A New Preparative Route to Substituted Dibenzofurans by Benzannulation Reaction. An Application to the Synthesis of Cannabifuran

Article abstract of DOI:10.1055/s-2003-42037

A new regioselective pathway to substituted dibenzofuran derivatives is described here. According to this procedure substituted 1-acetoxy-3- alkoxycarbonyl dibenzofurans are obtained by treatment of 6-(2-methoxyaryl)-3- alkoxycarbonylhex-3-en-5-ynoic acids with acetic anhydride in the presence of sodium acetate. The latter acids are prepared from the easily available substituted o-iodo-anisoles by Sonogashira coupling with propargylic alcohol and Wittig reaction as the key steps. The described benzannulation reaction proceeds in regioselective fashion and a range of substituents are tolerated. Its synthetic utility is demonstrated by a new synthesis of cannabifuran, a naturally occurring dibenzofuran.

Full text of DOI:10.1055/s-2003-42037

LETTER
2005
A New Preparative Route to Substituted Dibenzofurans by Benzannulation
Reaction. An Application to the Synthesis of Cannabifuran
A
New Route
t
to Subs
e
titute
d
D
ib
f
enzofura
a
ns no Serra,* Claudio Fuganti
C.N.R. Istituto di Chimica del Riconoscimento Molecolare, Sezione ‘Adolfo Quilico’ presso Dipatimento di Chimica, Materiali ed
Ingegneria Chimica ‘Giulio Natta’ del Politecnico, Via Mancinelli 7, 20133 Milano, Italy
Fax +39(2)23993080; E-mail: stefano.serra@polimi.it
Received 10 July 2003
CO2R'
Abstract: A new regioselective pathway to substituted dibenzo-
Ac2O
H
H
3-alkoxycarbonylhex-
3-en-5-ynoic acids
furan derivatives is described here. According to this procedure
substituted 1-acetoxy-3-alkoxycarbonyl dibenzofurans are obtained
by treatment of 6-(2-methoxyaryl)-3-alkoxycarbonylhex-3-en-5-
ynoic acids with acetic anhydride in the presence of sodium acetate.
The latter acids are prepared from the easily available substituted
o-iodo-anisoles by Sonogashira coupling with propargylic alcohol
and Wittig reaction as the key steps. The described benzannulation
reaction proceeds in regioselective fashion and a range of sub-
stituents are tolerated. Its synthetic utility is demonstrated by a new
synthesis of cannabifuran, a naturally occurring dibenzofuran.
R
OAc
NaOAc
AcO-
1
O
CO2R'
R
2
C
R= hydrogen,
alkyl, vinyl,
aryl, heteroaryl
O
R= o-methoxyaryl
Key words: annulations, enynes, benzofurans, phenols, natural
products
AcO-
AcO-
CO2R'
Me
O
CO2R'
R
C
O
C
Fused aromatic heterocycles are attractive targets of or-
ganic synthesis because of their biological activities and
their wide occurrence in nature.
R''
O
AcO
R
CO2R'
CO2R'
In this context, the dibenzofuran system was found in
several natural products1 arising from plant and lichens
reported to have phytoalexin,1a–c antifungal and anti-
biotic1d–f properties. These results have prompted the
development of versatile and regioselective synthetic
routes to benzofurans and dibenzofurans2 with functional
groups at specific positions.
O
3
4
OAc
OAc
R''
Scheme 1 Proposed pathways to 4-substituted 3,5-diacetoxy-
benzoates and 1-acetoxy-3-alkoxycarbonyl dibenzofurans.
