Sequential isomerization and ring-closing metathesis: Masked styryl and vinyloxyaryl groups for the synthesis of benzo-fused heterocycles

Article abstract of DOI:10.1016/S0040-4039(03)01545-4

The use of an aryl allyl ether and an arylallyl group as masked vinyl ether and 1-propenylphenyl groups for ring-closing metathesis (RCM) leading to the synthesis of benzo-fused heterocycles was demonstrated by using a ruthenium-mediated isomerization followed by a ruthenium-mediated RCM reaction. This resulted in the syntheses of a variety of products including two substituted benzo[1,4]dioxins, a naphtho[2,3-b][1,4]dioxin, a 2H-chromene and a benzo[b]furan.

Full text of DOI:10.1016/S0040-4039(03)01545-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6483–6486
Sequential isomerization and ring-closing metathesis: masked
styryl and vinyloxyaryl groups for the synthesis of
benzo-fused heterocycles
Willem A. L. van Otterlo,* E. Lindani Ngidi and Charles B. de Koning
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, Johannesburg, South Africa
Received 6 May 2003; accepted 20 June 2003
Abstract—The use of an aryl allyl ether and an arylallyl group as masked vinyl ether and 1-propenylphenyl groups for ring-closing
metathesis (RCM) leading to the synthesis of benzo-fused heterocycles was demonstrated by using a ruthenium-mediated
isomerization followed by a ruthenium-mediated RCM reaction. This resulted in the syntheses of a variety of products including
two substituted benzo[1,4]dioxins, a naphtho[2,3-b][1,4]dioxin, a 2H-chromene and a benzo[b]furan.
© 2003 Elsevier Ltd. All rights reserved.
The recent literature contains a myriad of examples of
the application of ruthenium-mediated ring-closing
metathesis (RCM).1–5 The RCM catalyst of choice for
this transformation is the Grubbs’ second-generation
catalyst 1 owing to its activity, stability and tolerance to
various functional groups and solvent impurities.
zenes, respectively, prior to RCM. This strategy thus
obviates the need to synthesize the required aryl vinyl
ethers or styrenes directly, the synthesis of which can be
problematic.
However, amongst the large numbers of examples
described in reviews, very few utilize RCM for the
metathesis of vinyl ether6–8 or silyl enol ether9,10 groups.
RCM using Grubbs’ catalysts on substrates containing
electron-rich vinylic olefins are known to be
problematic7,8 and earlier this year we communicated
the first examples of high-yielding metathesis reactions
with aryl vinyl ethers (e.g. the conversion of precursor 2
into 4H-chromene 3.)11 Nishida and co-workers also
recently published the related intramolecular RCM of
substituted enamines 4 to give indoles 5 in excellent
yields.12 This paper has prompted us to divulge our
successes in the RCM of other substrates containing
electron-rich olefins. Furthermore, we demonstrate the
in situ isomerization of aryl allyl ethers or arylallyl
groups into aryl 1-propenyl ethers or 1-propenylben-
Figure 1.
1. Benzo[1,4]dioxins
Previously we have shown that as part of our ongoing
interest in the synthesis of benzo-fused bicyclic
molecules,13–16 we were able to use RCM to synthesize
4H-chromenes, naphthols and indenols,11 all of which
are found as structural units in natural products.
Firstly, following our success in accomplishing RCM
on the vinyl ether-containing substrates, we decided to
test the boundaries of this methodology by the
intramolecular RCM of molecules containing aryl-bis-
O-vinylic olefins. This would then give us
benzo[1,4]dioxins,17 which are interesting compounds
with promising anti-tumour activity. Coudert has
recently published an approach to their synthesis.18 Our
methodological approach is shown in the disconnection
of compound 6 to the bis(vinyloxy)aryl precursors 7.
