Palladium-catalyzed borylation and Suzuki coupling (BSC) to obtain β-substituted dehydroamino acid derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01473-4

Several benzo[b]thienyldehydroamino acids were prepared by one-pot palladium-catalyzed borylation and Suzuki coupling (BSC) from bromobenzo[b]thiophenes containing EDG (OMe or Me), as the component to be borylated with pinacolborane, and pure stereoisomer

Full text of DOI:10.1016/S0040-4039(03)01473-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6007–6009
Palladium-catalyzed borylation and Suzuki coupling (BSC) to
obtain b-substituted dehydroamino acid derivatives
Ana S. Abreu, Nata´lia O. Silva, Paula M. T. Ferreira and Maria-Joa˜o R. P. Queiroz*
Departamento de Qu´ımica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Received 26 May 2003; revised 13 June 2003; accepted 14 June 2003
Abstract—Several benzo[b]thienyldehydroamino acids were prepared by one-pot palladium-catalyzed borylation and Suzuki
coupling (BSC) from bromobenzo[b]thiophenes containing EDG (OMe or Me), as the component to be borylated with
pinacolborane, and pure stereoisomers of b-bromodehydroamino acid derivatives. To our knowledge it is the first time that the
BSC reaction involves a non aromatic system.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
[b]thiophenes, as the component to be borylated, and
pure stereoisomers of b-bromodehydroamino acid
derivatives. To our knowledge it is the first time that
this BSC reaction involves a non aromatic system.
In the last few years we have been interested in the
synthesis of non-proteinogenic amino acids,1 in particu-
lar in the preparation of benzo[b]thienyldehydroamino
acids for biological and/or photochemical applications.2
2. Results and discussion
Recently we have described the successful application
of the BSC reaction3 to the synthesis of 2-methyl-2%-
nitro diaryl compounds in the benzo[b]thiophene
series.4 Here we describe the use of the same methodol-
ogy to synthesize benzo[b]thienyldehydroamino acids
from ortho-methylated or methoxylated bromobenzo-
The b-bromodehydroamino acid derivatives were pre-
pared according to a procedure already described by us
and when necessary the stereoisomers were separated
by column chromatography.2a The bromobenzo[b]-
thiophenes were obtained by bromination (using
Scheme 1.
Keywords: benzo[b]thiophenes; borylation; palladium; Suzuki coupling; dehydroamino acids.
* Corresponding author. Fax: +351-253678983; e-mail: mjrpq@quimica.uminho.pt
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01473-4

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A. S. Abreu et al. / Tetrahedron Letters 44 (2003) 6007–6009
Br2) of the corresponding methylated5 or methoxylated6
benzo[b]thiophenes. These were used as the component
to be borylated with pinacolborane and the other
Suzuki component was a b-bromodehydroamino acid
derivative (Scheme 1).
with maintenance of the stereochemistry, which was
determined by NOE difference experiments. In all cases
debrominated methoxy or methylbenzo[b]thiophenes
were isolated as by-products in 25–35% yield. When
b-bromodehydroalanine was used, addition of water in
the Suzuki coupling gave the products in lower yields.
In fact compound 1 was obtained only in 22% yield
when water was added in the second step and in 44%
The benzo[b]thienyldehydroamino acid derivatives 1–5
were obtained in moderate to good yields (Table 1),
Table 1. Brominated starting materials and product yields of the BSC reaction

