Regioselective Pd-catalyzed alkylative lactonizations of 4-hydroxy-2-alkynecarboxylates with organoboronic acids

Article abstract of DOI:10.1016/j.tetlet.2004.07.129

The Pd-catalyzed addition of organoboronic acids to 4-hydroxy-2- alkynecarboxylates and in situ lactonization gave the butenolides with a high control of regioselectivity.

Full text of DOI:10.1016/j.tetlet.2004.07.129

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7039–7042
Regioselective Pd-catalyzed alkylative lactonizations of
4-hydroxy-2-alkynecarboxylates with organoboronic acids
Chang Ho Oh,* Su Jin Park, Jin Hyang Ryu and Arun Kumar Gupta
Department of Chemistry, Hanyang University, Haengdang-17, Sungdong-Gu, Seoul 133-791, Korea
Received 4 July 2004; revised 22 July 2004; accepted 28 July 2004
Abstract—The palladium-catalyzed addition of aryl- and alkenylboronic acids to 4-hydroxy-2-alkynecarboxylates and in situ lact-
onization would constitute a novel methodology for the synthesis of various butenolides with an excellent stereoselectivity and a
high control of regioselectivity.
Ó 2004 Published by Elsevier Ltd.
Many butenolides exist in nature and some of them
exhibit interesting biological activities (Fig. 1).1 Because
of the enormous importance in chemical as well as phar-
maceutical research, a number of synthetic methods for
substituted butenolides have been reported.2 Among
them, ruthenium-catalyzed carbonylative cyclization of
allenols,3 palladium-catalyzed cyclization of allenecarb-
oxylic acids,4 and enyne metathesis5 are the most valua-
ble synthetic methodologies. There is still a continuing
need for simple and versatile synthetic methods for sub-
stituted butenolides. Palladium-catalyzed reactions
involving nucleophilic attack on p-alkene-, p-alkyne-,
and p-allyl-metal complexes provide convenient and
powerful tools for organic synthesis and also a large
number of selective organic transformations have been
reported.6,7
Recently, we reported the hydroarylation and hydroalk-
enylation of alkynes8 and allenes9 with a variety of
organoboronic acids. During our studies, we found that
incorporation of a specific functional group such as a
keto (Eq. 1), –OH (Eq. 2), or nitrogen of 2-pyridyl
(Eq. 3) could play a role in controlling the site of addi-
tion. Mechanistically, we anticipated that oxygen or
nitrogen atoms present in the alkyne substrate would
bind the Lewis acidic RB(OH)2 and thereby direct the
addition site.10,11 On the other hand, bulky substituents
might block addition to one end of the alkyne. The
regioselectivity can also be controlled by employing a
various types of ligands.12
O
O
O
O
20
H3C
H
1
2
Figure 1.
ð1Þ
It is worthy to explore the possibility of combining
arylation/alkenylation with lactonization in a one step;
thus the compounds 12a–g bearing both a –OH group
and a –COOEt group were prepared for Pd-catalyzed
Keywords: Palladium; Catalyst; Boronic acid; Lactonization;
Butenolides.
*
Corresponding author. Tel.: +82 2 2290 0932; fax: +82 2 2299
0762; e-mail: changho@hanyang.ac.kr
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.07.129

