Palladium-catalyzed reaction of arenediazonium tetrafluoroborates with methyl 4-hydroxy-2-butenoate: An approach to 4-aryl butenolides and an expeditious synthesis of rubrolide E

Article abstract of DOI:10.1055/s-0028-1088132

The palladium-catalyzed reaction of arenediazonium tetrafluoroborates with methyl 4-hydroxy-2-butenoate in MeOH under mild conditions gives 4-arylbutenolides usually in good to high yields through a domino vinylic substitution/cyclization process. The rea

Full text of DOI:10.1055/s-0028-1088132

LETTER
1277
Palladium-Catalyzed Reaction of Arenediazonium Tetrafluoroborates with
Methyl 4-Hydroxy-2-butenoate: An Approach to 4-Aryl Butenolides and an
Expeditious Synthesis of Rubrolide E
4
-Aryl Buteno
a
lides from
n
A
renediazon
d
ium Tetraflu
r
orobora
t
o
es Cacchi,* Giancarlo Fabrizi, Antonella Goggiamani, Alessio Sferrazza
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P. le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Received 10 February 2009
Ar
Abstract: The palladium-catalyzed reaction of arenediazonium
tetrafluoroborates with methyl 4-hydroxy-2-butenoate in MeOH
under mild conditions gives 4-arylbutenolides usually in good to
high yields through a domino vinylic substitution/cyclization pro-
cess. The reaction tolerates a variety of useful substituents including
the whole range of halogen substituents, nitro, ether, cyano, keto,
and ester groups and can be performed as a one-pot process gener-
ating the arenediazonium salt in situ. By using this method, the ma-
rine antibiotic rubrolide E has been synthesized via an expeditious
and efficient sequential protocol that omits the isolation of the
butenolide intermediate (two operative steps, 52% overall yield).
Pd catalyst
ArN2 BF4
+
HO
CO2R
O
O
1
2
3
Scheme 1
tant compounds.8 Herein we report the results of this
study.
We initiated our study by subjecting 2a (R = Et) to 2
equivalents of 4-methoxydiazobenzene tetrafluoroborate
(1a), a model of electron-rich arenediazonium salts, in the
presence of 5 mol% of Pd(OAc)2 in EtOH at 40 °C for 8
hours. The expected butenolide product 3a was isolated in
50% yield along with a 19% yield of the acyclic derivative
4a, most probably because of the low regioselectivity of
the carbopalladation step under these conditions (Table 1,
entry 1). The starting arenediazonium salt 1a was recov-
ered in 14% yield. We then switched to the methyl ester
2b (R = Me) in MeOH and found that 3a could be isolated
in a 63% yield after 5.5 hours and that a higher regioselec-
tivity in the carbopalladation step could be attained (4a
was isolated only in 6% yield; Table 1, entry 2). The rea-
son of the higher regioselectivity observed under these
conditions was not investigated. Optimization experi-
ments were then carried out. These investigations re-
vealed that the best result in terms of yield and excess of
1a could be obtained using 2 equivalents of 1a in MeOH
at room temperature (Table 1, entry 3). Increasing the ex-
cess of 1a led only to moderately higher yields of the
butenolide derivative (Table 1, compare entries 4 and 5
with entries 2 and 3, respectively) and using solvents such
as THF and MeCN met with failure (Table 1, entries 6 and
7). Using 4-methoxycarbonyldiazobenzene tetrafluoro-
borate (1b) under the same conditions (2 equiv of arene-
diazonium salt in MeOH), a model of electron-poor
arenediazonium salts, gave high yields of 3b both at 40 °C
(Table 1, entries 8) and at room temperature (Table 1, en-
try 9). A lower yield of 3b was obtained increasing the ex-
cess of 1b (Table 1, entry 10).
