Lithium benzocyclobuteneoxide as a precursor of a vinylogous enolate: Solvent-controlled synthesis of highly functionalized seven-membered benzocarbocycles

Article abstract of DOI:10.1002/anie.200501468

(Chemical Equation Presented) The reaction of alkynyl Fischer carbene complexes with the ortho-quinodimethane obtained from lithium benzocyclobuteneoxide leads to the preparation of highly functionalized seven-membered benzocarbocycles (see scheme). The p

Full text of DOI:10.1002/anie.200501468

Angewandte
Chemie
metric bistrialkylsilyloxy oQDMs, readily generated by
thermal ring opening of benzocyclobutenes, with alkynyl
FCCs follows a tandem [4+2] cycloaddition/cyclopentannu-
lation sequence that leads to benzo[b]fluorenes.[3] Choy and
Yang have pointed out that the ring opening of metalated
benzocyclobuteneoxides takes place at temperatures as low as
À258C, thus confirming that such a process is favored by the
presence of electron-donating groups on the cyclobutene
ring.[4] On the other hand, functionalized seven-membered
benzocarbocycles are both important synthetic intermediates
and key structural elements in various natural products and/or
pharmacologically active compounds, such as terpenes,
namely, (À)-presphaerene[5] and barbatusol;[6] alkaloids, for
example, dragmacidin E;[7] (À)-colchicine, an antitumour
agent;[8] nortriptyline and amitriptyline, which have antide-
pressant activities;[9] and hamigeran C, which is cytotoxic,[10]
among others. We describe herein the preliminary results of
the reaction of alkynyl FCCs with oQDM 1 prepared by Choy
and Yang, thus leading to the preparation of highly function-
alized seven-membered benzocarbocycles which have not
been previously accessed from FCCs.
In our initial experiment (Scheme 1), benzocyclobutenol 2
was deprotonated with nBuLi at À788C in THF and the
reaction mixture was allowed to reach À258C to permit the
formation of oQDM 1; subsequently, chromium FCC 3 was
added, and the reaction was monitored by TLC. However,
rather than the expected [4+2] cycloadduct 5 or benzo[b]-
fluorene 6, two benzoheptacarbocycles[11] 7a and 8a were
isolated as a mixture in low yield, among other products
(Table 1, entry 1). As far as we know, this reaction is the first
example in which oQDM 1 acts as a four-carbon synthon in a
formal [4+3] cycloaddition. We switched to the more stable
tungsten FCC 4a to find that the combined yield of the
isolated products, [4+3] cycloadducts 7a and 8a, was
improved to 65% (entry 2) under similar reaction conditions.
Other solvents (hexane, 1,2-dimethoxyethane, toluene, and
dioxane) were then examined but produced either low-
yielding mixtures of 7a and 8a or no identifiable products.
Synthetic Methods
DOI: 10.1002/anie.200501468
Lithium Benzocyclobuteneoxide as a Precursor
of a Vinylogous Enolate: Solvent-Controlled
Synthesis of Highly Functionalized
Seven-Membered Benzocarbocycles**
JosØ Barluenga,* Patricia García-García,
Manuel A. Fernµndez-Rodríguez, Enrique Aguilar, and
Isabel Merino
The role of Fischer carbene complexes (FCCs) as synthetic
intermediates in organic chemistry is today perfectly estab-
lished,[1] although new patterns of reactivity are still amena-
ble. In this context, we have initiated an exploration of the
reactivity of FCCs toward ortho-quinodimethanes[2]
(oQDMs) and reported recently that the reaction of sym-
Table 1: Reaction of 1 with alkynyl carbene complexes 3 and 4 in THF.
Entry[a]
FCC
Metal
R
7
Yield
[%][b]
8
Yield
[%][b]
[*] Prof. Dr. J. Barluenga, P. García-García,
Dr. M. A. Fernµndez-Rodríguez, Dr. E. Aguilar, Dr. I. Merino[+]
Instituto Universitario de Química Organometµlica “Enrique
Moles”, Unidad Asociada al C.S.I.C.
1
3
4a
4a
Cr
W
W
Ph
Ph
Ph
7a
7a
7a
8
49
–
8a
8a
8a
11
16
50
2
3[c]
4
5
4b
4c
W
W
7b
7c
71
67
8b
8c
14
30
Universidad de Oviedo
