Distant functionalization via incorporation of thiophene moieties in electrophilic reactions promoted by samarium diiodide

Article abstract of DOI:10.1021/ol006628w

(matrix presented) Methyl thiophene-2-carboxylate, methyl 3-(thien-2-yl)acrylate, and methyl 5,2′-bithiophene-2-carboxylate were utilized as the synthetic equivalents of pentanoate 5-anion, pentanoate 4,5-dianion, heptanoate 7-anion, and nonanoate-8,9-dia

Full text of DOI:10.1021/ol006628w

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3719-3721
Distant Functionalization via
Incorporation of Thiophene Moieties in
Electrophilic Reactions Promoted by
Samarium Diiodide
Shyh-Ming Yang, Sandip Kumar Nandy, Anandakathir Robinson Selvakumar, and
Jim-Min Fang*
Department of Chemistry, National Taiwan UniVersity,
Taipei, Taiwan 106, Republic of China
Received September 21, 2000
ABSTRACT
Methyl thiophene-2-carboxylate, methyl 3-(thien-2-yl)acrylate, and methyl 5,2′-bithiophene-2-carboxylate were utilized as the synthetic equivalents
of pentanoate 5-anion, pentanoate 4,5-dianion, heptanoate 7-anion, and nonanoate-8,9-dianion. By the promotion of samarium diiodide, these
thiophene-incorporating compounds reacted with aldehydes, ketones, and conjugated esters regioselectively at the thienyl rings. Long-chain
esters with remote hydroxyl and carboxyl groups, including an antiarthritis agent, a shellac component, and an inhibitory agent of spore
germination, were prepared after reductive desulfurization on Raney nickel.
Functionalization at the remote positions with respect to an
activating group remains a challenging task in organic
synthesis.1 We describe herein a new strategy by using 1a-c
to generate the synthetic equivalents of the terminal anions
and dianions of long-chain aliphatic esters.
of SmI2 and HMPA.2,3 The reaction may involve a dienolate
intermediate A, which could undergo protonation at C-2 to
give 2,5-dihydrothiophenes (e.g., 2a-g) or react further with
a second carbonyl compound to give 4,5-dihydrothiophenes
(e.g., 5a-d). Since dihydrothiophenes could undergo reduc-
tive desulfurization by using Raney nickel,4 methyl thiophene-
2-carboxylate thus served as an attractive mediator for the
synthesis of distant functionalized pentanoate esters with
(1) For generation of Cl3TiCH2CH2CO2R and ClZnCH2CH2CO2R as
nucleophilic reagents, see: (a) Nakamura, E.; Kuwajima, I. J. Am. Chem.
Soc. 1983, 105, 651. (b) Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc.
1984, 106, 3368. The organo-copper reagent IZn(CN)Cu(CH2)3CO2R has
been used as an equivalent of butanoate 4-anion, see: (c) Knochel, P.; Yeh,
M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2392. (d) Yeh,
M. C.; Knochel, P.; Santa, L. Tetrahedron Lett. 1988, 29, 3887. (e) Lipshutz,
B. H.; Wood, M. R.; Tirado, R. J. Am. Chem. Soc. 1995, 117, 6126.
(2) Yang, S.-M.; Fang, J.-M. Tetrahedron Lett. 1997, 38, 1589.
(3) Transfer of one electron from SmI2 to methyl thiophene-2-carboxylate
initiated the reaction sequence. The generated samarium-bound ketyl anion
radical did not trap hydrogen atom or undergo acyloin coupling, presumbly
because of the hindrance of the ligated HMPA molecules; see: (a) Hou,
Z.; Yoshimura, T.; Wakatszuki, Y. J. Am. Chem. Soc. 1994, 116, 11169.
(b) Shiue, J.-S.; Lin, C.-C.; Fang, J.-M. Tetrahedron Lett. 1993, 34, 335.
We reported previously that methyl thiophene-2-carboxy-
late (1a) reacts with carbonyl compounds by the promotion
10.1021/ol006628w CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/26/2000