A. S. Abreu et al. / Tetrahedron Letters 44 (2003) 6007–6009
6009
yield without water. With the other dehydroamino acid
derivatives the addition of a small amount of water
increased the product yields. For instance, the yield in
the synthesis of compound 3 was increased from 40 to
61% (see Ref. 7).
3. (a) Baudoin, O.; Gue´nard, D.; Gue´ritte, F. J. Org. Chem.
2000, 65, 9268–9271; (b) Baudoin, O.; Cesario, M.; Gue´-
nard, D.; Gue´ritte, F. J. Org. Chem. 2002, 67, 1199–1207.
4. Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G.
Tetrahedron Lett. 2003, 44, 4327–4329.
5. Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G. J.
As postulated by others for aromatic systems3 the
component to be borylated needs an EDG and the
Suzuki coupling component requires an EWG. In our
case experiments using bromobenzo[b]thiophenes with-
out an EDG were unsuccessful confirming the impor-
Het. Chem. 2001, 38, 749–754.
6. Queiroz, M.-J. R. P.; Dubest, R.; Aubard, J.; Faure, R.;
Guglielmetti, R. Dyes and Pigments 2000, 47, 219–229.
7. Boc-(E)-DAla-[b-(2,3-dimethyl-6-methoxybenzo[b]thien-7-
yl)]-OMe (1): A dry Schlenck tube was charged under Ar
with 7-bromo-2,3-dimethyl-6-methoxybenzo[b]thiophene
(0.5 mmol) in dioxane (2 mL), Et3N (4 equiv.), Pd(OAc)2
(5 mol%), 2-(dicyclohexylphosphino)biphenyl (20 mol%)
and pinacolborane (3 equiv.) and the mixture was heated
at 80°C for 1 h. After cooling Boc-(E)-DAla(b-Br)-OMe (1
equiv.) and Ba(OH)2·8H2O (3 equiv.) were added, and the
solution was heated at 100°C for 1 h 30 min. After
cooling, water and ethyl acetate were added. The phases
were separated, the aqueous phase was extracted with
more ethyl acetate and the organic phase was dried
(MgSO4) and filtered. Removal of the solvent gave a
brown solid which was submitted to column chromatogra-
phy using solvent gradient from neat petroleum ether
40–60°C to 30% ether/petroleum ether 40–60°C to give the
product as a beige solid (86 mg, 44%) which was recrystal-
lized from ether/petroleum ether 40–60°C to give colour-
less crystals mp 132–133°C; found C, 61.34; H, 6.53; N,
3.55; S, 8.22%, calcd for C20H25NO5S C, 61.36; H, 6.44; N,
3.58; S, 8.19%; lH (300 MHz, CDCl3) 1.36 (s, 9H,
CH3Boc), 2.27 (s, 3H, ArCH3), 2.45 (s, 3H, ArCH3), 3.90
(s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.76 (s, 1H, NH), 7.06
(d, 1H, ArH, J 8.7 Hz), 7.08 (s, 1H, bCH) 7.54 (d, 1H,
ArH, J 8.7 Hz); lC (75.4 MHz, CDCl3) 11.38 (CH3), 13.65
(CH3), 28.00 (CH3 Boc), 52.50 (OCH3), 56.89 (OCH3),
80.57 (C) 109.54 (CH), 116.39 (C), 119.29 (CH), 122.09
(CH), 126.58 (C), 128.46 (C), 132.26 (C), 135.56 (C),
139.03 (C), 152.49 (C), 153.57 (CꢀO), 165.62 (CꢀO).
Boc-(Z)-DAbu-[b-(2,3,7-trimethylbenzo[b]thien-6-yl)]-OMe
(4): Following the same procedure described above with
6-bromo-2,3,7-trimethylbenzo[b]thiophene (0.5 mmol) but
adding water (200 mL) and Boc-(Z)-DAbu(b-Br)-OMe in
the second step, the product was isolated as a white solid,
after column chromatography (84 mg, 43%) and was
recrystallized from petroleum ether 40–60°C to give
colourless crystals mp 87–88°C; found C, 64.69; H, 7.03;
N, 3.53; S, 8.23%, calcd for C21H27NO4S C, 64.76; H, 6.99;
N, 3.60; S, 8.23%; lH (300 MHz, CDCl3) 1.38 (s, 9H, CH3
Boc), 2.20 (s, 3H, CH3), 2.31 (s, 3H, ArCH3), 2.38 (s, 3H,
ArCH3), 2.52 (s, 3H, ArCH3), 3.88 (s, 3H, OCH3), 5.53 (s,
1H, NH), 7.07 (broad d, 1H, ArH, J 8 Hz), 7.49 (d, 1H,
ArH, J 8 Hz); lC (75.4 MHz, CDCl3) 11.40 (CH3), 13.78
(CH3), 17.05 (CH3), 20.80 (CH3), 28.00 (CH3 Boc), 51.94
(OCH3), 80.66 (C) 119.51 (CH), 123.77 (CH), 125.15 (C),
127.71 (C), 128.09 (C), 132.22 (C), 133.53 (C), 134.22 (C),
139.28 (C), 140.27 (C), 152.91 (CꢀO), 155.57 (CꢀO).
tance of the presence of such
a
group. The
dehydroamino acid derivative acts as the coupling com-
ponent having an EWG. However the carbamate group
has a slight electron donating effect which can have
some influence in the product yields.
3. Conclusion
With these results the scope of the BSC reaction was
extended to non aromatic Suzuki coupling components.
Despite the moderate to good yields obtained, this
reaction allows the palladium catalyzed borylation and
Suzuki coupling in a one pot procedure avoiding the
lithiation step and transmetalation to boron.
The benzo[b]thienyldehydroamino acids obtained are
non-proteinogenic amino acids that can be used either
as conformational constrains when inserted into pep-
tides or in the development of peptidomimetics. They
can also have biological activity as sulfur analogues of
dehydrotryptophan.
Acknowledgements
We thank the Foundation for Science and Technology
(Portugal) for financial support through IBQF-Univ.
Minho, project POCTI/1999/QUI/32689 and through
SFRH/BD/4709/2001, PhD financial support of A.S.A.
References
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teiro, L. S.; Sacramento, J. J. Chem. Soc., Perkin Trans. 1
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