Competitive pathways in the reaction of lithium oxy-ortho-quinodimethanes and fischer alkoxy alkynyl carbene complexes: Synthesis of highly functionalised seven-membered benzocarbocycles

Article abstract of DOI:10.1002/chem.201002092

Up to four different outcomes have been found for the reaction between 1-oxy-ortho-quinodimethanes (oQDMs) and alkoxy alkynyl Fischer carbene complexes (FCCs). The product formed depends on the structure of both reagents and on the reaction solvent. The pathways can be topologically classified as a [4C+2C], a [3(2C+O)+3C], and two different [4C+3C] processes and, in all these sequences, 1-oxy-oQDMs behave as enolates or as vinylogous enolates. The reaction of Choy and Yang's unsubstituted oQDM 1 with tungsten alkynyl FCCs is solvent controlled; thus, selective formation of benzocycloheptenones can be achieved in THF, whereas exclusive synthesis of benzocycloheptene ketals is reached in diethyl ether. On the other hand, THF is the solvent of choice to form benzocycloheptene ketals when an alkyl or aryl group is placed at position 1 of the oQDM in its reaction with tungsten carbene complexes; however, a pyranylidene carbene complex is formed when a chromium carbene complex is used. Alternatively, the presence of bulky alkoxy groups in the FCC component favours a Diels-Alder aromatisation sequence, which leads to 1-naphthyl FCCs. Furthermore, the isolation and the characterisation of several deuterated compounds by labelling experiments have provided some insight into the reaction pathways, and mechanisms consistent with those findings have been established and several reaction intermediates have been identified.

Full text of DOI:10.1002/chem.201002092

DOI: 10.1002/chem.201002092
Competitive Pathways in the Reaction of Lithium Oxy-ortho-
quinodimethanes and Fischer Alkoxy Alkynyl Carbene Complexes: Synthesis
of Highly Functionalised Seven-Membered Benzocarbocycles
Patricia Garcꢀa-Garcꢀa, Carlos Novillo, Manuel A. Fernꢁndez-Rodrꢀguez, and
Enrique Aguilar*[a]
Dedicated to our mentor, Professor J. Barluenga, on the occasion of his 70th birthday
Abstract: Up to four different out-
comes have been found for the reac-
tion between 1-oxy-ortho-quinodime-
thanes (oQDMs) and alkoxy alkynyl
Fischer carbene complexes (FCCs).
The product formed depends on the
structure of both reagents and on the
reaction solvent. The pathways can be
topologically classified as a [4C+2C],
FCCs is solvent controlled; thus, selec-
tive formation of benzocyclohepte-
nones can be achieved in THF, whereas
exclusive synthesis of benzocyclohep-
tene ketals is reached in diethyl ether.
On the other hand, THF is the solvent
of choice to form benzocycloheptene
ketals when an alkyl or aryl group is
placed at position 1 of the oQDM in its
reaction with tungsten carbene com-
plexes; however, a pyranylidene car-
bene complex is formed when a chro-
mium carbene complex is used. Alter-
natively, the presence of bulky alkoxy
groups in the FCC component favours
a Diels–Alder aromatisation sequence,
which leads to 1-naphthyl FCCs. Fur-
thermore, the isolation and the charac-
terisation of several deuterated com-
pounds by labelling experiments have
provided some insight into the reaction
pathways, and mechanisms consistent
with those findings have been estab-
lished and several reaction intermedi-
ates have been identified.
a [3ACHTUNGTRENNUNG(2C+O)+3C], and two different
[4C+3C] processes and, in all these se-
quences, 1-oxy-oQDMs behave as eno-
lates or as vinylogous enolates. The re-
action of Choy and Yangꢀs unsubstitut-
ed oQDM 1 with tungsten alkynyl
Keywords: carbenes · carbocycles ·
cycloaddition
tungsten
· solvent effects ·
Introduction
also offer either similar or complementary modes of reactiv-
ity. In this sense, we have initiated an exploration of the re-
activity of FCCs against ortho-quinodimethanes (oQDMs).
These highly reactive intermediates can be generated in situ
following different routes, with thermal ring opening of ben-
zocyclobutenes being the most straightforward.[3] Although
very high temperatures are usually required for the opening,
this process is known to be favoured by the presence of
electron-donating groups in the cyclobutene ring
(Scheme 1),[3,4] thus allowing the formation of oQDMS
under mild conditions compatible with FCCs. In this regard,
we have first shown that the reaction of symmetric bis-trial-
kylsilyloxy oQDMs with alkoxy arylalkynyl FCCs follows a
tandem [4+2]-cycloaddition–cyclopentannulation sequence
leading to benzo[b]fluorene derivatives (Scheme 2).[5]
Even though we are now deeply submerged in an age of cat-
alysis,[1] the role of Fischer carbene complexes (FCCs) as
stoichiometric synthetic intermediates in organic chemistry
remains a valuable tool,[2] because they provide a variety of
reactivity patterns that are not amenable for alternative cat-
alytic reagents. This fact is especially relevant in the case of
alkoxy alkynyl FCCs of chromium and tungsten, which may
[a] Dr. P. Garcꢁa-Garcꢁa, C. Novillo, Dr. M. A. Fernꢂndez-Rodrꢁguez,
Dr. E. Aguilar
Instituto Universitario de Quꢁmica Organometꢂlica
“Enrique Moles”
Universidad de Oviedo
C/Juliꢂn Claverꢁa, 8, 33006
Oviedo, Asturias (Spain)
Moreover, Choy and Yang have reported that, for meta-
lated benzocyclobuteneoxides, the ring opening takes place
at temperatures as low as À258C and the resulting electron-
rich dienes have been employed in Diels–Alder reactions
with a variety of electron-deficient dienophiles.[4] Taking ad-
Fax : (+34)985-103-446
E-mail: eah@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002092.
