New approach for two chromene carboxylic acids having a fully substituted benzene ring

Article abstract of DOI:10.1016/j.tetlet.2004.07.059

Two chromene carboxylic acids having a fully substituted benzene ring, 8-chlorocannabiorcichromenic acid (1) and myco-chromenic acid (2), were synthesized via thermal cyclization of the corresponding four substituted phenyl propargyl ethers. Two chromene

Full text of DOI:10.1016/j.tetlet.2004.07.059

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6971–6973
New approach for two chromene carboxylic acids having a
fully substituted benzene ring
Seiji Yamaguchi,* Mikiko Maekawa, Yohei Murayama, Masahiro Miyazawa
and Yoshiro Hirai
Department of Chemistry, Faculty of Science, Toyama University, Toyama 930-8555, Japan
Received 11 June 2004;revised 5 July 2004;accepted 8 July 2004
Available online 10 August 2004
Abstract—Two chromene carboxylic acids having a fully substituted benzene ring, 8-chlorocannabiorcichromenic acid (1) and myco-
chromenic acid (2), were synthesized via thermal cyclization of the corresponding four substituted phenyl propargyl ethers.
Ó 2004 Elsevier Ltd. All rights reserved.
Many 2H-chromenes, having a long side-chain at posi-
tion 2, have been isolated from various plants.1 In our
previous paper, we reported a new approach for natural
cannabichromene using condensation of a salicyl alde-
hyde with isopropylidenemalonate giving 2H-chrom-
ene-2-acetate and following side-chain conversion.2 We
also reported another approach for teretifolione B using
regioselective thermal cyclization of the corresponding
phenyl propargyl ether.3 Now, in this paper, the synthe-
ses of two 2H-chromene carboxylic acids having a fully
substituted benzene ring, 8-chlorocannabiorcichromenic
acid (1), isolated from Cylindrocapron olidum,4 and myco-
chromenic acid (2), isolated from Penicillium brevicom-
pactum,5 are described (Scheme 1).
Once, respective approaches to natural 8-chloro-
cannabiorcichromenic acid (1) and mycochromenic acid
(2) used the condensation method, but the results were
unsuccessful.6 For respective approaches of natural 1
and 2 using the thermal cyclization method, both effi-
cient preparation of the corresponding propargyl ethers
3 and 4 and effective cyclization might be needed. Some
papers described that some propargyl ethers having an
electron-withdrawing carbonyl group showed low yields
in cyclization, but we showed these were ambiguous, in
our previous paper.3 In the paper, we also described
the regioselectivity in thermal cyclization. These two
chromene carboxylic acids show a fully substituted
benzene ring. And we might expect more effective cycli-
zation of 3 and 4, because they have the only site for
cyclization.
OR
Cl
OH
OHC
HO C
2
The substrate 3 might be prepared by coupling of
3-chloro-4-hydroxy-2-methyl-6-(protected)oxybenzalde-
hyde 5 with 3,7-dimethyl-oct-6-en-1-yn-3-yl methyl car-
bonate 6b and the substrate 4 might be prepared by
coupling of 7-hydroxy-4-methyl-5-(protected)oxyphthal-
H C
3
O
H C
3
O
Cl
8-chlorocannabiorci-
(3)
chromenic acid (1)
OMe
OMe
ide
methyl carbonate 6c.
9
with 3-methyl-6-(protected)oxy-oct-1-yn-3-yl
H C
3
H C
3
OMOM
O
O
CO H
2
O
O
As the starting material for 1, 3-chloro-4,6-dihydroxy-2-
methylbenzaldehyde 5c, was prepared from 3,5-dimeth-
oxytoluene in three steps: (1) Vilsmeier formylation with
DMF–POCl3 (90%), (2) chlorination with NCS–DMF
(75%), (3) deprotection with BBr3 (95%), and then con-
verted to its 6-methoxy derivative 5a in three steps: (1)
MOM protection with MOMCl–diisopropylamine
(99%), (2) methylation with Me2SO4–K2CO3 (92%), (3)
O
O
mycochromenic acid (2)
(4)
Scheme 1. Strategy for 8-chlorocannabiorcichromenic acid (1) and
mycochromenic acid (2) via thermal cyclization.
*
Corresponding author. Tel.: +81-76-445-6617;fax: +81-76-445-
6549;e-mail: seiji@sci.toyama-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.059

