Application of organolithium and related reagents in synthesis. Part 25: Novel specific synthesis of the 4-arylisochroman-3-acetic acids via conversion of benzoic acids

Article abstract of DOI:10.1016/S0040-4039(01)02043-3

The transformation of the benzanilides 1 into 4-arylisochroman-3-acetic acids 8 applying the following sequence of reactions is described. At first, the 3-arylphthalides 3 were obtained via metallation [n-BuLi] of benzanilides 1 and subsequent treatment of the generated bis-lithiated anilides 2 with aromatic aldehydes. Next, the 3-arylphthalides 3 were reduced [LiBH₄] to phthalanes 5 and then, via reductive metallation [Li/C₁₀H₈] and reaction of the generated bis-lithiated species 6 with dimethylformamide, 3-hydroxy-4-arylisochromans 7 were produced. In the final step the isochromans 7 were treated with 1-methoxy-1-trimethylsilyloxyethene in the presence of titanium tetrachloride and furnished 4-arylisochromans-3-acetic acid methyl esters 8 as trans stereoisomers (Ψ-e/e).

Full text of DOI:10.1016/S0040-4039(01)02043-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9293–9295
Application of organolithium and related reagents in synthesis.
Part 25: Novel specific synthesis of the 4-arylisochroman-3-acetic
acids via conversion of benzoic acids†
Adam Bieniek, Jan Epsztajn,* Justyna A. Kowalska and Zbigniew Malinowski
Department of Organic Chemistry, Institute of Chemistry, University of Lodz, 90-136 Lodz, Narutowicza 68, Poland
Received 3 July 2001; revised 23 October 2001; accepted 30 October 2001
Abstract—The transformation of the benzanilides 1 into 4-arylisochroman-3-acetic acids 8 applying the following sequence of
reactions is described. At first, the 3-arylphthalides 3 were obtained via metallation [n-BuLi] of benzanilides 1 and subsequent
treatment of the generated bis-lithiated anilides 2 with aromatic aldehydes. Next, the 3-arylphthalides 3 were reduced [LiBH4] to
phthalanes 5 and then, via reductive metallation [Li/C10H8] and reaction of the generated bis-lithiated species 6 with dimethylfor-
mamide, 3-hydroxy-4-arylisochromans 7 were produced. In the final step the isochromans 7 were treated with 1-methoxy-1-
trimethylsilyloxyethene in the presence of titanium tetrachloride and furnished 4-arylisochromans-3-acetic acid methyl esters 8 as
trans stereoisomers (C-e/e). © 2001 Elsevier Science Ltd. All rights reserved.
'
R
In the past few years we have witnessed tremendous
activity directed towards the synthesis of the ben-
zo[c]pyrans, because some members of this family have
been found in nature and shown to possess a variety of
biological properties.1–10 This is the motive of the wide-
spread interest in their synthesis. In particular, our
attention has been focused on obtaining a synthetic
methodology for 3,4-disubstituted isochromans in
which a carboxymethyl group is attached at C-3. The
position and nature of that substituent is characteristic
for the benzo[c]pyran antibiotics.1–10
R"
OH
'
R
OMe
O
O
O
A
(+)
B
-
Scheme 1.
The reported available methods for the preparation of
this system generally require multi-step sequences.11–18
Most of them appeared to be unsatisfactory both in
yield and generality.
In a series of recent studies we have reported19–22 that
the secondary carboxamide moiety provides an excel-
lent possibility for the regioselective synthesis of 3-
arylphthalides, which are the key starting materials
here.
We now wish to report a methodology, which provides
access to a new and efficient regio- and diastereoselec-
tive synthetic sequence as a general strategy for trans-
formation of aromatic carboxylic acids (A) into the
desired 3,4-disubstituted isochromans (B), in a four-
step protocol, starting from benzoic acid anilides (1)
(Scheme 1).
Therefore, 3-arylphthalides were obtained by the lithia-
tion of benzoic acid anilides (1) using n-BuLi in
THF,19,21 followed by the reaction of the generated bis
(N- and C-ortho) lithiated anilides (2) with aromatic
aldehydes (Scheme 2). Upon acid cyclization, the ortho
hydroxyarylmethyl intermediates, gave the correspond-
ing phthalides (3).
The treatment of the phthalides (3) with lithium
borohydride23,24 produced the corresponding diols (4),
which after the usual acidic aqueous work-up furnished
the desired phthalanes (5).
Keywords: benzanilides; metallations; isochromans.
* Corresponding author. Tel.: +48-42-635-58-12; fax: +48-42-678-65-
83; e-mail: epsztajn@krysia.uni.lodz.pl
† For Part 24, see: Ref. 22.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02043-3

