Facile access to 4-(1-alkynyl)-2(5H)-furanones by Sonogashira coupling of terminal acetylenes with β-tetronic acid bromide: efficient synthesis of cleviolide

Article abstract of DOI:10.1016/j.tetlet.2006.10.156

A mild and convenient synthesis of 4-(1-alkynyl)-2(5H)-furanones has been achieved by Sonogashira or Heck-type alkynylation of β-tetronic acid bromide. As an illustration of this methodology, the natural product cleviolide was prepared in two steps and 78

Full text of DOI:10.1016/j.tetlet.2006.10.156

Tetrahedron Letters 48 (2007) 105–107
Facile access to 4-(1-alkynyl)-2(5H)-furanones by
Sonogashira coupling of terminal acetylenes with b-tetronic
acid bromide: efficient synthesis of cleviolide
*
John Boukouvalas, S e´ bastien C oˆ t e´ and Bruno Ndzi
D e´ partement de Chimie, Universit e´ Laval, Quebec City, Que., Canada G1K 7P4
Received 5 October 2006; revised 28 October 2006; accepted 30 October 2006
Available online 20 November 2006
Abstract—A mild and convenient synthesis of 4-(1-alkynyl)-2(5H)-furanones has been achieved by Sonogashira or Heck-type
alkynylation of b-tetronic acid bromide. As an illustration of this methodology, the natural product cleviolide was prepared in
two steps and 78% overall yield.
ꢀ
2006 Elsevier Ltd. All rights reserved.
The development of practical methods for constructing
-substituted 2(5H)-furanones is a prominent objective
R
4
Br
in synthetic chemistry due to the significant biological
activities of many natural and unnatural products con-
Pd
R
M
+
O
catalyst
O
1
taining this moiety. An appealing approach to these
O
O
M = SnBu3 (ref. 10)
M = ZnCl (ref. 11)
M = BF3K (ref. 12)
compounds, suitable for parallel synthesis, involves the
attachment of a C4-substituent onto a preformed fura-
none ring. This is best accomplished by cross-coupling
1
2
2
Scheme 1.
tactics, as first demonstrated by Negishi and co-workers
during a total synthesis of the 4-homoallyl-2(5H)-fura-
none makupalide. Recently, new protocols have been
3
Although some of these methods have been shown to
1
0,12
be efficient,
the preparation of the requisite tin or
developed for installing a variety of C4-substituents
4
5
6
4d,7
boron acetylides is an obvious inconvenience, especially
when other sensitive functional groups are present. In
addition, the frequently used Stille reaction produces
toxic organotin by-products which are difficult to
remove even on a small scale.
including aryl, alkenyl, alkyl, benzyl
and cycloprop-
8
9
yl among others.
A few simple 4-(1-alkynyl)-2(5H)-furanones (2) have
also been prepared in this manner, notably by palla-
dium-catalysed cross-coupling of b-tetronic acid bro-
1
0
Intrigued by the lack of literature reports on the alkynyl-
mide (1) with tributylstannylacetylenes, 1-alkynylzinc
1
6,17
1
1
ation of bromide 1 with terminal acetylenes,
we
chlorides, and more recently, potassium alkynyltri-
1
2
decided to explore this process as a potentially more util-
itarian, direct pathway to 4-(1-alkynyl)-2(5H)-furanones
(2). Herein we report, that under the appropriate condi-
tions, a variety of terminal acetylenes undergo smooth
coupling with 1 at room temperature to provide 2 in
good to high yields (Table 1). We also describe an appli-
cation of this methodology to an exceptionally simple
and efficient synthesis of cleviolide.
fluoroborates (Scheme 1). For example, the structurally
unusual monoterpene cleviolide (2, R = Me C@CH), a
2
1
3
constituent of the plant Senecio clevelandii and an
1
4
attractive target for testing new methodologies, has
been synthesized using the Stille coupling reaction
1
0b
15
depicted in Scheme 1
as well as its inverse variant.
Keywords: Cleviolide; Cross-coupling; Heck alkynylation; Sonogashira
reaction; b-Tetronic acid bromide.