* Corresponding author. Tel.: Int+27+11+717-6707; fax: Int+27+11+
717-6749; e-mail: willem@aurum.chem.wits.ac.za
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01545-4

6484
W. A. L. 6an Otterlo et al. / Tetrahedron Letters 44 (2003) 6483–6486
The first experimental sequence involved the isomeriza-
tion of commercially available 2-allylphenol 13 with
[RuClH(CO)(PPh3)3].23 This was followed by alkylation
of the phenol with allyl bromide and K2CO3 to give 14
in excellent yield over two steps (Scheme 2). Subsequent
treatment of this substrate with catalyst 1 then afforded
2H-chromene 1526 in excellent yield.27 Other
approaches to 2H-chromenes, of which abundant
examples exist in Nature,28 using ruthenium-mediated
RCM have already been communicated.29–32 However,
the major difference in our work is that the intramolec-
ular RCM occurred between an allyloxy substituent
and a styrene. Using this ruthenium-catalyzed allyl/pro-
penyl isomerization reaction therefore extends the sub-
strates available in this approach as allyl groups ortho
to a substituent on an aromatic ring are often easy to
introduce, e.g. by Claisen rearrangement, Kumada cou-
pling, directed ortho-metalation33 and electrochemical
coupling.34
Three differently substituted catechols 8a–c were sub-
jected to vinylation with tetravinyltin and copper(II)
acetate, according to a recently published procedure,19
to afford the bis(vinyloxy) compounds 9a–e in rather
poor yields (Scheme 1).20 These yields were lower than
expected and we postulate that competing formation of
copper–catechol complexes probably contributes to the
limited success of the reactions. Furthermore in cases
8a and 8b the experiments were poorly reproducible
and often gave complex mixtures of vinylated products.
Only 2,3-bis(vinyloxy)naphthalene 9c was easily iso-
lated.21,22 When it was treated with catalyst 1 under
standard reaction conditions, the corresponding known
compound, naphtho[2,3-b][1,4]dioxin 10c, was pro-
duced.18 To the best of our knowledge this is the first
use of the RCM methodology to synthesize this class of
compounds, and the first synthesis of the 1,4-benzodi-
oxins by direct ring-closure methods.17
Scheme 1. a. R1,R2=H; b. R1=Me, R2=H; c. R1,R2=fused
benzene ring. Reagents and conditions: For c. (a) Cu(OAc)2,
Sn(vinyl)4, acetonitrile, O2, rt, 47%; (b) 5% catalyst 1, toluene,
67%, 70–80°C.
Scheme 2. Reagents and conditions: (a) [RuClH(CO)(PPh3)3]
(1%), toluene, 80°C, 90%; (b) allyl bromide, K2CO3, acetone,
reflux, 86%; (c) 5% catalyst 1, CDCl3, rt, >80% (by H NMR
1
spectroscopy).
In addition, synthesis of benzo[1,4]dioxins was more
readily accomplished using our new allylation/isomer-
ization/RCM procedure. Bis(O-allylation) of catechols
8a–c afforded compounds 16a–c in good yields (Scheme
3). This was then followed by in situ isomerization as
described before to afford the aryl bis(vinyl) ethers
17a–c. The formation of the product was monitored by
1H NMR spectroscopy and the acid-sensitive enol ether
intermediates 17 were not isolated. Grubbs’ catalyst
1 was then added directly to the reaction mixture,
and the desired benzo[1,4]dioxins 10a–c were obtained
in good yields.27 Other reported examples of ‘one-pot’
multistep reactions featuring RCM include RCM/
2. Isomerizations of arylallyl and aryloxyallyl groups
followed by RCM
The O-vinylation reaction used above has the disadvan-
tage of using stoichiometric amounts of copper acetate
and an environmentally unfriendly, atom uneconomical
tetravinylstannyl reagent. Thus, having experienced
problems with the synthesis of the bis(vinyloxy) ethers
in the synthesis of the benzo[1,4]dioxins, we decided to
investigate an alternative approach. The isomerization
of aryloxyallyl ethers has attracted significant attention
in the last few years and several groups have used
efficient transition metal catalysts to achieve this goal.
Examples include the use of catalysts based on the
metals ruthenium,23 iridium24 and rhodium.25 Since
phenols are easily O-allylated by well established meth-
ods to produce 11, subsequent isomerization should
provide a useful aryl vinyl ether 12 as depicted in the
disconnection below. Compound 12 would then be
available for ruthenium-mediated RCM.
hydrogenation11,35
and
RCM/isomerization36,37
sequences. We have thus been successful in synthesizing
compounds with the benzo[1,4]dioxin structure using a
simple three-step two-reaction process. The desired
compounds were readily formed and this methodology
should stimulate further exploration of the properties
of this class of organic molecules.

W. A. L. 6an Otterlo et al. / Tetrahedron Letters 44 (2003) 6483–6486
6485
readily undergo ruthenium-mediated RCM reactions.42
We are currently extending this work to the synthesis of
natural products and other interesting systems.
Acknowledgements
This work was supported by the National Research
Foundation (NRF, GUN 2053652), Pretoria, and the
University of the Witwatersrand (University Research
Council). We also thank the Mellon Postgraduate Men-
toring Programme (sponsored by the Andrew W. Mel-
lon Foundation) for generous funding. Professor J. P.
Michael is thanked for many helpful discussions.