Numerous methods for the preparation of dibenzofurans
have been reported. The ring closure of substituted diaryl
ethers,3 the acid catalyzed intramolecular cyclization of hex-3-en-5-ynoic acids with acetic anhydride and sodium
hydroxylated biphenyls4 and the direct functionalization acetate affords the phenolic derivatives 3.
of dibenzofuran framework5 are the most employed strat-
egies. However, the main restriction of these approaches
This process probably involves the ynenylketene 2,
formed from mixed anhydride 1, which may be cyclized
lies in the harsh reaction conditions, the low yields, and
through electrophilic attack and nucleophilic addition to
the use of expensive catalysts. Therefore, an increasing
the triple bond. If the substituent in position 6 of the ynoic
acid shows the o-methoxyaryl framework, the phenolic
oxygen acts as nucleophile and gives addition to the triple
number of milder approaches based on annulation6 reac-
tions have received growing attention.
We have successfully developed the benzannulation reac- bond with concomitant evolution of methyl acetate. The
tion of 3-alkoxycarbonyl-3,5-hexadienoic acids7 and of 3- products of the latter process are the 1-acetoxy-3-alkoxy-
alkoxycarbonylhex-3-en-5-ynoic acids8 to give the 4-sub- carbonyl dibenzofurans 4a–f where both the furan ring
stituted 3-hydroxy-benzoic acid derivatives and the 4- and the phenolic ring are building up by benzannulation
substituted 3,5-dihydroxybenzoic acid derivatives, re- reaction.
spectively. We envisage that the latter process (Scheme 1)
Herein is documented the efficiency of this synthetic route
is suitable also for the preparation of dibenzofurans. In-
starting from a variety of 6-substituted-3-alkoxycarbonyl-
deed, we found that the treatment of 3-alkoxycarbonyl-
hex-3-en-5-ynoic acids 9a–f. These latter compounds
were obtained in three steps from the easily available sub-
stituted o-iodoanisoles9 5a–f (Scheme 2).
SYNLETT 2003, No. 13, pp 2005–2008
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42037; Art ID: G16603ST
© Georg Thieme Verlag Stuttgart · New York

2006
S. Serra, C. Fuganti
LETTER
OMe
OMe
OH
OH
OMe
O
OMe
R
I
R
a, b
c, d
a
b
43%
81%
R'
R'''
R'
R'''
OH
6a-f
5a-f
R''
R''
10
11
12
OMe
P3P
CO2Et
O
R
8
OMe
g
e, f
c
COOH
COOH
87%
77%
R'
R'''
7a-f
R''
CO2Et
13
OMe
CO2Et
COOH
CO2Et
O
R
d
R
O
h, i, j, k
52%
O
R'
R'
R'''
R'' 9a-f
OAc
CO2Et
R'''
R''
4a-f
HO
O
Ac
cannabifuran 15
14
Scheme 2 Reagents and conditions: a) Propargyl alcohol (2 equiv),
Et3N (3 equiv), CuI (0.01 equiv), (Ph3P)2PdCl2 (0.01 equiv); b) MnO2,
CH2Cl2, 8 h at r.t.; c) 7a–f, 8, toluene/CHCl3, r.t., 4 h; d) Ac2O (10
equiv.) and NaOAc (2 equiv), hydroquinone (0.05 equiv), then hea-
ting 1 h at reflux.
Scheme 3 Reagents and conditions: a) Hexamethylenetetramine,
glycerol, H3BO3, paraformaldehyde; b) K2CO3, Me2SO4, acetone, re-
flux, 6 h; c) Ph3P, CBr4, Zn, CH2Cl2; d) BuLi (2 equiv), then formal-
dehyde; e) MnO2, CHCl3, reflux, 5 h; f) 8, toluene, r.t., 3 h; g) Ac2O
(10 equiv), NaOAc (2 equiv), hydroquinone (0.05 equiv), then hea-
Sonogashira coupling10 of 5a–f with propargylic alcohol ting 1 h at reflux; h) LiAlH4, THF; i) DDQ, dioxane, r.t., 24 h; j) BuLi,
afforded alcohols 6a–f, which were smoothly oxidized
THF; k) Pd/C, EtOH, H2, 3 atm, HCl cat., 2 d.
