Oxyanion-Accelerated C2-C6 Cyclization of Benzannulated Enyne-allenes

Article abstract of DOI:10.1021/jo991876v

The cyclization of oxyanion-substituted, benzannulated enyne-allenes was found to proceed rapidly and efficiently at room temperature, producing substituted indanones and fluorenones through a C₂-C⁶ cyclization pathway. These reactions bear close resemblance to thermal C²-C⁶ cyclizations of enyne-allenes previously reported by Schmittel and others, though the oxyanion-substituted cases cyclize far more rapidly, and stand in noteworthy contrast to the C²-C⁷ (Myers) cyclization of (Z)-1,2,4-heptatrien-6-yne, the parent enyne-allene. The rate of reaction was found to be sensitive to the size of the alkyne and allene substituents, though the electronic effects of substitution are not known. The acceleration imparted by the oxyanion substituent is consistent with the electronic stabilization of a proposed diradicaloid transition state for the C²-C⁶ cyclization, but the available evidence does not permit the distinction between concerted and stepwise mechanisms. Studies are ongoing to further elucidate the mechanism and expand the scope of these transformations.

Full text of DOI:10.1021/jo991876v

5114
J . Org. Chem. 2000, 65, 5114-5119
Oxya n ion -Acceler a ted C2-C6 Cycliza tion of Ben za n n u la ted
En yn e-a llen es
Steven R. Brunette and Mark A. Lipton*
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907
E-mail: lipton@purdue.edu.
Received December 7, 1999
The cyclization of oxyanion-substituted, benzannulated enyne-allenes was found to proceed rapidly
and efficiently at room temperature, producing substituted indanones and fluorenones through a
C2-C6 cyclization pathway. These reactions bear close resemblance to thermal C2-C6 cyclizations
of enyne-allenes previously reported by Schmittel and others, though the oxyanion-substituted cases
cyclize far more rapidly, and stand in noteworthy contrast to the C2-C7 (Myers) cyclization of (Z)-
1,2,4-heptatrien-6-yne, the parent enyne-allene. The rate of reaction was found to be sensitive to
the size of the alkyne and allene substituents, though the electronic effects of substitution are not
known. The acceleration imparted by the oxyanion substituent is consistent with the electronic
stabilization of a proposed diradicaloid transition state for the C2-C6 cyclization, but the available
evidence does not permit the distinction between concerted and stepwise mechanisms. Studies are
ongoing to further elucidate the mechanism and expand the scope of these transformations.
Sch em e 1
In tr od u ction
The remarkable cyclization of the highly unsaturated
chromophore of the antitumor antibiotic neocarzinostatin
A (1) to an aromatic diradical (3) (Scheme 1)1 has inspired
numerous synthetic and mechanistic studies.2 The pro-
posed mechanism1d of this unprecedented cyclization was
given further support by the studies of Myers and Saito,
who reported the thermal cyclization of the (Z)-1,2,4-
heptatrien-6-yne skeleton to R,3-tolyl diradicals.3 These
initial reports stimulated further investigation of related
enyne-allene systems that, upon thermal cyclization,
afford aromatic diradicals.4 Among those studies are the
work of Schmittel5 and others6 in which an alternate
cyclization pathway was observed (Scheme 2), leading not
to the expected naphthyl products (5 and 7) but rather
to indenyl (4) and fluorenyl (6) products. Such reactions
were characterized by their apparent lack of diradical
character and formation of a five-membered, rather than
a six-membered, ring; these two alternative modes of
cyclization have been termed C2-C7 (Myers) and C2-C6.
Both the precise mechanism of the C2-C6 cyclization
and the factors responsible for toggling between the two
cyclizations continue to be investigated. Schmittel has
proposed that the C2-C6 cyclization, like the Myers
cyclization, produces a diradical intermediate,5 and re-
cently reported trapping such a diradical with 1,4-
cyclohexadiene.5g Recent theoretical work by Engels and
(1) (a) Ishida, N.; Miyazaki, K.; Kumagai, K.; Rikimaru, M. J .