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C. H. Oh et al. / Tetrahedron Letters 45 (2004) 7039–7042
ð2Þ
ð3Þ
hydroarylations and alkenylations.13 When 12a was
treated with 3mol% of palladium acetate, 3mol% of
dppe as a ligand, and 10mol% of acetic acid in the pres-
ence of 1.2equiv of 1-hexenylboronic acid 13a, addition
of 1-hexenyl group and then subsequent in situ lactoni-
zation occurred to give a 7:1 mixture of the correspond-
ing butenolides 14aa and 15aa in combined 87% yield.
To the best of our knowledge, there was no literature
report on this type of reaction. Hence, here we wish to
report a new Pd-catalyzed arylative- and alkenylative
lactonizations of 4-hydroxy-2-alkynecarboxylates with
a high control of regioselectivity and syn-stereo selectiv-
ity (Eq. 4). We have attempted investigation of this pro-
tocol for 12a–g with 13a–b (Scheme 1) under two
conditions.
of organoboronic acids under the condition A, implying
that the OH group did not show a good directing effect
compared to the primary –OH group in the substrate
12a. Since the ester group might have stronger directing
effect over hydroxyl group, the products from 13a and
13b gave a 7:1 mixture of 14aa and 15aa in 87% yield
and a 11:1 mixture of 14ab and 15ab in 74% yield,
respectively. The size of alkyl group in 4-hydroxy-2-
alkynecarboxylates has showed a dramatic effect on reg-
ioselectivity. Even in case of ethyl 4-hydroxy-2-butyne-
carboxylate 12b under condition A with both 13a and
13b gave only a 3:1 mixture of 14ba and 15ba and a
6:1 mixture of 14bb and 15bb, respectively. Similarly,
the substrate 12c contained n-butyl group under the
same condition with both 13a and 13b afforded a 3:1
mixture of 14ca and 15ca and a 4:1 mixture of 14cb
and 15cb, respectively. When we introduced an isoprop-
yl group at the propargylic position (12d), a little
improvement in regioselectivity with both 13a and 13b
was observed to give a 6:1 mixture of 14da and 15da
and a 7:1 mixture of 14db and 15db, respectively. Not
surprisingly with the substrate 12e bearing a tert-butyl
group at the propargylic position, the regioselectivities
with both 13a and 13b were dramatically diminished
to give a 1:2 mixture of 14ea and 15ea and a 2:1 mixture
of 14eb and 15eb, respectively. The more pronounced
effect was observed with tert-alcohol 12g with both
13a and 13b resulted in reversal of regioselectivities, giv-
ing a 1:2 mixture of 14ga and 15ga and a 1:3 mixture of
14gb and 15gb, respectively. But 12f bearing a phenyl
group gave a 4:1 mixture of 14fa and 15fa and a 10:1
mixture of 14fb and 15fb, respectively. Interestingly,
when the substrate 12a was applied to condition B gave
almost a 1:1 mixture of 14aa and 15aa, implying that the
substrate 12a has competitive effect by the primary OH
group and the ester group. The alkyl group size has also
showed the dramatic effect in regioselectivity in these
reactions. Ethyl-4-hydroxy-2-pentynecarboxylate 12b
with both 13a and 13b gave a 1:10 mixture of 14ba
and 15ba and almost 15bb, respectively. Similarly, the
substrate 12c with 13a gave a 1:12 mixture of 14ca and
15ca, while 13b gave exclusively 15cb. The 12d bearing
an isopropyl group at the propargylic position under
condition B with 13a afforded a 1:16 mixture of 14da
The condition A is composed of a catalytic system of
3mol% Pd(OAc)2 and 3mol% dppe, while the condition
B is composed of a catalytic system of 3mol% Pd(OAc)2
and 6mol% tri(tert-butyl)phosphine. The results,
obtained under both condition A and B, are summa-
rized in Table 1. It should be noted that both the ester
group and the hydroxyl group induced more b-addition
HO
R1
O
R1
R2
O
O
R1
R2
O
A
B
COOEt
R2
R
R
12
15
14
R1, R2 = -H, -H
12a
12b
R = n-BuCH=CH- 13a
= 4-CH3OC6H4- 13b
-H, -CH3
-H, -CH2CH2CH3 12c
= 4-CH3C6H4-
13c
-H, -CH(CH3)2
-H, -C(CH3)3
-H, -Ph
12d
12e
12f
12g
-CH3, -CH3
cond A: RB(OH)2 (13),
3 mol% Pd(OAc)2, 3 mol% dppe, 10 mol% AcOH
cond B: RB(OH)2 (13),
3 mol% Pd(OAc)2, 6 mol% (t-Bu)3P, 10 mol% AcOH
Scheme 1. Reagents and conditions: (A) RB(OH)2 (13), 3mol%
Pd(OAc)2, 3mol% dppe, 10mol% AcOH; (B) RB(OH)2 (13), 3mol%
Pd(OAc)2, 6mol% (t-Bu)3P, 10mol% AcOH.

