New Intramolecular α-Arylation Strategy of Ketones by the Reaction of Silyl Enol Ethers to Photosensitized Electron Transfer Generated Arene Radical Cations: Construction of Benzannulated and Benzospiroannulated Compounds

Article abstract of DOI:10.1021/jo9718612

Efficient intramolecular α-arylation of ketones is achieved by the reaction of silyl enol ethers to photosensitized electron transfer (PET) generated arene radical cations. The arene radical cations are generated by one-electron transfer from the excited state of the methoxy-substituted arenes to ground-state 1,4-dicyanonaphthalene (DCN). This arylation strategy has provided the unique opportunity of constructing five- (23), six- (18), seven- (25) and eight-membered (27) benzannulated as well as benzospiroannulated (34) compounds. The explanation for the formation of 27 has been advanced by considering the proximity between the arene radical cation and silyl enol ether due to the self-coiling in the aqueous environment.

Full text of DOI:10.1021/jo9718612

J . Org. Chem. 1998, 63, 2867-2872
2867
New In tr a m olecu la r r-Ar yla tion Str a tegy of Keton es by th e
Rea ction of Silyl En ol Eth er s to P h otosen sitized Electr on Tr a n sfer
Gen er a ted Ar en e Ra d ica l Ca tion s: Con str u ction of Ben za n n u la ted
a n d Ben zosp ir oa n n u la ted Com p ou n d s†
Ganesh Pandey,* M. Karthikeyan, and A. Murugan
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune-411 008, India
Received October 8, 1997
Efficient intramolecular R-arylation of ketones is achieved by the reaction of silyl enol ethers to
photosensitized electron transfer (PET) generated arene radical cations. The arene radical cations
are generated by one-electron transfer from the excited state of the methoxy-substituted arenes to
ground-state 1,4-dicyanonaphthalene (DCN). This arylation strategy has provided the unique
opportunity of constructing five- (23), six- (18), seven- (25) and eight-membered (27) benzannulated
as well as benzospiroannulated (34) compounds. The explanation for the formation of 27 has been
advanced by considering the proximity between the arene radical cation and silyl enol ether due to
the self-coiling in the aqueous environment.
In tr od u ction
arylation of enol silanes with diazonium salts,10 and the
nickel(II)-catalyzed coupling of R-bromo enol silane with
an aryl Grignard reagent,11 are also not easily adaptable
for intramolecular reactions. Furthermore, these proce-
dures suffer from limitations such as the requirement of
special reagents, a large excess of substrates, drastic
reaction conditions, or multistep operations. Visualizing
the interesting application of intramolecular R-arylation
reaction of ketones for constructing polycyclic compounds,
our attention was drawn toward the possible utilization
of a direct nucleophilic reaction of an aromatic ring with
highly polarized ionic structure of enol silyl ether12 via
photosensitized electron transfer (PET) generated arene
radical cation intermediate. The origin of this concept
may be found from our broad research interest in the area
of PET reactions of synthetic relevance in general13 and
intramolecular nucleophilic additions to the PET-gener-
ated arene radical cation in particular14 (Figure 1). We
have explored the intramolecular arylation of silyl enol
ethers via PET-generated arene radical cation in detail15
and report herein the construction of five-, six-, seven-
and eight-membered aromatic annulated products and
spirocyclic compounds, in good yields.
R-Arylation of ketones, although infrequently used, is
an important carbon-carbon bond formation strategy
that could be utilized for the rapid access of an otherwise
inaccessible molecule. For example, the intramolecular
version of such an approach could provide a unique
means of constructing aromatic annulated products.1-4
Semmelhack5 and Bunnett6 have used the photo SRN
1
reaction protocol for the intramolecular arylation reaction
by coupling ketone enolate anions with halo arenes;
however, due to the predominance of â-hydrogen transfer,
of the annulation yields are reduced. Moreover, experi-
mental conditions for such cyclizations are drastic and
difficult. Another intramolecular arylation approach
reported by Urabe et al.7 employed addition of arene
radical, generated by the reaction of Bu3SnH on the
aromatic bromide, to the enol ether double bond; how-
ever, this strategy suffers from the usual problems of
radical reactions. Other ketone arylation procedures, for
example, the dichlorobis(tri-o-tolylphosphine)palladium(II)-
catalyzed reaction of an R-stannyl ketone8 or enol stan-
nane9 intermediates with an aryl bromide, electrophilic
* To whom correspondence should be addressed. Fax: 91-212-
335153. E-mail: pandey@ems.ncl.res.in.
(8) Kosugi, M.; Suzuki, M.; Hagiwara, I.; Goto, K.; Saitoh, K.; Migita,
T. Chem. Lett. 1982, 939. (b) Kosugi, M.; Hagiwara, I.; Sumiya, T.;
Migita, T. Bull. Chem. Soc. J pn. 1984, 57, 7, 242.