Antibiot. 1965, 18, 68-76. (b) Koide, Y.; Ishii, F.; Hasuda, K.; Koyama,
Y.; Edo, K.; Katamine, S.; Kitame, F.; Ishida, N. J . Antibiot. 1980, 33,
342-346. (c) Myers, A. G.; Proteau, P. J .; Handel, T. M. J . Am. Chem.
Soc. 1988, 110, 7212-7214. (d) Myers, A. G. Tetrahedron Lett. 1987,
39, 4493-4496. (e) Myers, A. G.; Proteau, P. J . J . Am. Chem. Soc. 1989,
111, 1146-1147.
(2) (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl.
1991, 30, 1387-1416. (b) Lhermitte, H.; Grierson, D. S. Contemp. Org.
Synth. 1996, 3, 41-63. (c) Lhermitte, H.; Grierson, D. S. Contemp.
Org. Synth. 1996, 3, 93-124.
(3) (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J . Am. Chem. Soc.
1989, 111, 8057-8059. (b) Myers, A. G.; Dragovich, P. S. J . Am. Chem.
Soc. 1989, 111, 9130-9132. (c) Myers, A. G.; Dragovich, P. S.; Kuo, E.
Y. J . Am. Chem. Soc. 1992, 114, 9369-9386. (d) Nagata, R.; Yamanaka,
H.; Okazaki, E.; Saito, I. Tetrahedron Lett. 1989, 30, 4995-4998. (e)
Nagata, R.; Yamanaka, H.; Murahashi, E.; Saito, I. Tetrahedron Lett.
1990, 31, 2907-2910.
(4) (a) Nicolaou, K. C.; Maligres, P.; Shin, J .; de Leon, E.; Rideout,
D. J . Am. Chem. Soc. 1990, 112, 7825-7826. (b) Grissom, J . W.;
Slattery, B. J . Tetrahedron Lett. 1994, 35, 5137-5140. (c) Wang, K.
K.; Wang, Z. J . Org. Chem. 1996, 61, 1516-1518. (d) Liu, B.; Wang,
K. K.; Petersen, J . L. J . Org. Chem. 1996, 61, 8503-8507. (e) Wang,
K. K. Chem. Rev. 1996, 96, 207-222. (f) Wang, K. K.; Zhang, H.-R.;
Petersen, J . L. J . Org. Chem. 1999, 64, 1650-1656.
(5) (a) Schmittel, M.; Strittmatter, M.; Vollmann, K.; Kiau, S.
Tetrahedron Lett. 1996, 37, 999-1002. (b) Schmittel, M.; Strittmatter,
M.; Kiau, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1843-1845. (c)
Schmittel, M.; Maywald, M.; Strittmatter, M. Synlett 1997, 165-166.
(d) Schmittel, M.; Strittmatter, M.;, Kiau, S. Tetrahedron Lett. 1995,
36, 4975-4978. (e) Schmittel, M.; Keller, M.; Kiau, S.; Strittmatter,
M. Chem.s Eur. J . 1997, 3, 807-816. (f) Schmittel, M.; Steffen, J .-P.;
Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38, 6177-6180. (g)
Engels, B.; Lennartz, C.; Hanrath, M.; Schmittel, M.; Strittmatter, M.
Angew. Chem., Int. Ed. Engl. 1998, 37, 1960-1963. (h) Schmittel, M.;
Kiau, S.; Siebert, T.; Strittmatter, M. Tetrahedron Lett. 1996, 37,
7691-7694.
(6) (a) de Frutos, O.; Echavarren, A. M. Tetrahedron Lett. 1997, 38,
7941-7942. (b) Gillmann, T.; Hu¨¨lsen, T.; Massa, W.; Wocadlo, S.
Synlett 1995, 1257-1259. (c) Garcia, J . G.; Ramos, B.; Pratt, L. M.;
Rodr´ıguez, A. Tetrahedron Lett. 1995, 36, 7391-7394.
10.1021/jo991876v CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/21/2000

Accelerated Cyclization of Benzannulated Enyne-Allenes
J . Org. Chem., Vol. 65, No. 17, 2000 5115
Sch em e 2
rapid formation of unidentifiable side-products. The
methyl-substituted allene 12a was chosen for our initial
studies. Regeneration of the enolate using methyllithium
at -20 °C (Scheme 4) led to the rapid formation of a new,
highly UV-active species that proved upon investigation
to be the indanone 14a , the product of a C2-C6 cyclization
of the enyne-allene core. Although similar, formal Alder
ene reactions had been previously observed by Schmittel,5
in general these transformations required elevated tem-
peratures. The remarkably facile cyclization of the oxy-
anion-substituted allene 13a led us to examine the
reaction in more detail.