Key words: diazonium salts, Heck reaction, cyclization, buten-
olides, rubrolides
Because of their availability from inexpensive anilines,
higher reactivity, utilization under aerobic and phosphine-
free conditions in the absence of added bases, arenediazo-
nium salts are an attractive alternative to aryl halides or
triflates in Heck reactions.1,2–5 Most of the applications
described have been based on the palladium-catalyzed
reaction of arenediazonium salts with monosubstituted
olefins.2 A variety of cyclic olefinic systems have also
been investigated.3 Very little, however, has been done
with acyclic disubstituted olefins. Acyclic 1,1-disubstitut-
ed olefins have been used to prepare a-benzyl-b-keto
esters4 and (E)-dimethyl 2-benzylidensuccinates,3e the
reactivity of acyclic b-substituted and a,b-disubstituted
acrylates has been investigated by Correia et al.,3e and (E)-
4,4,4-trifluoro-1-phenyl-2-buten-1-one has been convert-
ed into the corresponding a-arylated derivatives.5
Our interest in the palladium chemistry of arenediazoni-
um salts3n,6 prompted us to investigate whether their reac-
tion with 1,2-disubstituted olefins bearing a nucleophile at
one olefinic terminus and an electrophile at the other one
might lead to the de novo construction of functionalized
cyclic derivatives through a domino Heck reaction–
cyclization process. In particular, we decided to explore
the palladium-catalyzed reaction of arenediazonium salts
with readily available alkyl 4-hydroxy-2-butenoate7 (2) to
develop a new route to the 4-arylbutenolide [or 4-aryl-
2(5H)-furanone] skeleton 3 (Scheme 1), a structural unit
that characterizes a large number of biologically impor-
Using 1 equivalent of 2b, 2 equivalents of the arenedi-
azonium salt in MeOH at room temperature or 40 °C, we
next explored the scope and generality of the process.9
SYNLETT 2009, No. 8, pp 1277–1280
Advanced online publication: 08.04.2009
DOI: 10.1055/s-0028-1088132; Art ID: G05209ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
9
As shown in Table 2, the reaction tolerates a variety of
useful substituents including the whole range of halogen
substituents, nitro, ether, cyano, keto, and ester groups.

1278
S. Cacchi et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa
Ar
3
O
O
Pd(OAc)2
ArN2 BF4
HO
CO2R
O
Ar
1
2
H
CO2R
4
Entry
1 Ar (equiv)
2 R
Et
Solvent
EtOH
Temp (°C) Time (h) Yield of 3 (%)b
Yield of 4 (%)b
1
2
4-MeOC6H4 (2)
4-MeOC6H4 (2)
4-MeOC6H4 (2)
4-MeOC6H4 (3)
4-MeOC6H4 (3)
4-MeOC6H4 (3)
4-MeOC6H4 (3)
4-MeO2CC6H4 (2)
4-MeO2CC6H4 (2)
4-MeO2CC6H4 (3)
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
2a
40
40
r.t.
40
r.t.
40
r.t.
40
r.t.
r.t.
8
50c
63
73
74
79
–
3a
3a
3a
3a
3a
–
19
6
4a
4a
4a
4a
4a
–
Me
Me
Me
Me
Me
Me
Me
Me
Me
2b
2b
2b
2b
2b
2b
2b
2b
2b
MeOH
MeOH
MeOH
MeOH
THF
5.5
3
24
3
4
6
16
7
5
5
6
6
–
7
MeCN
MeOH
MeOH
MeOH
6
–
–
–
–
8
4
77
79
74
3b
3b
3b
–
–
9
24
24
–
–
10
–
–
a Reactions were carried out on a 0.5 mmol scale in 5 mL of solvent.
b Yields are given for isolated products.
c Compound 2a was recovered in 14% yield.
Arenediazonium salts containing ortho substituents such carbomethoxybenzenediazonium tetrafluoroborate con-
as chloro, methoxy, and methyl groups also give the cor- centrated under reduced pressure.
responding butenolide products in good to high yields
(Table 2, entries 8, 14–17).
