New strategies for the synthesis of heteroannulated 2-pyridinones, substituted 2-quinolinones and coumarins from dehydroamino acid derivatives

Article abstract of DOI:10.1016/j.tet.2008.03.057

Several heteroannulated pyridinones were prepared from the methyl esters of N-Boc-β,β-diheteroaryldehydroalanines by treatment with acetic acid. The latter were obtained by a bis-Suzuki coupling of a β,β-dibromodehydroalanine with heteroarylboronate compounds. The products were obtained in good yields and the cyclization reaction involves the nucleophilic attack of one of the heteroaromatic rings on the carbonyl of the Boc group. The scope of this reaction was extended to the Z-isomer of N-Boc-β-heteroaryldehydrophenylalanines to give 4-phenylpyridinones. A tandem Suzuki coupling-cyclization protocol was developed for the synthesis of 2-quinolinones and coumarins. Thus, β-brominated dehydroamino acids were reacted with 2-(pinacolboronate)aniline or phenol in a one-pot Suzuki coupling followed by lactamization or lactonization to give the corresponding 3-amino-2-quinolinones or 3-aminocoumarins in good to high yields. This type of strategy was also applied to the synthesis of 2-quinolinones and coumarins linked in position-3 to amino acids, using as starting materials brominated dehydropeptides.

Full text of DOI:10.1016/j.tet.2008.03.057

Tetrahedron 64 (2008) 5139–5146
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New strategies for the synthesis of heteroannulated
2-pyridinones, substituted 2-quinolinones and coumarins
from dehydroamino acid derivatives
*
Maria Joa˜o R.P. Queiroz , Ana S. Abreu, Ricardo C. Calhelha,
*
M. Solange D. Carvalho, Paula M.T. Ferreira
´
Centro de Quımica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Several heteroannulated pyridinones were prepared from the methyl esters of N-Boc-b,b-diheteroar-
yldehydroalanines by treatment with acetic acid. The latter were obtained by a bis-Suzuki coupling of
a b,b-dibromodehydroalanine with heteroarylboronate compounds. The products were obtained in good
yields and the cyclization reaction involves the nucleophilic attack of one of the heteroaromatic rings on
the carbonyl of the Boc group. The scope of this reaction was extended to the Z-isomer of N-Boc-
b-heteroaryldehydrophenylalanines to give 4-phenylpyridinones. A tandem Suzuki coupling–cyclization
protocol was developed for the synthesis of 2-quinolinones and coumarins. Thus, b-brominated dehy-
droamino acids were reacted with 2-(pinacolboronate)aniline or phenol in a one-pot Suzuki coupling
followed by lactamization or lactonization to give the corresponding 3-amino-2-quinolinones or
3-aminocoumarins in good to high yields. This type of strategy was also applied to the synthesis of
2-quinolinones and coumarins linked in position-3 to amino acids, using as starting materials bromi-
nated dehydropeptides.
Received 31 January 2008
Received in revised form 13 March 2008
Accepted 17 March 2008
Available online 21 March 2008
Keywords:
Dehydroamino acids
Suzuki coupling
Intramolecular cyclizations
Heteroannulated 2-pyridinones
2-Quinolinones
Coumarins
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
reverse transcriptase, some of them showing activity against drug-
resistant mutants.5
Ring fused 2-pyridinones involving the nitrogen atom have been
used as lead compounds for the preparation of several type of drugs
such as selective anticancer agents,1 antiviral agents2 or inhibitors
of Ab-peptide aggregation, which play an important role in amyloid
formation in Alzheimer’s disease.3
Heck et al.6 prepared 2-quinolinones from 2-iodoanilines and
dimethyl maleate using Pd(OAc)2 and NEt3. Recently, Cho and Kim
used a similar approach to obtain the same type of quinolinones
from 2-iodoanilines and dialkyl itaconates.7
The coumarin moiety is present in several natural products
exhibiting a broad range of biological activities, including anti-
cancer8 and anti-HIV.9 Coumarins have also been used as lumi-
nescent probes,10 photostable laser dyes11 and triplet sensitizers.12
Larock and Kadnikov reported the synthesis of coumarins13 and
2-quinolinones14 by palladium-catalyzed carbonylative annulation
of internal alkynes with o-iodophenols or o-iodoanilines.
Morerecently, Cachietal. prepared4-aryl-2-quinolinones15 and4-
arylcoumarins16 from o-bromocinnamamide or alkyl 3-(o-hydroxy-
aryl)acrylates and aryl iodides and bromides using Pd(OAc)2 and
a molten tetra(n-butyl)ammonium acetate/tetra(n-butyl)ammonium
bromide. These domino processes involve in the first case sequential
catalytic cycles of a Heck reaction followed by an intramolecular
Buchwald–HartwigC–Nbondformingreactionandinthesecondcase
a Heck reaction and a nucleophilic attack of the OH group in the
carbonyl of the ester.
Several thieno[2,3-b]pyridine-6(7H)-ones were prepared by
Berger et al. from substituted methyl 2-aminothiophene-3-carbox-
ylates and phenylacetyl chloride to give amides that subsequently
cyclized using potassium hexamethyldisilazide in THF at low
temperatures. These thienopyridinones were designed by a bio-
isosteric approach with 3-phenyl-4-hydroxy-quinolin-2-(1H)-one
by replacement of the benzene nucleus by thiophene and are
cytoprotectants and inhibitors of the glycine binding to the
N-Methyl-
series of 2-quinolinones have been synthesized from
D
-aspartate (NMDA) receptor.4
A
substituted anilines and diethylmalonate in diphenylether at
250 ꢀC and, were evaluated as non-nucleoside HIV-1 inhibitors of
* Corresponding authors.
In the course of our long experience in dehydroamino acid
chemistry and metal-mediated reactions, we have synthesized
E-mail addresses: mjrpq@quimica.uminho.pt (M.J.R.P. Queiroz), pmf@quimica.
uminho.pt (P.M.T. Ferreira).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.057

5140
M.J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 5139–5146
a large variety of new heterocyclic compounds. Thus, by reacting
b-bromo or b,b-dibromodehydroamino acid derivatives with aryl or
heteroarylboronic acids or boronates under Suzuki cross-coupling
conditions we were able to prepare b,b-disubstituted dehy-
droamino acids, which were successfully cyclized to thienoindoles,
benzo[b]thienopyrroles and indoles using an unprecedent metal-
assisted C–N intramolecular cyclization.17–19
Here, we report an important method for the synthesis of new
heteroannulated 2-pyridinones and substituted 2-quinolinones
and coumarins using Suzuki and Suzuki–Miyaura cross-cou-
plings20 and intramolecular cyclizations, taking advantage of the
reactivity of the amino acid protecting groups. Although several
palladium-catalyzed reactions have been used in the synthesis of
heterocycles,21 to our knowledge this is the first time this strat-
egy was successfully applied to dehydroamino acids and
dehydropeptides.
to the fact that in the benzo[b]thiophene ring position-2 and 3 reacted
almost in the same way.
H
H
O
S
N
CO2Me
N
CO2Me
Boc
S
iii)
S
S
17
10
12, 49%
H
H
N
CO2Me
S
O
N
CO2Me
Boc
S
iii)
S
S
17
11
13, 58%
Scheme 2. (iii) 10 equiv CH3COOH, DMF, 160 ꢀC.
2. Results and discussion
Several new b,b-bis-heteroaryldehydroalanines were prepared
by a bis-Suzuki cross-coupling of b,b-dibromodehydroalanine 1,
earlier prepared by us,22 with heteroarylboronated compounds, in
good to excellent yields (Scheme 1). The conditions used for the
coupling of potassium 3-trifluoroboratethiophene were those
described by Molander and Fumagalli in a palladium-catalyzed
Suzuki cross-coupling of potassium aryl and heteroaryltri-
fluoroborates with alkenyl bromides.23 The other Suzuki couplings
were carried out using conditions earlier developed by us.19
The coupling products 2–5 were treated with acetic acid in DMF
at 160 ꢀC (Scheme 1). Compounds 2 and 3 afforded the hetero-
annulated 2-pyridinones 6 and 7 in good yields, by nucleophilic
attack of position-2 of the thiophene or furan rings on the carbonyl
of the Boc group with loss of t-BuOH. This constitutes, as far as our
knowledge, a new method for the synthesis of this type of com-
pounds. When compounds 4 and 5 were subjected to the same
conditions, no lactamization occurred and the only products
obtained were the very unstable free amines 8 and 9 resulting from
cleavage of the Boc group (Scheme 1). This can be due to the fact
that position-3 is not so nucleophilic as position-2 in furan and
thiophene rings.
