Ring-closing metathesis for the synthesis of benzo-fused bicyclic compounds

Article abstract of DOI:10.1016/S0040-4039(02)02522-4

Ring-closing metathesis (RCM) was used to synthesise five 4H-chromenes, a naphthol and an indenol. These are the first examples of RCM applied to the synthesis of such benzo-fused bicyclic compounds.

Full text of DOI:10.1016/S0040-4039(02)02522-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 311–313
Ring-closing metathesis for the synthesis of benzo-fused
bicyclic compounds
Willem A. L. van Otterlo,* E. Lindani Ngidi, E. Mabel Coyanis and Charles B. de Koning
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, Johannesburg, South Africa
Received 13 September 2002; revised 28 October 2002; accepted 8 November 2002
Abstract—Ring-closing metathesis (RCM) was used to synthesise five 4H-chromenes, a naphthol and an indenol. These are the
first examples of RCM applied to the synthesis of such benzo-fused bicyclic compounds. © 2002 Elsevier Science Ltd. All rights
reserved.
Small molecules with bicyclic skeletons are ubiquitous
in Nature and often show interesting biological activi-
ties. This feature has been capitalised on in the pharma-
ceutical industry as bicyclic molecular scaffolds have
been models for the design of interesting pharma-
cophores with a plethora of bioactivities.1,2 It should
then come as no surprise that there is a wide range of
approaches to the syntheses of these compounds,
including the use of the versatile metathesis reaction
using the Grubbs’ catalysts.3–10 However, amongst the
large numbers of examples described in reviews, rela-
tively few examples utilise RCM for the synthesis of
benzo-fused bicyclic molecules.11–17 As part of our
ongoing interest18–20 in the synthesis of this class of
compounds, we report our preliminary results on a
general synthetic approach to a range of benzo-fused
bicyclic molecules, using the Grubbs’ second-generation
catalyst 1 in the key ring-closing step. Using simple
precursors we were able to synthesize specific examples
of 4H-chromenes, naphthols and indenols, all of which
are found as structural units in natural products.21
1. 4H-Chromenes
The 4H-chromenes (also known as 4H-1-benzopyrans),
are interesting compounds that have been isolated from
natural sources.22 We decided to examine the possibility
of using the RCM strategy for the synthesis of this class
of compounds. Three differently substituted phenols, 2,
were subjected to O-allylation, followed by Claisen
rearrangement to form the substituted phenols 3a–e in
moderate yields (Scheme 1). Vinylation of 3a–e with
tetravinyltin according to
a
recently published
procedure23 gave the bis-alkenes 4a–e in excellent
yields. These compounds were then easily converted
into their corresponding 4H-chromene derivatives 5a–e
using catalyst 1 under standard reaction conditions.24
RCM using Grubbs’ catalysts on substrates containing
electron-rich vinylic olefins is known to be
problematic25,26 and to our knowledge these results are
the first examples of high-yielding metathesis reactions
with phenolic vinyl ethers.
Scheme 1. Reagents and conditions: (a) K2CO3, allyl bromide
or crotyl bromide, acetone; (b) D (240°C), neat; (c) Cu(OAc)2,
Sn(vinyl)4, acetonitrile, O2; (d) 5% catalyst 1, toluene (for
yields see Table 1).
* Corresponding author. Tel.: +27+11+717-6707; fax: +27+11+717-
6749; e-mail: willem@aurum.chem.wits.ac.za
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02522-4