Initial attempts to couple 1 with phenylacetylene under
classical conditions used for the Sonogashira reaction,
for example, treatment of the coupling partners with
*
Corresponding author. Tel.: +1 418 656 5473; fax: +1 418 656
916; e-mail: john.boukouvalas@chm.ulaval.ca
7
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.156

106
J. Boukouvalas et al. / Tetrahedron Letters 48 (2007) 105–107
Table 1. Preparation of 4-(1-alkynyl)-2(5H)-furanones from b-tetronic
OH
acid bromide and terminal acetylenes
R
P O , PhH, 80 ºC, 1 h
2
5
Br
O
O
(
96%)
Method A or B
O
O
R
H
+
O
O
2j
cleviolide
O
O
1
2a-j
Scheme 2.
a
Entry
R
Product
Method
Isolated
yield (%)
b
foregoing alkynylation procedures are operationally
simple, do not require strong bases and work well at
room temperature. Moreover, the effectiveness of the
1
2
3
4
Ph
2a
2b
2c
2d
A
A
A
A
71
74
80
73
p-F–Ph
n-octyl
t-Bu
water-soluble Pd(OAc) –TPPMS catalyst, as demon-
2
strated by the straightforward synthesis of cleviolide,
renders this methodology both ‘green’ and practical
for potential large-scale applications.
5
2e
A
65
6
7
8
9
THPOCH
2
2f
A
A
A
B
77
86
50
63
t-BuOCHMe
HOCH CH
2g
2h
2
2
Acknowledgements
OH
OH
1
1
0
1
2i
2j
A
B
62
78
We are indebted to the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC), Merck
Frosst Canada and Eisai Research Institute (Andover,
MA, USA) for financial support. We also thank
NSERC for a postgraduate scholarship to S.C., and
AUPELF (France) for a postdoctoral fellowship to B.N.
12
B
81
a
Method A: bromide (1), PdCl
THF, 0.5 h, rt, then i-Pr NH, 1-alkyne, 16 h, rt. Method B: Pd(OAc)
3 mol %), TPPMS (5 mol %), Et N, MeCN/H O (15:1), 20 h, rt.
All yields refer to isolated products after flash chromatography.
2 3 2
(PPh ) (10 mol %), CuI (2 mol %),
2
2
(
3
2
b
References and notes
PdCl (PPh ) , CuI and diisopropylamine in THF at var-
1. For select examples of bioactive 4-substituted 2(5H)-
furanones see: (a) Carotenuto, A.; Fattorusso, E.; Lan-
zotti, V.; Magno, S.; Carnuccio, R.; D’Acquisto, F.
Tetrahedron 1997, 53, 7305–7310; (b) Luszniak, M.;
Pickett, J. Chem. Br. 1998, 34, 29–32; (c) D’Acquisto, F.;
Lanzotti, V.; Carnuccio, R. Biochem. J. 2000, 346, 793–
2
3 2
ious temperatures, or heating 1 with the metal salts and
1
8
base in THF before adding the acetylene, provided the
1
9
desired product 2a in only 10–20% yield. Further
experimentation revealed that by simply altering the
2
0
order of addition (Table 1, method A), the yield of 2a
could be substantially improved without a need for heating,
strong bases or expensive phosphine additives. Using
this procedure, several 4-(1-alkynyl)-2(5H)-furanones
7
98; (d) Menta, E.; Conti, M.; Pescalli, N. PCT Int. Appl.
WO 2000053581, 2000; (e) Scio, E.; Ribeiro, A.; Roma-
nha, A. J.; de Souza Filho, J. D.; Cordell, G. A.; Zani, C.
L. Phytochemistry 2003, 64, 1125–1131; (f) Van Qua-
quebeke, E.; Simon, G.; Andr e´ , A.; Dewelle, J.; El Yazidi,
M.; Bruyneel, F.; Tuti, J.; Nacoulma, O.; Guissou, P.;
Decaestecker, C.; Braekman, J.-C.; Kiss, R.; Darro, F. J.
Med. Chem. 2005, 48, 849–856, and references cited
therein; (g) Bousserouel, H.; Litaudon, M.; Morleo, B.;
Martin, M.-T.; Thoison, O.; Nosjean, O.; Boutin, J. A.;
Renard, P.; S e´ venet, T. Tetrahedron 2005, 61, 845–851; (h)
Dai, S.-J.; Tao, J.-Y.; Liu, K.; Jiang, Y.-T.; Shen, L.