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FULL PAPER
as a formal [4C+3C] process in terms of skeletal analysis.[7,8]
Interestingly, the benzoheptacarbocycle skeleton, as a key
structural element, is present in important synthetic inter-
mediates and in various natural products and/or pharmaco-
logically active compounds such as terpenes (i.e., (À)-pre-
sphaerene[9] (2), barbatusol[10] (3)), alkaloids (dragmacidin E
(4)),[11] (À)-colchicine (5; an anti-tumour agent),[12] nortrip-
tyline (6) and amitriptyline (7) (anti-depressant activity)[13]
or hamigeran C (8; cytotoxic)[14] among others. Therefore,
Scheme 1. Effect of the nature of the benzocyclobutene substituent in
thermal o-QDM generation.
Scheme 2. Synthesis of benzo[b]fluorene derivatives by reaction of sym-
metric bis-trialkylsilyloxy oQDMs with alkoxy arylalkynyl FCCs. TMS=
trimethylsilyl, TBS=tert-butyldimethylsilyl.
vantage of the ease of lithium benzocyclobuteneoxide ring
opening at low temperature, we have recently reported that
the reaction of alkoxy alkynyl FCCs with oQDM 1 leads to
the preparation of highly functionalised seven-membered
benzocarbocycles;[6] this transformation can be considered
we decided to carefully analyse such reactions and, in this
manuscript, we present a full account regarding its scope
and limitations. Thus, the reaction of oQDM 1 and 1-substi-
tuted oQDM 9 against alkoxy alkynyl FCCs of chromium 10
and tungsten 11 and 12, has been explored, and we have
found that up to four different reaction pathways may take
place, depending on the structure of both reagents (oQDM
and FCC) and on the reaction solvent. Such transformations
Abstract in Spanish: Las reacciones entre 1-oxi-orto-quinodi-
metanos (oQDMs) y complejos alcoxi alquinil carbeno de
Fischer (FCCs) pueden seguir cuatro posibles rutas diferen-
tes, dependiendo de la estructura de los reactivos y del disol-
vente empleado. Topolꢀgicamente, estos procesos se pueden
can be classified as a [4C+2C], a [3ACTHNUTRGNEUNG(2C+O)+3C], and two
clasificar como [4C+2C], [3 ACTHNUGRTNEUNG(2C+O)+3C], y dos [4C+3C]
different [4C+3C] processes, from a topological point of
view. In addition, labelling experiments have also been per-
formed to gain some insight into the reaction pathways;
consequently, mechanisms accounting for the different trans-
formations are proposed below, including a modification of
our originally reported mechanism.[6]
diferentes y, en todas estas secuencias, los 1-oxi-oQDMs se
comportan como enolatos o como enolatos vinꢁlogos. Las
reacciones entre el oQDM de Choy y Yang no-sustituido 1 y
alquinil FCCs de volframio estꢂn controladas por el disolven-
te de las mismas; asꢁ, la formaciꢀn de benzocicloheptenonas
tiene lugar selectivamente en THF mientras que, en dietil ꢃter,
se obtienen benzocicloheptenoacetales de forma exclusiva.
Por otra parte, cuando en la posiciꢀn 1 del oQDM estꢂ situa-
do un grupo alquilo o arilo, la reacciꢀn con complejos carbe-
no de volframio en THF permite obtener benzociclohepte-
noacetales mientras que cuando se emplea un complejo car-
beno de cromo se accede a un complejo piranilideno carbe-
no. Alternativamente, la presencia de grupos alcoxilo volumi-
nosos en el FCC favorece una secuencia Diels–Alder
aromatizaciꢀn que conduce a 1-naftil FCCs. Finalmente, ex-
perimentos de marcaje isotꢀpico han conducido al aislamien-
to y a la caracterizaciꢀn de varios compuestos deuterados,
proporcionando valiosa informaciꢀn acerca de los posibles
mecanismos lo que, a su vez, ha permitido la identificaciꢀn
de varios intermedios y la propuesta de mecanismos de reac-
ciꢀn consistentes con los hechos observados.
Results and Discussion
Optimisation of the reaction conditions and scope of the re-
action: A set of preliminary experiments were carried out
under conditions similar to those reported by Choy and
Yang, which involved mixing the lithium benzocyclobutene-
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565

E. Aguilar et al.
oxide and the dienophile at low temperature, in different
solvents. Thus, benzocyclobutenol 13 was deprotonated with
nBuLi in THF at À788C; chromium FCC 10a was added at
À608C, and the reaction mixture was allowed to reach room
temperature before silica gel was added. FCC 14 was isolat-
ed in 60% yield, not surprisingly, as a result of alkoxide 1,4-
addition to FCC 10a (Scheme 3).[15] On the other hand,
Scheme 4. Reaction of o-QDM 1 with FCC 10a: unexpected outcome
and formation of benzocycloheptene derivatives.
Table 1. Reaction of oQDM 1 with alkynyl carbene complexes 10 and 11
in THF.
Scheme 3. Solvent-dependent addition of lithium benzocyclobuteneoxide
to FCC 10a. DME=1,2-dimethoxyethane.