The deuterated analogue 12b was used to trace the
source of the hydrogen substituent on the exocyclic olefin;
1H NMR analysis of 14b indicated that the deuterium
had been quantitatively and stereoselectively transferred
to the alkene. The stereochemistry of 14a was established
through 1H NMR (NOESY) analysis of the stable enol
acetate 15, the result of acetic anhydride trapping of the
cyclized product prior to workup, as the exocyclic olefin
in 14a was found to slowly isomerize. The observed
geometry is consistent with an intramolecular transfer
of the hydrogen or deuterium substituent; however,
efforts to trap a putative diradical intermediate with 1,4-
cyclohexadiene proved unsuccessful. Allene 12e, bearing
a tert-butyl alkyne substituent, behaved similarly to 12a ,
but cyclized more slowly, presumably a result of the
increased steric bulk of the tert-butyl substituent.
Schreiner on the parent (Z)-1,2,4-heptatrien-6-yne sys-
tem7 supports a diradical C2-C6 cyclization pathway and
estimates a 10 kcal mol-1 preference for the C2-C7
transition state (25 vs 35 kcal mol-1). Schmittel has
identified several factors that may switch a C2-C6 to a
C2-C7 cyclization: bulky alkyne substituents that pref-
erentially destabilize the C2-C7 transition state by steric
congestion, aromatic allene substituents that stabilize an
incipient radical at C7, and ring strain.
Herein we report the preparation and cyclization of
oxyanion-substituted, benzannulated enyne-allenes at
cryogenic temperatures. These substrates were chosen
to study the electronic role of substituents on enyne-
allene cyclizations, with the goal of providing additional
mechanistic information and investigating the factors
responsible for preferential C2-C6 cyclization.
The cyclopropyl-bearing allenes 12d and 12g failed to
cyclize altogether when deprotected with methyllithium,
affording only monocyclic enones after prolonged reaction
time (Scheme 4). Successful cyclization of a cyclopropyl-
substituted allene was finally realized when phenyl-
substituted enol acetate 12h was treated with methyl-
lithium at -20 °C. This led to rapid consumption of
starting material and formation of a modest amount of
a cyclized product 14d , retaining an intact cyclopropyl
substituent. Although this result argues against the
existence of a long-lived diradical intermediate, a tran-
sient diradical or diradicaloid transition state cannot be
discounted. Furthermore, the enhanced stability of enyne-
allenes bearing TMS or tert-butyl substitution relative
to the phenyl-substituted example clearly illustrates the
relationship between steric bulk at both the allenic and
acetylenic termini and the inherent propensity for cy-
clization.
Phenyl-substituted enol acetate 12c (Scheme 5) was
synthesized to investigate the effect of preventing an
intramolecular hydrogen transfer by removal of all allylic
hydrogen atoms. In this case, liberation of the enolate
using methyllithium at -20 °C resulted in the rapid
formation of benzofluorenone 17a . An analogous reaction
of 12f resulted in formation of 17b, although the cycliza-
tion was slower than that of 12c and is again believed to
be derived from the increased steric bulk of tert-butyl
versus TMS. Several features of these cyclizations are
noteworthy. First, these cyclizations are formally [4+2]
Resu lts a n d Discu ssion
The synthesis of oxygen-substituted allenes was envis-
aged to arise from the trapping of enolates resulting from
conjugate addition to an acetylenic ketone. To this end,
several acetylenic ketones were prepared from 2-iodo-
benzoic acid (8, Scheme 3) in a three-step sequence
involving Weinreb amide formation,8 Sonogashira cou-
pling,9 and lithium acetylide addition. Employing differ-
ent alkynes in the Sonogashira coupling resulted in the
formation of substituted acetylenic ketones 11a -d in
generally high yields.