312
W. A. L. 6an Otterlo et al. / Tetrahedron Letters 44 (2003) 311–313
aromatised to the corresponding naphthalene 9b in
Table 1. Yields for Scheme 1
deuterated chloroform or on silica gel.33,34
2“3
3“4
4“5
a R2, R3=OMe, R1, R4, R5=H
b R1, R3=OMe, R2, R4, R5=H
c R1, R4=OMe, R2, R3, R5=H
d R2, R3=OMe, R1, R4=H; R5=Me
e R1, R3=OMe, R2, R4=H; R5=Me
45%
91%
63%
65%
42%
98%
99%
99%
98%
98%
90%
80%
85%
98%
82%
3. Indenols
Indenols and indenones are also important compounds
as a result of their biological activities and they have
been successfully used as intermediates in the syntheses
of a variety of natural products.35 The conjugated
styrene system 11 was readily synthesized as previously
reported.18 Addition of vinylmagnesium bromide to the
aldehyde group of 11 then afforded alcohol 12 (Scheme
3). Subsequent RCM on substrate 12 then gave the
indenol 1336 in reasonable yield. A noteworthy point is
that this reaction worked unusually well considering the
internal alkene involved in the metathesis.
Although substituted 2H-chromenes have been synthe-
sized before13–16 by the RCM approach, our strategy
represents
a direct synthesis of the related 4H-
chromene skeleton. In addition, we have achieved a
concise synthesis of 6,7-dimethoxy-4H-chromene 5a,24
a natural product with interesting organoleptic proper-
ties,27 isolated from Wisteria sinensis.28
2. Naphthols
We also wish to report progress in the application of
RCM to the synthesis of substituted naphthols. Treat-
ment of readily available 618 with vinylmagnesium bro-
mide gave alcohol 7 in moderate yield (Scheme 2).
Oxidation of 7 with MnO2 gave the a,b-unsaturated
system 8 and subsequent treatment with Grubbs’ cata-
lyst 1 afforded the naphthol 9a29 in good yield, while
reaction of alcohol 7 under similar conditions gave
naphthalene 9b as previously reported in the litera-
ture.11 This facile method of synthesizing the naphthol
is complementary to our previously reported naphtha-
lene synthesis18 and is important in light of the common
occurrence of the naphthol skeleton in natural prod-
ucts.30 Another point to note is that when alcohol 7 was
subjected to metathesis with catalyst 1, immediately
followed by hydrogenation,31 the dihydronaphthalene
10 was obtained as an intermediate32 which readily
Scheme 3. Reagents and conditions: (a) vinylmagnesium bro-
mide, THF, 0°C (54%); (b) 5% catalyst 1, dichloromethane
(67%).
We have thus shown that the versatile RCM reaction,
with the Grubbs’ second-generation catalyst 1, can be
applied to the synthesis of a number of benzo-fused
bicyclic compounds, namely 4H-chromenes, naphthols
and indenols. The extension of this work to the synthe-
sis of various natural products as well as other interest-
ing systems is currently under investigation.
Acknowledgements
This work was supported by the National Research
Foundation (NRF), Pretoria, and the University of the
Witwatersrand (University Research Council). We also
thank the Mellon Postgraduate Mentoring Programme
(sponsored by the Andrew W. Mellon Foundation) for
generous funding. Professor J. P. Michael is thanked
for many helpful discussions.
References
Scheme 2. Reagents and conditions: (a) vinylmagnesium bro-
mide, THF, 0°C (50%); (b) MnO2, benzene (54%); (c) 5%
catalyst 1, dichloromethane; (d) 5% catalyst 1,
dichloromethane; then H2 (g) (65%, two steps).
1. Souers, A. J.; Ellman, J. A. Tetrahedron 2001, 57, 7431–
7448.