The same approach was applied to the synthesis of hetero-
annulated pyridinones 16, 18 and 20 from b-thienyl or benzo[b]-
thienyldehydrophenylalanines 15, 17 and 19 increasing the scope of
this reaction (Scheme 3). However, the product yields were slightly
lower when compared with those obtained for compounds 7, 12
and 13.
The b-brominated dehydroamino acids were also used as pre-
cursors of 2-quinolinones. Thus, by reacting the former with
2-(pinacolboronate)aniline, we were able to obtain compounds 21,
22, 24 and 25 in a tandem one-pot Suzuki cross-coupling and
lactamization, which occur by nucleophilic attack of the NH2 on the
carbonyl of ester group with loss of methanol (Table 1).
The b,b-dibromodehydroalanine 1 gave quinolinone 21 as major
product, after a bis-Suzuki coupling and lactamization and quino-
linone 22 as minor product, possibly resulting from the reduction of
one of the vinyl-Pd-Br species (Entry 1, Table 1).
CompoundE-23gavewithidenticalconditionsbutusing1.3 equiv
of 2-(pinacolboronate)aniline the corresponding quinolinone 24 in
an excellent yield (entry 2, Table 1). Using the conditions already
applied by us in Suzuki couplings of sterically hindered substrates
(condition C, namely 2-(dicyclohexylphosphane)biphenyl as ligand
and Ba(OH)2$8H2O as base),18 the 2-quinolinone 25 was obtained
from E-14 in 50% yield with cleavage of the Boc group (entry 3, Table
1). This may due to the use of a stronger base and higher temperature.
Having these results in hand, we decided to apply the same
methodology to our previously synthesized b,b-bis(benzo[b]thi-
enyl)dehydroalanines10 and 11.17 The corresponding heteroannulated
2-pyridinones 12 and 13 were obtained in good yields (Scheme 2) due
Y
H
H
N
CO2Me
X
O
X
N
CO2Me
X
Boc
X
X
X = O, Y= B(pin), i)
X = S, Y= BF3K, ii)
iii)
iii)
2, X=O, 75%,
3, X=S, 99%
H
6, X=O, 52%
7, X=S, 68%
N
CO2Me
Br
Boc
Br
H
i)
H2N
X
CO2Me
X
N
CO2Me
X
1
Boc
X
Z
X
X = O, Y=B(OH)2
X = S, Y=B(OH)2
4, X=O, 87%
5, X=S, 56%
8, X=O, very unstable
9, X=S, very unstable
Scheme 1. (i) 20 mol % PdCl2(dppf)$CH2Cl2 (1:1), 1.4 equiv Cs2CO3, THF/H2O (1:1); (ii) 4 mol % PdCl2(dppf)$CH2Cl2 (1:1), 6 equiv K2CO3, toluene/H2O (2.7:1); (iii) 10 equiv CH3COOH,
DMF, 160 ꢀC.

M.J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 5139–5146
5141
BF3K
H
H
N
H
N
CO2Me
N
CO2Me
Boc
O
S
CO2Me
Boc
S
iii)
Br
ii)
S
24
Z-14
15, 91%
16, 33%
H
N
H
O
S
CO2Me
N
CO2Me
Boc
iii)
iii)
S
24
17
18, 20%
H
H
N
CO2Me
O
N
CO2Me
Boc
S
S
24
19
20, 34%
Scheme 3. (ii) 2 mol % PdCl2(dppf)$CH2Cl2 (1:1), 6 equiv K2CO3, toluene/H2O (2.7:1); (iii) 10 equiv CH3COOH, DMF, 160 ꢀC.
Compound Z-14 was also reacted with 2-(pinacolboronate)ani-
line using conditions B and only gave the Suzuki coupling product
26 in 51% yield.
Table 1
Synthesis of substituted 2-quinolinones by one-pot Suzuki coupling and
lactamization
O
H
N
Boc
OMe
O
H
N
H
N
COOCH3
Br
R2
NH
Suzuki
Boc
coupling
R3
R1
NH2
NH2
O
26
B
R2 = H or Boc
3 = H, CH3 or aryl
R1 = Br, CH3 or C6H5
O
R
Using a similar methodology, it was also possible to obtain
several substituted coumarins using 2-(pinacolboronate)phenol as
coupling component (Table 2).
21, 22, 24, 25
Entry Dehydroamino acid Conditions
2-Quinolinones (%)
When b,b-dibromodehydroalanine 1 was used as coupling
component (entry 1, Table 2), we have obtained the coumarin 27 in
good yield, adding a KHSO4 1 M solution to acidify the reaction
mixture. In this case, the product resulting from elimination of
a bromine atom was not isolated as observed in the reaction of
compound 1 with 2-(pinacolboronate)aniline.
O
O
H
N
H
N
H
Boc
NH
Boc
NH
N
CO2Me
Br
Boc
1
A, 3 h
+
Br
NH2
1
21, 70%
22, 10%
Coumarins 28 and 29 were obtained from compounds E-23 and
E-14, respectively, in excellent yields (entries 2 and 3, Table 2).
Compound E-30, gave coumarin 31 in good yield with cleavage of
the 4-nitrobenzyloxycarbonyl group [Cbz(NO2)].
O
H
N
H
N
CO2Me
Boc
NH
Boc
Boc
We have also tried this reaction with b-brominated dehy-
drodipeptides 3226 and 33, which were obtained by bromination of
the corresponding dehydrodipeptides with N-bromosuccinimide
(NBS) followed by treatment with triethylamine. Compound 32
reacted with 2-(pinacolboronate)phenol to give coumarin 34 in 53%
yield. The 2-quinolinone 35 was obtained in 60% yield by
reacting the dehydrodipeptide 33 with 2-(pinacolboronate)aniline
(Scheme 4).
These results show that brominated dehydropeptides are also
good substrates for this type of reactions giving interesting cou-
marins and 2-quinolinones linked in position-3 to an amino acid
derivative.
2
B, 3 h
Br
25
E-23
24, 97%
O
H
N
CO2Me
Br
H2N
NH
3
C, 1 h
24
E-14
25, 50%
A: 5 equiv 2-(pinacolboronate)aniline, 20 mol % PdCl2(dppf)$CH2Cl2 (1:1), 1.4 equiv
Cs2CO3, THF/H2O (1:1), 90 ꢀC.
B: 1.3 equiv 2-(pinacolboronate)aniline, 10 mol % PdCl2(dppf)$CH2Cl2 (1:1), 1.4 equiv
Cs2CO3, THF/H2O (1:1), 90 ꢀC.
3. Conclusions
We have developed new and efficient strategies for the syn-
thesis of heteroannulated 2-pyridinones, substituted 2-
C: 1.3 equiv 2-(pinacolboronate)aniline, 5 mol % Pd(OAc)2, 20 mol % 2-(dicyclohex-
ylphosphane)biphenyl, 3 equiv Ba(OH)2$8H2O, dioxane, 120 ꢀC.

5142
M.J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 5139–5146
Table 2
cyclization. The latter occurs by nucleophilic attack either by the
substituents (NH2 or OH) on the carbonyl of the ester or by the
heteroaromatic ring on the carbonyl of the Boc group.
The tandem one-pot Suzuki coupling and intramolecular cycli-
zation methodology, which takes advantage of the presence of an
ester as carboxylic acid protecting group, was also applied suc-
cessfully to brominated dehydropeptides giving coumarins and
2-quinolinones linked to amino acids.
Synthesis of substituted coumarins by one-pot Suzuki coupling and lactonization
O
H
N
H
N
COOCH3
Br
R3
O
R2
Suzuki
coupling
R4
R1
OH
O
R1 = Br, R2 = Boc
R
R
B
R3 = H or Boc
O
1 = CH3 or C6H5, R2 = Boc
1 = CH3, R2 = Cbz(NO2)
R
4 = CH3 or aryl
The new compounds obtained are heteroannulated 2-pyr-
idinones, 2-quinolinones and coumarins, and therefore may have
several interesting biological applications.