FCC 15 was isolated, also in 60% yield, when the whole de-
protonation–FCC addition–SiO2 quenching sequence was
carried out at À508C in DME;[16] interestingly, FCC 15 is
formed from 1,2-addition of alkoxide to the initial carbene
complex, which has not been previously observed.[15] These
results confirm that benzocyclobuteneoxide does not open
to form oQDM 1 at or below À508C, and indicate that
there is a remarkable solvent effect in the addition of the
alkoxide to FCC 10a.
Entry[a] FCC Metal R1
18
Yield
[%][b]
19
Yield
[%][b]
1
10a Cr
Ph
Ph
Ph
18a
18a 49
18a
8
19a 11
19a 16
19a 50
2
11a
11a
W
W
3[c]
–
4
5
11b
11c
W
W
18b 71
18c 67
19b 14
19c 30
Considering these results, we performed a series of ex-
periments at several temperatures and with different sol-
vents, allowing the formation of the dienic system prior to
addition of the alkynyl FCC. In one of the most promising
tests, benzocyclobutenol 13 was deprotonated with nBuLi at
À788C in THF and the reaction mixture was allowed to
reach À258C to permit the formation of oQDM 1; chromi-
um FCC 10a was added and the evolution of the reaction
was monitored by TLC. However, instead of the expected
[4+2] cycloaddition product 16 or benzo[b]fluorene 17 (see
also Scheme 2), we isolated a mixture of two benzoheptacar-
bocycles 18a and 19a in low yield (Scheme 4 and Table 1,
entry 1), among other low-yielding products (FCCs 14 and
15).
6
7
11d
11e
W
W
18d 43
18e 52
19d
–
19e 22
8
9
11 f
11g
W
W
18 f 35
19 f 22
tBu
18g 50[d]
19g 5[d]
[a] All the reactions were carried out on a 0.5 mmol scale of carbene
complex (0.033m) with 1.5 equiv of benzocyclobutenol (0.05m). [b] Isolat-
ed yields based on the starting alkynyl carbene complexes. [c] Reaction
performed in diethyl ether. [d] Products could not be separated; yield es-
timated by 1H NMR spectroscopic analysis (300 MHz) of a fraction en-
riched in 18g after flash column chromatography.
The identities of all new compounds were unequivocally
ascertained by NMR spectroscopic experiments, including
COSY, HSQC, HMBC and NOESY for selected com-
pounds. For instance, correlations between the signal at d=
4.27 ppm, which corresponds to the proton linked to the
carbon atom with the methoxy group, and both CH2 signals
(d=3.22 and 3.44 ppm) and the olefin proton (d=
6.82 ppm), were observed in the COSY spectrum of com-
pound 18a, which was crucial to establish the proposed
structure. Moreover, long-range correlations in the HMBC
spectrum, for example, between the carbonyl carbon (d=
195 ppm) and the olefin proton (d=6.82 ppm), were also in
full agreement with the proposed structure. Furthermore, an
X-ray structural elucidation for 19a revealed that two
planes, with a dihedral angle of 108.518, contain all non-hy-
drogen atoms of the molecule except those of the methoxy
group and the oxygen on the bridge.[17]
Taking into account that this is the first example in which
oQDM (1) acts as a four-carbon synthon in a formal [4+3]
cycloaddition, we decided to optimise the reaction condi-
tions. To this end, we switched to the more stable tungsten
FCC (11a) which, under similar reaction conditions, led to
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Functionalised Benzocarbocycles
FULL PAPER
Table 2. Reaction of oQDM 1 with tungsten alkynyl carbene complexes
11 in Et2O.
an improved 65% isolated combined yield of both [4+3] cy-
cloadducts 18a and 19a (Table 1, entry 2). Other solvents
(hexane, 1,2-dimethoxyethane, toluene and dioxane) were
examined, but they produced either low yielding mixtures of
18a and 19a, or no identifiable products. Interestingly, com-
pound 19a was the only adduct detected when the reaction
was performed in diethyl ether (Table 1, entry 3). Such
strong solvent effects[18] prompted us to consider the possi-
bility of increasing the reaction yield by introducing addi-
tives or by varying the counterion; however, neither the ad-
dition of different coordinating reagents (pentamethyldi-
Entry[a]
1[c]
FCC
R1
Ph
19
Yield [%][b]
70
11a
19a
2
3
11b
11c
19b
19c
56
86
ACHTUNGTRENNUNGethylentriamine (PMDTA), [12]crown-4 ether or N,N’-dime-
thylpropyleneurea (DMPU)), nor the use of different bases
(potassium hexamethyldisilazide (KHMDS), sodium hexa-
ACHTUNGTRENNUNGmethyldisilazide (NaHMDS) or EtMgBr) or transmetalla-
tion strategies (BuLi/ZnCl2), in either diethyl ether or THF,
led to improved results.
4
11d
19d
51
55[d]
33[e]
Considering that, at this point, we had already developed
conditions that allowed for the selective formation of two
differently functionalised benzoheptacarbocycles, we then
expanded the scope of the transformations by examining the
nature of the substituents of the carbene complex. Thus, car-
bene complexes 11b–g were treated with 1 in THF to obtain
moderate to good yields of benzocycloheptenones 18
(Table 1, entries 4–9); the transformation was usually ac-
companied by the formation of small amounts of benzocy-
cloheptene ketals 19, which could usually be separated by
flash column chromatography. The best yields were achieved
when R1 was a para-substituted aromatic group (Table 1, en-
tries 4 and 5), although the reaction also took place selec-
tively for ortho-substituted aryl, alkenyl and alkyl substitut-
ed alkynyl FCCs 11d–g (Table 1, entries 6–9).