Preparation of the oxygen-substituted allenes was
accomplished by treating the acetylenic ketones 11a -d
with several cuprates and trapping the resultant enolates
with acetic anhydride to afford the enol acetates 12a -h
(Scheme 3). Although this strategy proved largely suc-
cessful, the n-butyl-substituted ketone 11d failed to
afford any enol acetate when subjected to the reaction
conditions; instead, reaction with cuprates resulted in the
(7) (a) Engels, B.; Hanrath, M. J . Am. Chem. Soc. 1998, 120, 6356-
6361. (b) Schreiner, P. R.; Prall, M. J . Am. Chem. Soc. 1999, 121, 8615-
8627.
(8) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.

5116 J . Org. Chem., Vol. 65, No. 17, 2000
Brunette and Lipton
Sch em e 3
Sch em e 4
Sch em e 5
cycloadditions, but the geometric constraints of a peri-
cyclic transition state would appear to disfavor a con-
certed transition state. Second, transformation of 12c and
12f to the products 17a and 17b involves dehydrogena-
tion, and likely results from a rapid atmospheric oxida-
tion of the presumed initial products 16a and 16b. The
structures of 16a and 16b indicate that the aromaticity
of a benzene ring is lost during reaction; thus, the
cyclization of 12c appears to be exothermic enough to
result in the dearomatization of benzene at cryogenic
temperature. This notion was corroborated by the results
obtained through treatment of acetylenic ketones 11a
and 11b (Scheme 6) with vinyl cuprate reagents, in which
cyclization of the initially formed enolate at -78 °C led
to the rapid formation of fluorenones 18a and 18b. Thus,
when the cyclization is unencumbered by the dearoma-
tization of benzene, it proceeds rapidly even at -78 °C.
That the presumed intermediate fluorenyl acetates could
not be isolated suggests that aromatization by autoxi-
dation is extremely facile.
Although the observed C2-C6 cyclization regiochem-
istry has been reported for analogous enyne-allenes, the
rate at which the oxyanion-bearing systems cyclize is
markedly faster than nearly all known examples.5d To

Accelerated Cyclization of Benzannulated Enyne-Allenes
J . Org. Chem., Vol. 65, No. 17, 2000 5117
Sch em e 6
Sch em e 8
minal substitution, the theoretical system investigated
by Engels differs from most systems known to undergo
C2-C6 cyclization by its lack of benzannulation. The
consequence of this difference, in the event of a C2-C7
cyclization, would be to form the second ring of naph-
thalene rather than an isolated phenyl ring. In this case,
given the difference in resonance energy gained by the
system upon cyclization, benzannulation of the enyne-
allene system is expected to reduce the energetic prefer-
ence of a C2-C7 event over that of a C2-C6 event by
roughly 10 kcal mole-1 10
.
Evidence for the role of benzannulation in the C2-C6
cyclization event is provided by Wang, whose examples
of acyclic enyne-allene systems bearing terminal aryl
substitution were expected to result in C2-C6 cyclization,
but instead cyclize with C2-C7 regiochemistry.4d At the
very least, these examples suggest that benzannulation
of the enyne-allene system is not an innocuous modifica-
tion to the parent system and have led us to begin the
investigation of oxyanion-bearing enyne-allene systems
without a central benzene ring, the results of which will
be disclosed in due course.
Sch em e 7
distinguish between the steric and electronic roles of the
oxyanion substituent on cyclization, the neutral enol
acetate 12e was heated to 50 °C and monitored by H
1
NMR spectroscopy (Scheme 7). Integration of the acetate
methyl signal of 12e was monitored using the residual
methyl signal of toluene-d8 as an internal standard. It
was found that 12e slowly cyclized to the corresponding
indenol acetate 19, with an estimated unimolecular rate
constant of 4.2 × 106 sec-1, a value that places the half-
life of 12e at 50 °C more than 45 times longer than that
of the corresponding oxyanion 13e.