C/Juliµn Clavería, 8, 33006 Oviedo (Spain)
Fax: ( +34)985-103-450
E-mail: barluenga@uniovi.es
[+] NMR spectroscopic studies.
6
7
4d
4e
W
W
7d
7e
52
8d
8e
22
tBu
50[d]
5[d]
[**] We thank the Ministerio de Ciencia y Tecnología (Spain; BQU2001-
3853), the Consejería de Educación y Cultura del Principado de
Asturias (PR-01-GE-11), and the Fundación Ramón Areces for
financial support. We also appreciate the generous support given by
Merck Sharp and Dohme. P.G.-G. is indebted to the Ministerio de
Educación y Ciencia (Spain) for a MEC-FPU predoctoral fellowship.
[a] All the reactions were carried out on a 0.5-mm scale for the carbene
complex(0.033 m) with 1.5 equivalents of benzocyclobutenol (0.05m).
[b] Yields of isolated product based on the starting alkynyl carbene
complexes. [c] Reaction performed in diethyl ether. [d] Products could
not be separated; yield estimated by 1H NMR (300 MHz) spectroscopic
analysis from a fraction enriched in 7e after flash column chromatog-
raphy.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
as a vinylogous enolate rather than a 1,3-
diene, and a nucleophilic attack[13,14] on
the carbene carbon of 4 would take place
to form intermediate A. A 1,2-metal
migration,[14] promoted by the methoxy
group, would cause simultaneous ring
closure to form intermediate B. The
evolution of B could occur by two
different routes: In the first (via A), an
intramolecular
would produce the metalated benzocy-
cloheptene ketal C, which would
nucleophilic
attack
Scheme 1. Reaction of 1 with alkynyl carbene complexes.
account for the formation of 8, whereas
Interestingly, the reaction led exclusively to 8a when per-
formed in diethyl ether (entry 3). Such a strong solvent
effect[12] prompted us to consider the possibility of increasing
the yield through additives or by variation of the counterion.
However, none of the following approaches led to improved
results: the addition of different coordinating reagents
(N,N,N’,N’’,N’’’-pentamethyldiethylenetriamine (PMDTA),
[12]crown-4, N,N’-dimethyl-N,N’-propyleneurea (DMPU)),
the use of different bases (potassium hexamethyldisilazane
(KHMDS), NaHMDS, EtMgBr), and transmetalation strat-
egies (BuLi/ZnCl2) in both diethyl ether or THF.
Considering that at this point we had already created
conditions that allowed for the selective formation of two
differently functionalized benzoheptacarbocycles, we next
tried to expand the scope of such transformations by
examining of the nature of the substituents of the carbene
complex. Thus, carbene complexes 4b–e were treated with 1
in THF to obtain moderate to good yields of benzocyclohep-
tenones 7 (Table 1, entries 4–7), which were accompanied by
small amounts of benzocycloheptene ketals 8 that could be
readily separated by flash column chromatography. The best
yields were achieved when the R group was a para-substituted
aromatic moiety (entries 4 and 5), although the reaction also
took place selectively for alkenyl- and alkyl-sub-
stituted alkynyl FCCs 4d,e (entries 6 and 7).
in the second (via B), an intramolecular acid/base reaction
would generate the metalated intermediate D, thus leading to
E through a 1,5-hydrogen shift and finally to 7.
Table 2: Reaction of 1 with tungsten alkynyl carbene complexes 4 in
Et2O.
Entry[a]
FCC
4a
R
8
Yield [%][b]
70
1[c]
Ph
8a
8b
2
4b
56[d]
3
4
4c
4d
8c
8d
86
55[d]
5
6
7
4e
4 f
4g
tBu
nBu
TMS
8e
8 f
8g
50[e]
25[d]
38[e]
[a] All the reactions were carried out on a 0.5-mm scale for the carbene
complex(0.033 m) with 1.5 equivalents of benzocyclobutenol (0.05m),
unless otherwise stated. [b] Yields of isolated product based on the
starting alkynyl carbene complexes 4. [c] Reaction carried out with
5 equivalents of benzocyclobutenol (0.33m). [d] It was necessary to
reach room temperature for the reaction to proceed. [e] It was necessary