with MnO2 to the corresponding aldehydes 7a–f in quan-
titative yields. The following Wittig reaction with tri-
phenyl-(a-ethoxycarbonyl-b-carboxyethyl)phosphonium
ylide 811 gave regioselectively12 the suitable 6-(o-meth-
oxyaryl)-3-alkoxycarbonylhex-3-en-5-ynoic acids 9a–f in
yields ranging from 80% to 89% (Table 1). The conver-
sion of 9a–f into benzannulated dibenzofurans was estab-
lished by treatment13 of the latter acids with an excess of
acetic anhydride (10 equiv) in presence of sodium acetate
(2 equiv) and hydroquinone (0.05 equiv) heating at reflux
for one hour. The 1-acetoxy-3-alkoxycarbonyl dibenzo-
furans 4a–f were obtained regioselectively in very good
yields (87–97%). The examination of the substitution
pattern of the aromatic ring of the acids 9a–f shows the
flexibility of this synthetic method: alkoxy, alkyl, nitro,
carboxyalkyl, halo and aryl groups were unaffected under
the reaction conditions.
Therefore, we designed the synthesis of 13 starting from
the commercially available carvacrol 10. The latter phenol
was submitted to regioselective Duff formylation15 and
the resulting substituted salicylaldehyde was protected by
transformation in its ether 11 by methylation with dimeth-
yl sulphate. The following formyl–ethynyl conversion16
was performed by chain extension of the aldehyde by one
carbon to form the corresponding dibromoolefin. This
was treated with two equivalents of BuLi to give the relat-
ed lithium acetylide. The reaction of the latter salt with
formaldehyde gave propyn-ol 12,17 which was submitted
to the MnO2 oxidation–Wittig homologation procedure
described above to afford the desired acid 13.
As expected, treatment of 13 with acetic anhydride in the
presence of sodium acetate and hydroquinone gave diben-
zofuran 14 as a single regioisomer. It is noteworthy that
though the yield of the latter conversion was good (77%)
it was not quite complete as reported for compound 4a–f.
We assume that the intermediate ynenylketene should be
close to the bulky isopropyl group to achieve the adequate
conformation for the annulation process. According to our
explanation the above mentioned reaction was not effect-
ed by the activating or deactivating effect of the substitu-
ents on the aromatic ring (compounds 4a–f) and was
faintly depressed by the steric hindrance of the groups
placed in position ortho to the ethynyl group (compound
14).
In view of these results we decided to test our method in
the synthesis of natural dibenzofurans and we selected as
our target the minor cannabis constituent cannabifuran1h
15 (Scheme 3). The latter compound was previously pre-
pared by a variety of methods including acid catalyzed in-
tramolecular cyclization of biphenyls,4c,d transformation
of the natural cannabidiol in the dibenzofuran14 frame-
work and cycloaddition or benzannulation of benzofuran
derivatives.6c,f,g In this work we propose a different syn-
thetic approach in which both the furan ring and one aro-
matic ring are formed in a single annulation step.
Retrosynthetic analysis suggests that the acid 13 should
yield 1-acetoxy-3-ethoxycarbonyl-6-methyl-9-isopropyl
dibenzofuran 14 that shows the right functionalization for
conversion to cannabifuran.