C. H. Oh et al. / Tetrahedron Letters 45 (2004) 7039–7042
7041
Table 1. Reactions of 4-hydroxy-2-alkynecarboxylate 12 with organoboronic acids 13a–b under conditions A and B
Entry
12
13
Conditions
Temperature (°C)/time (h)
Products
%Yield (ratio)
1
2
3
4
12a
13a
A, CHCl3
B, THF
50/5
60/4
50/5
60/4
14aa, 15aa
87 (7:1)
97 (1:1.4)
74 (11:1)
98 (1:1.5)
12a
13b
A, CHCl3
B, THF
14ab, 15ab
5
6
7
8
12b
12b
13a
13b
A, CHCl3
B, THF
60/20
60/4
14ba, 15ba
14bb, 15bb
74 (3:1)
97 (1:10)
75 (6:1)
94 (15bb only)
A, CHCl3
B, 1,4-dioxane
60/24
60/4
9
12c
12c
13a
13b
A, CHCl3
B, THF
50/24
60/4
14ca, 15ca
14cb, 15cb
67 (3:1)
10
11
12
95 (1:12)
76 (4:1)
96 (15cb only)
A, CHCl3
B, 1,4-dioxane
50/12
60/4
13
14
15
16
12d
12d
13a
13b
A, CHCl3
B, THF
50/12
60/6
14da, 15da
14db, 15db
85 (6:1)
98 (1:16)
73 (7:1)
96 (15db only)
A, CHCl3
B, 1,4-dioxane
50/12
60/4
17
18
19
20
12e
12e
13a
13b
A, 1,4-dioxane
B, 1,4-dioxane
A, 1,4-dioxane
B, THF
100/24
100/24
80/24
14ea, 15ea
14eb, 15eb
89 (1:2)
96 (1:11)
80 (2:1)
98 (15eb only)
70/10
21
22
23
24
12f
12f
13a
13b
A, CHCl3
B, THF
60/12
60/8
14fa, 15fa
14fb, 15fb
73 (4:1)
96 (1:10)
A, CHCl3
B, THF
60/12
60/4
75 (10:1)
96 (15fb only)
25
26
27
28
12g
12g
13a
13b
A, 1,4-dioxane
B, THF
80/48
60/4
14ga, 15ga
14gb, 15gb
77 (1:2)
97 (15ga only)
79 (1:3)
98 (15gb only)
A, 1,4-dioxane
B, THF
80/48
60/4
and 15da, but surprisingly that with 13b gave 15db as a
sole product. The similar trend was observed in case of
12e bearing a tert-butyl, 12f bearing a phenyl group with
both 13a and 13b. An excellent regioselectivity was
obtained with 12g. It is implying that the bulkiness of
the alkyl group near the triple bond affects the regiose-
lectivity. In general, the regioselectivities raised from
the use of the bulky ligand under condition B were much
higher than those obtained under condition A. In order
to prove the application of this methodology, we synthe-
sized a racemic version of 2 (Eq. 4). When the condition
B was applied to a mixture of 12h and p-tolueneboronic
acid (13c) at 60°C for 2h in THF, a 1:11 mixture of iso-2
and 2 were synthesized in combined 98% yield.
we have demonstrated the Pd-catalyzed addition of aryl
and alkenylboronic acids to 4-hydroxy-2-alkynecarb-
oxylates and in situ lactonization with an excellent
stereoselectivity and a high control of regioselectivity.
No doubt that this investigation would constitute a no-
vel methodology for the synthesis of various buteno-
lides, which are interest of natural and pharmaceutical
research. We are currently pursuing the application of
this methodology to the combinatorial synthesis of a
butenolid library.
Acknowledgements
We wish to acknowledge the financial support of Korea
Research Foundation (2001-015-DP0334) and Center of
Molecular Design and Synthesis (CMDS).
ð4Þ
References and notes
1. (a) Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387; (b)
Kazauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J.
Tetrahedron Lett. 1977, 18, 37; (c) Pettus, J. A., Jr.; Wing,
R. M.; Sims, J. J. Tetrahedron Lett. 1977, 18, 41.
2. (a) Repke, K. R. H.; Megges, R.; Weiland, J.; Schon, R.
Angew. Chem., Int. Ed. Engl. 1995, 34, 282; (b) Zapf, S.;
The phenomena of in situ lactonization are the convinc-
ing evidence of syn-addition of the organic group from
organoboronic acids to alkynecarboxylates. In precise,

