Double benzyne-furan cycloaddition and the assembly of 1,1′- binaphthyl and 1,1′-dinaphthyl ether systems

Article abstract of DOI:10.1016/j.tetlet.2004.03.002

1,1^′-Binaphthyl and 1,1^′-dinaphthyl ether systems have been prepared via double benzyne-furan cycloadditions, and a dibenzofuran derivative was formed as a major product in the lithiation of two di-(chloroaryl) ethers.

Full text of DOI:10.1016/j.tetlet.2004.03.002

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3181–3184
Double benzyne–furan cycloaddition and the assembly of 1,10-
binaphthyl and 1,10-dinaphthyl ether systems
Andreas S. Biland-Thommen,a Gurubaran S. Raju,a Julian Blagg,b Andrew J. P. Whitea
and Anthony G. M. Barretta,*
aDepartment of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
bPfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 23 December 2003; revised 14 February 2004; accepted 1 March 2004
Abstract—1,10-Binaphthyl and 1,10-dinaphthyl ether systems have been prepared via double benzyne–furan cycloadditions, and a
dibenzofuran derivative was formed as a major product in the lithiation of two di-(chloroaryl) ethers.
Ó 2004 Published by Elsevier Ltd.
The palmarumycins,1 diepoxins,2 preussomerins3 and
spiroxins 4 are structurally remarkable classes of natural
products isolated from various fungal cultures. They are
all graced with a spiro-ketal entity formally derived
from 1,8-naphthalenediol and 1,4-naphthoquinone, but
at rich and varied oxidation levels. These unusual nat-
ural products are exemplified by palmarumycin CP1 1,
diepoxin r 2, preussomerin G 3 and spiroxin C 4 (Fig.
1). All four classes of fungal metabolites are undoubt-
edly closely interrelated biosynthetically and may well
be derived from a 1,8-naphthalenediol spiro-ketal with
late introduction of the unusual oxygenation patterns.
They collectively show diverse biological effects includ-
ing antifungal, antibacterial and antitumour activities.1
Since our original publication on the palmarumycins,5
other routes for the total synthesis of several palm-
arumycins, diepoxins, preussomerins and spiroxins have
been published by our group and others.4c;6
In connection with further work on spirocyclic naph-
thalene natural products, we now report our recent
investigations on the synthesis of 1,10-binaphthyl 5 and
dinaphthyl ethers 6 (Fig. 2). Initially we sought to access
5 and 6, both key intermediates, via double benzyne–
furan Diels–Alder reactions. The key step in both routes
involves the generation of either a simple benzyne,
which was trapped by 2,20-bifuryl 7 or the elaboration of
a double benzyne capable of undergoing reaction with
2-methoxyfuran 15 twice.
The binaphthyl system 5 was prepared using 2,20-bifuryl
7 and 2-chloro-1,4-dimethoxybenzene 8. Chloride 8 was
allowed to react with sec-butyllithium in THF at
)100 °C7;8 for 15 min, and the resultant ortho-lithiated
product allowed to warm up to room temperature in the
OH
O
OH
O
O
OH
O
OH
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
OMe OMe
OH OMe
O
O
1
2
3
4
OMe
OH
OMe
O
OH
Figure 1.
OMe OH
Keywords: 1,10-Binaphthyl; 1,10-Dinaphthyl ether; Benzyne; Cycload-
dition; Dibenzofuran.
OMe OMe
5
6
*Corresponding author. Tel.: +44-207-594-5766; fax: +44-207-594-
5805; e-mail: agmb@imperial.ac.uk
Figure 2.
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.03.002