Finally, we converted the dibenzofuran 14 in the canna-
bifuran 15 by modification of some reported procedures.6g
Synlett 2003, No. 13, 2005–2008 © Thieme Stuttgart · New York

LETTER
A New Route to Substituted Dibenzofurans
2007
Table 1 Synthesis of Acids 9 and Dibenzofurans 4 from Aldehydes 7 (Scheme 2)
Entry
Aldehydes 7
Acids 9
Wittig
Dibenzofuran 4
Benzannulation
(yields, %)a
(yields, %)a
a
89
87
92
OMe
OMe
CO2Et
COOH
CO2Et
O
O
OAc
b
c
97
OMe
CO2Et
CO2Et
OMe
O
O
COOH
OAc
MeO
OMe
OMe
OMe
OMe
89
93
CO2Et
CO2Et
O
O
O
COOH
OAc
O2N
NO2
NO2
d
e
f
85
80
88
95
89
87
OMe
CO2Et
COOH
CO2Et
OMe
O
OAc
MeO2C
CO2Me
OMe
COOMe
OMe
CO2Et
CO2Et
O
O
COOH
I
OAc
I
I
MeO
OMe
OMe
OMe
OMe
CO2Et
CO2Et
O
O
COOH
OAc
a After chromatography and/or crystallization.
Reduction of 14 with LiAlH4 followed by the DDQ
oxidation18 of the resulting benzyl alcohol gave directly
the corresponding 1-hydroxy-3-formyl dibenzofuran
without protection–deprotection manipulation of phenolic
hydroxyl group. The following treatment with BuLi and
hydrogenolysis of the resulting carbinol gave the title
compound in good yield (52% over four steps).
References
(1) (a) Tanahashi, T.; Takenaka, Y.; Nagakura, N.; Hamada, N.
Phytochemistry 2001, 58, 1129. (b) Miyagawa, H.;
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Comprehensive Heterocyclic Chemistry, Part 3, Vol. 4; Bird,
C. W.; Cheeseman, G. W. H., Eds.; Pergamon Press: New
York, 1984, 89. (c) Benassi, R. In Comprehensive
In conclusion, we have described a new preparative meth-
od to 1-acetoxy-3-alkoxycarbonyl dibenzofurans starting
from substituted o-iodoanisoles. Our approach is effi-
cient, experimentally simple and the starting materials are
easily available. This route shows some advantages over
the classical processes as demonstrated in the synthesis of
the natural dibenzofuran cannabifuran.
Acknowledgment
We thank MURST for partial financial support.
Heterocyclic Chemistry II, Vol. 2; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon Press: New York,
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Synlett 2003, No. 13, 2005–2008 © Thieme Stuttgart · New York

2008
S. Serra, C. Fuganti
LETTER
Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press: New
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Heterocyclic Chemistry II, Vol. 2; Katritzky, A. R.; Rees, C.
W.; Scriven, E. F. V., Eds.; Pergamon Press: New York,
1996, 395.
(12) The Wittig reaction of ylide 8 with the aldehydes affords the
3-E-alkylidene-succinic acid monoalkyl esters in a highly
stereoselective way; for previous studies on this reaction
see: (a) Paquette, L. A.; Schulze, M. M.; Bolin, D. J. Org.
Chem. 1994, 59, 2043. (b) Röder, E.; Krauss, H. Liebigs
Ann. Chem. 1992, 177.
(13) Acids 9a–f (50 mmol) were dissolved in acetic anhydride
(48 mL, 0.5 mol). To this solution, anhyd sodium acetate
(8.2 g, 0.1 mol) and hydroquinone (275 mg, 2.5 mmol) were
added in one portion. The obtained heterogeneous mixture
was heated at reflux for 1 h under a nitrogen atmosphere.
After cooling to r.t., the acetic anhydride was removed in
vacuo and the residue was treated with ethyl acetate (250
mL) and water (100 mL). The organic phase was separated,
dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by chromatography and
(3) (a) Carvalho, C. F.; Sargent, M. V. J. Chem. Soc., Perkin
Trans. 1 1984, 1621. (b) Carvalho, C. F.; Sargent, M. V. J.
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Eberson, L.; Jonsson, E.; Pettersson, E. J. Org. Chem. 1975,
40, 1365.
