Reinvestigation of mucohalic acids, versatile and useful building blocks for highly functionalized alpha,beta-unsaturated gamma-butyrolactones.

Article abstract of DOI:10.1021/ol027122b

[reaction: see text] Mucohalic acids (mucochloric acid (1, 3,4-dichloro-5-hydroxy-5H-furan-2-one) and mucobromic acid (2, 3,4-dibromo-5-hydroxy-5H-furan-2-one)) are inexpensive, commercially available starting materials with multiple functional groups. These compounds have been modified by way of reduction followed by Suzuki cross-coupling reactions involving arylboronic acids to afford highly functionalized alpha,beta-unsaturated gamma-butyrolactones in excellent yield. The synthetic utility of these building blocks was effectively demonstrated through preparation of the antiinflammatory drug Vioxx.

Full text of DOI:10.1021/ol027122b

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4559-4561
Reinvestigation of Mucohalic Acids,
Versatile and Useful Building Blocks for
Highly Functionalized r,â-Unsaturated
γ-Butyrolactones
Ji Zhang,* Peter G. Blazecka, Daniel Belmont, and James G. Davidson
Chemical Research and DeVelopment, Pfizer, Inc., Global Research & DeVelopment,
Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105
ji.zhang@pfizer.com
Received October 17, 2002
ABSTRACT
Mucohalic acids (mucochloric acid (1, 3,4-dichloro-5-hydroxy-5H-furan-2-one) and mucobromic acid (2, 3,4-dibromo-5-hydroxy-5H-furan-2-
one)) are inexpensive, commercially available starting materials with multiple functional groups. These compounds have been modified by
way of reduction followed by Suzuki cross-coupling reactions involving arylboronic acids to afford highly functionalized r,â-unsaturated
γ-butyrolactones in excellent yield. The synthetic utility of these building blocks was effectively demonstrated through preparation of the
antiinflammatory drug Vioxx.
Mucohalic acids (mucochloric acid (1, 3,4-dichloro-5-hy-
droxy-5H-furan-2-one) and mucobromic acid (2, 3,4-di-
bromo-5-hydroxy-5H-furan-2-one)) are inexpensive, com-
mercially available starting materials with multiple functional
groups. Mucochloric acid has been known for more than 100
years and was first prepared in 1890 from â,γ-dichloropy-
romucic acid and bromine water,1a later by heating furfural
with manganese dioxide and hydrochloric acid (1899),1b and
more recently by chlorination of butyne-1,4-diol (1960).1c
These four-carbon molecules have seen limited use2 in
organic synthesis, presumably for reasons associated with
the many reactive sites, poor stability under basic conditions,
and assumed difficulty in the selective manipulation of the
halogen atoms. However, these two highly functionalized
molecules are very attractive as potential useful building
blocks in synthesis because they can be viewed as R,â-
unsaturated acids, R,â-unsaturated aldehydes, fully substi-
tuted (Z)-olefins, vinyl halides, masked hemiacetals, or
pseudo lactones. The ever-increasing importance of transition
metal-catalyzed cross-coupling reactions3 has driven us to
apply this chemistry to these intriguing structures and explore
this untapped chemical resource. Herein we report a means
of selectively manipulating these densely functionalized
molecules through Suzuki cross-coupling reactions.
Recently, we reported the first direct reductive amination
of mucohalic acids to prepare highly functionalized R,â-
unsaturated γ-butyrolactams and γ-amino acids.4 Interest-
(1) (a) Hill, H. B.; Jackson. O. R. Am. Chem. J. 1890, 12, 37. (b) Simonis,
H. Ber. 1899, 32, 2085. (c) Dury, K. Angew. Chem. 1960, 72, 864.
(2) (a) Wasserman, H. H.; Precopio, F. M. J. Am. Chem. Soc. 1954, 76,
1242 and references therein. (b) Fishbein, P. L.; Moore, H. W. Org. Synth.
1990, 69, 205. (c) Sulikowski, G. A.; Agnelli, F.; Corbett, R. M. J. Org.
Chem. 2000, 65, 337.
(3) Tsuji, J. Palladium Reagents and Catalysts; Wiley & Sons, Ltd.; New
York, 1995.
10.1021/ol027122b CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002