5
6
11e
11h
19e
19h
7
8
9
11g
11i
11j
tBu
nBu
TMS
19g
19i
19j
50
25
38[d]
[a] All the reactions were carried out on a 0.5 mmol scale of carbene
complex (0.033m) with 1.5 equiv of benzocyclobutenol (0.05m), unless
otherwise stated. [b] Isolated yields based on the starting alkynyl carbene
complexes 4. [c] Reaction carried out with 5 equiv of benzocyclobutenol
(0.33m). [d] It was necessary to heat the reaction to reflux to make it pro-
ceed. [e] Reaction was carried out with 3 equiv of benzocyclobutenol
(see the Supporting Information).
On the other hand, benzocycloheptene ketals 19 were ob-
tained as unique products when carbene complexes 11 were
treated with 1 in diethyl ether (Table 2), as expected (see
also Table 1, entry 3). This reaction was much slower and
usually required somewhat higher temperatures (room tem-
perature or diethyl ether reflux temperature; Table 2, en-
tries 5 and 9). Again, para-substituted aryl alkynyl carbene
complexes gave the best yields (Table 2, entries 2 and 3).
These reaction conditions tolerated ortho-substituted aryl
(Table 2, entry 4), alkenyl (entries 5 and 6), alkyl (entries 7
and 8) and silyl (entry 9) groups as substituents in the alkyn-
yl FCC. We also observed that the yield may be improved
by performing the reaction at a higher concentration and
with a larger excess of benzocyclobutenol (Table 2, entry 1
vs. Table 1, entry 3).
Scheme 5. Retrosynthetic route to 1-substitued o-quinodimethides 9.
lowed by addition of FCC 11a[19] and warming of the reac-
tion mixture to room temperature, ketal 22a was obtained
as the major product, albeit in a modest 22% yield. The
yield could be slightly improved by performing the reaction
in THF (Table 3, entry 2). It should be noted that, in the
case of substituted oQDMs 9, the formation of benzocyclo-
heptenes 18, which are obtained as major compounds when
the reaction with oQDM 1 was performed in THF, is not
possible (see mechanism below).
Attempts to optimise the reaction conditions were carried
out by varying factors such as the temperatures of the reac-
tion and during addition, the solvents, the additives (hexa-
Reaction with 1-substituted oQDMs: We then expanded the
scope of the reaction by analysing the reactivity of 1-substi-
tuted oQDMs 9. In principle, these intermediates may be ac-
cessed by direct addition of alkyl or aryl lithium compounds
to benzocyclobutenone 20 followed by ring opening of the
formed benzocyclobuteneoxide 21 (Scheme 5).
AHCTUNGTREGmNNUN ethylphosphoric triamide (HMPA), [12]crown-4, DMPU
or PMDTA), and the metal-ion exchange (Na, K, Zn or
Cu). However, further improvement in the reaction yield
was not observed under any of the conditions.
Initially, nBuLi was used as the nucleophile to react with
benzocyclobutenone. Thus, when nBuLi was added to a so-
lution of benzocyclobutenone in diethyl ether at À358C, fol-
By employing the best conditions found, the reaction was
also extended to FCC 11b (Table 3, entry 3) and to the sec-
ondary alkyl lithium reagent secBuLi (Table 3, entry 4) with
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567

E. Aguilar et al.
Table 3. Reaction of oQDM 9 with alkynyl carbene complexes 11.
Entry[a]
FCC
R1
R
22
Yield [%][b]
1[c]
2
11a
11a
Ph
Ph
nBu
nBu
22a
22a
22
32
3
11b
nBu
22b
35
4
5
6
7
11a
11a
11a
11a
Ph
Ph
Ph
Ph
secBu
tBu
Me
22c
22d
22e
22 f
31[d]
11
11
Scheme 7. Influence of steric hindrance at the carbene carbon. Synthesis
of naphthyl FCCs 26.
Ph
21
[a] All the reactions were carried out on a 1.0 mmol scale of carbene
complex (0.05m) with 1.1 equiv of benzocyclobutenone (0.055m) and
1.1 equiv of organolithium reagent. [b] Isolated yields based on the start-
ing alkynyl carbene complexes. [c] Reaction performed in diethyl ether.
[d] Isolated as a 1:1 mixture of diastereoisomers.
FCC 12b was used, naphthyl FCC 26b was formed exclu-
sively and in good yield.
These results demonstrate how fine-tuning of the steric
hindrance of the alkoxy group allows the outcome of the re-
action of lithium oxy-ortho-quinodimethanes and Fischer al-
koxyalkynyl carbene complexes to be controlled.
similar yields. However, a decrease in yield was observed
when tBuLi (Table 3, entry 5), MeLi (entry 6) or PhLi
(entry 7) were used.
Reaction mechanism: The different reaction pathways de-
picted above can be rationalised from a mechanistic point of
view. The oQDM (1 or 9), initially formed by deprotonation
of benzocyclobutenol 13 or by addition of RLi to benzocy-
clobutenone 20, can behave in distinct fashions depending
on the characteristics of both the oQDM and the FCC
(Scheme 8). The [4+2] cycloaddition-derived product, gen-
erally observed in the reaction of oQDMs with dienophiles,
is only formed when a FCC with a bulky R2 group is used.