27-29, 31
Entry
Dehydroamino acid
Conditions
Coumarins (%)
O
4. Experimental
H
N
Boc
O
4.1. Suzuki couplings
1
1
A, 3 h 30 min
4.1.1. Boc-DAla[b,b-bis-(fur-3-yl)]-OMe (2)
OH
To
a solution of N-tert-butoxycarbonyl-,b,b-dibromodehy-
droalanine [Boc-DAla(b,b-Br)-OMe] 122 (150 mg, 0.418 mmol) in
4 mL of THF/H2O (1:1), the 3-(pinacolboronate)furan (5 equiv),
Cs2CO3 (1.4 equiv) and PdCl2(dppf)$CH2Cl2 (1:1) (20 mol %) were
added and the mixture was heated at 90 ꢀC for 4 h. THF was
removed under reduced pressure and the residue was dissolved in
ethyl acetate (25 mL). The organic layer was washed with water and
brine (2ꢁ10 mL each), dried over MgSO4 and evaporated at reduced
pressure to give an oil. Column chromatography using solvent
gradient from neat petroleum ether to 40% diethyl ether/petroleum
ether gave compound 2 (104 mg, 75%) as a yellow solid, mp
157–159 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.47 (s, 9H, CH3Boc), 3.68
(s, 3H, OCH3), 6.21 (br s, 1H, NH), 6.31 (m, 1H, ArH), 6.51 (br s, 1H,
ArH), 7.35 (m, 1H, ArH), 7.39 (m, 1H, ArH), 7.43 (m, 1H, ArH), 7.47(m,
1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 28.1 [C(CH3)3], 52.1 (OCH3),
81.3 [OC(CH3)3], 110.5 (CH), 111.1 (CH), 115.9 (C), 123.0 (C), 123.3 (C),
124.4 (C), 141.5 (CH), 142.9 (CH), 143.3 (CH), 143.5 (CH), 152.6
(C]O), 166.3(C]O); MS (FAB) m/z (%) 335 (Mþþ2), 334 (Mþþ1),
333 (Mþ); HRMS m/z [MþþH] calcd for C17H20NO6 334.1291, found
334.1288.
27, 60%
O
H
N
Boc
Boc
O
2
3
E-23
B, 3 h
28, 99%
O
H
N
O
E-14
B, 3 h
29, 97%
O
H
H2N
N
CO2Me
Br
O
Cbz(O2N)
4
B, 7 h
26
E-30
31, 47%
A: 5 equiv 2-(pinacolboronate)phenol, 20 mol % PdCl2(dppf)$CH2Cl2 (1:1), 1.4 equiv
Cs2CO3, THF/H2O (1:1), 90 ꢀC.
B: 1.3 equiv 2-(pinacolboronate)phenol, 10 mol % PdCl2(dppf)$CH2Cl2 (1:1), 1.4 equiv
Cs2CO3, THF/H2O (1:1), 90 ꢀC.
4.1.2. Boc-DAla[b,b-bis-(thien-3-yl)]-OMe (3)
To a solution of compound 1 (101 mg, 0.280 mmol) in 2.05 mL of
toluene/H2O (2.7:1), potassium 3-thiophene trifluoroborate
(3.5 equiv), K2CO3 (6 equiv) and PdCl2(dppf)$CH2Cl2 (4 mol %) were
added, and the mixture was heated at 90 ꢀC for 3 h 30 min. Toluene
was removed under reduced pressure and the residue was dis-
solved in ethyl acetate (25 mL). The organic layer was washed with
water and brine (2ꢁ10 mL each), dried over MgSO4 and evaporated
at reduced pressure to give an oil. Column chromatography using
solvent gradient from neat petroleum ether to 40% diethyl ether/
petroleum ether gave compound 3 (101 mg, 99%) as a brown solid,
mp 124–126 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.47 (s, 9H, CH3Boc),
3.61 (s, 3H, OCH3), 6.23 (br s,1H, NH), 6.87 (dd, J¼5.0 and 1.2 Hz,1H,
ArH), 7.08 (dd, J¼5.0 and 1.2 Hz, 1H, ArH), 7.14 (dd, J¼3.0 and 1.2 Hz,
1H, ArH), 7.20 (dd, J¼3.0 and 1.2 Hz, 1H, ArH), 7.26 (dd, J¼5.0 and
3.0 Hz, 1H, ArH), 7.36 (dd, J¼5.0 and 3.0 Hz, 1H, ArH); 13C NMR
(75.4 MHz, CDCl3) d 28.1 [C(CH3)3], 52.1 (OCH3), 81.4 [OC(CH3)3],
122.7 (C), 124.2 (CH), 125.2 (CH), 126.0 (CH), 126.5 (CH), 128.2 (CH),
128.4 (CH), 138.4 (C), 139.6 (C), 152.6 (C]O), 166.5 (C]O); MS (FAB)
m/z 367 (Mþþ2), 366 (Mþþ1), 365 (Mþ); HRMS [MþþH] m/z calcd
for C17H20NO4S2 366.0834, found 366.0827.
quinolinones and coumarins using brominated dehydroamino
acids as building blocks. As far as our knowledge, it is the first
time that these compounds were prepared using Suzuki cross-
couplings of aryl or heteroarylboron compounds with b-bromo or
b,b-dibromodehydroamino acids followed by intramolecular
OH
O
H
N
O
Boc
B
O
N
H
O
O
(1.3 equiv.)
R
H
N
Boc
CO2Me
Br
N
H
PdCl2(dppf).CH2Cl2 (1:1) (10 mol%)
Cs2CO3 (1.4 equiv.)
THF:H2O (1:1), 90 °C
34, 53%
O
E-3226 R=H
E-33 R=CH(CH3)2
NH2
O
H
Boc
N
4.1.3. Boc-DAla[b,b-bis-(fur-2-yl)]-OMe (4)
O
N
H
NH
B
To a solution of compound 1 (150 mg, 0.418 mmol) in 4 mL of
THF/H2O (1:1), fur-2-ylboronic acid (8 equiv), Cs2CO3 (1.4 equiv)
and PdCl2(dppf)$CH2Cl2 (1:1) (20 mol %) were added, and the
mixture was heated at 90 ꢀC for 3 h. THF was removed under re-
duced pressure and the residue was dissolved in ethyl acetate
O
O
(1.3equiv.)
35, 60%
Scheme 4.

M.J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 5139–5146
5143
(25 mL). The organic layer was washed with water and brine
(2ꢁ10 mL each), dried over MgSO4 and evaporated at reduced
pressure to give an oil. Column chromatography using solvent
gradient from neat petroleum ether to 40% diethyl ether/petroleum
ether gave compound 4 (121 mg, 87%) as an oil; 1H NMR (300 MHz,
CDCl3) d 1.49 (s, 9H, CH3Boc), 3.68 (s, 3H, OCH3), 6.34 (br d, J¼3.3 Hz,
1H, ArH), 6.38 (br d, J¼3.3 Hz, 1H, ArH), 6.42–6.43 (m, 1H, ArH),
6.46–6.48 (m, 1H, ArH), 7.44 (d, J¼1.8 Hz, 1H, ArH), 7.54 (d, J¼1.8 Hz,
1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 28.1 [C(CH3)3], 52.3 (OCH3),
81.8 [OC(CH3)3], 110.9 (CH), 111.0 (CH), 111.7 (CH), 112.5 (CH), 126.7
(C), 142.7 (CH), 142.9 (CH), 144.1 (C), 148.8 (C), 150.6 (C), 152.0
(C]O), 165.4 (C]O); MS (FAB) m/z 335 (Mþþ2), 334 (Mþþ1), 333
(Mþ), 233 (MþꢂBoc); HRMS [MþþH] m/z calcd for C17H20NO6
334.1291, found 334.1285.
diethyl ether and compound 7 (47.0 mg, 68%) was obtained as
a beige solid, mp 198–200 ꢀC; 1H NMR (300 MHz, CDCl3) d 3.74 (s,
3H, OCH3), 7.00 (d, J¼5.4 Hz,1H, ArH), 7.07 (dd, J¼5.1 and 1.5 Hz,1H,
ArH), 7.25–7.27 (m, 2H, ArH), 7.44 (dd, J¼5.1 and 3.0 Hz, 1H, ArH),
7.71 (d, J¼5.4 Hz, 1H, ArH), 9.45 (br s, 1H, NH); 13C NMR (75.4 MHz,
CDCl3) d 53.1 (OCH3), 118.3 (C), 124.2 (CH), 125.2 (CH), 126.1 (CH),
126.3 (C), 129.0 (CH), 133.6 (C), 133.7 (CH), 135.0 (C), 147.3 (C), 157.2
(C]O), 162.2 (C]O); MS (EI) m/z 291 (Mþ), 231 (MþꢂCOOMe),
69(Mþꢂ222); HRMS m/z Mþ calcd for C13H9NO3S2 291.0024, found
291.0026.
4.2.3. H-DAla[b,b-bis-(fur-2-yl)]-OMe (8)
Compound 8 was prepared from Boc-DAla-[b,b-bis-(fur-2-yl)]-
OMe 4 (0.340 mmol, 113 mg) according to the general procedure
described above and heating for 5 h giving the unstable compound
8 (78.0 mg, 98%) as an oil; 1H NMR (300 MHz, CDCl3) d 3.65 (s, 3H,
OCH3), 5.22 (br s, 2H, NH2), 6.10 (dd, J¼3.3 Hz, 1H, ArH), 6.25 (dd,
J¼3.3 and 0.9 Hz, 1H, ArH), 6.42–6.44 (m, 2H, ArH), 7.43 (dd, J¼1.8
and 0.9 Hz, 1H, ArH), 7.49 (dd, J¼1.8 and 0.9 Hz, 1H, ArH).