(4) (a) Arienti, A.; Bigi, F.; Maggi, R.; Moggi, P.; Rastelli, M.;
Sartori, G.; Trerè, A. J. Chem. Soc., Perkin Trans. 1 1997,
1391. (b) Yamato, T.; Hideshima, C.; Prakash, G. K. S.;
Olah, G. A. J. Org. Chem. 1991, 56, 3192. (c) Novák, J.;
Salemink, C. A. Tetrahedron Lett. 1983, 24, 101.
(d) Novák, J.; Salemink, C. A. J. Chem. Soc., Perkin Trans.
1 1983, 2873.
crystallization to give phenol derivatives 4a–f.
(14) Jorapur, V. S.; Duffley, R. P.; Razdan, R. K. Synth.
Commun. 1984, 14, 203.
(15) Duff, J. C. J. Chem. Soc. 1941, 547.
(5) (a) Jean, F.; Melnyk, O.; Tartar, A. Tetrahedron Lett. 1995,
36, 7657. (b) Tye, H.; Eldred, C.; Wills, M. Synlett 1995,
770.
(16) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(17) All new compounds were fully characterized. Selected
analytical data:
(6) (a) Katritzky, A. R.; Fali, C. N.; Li, J. J. Org. Chem. 1997,
62, 8205. (b) Sha, C.-K.; Lee, R.-S. Tetrahedron 1995, 51,
193. (c) Iwasaki, M.; Kobayashi, Y.; Li, J.-P.; Matsuzaka,
H.; Ishii, Y.; Hidai, M. J. Org. Chem. 1991, 56, 1922.
(d) Carvalho, C. F.; Sargent, M. V. J. Chem. Soc., Perkin
Trans. 1 1984, 1605. (e) Scannell, R. T.; Stevenson, R. J.
Chem. Soc., Perkin Trans. 1 1983, 2927. (f) Scannell, R. T.;
Stevenson, R. J. Chem. Res., Synop. 1983, 319. (g)Sargent,
M. V.; Stransky, P. O. J. Chem. Soc., Perkin Trans. 1 1982,
1605. (h) Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.;
Taniguchi, H. J. Org. Chem. 1981, 46, 851.
12: Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C,
77.15; H, 8.35. Bp 150 °C/0.5 mmHg. 1H NMR (250 MHz,
CDCl3): d = 1.22 (6 H, d, J = 6.9 Hz), 2.23 (3 H, s), 2.50–
2.85 (1 H, bs), 3.38 (1 H, m), 3.86 (3 H, s), 4.58 (2 H, s), 6.93
(1 H, d, J = 8.0 Hz), 7.10 (1 H, d, J = 8.0 Hz). EI-MS: m/z =
219 (M+ + 1), 218 (M+), 203, 187, 172, 159, 141, 128, 115,
105, 91, 77. FT-IR (film): n = 813, 1029, 1077, 1237, 1273,
1405, 1459, 1481, 1571, 2225, 2929, 3407 cm–1.
13: Anal. Calcd for C20H24O5: C, 69.75; H, 7.02. Found: C,
69.60; H, 7.10. Mp 59–60 °C (hexane). 1H NMR (250 MHz,
CDCl3): d = 1.22 (6 H, d, J = 6.9 Hz), 1.31 (3 H, t, J = 7.1
Hz), 2.24 (3 H, s), 3.34 (1 H, m), 3.77 (2 H, s), 3.83 (3 H, s),
4.26 (2 H, q, J = 7.1 Hz), 6.95 (1 H, d, J = 8.0 Hz), 7.15 (1
H, d, J = 8.0 Hz), 7.15 (1 H, s). EI-MS: m/z = 345 (M+ + 1),
344 (M+), 316, 300, 285, 270, 255, 239, 225, 209, 195, 173,
165, 152, 128, 115, 97. FT-IR (nujol): n = 762, 1031, 1093,
1212, 1265, 1376, 1459, 1619, 1699, 1719, 2193 cm–1.