ingly, attempted reductive aminations of mucohalic acids
with ammonium formate or ammonium acetate as the NH3
equivalent failed to give expected lactams 5 and 6, but rather
lactones 3 and 4 were isolated (Scheme 1).5 This serendipi-
system was a key issue because carrying out the coupling
reaction under strongly basic conditions would result in side
reactions such as hydrolysis of the γ-lactone, ring opening,
or bromide-hydroxyl exchange if a homogeneous system was
employed. We believed that using phase-transfer methodol-
ogy13 would favor the desired palladium insertion (in the
organic layer) and minimize unwanted side reactions (in the
aqueous layer). Results of a base screen (Table 1) suggested
Scheme 1. Attempted Reductive Aminations of Mucohalic
Acids
Table 1. Suzuki Coupling Using Different Basesa
tous finding led us to investigate the chemical behavior of
these lactones.
entry
base (reaction time)
yieldb (%)
Both γ-butyrolactones and R,â-unsaturated γ-butyrolac-
tones have attracted considerable attention due to their
interesting biological properties and ubiquitous nature.6 For
example, (-)-arctigenin is a bisbenzylbutyrolactone that
exhibits anti-HIV properties,7 and the antiinflammatory
Vioxx8 and the vasodilator Eucilat9 are pharmaceutical
agents; monomeric substance 8a is used in polymer science.
Although it has been reported that the marine antibiotics
rubrolides C and E were synthesized by palladium(0)-
catalyzed cross-coupling of bromobutenolides with aryl-
boronic acids10 and that Bellina and Rossi have converted
lactone 4 to unsymmetric 3,4-disubstituted and 4-substituted
5H-furan-2-ones, such as cytotoxic rubrolide M,11 we decided
to study carbon-carbon bond formation of 3 and 4 in the
form of a bis-Suzuki cross-coupling reaction. Suzuki cross-
coupling reactions are commonly used and amenable to a
combinatorial approach to early lead development in drug
discovery.
1
2
3
4
5
6
7
8
9
K3PO4 (2 h)
K2CO3 (3 h)
Cs2CO3 (3 h)
Na2CO3 (3 h)
NaHCO3 (3 h)
K2HPO4 (3 h)
KF (3 h)
56
42
51
41
68
68
71
78
88
CsF (3 h)
CsF (24 h)
a Reaction conditions: 2.5 mmol of 4, 2.4 equiv of 7a, 4.0 equiv of
base, 5 mol % PdCl2(PPh3)2, 5 mol % BnEt3N+Cl-, reflux. b Isolated yield
after chromatography.
that CsF and KF promoted the coupling reactions to give
good yields (Table 1, entries 7 and 8) under very mildly
basic conditions. These results are consistent with Wright’s
finding14 that fluorides are valuable and advantageous in
boronic acid coupling reactions. Extending the reaction time
to 24 h resulted in an 88% yield of compound 8a (Table 1,
entry 9).
The reaction between lactone 4 and phenylboronic acid
(7a) was examined initially.12 The choice of base in our
Success with the coupling reaction between 7a and 4
prompted us to explore the possibility of coupling 7a with
3. The use of chlorides in Suzuki coupling reactions has
encountered significant difficulty, which has only recently
been overcome.15 In view of its lower cost and the greater
synthetic challenge that it posed, lactone 3 was employed in
(4) Zhang, J.; Blazecka, P. G.; Davidson, J. G. Patent pending.
(5) (a) Lalonde reported preparation of 3 from mucochloric acid:
Lalonde, R. T.; Perakyla, H.; Cook, G. P.; Dence, C. W. EnViron. Toxicol.
Chem. 1990, 9, 687. (b) Rossi reported that 4 was prepared in 75% yield
by reduction of mucobromic acid by NaBH4: Rossi, R.; Bellina, F.; Raugei,
E. Synlett. 2000, 12, 1749.
(6) (a) Chatani, N.; Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am. Chem.
Soc. 1998, 120, 5335. (b) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc.
1999, 121, 11680. (c) Tobisu, M.; Chatani, N.; Asaumi, T.; Amako, K.; Ie,
Y.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12663. (d)
Mandal, S. K.; Amin, S. R.; Crowe, W. E. J. Am. Chem. Soc. 2001, 123,
6457. (e) Movassaghi, M.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
2456. (f) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
3500. (g) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 8198.
(7) Sibi, M. P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-X. J. Org. Chem. 2002,
67, 1738 and references therein.
(12) Diphenylbutyrolactone 8a was once produced by the carbonylation
of diphenylacetylene in ethanol using PdCl2/HCl under 100 atm at 100 °C.
This process generated a significant amount of diethyl diphenylmaleate (18)
as side product. See: Tsuji, J.; Nogi, T. J. Am. Chem. Soc. 1966, 88, 1289.
(8) (a) Therien, M.; Gauthier, J. Y.; Leblanc, Y.; Leger, S.; Perrier, H.;
Prasit, P.; Wang, Z. Synthesis 2001, 12, 1778. (b) Forgione, P.; Wilson, P.
D.; Fallis, A. G. Tetrahedron Lett. 2000, 41, 17.
(9) (a) Schmit, J.; Suquet, M.; Salle, J.; Comoy, P.; Callet, G.; LeMeur,
J. Chim. Ther. 1966, 5-6, 305. (b) Schmitt, J.; Suquet, M.; Callet, G.; Le
Meur, J.; Comoy, P. Bull. Soc. Chim. Fr. 1967, 1, 74. (c) Vallat, J. N.;
Grossi, P. J.; Boucherle, A.; Simiand, J. Eur. Med. Chem. 1981, 16, 409.
(10) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau, M. Tetrahe-
dron Lett. 1998, 39, 7665.
(11) (a) Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett. 2002, 43,
2023. (b) Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett. 2001, 42,
3851. (c) Bellina, F.; Anselmi, C.; Viel, S.; Mannina, L.; Rossi, R.
Tetrahedron 2000, 57, 9997.
(13) For lead references on the use of phase-transfer methodology in
palladium-catalyzed carbon-carbon bond-forming reactions, see: (a) Jef-
frey, T. Tetrahedron Lett. 1994, 35, 3051. (b) Jeffrey, T.; Galland, J.-C.
Tetrahedron Lett. 1994, 35, 4103. (c) Mukhopadhyay, S.; Rothenberg, G.;
Gitis, D.; Sasson, Y. J. Org. Chem. 2000, 65, 3107. (d) Chow, H.-F.; Wan,
C.-W.; Low, K.-H.; Yeung, Y.-Y. J. Org. Chem. 2001, 66, 1910. (e) Wang,
J.-X.; Liu, Z.; Hu, Y.; Wei, B.; Bai, L. Synth. Commun. 2002, 32, 1607.
(14) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095.
4560
Org. Lett., Vol. 4, No. 25, 2002