Phytochemistry 2006, 67, 1326–1330.
2
0
(
2a–i) were readily prepared in a single step from com-
mercially available acetylenes. Yields were generally
good with aryl, alkyl, alkenyl and protected hydroxy-
alkyl acetylenes (65–86%), but less so with substrates
bearing a free hydroxyl group (50–62%; entries 8 and
1
0). However, we were able to prepare hydroxyalkynyl-
furanones 2h and 2i more efficiently (entries 9 and 11) by
Heck-type alkynylation of 1 (a.k.a. copper-free Sono-
2
1
gashira reaction) using the procedure of Gen eˆ t et al.
2
. For a recent review on the use of cross-coupling reactions
in total synthesis, see: Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442–4489.
which employs palladium acetate in conjunction with
an inexpensive water-soluble ligand such as sodium
triphenylphoshine monosulfonate (TPPMS, method
3. (a) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45,
5223–5225; For more recent applications of the Negishi
protocol see: (b) Piers, E.; Breau, M. L.; Han, Y.; Ploudre,
G. L.; Yeh, W.-L. J. Chem. Soc., Perkin Trans. 1 1995,
22
B). Likewise, alcohol 2j was prepared from bromide
2
2
1
and 4-methyl-1-pentyn-3-ol in 81% yield (entry 12).
Heating 2j with phosphorus pentoxide in benzene
cleanly provided cleviolide (96% yield, Scheme 2) whose
mp (63–64 ꢁC) and NMR data were in excellent agree-
9
3
63–966; (c) Boukouvalas, J.; Lachance, N. Synlett 1998,
1–32.
4
. (a) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau,
M. Tetrahedron Lett. 1998, 39, 7665–7668, and references
cited therein; (b) Wu, J.; Zhu, Q.; Wang, L.; Fathi, R.;
Yang, Z. J. Org. Chem. 2003, 68, 670–673; (c) Tang, Z.-Y.;
Hu, Q.-S. Adv. Synth. Catal. 2004, 346, 1635–1637; (d)
Wu, J.; Zhang, L. Chem. Lett. 2005, 34, 796–797; see also:
1
0b,15b
ment with those reported in the literature.
In conclusion, we have developed a methodology that
allows direct and easy access to a variety of 4-(1-alkyn-
yl)-2(5H)-furanones from commercial acetylenes. The

J. Boukouvalas et al. / Tetrahedron Letters 48 (2007) 105–107
107
(
e) Zhang, J.; Blazecka, P. G.; Belmont, D.; Davidson, J.
acetate/hexanes (·3), and the combined extracts were
dried (Na SO ) and evaporated in vacuo. Purification by
G. Org. Lett. 2002, 4, 4559–4561; (f) Bellina, F.; Rossi, R.
Curr. Org. Chem. 2004, 8, 1089–1103; (g) Boukouvalas, J.;
Pouliot, M. Synlett 2005, 343–345.
2
4
flash chromatography (ethyl acetate/hexanes: 1/4) affor-
1
ded 2f as an oil (476 mg, 77%); H NMR (300 MHz,
5
. (a) Lattmann, E.; Hoffmann, H. M. R. Synthesis 1996,
CDCl
3
) d 6.13 (t, J = 1.9 Hz, 1H), 4.75 (d, J = 1.9 Hz,
1
55–163; (b) Honda, T.; Mizutani, H.; Kanai, K. J. Org.
2H), 4.72 (t, J = 2.9 Hz, 1H), 4.48–4.35 (m, 2H), 3.80–3.72
1
3
Chem. 1996, 61, 9374–9378.
(m, 1H), 1.81–1.46 (m, 6H); C NMR (75 MHz, CDCl ) d
3
6
7
8
9
. Grigg, R.; Kennewell, P.; Savic, V. Tetrahedron 1994, 50,
172.8, 146.5, 122.8, 101.8, 97.2, 75.8, 72.7, 61.9, 54.3, 29.9,
25.1, 18.7. Anal. Calcd for C12H O : C, 64.85; H, 6.35.
14 4
5
489–5494.