Scheme 3. a. R1,R2=H; b. R1=Me, R2=H; c. R1,R2=fused
benzene ring; Reagents and conditions: (a) allyl bromide,
K2CO3, acetone, reflux, 16a 76%, 16b 93%, 16c 96%; (b)
1
[RuClH(CO)(PPh3)3] (1%), toluene-d8, 80°C (complete by H
NMR spectroscopy); (c) 5% catalyst 1, toluene-d8, yields over
two steps: 10a38 >70% (by 1H NMR spectroscopy), 10b39
>70% (by 1H NMR spectroscopy, isolated yield after chro-
matography 58%), 10c18 >90% (by 1H NMR spectroscopy).
References
1. Grubbs, R.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
2. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18–29.
3. Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043.
4. Dragutan, V.; Dragutan, I.; Balaban, A. T. Platinum
Metals Rev. 2000, 44, 58–66 112–118, 168–172.
5. Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371–388.
6. Gurjar, M. K.; Krishna, L. M.; Reddy, B. S.; Chorghade,
M. S. Synthesis 2000, 557–560.
7. Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998,
39, 9623–9626.
Finally, we decided to further extend our novel one-pot
isomerization/RCM reaction. 2-Allylphenol was thus
converted into allyl-2-(allyloxy)benzene 18 under stan-
dard conditions. [RuClH(CO)(PPh3)3] was then added
to a solution of 18 in benzene-d6 or toluene-d8 and the
reaction mixture was heated at 60–80°C for 18 h
1
(Scheme 4). Analysis by H NMR spectroscopy confi-
rmed that the isomerization of both allyl substituents
had occurred to afford the acid-labile compound 19
which was not isolated. The introduction of catalyst 1
then readily afforded the benzo[b]furan 2040 in excellent
conversion as determined by further 1H NMR spec-
troscopy.27 This result constitutes a novel approach to
the ubiquitous benzo[b]furan skeleton41 and parallels
Nishida’s approach12 to indoles as depicted in Figure 1.
The methodology once again utilizes readily accessible
starting materials, and work is now in progress to
demonstrate the general applicability of this approach.
8. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 3783–3784.
9. Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 8023–8027.
10. Arisawa, M.; Theeraladanon, C.; Nishida, A.; Naka-
gawa, M. Tetrahedron Lett. 2001, 42, 8029–8033.
11. van Otterlo, W. A. L.; Ngidi, E. L.; Coyanis, E. M.; de
Koning, C. B. Tetrahedron Lett. 2003, 44, 311–313.
12. Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A.
Angew. Chem., Int. Ed. 2002, 41, 4732–4734.
13. de Koning, C. B.; Michael, J. P.; Rousseau, A. L. J.
Chem. Soc., Perkin Trans. 1 2000, 787–797.
14. de Koning, C. B.; Michael, J. P.; van Otterlo, W. A. L. J.
Chem. Soc., Perkin Trans. 1 2000, 799–811.
15. de Koning, C. B.; Green, I. R.; Michael, J. P.; Oliveira, J.
R. Tetrahedron 2001, 57, 9623–9634.
In conclusion, we have shown that the versatile RCM
reaction with ruthenium catalyst 1 can be applied to
substrates containing electron-rich aryl 1,2-bis(viny-
loxy) substituents to afford benzo[1,4]dioxins. Further-
more we have demonstrated that the aryloxyallyl and
arylallyl groups can function as masked aryl vinyl
ethers and 1-propenylbenzenes, respectively, which
16. de Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L.
Tetrahedron 2003, 43, 7–36.
17. Palar, H.; Angerho¨fer, D. In Houben–Weyl Methods of
Organic Chemistry, Hetarenes IV, Six-Membered and
Larger Hetero-Rings with Maximum Unsaturation;
Schaumann, E., Ed. 6-Ring Systems with Two O-Atoms,
1,4-Dioxins and Annulated Derivatives; Georg Thieme
Verlag: Stuttgart, 1997; Vol. E9a, pp. 3–38.
18. Clavier, S.; Khouili, M.; Bouyssou, P.; Coudert, G. Tet-
rahedron 2002, 58, 1533–1540.
19. Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66, 9043–
9045.
20. Some of this work was taken from the MSc dissertation
of Mr. E. L. Ngidi.
Scheme 4. Reagents and conditions: (a) [RuClH(CO)(PPh3)3]
(1%), benzene-d6 or toluene-d8, 90–100°C (complete by 1H
NMR spectroscopy); (b) 5% catalyst 1, CH2Cl2, 60–70°C
1
>80% over two steps (by H NMR spectroscopy).

