Ruthenium(II)-catalyzed cyclization of oxabenzonorbornenes with propargylic alcohols: Formation of isochromenes

Article abstract of DOI:10.1002/ejoc.200600836

The ruthenium-catalyzed cyclization of a propargylic alcohol with an oxabenzonorbornene in methanol leads to an unanticipated isochromene framework. The catalytic cycle to form this product is believed to go through an oxidative cyclization of the two uns

Full text of DOI:10.1002/ejoc.200600836

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600836
Ruthenium(II)-Catalyzed Cyclization of Oxabenzonorbornenes with
Propargylic Alcohols: Formation of Isochromenes
[a]
[a]
Karine Villeneuve and William Tam*
Keywords: Ruthenium / Catalysis / Cyclization / Isochromene / Oxabenzonorbornenes
The ruthenium-catalyzed cyclization of a propargylic alcohol
with an oxabenzonorbornene in methanol leads to an unan-
ticipated isochromene framework. The catalytic cycle to form
this product is believed to go through an oxidative cyclization
of the two unsaturated partners with the ruthenium catalyst,
followed by β-hydride elimination, tautomerization and
hydroruthenation. The ruthenacyclobutane thus obtained
further undergoes [2+2] cycloreversion to form a ruthenium–
carbene intermediate that atypically rearranges via a [1,3]-
alkoxide shift and finally reductively eliminates to produce
the desired compound.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
thenium-catalyzed reactions involving oxabenzonorborn-
enes 2, and observed that depending on the reaction con-
[
9]
The utilization of Cp*Ru(COD)Cl (1a) (Cp* = pentameth- ditions, several products could be obtained (Scheme 1).
ylcyclopentadienyl; COD = 1,5-cyclooctadiene) in C–C When the alkene 2a is treated with Cp*Ru(COD)Cl, isom-
bond formation has considerably increased over the last few erization to the corresponding naphthalene oxide (3) is ob-
[
1,2]
The presence of the labile COD ligand offers a served.[9b] In the presence of an alkyne, Ru-catalyzed [2+2]
years.
4-electron complex, which is readily available for oxidative cycloaddition usually occurs as the only pathway,
[
6a–6e]
1
, but
cyclization with two unsaturated moieties. This is the case when the alkyne is a secondary propargylic alcohol such
in several ruthenium-catalyzed reactions such as cyclo- as 4a, the cyclopropane 6 is often obtained as the major
[
3]
[4]
[9a]
trimerization, enyne cyclization, formation of 1,2,3-tri- product.
[
5]
[6]
azole and [2+2] cycloaddition. On the other hand, 1a is
When performing the reaction in methanol, we found the
also known to form ruthenium carbenes with diazo- formation of a new isochromene product 7a (Scheme 2).[
10]
[
7]
alkanes and to be a useful precatalyst for allylation reac- Isochromenes are a class of compounds that exhibit diverse
tions. We have recently examined different aspects of ru- biological activities,
[
8]
[11]
and the interest for their synthesis
Scheme 1. Different products generated by ruthenium-catalyzed reactions involving oxabenzonorbornenes.
[
a] Guelph-Waterloo Centre for Graduate Work in Chemistry and
Biochemistry, Department of Chemistry, University of Guelph,
Guelph, Ontario, N1G 2W1, Canada
has recently exploded.[12,13] In this paper, we wish to reveal
how this unprecedented Ru-catalyzed construction of iso-
chromene may occur. Although yields are moderate in some
cases, this method allows the use of readily available start-
ing materials for the construction of the synthetically useful
Fax: +1-519-766-1499
E-mail: wtam@uoguelph.ca
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2006, 5449–5453
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5449