† Dedicated with respect to Dr. H. R. Sonawane on the occasion of
his 65th birthday.
(1) Taylor, S. K.; Blankespoor, C. L.; Harvey, S. M.; Richardson, L.
J . J . Org. Chem. 1988, 53, 3309. (b) Manas, A. R. B.; Smith, R. A. J .
Tetrahedron 1987, 43, 1847. (c) Trost, B. M.; Reiffen, M.; Crimmin,
M. J . Am. Chem. Soc. 1979, 101, 257. (d) Birch, A. J .; Rao, G. S. R.
Aust. J . Chem. 1970, 23, 547. (e) Posner, G. H.; Chapdelaine, M. J .;
Lentz, C. M. J . Org. Chem. 1979, 44, 3661. (f) Tamura, Y.; Choi, H.
D.; Shindo, H.; Uenishi, J .; Ishibashi, H. Tetrahedron Lett. 1981, 22,
81. (g) Rigby, J . H.; Kotnis, A.; Kramer, J . Tetrahedron Lett. 1983, 24,
2939.
(2) Shishido, K.; Yamashita, A.; Hiroya, K.; Fukumoto, K. Tetrahe-
dron 1989, 45, 5791 and references therein.
(3) Larock, R. C.; Fried, C. A. J . Am. Chem. Soc. 1990, 112, 5882.
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1989, 54, 2703.
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Commun. 1985, 1545.
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1239.
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Mukiama, T. Org. React. 1982, 28, 203. (c) Rasmussen, J . K. Synthesis
1977, 91. (d) Brownbridge, P. Synthesis 1983, 1 and 85.
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Organic Photochemistry: Molecular and Supramolecular Photochem-
istry series 1; Ramamurthy, V., Schanze, K. S., Ed.; Marcel Dekker:
New York, 1997; Chapter 7, p 245.
(14) Pandey, G.; Rao, J . M.; Krishna, A. Tetrahedron Lett. 1986, 27,
4075. (b) Pandey, G.; Krishna, A. J . Org. Chem. 1988, 53, 2364. (c)
Pandey, G.; Sridhar, M.; Bhalerao U. T. Tetrahedron Lett. 1990, 31,
5373.
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7765.
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(15) For a preliminary communication, see: Pandey, G.; Krishna,
A.; Girija, K.; Karthikeyan, M. Tetrahedron Lett. 1993, 34, 6631.
S0022-3263(97)01861-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/07/1998

2868 J . Org. Chem., Vol. 63, No. 9, 1998
Pandey et al.
Sch em e 1a
a
Reagents: (a) thermodynamic enolization, (b) hν, DCN, PET reaction; (c) kinetic enolization.
Sch em e 2a
F igu r e 1.
Resu lts a n d Discu ssion
Ben za n n u la tion Rea ction . It was obvious to us at
the beginning of our project that two different types of
silyl enol ethers could be obtained from a substrate of
type 4 by following the reported procedures16 of synthe-
sizing either thermodynamic 5 or kinetic 8 silyl enol
ethers. Therefore, the arylation of these enol silanes was
expected to produce two different types of annulated
compounds 7 or 10, varying in ring sizes from the same
ketone 4 as shown in Scheme 1.
Initially, substrate 14a was selected for evaluating the
intramolecular arylation reaction as per the depictions
shown in Scheme 1. The methoxy substitution on the
benzene ring was essential for making the arene ring
capable of participating in PET processes14 from their
excited state in the presence of DCN (1,4-dicyanonaph-
thalene) as an electron acceptor. Compounds 14 were
easily obtained in 96% yield by the catalytic hydrogena-
tion of 13, prepared by the reaction of methoxy-substi-
tuted benzaldehydes 11 and acetone in the presence of
10% NaOH (Scheme 2). Silyl enol ethers 15 could be
prepared quantitatively (98%) by the reaction of tert-
butyldimethylsilyl chloride (TBDMSCl) (6 mmol) on the
lithium enolate of 14, generated by the reaction of LDA
(5 mmol) at -78 °C. Compounds 15 were sufficiently
pure enough to proceed to the next step.
a
Reagents: (a) acetone (12), 10% aqueous NaOH, dilute HCl;
(b) H2, 10% Pd/C, EtOH.