4.1.4. Boc-DAla[b,b-bis-(thien-2-yl)]-OMe (5)
To a solution of compound 1 (150 mg, 0.418 mmol) in (4 mL)
THF/H2O (1:1), thien-2-ylboronic acid (8 equiv), Cs2CO3 (1.4 equiv)
and PdCl2(dppf)$CH2Cl2 (1:1) (20 mol %) were added, and the
mixture was heated at 90 ꢀC for 7 h. THF was removed under re-
duced pressure and the residue was dissolved in ethyl acetate
(25 mL). The organic layer was washed with water and brine
(2ꢁ10 mL each), dried over MgSO4 and evaporated at reduced
pressure to give an oil. Column chromatography using solvent
gradient from neat petroleum ether to 30% diethyl ether/petroleum
ether gave compound 5 (85.0 mg, 56%) as an oil; 1H NMR (300 MHz,
CDCl3) d 1.49 (s, 9H, CH3Boc), 3.60 (s, 3H, OCH3), 6.43 (br s, 1H, NH),
6.97–7.11 (m, 4H, ArH), 7.36 (dd, J¼5.0 and 1.5 Hz, 1H, ArH), 7.44
(dd, J¼5.0 and 1.5 Hz, 1H, ArH); 13C NMR (75.4 MHz, CDCl3) d 28.1
[C(CH3)3], 52.2 (OCH3), 81.7 [OC(CH3)3], 119.6 (C), 125.9 (C), 126.5
(CH), 127.2 (2ꢁCH), 128.2 (CH), 128.4 (CH), 130.1 (CH), 140.2 (C),
140.5 (C), 152.5 (C]O), 165.9 (C]O); MS (FAB) m/z 367 (Mþþ2),
366 (Mþþ1), 365 (Mþ); HRMS [MþþH] m/z calcd for C17H20NO4S2
366.0834, found 366.0850.
4.2.4. H-DAla[b,b-bis-(thien-2-yl)]-OMe (9)
Compound 9 was prepared from Boc-DAla-[b,b-bis-(thien-
2-yl)]-OMe 5 (0.328 mmol, 120.0 mg) according to the general
procedure described above and heating for 3 h 30 min giving the
unstable compound 9 (80.0 mg, 92%) as an oil; 1H NMR (300 MHz,
CDCl3) d 3.59 (s, 3H, OCH3), 4.46 (br s, 2H, NH2), 6.87 (dd, J¼3.6 and
1.2 Hz, 1H, ArH), 6.97 (dd, J¼5.3 and 3.6 Hz, 1H, ArH), 7.05 (dd, J¼5.3
and 3.6 Hz, 1H, ArH), 7.12 (dd, J¼3.6 and 1.2 Hz, 1H, ArH), 7.29 (dd,
J¼5.3 and 1.2 Hz, 1H, ArH), 7.33 (dd, J¼5.3 and 1.2 Hz, 1H, ArH).
4.2.5. Methyl 4-(benzothien-3-yl)-2H-benzothieno[2,3-c]pyridin-1-
one-3-carboxylate (12)
Compound 12 was prepared from compound 1017 (100 mg,
0.215 mmol) according to the general procedure described above
and heating for 5 h. Column chromatography using solvent
dichloromethane gave compound 12 (40.0 mg, 48%) as a white
solid, mp 287–288 ꢀC; 1H NMR (400 MHz, CDCl3) d 3.58 (s, 3H,
OCH3), 6.54 (br d, J¼8.4 Hz, 1H, ArH), 7.00–7.05 (m, 1H, ArH) 7.29–
7.45 (m, 5H, ArH), 7.93 (br d, J¼8.4 Hz,1H, ArH), 8.02 (br d, J¼8.4 Hz,
1H, ArH), 9.93 (br s, 1H, NH); 13C NMR (100.6 MHz, CDCl3) d 53.3
(OCH3), 116.5 (C), 122.4 (CH), 123.0 (CH), 123.4 (CH), 124.8 (CH),
125.0 (CH), 125.1 (CH), 125.2 (CH), 125.4 (CH), 127.8 (CH), 128.2 (C),
130.5 (C), 135.4 (C),135.9 (C),139.0 (C),139.4 (C),140.9 (C),142.5 (C),
157.6 (C]O), 161.9 (C]O); MS (EI) m/z 391 (Mþ), 331, 302; HRMS
m/z calcd for C21H13NO3S2 391.0337, found 391.0330.
4.2. General procedure for the synthesis of 2-pyridinones
In a Schlenk tube containing a solution of compounds 2, 3, 10,17
11,17 15,1724 or 1924 in dry DMF (0.1 M), glacial acetic acid (10 equiv)
was added and the mixture was stirred under Ar at 160 ꢀC for
several hours. After cooling, ethyl acetate (30 mL) was added and
the solution was washed with water and brine (2ꢁ10 mL each),
dried over MgSO4 and the removal of solvent under reduced
pressure gave an oil.
4.2.1. Methyl 4-(fur-3-yl)-6H-furo[2,3-c]pyridin-7-one-5-
carboxylate (6)
4.2.6. Methyl 4-(benzothien-2-yl)-2H-benzothieno[3,2-c]pyridin-1-
one-3-carboxylate (13)
Compound
6 was prepared from compound 2 (100 mg,
0.300 mmol) according to the general procedure described above
and heating for 5 h 30 min. Column chromatography using solvent
gradient from diethyl ether to 50% chloroform/diethyl ether gave
compound 6 (42.0 mg, 52%) as a beige solid, mp 204–205 ꢀC; 1H
NMR (300 MHz, CDCl3) d 3.84 (s, 3H, OCH3), 6.48 (dd, J¼2.4 and
0.6 Hz, 1H, ArH), 6.65 (d, J¼1.8 Hz, 1H, ArH), 7.54–7.56 (m, 2H, ArH),
7.80 (d, J¼1.8 Hz, 1H, ArH), 9.89 (br s, 1H, NH); 13C NMR (75.4 MHz,
CDCl3) d 53.0 (OCH3), 108.4 (CH), 112.2 (CH), 112.7 (C), 118.7 (C),
125.7 (C), 135.6 (C), 141.2 (CH), 142.7 (CH), 144.9 (C), 148.9 (CH),
151.7 (C]O), 161.8 (C]O); MS m/z 259 (Mþ), 244 (MþꢂCH3), 215
(Mþꢂ44), 69 (Mþꢂ190); HRMS m/z Mþ calcd for C13H9NO5
259.0481, found 259.0483.
Compound 13 was prepared from compound 1117 (100 mg,
0.215 mmol) according to the general procedure described above
andheating for2 h. Columnchromatographyusing dichloromethane
gave compound 13 (49.0 mg, 63%) as a beige solid, mp 255–256 ꢀC;
1H NMR (400 MHz, CDCl3) d 3.79 (s, 3H, OCH3), 7.40–7.61 (m, 5H,
ArH), 7.81 (d, J¼8.0 Hz, 1H, ArH), 7.87–7.93 (m, 2H, ArH), 8.95 (d,
J¼8.0 Hz, 1H, ArH), 9.72 (br s, 1H, NH); 13C NMR (100.6 MHz, CDCl3)
d 53.5 (OCH3),114.6 (C),121.9 (CH),122.3 (CH),124.1 (CH),124.6 (CH),
125.0 (CH),125.4 (CH),125.91 (CH),125.94 (CH),126.7 (C),127.0 (CH),
127.5 (C), 136.0 (C), 136.1 (C), 139.4 (C), 139.9 (C), 140.8 (C), 153.8 (C),
157.4 (C]O), 161.4 (C]O). Anal. Calcd for C21H13NO3S2: C, 64.43; H,
3.35; N, 3.58; S, 16.38. Found: C, 64.06; H, 3.51; N, 3.59; S, 16.34.
