mmol, 63.6 mg) in DME/H2O (10:1) at 90 °C for 3 h. After
cooling, water and ethyl acetate were added and the phases were
separated. The organic phase was washed with brine, dried with
MgSO4, filtered, and the solvents were evaporated at reduce pressure
to give an oil. Column chromatography on silica using a solvent
gradient from neat petroleum ether to 30% diethyl ether/petroleum
ether, gave product (E)-3 (65.0 mg, 50%) as a white solid. Recrystalli-
zation from diethyl ether/petroleum ether gave colourless crystals,
m.p. 142.8Ϫ144.0 °C. 1H NMR (CDCl3): δ ϭ 1.53 (s, 9 H, CH3
Boc), 3.87 (s, 3 H, OCH3), 6.32 (s, 1 H, βCH), 6.58 (s, 1 H, NH),
7.40Ϫ7.44 (m, 2 H, ArH), 7.46 (s, 1 H, ArH), 7.60 (s, 4 H, ArH),
7.90Ϫ7.95 (m, 2 H, ArH) ppm. 13C NMR (CDCl3): δ ϭ 28.10
[C(CH3)3], 52.72 (OCH3), 81.47 [OC(CH3)3], 84.78 (C), 102.45 (C),
105.77 (CH), 121.58 (C), 122.66 (CH), 122.98 (CH), 124.12 (CH),
124.50 (CH), 124.56 (CH), 128.59 (CH), 132.10 (CH), 134.85 (C),
136.70 (C), 137.12 (C), 137.40 (C), 140.69 (C), 151.66 (CϭO), 164.39
(CϭO) ppm. MS: m/z (%) ϭ 433 (18) [Mϩ], 333 (100) [Mϩ Ϫ Boc],
273 (30), 245 (23). HRMS: calcd. for C25H23NO4S [Mϩ] 433.1328;
found 433.1348.
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Eur. J. Org. Chem. 2004, 3985Ϫ3991

Sonogashira Cross-Couplings of Dehydroamino Acid Derivatives and Phenylacetylenes
FULL PAPER
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