It has been ascertained by comparative UV spectroscopy
that almost all light (>99%) is absorbed by 15a under
the present photolysis reaction conditions. The irradia-
tion was continued until most of the 15a disappeared (4
h, monitored by TLC). Removal of the solvent at reduced
pressure followed by chromatographic purification gave
17a (72%, isolated yield) and starting ketone 14a (∼10%).
DCN was recovered quantitatively (98%) at the end of
the reaction. Partial reversal of 15a to 14a in the dark
is ascertained by an adequate control experiment. Prod-
uct 17a was characterized by IR, 1H NMR, 13C NMR, and
mass spectral data.
Mechanistically, the formation of 18a from 15a could
be explained by considering the steps as shown in Scheme
3. Intermediate 16a is formed by an electron transfer
from the excited singlet state of the arene moiety of 15a
to the ground state of DCN. Intramolecular nucleophilic
reaction of silyl enol ether to the electron-deficient arene
radical cation followed by the aromatization of 17a leads
to the formation of 18a . Compound 18a was character-
ized by detailed H NMR, 13C NMR, mass spectral, and
HRMS data and further confirmed by comparing the H
1
1
PET reaction of 15a utilized essentially the conditions
that had been successfully used in a number of earlier
cyclization reactions of electron-rich arenes tethered with
nucleophiles.14 These conditions consisted of the irradia-
tion of 15a (2 mmol) in the presence of DCN (0.34 mmol)
in CH3CN/H2O (4:1) solvent using Pyrex-filtered light
(>280 nm, 450 W Hanovia medium-pressure lamp)
without removing dissolved air from the reaction mixture.
NMR spectral data with the reported values.17a DCN•-
produced by the acceptance of an electron from the
excited arene moiety reverts back to its original state via
ET mediated by oxygen as shown in Figure 1. Photore-
action in an inert atmosphere leads to the fast consump-
tion of DCN along with the formation of complicated
mixture of products.
(16) House, H. O.; Czuba, L. J .; Gall, M.; Olmstead, H. D. J . Org.
Chem. 1969, 34, 2324. (b) Flemming, I.; Paterson, I. Synthesis 1979,
736.
(17) Registry no. provided by the author: 4133-34-0. Aldrich FT-
NMR 1(2), 797A. (b) Registry no. provided by the author: 2472-13-1.
Aldrich FT-NMR 1(2), 797B.

Intramolecular R-Arylation Strategy of Ketones
J . Org. Chem., Vol. 63, No. 9, 1998 2869
Sch em e 3a
Sch em e 4a
a
Reagents: (a) n-BuLi, THF, -78 °C; (b) Ar(CH2)nBr (20); (c)
NaIO4, MeOH/THF, phosphate buffer.
from 22b also produced 23b in 70% yield, confirming the
generality of the reaction. It was further envisaged that
the kinetically produced silyl enol ethers 24 upon PET
activation should produce corresponding benzocyclohep-
tanones 25. In this context, when the PET cyclizations
of 24a and 24b were carried out by following the identical
PET reaction as described earlier, which produced cor-
responding benzocycloheptanone derivatives 25a (65%)
and 25b (74%), respectively. These compounds displayed
characteristic 1H NMR, 13C NMR, and mass spectral
data. The observed efficiency and the good cyclization
yields of 25 encouraged us to include substrate 21c also
as an example in our study as the cyclization of its
corresponding silyl enol ether 24c would lead to an easy
construction of 25c, which was initially utilized by
Schreiber et al.22 and subsequently by others23 as a
precursor for the synthesis of a potent mitotic inhibitor
colchicine.24 PET activation of 24c indeed, produced 25c
in 66% yield.
a
Reagents: (a) LDA, TBDMSCl, THF, -78 °C; (b) hν, DCN,
CH3CN; H2O (4:1), 4 h.