4.2.2. Methyl 4-(thien-3-yl)-thieno[2,3-c]pyridin-7-one-5-
carboxylate (7)
4.2.7. Boc-(Z)-DPhe[b-(thien-3-yl)]-OMe (15)
To a solution of compound Z-1424 (200 mg, 0.560 mmol) in
4.1 mL toluene/H2O (2.7:1), the potassium 3-thiophene tri-
fluoroborate (1.3 equiv), K2CO3 (6 equiv) and PdCl2(dppf)$CH2Cl2
(1:1) (2 mol %) were added, and the mixture was heated at 90 ꢀC for
Compound
7 was prepared from compound 3 (87.0 mg,
0.238 mmol) according to the general procedure described above
and heating for 5 h 30 min. The oil obtained was washed with

5144
M.J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 5139–5146
3 h 30 min. Toluene was removed under reduced pressure and the
residue was dissolved in ethyl acetate (25 mL). The organic layer
was washed with water and brine (2ꢁ10 mL each), dried over
MgSO4 and evaporated at reduced pressure to give an oil. Column
chromatography using solvent gradient from neat petroleum ether
to 30% diethyl ether/petroleum ether gave compound 15 (0.183 g,
91%) as a yellow solid, mp 128–130 ꢀC; 1H NMR (300 MHz, CDCl3)
d 1.48 (s, 9H, CH3Boc), 3.50 (s, 3H, OCH3), 6.23 (br s, 1H, NH), 7.06
(dd, J¼5.3 and 1.2 Hz,1H, ArH), 7.14–7.18 (m, 3H, ArH), 7.29–7.36 (m,
4H, ArH); 13C NMR (75.4 MHz, CDCl3) d 28.1 [C(CH3)3], 51.9 (OCH3),
81.3 [OC(CH3)3], 125.2 (C), 125.9 (CH), 126.9 (CH), 127.9 (CH), 128.0
(2ꢁCH), 128.4 (CH), 129.0 (2ꢁCH), 139.2 (C), 139.7 (C), 152.8 (C]O),
166.4 (C]O); MS (FAB) m/z 361 (Mþþ2), 360 (Mþþ1), 359 (Mþ);
HRMS m/z [MþþH] calcd for C19H22NO4S 360.1270, found 360.1275.
or 2-(pinacolboronate)phenol, Cs2CO3 (1.4 equiv) and PdCl2(dppf)$
CH2Cl2 (1:1) were added and the mixture was heated at 90 ꢀC. THF
was removed under reduced pressure and the residue was dis-
solved in ethyl acetate (25 mL). The organic layer was then washed
with water and brine (2ꢁ10 mL each), dried over MgSO4 and
evaporated at reduced pressure to give an oil.
Procedure 2. A dried Schlenk tube was charged under Ar with dry
dioxane (3 mL), E-14 (0.500 mmol), Pd(OAc)2 (5 mol %), 2-(dicy-
clohexylphosphino)biphenyl (20 mol %), Ba(OH)2$8H2O (3 equiv)
and 2-(pinacolboronate)aniline (1.3 equiv). The mixture was heated
at 100 ꢀC for 1 h. Water and ethyl acetate were added, the phases
were separated, and the aqueous phase was extracted with more
ethyl acetate. The organic phases were collected, dried (MgSO4),
filtered and the solvent was evaporated at reduced pressure to give
a brown oil, which was subjected to column chromatography.
4.2.8. Methyl 4-phenyl-6H-thieno[2,3-c]pyridin-7-one-5-
carboxylate (16)
4.3.1. 3-(tert-Butoxycarbonyl)amino-4-(2-aminophenyl)quinolin-
2-one (21) and 3-(tert-butoxycarbonyl)aminoquinolin-2-one (22)
2-Quinolinones 21 and 22 were prepared from compound 1
(72.0 mg, 0.200 mmol), 5 equiv of 2-(pinacolboronate)aniline and
20 mol % PdCl2(dppf)$CH2Cl2 (1:1) according to general procedure
1 and heating for 3 h. Crystallization from ethyl acetate gave
a brown solid 21 (47.0 mg, 70%), mp 200–202 ꢀC; 1H NMR
(300 MHz, CDCl3) d 1.36 (s, 9H, CH3Boc), 3.80 (br s, 2H, NH2), 6.51
(br s,1H, NHBoc), 6.84–6.89 (m, 2H, ArH), 7.03 (dd, J¼8.1 and 1.5 Hz,
1H, ArH), 7.09–7.14 (m, 1H, ArH), 7.22–7.32 (m, 2H, ArH), 7.39–7.47
(m, 2H, ArH), 12.38 (br s, 1H, NH); 13C NMR (75.4 MHz, CDCl3) d 28.0
[C(CH3)3], 80.4 [OC(CH3)3], 116.1 (CH), 116.3 (CH), 118.5 (CH), 119.7
(C), 120.5 (C), 122.8 (CH), 126.4 (C), 127.0 (CH), 129.48 (CH), 129.51
(CH), 129.8 (CH), 136.5 (C), 142.2 (C), 144.4 (C), 153.3 (C]O), 161.1
(C]O); MS (FAB) m/z 353 (Mþþ2), 352 (Mþþ1) 351 (Mþ); HRMS
m/z 352.1664 [MþþH] (calcd C20H22N3O3 352.1661). Column chro-
matography of the remaining residue using solvent gradient from
neat petroleum ether to 20% diethyl ether/petroleum ether gave
2-quinolinone 22 (5.0 mg,10%) as a brown solid, mp 178–180 ꢀC; 1H
NMR (300 MHz, CDCl3) d 1.58 (s, 9H, CH3Boc), 7.22–7.27 (m, 1H,
ArH), 7.33–7.46 (m, 2H, ArH), 7.57 (d, J¼7.8 Hz, 1H, ArH), 7.77 (s, 1H,
NHBoc), 8.44 (s, 1H, b-CH), 11.53 (br s, 1H, NH); 13C NMR (75.4 MHz,
CDCl3) d 28.3 [C(CH3)3], 81.2 [OC(CH3)3], 115.4 (CH), 119.3 (CH),
120.9 (C), 123.4 (CH), 127.3 (CH), 127.9 (CH), 128.4 (C), 133.2 (C),
152.7 (C]O), 158.7 (C]O); MS (FAB) m/z 261 (Mþþ1), 260 (Mþ),
205 (MþꢂC(CH3)3); HRMS m/z [MþþH] calcd for C14H17N2O3
261.1239, found 261.1244.
Compound 16 was prepared from compound 15 (143 mg,
0.398 mmol) according to the general procedure described above
and heating for 4 h. Column chromatography using diethyl ether
gave compound 16 as a yellow solid (37.0 mg, 33%), mp 181–183 ꢀC;
1H NMR (300 MHz, CDCl3) d 3.67 (s, 3H, OCH3), 6.89 (d, J¼5.4 Hz,
1H, ArH), 7.26–7.30 (m, 2H, ArH), 7.45–7.48 (m, 3H, ArH), 7.69 (d,
J¼5.4 Hz, 1H, ArH), 9.46 (br s, 1H, NH); 13C NMR (75.4 MHz, CDCl3)
d 52.8 (OCH3), 123.3 (C), 125.8 (C), 126.1 (CH), 128.0 (CH), 128.2
(2ꢁCH), 129.2 (2ꢁCH), 133.6 (CH), 135.8 (C), 147.2 (C), 157.3 (C]O),
162.3 (C]O); MS (FAB) m/z 287 (Mþþ2), 286 (Mþþ1), 285 (Mþ);
HRMS m/z [MþþH] calcd for C15H12NO3S 286.0538, found
286.0536.
4.2.9. Methyl 4-phenyl-2H-benzothieno[2,3-c]pyridin-1-one-3-
carboxylate (18)
Compound 13 was prepared from compound 17 (196 mg,
0.479 mmol) according to the general procedure described above
and heating for 5 h. The crude was washed with diethyl ether giving
compound 18 (31.0 mg, 20%) as a yellow solid, mp 266–268 ꢀC; 1H
NMR (300 MHz, CDCl3) d 3.69 (s, 3H, OCH3), 6.48 (d, J¼8.4 Hz, 1H,
ArH), 7.09 (t, J¼8.1 Hz, 1H, ArH), 7.33–7.37 (m, 2H, ArH), 7.44 (t,
J¼8.1 Hz, 1H, ArH), 7.53–7.57 (m, 3H, ArH), 7.93 (d, J¼8.4 Hz, 1H,
ArH), 9.94 (br s, 1H, NH); 13C NMR (75.4 MHz, CDCl3) d 53.0 (OCH3),
123.4 (CH), 123.8 (C), 124.9 (CH), 125.9 (CH), 126.3 (C), 127.7 (CH),
128.5 (CH),128.8 (2ꢁCH), 129.3 (2ꢁCH),135.7 (C), 135.78 (C),135.81
(C),140.7 (C),142.5 (C),157.6 (C]O),162.0 (C]O); MS (FAB) m/z 337
(Mþþ2), 336 (MþþH), 335 (Mþ), 304 (MþꢂOMe); HRMS m/z
[MþþH] calcd for C19H14NO3S 336.0694, found 336.0692.