remote hydroxyl and carboxyl groups (e.g., 3a-g and 6a-
d).
Scheme 1
The coupling reactions were simply carried out by mixing
thiophenecarboxylate 1a with appropriate electrophiles in a
freshly prepared SmI2/THF/HMPA solution. As shown in
this study (Table 1), hydroxyalkylations with aldehydes and
Table 1. SmI2-Promoted Coupling Reactionsa and Subsequent
Reductive Desulfurizations on Raney Nickel
coupling desulfrzn
products products
no. substr
electrophiles
(% yield) (% yield)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
4-CH3C6H4CHO/H+
2a (85%)b 3a (66%)c
2b (74%)b 3b (91%)c
2c (74%)b 3c (64%)c
2d (81%)b 3d (91%)c
2e (73%)b 3e (90%)c
2f (55%)b 3f (87%)c
2g (60%)b 3g (81%)c
5a (91%)d 6a (80%)
5b (57%)d 6b (81%)
5c (63%)b 6c (73%)e
6-methoxy-2-naphthaldehyde/H+
4-ClC6H4COMe/H+
CH3(CH2)4CHO/H+
CH3(CH2)7CHO/H+
4-MeOC6H4CHdCHCO2Me/H+
MeCHdCHCO2Me/H+
cyclohexanone/cyclohexanone
cyclopentanone/cyclopentanone
4-CH3C6H4CHO/4-ClC6H4COMe
4-CH3C6H4COMe/4-CH3C6H4COMe 5d (62%)b 6d (75%)f
4-MeOC6H4CHO/H+
7a (78%)b 8a (86%)c
7b (68%)b 8b (89%)c
7c (69%)b 8c (62%)c
7d (70%)b 8d (83%)c
10 (43%)b 11 (85%)c
CH3(CH2)7CHO/H+
4-CH3C6H4COMe/H+
4-MeOC6H4CHdCHCO2Me/H+
cyclohexanone/cyclohexanone
a The coupling reactions were generally conducted in SmI2/THF/HMPA
solution at 0 °C, except for the Michael reactions (entries 6, 7, and 15),
which were conducted at -78 °C. For 1 mmol of substrate, 3.6 mmol of
SmI2 and 16 mmol of HMPA were used. b The coupling product was
obtained as a mixture of diastereomers. c Reductive desulfurization of the
isomeric mixture of coupling product gave a single product. d Compounds
5a and 5b with the 4,5-trans configuration were obtained. e The reductive
desulfurization of (4S*,5R*,1′S*,1′′S*)-5c gave (4R*,6R*,1′S*)-6c. f The
reductive desulfurization of (4S*,5R*,1′S*,1′′R*)-5d gave (4R*,6S*,1′S*)-
6d.
ketones and Michael additions with R,â-unsaturated esters
were accomplished in highly regioselective manners. The
possible self-coupling reactions5 of esters and carbonyl
compounds were suppressed under such reaction conditions.
Although individual coupling product (2a-g) existed as
a mixture of diastereomers, a single long-chain ester was
obtained after removal of the sulfur atom (Scheme 1). For
example, an antiarthritis agent 4b, 6-hydroxy-6-(6-methox-
ynaphth-2-yl)hexanoic acid,6 was prepared in an overall 67%
yield by a three-step sequence: (i) coupling of 1a with
6-methoxy-2-naphthaldehyde by the promotion of SmI2, (ii)
reductive desulfurization using Raney Ni in MeOH, and (iii)
saponification using LiOH in aqueous THF. A shellac
component 4e, 6-hydroxytetradecanoic acid,7 was prepared
in 66% yield from 1a and nonanal by a similar procedure.
Saponification of 3a and 3d afforded the corresponding
6-hydroxyacids, which were subjected to lactonization by
treatment with 1,1′-carbonyldiimidazole/DBU or p-TsOH to
give 7-tolyl and 7-pentyloxepan-2-ones in 86% and 91%
yields.
We also demonstrated the efficient use of methyl thiophene-
2-carboxylate as an equivalent of pentanoate 4,5-dianion
(entries 8-11). The double electrophilic reaction of 1a,
followed by reductive desulfurization, provided a route for
the generation of functionalized 1,4-diols such as 6a-d.
The methodology using SmI2-promoted electrophilic reac-
tions was easily extended to its higher vinylogous compounds
(4) Reviews of desulfurization on Raney nickel: (a) Caubere, P.; Coutrot,
P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.,
Pergamon: Oxford, 1991; Vol. 8, pp 835-870. (b) Pettit, G. R.; van
Tamelen, E. E. Org. React. 1962, 12, 356. (c) Gol’dfarb, Y. L.; Fabrichnyi,
B. P.; Shalavina, I. F. Tetrahedron 1962, 18, 21. (d) Meyers, A. I.
Heterocycles in Organic Synthesis; Wiley: New York, 1974.
(5) On treatment with SmI2, carbonyl compounds and conjugated esters
could undergo reductive self-coupling reactions; see: (a) Namy, J. L.;
Souppe, J.; Kagan, H. B. Tetrahedron Lett. 1983, 24, 765. (b) Inanaga, J.;
Handa, Y.; Tabuchi, T.; Otsubo, K. Tetrahedron Lett. 1991, 32, 6557. (c)
Fujita, Y.; Fukuzumi, S.; Otera, J. Tetrahedron Lett. 1997, 38, 2121. (d)
Caberera, A.; Le Lagadec, R.; Sharma, P.; Arias, J. L.; Toscano, R. A.;
Velasco, L.; Gavino, R.; Alvarez, C.; Salmon, M. J. Chem. Soc., Perkin
Trans. 1 1998, 3609.
(6) Murray, W. V.; Wachter, M. P.; Kasper, A. M.; Argentieri, D. C.;
Capetola, R. J.; Ritchie, D. M. Eur. J. Med. Chem. Chim. Ther. 1991, 26,
159.
(7) Wadia, M. S.; Khurana, R. G.; Mhaskar, V. V.; Dev. S. Tetrahedron
1969, 25, 3841.
3720
Org. Lett., Vol. 2, No. 23, 2000