W. A. L. 6an Otterlo et al. / Tetrahedron Letters 44 (2003) 311–313
313
2. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555–600.
23. Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66, 9043–
9045.
3. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450.
4. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29.
5. Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
6. Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7,
945–950.
7. Jørgensen, M.; Hadwiger, P.; Madsen, R.; Stu¨tz, A. E.;
Wrodnigg, T. M. Curr. Org. Chem. 2000, 4, 565–588.
8. Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036–2056.
9. Dragutan, V.; Dragutan, I.; Balaban, A. T. Platinum
Metals Rev. 2000, 44, 58–66, 112–118, 168–172.
10. Dragutan, V.; Dragutan, I.; Balaban, A. T. Platinum
Metals Rev. 2001, 45, 155–163.
11. Huang, K.-S.; Wang, E.-C. Tetrahedron Lett. 2001, 42,
6155–6157.
12. Arisawa, M.; Theeraladanon, C.; Nishida, A.; Naka-
gawa, M. Tetrahedron Lett. 2001, 42, 8029–8033.
13. Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 8023–8027.
24. A representative example, 6,7-dimethoxy-4H-chromene
1
5a: H NMR (CDCl3, 200 MHz, assignments with super-
scripts can be interchanged): l 3.31–3.33 (2H, m, H-4);
3.82 (6H, s, 2×OCH3); 4.86–4.93 (1H, m, H-3); 6.42 (1H,
s, H-8);a 6.46 (1H, s, H-5);a 6.42–6.46 (1H, m, H-2).
25. Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998,
39, 9623–9626.
26. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 3783–3784.
27. Demyttenaere, J.; Van Syngel, K.; Markusse, A. P.;
Vervisch, S.; Debenedetti, S.; De Kimpe, N. Tetrahedron
2002, 58, 2163–2166.
28. Joulain, D.; Tabacchi, R. Phytochemistry 1994, 37, 1769–
1770.
29. 5-Isopropoxy-6-methoxy-1-naphthol 9a: 1H NMR
(CDCl3, 200 MHz): l 1.28 (6H, d, J=6.2, (CH3)2CH);
3.88 (3H, s, OCH3); 4.55 (1H, sept., J=6.2, (CH3)2CH);
5.82 (1H, br s, OH); 6.59 (1H, d, J=7.3, H-7); 7.12–7.20
(2H, m, 2×Ar-H); 7.63 (1H, d, J=7.9, Ar-H); 7.86 (1H,
d, J=9.2, H-4).
30. de Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L.
Tetrahedron 2003, 59, submitted for publication.
31. Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 11312–11313.
14. Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63,
864–866.
15. Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda,
A. H. J. Am. Chem. Soc. 1997, 119, 1488–1489.
16. Ackermann, L.; Fu¨rstner, A.; Weskamp, T.; Kohl, F. J.;
Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787–4790.
17. Kinderman, S. S.; Doodeman, R.; van Beijma, J. W.;
Russcher, J. C.; Tjen, K. C. M. F.; Kooistra, T. M.;
Mohaselzadeh, H.; van Maarseveen, J. H.; Hiemstra, H.;
Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal.
2002, 344, 736–748.
18. de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J.
Chem. Soc., Perkin Trans. 1 2000, 787–797.
19. de Koning, C. B.; Michael, J. P.; van Otterlo, W. A. L. J.
Chem. Soc., Perkin Trans. 1 2000, 799–811.
20. de Koning, C. B.; Green, I. R.; Michael, J. P.; Oliveira, J.
R. Tetrahedron 2001, 57, 9623–9634.
32. Evidence for the structure of dihydronaphthalene 10
1
included key vinylic signals in the H NMR spectrum at
l 5.98 (1H, dt, J=9.9 and 4.1) and 6.91 (1H, br d,
J=9.9).
33. De, B.; DeBernardis, J. F.; Prasad, R. Synth. Commun.
1988, 18, 481–485.
34. Marco, M.-P.; Hammock, B. D.; Kurth, M. J. J. Org.
Chem. 1993, 58, 7548–7556.
35. Vicente, J.; Abad, J.-A.; Gil-Rubio, J. Organometallics
1996, 15, 3509–3519.
36. 4-Isopropoxy-5-methoxy-3-phenyl-1H-inden-1-ol 13: 1H
NMR (CDCl3, 200 MHz): l 0.67 (3H, d, J=6.1,
(CH3)2CH); 0.73 (3H, d, J=6.1, (CH3)2CH); 2.02 (1H, s,
OH, D2O exchangeable); 3.83 (3H, s, OCH3); 3.92 (1H,
sept., J=6.1, (CH3)2CH); 5.17 (1H, br s, CHOH); 6.23
(1H, d, J=2.0, -CHꢀC); 6.77 (1H, d, J=7.9, 6-H); 7.23
(1H, d, J=7.6, 7-H); 7.31–7.38 (3H, m, Ar-H); 7.47–7.52
(2H, m, Ar-H).
21. This work is taken from the MSc work of E. L. Ngidi
and the postdoctoral fellowship of Dr. E. M. Coyanis.
22. Schweizer, E. E.; Meeder-Nycz, D. 2H- and 4H-1-Ben-
zopyrans. In The Chemistry of Heterocyclic Compounds;
31; Chromenes, Chromanones and Chromones; Ellis, G. P.,
Ed.; John Wiley & Sons: New York, 1977; pp. 11–139.