In this case, the carbene carbon is sterically blocked and re-
mains untouched during the reaction. Otherwise, the addi-
tion of the oQDM to the carbene carbon is preferred, finally
leading to seven-membered benzoheptacarbocycles 18, 19 or
22 (see below). On the other hand, when R=CH2R’ tauto-
merisation of the oQDM to enolate B is possible. In this
case the reaction can then proceed through B, and the sub-
stituted enolate adds to the triple bond of the carbene com-
plex, which is less hindered than the carbene carbon, to gen-
erate allenoate intermediate E. The evolution of E through
a 1,3-H shift to F, followed by cyclisation, leads to pyranyli-
dene FCC 23.
In contrast, instead of a seven-membered carbocycle, py-
ACHTUNGTRENNUNG
ranylidene FCC 23 was isolated as the major product[20]
when chromium FCC 10a was employed. The best yield in
this case was obtained by using DME as solvent and by
adding the reagents at À508C (Scheme 6). The structure of
Scheme 6. Synthesis and oxidation of pyranylidene FCC 23.
pyranylidene carbene complex 23 was determined by NMR
spectroscopic analysis. Moreover, the oxidation of FCC 23
to its analogous ester 24 by air, with tetrabutylammonium
fluoride (TBAF) in DME,[21] allowed complete confirmation
of the proposed structure (Scheme 6). Topologically, this
transformation can be classified as a [3ACHTNUTRGNEUNG(2C+O)+3C] cyclo-
addition.
Moreover, the mechanism of the most synthetically useful
transformation of those described above, the formation of
seven-membered benzoheptacarbocycles, has been studied
in detail. To this end, regiospecifically deuterated benzocy-
clobutenol ([D]13) was synthesised, through reduction of
benzocyclobutenone 20 with sodium borodeuteride, and
used as a precursor of oQDM [D]1, under standard condi-
tions. The obtained results, depicted in Scheme 9, show that
conducting the reaction at reflux temperature in Et2O led to
the formation of deuterated benzocycloheptene ketal
[D]19a in 61% yield. In contrast, by conducting the reaction
in THF, a mixture of both deuterated benzoheptacarbocy-
cles [D]18a and [D]19a was obtained in slightly lower yields
Reaction with bulky FCCs: The reactivity of oQDM 1
toward FCCs with bulky alkoxy groups was then assessed.
Thus, oQDM 1 was generated from benzocyclobutenol 13
following the usual procedure, and isopropoxy-derived tung-
sten alkynyl FCC 12a was added at À258C. Once the car-
bene complex was consumed, and the usual workup and pu-
rification was followed, a mixture of benzocycloheptene
ketal 25 and naphthyl FCC 26a, coming from a formal
Diels–Alder cycloaddition (topologically, [4C+2C]), was
isolated in a combined 80% yield (Scheme 7). Moreover,
when the even more sterically hindered menthyloxy-derived
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Functionalised Benzocarbocycles
FULL PAPER
Scheme 9. Labelling experiments.
Scheme 8. Mechanistic pathways for the reaction of oQDMs with FCCs.
than in the non-deuterated, analogous process. In both
cases, benzocycloheptene ketal [D]19a was quantitatively
deuterated in position 5, whereas [D]18a was deuterated,
also quantitatively, in position 8.
Further mechanistic evidence was obtained when secBuLi
was added to benzocyclobutenone, followed by the addition
of tungsten FCC 11a under the optimised reaction condi-
tions and the final quenching was performed with deuterium
oxide (Scheme 9). Under these conditions, an 11% yield of
benzocycloheptene ketal [D]22c was isolated that had 90%
deuterium incorporation at position 7, indicating the pres-
ence of the metal at this position prior to hydrolysis.
These observations are consistent with a common mecha-
nism (Scheme 10). We propose that, after the initial depro-
tonation of benzocyclobutenol 13 at À788C (or alkyl lithium
addition to benzocyclobutenone 20), the resulting lithium
benzocyclobuteneoxide opens to give 1 (or 9) upon warming
to À258C. Subsequently, oQDM 1 (or 9) behaves as a vinyl-
ogous enolate, rather than a 1,3-diene, and nucleophilic
attack[22,23] on the carbene carbon of 11 would take place to
form intermediate C. A 1,2-metal migration,[23] promoted by
the methoxy group, would cause ring closure to form inter-
mediate D. The evolution of D could follow two different
Scheme 10. Proposed mechanism for the formation of seven-membered
benzocarbocycles 18, 19 and 22 (Li+ in intermediates 1,9 and C–I has
been omitted for clarity).
routes: in the first one (via A, Scheme 10) an intramolecular
nucleophilic attack would produce metalated benzocyclo-
heptene ketal G, which would account for the formation of
19 (or 22). On the other hand, evolution according to via B
mechanistic pathway (Scheme 10) may involve the forma-
tion of intermediate H through an intramolecular acid–base
interchange; a subsequent 1,5-hydrogen-migration would
give metalated intermediate I. Final protonation leads to the
isolated compounds 18.