6486
W. A. L. 6an Otterlo et al. / Tetrahedron Letters 44 (2003) 6483–6486
21. 2,3-Bis-vinyloxynaphthalene 9c: 1H NMR (CDCl3, 300
MHz): l 4.53 (2H, dd, J=6.1 and 1.9, 2%-Hcis); 4.85 (2H,
dd, J=13.7 and 1.9, 2%-Htrans); 6.70 (2H, dd, J=13.7
and 6.1, 1%-H); 7.36 (2H, s, 1- and 4-Ar-H); 7.38 (2H, dd,
J=6.2 and 3.3, 6- and 7-Ar-H); 7.70 (2H, dd, J=6.2 and
3.3, 5- and 8-Ar-H). 13C NMR (CDCl3, 75 MHz): l 96.0;
114.2; 125.3; 126.7; 130.3; 146.5; 148.3.
22. All new compounds were fully characterized and gave
satisfactory spectroscopic data.
23. Krompiec, S.; Kuz´nik, N.; Bieg, T.; Adamus, B.;
Majnusz, J.; Grymel, M. Pol. J. Chem. 2000, 74, 1197–
1200.
31. Hardouin, C.; Burgaud, L.; Valleix, A.; Doris, E. Tetra-
hedron Lett. 2003, 44, 435–437.
32. Ackermann, L.; Fu¨rstner, A.; Weskamp, T.; Kohl, F. J.;
Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787–4790.
33. Snieckus, V. Chem. Rev. 1990, 90, 879–933.
34. Gomes, P.; Gosmini, C.; Pe´richon, J. J. Org. Chem. 2003,
68, 1142–1145.
35. Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 11312–11313.
36. Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper,
M. L. J. Am. Chem. Soc. 2002, 124, 13390–13391.
37. Schmidt, B. Eur. J. Org. Chem. 2003, 816–819.
38. Kashima, C.; Tomotake, A.; Omote, Y. J. Org. Chem.
1987, 52, 5616–5621.
24. Baxendale, I. R.; Lee, A.-L.; Ley, S. V. Synlett 2002,
516–518.
25. Clive, D. L. J.; Sannigrahi, M.; Hisaindee, S. J. Org.
39. 6-Methylbenzo[1,4]dioxin 10b: 1H NMR (CDCl3, 300
MHz): l 2.18 (3H, s, ArCH3); 5.84 (2H, s, 2×OCH); 6.44
(1H, br s, 5-H); 6.49 (1H, d, J=8.1, 8-H); 6.60 (1H, dd,
J=8.1 and 1.2, 7-H). 13C NMR (CDCl3, 75 MHz): l
20.3; 115.8; 116.8; 124.3; 126.6; 126.8; 134.0; 140.3; 142.2.
40. Topolski, M. J. Org. Chem. 1995, 60, 5588–5594.
41. Hurst, D. T. In Second Supplements to the 2nd Edition of
Rodd’s Chemistry of Carbon Compounds, Vol IV: Hetero-
cyclic Compounds, Pt A: Three, Four and Five Membered
Monoheterocyclic Compounds; Sainsbury, M., Ed.
Furans, benzofurans, isobenzofurans, and their reduced
forms; Elsevier Science: Amsterdam, 1997; pp. 283–335.
42. On the day of submission of this manuscript we became
aware of a related, recent communication by the De
Kimpe group that describes the synthesis of a range of
substituted coumarins. The key step described in this
paper is the RCM of an isomerized 1-propenylbenzene
with an a,b-unsaturated ester to afford the coumarin
skeleton: Nguyen Van, T.; Debenedetti, S.; De Kimpe, N.
Tetrahedron Lett. 2003, 44, 4199–4201.
Chem. 2001, 66, 954–961.
26. Billeret, D.; Blondeau, D.; Sliwa, H. Synthesis 1993,
881–884.
27. The NMR spectroscopic data for known compounds
synthesized on an NMR tube scale were compared to
their literature data and gave excellent comparisons.
After the reaction was deemed complete by 1H NMR
spectroscopy, unsaturated gases were allowed to diffuse
from the solvent before final 1H and 13C NMR spec-
troscopy was performed to confirm the product structure.
Where necessary the solvent was replaced with CDCl3 to
facilitate comparison with literature data.
28. Schweizer, E. E.; Meeder-Nycz, D. In Heterocyclic Com-
pounds: Chromenes, Chromanones and Chromones; Ellis,
G. P., Ed. 2H- and 4H-1-Benzopyrans; John Wiley &
Sons: New York, 1977; pp. 11–139.
29. Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63,
864–866.
30. Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda,
A. H. J. Am. Chem. Soc. 1997, 119, 1488–1489.