Similar PET activation of 15b gave 18b (70%). The
regiochemistry of methoxy groups in 18b is assigned on
the basis of the detailed H NMR spectral analysis of the
1
aromatic protons and further confirmed by comparing it
with the reported values.17b The observed regiospecificity
of these cyclizations is in accord with the earlier calcu-
lated electron densities (Huckel or MNDO) at different
carbons of the HOMO of the arene radical cation.18 It
may be worthy of note that this cyclization strategy
provides a direct access to arene-substituted â-tetralones,
which are very important precursors in the synthesis of
many biologically/medicinally active compounds.19 â-Tet-
ralones are otherwise generally prepared with difficulty,
via 1,2-transposition of R-tetralones.20
Next, we decided to explore the scope and limitations
of this methodology by envisaging the construction of the
benzocyclooctane moiety as it is often most difficult25 to
prepare because of entropy factors and transannular
interactions. In comparison to five- and six-membered
ring-forming reactions, few methods for direct formation
of eight-membered rings are available.26,27 In this con-
text, compound 21d was selected. This compound was
obtained (82%) by following the same reaction sequences
as outlined in Scheme 6. Kinetically produced silyl enol
ether 26 was subjected to the usual PET reaction as
described for 15a . To our pleasant surprise, 26 under-
went smooth cyclization to produce 27 in 70% yield as a
solid, mp 85-86.5 °C. Small amounts (>10%) of starting
ketone wrtr recovered in this case too (Scheme 6). The
ease observed during this cyclization may possibly be
explained by considering the proximity between the arene
radical cation and enol silyl ethers in aqueous medium
due to self-coiling as demonstrated by J iang et al.28
However, further study is in progress in this regard and
would be published separately somewhere else.
Because we hoped to maintain the versatility of this
cyclization reaction irrespective of the number of meth-
ylene groups or the position of the silyl enol ether group,
substrates 21 were synthesized. The preparation of 21
(80-84%) involved the alkylation of acetone hydrazone
19 (5 mmol) with the corresponding phenyl alkyl bro-
mides 20 (5 mmol) through the steps as shown in Scheme
4. It was envisaged that the cyclization of thermody-
namically prepared enol silyl ether 22 would provide
indan systems 23, while kinetically produced enol silyl
ethers 24 will give benzocycloheptanone frameworks.
To evaluate the feasibility of transforming 21 into
corresponding indan systems21 (23), silyl enol ether 22a
was first prepared in 83% yield by heating a mixture of
21a (5 mmol), TBDMSCl (6 mmol), and imidazole (12
mmol) in DMF (10 mL) for 48 h (Scheme 5). PET
activation of 22a by following the usual irradiation
conditions, as described for 15a , produced 23a in 65%
1
yield. Product 23a was characterized by IR, H NMR,
and 13C NMR spectral analysis. An identical reaction
(18) Pandey, G.; Krishna, A.; Bhalerao, U. T. Tetrahedron Lett. 1989,
30, 1867. (b) Krishna, A. Ph.D. Thesis, Osmania University, Hydera-
bad, 1988.
(19) Aristoff, P. A.; J ohnson, P. D.; Harrison, A. W. J . Am. Chem.
Soc. 1985, 107, 7967. (b) Xia, Y.; Reddy, E. R.; Kozikowski, A. P.
Tetrahedron Lett. 1989, 30, 3291. (c) Cannon, J . G.; Koble, D. L. J .
Med. Chem. 1980, 23, 750. (d) Sodeoka, M.; Iimori, T.; Shibasaki, M.
Tetrahedron Lett. 1985, 26, 6497.
(20) Fristad, W. E.; Bailey, T. R.; Paquette, L. A. J . Org. Chem. 1978,
43, 1620. (b) Fristad, W. E.; Bailey, T. R.; Paquette, L. A. J . Org. Chem.
1980, 45, 3028. (c) Thies, R. W.; Chiarello, R. H. J . Org. Chem. 1979,
44, 1342. (d) Kane, V. V.; Singh, V.; Martin, A.; Doyle, D. L.
Tetrahedron 1983, 39, 345.
(22) Schreiber, J .; Leimgruber, W.; Pesaro, M.; Schudel, P.; Threlfall,
T.; Eschenmoser, A. Helv. Chim. Acta 1961, 44, 540.
(23) Boger, D. L.; Brotherton, C. E. J . Am. Chem. Soc. 1986, 108,
6713 and references therein.
(24) For reviews, see: Capraro, H.-G.; Brossi, A. The Alkaloids;
Academic: Orlando, FL, 1984; Vol. 23, pp 1-70.
(25) For a discussion. see: Illuminati, G.; Mandolini, L. Acc. Chem.
Res. 1981, 14, 95.
(26) For an excellent review, see: Patasis, N. A.; Patane, M. A.
Tetrahedron 1992, 48, 5757.
(27) Grimm, E. L.; Coutu, M. L.; Trimble, L. A. Tetrahedron Lett.
1993, 34, 7017.