By using this method, we developed an expeditious ap-
proach to the synthesis of rubrolide E, a naturally occur-
A plausible catalytic cycle for this reaction is shown in ring butenolide derivative belonging to rubrolides, a
Scheme 2. The arylpalladium complex, formed in situ via family of biologically active marine ascidian metabolites
the reaction of the arenediazonium salt with Pd(0), reacts isolated from tunicate Ritterella rubra10 and Synoicum
with methyl 4-hydroxy-2-butenoate to give regioselec- blochmanni.11 Because of their antibiotic and cytotoxic
tively the carbopalladation adduct A. Subsequent syn-b- activities, the synthesis of these compounds is a subject of
elimination of HPd species and cyclization, not necessar- great current interest.12 We prepared rubrolide E as fol-
ily in that order, afford the butenolide product.
lows: the Knoevenagel condensation product 5 was ob-
tained in 55% yield through a one-pot process by adding
piperidine and 4-anisaldehyde to the crude mixture de-
rived from the reaction of 1a with methyl 4-hydroxy-2-
butenoate; subsequent treatment of 5 with BBr3 gave ru-
brolide E in 52% overall isolated yield (Scheme 4). In a
recent synthesis from N-phenylmaleimide rubrolide E
was obtained in 32% overall yield in five steps.12e
The reaction was also performed generating the arenedia-
zonium salt in situ.13 This protocol was attempted with 4-
carbomethoxylaniline and 2b (Scheme 3).14 The best re-
sult was obtained by adding MeOH, Pd(OAc)2, and 2b to
the crude mixture resulting from the preparation of 4-
+
ArN2
H+
1
Pd(0)
N2
MeO2C
HPd+
ArPd+
Ar
1. t-BuNO2, BF3⋅OEt2
THF, –15 °C to r.t.
2. HO
CO2Me
Pd+
O
Ar
HO
CO2Me
O
Pd(OAc)2, MeOH, 40 °C, 4 h
3
2b
MeO2C
NH2
MeOH
O
CO2Me
O
OH
3b (73%)
A
Scheme 2
Scheme 3
Synlett 2009, No. 8, 1277–1280 © Thieme Stuttgart · New York

LETTER
4-Aryl Butenolides from Arenediazonium Tetrafluoroborates
1279
In conclusion, we have shown that arenediazonium tet-
rafluoroborates react with readily available methyl 4-hy-
droxy-2-butenoate in the presence of catalytic amounts of
Pd(OAc)2 in methanol under mild conditions to give 4-
arylbutenolides usually in good to high yields. The reac-
tion tolerates a variety of useful substituents including the
whole range of halogen substituents, nitro, ether, cyano,
keto, and ester groups and can be performed as a one-pot
process generating the arenediazonium salt in situ. The
ortho substituents such as methoxy, methyl, and chloro
are also tolerated. By using this method, the rubrolide
skeleton can be constructed via an efficient two-step pro-
tocol omitting the isolation of butenolide intermediates.
Table 2 Synthesis of 4-Arylbutenolides 3 from Arenediazonium
Tetrafluoroborates 1 and Methyl 4-Hydroxy-2-butenoate 2ba
Entry 1 Ar
Time (°C)Time (h) Yield of 3 (%)b
1
2
4-MeOC6H4
r.t.
r.t.
40
r.t.
40
40
40
40
40
40
40
r.t.
r.t.
40
r.t.
40
r.t.
24
24
6
3a
3b
3c
3d
3e
3f
73
79
67
87c
71
73
54
72
62
81
67
86
91d
67
87e
75
81
4-MeO2CC6H4
4-MeCOC6H4
4-O2NC6H4
4-MeC6H4
3-F3CC6H4
4-NCC6H4
2-ClC6H4
3
4
24
24
5
5
6
7
24
7
3g
3h
3i
Acknowledgment
8
We gratefully acknowledge GlaxoSmithKline for their generous fi-
nancial support and a fellowship position and Dr. Alcide Perboni
and Dr. Paolo Stabile of GlaxoSmithKline for valuable discussions.