the Suzuki reaction. The coupling of 7a with 3 was very
successful under our reaction conditions, and lactone 8a was
isolated in 93% yield without need of any special ligands.15b-g
Equation 3 (Table 2) represents by far a superior means
4-aryl-3-halogenated R,â-unsaturated γ-butyrolactones were
prepared from 3 and 4, we found these methods to be
unsatisfactory for practical application. The expensive reagent
Ag2O (3.0 equiv) and highly toxic triphenylarsine (20%) were
used to control the regioselectivity when bromide 4 was the
starting material, and aryl(tributyl) stannanes were used in
NMP at 85 °C for 21-22 h (yield ) 55-78%, with side
product) when chloride 3 was the starting material. However,
under our conditions (25 °C, 48-72 h) 4-aryl-3-chloro-R,â-
unsaturated γ-butyrolactone 16 was prepared from 3 and 12
in 91-99% yield. The regioisomer was not observed. The
methodology described herein has been successfully applied
to the synthesis of Vioxx (15, Scheme 3).16
Table 2. Suzuki Coupling of 3 with Different Arylboronic
Acidsa
Scheme 3. Preparation of Vioxxa
entry
R
8
yieldb (%)
1
2
3
4
5
6
H
8a
8b
8c
8d
8e
8f
93
87
94
89
89
99
CH3
OMe
Cl
F
CF3
a Reaction conditions: 1.8-2.5 mmol of 3, 3.0 equiv of 7, 4.0 equiv of
CsF, 5 mol % PdCl2(PPh3)2, 5 mol % BnEt3N+Cl-, reflux, 16-18 h.
b Isolated yield after chromatography.
of producing 8a. It employs very mild conditions, affords
product in excellent chemical yield, and is devoid of
significant side reactions. The reaction has been further
extended to encompass several differently substituted aryl-
boronic acids (Table 2) with excellent results.
To further the synthetic utility of this bis-Suzuki reaction,
mucochloric acid (1) was used in the direct coupling with
phenylboronic acid (7a), and product 9 was isolated in 71%
yield (Scheme 2). When benzylacetal 10 was used in the
a Conditions: (a) 2.3 mmol of 3 or 4, 2.0 equiv of 12, 5 mol %
PdCl2(PPh3)2, 2.7 equiv of CsF, 5 mol % BnEt3N+Cl-, 1:1 toluene/
H2O, 25 °C; (b) 2.0 equiv of PhB(OH)2, 5 mol % PdCl2(PPh3)2,
3.0 equiv of CsF, 5 mol % BnEt3N+Cl-, 1:1 toluene/H2O, reflux;
(c) 3.0 equiv of Oxone, wet acetone, 0-25 °C.
In summary, we have developed a simple, efficient, and
selective method for preparing bisaryl-γ-butyrolactones and
substituted γ-butyrolactones. Mucohalic acids possess a
geometrically defined tetrasubstituted olefin and two dif-
ferentiated vinyl halides and could be used in the synthesis
of a variety of biologically active natural products or
pharmaceutically important compounds. Further investiga-
tions, including extension of the use of these building blocks,
will be reported in due course.
Scheme 2. Suzuki Coupling of Mucochloric Acid
Acknowledgment. We thank Dr. Derek Pflum for
reviewing this manuscript and providing valuable sugges-
tions.
coupling, product 11 was isolated in 90% yield.
Regioselective monoarylation of 3 and 4 is very important,
and the products are useful as building blocks for preparing
more complex molecules. Although it was reported5,11 that
Supporting Information Available: Experimental pro-
cedures, spectral and analytical data for all products, and
additional structures. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) (a) Shen, W. Tetrahedron Lett. 1997, 38, 5575. (b). Old, D. W.;
Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722. (c) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 37, 3387. (d) Wolfe, J.;
Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (e) Zhang, C.;
Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804. (f)
Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem, Int. Ed. 2002, 41, 1945.
(g) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553.
OL027122B
(16) Rossi reported preparation of Vioxx in 32% overall yield, starting
from 4, via a Stille-type reaction between tributyl(phenyl)tin and 3-bromo-
4-(4-methylthio)phenyl-5H-furan-2-one: Rossi, R.; Bellina, F.; Raugei, E.
Synlett 2000, 12, 1749.
Org. Lett., Vol. 4, No. 25, 2002
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