6972
S. Yamaguchi et al. / Tetrahedron Letters 45 (2004) 6971–6973
deprotection with MeOH–concd. HCl (57%) and to its
6-MOMoxy derivative 5b in three steps: (1) acetylation
with Ac2O–pyridine (81%), (2) MOM protection with
MOMCl–diisopropylamine (99%), (3) deprotection with
aq NaOH–EtOH (63%) (Scheme 2).
Similar coupling of 5a with 3,7-dimethyl-oct-6-en-1-yn-
3-yl methyl carbonate 6b gave propargyl ether 3ab
(76%), and the following thermal cyclization gave the
corresponding 2H-chromene 7ab (82%). Demethylation
of 7ab with MgI2–OEt2 gave 5-hydroxy-6-carb-
aldehyde 7cb (45%), and oxidation of 7ab gave 5-meth-
oxy-6-carboxylic acid 8ab (71%). But, for both
conversions to 1, oxidation of 7cb and demethyl-
ation of 8ab (50%) were unsuccessful. So, MOM-
protected 5b was prepared and subjected to a similar
conversion.
As the stating material for 2, 7-hydroxy-5-methoxy-4-
methylphthalide 9, was prepared from 3,5-dimethoxy-
benyl methyl ether in six steps: (1) Vilsmeier formylation
with DMF–POCl3 (93%), (2) Wolf-Kishner reduction
with NH2NH2–KOH (89%), (3) Vilsmeier formyla-
tion with DMF–POCl3 (75%), (4) oxidation with
NaClO2 (61%), (5) lactonization with NaOH (64%),
(6) selective demethylation with MgI2–OEt2 (72%).
Similar coupling of 5b with 3,7-dimethyl-oct-6-en-1-yn-
3-yl methyl carbonate 6b gave propargyl ether 3bb
(56%), and the following thermal cyclization gave the
corresponding 2H-chromene 7bb (62%). And, 7bb was
converted to 5-hydroxy-6-carboxylic acid 1 by oxidation
with NaClO2 followed by deprotection (43% in two
steps) (Scheme 3).
Coupling and thermal cyclization of 5a were prestudied
with a dimethyl analog;coupling of 5a with methyl 2-
methylbut-3-yn-2-yl carbonate 6a using CuCl2–DBU
gave the corresponding propargyl ether 3aa (77%), and
the following thermal cyclization gave 2,2-dimethyl-
2H-chromene 7aa (68%). And, 7aa was converted to 5-
hydroxy-6-carboxylic acid 8ca by demethylation with
MgI2–OEt2 (50%) followed by oxidation with NaClO2
(41%).
Coupling and thermal cyclization of 7-hydroxyph-
thalide 9 were also prestudied with a dimethyl analog;
coupling of 9 with methyl 2-methylbut-3-yn-2-yl
carbonate 6a using CuCl2–DBU gave the correspond-
o
160 C
OR
OR
Cl
OR
Cl
R
1
OHC
OHC
Me
OHC
Me
MeO CO
2
N,N-dimethylaniline
R
1
R
1
(6a; R = H)
Me
O
O
(thermal cyclization)
OH
1
Cl
(6b; R = prenyl)
1
(7aa; R = Me, R = H) 68% from 3aa
(5a; R = Me)
(5b; R = MOM)
(5c; R = H)
(3aa; R = Me, R = H) 77%
1
1
(7ab; R = Me, R = prenyl) 82% from 3ab
(3ab; R = Me, R = prenyl) 76%
1
1
(7bb; R = MOM, R = prenyl) 62% from 3bb
(3bb; R = MOM, R = prenyl) 56%
1
1
(7ca; R = H, R = H) 50% from 7aa
1
(7cb; R = H, R = prenyl) 45% from 7ab
1
(oxidation)
NaClO
2
OR
HO C
2
R
1
Me
O
Cl
(8ca; R = H, R = H) 41% from 7ca
1
(8ab; R = Me, R = prenyl) 71% from 7ab
1
(8ba; R = MOM, R = prenyl)
1
(1; R = H, R = prenyl) 43% in two steps from 7bb
1
Scheme 2. Approach for 8-chlorocannabiorcichromenic acid (1) via thermal cyclization.
o
160 C
OMe
OMe
OMe
R
MeO CO
2
N,N-dimethylaniline
Me
Me
Me
R
R
6a (R = H)
(thermal cyclization)
O
O
1
OH
O
O
O
6c (R = CH CH CH OMOM)
1
2
2
2
O
O
O
(10a; R = H) 64% from 4a
(4a; R = H) 63%
(4c; R = CH CH CH OMOM) 66%
9
(10c; R = CH CH CH OMOM) 89% from 4c
2
2
2
2
2
2
(10d; R = CH CH CH OH) 99% from 10c
2
2
2
(10c; R = CH CH CHO) 30% from 10d
2
2
(2; R = CH CH CO H) 89% in two steps from 10d
2
2
2
Scheme 3. Approach for mycochromenic acid (2) via thermal cyclization.

S. Yamaguchi et al. / Tetrahedron Letters 45 (2004) 6971–6973
6973
ing propargyl ether 4a (63%), and the following ther-
mal cyclization gave 2,2-dimethyl-2H-chromene 10a
(64%).
mycochromenic acid in all reported spectral
data.4,5
References and notes
Similar coupling of 9 with 6-MOMoxy-3-methylhex-1-
yn-3-yl methyl carbonate 6c gave propargyl ether 4c
(66%), and the following thermal cyclization gave the
corresponding 2H-chromene 10c (89%). And, 10c was
converted to mycochromenic acid 2 (49%) in three steps:
(1) deprotection with MeOH–concd. HCl giving 10d, (2)
oxidation with PDC giving 10e, (3) oxidation with Ag2O
giving mycochromenic acid 2.
1. Ellis, G. P. Chromenes, Chromanones and Chromones;John
Wiley & Sons: New York, 1977;p 31.
2. Yamaguchi, S.;Shouji, N.;Kuroda, K. Bull. Chem. Soc.
Jpn. 1995, 68, 305.
3. Yamaguchi, S.;Ishibashi, M.;Akasaka, K.;Yokoyama, H.;
Miyazawa, M.;Hirai, Y. Tetrahedron Lett. 2001, 42, 1091.
4. Quaghebeur, K.;Coosemans, J.;Toppet, S.;Compernolle,
F. Phytochemistry 1994, 37, 159.
5. Campbel, I. M.;Calzadilla, C. H.;McCorkindale, N. J.
Tetrahedron Lett. 1966, 42, 51.
6. These details will be reported soon in a full paper.
Both chromene carboxylic acid 1 and 2 were identical
with natural 8-chlorocannabiorcichromenic acid and