. Kamlage, S.; Sefkow, M.; Pool-Zobel, B. L.; Peter, M. G.
Chem. Commun. 2001, 331–332.
. Yao, M.-L.; Deng, M.-Z. J. Org. Chem. 2000, 65, 5034–
Found: C, 64.52; H, 6.56. Data for other new compounds:
1
Compound 2b: mp 70–71 ꢁC; H NMR (300 MHz,
CDCl ) d 7.50 (m, 2H), 7.08 (m, 2H),1 6.24 (t,
3
3
5
036.
J = 1.9 Hz, 1H), 4.88 (d, J = 1.9 Hz, 2H); C NMR
. For a recent synthesis of 4-homoallyl-2(5H)-furanones
(75 MHz, CDCl ) d 173.0, 163.5 (d, J = 253 Hz), 146.8,
3
3
3
using sp –sp cross-coupling, see: Boukouvalas, J.; Robi-
134.1 (d, J = 8.7 Hz), 122.1, 116.1 (d, J = 22 Hz), 103.8,
chaud, J.; Maltais, F. Synlett 2006, 2480–2482.
79.0, 72.8; HRMS m/z 202.0435 (calcd for C12H FO
7 2
1
1
0. (a) Hoffmann, H. M. R.; Gerlach, K.; Lattmann, E.
Synthesis 1996, 164–170; (b) Rossi, R.; Bellina, F.;
Biagetti, M. Synth. Commun. 1999, 29, 3415–3420.
1. Bellina, F.; Rossi, R.; Biagetti, M.; Mannina, L. Tetra-
hedron Lett. 1998, 39, 7599–7602.
202.0430). Compound 2c: mp 106–108 ꢁC; H NMR
(300 MHz, CDCl ) d 6.08 (t, J = 1.6 Hz, 1H), 4.75 (d,
3
J = 1.6 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 1.58 (q, J =
1
1
1
1
7.1 Hz, 2H), 1.41–1.08 (m, 10H), 0.87 (t, J = 6.6 Hz, 3H);
1
3
C NMR (75 MHz, CDCl ) d 173.5, 148.1, 121.3, 108.2,
3
2. Kabalka, G. W.; Dong, G.; Venkataiah, B. Tetrahedron
Lett. 2004, 45, 5139–5141.
3. Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H.
Phytochemistry 1981, 20, 2425–2427.
4. For a synthesis of cleviolide from acyclic precursors by a
novel palladium–tin cocatalysed tandem process, see:
Trost, B. M.; McIntosh, M. C. J. Am. Chem. Soc. 1995,
73.1, 71.4, 31.7, 29.0, 28.9, 28.8, 27.8, 22.5, 19.8, 13.9;
+
HRMS m/z (MH ) 221.1540 (calcd for 1
221.1541). Compound 2g: mp 73–74 ꢁC;
14 21 2
C H O
H NMR
(300 MHz, CDCl ) d 6.13 (t, J = 1.7 Hz, 1H), 4.77 (d,
3
J = 1.9 Hz, 2H), 4.47 (q, J = 6.7 Hz, 1H), 1.43 (d,
1
3
3
J = 6.7 Hz, 3H); 1.25 (s, 9H); C NMR (75 MHz, CDCl )
d 173.0, 146.7, 121.6, 108.5, 74.7, 73.1, 72.4, 57.4, 27.4, 23.1;
+
1
17, 7255–7256.
5. (a) Hollingworth, G. J.; Sweeney, J. B. Synlett 1993, 463–
65; (b) Hollingworth, G. J.; Richecoeur, A. M. E.;
Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1 1996, 2833–
836.
6. (a) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975,
3, 259–263; (b) Sonogashira, K.; Tohda, Y.; Hagihara,
HRMS (MH ) m/z 209.1181 (calcd for C H O
1
2
17
3
1
1
1
1
209.1178). Compound 2h: H NMR (300 MHz, CDCl
3
) d
4
6.15 (s, 1H), 4.78 (d, J = 1.6 Hz), 3.83 (t, J = 6.3 Hz, 2H),
13
2.74 (t, J = 6.3 Hz, 2H), 1.72 (br s, 1H); C NMR (75 MHz,
2
CDCl ) d 173.8, 148.0, 121.7, 105.0, 74.9, 73.2, 60.1, 24.0;
3
HRMS m/z 152.0481 (calcd for C
Compound 2i: H NMR (300 MHz, CDCl
8
H
8
O
3
152.0473).