7042
C. H. Oh et al. / Tetrahedron Letters 45 (2004) 7039–7042
Anke, J.-I.; Sterner, O. Acta Chem. Scand. 1995, 49, 233;
7. (a) Ma, S.; Jiao, N.; Zhao, S.; Hou, H. J. Org. Chem. 2002,
67, 2837; (b) Ma, S.; Shi, Z. Chem. Commun. 2002, 540; (c)
Ma, S.; Li, L. Org. Lett. 2000, 2, 941; (d) Ma, S.; Duan,
D.; Shi, Z. Org. Lett. 2000, 2, 1419; (e) Ma, S.; Zhao, S.
Org. Lett. 2000, 2, 2495; (f) Anwar, U.; Grigg, R.;
Sridharan, V. Chem. Commun. 2000, 933; (g) Grigg, R.;
MacLachlan, W.; Rasparini, M. Chem. Commun. 2000,
(c) Scott, L. I.; Lamb, H. M. Drugs 1999, 3, 499; (d) Guo,
Y.-W.; Gavagnin, M.; Mollo, E.; Trivellone, E.; Cimino,
G. J. Nat. Prod. 1999, 62, 1194; (e) Mukku, V. J. R. V.;
Speitling, M.; Laatsch, H.; Helmke, E. J. Nat. Prod. 2000,
63, 1570.
3. Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.;
Takahashi, S. Org. Lett. 2000, 2, 441.
´
2241; (h) Franzen, J.; Ba¨ckvall, J.-E. J. Am. Chem. Soc.
4. Ma, S.; Shi, Z.; Yu, Z. Tetrahedron Lett. 1999, 40, 2393.
5. Hoye, T. R.; Donaldson, S. M.; Vos, T. J. Org. Lett. 1999,
1, 277.
2003, 125, 6056; (i) Rubin, M.; Markov, J.; Chuprakov, S.;
Wink, D. J.; Gevorgyan, V. J. Org. Chem. 2003, 68, 6251.
8. (a) Oh, C. H.; Jung, H. H.; Kim, K. S. Angew. Chem., Int.
Engl. 2003, 42, 805; (b) Oh, C. H.; Jung, H. H.; Sung, H.
R.; Kim, J. D. Tetrahedron 2001, 57, 1723.
9. (a) Oh, C. H.; Ahn, T. W.; Reddy, V. R. Chem. Commun.
2003, 22, 2622; (b) Oh, C. H.; Jung, S. H.; Bang, S. Y.;
Park, D. I. Org. Lett. 2002, 4, 3325.
10. Oh, C. H.; Kim, K. S.; Gupta, A. K. Chem. Commun.
2004, 22, 618.
11. Itami, K.; Kamei, T.; Yoshida, J.-I. J. Am. Chem. Soc.
2003, 125, 14670.
6. (a) Trost, B. M.; Toste, F. D.; Greenman, K. J. Am.
Chem. Soc. 2003, 125, 4518; (b) Trost, B. M.; Hachiya, I.;
McIntosh, M. C. Tetrahedron Lett. 1998, 39, 6445; (c) Liu,
G.; Lu, X. Tetrahedron Lett. 2002, 43, 6791; (d) Pletnev,
A. A.; Tian, Q.; Larock, R. C. J. Org. Chem. 2002, 67,
9276; (e) Larock, R. C.; Tian, Q. J. Org. Chem. 2001, 66,
7372; (f) Oyamada, J.; Lu, W.; Jia, C.; Kitamura, T.;
Fujiwara, Y. Chem. Lett. 2002, 20; (g) Jia, C.; Lu, W.;
Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.;
Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252; (h)
Arcadi, A.; Bernocchi, E.; Burini, A.; Cacchi, S.; Marin-
elli, F.; Pietroni, B. Tetrahedron 1988, 44, 481.
12. Oh, C. H.; Sung, H. R. Bull. Korean Chem. Soc. 2003, 24,
1563.
13. Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889.