14: Anal. Calcd for C21H22O5: C, 71.17; H, 6.26. Found: C,
71.10; H, 6.25. Mp 113–114 °C (isopropyl ether). 1H NMR
(250 MHz, CDCl3): d = 1.36 (6 H, d, J = 6.9 Hz), 1.42 (3 H,
t, J = 7.2 Hz), 2.45 (3 H, s), 2.54 (3 H, s), 3.99 (1 H, m), 4.42
(2 H, q, J = 7.2 Hz), 7.19 (1 H, d, J = 7.7 Hz), 7.30 (1 H, d,
J = 7.7 Hz), 7.75 (1 H, d, J = 1.2 Hz), 8.16 (1 H, d, J = 1.2
Hz). EI-MS: m/z = 355 (M+ + 1), 354 (M+), 312, 297, 283,
267, 255, 239, 224, 205, 195, 178, 165, 152, 139, 128, 115,
102, 89. FT-IR(nujol): n = 770, 1065, 1195, 1229, 1310,
1368, 1411, 1463, 1510, 1571, 1712, 1771 cm–1.
(7) Serra, S.; Fuganti, C.; Moro, A. J. Org. Chem. 2001, 66,
7883; and references cited therein.
(8) Serra, S.; Fuganti, C. Synlett 2002, 1661.
(9) 2-Iodoanisole 5a is commercially available. The substituted
2-iodoanisoles 5b, 5c and 5e were prepared from 1,4-
dimethoxy-3-methylbenzene, p-nitroanisole and
hydroquinone dimethyl ether, respectively by halogenation
according to the following references: (a) Lucht, B. L.;
Mao, S. S. H.; Tilley, T. D. J. Am. Chem. Soc. 1998, 120,
4354. (b) Robinson, G. M. J. Chem. Soc. 1916, 109, 1078.
(c) Wariishi, K.; Morishima, S.-I.; Inagaki, Y. Org. Proc.
Res. Dev. 2003, 7, 98; respectively. (d) The substituted 2-
iodoanisoles 5d and 5f were prepared from p-
hydroxybenzoic acid and b-naphthol respectively, by
halogenation followed by methylation with Me2SO4/K2CO3
in dry acetone. The above mentioned halogenation reaction
was performed according to: Edgar, K. J.; Falling, S. N. J.
Org. Chem. 1990, 55, 5287.
Cannabifuran 15: Anal. Calcd for C21H26O2: C, 81.25; H,
8.44. Found: C, 81.00; H, 8.45. Mp 79–80 °C (hexane). 1H
NMR (250 MHz, CDCl3): d = 0.89 (3 H, t, J = 6.6 Hz), 1.34
(6 H, d, J = 6.8 Hz), 1.20–1.46 (4 H, m), 1.55–1.81 (2 H, m),
2.53 (3 H, s), 2.66 (2 H, t, J = 7.5 Hz), 4.41 (1 H, m), 5.55
(1 H, bs), 6.46 (1 H, s), 7.01 (1 H, s), 7.17 (2 H, m). EI-MS:
m/z = 311 (M+ + 1), 310 (M+), 295, 281, 267, 254, 238, 225,
211, 191, 178, 165, 152, 139, 119, 105, 89. FT-IR (nujol):
n = 760, 815, 1048, 1061, 1219, 1252, 1426, 1514, 1588,
1618, 1635, 3500 cm–1.
(10) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) The coupling reaction was performed
in THF solution using 2 equiv of propargyl alcohol, Et3N as
base and an equimolar amount of copper and palladium
catalysts (0.01 equiv). When the coupling reaction was
performed with diiodoanisole 5e, only 1 equiv of propargyl
alcohol was used in the preparation.
(11) For the preparation of this ylide see: Hudson, R. F.; Chopard,
P. A. Helv. Chim. Acta 1963, 46, 2178.
(18) Becker, H.-D.; Björk, A.; Adler, E. J. Org. Chem. 1980, 45,
1596.
Synlett 2003, No. 13, 2005–2008 © Thieme Stuttgart · New York