To account for the formation of compounds 18, in our
previous communication we suggested that an intramolecu-
lar acid–base reaction involving the hydrogen atoms of the
CH2 moiety (Scheme 11, via B’) would generate a metalated
intermediate H’, which, via a 1,5-deuterium shift and keto–
enol tautomerisation, would lead to I’ and finally to 18
Chem. Eur. J. 2011, 17, 564 – 571
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
569

E. Aguilar et al.
Experimental Section
General synthesis of benzocyclohepte-
nones 18: nBuLi (1.6m in hexane,
1.6 equiv) was added to a solution of
benzocyclobutenol (1.5 equiv) in anhy-
drous THF (15 mL) at À788C. After
30 min, the temperature was raised to
À258C and, after a further 10–15 min
(red solution observed), the corre-
sponding tungsten FCC 11 (1 equiv,
0.5 mmol) was added in portions. The
mixture was stirred until complete dis-
appearance of the carbene complex
was observed by TLC. The solvent
was removed under reduced pressure,
and the residue was purified by flash
chromatography; the corresponding
benzocycloheptenone 18 was isolated
in the yield reported in Table 1.
Scheme 11. Initially proposed mechanism and the corrected mechanism for the formation of seven-membered
benzocarbocycles 18.
Compound 18a: Yield: 49%; yellow
oil; Rf =0.24 (hexane/AcOEt, 5:1); 1H NMR (200 MHz, CDCl3, 258C,
through a 1,5-hydrogen shift and keto–enol tautomerisation.
However, if this was the operating mechanism, deuterium
incorporation should have been found at position 9 instead
of in position 8 as observed in benzocycloheptene ketal
[D]18a, and this was not the case. Moreover, the presence
of the metal fragment in position 7 at the end of the reac-
tion, prior to hydrolysis, was confirmed by trapping a type-
TMS): d=7.81 (d, 3J
(H,H)=7.7 Hz, 1H), 6.82 (m, 1H), 4.27 (m, 1H), 3.49 (s, 3H), 3.44 (m,
1H), 3.22 ppm (app. d, 2J(H,H)=14.5 Hz, 1H); 13C NMR (CDCl3,
(H,H)=7.7 Hz, 1H), 7.53–7.34 (m, 7H), 7.30 (d, 3J-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
75 MHz, 258C): d=195.1 (s), 142.7 (d), 142.4 (s), 140.1 (s), 139.0 (s),
135.0 (s), 132.0 (d), 129.8 (d), 129.4 (d), 128.4 (d, 2 CH), 127.9 (d, 2 CH),
127.7 (d), 127. 0 (d), 77.2 (d), 56.5 (q), 39.2 ppm (t); FTIR (film): n˜ =
1772, 1975, 1597 cmÀ1; MS (FAB): m/z
(%): 265 (100) [M++H], 233 (35), 205
G
intermediate with deuterium, leading to [D]22c
(36); HRMS (FAB): m/z calcd for
C11H17O2: 265.1229 [M++H]; found:
(Scheme 9).
265.1224; elemental analysis calcd (%)
for C11H19O2 (264.32): C 81.79, H 6.10;
found: C 81.75, H 6.08.
Conclusion
General synthesis of benzocyclohep-
tene ketals 19: nBuLi (1.6m in hexane, 1.6 equiv) was added to a solution
of benzocyclobutenol (1.5 equiv) in anhydrous diethyl ether (15 mL) at
À788C. After 30 min, the temperature was raised to À258C and, after
10–15 min, carbene complex 11 (1 equiv, 0.5 mmol) was added in por-
tions. The mixture was stirred until complete disappearance of the car-
bene complex was observed by TLC. The solvent was removed under re-
duced pressure and the residue was purified by flash chromatography;
the corresponding benzocycloheptene ketal 19 was isolated in the yield
reported in Table 2.
The reaction between 1-oxy-oQDMs and alkoxy alkynyl
FCCs may result in up to four different reaction outcomes,
depending on the structure of both reagents and on the re-
action solvent. The reactions can be topologically classified
as a [4C+2C], a [3ACHTUNGTRENNUNG(2C+O)+3C], and two different [4C+
3C] processes; in all these sequences, the 1-oxy-oQDMs
behave either as enolates or as vinylogous enolates. The re-
action of Choy and Yangꢀs oQDM 1 with tungsten alkynyl
FCCs is solvent controlled; thus, new direct routes to differ-
ent types of seven-membered functionalised benzocarbocy-
cles have been established (selective formation of benzocy-
cloheptenones can be achieved in THF and exclusive synthe-
sis of benzocycloheptene ketals is accomplished in diethyl
ether). Moreover, THF is the solvent of choice to form ben-
zocycloheptene ketals when an alkyl or aryl group is present
at position 1 of the oQDM in its reaction with tungsten car-
bene complexes; however, pyranylidene carbene complexes
are formed when chromium carbene complexes are used.
On the other hand, the presence of bulky alkoxy groups in
the FCC component favours an alternative Diels–Alder
pathway.
Compound 19a: Yield: 50%; yellow solid; Rf =0.27 (hexane/AcOEt,
5:1); 1H NMR (200 MHz, CDCl3, 258C, TMS): d=7.58–7.10 (m, 9H),
6.24 (s, 1H), 5.88 (s, 1H), 3.59 (s, 3H), 3.29 (d, 2J
ACHTUNGTRENNUNG
2.93 ppm (d, 2J
ACHTUNGTRENNUNG
d=151.8 (s), 137.8 (s), 134.1 (s), 131.2 (s), 130.0 (d), 128.7 (d), 128.6 (d, 2
CH), 127.1 (d), 126.2 (d, 2 CH), 125.3 (d), 123.8 (d), 121.3 (d), 110.9 (s),
80.4 (d), 51.2 (q), 35.4 ppm (t); FTIR (film): n˜ =1190, 1009 cmÀ1; m.p.