4.3.2. 3-(tert-Butoxycarbonyl)amino-4-methylquinolin-2-one (24)
2-Quinolinone 24 was prepared from compound E-23 (60.0 mg,
0.200 mmol), 1.3 equiv of 2-(pinacolboronate)aniline and 10 mol %
PdCl2(dppf)$CH2Cl2 (1:1) according to general procedure 1 de-
scribed above and heating for 3 h. Crystallization from ethyl ace-
tate/petroleum ether gave compound 24 as a brown solid (53.0 mg,
97%), mp 211–213 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.53 (s, 9H,
CH3Boc), 2.47 (s, 3H, CH3), 7.08 (br s, 1H, NHBoc), 7.22–7.27 (m, 1H,
ArH), 7.36–7.46 (m, 2H, ArH), 7.72 (d, J¼7.8 Hz, 1H, ArH), 12.11 (br s,
1H, NH); 13C NMR (75.4 MHz, CDCl3) d 15.7 (CH3), 28.2 [C(CH3)3],
80.7 [OC(CH3)3], 116.1 (CH), 121.3 (C), 122.8 (CH), 124.7 (CH), 125.4
(C), 129.2 (CH), 135.3 (C), 139.1 (C), 153.6 (C]O), 160.8 (C]O); MS
(FAB) m/z 276 (Mþþ2), 275 (Mþþ1), 274 (Mþ); HRMS m/z [MþþH]
calcd for C15H19N2O3 275.1396, found 275.1397.
4.2.10. Methyl 4-phenyl-2H-benzothieno[3,2-c]pyridin-1-one-3-
carboxylate (20)
Compound 20 was prepared from compound 19 (113 mg,
0.287 mmol) according to the general procedure described above
and heating for 4 h. The crude was washed with diethyl ether giving
compound 20 (33.0 mg, 34%) as a beige solid, mp 282–284 ꢀC; 1H
NMR (400 MHz, CDCl3) d 3.72 (s, 3H, OCH3), 7.38–7.40 (m, 2H, ArH),
7.48–7.59 (m, 5H, ArH), 7.80 (d, J¼7.6 Hz, 1H, ArH), 8.97 (br d,
J¼7.2 Hz, 1H, ArH), 9.78 (br s, 1H, NH); 13C NMR (100.6 MHz, CDCl3)
d 53.1 (OCH3), 121.8 (CH), 122.4 (C), 125.6 (C), 125.8 (CH), 126.0 (CH),
126.9 (CH), 128.5 (2ꢁCH), 128.6 (C), 128.7 (CH), 129.1 (2ꢁCH), 129.3
(C), 135.6 (C), 136.1 (C), 140.1 (C), 157.7 (C]O), 161.8 (C]O); MS
(FAB) m/z 337 (Mþþ2), 336 (Mþþ1), 335 (Mþ); HRMS m/z [MþþH]
calcd C19H14NO3S 336.0694, found 336.0687.
4.3.3. 3-Amino-4-phenylquinolin-2-one (25)
2-Quinolinone 25 was prepared from compound E-14 (175 mg,
0.500 mmol) according to general procedure 2 and heating for 1 h.
Column chromatography using solvent gradient from pure petro-
leum ether to diethyl ether gave compound 25 as a brown solid
(59.0 mg, 50%), mp 238–240 ꢀC; 1H NMR (300 MHz, CDCl3) d 4.37
(br s, 2H, NH2), 7.08–7.11 (m, 2H, ArH), 7.26–7.32 (m, 1H, ArH), 7.38–
4.3. General procedures for the synthesis of 3,4-disubstituted
2-quinolinones and coumarins
Procedure 1. To a solution of compound 1,22 E-14,24 E-23,25
E-30,26 E-3226 or E-33 in THF/H2O (1:1), 2-(pinacolboronate)aniline

M.J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 5139–5146
5145
7.42 (m, 3H, ArH), 7.46–7.52 (m, 1H, ArH), 7.56–7.62 (m, 2H, ArH),
11.78 (br s, 1H, NH); 13C NMR (75.4 MHz, CDCl3) d 115.6 (CH), 122.1
(C), 122.2 (C), 122.7 (CH), 124.0 (CH), 125.6 (CH), 128.2 (CH), 129.5
(2ꢁCH), 129.7 (2ꢁCH), 132.1 (C), 133.4 (C), 134.8 (C), 159.2 (C]O);
MS m/z 236 (Mþ), 235 (Mþꢂ1), 217 (Mþꢂ19), 190 (Mþꢂ46); HRMS
m/z Mþ calcd for C15H12N2O 236.0950, found 236.0952.
solvent gradient from neat petroleum ether to 40% diethyl ether/
petroleum ether gave compound 29 (111 mg, 97%) as a white solid,
mp 153–154 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.28 (s, 9H, CH3Boc),
6.14 (br s, 1H, NH), 7.18–7.22 (m, 1H, ArH), 7.29–7.33 (m, 1H, ArH),
7.37–7.40 (m, 3H, ArH), 7.45–7.54 (m, 4H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 27.8 [C(CH3)3], 80.8 [OC(CH3)3], 116.7 (CH), 120.1 (C), 120.7
(C), 124.4 (CH), 127.1 (CH), 128.5 (2ꢁCH), 128.68 (2ꢁCH), 128.72
(CH), 130.9 (CH), 133.0 (C), 145.9 (C), 151.8 (C), 152.2 (C), 159.9 (C);
MS (FAB) m/z 338 (Mþþ1), 282 (Mþþ1ꢂ(CH3)3C), 238
(Mþþ1ꢂBoc); HRMS m/z [MþþH] calcd for C20H20NO4 338.1392,
found 338.1394.
4.3.4. Boc-(Z)-DPhe[b-(2-aminophenyl)]-OMe (26)
Compound 26 was prepared from Z-14 (100 mg,
0.280 mmol), 1.3 equiv of 2-(pinacolboronate)aniline and 10 mol %
PdCl2(dppf)$CH2Cl2 (1:1) according to general procedure 1 de-
scribed above and heating for 2 h 30 min. Column chromatog-
raphy using solvent gradient from pure petroleum ether to 50%
diethyl ether in petroleum ether gave compound 26 (53.0 mg,
51%), mp 149–151 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.45 (s, 9H,
CH3Boc), 3.59 (s, 3H, OCH3), 3.86 (br s, 2H, NH2), 6.01 (br s, 1H,
NH), 6.69–6.76 (m, 2H, ArH), 6.88 (br d J¼7.5 Hz, 1H, ArH), 7.12–
7.19 (m, 3H, ArH), 7.26–7.30 (m, 3H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 28.1 [C(CH3)3], 52.0 (OCH3), 81.3 [OC(CH3)3], 115.8 (CH),
118.3 (CH), 122.5 (C), 126.9 (C), 127.9 (CH), 128.2 (2ꢁCH), 128.6
(2ꢁCH), 129.2 (C), 129.6 (CH), 131.1 (CH), 139.1 (C), 143.9 (C),
153.1 (C]O), 166.2 (C]O); MS (FAB) m/z 370 (Mþþ2), 369
(Mþþ1), 251 (Mþꢂ118); HRMS m/z [MþþH] calcd C21H25N2O4
369.1814, found 369.1822.
4.3.8. 3-Amino-4-methylcoumarin (31)
Coumarin 31 was prepared from compound E-30 (110 mg,
0.290 mmol), 1.3 equiv of 2-(pinacolboronate)phenol and 10 mol %
PdCl2(dppf)$CH2Cl2 (1:1) according to general procedure 1 and
heating for 7 h. Column chromatography using a solvent gradient
from neat petroleum ether to 40% diethyl ether/petroleum ether
gave compound 31 (24.0 mg, 47%) as a yellow solid, mp 104–106 ꢀC;
1H NMR (300 MHz, CDCl3) d 2.24 (s, 3H, CH3), 4.18 (br s, 2H, NH2),
7.24–7.33 (m, 3H, ArH), 7.46–7.50 (m, 1H, ArH); 13C NMR (75.4 MHz,
CDCl3) d 11.7 (CH3), 116.4 (CH), 118.8 (C), 121.7 (C), 122.5 (CH), 124.5
(CH),126.9 (CH),128.9 (C),148.5 (C),159.0 (C); MS (EI) m/z 175 (Mþ),
146 (Mþꢂ 29); HRMS Mþ m/z calcd for C10H9NO2 175.0633, found
175.0632.