Bithiophenecarboxylate 1c could also be utilized as an
equivalent of nonanoate-8,9-dianion (Scheme 3). Thus,
Scheme 2
Scheme 3
treatment of 1c with cyclohexanone (2.5 equiv) in SmI2/THF/
HMPA, at 0 °C for 30 min and 25 °C for 3 h, afforded the
C-8,9 double hydroxyalkylation products 10 (43%) ac-
companied by 25% recovery of 1c. This reaction was
somewhat complicated by side products 12 (10%), 13 (6%),
and 14 (14%) derived from additions at C-3 or C-3′ of 1c.
such as 3-(thien-2-yl)acrylate 1b (Scheme 2). The protocol
featured an excellent regioselectivity wherein the incoming
electrophile reacted exclusively at the C-5 position of the
thiophene ring, giving 7a-d after protonation. Thus 3-(thien-
2-yl)acrylate played as an equivalent of heptanoate-7-anion
to furnish long-chain esters 8a-d. Our current method for
the synthesis of methyl 8-hydroxyhexadecanoate8 (8b), an
inhibitory agent of spore germination, appeared to have the
advantage of simple operation, few steps, and high overall
yield (61%), by comparison with the previous preparation8
with 8-12 steps in merely 10-12% yields.
Stirring of 10 with Raney Ni in refluxing EtOH for 16 h
furnished the long-chain ester 11 (85%). The H NMR
spectrum of 11 exhibited a vinyl proton at δ 4.83 as a doublet
(J ) 10.5 Hz).
1
Acknowledgment. We thank the National Science Coun-
cil for financial support.
Supporting Information Available: Experimental pro-
cedures, physical and spectral data for new compounds, and
ORTEP drawings of compounds 5a, 5c, 6d, and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) (a) Tulloch, A. P. Can. J. Chem. 1965, 43, 415. (b) Yamane, H.;
Sato, Y.; Takahashi, N.; Takeno, K.; Furuya, M. Agric. Biol. Chem. 1980,
44, 1697. (c) Masaoka, Y.; Sakakibara, M.; Mori, K. Agric. Biol. Chem.
1982, 46, 2319. (d) Sugai, T.; Mori, K. Agric. Biol. Chem. 1984, 48, 2155.
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