Con clu sion
Direct comparison of our data to the examples of
Schmittel is complicated by the use of different synthetic
routes to obtain the respective enyne-allenes. The most
relevant comparison that can be drawn is between the
cyclization of 12c in this work and Schmittel’s observed
cyclization of the related enyne-allene 20 (Scheme 8).5e
Whereas the cyclization of 12c is complete within 20 min
at -20 to 0 °C, the complete cyclization of 20 required
heating it at 60-70 °C for 18 h. This suggests a minimum
rate acceleration of approximately 3000-fold. When one
additionally considers the steric difference between the
alkyne subsituents in 20 and 12c, the rate difference
quoted above is almost certainly underestimated.
Direct comparison of the cyclization of enol acetate 12e
with that of its corresponding enolate 13e shows roughly
a 45-fold rate enhancement that accompanies ionization.
This further suggests that placing a negative charge on
the oxygen substituent results in a stabilization of the
C2-C6 cyclization. This argues for an electronic stabiliza-
tion of the C2-C6 transition state, in addition to any
steric role of the oxygen substituent. The relatively small
rate difference between the neutral and anionic cycliza-
tions stands in stark contrast to our comparison with
Schmittel’s data and implies that the acetoxy substituent
imparts much of the stabilization to the C2-C6 transition
state that the oxyanion substituent also provides.
The mechanism of these transformations remains open
to question. Although indanone products arise from a
formal Alder ene reaction, and benzofluorenone products
arise from a formal Diels-Alder reaction, there is no
compelling evidence for a concerted mechanism at this
point. In addition, the requisite geometry of a cyclic
transition state appears quite unfavorable in these highly
constrained, unsaturated systems. Alternatively, one can
envisage a stepwise process involving either diradical or
anionic intermediates. While the lack of ring opening of
the cyclopropyl substituent in 14d is inconsistent with a
long-lived cyclopropylmethyl radical intermediate, a tran-
sient diradical intermediate cannot be ruled out. A
similar, cyclopropyl-substituted enyne-allene is reported
to proceed through a C2-C6 reaction pathway to yield a
cyclized product bearing an intact cyclopropyl ring.5b
The computational studies of Engels and Schreiner
suggest that the favorability of the C2-C6 cyclization may
arise from the stabilization afforded through orbital
overlap of a developing radical center with the existing
conjugated π system. Within the context of this inter-
pretation, the role of the oxyanion substituent at this
center would be one of additional stabilization and
consistent with the observed rate enhancement of the
oxyanion-bearing systems over that of nonionic ana-
logues. Importantly, along with lacking any bulky ter-
(10) (a) Dewar, M. J . S.; de Llano, C. J . Am. Chem. Soc. 1969, 91,
789-795. (b) Herndon, W. C.; Ellzey, M. L., J r. J . Am. Chem. Soc. 1974,
96, 6631-6642. (c) Hess, B. A., J r.; Schaad, L. J . J . Am. Chem. Soc.
1971, 93, 2413-2416. (d) Aihara, J . J . Am. Chem. Soc. 1977, 99, 2048-
2053. (e) Swinborne-Sheldrake, R.; Herndon, W. C. Tetrahedron Lett.
1975, 755-758.

5118 J . Org. Chem., Vol. 65, No. 17, 2000
Brunette and Lipton
The acceleration afforded C2-C6 cyclization by oxy-
anion substituents may have the same origin as the well-
known acceleration of sigmatropic rearrangements.11 In
those cases, it has been proposed that the oxyanion
substituent stabilizes a diradicaloid transition state
(50 mL) was added oxalyl chloride (3.53 mL, 40.4 mmol),
followed by catalytic DMF (50 µL). The reaction was stirred
at 25 °C for 2 h, at which time the clear, colorless solution
was concentrated in vacuo. The crude acid chloride was
resuspended in CH2Cl2 (50 mL) and cooled to 0 °C. To this
solution was added ClH2N(OMe)Me (2.17 g, 22.2 mmol),
followed by pyridine (3.95 mL, 48.8 mmol). The reaction was