4.3.5. 3-(tert-Butoxycarbonyl)amino-4-(2-hydroxyphenyl)-
coumarin (27)
4.3.9. Boc-Val-Z-DAbu-OMe
Coumarin 27 was prepared from compound
1
(72.0 mg,
Boc-Val-Z-DAbu-OMe was prepared from Boc-Val-Thr-OMe
(3.14 g,10 mmol), tert-butylpyrocarbonate (Boc2O) (2.18 g,10 mmol)
and 4-dimethylaminopyridine (DMAP) (122 mg,1 mmol,), according
to the procedure described by us elsewhere.27 Boc-Val-Z-DAbu-OMe
(2.39 g, 76%) was obtained as white solid, mp 107.5–108.0 ꢀC from
diethyl ether/n-hexane; 1H NMR (300 MHz, CDCl3) d 0.97 (d,
J¼6.9 Hz, 3H, g-CH3Val), 1.02 (d, J¼6.9 Hz, 3H, g-CH3Val), 1.43 (s, 9H,
CH3Boc), 1.75 (d, J¼7.2 Hz, 3H, g-CH3DAbu), 2.13–2.25 (m, 1H, b-
CHVal), 3.73 (s, 3H, OCH3), 4.05–4.12 (m, 1H, a-CHVal), 5.18 (d,
J¼8.4 Hz, 1H, NHVal), 6.80 (q, J¼7.2 Hz, 1H, b-CHDAbu), 7.61 (s, 1H,
NHDAbu); 13C NMR (75.4 MHz, CDCl3) d 14.5 (g-CH3DAbu), 17.7 (g-
CH3Val),19.2 (g-CH3Val), 28.2 [C(CH3)3], 30.7 (b-CHVal), 52.2 (OCH3),
60.0 (a-CHVal), 80.0 [OC(CH3)3], 126.0 (C), 134.5 (b-CHDAbu), 155.9
(C), 164.7 (C), 170.2 (C). Anal. Calcd for C15H26N2O5: C, 57.31; H, 8.34;
N, 8.91. Found: C, 57.34; H, 8.15; N, 8.86.
0.200 mmol), 5 equiv of 2-(pinacolboronate)phenol and 20 mol %
PdCl2(dppf)$CH2Cl2 (1:1) according to general procedure 1 and
heating for 3 h 30 min. After removing THF under reduced pressure,
the residue was dissolved in ethyl acetate (25 mL). The organic
layer was washed with a solution of 1 M KHSO4, water and brine
(2ꢁ10 mL each), dried over MgSO4 and evaporated at reduced
pressure to give an oil. Crystallization from diethyl ether gave
a brown solid 27 (43.0 mg, 61%), mp 194–196 ꢀC; 1H NMR
(300 MHz, acetone-d6) d 1.36 (s, 9H, CH3Boc), 7.03–7.12 (m, 2H,
ArH), 7.19–7.32 (m, 3H, ArH), 7.38–7.44 (m, 2H, ArH), 7.59–7.64 (m,
1H, ArH), 8.54 (br s,1H, NH); 13C NMR (75.4 MHz, acetone-d6) d 28.2
[C(CH3)3], 80.1 [OC(CH3)3], 117.1 (CH), 117.2 (CH), 120.6 (CH), 120.9
(C), 121.0 (C), 123.6 (C), 125.0 (CH), 128.3 (CH), 130.9 (CH), 131.3
(CH), 131.8 (CH), 146.5 (C), 153.1 (C), 154.3 (C), 155.0 (C), 159.5 (C);
MS (FAB) m/z 355 (Mþþ2), 354 (Mþþ1), 353 (Mþ); HRMS m/z
[MþþH] calcd C20H20NO5 354.1341, found 354.1342.
4.3.10. Boc-Val-DAbu(b-Br)-OMe (Z- and E-33)
Boc-Val-Z-DAbu-OMe (1.57 g, 5 mmol) was reacted with NBS
(0.900 g, 5 mmol) followed by treatment with triethylamine
(2.5 equiv) according to the procedure described by us elsewhere26
giving Boc-Val-DAbu(b-Br)-OMe (1.88 g, 96%) as a 1:1 mixture of
E and Z-isomer. Column chromatography using solvent gradient
from neat petroleum ether to 40% diethyl ether/petroleum ether
gave Boc-Val-Z-DAbu(b-Br)-OMe (Z-33) as a white solid, mp
137.5–138.0 ꢀC from diethyl ether/n-hexane; 1H NMR (300 MHz,
CDCl3) d 0.96 (d, J¼6.9 Hz, 3H, g-CH3Val), 1.07 (d, J¼6.9 Hz, 3H,
g-CH3Val), 1.45 (s, 9H, CH3Boc), 2.16–2.27 (m, 1H, b-CHVal), 2.57 (s,
3H, g-CH3DAbu), 3.79 (s, 3H, OCH3), 3.94–4.09 (m, 1H, a-CHVal),
5.05 (d, J¼8.7 Hz, 1H, NHVal), 7.75 (s, 1H, NHDAbu); 13C NMR
4.3.6. 3-(tert-Butoxycarbonyl)amino-4-methylcoumarin (28)
Compound 28 was prepared from E-23 (100 mg,
0.340 mmol), 1.3 equiv of 2-(pinacolboronate)phenol and 10 mol %
PdCl2(dppf).CH2Cl2 (1:1) according to general procedure 1 de-
scribed above and heating for 3 h 30 min. Column chromatography
using solvent gradient from 50% dichloromethane in petroleum
ether to neat dichloromethane gave compound 28 (93.0 mg, 99%)
as a beige solid, mp 137–139 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.51 (s,
9H, CH3Boc), 2.40 (s, 3H, CH3), 6.60 (br s, 1H, NH), 7.29–7.35 (m, 2H,
ArH), 7.46–7.51 (m, 1H, ArH), 7.64 (dd, J¼8.1 and 1.5 Hz, 1H, ArH);
13C NMR (75.4 MHz, CDCl3) d 15.4 (CH3), 28.1 [C(CH3)3], 81.2
[OC(CH3)3], 116.6 (CH), 120.8 (C), 121.0 (C), 124.6 (CH), 124.9 (CH),
130.5 (CH),141.8 (C),150.8 (C),153.1 (C),159.8 (C); MS m/z 275 (Mþ),
201 (Mþꢂ(CH3)3CO), 175 (MþꢂBoc), 146 (Mþꢂ129); HRMS m/z Mþ
calcd for C15H17NO4 275.1158, found 275.1152.
(75.4 MHz, CDCl3)
d 17.6 (g-CH3Val), 19.1 (g-CH3Val), 24.7
(g-CH3DAbu), 28.3 [C(CH3)3], 30.5 (b-CHVal), 52.5 (OCH3), 59.5
(a-CHVal), 80.2 [OC(CH3)3], 125.2 (C), 126.7 (C), 155.8 (C]O), 162.8
(C]O), 170.1 (C]O). Anal. Calcd for C15H25BrN2O5: C, 45.81; H,
6.41; N, 7.12. Found: C, 45.80; H, 6.32; N, 7.27. Boc-Val-E-D-
Abu(b-Br)-OMe (E-33) was obtained as a white solid, mp 158.5–
159.0 ꢀC from diethyl ether/n-hexane; 1H NMR (300 MHz, CDCl3)
d 0.95 (d, J¼6.9 Hz, 3H, g-CH3Val), 0.99 (d, J¼6.9 Hz, 3H, g-CH3Val),
1.42 (s, 9H, CH3Boc), 2.08–2.19 (m, 1H, b-CHVal), 2.35 (s, 3H,
g-CH3DAbu), 3.78 (s, 3H, OCH3), 3.99–4.04 (m, 1H, a-CHVal), 5.28
4.3.7. 3-(tert-Butoxycarbonyl)amino-4-phenylcoumarin (29)
Coumarin 29 was prepared from compound E-14 (122 mg,
0.340 mmol), 1.3 equiv of 2-(pinacolboronate)phenol and 10 mol %
PdCl2(dppf)$CH2Cl2 (1:1) according to general procedure 1 de-
scribed above and heating for 3 h. Column chromatography using

5146
M.J.R.P. Queiroz et al. / Tetrahedron 64 (2008) 5139–5146
(d, J¼8.4 Hz, 1H, NHVal), 8.27 (s, 1H, NHDAbu); 13C NMR (75.4 MHz,
CDCl3) d 18.0 (g-CH3Val), 19.1 (g-CH3Val), 25.6 (g-CH3DAbu), 28.2
[C(CH3)3], 30.5 (b-CHVal), 52.2 (OCH3), 59.7 (a-CHVal), 80.4
[OC(CH3)3], 122.9 (C), 126.0 (C), 156.2 (C]O), 164.0 (C]O), 170.5
(C]O). Anal. Calcd for C15H25BrN2O5: C, 45.81; H, 6.41; N, 7.12.
Found: C, 45.75; H, 6.38; N, 7.28.
59407/2004, for a post-doc. grant awarded to A.S.A. (SFRH/BPD/
24548/2005) and for a Ph.D. grant awarded to R.C.C. (SFRH/BD/
29274/2006) was acknowledged.
References and notes
1. (a) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G. A.
J. Am. Chem. Soc. 1966, 88, 3888–3890; (b) Comins, D. L.; Nolan, J. M. Org. Lett.
2001, 3, 4255–4257.
2. Josien, H.; Curran, D. P. Tetrahedron 1997, 53, 8881–8886.
3. Thorsett, E. D.; Latimer, L. H. Curr. Opin. Chem. Biol. 2000, 4, 377–382.
4. Buchstaller, H.-P.; Siebert, C. D.; Steinmetz, R.; Frank, I.; Berger, M. L.;
Gottschlich, R.; Leibrock, J.; Krug, M.; Steinhilber, D.; Noe, C. R. J. Med. Chem.