3182
A. S. Biland-Thommen et al. / Tetrahedron Letters 45 (2004) 3181–3184
OMe
OH OMe
OMe
O
O
i, ii
iii
OMe
OMe
OMe
OMe
OMe
O
Cl
O
OMe
7
8
OMe OH
9
5
Scheme 1. Reagents and conditions: (i) s-BuLi, 8, )100 °C; (ii) 7, )100–25 °C, 38%; (iii) TFA, CH2Cl2, 25 °C, 83%.
presence of the 2,20-bifuryl 7. This produced the double
Diels–Alder cycloadduct 9 in 38% yield. Diether 9 was
aromatized by reaction with trifluoroacetic acid in
dichloromethane to provide the desired binaphthyl sys-
tem 5 (Scheme 1).9
lithium (2 equiv) and 2-methoxyfuran 15, no dinaphthyl
ether 6 was observed. Instead the dibenzofuran 1614 was
isolated as the only product (72–82%) (Scheme 3).
Barluenga has reported similar observations on the
formation of benzo-fused heterocyclic derivatives from
benzyne precursors.15
This double benzyne cycloaddition strategy was
extended to the three dichloro-diaryl ethers 14a–c. We
considered that double ortho-lithiation should provide a
dibenzyne, or its synthetic equivalent. In situ trapping
with 2-methoxyfuran 15 was expected to provide the
dinaphthyl ether 6 on aromatization. Initial attempts to
synthesize the compounds 14a–c by Ullmann-cou-
pling10;11 proceeded in poor yields. However, nucleo-
philic aromatic substitution of fluorobenzaldehydes
10a–b by reaction with the methoxyphenols 11a–b
mediated by the Barton base, (Me2N)2C¼NtBu,
followed by Baeyer–Villiger oxidation and methyla-
tion12 of the resultant phenols 13a–c gave the desired
benzyne precursors 14a–c13 (58%, 63% and 56% overall
yields, respectively) (Scheme 2). When chlorides 14a and
b were allowed to react with an excess of sec-butyl-
Formation of the dibenzofuran ring system 16 probably
proceeds via the intermediates 19 and 20 in which the
benzyne is trapped intramolecularly by the aryllithium
to form 21 (Scheme 4). This process is undoubtedly very
fast and takes place at very low temperatures.7 Thus
2-methoxyfuran 15 is unable to react with the double
benzyne to form the dinaphthyl system 6. In support of
the proposed mechanism 14a was allowed to react with
sec-butyllithium (2 equiv) in the presence of iodine
(4 equiv) at )100 °C to give the expected iodo com-
pounds 17 and 18 in 16% and 53% yields, respectively,
(Scheme 3). This result is consistent with the fact that
ortho-lithiation has taken place prior to the heterocy-
clization reaction. The structure of dibenzofuran 16
(CCDC 231192) was confirmed by ring iodination and
R2
R3
Cl
Cl
Cl
Cl
R1
MeO
O
R4
F
HO
O
i
iii
OHC
OMe
X
OMe
OMe
14a R1 = R4 = Cl, R2 = R3 = H
14b R1 = R3 = Cl, R2 = R4 = H
14c R1 = R4 = H, R2 = R3 = Cl
10a-b
11a-b
12a-c X = CHO
13a-c X = OH
ii
Scheme 2. Reagents and conditions: (i) (Me2N)2C¼NtBu, MeCN, 70 °C, 1 h 15 min, 68–74%; (ii) m-CPBA, CH2Cl2, 25 °C, 24 h, 70–74%
(iii) (MeO)2SO2, K2CO3, Me2CO, 25 °C, 3 h, (80–86%).
O
O
O
MeO
OMe
Cl
OMe
15
OMe
15
i
i
16
O
O
MeO
OMe
MeO
OMe
Cl
OMe
Cl
Cl
Cl
ii
14a
O
O
I
14b
I
I
MeO
OMe MeO
Cl
Cl
Cl
Cl
17
18
Scheme 3. Reagents and conditions: (i) s-BuLi (2 equiv), )100–25 °C, 20 min, 82% (from 14a) or 72% (from 14b); (ii) s-BuLi (2 equiv), I2 (4 equiv),
)100–25 °C, 20 min, 16% (17) and 53% (18).

A. S. Biland-Thommen et al. / Tetrahedron Letters 45 (2004) 3181–3184
3183
OMe
Cl
OMe
O
O
Cl
Cl
OMe
OMe
14a
16
H+
sec-BuLi
Figure 4.
OMe
Cl
OMe
Cl
OMe
Cl
synthesis of dibenzofuran 16, which is relevant to other
classes of natural products.17
O
Li
O
O
Li
Li
Cl
Li
OMe
OMe
20
OMe
19
21
Acknowledgements
Scheme 4.
We thank the Swiss National Science Foundation,
€
Novartis-Stiftung vormals Ciba-Geigy Jubilaumsstif-
an X-ray crystallographic structure determination (Fig.
3).
tung, Freiwillige Akademische Gesellschaft (FAG)
Basel, the EPSRC and Pfizer for support of this
research, GlaxoSmithKline for the generous endowment
(to A.G.M.B.), the Royal Society and the Wolfson
Foundation for a Royal Society-Wolfson Research
Merit Award (to A.G.M.B.), and the Wolfson Foun-
dation for establishing the Wolfson Centre for Organic
Chemistry in Medical Science at Imperial College Lon-
don.
In contrast to chlorides 14a and 14b, the reaction of
chloride 14c with 2-methoxyfuran 15, under the same
conditions, gave a mixture of the mono-cycloadducts, 23
and 24, and the desired 1,10-dinaphthyl ethers 6 and 2216
after facile aromatization during purification in 7%, 5%,
9% and 12% yields, respectively, (Scheme 5). It should
be noted that 14c is clearly not capable of forming the
dibenzofuran 16 via intramolecular carbanion attack
onto a benzyne. The structure of dinaphthyl ether 22
(CCDC 231193) was confirmed by X-ray crystallogra-
phy (Fig. 4).
References and notes
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OMe OMe
OMe OMe
OMe
O
OMe OMe
OMe OH
i
Cl
Cl
OH
OH
O
O
O
OH
Cl
O
OMe
Cl
OH
OMe
OMe
OMe OMe
OMe OH
OMe
OMe
14c
6
22
23
24
Scheme 5. Reagents and conditions: (i) s-BuLi (4 equiv), 15 )100–25 °C, 20 min, 9% (6), 12% (22), 7% (23) and 5% (24).