9294
A. Bieniek et al. / Tetrahedron Letters 42 (2001) 9293–9295
Scheme 2.
The phthalanes (5) were converted into the bis-lithiated
species (6) via reductive-lithiation25–28 (Li/C10H8 in
THF), which after reaction with dimethylformamide
(DMF) gave the 3-hydroxy-4-arylisochromans (7) as a
mixture of anomers. The structures of the crystallized
(ethanol) isochromans (7) exemplified by compounds
(7a) and (7d) were determined by X-ray crystallogra-
phy,29 which indicated that they were diastereoisomers
(C-a/a). The proton NMR data in DMSO-d6 indicated
that the trans isomers predominated. On the other
hand, in CDCl3 the spectroscopic data showed that
both anomers were present and that their ratio varied
with time.
In the final step, the Mukaiyama procedure30–34 was
used for the introduction of the carboxymethyl group
at the 3-position of the isochroman skeleton.
It was expected that the reaction of the 3-hydroxy-
isochromans (7) with 1-methoxy-1-trimethylsilyl-
oxyethene would provide an effective route for the
desired benzo[c]pyran-3-acetic acid methyl esters (8). In
reality, 3-hydroxyisochromans (7) when reacted with
1-methoxy-1-trimethylsilyloxyethene in the presence of
titanium tetrachloride furnished the corresponding 4-
arylisochroman-3-acetic acid methyl esters (8). The pro-
ton NMR data suggests that the compounds formed

A. Bieniek et al. / Tetrahedron Letters 42 (2001) 9293–9295
9295
Table 1. Detailed yields (%) of the conversion 1“8
J.; Masuma, R.; Oiwa, R.; Omura, S. J. Antibiot. 1978,
31, 959.
8. Kulanthaivel, P.; Perun, Jr., T. J.; Belvo, M. D.; Strobel,
R. J.; Paul, D. C.; Williams, D. C. J. Antibiot. 1999, 52,
256.
9. Tsukamoto, M.; Nakajima, S.; Murooka, K.; Hirayama,
M.; Hirano, K.; Yoshida, S.; Kojiri, K.; Suda, H. J.
Antibiot. 2000, 53, 26.
1“3
3“5
5“7
7“8
a
b
c
68
67
75
68
94
88
92
96
74
70
72
68
81
80
83
80
d
10. Tsukamoto, M.; Nakajima, S.; Murooka, K.; Naito, M.;
Suzuki, H.; Hirayama, M.; Hirano, K.; Kojiri, K.; Suda,
H. J. Antibiot. 2000, 53, 687.
11. Tatsuta, K.; Akimoto, K.; Annako, M.; Ohno, Y.;
Kinoshita, M. Bull. Chem. Soc. Jpn. 1985, 58, 1699.
12. Foland, L. D.; Decker, O. H. W.; Moore, H. W. J. Am.
Chem. Soc. 1989, 111, 989.
13. Fijioka, H.; Yamamoto, H.; Anuoura, H.; Miyazaki, M.;
Kita, Y. Chem. Pharm. Bull. 1990, 38, 1872.
14. Brunble, M. A.; Stuart, S. J. J. Chem. Soc., Perkin Trans.
1 1990, 881.
are trans isomers (C-e/e). The coupling constant of the
hydrogen atoms (C-a/a) ranged between 6.4 and 9.2
Hz.35 The structure of the isochromans 8, exemplified
by compound 8c was confirmed by X-ray crystallogra-
phy.29 The formation of the trans isomers is most
probably due to the fact that the approach trajectory of
the incoming nucleophile, is opposite to the aryl sub-
stituents of the oxonium cation generated from the
3-hydroxy-4-arylisochromans (7).
15. Trost, B. Chem. Rev. 1978, 78, 363.
16. Mosquelin, T.; Hengartner, U.; Streith, J. Synthesis 1995,
780.
Overall yields for the regio- and diastereotransforma-
tion of the starting benzoic acid anilides (1) into ben-
zo[c]pyran-3-acetic acids methyl esters (8) are about
40% (Table 1).
17. Mosquelin, T.; Hengartner, U.; Streith, J. Helv. Chim.
Acta 1997, 80, 43.
18. Cantant, P.; Haess, M.; Riegl, J.; Scalone, M.; Visnick,
M. Synthesis 1999, 821.
19. Epsztajn, J.; Bieniek, A.; Kowalska, J. A. Tetrahedron
In conclusion, we have shown a novel general strategy
for the preparation of the 3,4-disubstituted isochro-
mans. The procedure is particularly useful because of
its efficiency, ready availability of the starting materials
and ease of operation, as well as its applicability to the
synthesis of important natural products.
1991, 47, 1697.
20. Epsztajn, J.; Bieniek, A.; Kowalska, J. A.; Scianowski, J.
Monatsh. Chem. 1992, 123, 1125.
21. Epsztajn, J.; Bieniek, A.; Kowalska, J. A. Monatsh.
Chem. 1996, 127, 701.
22. Epsztajn, J.; Bieniek, A.; Kowalska, J. A.; Kulikiewicz,
K. K. Synthesis 2000, 1603.
23. Adams, R.; Hartenist, M.; Loeve, S. J. Am. Chem. Soc.
Acknowledgements
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24. Takahashi, T.; Jkeda, H.; Tsuji, J. Tetrahedron Lett.
1980, 21, 3885.
25. Azzena, U.; Demartis, S.; Fiori, M. G.; Melloni, G.;
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26. Azzena, U.; Demartis, S.; Hellani, G. J. Org. Chem. 1996,
61, 4913.
This work was supported by Grant-in-Aid for Scientific
Research from the State Committee for Scientific
Research (KBN), and is gratefully acknowledged.
27. Yus, M.; Foubelo, F. Rev. Heteroatom Chem. 1997, 17,
73.
28. Ramon, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225.
29. The X-ray data for compounds 7 and 8 will be described
elsewhere.
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