to reach refluxfor the reaction to proceed. TMS =trimethylsilyl.
On the other hand, benzocycloheptene ketals 8
were obtained as the unique reaction products, as
expected, when carbene complexes 4a–g were
treated with 1 in diethyl ether (Table 2; see also
Table 1, entry 3). This reaction was much slower
and usually required reaching either room temper-
ature (Table 2, entries 2, 4, and 6) or reflux
(entries 5 and 7) to proceed. Again, para-substi-
tuted alkynylaryl carbene complexes gave the best
yields (entries 2 and 3). These reaction conditions
tolerate alkenyl (entry 4), alkyl (entries 5 and 6),
and silyl (entry 7) groups as substituents in the
alkynyl FCC. We also observed that the yield may
be improved by performing the reaction at a higher
concentration with a higher excess of benzocyclo-
butenol (Table 2, entry 1 versus Table 1, entry 3).
As a basis for the mechanism, we propose that
after the initial deprotonation of benzocyclobute-
nol 2 at À788C, the resulting lithium benzocyclo-
butenoxide opens to 1 by warming to À258C
Scheme 2. Proposed mechanism for the formation of seven-membered benzocarbo-
(Scheme 2). Subsequently, oQDM 1 would behave cycles 7 and 8.
5876
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Our preliminary results into the reactivity of benzocyclo-
heptene ketals 8 indicate that it is possible to break the
heteroatom bridge of 8 by treatment with nBuLi or tBuLi to
form benzocycloheptadienols 9 in good to excellent yields
(Scheme 3); therefore, this breakage acts as a direct entry to a
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Scheme 3. Chemical transformations of benzocycloheptene ketals 8. IPy2BF4 =bis(pyridine)-
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(Ed.: G. Bertrand), Marcel Dekker, New York, 2002; l) F.
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[16]
with IPy2BF4
to give 10 in 61% yield. This apparently
simple compound has now been prepared for the first time;[17]
thus, by using this approach the difficulties that derived from
both the electronic nature and the relative position of its
substituents have been overcome. Naphthyl aldehyde 10
could be iodinated with IPy2BF4 in acidic medium at the
C4 position of the naphthalene skeleton to form 11 in 72%
yield (Scheme 3), thus expanding the possibilities for further
transformations.
In summary, we have established a new and direct route to
seven-membered functionalized benzocarbocycles from tung-
sten alkynyl FCCs. In this transformation, oQDM 1 prepared
by Choy and Yang behaves as a vinylogous enolate which acts
for the first time as a four-carbon component in a formal
[4+3] cycloaddition. The outcome of the reaction is solvent
controlled: selective formation of benzocycloheptenones 7
can be achieved in THF, whereas exclusive synthesis of
benzocycloheptene ketals 8 occurs in diethyl ether. The latter
compounds can be readily transformed in benzocyclohepta-
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[11] The identity of all the new compounds was ascertained
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COSY, HMQC, HMBC, and NOESY for selected compounds
(see the Supporting Information); an X-Ray structure elucida-
tion for 8a was also obtained: P. García-García, F. Andina, M. A.
Fernµndez-Rodríguez, E. Aguilar, in preparation.
Received: April 28, 2005
Keywords: carbene ligands · carbocycles · cycloaddition ·
enolates · solvent effects
[12] Solvent-controlled processes that involve FCCs in the synthesis
of five-membered carbocycles have been recently highlighted:
.
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5877

Communications
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5878
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Angew. Chem. Int. Ed. 2005, 44, 5875 –5878