allowed to warm to 25 °C and continued for 12 h. The reaction
product was diluted with EtOAc and poured into saturated,
aqueous CuSO4. The aqueous phase was extracted twice with
EtOAc. The combined organic layers were dried over Na2SO4,
decanted, and concentrated in vacuo. The resultant oil was
purified via flash chromatography with EtOAc/petroleum ether
(50:50) to afford 9 as a white solid (5.64 g, 96%). Mp ) 55-57
through electronic interaction with an R radical.11a,b
A
similar interaction can be proposed in the present study
by invoking a diradicaloid transition state for C2-C6
cyclizations, leading either to a diradical intermediate,
as Schmittel has suggested,5 or directly to product
through an asynchronous, concerted transition state.12
The C2-C6 regiochemistry of cyclization can be traced
to both the bulky acetylenic substituents and the ben-
zannulation of the substrates. Engels and Schreiner have
estimated that the C2-C6 transition state is destabilized
by 10 kcal mol-1 relative to that of the C2-C7 path for
(Z)-1,2,4-heptatrien-6-yne.7 When one adjusts this value
for the difference in resonance energy gained from
formation of benzene and naphthalene, the energy of the
C2-C6 transition state appears to be roughly comparable
to that of the Myers (C2-C7) transition state. Thus,
substituent effects, both steric and electronic, are likely
to play the major role in the discrimination between the
two competing reaction pathways. Recent studies by
Schmittel5f and Wang4f have shown that the introduction
of ring strain can also be used to disfavor C2-C6 cycliza-
tion and promote C2-C7 instead. In the present instance,
the trimethylsilyl, tert-butyl, and phenyl substituents are
sufficiently bulky to favor the C2-C6 pathway to the
exclusion of C2-C7 cyclization.
1
°C. H NMR (500 MHz, C6D6, 50 °C): δ 7.49 (d, J ) 7.8, 1H),
6.95 (m, 1H), 6.81 (m, 1H), 6.47 (m, 1H), 2.95 (b, 6H). IR
(KBr): νmax 1636 cm-1. Anal. Calcd for C9H10INO2: C, 37.14;
H, 3.46; N, 4.81. Found: C, 37.24; H, 3.20; N, 4.70. EIMS m/z:
291 (M+).
Son oga sh ir a Cou p lin g of Ter m in a l Alk yn es w ith Ar yl
Iod id e 9, Gen er a l P r oced u r e. A 0.149-g portion of Pd[PPh3]4
(0.129 mmol) was dissolved in THF (20 mL) and the reaction
vessel was thoroughly flushed with N2. To this solution was
added 9 (1.49 g, 5.14 mmol), alkyne (10.3 mmol), CuI (0.196
g, 1.03 mmol), and n-BuNH2 (1.02 mL, 10.3 mmol). The
solution was stirred for 2 h at 25 °C, diluted with EtOAc, and
poured into saturated, aqueous NH4Cl. The aqueous phase was
separated and extracted twice with EtOAc. The combined
organic layers were dried over Na2SO4, decanted, and concen-
trated in vacuo. The resultant residue was purified via flash
chromatography with EtOAc/petroleum ether (25:75).
Acetylid e Ad d ition to Am id es 10a -d , Gen er a l P r oce-
d u r e. Trimethylsilylacetylene (0.952 g, 6.75 mmol) was dis-
solved in THF (15 mL) and cooled to 0 °C. To this solution
was added n-BuLi as a 2.6 M solution in hexanes (2.1 mL,
5.46 mmol), dropwise. After 20 min, Weinreb amide 10 (4.50
mmol) in THF (3 mL) was added dropwise via syringe, and
the reaction was allowed to slowly warm to 25 °C over 2 h.
The reaction was diluted with Et2O, the mixture was poured
into saturated aqueous NH4Cl solution, and the aqueous phase
was extracted twice with Et2O. The combined organic layers
were dried over Na2SO4, decanted, and concentrated in vacuo.
The resultant residue was purified by flash chromatography
with Et2O/pentane (5:95).
The ability of an oxyanion substituent to accelerate the
C2-C6 cyclization should facilitate the use of these
reactions in organic synthesis. Likewise, the carbonyl
functionality of the products permits the introduction of
a wide variety of functional groups. Studies are currently
underway in our laboratory to further examine the
nature of the C2-C6 transition state and to determine
whether the same acceleration applies to the Myers
cyclization.
P r ep a r a tion of Cu p r a te Rea gen ts, Gen er a l P r oced u r e.