We are also indebted to Ministero dell’Università e della Ricerca
Scientifica e Tecnologica and to the University ‘La Sapienza’.
9
4-IC6H4
8.5
10
11
12
13
14
15
16
17
4-ClC6H4
6
3
3j
4-FC6H4
3k
3l
4-BrC6H4
12
24
22
24
16
24
References and Notes
Ph
3m
3n
3o
3p
3q
(1) For an excellent recent review on the palladium chemistry of
arenediazonium salts, see: Roglans, A.; Pla-Quintana, A.;
Moreno-Mañas, M. Chem. Rev. 2006, 106, 4622.
2-MeOC6H4
2,4-Me2C6H3
2-Me-4-MeOC6H3
2-Me-4-FC6H3
(2) For some recent selected references, see: (a) Brunner, H.;
Le Cousturier de Courcy, N.; Genêt, J.-P. Synlett 2000, 201.
(b) Cai, M. Z.; Hu, R. H.; Zhou, J. Chin. Chem. Lett. 2001,
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2001, 136, 355024. (d) Darses, S.; Pucheault, M.; Genêt,
J.-P. Eur. J. Org. Chem. 2001, 1121. (e) Sengupta, S.;
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Ma, Y.; Zang, Y.; Song, C. Tetrahedron Lett. 2002, 43,
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Hu, H.-W.; Xu, J.-H. Synth. Commun. 2003, 33, 773.
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a Reactions have been carried out on a 0.5 mmol scale using 1 equiv
of 2b, 2 equiv of 1 in 5 mL of anhyd MeOH.
b Yields are given for isolated products.
c A 55% yield at 40 °C (3.5 h).
d A 62% yield at 40 °C (24 h).
e A 51% yield at 40 °C (6 h).
OMe
1. Pd(OAc)2, MeOH, r.t., 24 h
2. piperidine, 4-anisaldehyde
70 °C, 8 h
+
HO
CO2Me
55%
N2 BF4
1a
MeO
HO
BBr3, CH2Cl2
–78 °C to r.t., 24 h
(q) Masllorens, J.; Bouquillon, S.; Roglans, A.; Hénin, F.;
Muzart, J. J. Organomet. Chem. 2005, 690, 3822.
O
95%
O
O
O
(r) Farina, A.; Ferranti, C.; Marra, C.; Guiso, M.; Norcia, G.
Nat. Prod. Res. 2007, 21, 564. (s) Moro, A. V.; Cardoso, F.
S. P.; Correia, C. R. D. Tetrahedron Lett. 2008, 49, 5668.
(3) For some recent references, see: (a) Severino, E. A.;
Costenaro, E. R.; Garcia, A. L. L.; Correia, C. R. D. Org.
Lett. 2003, 5, 305. (b) Garcia, A. L. L.; Correia, C. R. D.
Tetrahedron Lett. 2003, 44, 1553. (c) Montes de Oca,
A. C. B.; Correia, C. R. D. ARKIVOC 2003, (x), 390.
(d) Schmidt, B. Chem. Commun. 2003, 1656.
MeO
HO
5
rubrolide E
Scheme 4
(e) Garcia Ariel, L. L.; Carpes, M. J. S.; Montes de Oca,
Synlett 2009, No. 8, 1277–1280 © Thieme Stuttgart · New York

1280
S. Cacchi et al.
LETTER
with aluminum film). After cooling, the reaction mixture
A. C. B.; dos Santos, M. A. G.; Santana, C. C.; Correia,
C. R. D. J. Org. Chem. 2005, 70, 1050. (f) Sabino, A. A.;
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A. H. L.; Correia, C. R. D.; Eberlin, M. N. Angew. Chem. Int.
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Miranda, K. C.; Correia, C. R. D. Synlett 2006, 3145.
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R. Tetrahedron 2006, 62, 3146. (k) Meira, P. R. R.; Moro,
A. V.; Correia, C. R. D. Synthesis 2007, 2279.
(l) Peixoto da Silva, K.; Godoi, M. N.; Correia, C. R. D. Org.