3184
A. S. Biland-Thommen et al. / Tetrahedron Letters 45 (2004) 3181–3184
€
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298 (M)þ, 283, 52; HRMS m=z calcd for C14H12Cl2O3:
(M)þ, 298.0164; found: 298.0170. Anal. Calcd for
C14H12Cl2O3: C, 56.21; H, 4.04. Found: C, 56.36; H,
1
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(s, 3H), 3.89 (s, 3H), 6.76–6.91 (m, 3H), 6.92–7.05 (m, 3H);
13C NMR (CDCl3, 75.5 MHz) d 56.2, 57.0, 113.2, 114.2,
116.2, 116.3, 119.5, 122.6, 123.4, 127.1, 146.0, 151.2, 152.0,
156.9; MS (CI) m=z 316 (MþNH4)þ, 298 (M)þ, 283, 52;
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4H), 6.91–7.14 (m, 2H); 13C NMR (CDCl3, 75.5 MHz) d
56.2, 113.9, 116.2, 120.3, 125.7, 146.9, 156.3; MS (CI) m=z
316 (MþNH4)þ, 298 (M)þ, 283, 52; HRMS m=z calcd for
C14H16Cl2NO3: (MþNH4)þ, 316.0507; found: 316.0502.
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56.31; H, 3.94.
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14. Spectroscopic data: dibenzofuran 16: 1H NMR (CDCl3,
300 MHz) d 3.95 (s, 3H), 3.99 (s, 3H), 7.03–7.14 (m, 2H),
7.35–7.48 (m, 2H), 7.89 (s, 1H); 13C NMR (CDCl3,
75.5 MHz) d 56.4, 57.8, 103.9, 106.3, 110.1, 112.2 (2C),
112.6, 116.5, 124.0, 124.4, 151.4, 152.0, 156.0; MS (CI) m=z
280 (MþNH4)þ, 262 (M)þ, 247, 229, 52; HRMS m=z calcd
for C14H15ClNO3: (MþNH4), 280.0740; found 280.0744.
Anal. Calcd for C14H11ClO3: C, 64.01; H, 4.22. Found: C,
64.01; H, 4.27.
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~
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1
16. Spectroscopic data: ether 6: H NMR (CDCl3, 300 MHz)
9. Spectroscopic data: Compound 5: 1H NMR (CDCl3,
300 MHz) d 3.81 (s, 6H), 3.84 (s, 6H), 5.98 (s, 2H), 6.65–
6.70 (m, 4H), 7.05–7.20 (m, 4H); 13C NMR (CDCl3,
75.5 MHz) d 79.8, 80.5, 110.8, 114.8, 139.2, 142.2, 143.6,
144.1, 144.3, 147.3, 147.4, 148.5; MS (CI) m=z 407
(MþH)þ, 424 (MþNH4)þ; HRMS m=z calcd for
C24H23O6: (MþH)þ, 407.1495; found: 407.1495.
d 3.89–4.01 (m, 12H), 6.70 (d, J ¼ 8:5 Hz, 2H), 6.86 (d,
J ¼ 8:5 Hz, 2H), 6.91–7.01 (m, 4H), 8.36 (s, 2H); MS (CI)
m=z 440 (MþNH4)þ, 423 (MþH)þ, 203; HRMS m=z calcd
for C24H23O5: (MþH)þ, 423.1443; found: 423.1433. Ether
22: 1H NMR (CDCl3, 300 MHz) d 3.47 (s, 3H), 3.87 (s,
3H), 3.93 (s, 3H), 4.10 (s, 3H), 6.24 (d, J ¼ 8:5 Hz, 1H),
6.55 (d, J ¼ 8:5 Hz, 1H), 6.76 (d, J ¼ 8:5 Hz, 1H), 6.90–
6.98 (m, 4H), 7.12 (d, J ¼ 8:5 Hz, 1H), 9.26 (s, 1H), 9.51 (s,
1H); 13C NMR (CDCl3, 75.5 MHz) d 56.4, 56.9, 57.6, 58.5,
104.7, 106.8, 108.3, 109.3, 111.1, 111.2, 111.3, 111.5, 116.3,
118.0, 119.9, 121.0, 143.8, 148.3, 148.6, 149.1, 150.0, 151.4,
152.2, 154.1; MS (CI) m=z 440 (MþNH4)þ, 423 (MþH)þ,
203; HRMS m=z calcd for C24H23O5: (MþH)þ, 423.1443;
found: 423.1437.
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