110–1128C; MS (FAB): m/z (%): 265
(39) [M++H], 257 (74), 205 (100), 202
(80), 195 (99); HRMS (FAB): m/z
calcd for C11H17O2: 265.1229 [M++H];
found: 265.1231; elemental analysis
calcd (%) for C11H19O2 (264.32):
C
81.79, H 6.10; found C 81.74, H 6.09.
Labelling experiments have provided insights into the re-
action pathways; the isolation and characterisation of sever-
al deuterated compounds have led to the identification of
reaction intermediates and to mechanisms consistent with
those findings.
Acknowledgements
We are deeply grateful to Professor Barluenga for his constant support
and for fruitful discussions. We thank Dr. Facundo Andina for his help
with the X-ray structure of 19a. We also appreciate the financial support
570
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Chem. Eur. J. 2011, 17, 564 – 571

Functionalised Benzocarbocycles
FULL PAPER
received from the Ministerio de Ciencia y Tecnologꢁa (Spain) (grants
CTQ2004-08077-C02-01 and CTQ2007-61048, predoctoral fellowships to
P.G.-G. and C.N., and a Juan de la Cierva postdoctoral contract to
M.A.F.-R.) and Principado de Asturias (project IB08-088).
[9] a) J. Lee, J. Hong, J. Org. Chem. 2004, 69, 6433–6440; b) F. Cafieri,
P. Ciminiello, C. Santacroce, E. Fattorusso, Phytochemistry 1983, 22,
1824–1825.
[10] a) G. Majetich, Y. Zhang, T. L. Feltman, S. Duncan, Jr., Tetrahedron
Lett. 1993, 34, 445–448; b) E. R. Koft, Tetrahedron 1987, 43, 5775–
5780; c) A. Kelecom, Tetrahedron 1983, 39, 3603–3608.
[11] R. J. Capon, F. Rooney, L. M. Murray, E. Collins, A. T. R. Sim,
J. A. P. Rostas, M. S. Butler, A. R. Carroll, J. Nat. Prod. 1998, 61,
660–662.
[12] a) H.-G. Capraro, A. Brossi in The Alkaloids (Ed.: A. Brossi), Aca-
demic Press: New York, 1984, Vol. 23, pp. 1–70; b) A. Brossi, J.
Med. Chem. 1990, 33, 2311–2319; c) O. Boye, A. Brossi in The Al-
kaloids (Eds.: A. Brossi, G. A. Cordell), Academic Press: New
York, 1992, Vol. 41, pp. 125–176.
[13] M. Williams, E. A. Kovaluk, S. P. Arneric, J. Med. Chem. 1999, 42,
1481–1500.
[14] a) K. Wellington, R. Cambie, P. Rutledge, P. Bergquist, J. Nat. Prod.
2000, 63, 79–85; b) R. Cambie, A. Lai, M. Kernan, J. Nat. Prod.
1995, 58, 940–942.
[15] The addition of alcohols to alkoxy alkynyl carbene complexes of
chromium and tungsten takes place in a conjugate manner with
complete regioselectivity, see: a) A. Llebaria, J. M. Moretꢅ, S.
Ricart, J. Ros, J. M. ViÇas, R. YꢂÇez, J. Organomet. Chem. 1992,
440, 79–90; b) F. Camps, A. Llebaria, J. M. Moretꢅ, S. Ricart, J.
Ros, R. YꢂÇez, J. Organomet. Chem. 1991, 401, C17-C19.
[16] The different reaction temperature required when DME was used
instead of THF is due to the fact that DME freezes at À588C.
[17] CCDC-775753 (19a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[18] Solvent-controlled processes involving FCCs in the synthesis of five-
membered carbocycles have been recently highlighted, see: a) F.
Zaragoza Dçrwald, Angew. Chem. 2003, 115, 1372–1374; Angew.
Chem. Int. Ed. 2003, 42, 1332–1334; b) J. Barluenga, S. Lꢅpez, J.
Flꢅrez, Angew. Chem. 2003, 115, 241–243; Angew. Chem. Int. Ed.
2003, 42, 231–233.
[1] For selected recent reviews on catalysis, see: a) C. Grondal, M.
Jeanty, D. Enders, Nat. Chem. 2010, 2, 167–178; b) S. Dꢁez-Gon-
zꢂlez, N. Marion, S. P. Nolan, Chem. Rev. 2009, 109, 3612–3676;
c) G. C. Hargaden, P. J. Guiry, Chem. Rev. 2009, 109, 2505–2550;
d) A. Fꢄrstner, Chem. Soc. Rev. 2009, 38, 3208–3221; e) D. J. Gorin,
B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351–3378; f) A.
Dondoni, A. Massi, Angew. Chem. 2008, 120, 4716–4739; Angew.
Chem. Int. Ed. 2008, 47, 4638–4660; g) for a nice insight comprised
of a series of commentaries and reviews, see “Small-Molecule Catal-
ysis”: Nature 2008, 455, 303–349, edited by A. Mitchinson, J. Finkel-
stein; h) for a special issue on Organocatalysis, see: Chem. Rev.
2007, 107, 5413–5883, edited by B. List.
[2] For selected recent reviews, see: a) M. A. Fernꢂndez-Rodrꢁguez, P.
Garcꢁa-Garcꢁa, E. Aguilar, Chem. Commun. 2010, 254, 103–194;
b) K. H. Dçtz, J. Stendel, Chem. Rev. 2009, 109, 3227–3274; c) J.