The cuprate reagents Me2CuLi, CD3CuLi, and Ph2CuLi, were
prepared by reacting MeLi, CD3Li‚LiI, and PhLi (2.05 equiv),
as commercially provided solutions, with CuI (1.0 equiv)
suspended in Et2O at 0 °C then cooled to -78 °C for immediate
use. The c-Pr2CuLi was prepared as follows. Cyclopropyl
bromide (0.106 mL, 1.32 mmol) in Et2O (2.0 mL) was cooled
to -78 °C. To this solution was added t-BuLi as a 1.99 M
solution in hexanes (0.663 mL, 1.32 mmol), dropwise, and the
resultant mixture was allowed to warm to 0 °C over 20 min.
This solution was transferred to a suspension of CuI (0.126 g,
0.662 mmol) in Et2O (1.0 mL) by syringe and, after complete
addition, the mixture was cooled to -78 °C for immediate use.
Cu p r a te Ad d ition to Keton es 11a -d a n d Su bsequ en t
Acetic An h yd r id e Tr a p of Resu lta n t En ola te, Gen er a l
P r oced u r e. To a solution of the cuprate reagent (0.71 mmol)
in Et2O (3.5 mL) at -78 °C was added the acetylenic ketone
11 (0.47 mmol), dropwise, as a solution in Et2O (0.5 mL). Acetic
anhydride (0.226 mL, 2.4 mmol) in Et2O (0.5 mL) was then
added dropwise to the reaction. The reaction was allowed to
slowly warm to 25 °C over 2 h and diluted with Et2O. The
reaction mixture was poured into saturated aqueous NH4Cl,
and the aqueous phase was separated and extracted twice with
Et2O. The combined organic layers were dried over Na2SO4,
decanted, and concentrated in vacuo. The resultant residue
was purified by flash chromatography with Et2O/pentane (5:
95).
Exp er im en ta l Section
Gen er a l. All reactions requiring an anhydrous or oxygen-
free environment were performed in flame- or oven-dried
glassware under positive N2 pressure. Tetrahydrofuran (THF)
and diethyl ether (Et2O) were distilled from sodium benzophe-
none ketyl. Toluene (PhCH3) and acetonitrile (CH3CN) were
distilled from calcium hydride. Acetic anhydride was redistilled
from quinoline and stored over 4 Å molecular sieves. CuI was
purchased 99.999% pure and azeotropically dried from toluene.
Grignard and alkyl/aryllithium reagents were titrated prior
to use. All other reagents were used as commercially provided
without further purification. Thin-layer chromatography (TLC)
was performed using silica gel 60 F-254 (EM reagents, 0.25
mm) filmed-glass plates. Flash chromatography was performed
using 230-400-mesh silica gel 60. Melting points of all solids
are reported uncorrected. Combustion analysis was performed
in the microanalysis laboratory at Purdue University.
2-Iod o-N-m eth oxy-N-m eth ylben za m id e (9). To a sus-
pension of 2-iodobenzoic acid (5.00 g, 20.2 mmol) in CH2Cl2
(11) (a) Evans, D. A.; Golob, A. M. J . Am. Chem. Soc. 1975, 97,
4765-4766. (b) Steigerwald, M. L.; Goddard, W. A., III; Evans, D. A.
J . Am. Chem. Soc. 1979, 101, 1994-1997. (c) Danheiser, R. L.;
Martinez-Davila, C.; Morin, J . M. J . Org. Chem. 1980, 45, 1340-1341.
(d) Thies, R. W.; Seitz, E. P. J . Org. Chem. 1978, 43, 1050-1057.
(12) (a) Dewar, M. J . S.; Pierini, A. B. J . Am. Chem. Soc. 1984, 106,
203-208. (b) Dewar, M. J . S. J . Am. Chem. Soc. 1984, 106, 209-219.
(c) Dewar, M. J . S.; Olivella, S.; Stewart, J . J . P. J . Am. Chem. Soc.
1986, 108, 5771-5779.
Dep r otection a n d Cycliza tion of En ol Aceta tes 12a -
h , Gen er a l P r oced u r e. To a solution of the enol acetate 12
(0.24 mmol) in PhCH3/1,4-cyclohexadiene (1:1, 3.0 mL), cooled
to -20 °C, was added MeLi as a 1.4 M solution in Et2O (0.35

Accelerated Cyclization of Benzannulated Enyne-Allenes
J . Org. Chem., Vol. 65, No. 17, 2000 5119
mL, 0.49 mmol). The reaction was slowly allowed to warm to
25 °C over 30 min and monitored via TLC for reactivity.