) d 6.00 (t,
1
9
3
N. Tetrahedron Lett. 1975, 4467–4470; (c) Negishi, E.;
Anastasia, L. Chem. Rev. 2003, 103, 1979–2017.
J = 1.9 Hz, 1H), 4.66 (d, J = 1.9 Hz, 2H), 3.73 (s, 1H), 1.91–
13
1.57 (m, 8H); C NMR (75 MHz, CDCl
121.6, 110.3, 74.1, 73.0, 72.8, 41.9, 23.3; HRMS (MH ) m/z
193.0863 (calcd for C11 193.0865).
3
) d 173.6, 147.6,
+
7. A couple of 4-(1-alkynyl)-(5H)-furanones have been
prepared in modest overall yield (33–53%) by regioselec-
tive Sonogashira coupling of 1-alkynes with 3,4-dibromo-
12 3
H O
21. (a) Gen eˆ t, J. P.; Blart, E.; Savignac, M. Synlett 1992, 715–
717; (b) Amatore, C.; Blart, E.; Gen eˆ t, J. P.; Jutand, A.;
Lemaire-Audoire, S.; Savignac, M. J. Org. Chem. 1995,
60, 6829–6839; see also: (c) Casalnuovo, A. L.; Calabrese,
J. C. J. Am. Chem. Soc. 1990, 112, 4324–4330.
2
(5H)-furanone and subsequent reductive removal of the
3
-bromo substituent: (a) Bellina, F.; Falchi, E.; Rossi, R.
Tetrahedron 2003, 59, 9091–9100; For the alkynylation of
-alkyl-4-iodo-2(5H)-furanones, see: (b) Ma, S.; Shi, Z.;
5
Yu, Z. Tetrahedron 1999, 55, 12137–12148.
8. Buszek, K. R.; Jeong, Y. Synth. Commun. 1994, 24, 2461–
22. Typical procedure (method B): 4-Methyl-1-pentyn-3-ol
(321 lL, 3.04 mmol), triethylamine (564 lL, 4.05 mmol),
Pd(OAc)2 (14 mg, 0.06 mmol) and TPPMS (37 mg,
0.10 mmol) were added to a solution of 1 (330 mg,
1
1
2
472.
9. For some limitations of the Sonogashira reaction see:
Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski,
D. Org. Lett. 2003, 5, 1597–1600, and references cited
therein.
2
2.02 mmol) in MeCN/H O (15:1, 5 mL) and the mixture
was stirred for 20 h at room temperature, filtered through
Celite, and diluted with water before extraction with ethyl
2
0. Typical procedure (method A): To a solution of 1 (448 mg,
acetate (·3). The combined extracts were dried (Na
evaporated in vacuo, and the crude product was purified
by flash chromatography (Et O) to deliver 2j as an oil
2 4
SO ),
2
0
.75 mmol) in THF (4 mL) was added CuI (10 mg,
.05 mmol) and PdCl (PPh (193 mg, 0.27 mmol). After
2
3
)
2
2
1
stirring the mixture for 30 min at room temperature, a
solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (385
lL, 2.75 mmol) and N,N-diisopropylamine (775 lL, 5.48
mmol) in THF (4 mL) was added. Stirring continued for
(296 mg, 81%); H NMR (300 MHz, CDCl ) d 6.15 (s,
3
1H), 4.78 (s, 2H), 4.36 (d, J = 5.6 Hz, 1H), 2.75 (br s, 1H),
1
3
1.93 (m, 1H), 0.98 and 0.99 (2d, J = 6.6 Hz, 6H);
C
NMR (75 MHz, CDCl ) d 173.2, 146.8, 122.5, 105.9, 75.3,
3
1
6 h (rt) and the reaction mixture was quenched with
72.9, 68.0, 34.2, 17.9, 17.5; HRMS m/z 180.0784 (calcd for
saturated aq ammonium chloride, extracted with 1:1 ethyl
10 12 3
C H O 180.0786).