K. Villeneuve, W. Tam
SHORT COMMUNICATION
isochromene skeleton. These results also provide new in- Table 1. Scope of the reaction (see Scheme 3).
sight about the reactivity of Cp*Ru(COD)Cl and ruthena-
cyclobutane intermediates.
Scheme 2. Preparation of isochromene 7a from a Ru-catalyzed cyc-
lization of 2a with 4a.
Results and Discussion
Table 1 presents several alkyne and alkene partners that
were subjected to the optimal reaction conditions with the
precatalyst 1a [Cp*Ru(COD)Cl (5 mol-%)/MeOH/60 °C].
We first turned our attention to different groups at the pro-
pargylic position of the acetylene moiety, and found that
the steric demand of this group greatly influences the yield
of isochromene (Entries 1–4), Scheme 3 and Table 1. When
the alcohol side of the alkyne becomes too bulky, such as
in the acetylene 4c, the formation of the [2+2] cycloadduct
predominates (Entry 3). However, when the tert-butyl
group is installed at the homopropagylic position (4d, Entry
4), this seems to benefit the formation of the isochromene,
and product 7d was obtained in 70% yield. As for the olefin
moiety, other symmetrical oxabenzonorbornenes (2b and
2c) were found to display reactivity comparable to 2a (En-
tries 5 and 6). Unsymmetrical alkenes were also tested, and
the presence of a polar group at the bridge junction such
as methyl ester (2d, Entry 7) or methyl ketone (2e, Entry 8)
appears to favor the sole formation of the isochromenes 7g
and 7h, respectively. Hence, the presence on the olefin of a
group capable of coordinating to the Ru metal seems to
dictate the regiochemistry, but also works synergistically
with the propargylic alcohol to yield exclusively the isochro-
mene product. The alkene 2f, bearing two potentially reac-
tive double bonds, also underwent cyclization reaction (En-
try 9). Although non-strained alkenes are known to un-
dergo Ru-catalyzed Alder-ene reaction with propargylic
[
14]
alcohols,
we were delighted to only isolate the highly
Scheme 3. Synthesis of some isochromenes (see Table 1).
450
5
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II
Ru -Catalyzed Formation of Isochromenes
SHORT COMMUNICATION
functionalized isochromene 7i in 74% yield. Conversely, al- clization, β-hydride elimination of the ruthenacycle 9 would
kene 2g lacking the aromatic ring, did not provide the re- afford the ruthenium hydride 10 (Path B). Alternatively, re-
arranged product but rather the cyclopropane 8 (Scheme 4). ductive elimination of 9 would produce the [2+2] cycload-
Thus, the strain in the alkene moiety might play an impor- duct 5a (Path A). Hydroruthenation of the intermediate 10
tant role in the formation of the isochromene over the cy- would generate the ruthenacyclobutane 11, which is be-
clopropane product.
lieved to be the second key intermediate in this catalytic
pathway, from which the second reaction competition
would arise. If 11 reductively eliminates, the cyclopropane
6a would be obtained (Path C). In contrast, [2+2] cyclore-
version of 11, another important reactivity pattern of ru-
thenacyclobutanes, would provide the Ru carbene 12 (Path
D). The Ru intermediate 12 is then proposed to rearrange
to 13 through an atypical 1,3-migration of the alkoxyl
group and finally reductively eliminate to produce the
[
17]
isochromene 7a.
To verify that the formation of the isochromene 7a is
related to the generation of the cyclopropane 6a, the reac-
tion was performed with the acetylene 4a-d bearing a deute-
rium at the propargylic position (Scheme 6). The deuterium
was found on the carbon atom adjacent to the ketone func-
Scheme 4. Ru-catalyzed cyclopropanation of alkene 2g with 4a.
Complex 1a has been postulated by Mitsudo and co- tionality, as in cyclopropane 6a-d. A significant qualitative
workers to form a neutral [Cp*RuCl] species for ruthenium- isotopic effect was also observed as longer reaction time
catalyzed [2+2] cycloaddition.[
6f,6g]
On the other hand, it is was required, and the 5a/6a/7a ratio changed from 20:6:74
believed that the cationic ruthenium species is formed in with 4a to 41:10:49 with 4a-d. This indicates that the ease
[
15]
MeOH.
When the cationic complex [Cp*Ru(CH CN) ]- of breaking the propargylic C–H bond is a determinant fac-
3 3
PF was utilized in THF with 2a and 4a, the isochromene tor in the formation of 7a, which is very comparable to
6
7
a was obtained as the major product (5a/6a/7a, 20:25:55), what we found in our previous study of the formation of 6a
+
[16]
[9a]
suggesting that [Cp*Ru] is the active species.
(in THF, 5a/6a, 31:69 with 4a and 54:46 with 4a-d).
A mechanistic hypothesis accounting for the generation
Utilizing the same precatalyst Cp*Ru(COD)Cl (1a),
of isochromene is pictured in Scheme 5. After oxidative cy- Mori and co-workers recently trapped a similar Ru car-
Scheme 5. Proposed mechanism for the formation of 7a.
Eur. J. Org. Chem. 2006, 5449–5453
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5451