Results were identical to those obtained in the absence of 1,4-
cyclohexadiene. For TMS analogues (12a -d ), cyclization was
complete in 20 min, but tert-butyl analogues (12e-g) required
an additional 2 h at 50 °C. When complete, the reaction was
diluted with Et2O and poured into saturated aqueous NH4Cl.
The aqueous phase was extracted twice with Et2O and the
combined organic layers were dried over Na2SO4, decanted,
and concentrated in vacuo. The resultant residue was purified
by flash chromatography.
155.9, 154.6, 147.9, 144.3, 143.3, 142.3, 140.8, 137.3, 134.7,
132.3, 126.9, 30.1, 8.4, 7.8. IR (film): νmax 1772, 773, 755 cm-1
.
Anal. Calcd for C20H28O2Si2: C, 67.36; H, 7.91; Si, 15.75.
Found: C, 67.56; H, 8.00; Si, 15.52.
Vin yl Cu p r a te Ad d ition a n d In Situ Cycliza tion of
Acetylen ic Keton es 11a -b, Gen er a l P r oced u r e. A 0.135-g
portion of CuI (0.710 mmol) was suspended in Et2O (2 mL)
and cooled to 0 °C. To this suspension was added vinylmag-
nesium bromide as a 0.93 M solution in THF (1.5 mL, 1.40
mmol). The mixture was stirred for 5 min and then cooled to
-78 °C. Acetylenic ketone 11 (0.355 mmol) in Et2O (0.5 mL)
was added to the cuprate reagent, dropwise. After 5 min, acetic
anhydride (0.168 mL, 1.78 mmol) in Et2O (0.25 mL) was added
dropwise, and the reaction was allowed to warm to 25 °C over
2 h. The reaction was worked up analogously to the lithium
cuprate additions to 11a -d . The resultant residue was purified
by flash chromatography with Et2O/pentane (2:98).
Acet ic Acid 3-Tr im et h ylsila n ylm et h ylen e-2-(1-t r i-
m eth ylsila n yl-vin yl)-3H-in d en -1-yl Ester (15). A 0.192 g
portion of CuI (1.01 mmol) was suspended in Et2O (3 mL) and
cooled to 0 °C. MeLi as a 0.58 M solution in Et2O (3.5 mL)
was added dropwise. The suspension was stirred for 5 min and
transferred via cannula to acetylenic ketone 11a (0.200 g, 0.671
mmol) in Et2O (2 mL), whereupon the solution immediately
turned deep red. After 5 min, acetic anhydride (0.127 mL, 1.34
mmol) in Et2O (0.5 mL) was added slowly. The solution was
allowed to warm slowly to 25 °C, changing from red to yellow-
orange as it warmed. The reaction was diluted with Et2O, the
mixture was poured into saturated aqueous NH4Cl, and the
aqueous phase was extracted twice with Et2O. The combined
organic layers were dried over Na2SO4, decanted, and concen-
trated in vacuo. The resultant residue was purified by flash
chromatography with Et2O/pentane (5:95) to give 15 as a dark
Ack n ow led gm en t. This paper is dedicated to the
late Prof. Robert Squires, whose suggestion first in-
spired the present study. We thank him and Prof. J ohn
Grutzner for helpful comments and advice. Acknowl-
edgment is made to the donors of the Petroleum
Research Fund for partial support of this research.
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data for 10a -d , 11a -d , 12a -h , 14a -d , 17a -b, and
18a -b. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
yellow oil (0.170 g, 71%). H NMR (300 MHz, acetone-d6): δ
7.71 (m, 1H), 7.25 (m, 2H), 7.09 (m, 1H), 6.30 (s, 1H), 5.91 (d,
J ) 3.4, 1H), 5.71 (d, J ) 3.6, 1H), 2.29 (s, 3H), 0.36 (s, 9H),
0.12 (s, 9H). 13C NMR (75 MHz, acetone-d6): δ 177.2, 161.4,
J O991876V