2006, 49, 864–871.
5. Freeman, G. A.; Andrews, C. W., III; Hopkins, A. L.; Lowell, G. S.; Schaller, L. T.;
Cowan, J. R.; Gonzales, S. S.; Koszalka, G. W.; Hazen, R. J.; Boone,
L. R.; Ferris, R. G.; Creech, K. L.; Roberts, G. B.; Short, S. A.; Weaver, K.; Reynolds,
D. J.; Milton, J.; Ren, J.; Stuart, D. I.; Stammers, D. K.; Chan, J. H. J. Med. Chem.
2004, 47, 5923–5936.
4.3.11. tert-Butyl 2-(4-methyl-2-oxo-2H-chromen-3-ylamino)-2-
oxoethylcarbamate (34)
Compound 34 was prepared from E-3226 (90.0 mg, 0.260 mmol)
according to general procedure 1 described above and heating for
3 h. Column chromatography using 50% diethyl ether/petroleum
ether gave compound 34 (45.0 mg, 53%) as an oil. Crystallization
from diethyl ether/petroleum ether gave a white solid, mp 110–
111 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.47 (s, 9H, CH3Boc), 2.35 (s, 3H,
g-CH3DAbu), 4.04 (d, J¼5.1 Hz, 2H, CH2Gly), 5.52 (br s, 1H, NHGly),
7.28–7.34 (m, 2H, ArH), 7.47–7.52 (m, 1H, ArH), 7.65 (d, J¼8.4 Hz,1H,
ArH), 8.21 (br s, 1H, NH); 13C NMR (75.4 MHz, CDCl3) d 15.5
(g-CH3DAbu), 28.2 [C(CH3)3], 44.7 (CH2Gly), 80.5 [OC(CH3)3], 116.7
(CH),119.9 (C),120.4 (C),124.7 (CH),125.2 (CH),131.1 (CH),144.7 (C),
151.2 (C), 156.1 (C), 159.5 (C), 168.8 (C); MS (FAB) m/z 334 (Mþþ2),
333 (Mþþ1), 332 (Mþ), 307 (Mþꢂ25), 289 (Mþꢂ(CH3)3), 277
(Mþꢂ(CH3)3C); HRMS m/z [MþþH] calcd for C17H21N2O5 333.1450,
found 333.1451.
6. Cortese, N. A.; Zielger, C. B.; Hrnjez, B. J.; Heck, R. F. J. Org. Chem. 1978, 43,
2953–2958.
7. Cho, C. S.; Kim, J. U. Tetrahedron Lett. 2007, 48, 3775–3778.
8. (a) Hecht, S. S.; Kenney, P. M. J.; Wang, M.; Trushin, N.; Agarwal, S.; Rao, A. V.;
Upadhyaya, P. Cancer Lett. 1999, 137, 123–130; (b) Georgieva, M. C.;
Konstantinov, S. M.; Berger, M. R. Cancer Lett. 2002, 182, 163–174.
9. (a) Palmer, C. J.; Josephs, J. L. J. Chem. Soc., Perkin Trans. 1 1995, 3135–3152; (b)
Kucherenko, A.; Flavin, M. T.; Boulanger, W. A.; Khilevich, A.; Shone, R. L.; Rizzo,
J. D.; Sheinkman, A. K.; Xu, Z.-Q. Tetrahedron Lett. 1995, 36, 5475–5478.
10. Murata, C.; Masuda, T.; Todoroki, K.; Yoshida, H.; Nohta, H.; Yamaguchi, M.;
Takadate, A. Chem. Pharm. Bull. 2005, 53, 750–758.
11. Jusinski, L. E.; Taatjes, C. A. Rev. Sci. Instrum. 2001, 72, 2837–2838.
12. Raviv, U.; Klein, J. Polym. Adv. Technol. 1998, 9, 825–830.
13. (a) Kadnikov, D. V.; Larock, R. C. Org. Lett. 2000, 2, 3643–3646; (b) Kadnikov,
D. V.; Larock, R. C. J. Org. Chem. 2003, 68, 9423–9432.
14. Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69, 6772–6780.
15. Battistuzzi, G.; Bernini, R.; Cachi, S.; De Salve, I.; Fabrizi, G. Adv. Synth. Catal.
2007, 349, 297–302.
16. Battistuzzi, G.; Cachi, S.; De Salve, I.; Fabrizi, G.; Parisi, L. M. Adv. Synth. Catal.
2005, 347, 308–312.
17. Abreu, A. S.; Silva, N. O.; Ferreira, P. M. T.; Queiroz, M.-J. R. P.; Venanzi, M. Eur. J.
Org. Chem. 2003, 4792–4796.
18. Abreu, A. S.; Ferreira, P. M. T.; Queiroz, M.-J. R. P.; Ferreira, I. C. F. R.; Calhelha,
R. C.; Estevinho, L. M. Eur. J. Org. Chem. 2005, 2951–2957.
19. Abreu, A. S.; Castanheira, E. M. S.; Ferreira, P. M. T.; Queiroz, M.-J. R. P.
Tetrahedron 2007, 63, 2215–2222.
4.3.12. tert-Butyl 3-methyl-1-(4-methyl-2-oxo-1,2-
dihydroquinolin-3-ylamino)-1-oxobutan-2-ylcarbamate (35)
Compound 35 was prepared from E-33 (100 mg, 0.254 mmol)
according to general procedure 1 described above and heating for
4 h 30 min. Column chromatography using chloroform gave com-
pound 35 (57.0 mg, 60%) as a beige solid, mp 229–231 ꢀC; 1H NMR
(300 MHz, DMSO-d6) d 0.92 (d, J¼6.6 Hz, 3H, g-CH3Val), 0.98 (d,
J¼6.6 Hz, 3H, g-CH3Val), 1.39 (s, 9H, CH3Boc), 2.02–2.09 (m, 1H,
b-CHVal), 2.23 (s, 3H, g-CH3DAbu), 3.97–4.03 (m,1H, a-CHVal), 6.84
(d, J¼8.7 Hz, 1H, NHVal), 7.18–7.23 (m, 1H, ArH), 7.30 (d, J¼8.1 Hz,
1H, ArH), 7.45–7.50 (m,1H, ArH), 7.74 (d, J¼8.1 Hz,1H, ArH), 9.26 (br
s,1H, NH),11.88 (br s,1H, NH); 13C NMR (75.4 MHz, DMSO-d6) d 14.7
(g-CH3DAbu), 18.3 (g-CH3Val), 19.5 (g-CH3Val), 28.2 [C(CH3)3], 30.3
(b-CHVal), 60.3 (a-CHVal), 78.1 [OC(CH3)3], 115.2 (CH), 119.7 (C),
122.0 (CH), 125.0 (CH), 125.7 (C), 129.6 (CH), 136.6 (C), 140.6 (C),
155.7 (C), 159.0 (C), 170.9 (C); MS (FAB) m/z 375 (Mþþ2), 374
(Mþþ1), 373 (Mþ), 318 (Mþꢂ(CH3)C), 175 (MþꢂBoc–Val–CO);
HRMS m/z [MþþH] calcd for C20H28N3O4 374.2080, found 374.2079.
20. For a recent review, see: Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633–9695.
21. (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127–2198; (b) Zeni, G.;
Larock, R. C. Chem. Rev. 2006, 106, 4644–4680; (c) Ka´lai, T.; Jeko, J.; Berente, Z.;
Hideg, K. Synthesis 2006, 3, 439–446.
22. Abreu, A. S.; Silva, N. O.; Ferreira, P. M. T.; Queiroz, M.-J. R. P. Tetrahedron Lett.
2003, 44, 3377–3379.
23. Molander, G. A.; Fumagalli, T. J. Org. Chem. 2006, 71, 5743–5747.
24. Abreu, A. S.; Ferreira, P. M. T.; Monteiro, L. S.; Queiroz, M.-J. R. P.; Ferreira, I. C. F.
R.; Calhelha, R. C.; Estevinho, L. M. Tetrahedron 2004, 60, 11821–11828.
25. Silva, N. O.; Abreu, A. S.; Ferreira, P. M. T.; Monteiro, L. S.; Queiroz, M.-J. R. P. Eur.
J. Org. Chem. 2002, 2524–2528.
Acknowledgements
26. Ferreira, P. M. T.; Monteiro, L. S.; Pereira, M. G.; Ribeiro, L.; Sacramento, J.;
Silva, L. Eur. J. Org. Chem. 2007, 5934–5949.
27. Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S.; Sacramento, J. J. Chem. Soc., Perkin
Trans. 1 1999, 3697–3703.
Foundation for the Science and Technology (FCT)dPortugal and
FEDER (European Communautaire fund), for financial support
´
through Centro de Quımica of Univ. Minho, Project POCI/QUI/