Santamarꢁa, Curr. Org. Chem. 2009, 13, 31–46; d) M. L. Waters,
W. D. Wulff, Org. React. 2008, 70, 121–623; e) M. A. Sierra, I.
Fernꢂndez, F. P. Cossꢁo, Chem. Commun. 2008, 4671–4682; f) J. Bar-
luenga, M. A. Fernꢂndez-Rodrꢁguez, E. Aguilar, J. Organomet.
Chem. 2005, 690, 539–587; g) J. Barluenga, J. Santamarꢁa, M.
Tomꢂs, Chem. Rev. 2004, 104, 2259–2283; h) A. de Meijere, H.
Schirmer, M. Duestsch, Angew. Chem. 2000, 112, 4124–4162;
Angew. Chem. Int. Ed. 2000, 39, 3964–4002. For recent books, see:
i) Metal Carbenes in Organic Synthesis In Topics in Organometallic
Chemistry (Ed.: K. H. Dçtz) John Wiley & Sons, 2004, Vol. 13;
j) Carbene Chemistry: from Fleeting Intermediates to Powerful Re-
agents (Ed.: G. Bertrand) Dekker, New York, 2002; k) F. Zaragoza
Dçrwald in Metal Carbenes in Organic Synthesis, Wiley-VCH, 1999.
[3] For reviews on oQDM chemistry, see: a) G. Mehta, S. Cota, Tetrahe-
dron 2001, 57, 625–659; b) J. L. Segura, N. Martꢁn, Chem. Rev. 1999,
99, 3199–3246; c) P. Y. Michellys, H. Pellisier, M. Santelli, Org.
Prep. Proced. Int. 1996, 28, 545–608; d) T. Chou, Rev. Heteroatm.
Chem. 1993, 8, 65–104; e) N. Martꢁn, C. Seoane, M. Hanack, Org.
Prep. Proced. Int. 1991, 23, 237–272.
[19] In contrast to what was observed for oQDM 1, addition of alcohol-
ate 21 (R=Bu) to the FCC did not take place, thus allowing the ad-
dition of the FCC at low temperature.
[20] The formation of pyranylidene FCCs by reaction of alkoxy alkynyl
FCCs and 1,3-dicarbonyl compounds in the presence of substoichio-
metric amounts of KOtBu has been previously described, see:
S. L. B. Wang, W. D. Wulff, J. Am. Chem. Soc. 1990, 112, 4550–4552.
[21] J. Barluenga, F. Andina, M. A. Fernꢂndez-Rodrꢁguez, P. Garcꢁa-
Garcꢁa, I. Merino, E. Aguilar, J. Org. Chem. 2004, 69, 7352–7354.
[22] a) The nucleophilic attack of methyl ketone-derived lithium enolates
takes place at the carbene carbon of a,b-unsaturated FCCs, see: J.
Barluenga, J. Alonso, F. J. FaÇanꢂs, Angew. Chem. 2004, 116, 5626–
5629; Angew. Chem. Int. Ed. 2004, 43, 5510–5513 and references
cited therein; on the other hand, substituted lithium enolates add to
a,b-unsaturated FCCs in a Michael fashion; for an example, see:
b) I. Merino, Y. R. S. Laxmi, J. Flꢅrez, J. Barluenga, J. Ezquerra, C.
Pedregal, J. Org. Chem. 2002, 67, 648–655.
[23] 1,2-Metal migrations have been invoked in related transformations,
see: a) J. Barluenga, M. Tomꢂs, E. Rubio, J. A. Lꢅpez-Pelegrꢁn, S.
Garcꢁa-Granda, P. Pertierra, J. Am. Chem. Soc. 1996, 118, 695–696;
actually, this rearrangement could be monitored by NMR spectro-
scopic analysis, see: b) J. Barluenga, M. Tomꢂs, A. Ballesteros, J.
Santamarꢁa, R. J. Carbajo, F. Lꢅpez-Ortiz, S. Garcꢁa-Granda, P. Per-
tierra, Chem. Eur. J. 1996, 2, 88–97.
[4] W. Choy, H. Yang, J. Org. Chem. 1988, 53, 5796–5798.
[5] J. Barluenga, M. A. Fernꢂndez-Rodrꢁguez, E. Aguilar, Org. Lett.
2002, 4, 3659–3662.
[6] J. Barluenga, P. Garcꢁa-Garcꢁa, M. A. Fernꢂndez-Rodrꢁguez, E.
Aguilar, I. Merino, Angew. Chem. 2005, 117, 6025–6028; Angew.
Chem. Int. Ed. 2005, 44, 5875–5878.
[7] a) For an excellent recent review on the synthesis of natural prod-
ucts containing carbocyclic seven-membered rings in which the
[4C+3C] notation is employed, see: M. A. Battiste, P. M. Pelphrey,
D. L. Wright, Chem. Eur. J. 2006, 12, 3438–3447; b) for an interest-
ing review on polyoxygenated building blocks, with special emphasis
on [4+3] cycloadditions, see: I. V. Hartung, H. M. R. Hoffmann,
Angew. Chem. 2004, 116, 1968–1984; Angew. Chem. Int. Ed. 2004,
43, 1934–1949.
[8] We have employed a topological notation throughout this manu-
script that is closely related to that used by Battiste et al.[7a] The first
number (in italics) indicates the number of atoms in the final carbo-
or heterocyclic structure of the product that come from the oQDM
moiety; the second number (in italics) shows the number of atoms
that come from the FCC; the nature of such atoms is indicated by
the chemical symbols placed after the numbers.
Received: July 22, 2010
Published online: November 5, 2010
Chem. Eur. J. 2011, 17, 564 – 571
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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