K. Villeneuve, W. Tam
SHORT COMMUNICATION
Scheme 6. Deuterium labeling.
bene.[4b] So far, all our attempts to trap the intermediate 12 rials in mild reaction conditions. The catalytic cycle that
have failed. However, Dixneuf and co-workers have re- leads to this product is believed to implicate an oxidative
ported the generation of the ruthenium carbene complex by cyclization of the two unsaturated partners with the ruthe-
reacting 1a with ethyl diazoacetate.[ On the basis of this nium catalyst, followed by a β-hydride elimination, tauto-
work, if one could react 2a with a similar Ru carbene ob- merization and hydroruthenation. The ruthenacyclobutane
tained from [Cp*Ru(CH CN) ]PF (1b) and ethyl diazoace- obtained further undergoes [2+2] cycloreversion to form a
7]
3
3
6
ate, the related ruthenacycle 14 would be formed (Scheme 7) Ru-carbene intermediate that uncommonly rearranges
and the proposed formation of isochromene 7a from the through a [1,3]-alkoxide shift and finally reductively elimin-
ruthenacyclobutane intermediate 11 (Scheme 5) could be ates to produce the desired compound. Further investiga-
tested. Indeed, we were pleased to observe that treating 2a tion of the reaction mechanism and the factors influencing
with ethyl diazoacetate in the presence of 1b produced the the product distribution are currently in progress.
isochromene 15. Such Ru carbene reactivity is very different
from what is usually observed.[18] In addition, only the cy-
clopropane products 16 and 17 were formed when sub-
jecting 2g to the same reaction conditions (Scheme 7).
Experimental Section
Representative Procedure (Isochromene 7a): A mixture of alkene 2a
These results strongly support our mechanistic hypothesis (204.9 mg, 1.421 mmol), propargylic alcohol 4a (180.0 mg,
and are also in agreement with the trend of reactivity of 1.266 mmol) and MeOH (1.6 mL) in an oven-dried vial was added
these two alkenes (entry 1, Table 1 and Scheme 4).
by a cannula to an oven-dried screw-cap vial containing Cp*Ru-
COD)Cl (weighed out from a dry box, 17.2 mg, 0.0453 mmol) un-
(
der nitrogen. The reaction mixture was stirred at 60 °C for 1 h.
The solvent was evaporated and the crude product was purified by
column chromatography (gradient EtOAc/hexanes, 1:19 to 1:4) to
provide 7a (181.2 mg, 0.6330 mmol, 50%).
Supporting Information (see also the footnote on the first page of
this article): Experimental and spectroscopic details.
Acknowledgments
This work was supported by NSERC(Canada). K. V. thanks
NSERC for a posgraduate scholarship (CGS-D2).
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Conclusions
[
[
To conclude, we have disclosed an unprecedented cat-
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pargylic alcohol and an oxabenzonorbornene. This strategy
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II
Ru -Catalyzed Formation of Isochromenes
SHORT COMMUNICATION
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Received: September 25, 2006
Published Online: November 3, 2006
[
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