Lett. 2007, 9, 2815. (m) Barreto, R. de L.; Nascimbem, L. B.
L. R.; Correia, C. R. D. Synth. Commun. 2007, 37, 2011.
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Synlett 2008, 2508.
was diluted with EtOAc, washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was purified by chromatography on SiO2 [n-hexane–
EtOAc, 60:40] to afford 83.9 mg of 3b (77% yield); mp:
192–194 °C. IR (KBr): 1745, 1710, 1280 cm–1. 1H NMR
(400 MHz, CDCl3): d = 8.15 (d, J = 8.4 Hz, 2 H), 7.60 (d,
J = 8.4 Hz, 2 H), 6.21 (t, J = 1.6 Hz, 2 H), 5.16 (d, J = 1.6
Hz, 2 H), 3.97 (s, 3 H). 13C NMR (100.6 MHz, CDCl3): d =
173.2, 166.0, 162.5, 133.6, 132.9, 130.5, 126.5, 115.3, 70.9,
52.6. MS: m/z (%) = 216 (8) [M+], 75 (42), 59 (100).
(10) Miao, S.; Andersen, R. J. J. Org. Chem. 1991, 56, 6275.
(11) Ortega, M. J.; Zubia, E.; Ocana, J. M.; Naranjo, S.; Salva, J.
Tetrahedron 2000, 56, 3963.
(12) For selected recent syntheses of rubrolides, see: (a) Bellina,
F.; Anselmi, C.; Stephane, V.; Mannina, L.; Rossi, R.
Tetrahedron 2001, 57, 9997. (b) Bellina, F.; Anselmi, C.;
Rossi, R. Tetrahedron Lett. 2002, 43, 2023. (c) Bellina, F.;
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Soc. Chim. Fr. 1934, 1, 1317. (b) Hassner, A.; Friedman,
O.; Dehaen, W. Liebigs Ann./ Recl. 1997, 587.
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(14) One-Pot Procedure for the Preparation of Butenolides
(3) from Anilines
(8) (a) Bezuidenhoudt, B. C. B.; Swanepoel, A.; Brandt, E. V.;
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(9) Typical Procedure for the Preparation of Butenolides (3)
To a stirred solution of 2b (58.0 mg, 0.50 mmol) and
Pd(OAc)2 (5.6 mg, 0.025 mmol) in anhyd MeOH (5.0 mL),
1b (250.0 mg, 1.0 mmol) was added at r.t. under argon. The
reaction mixture was warmed at 40 °C and stirred at that
temperature for 4 h (the reactor was protected from light
A solution of BF3·OEt2 (140 mL, 1.1 mmol) in anhyd THF (1
mL) was cooled at –15 °C, and 4-carbomethoxylaniline
(151.2 mg, 1 mmol) was added. Then, tert-butyl nitrite (160
mL, 1.3 mmol) in 1 mL of the same solvent was added
dropwise to the rapidly stirred solution over a 10 min period.
After that, the reaction temperature was maintained at –15 °C
for 10 min, allowed to warm to 5 °C (ice-water bath) over a
20 min period, warmed to r.t., and stirred at the same
temperature till the disappearance of the starting aniline. The
reaction mixture was subsequently concentrated under
reduced pressure and diluted with anhyd MeOH (5 mL).
Then, 2b (58.0 mg, 0.50 mmol) and Pd(OAc)2 (5.6 mg,
0.025 mmol) were added, the reaction mixture was warmed
at 40 °C, and stirred at that temperature for 4 h (the reactor
was protected from light with aluminum film). After
cooling, the reaction mixture was diluted with EtOAc,
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by
chromatography on SiO2 [n-hexane–EtOAc, 60:40] to afford
80.0 mg of 3b (73% yield).
Synlett 2009, No. 8, 1277–1280 © Thieme Stuttgart · New York

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