(21) For the importance of the indane framework, see: Fukuyama,
T.; Chatani, N.; Kakinchi, F.; Murai, S. J . Org. Chem. 1997, 62, 2,
5647 and references therein.
(28) J iang, X.-K.; Hui, Y.-Z.; Fei, Z.-X. J . Am. Chem. Soc. 1987, 109,
5862. (b) Winnik, F. M.; Winnik, M. A.; Tazuke, S. J . Phys. Chem. 1987,
91, 594.

2870 J . Org. Chem., Vol. 63, No. 9, 1998
Pandey et al.
Sch em e 5a
a
Reagents: (a) ImH, TBDMSCl, DMF, reflux, 80%; (b) hν, DCN, CH3CN/H2O (4:1); (c) LDA, TBDMSCl, THF, -78 °C (93%).
Sch em e 6a
Sch em e 8a
a
Reagents: (a) LDA, TBDMSCl, THF, -78 °C; (b) hν, DCN,
CH3CN.
Sch em e 7
a
Reagents: (a) t-BuLi, THF, -78 °C; (b) Ar(CH2)nBr (31); (c)
acetone, HCl, reflux; (d) HMDS, ImH, reflux; (e) hν, DCN, CH3CN.
pared (78-82%) by following the reported32 procedure as
shown in Scheme 8. Heating 32 (5 mmol) with hexa-
methyldisilazane (HMDS) (25 mmol) in the presence of
freshly crystallized imidazole (8 mmol) produced33 enol
silanes 33a (80%) and 33b (76%), respectively. Usual
PET activation of 33a as well as 33b. in an identical
manner as described for 15a , gave spirocyclic compounds
34a (71%) and 34b (69%), respectively (Scheme 8). These
Ben zosp ir oa n n u la tion Rea ction . Once it was es-
tablished that intramolecular arylation of ketones can
be efficiently effected by the reaction of the corresponding
silyl enol ethers to PET-generated arene radical cation
and five-, six-, seven-, and eight-membered benzannu-
lated compounds could easily be constructed, our atten-
tion was focused on the possible exploitation of this
strategy for the construction of benzospiroannulated
molecules 29 starting from 28 (Scheme 7). The spiroan-
nulated compounds of general structures 29 are either
the part of biologically active Cannabis spiranoids29 29a
(m ) 1) or have been utilized 29b (m ) 2) for the
synthesis of other biologically important molecules.30
The known syntheses of these spirocyclics are rather
cumbersome.29-31 In this context, diones 32 were pre-
1
compounds were characterized by H NMR, 13C NMR,
and mass spectral data.
In conclusion, we have developed a new intramolecular
R-arylation strategy of ketones by the reaction of silyl
enol ethers with the PET-generated arene radical cations.
(30) Le Dreau, M.-A.; Desmaele, D.; Dumas, F.; d′Angelo, J . J . Org.
Chem. 1993, 58, 2933. (b) Chatterjee, S. J . Chem. Soc., Chem. Commun.
1979, 622.
(31) Berrier, C.; J acquesy J .-C.; Renoux, A. Bull Soc. Chim. Fr. I
1987, 212. (b) Schwartz, M. A.; Rose, B. F.; Holton, R. A.; Scott, S. W.;
Vishnuvajjala, B. J . Am. Chem. Soc. 1977, 99, 2571. (c) Schwartz, M.
A.; Rose, B. F.; Vishnuvajjala, B. J . Am. Chem. Soc. 1973, 95, 612. (d)
Kotani, E.; Takeuchi, N.; Tobinaga, S. J . Chem. Soc., Chem. Commun.
1973, 550.
(29) J acquesy, J . C.; J ouannetaud, M. P. Bull. Soc. Chim. Fr. II
1977, 202. (b) Novak, J .; Salemink, C. A. Tetrahedron Lett. 1981, 22,
1063. (c) Crombie, L.; Powell, M. J .; Tuchinda, P. Tetrahedron Lett.
1980, 21, 3603. (d) Novak, J .; Salemink, C. A. J . Chem. Soc., Perkin
Trans. 1 1982, 2403. (e) Crombie, L.; Crombie, W. M. L.; J amieson, S.
V.; Tuchinda, P.; Whitaken, A. J . J . Chem. Soc., Perkin Trans. 1 1982,
1485.
(32) Piers, E.; Grierson, J . R. J . Org. Chem. 1977, 42, 3755.
(33) Torkelson, S.; Ainsworth, C. Synthesis 1977, 431. (b) Torkelson,
S.; Ainsworth, C. Synthesis 1976, 722.

Intramolecular R-Arylation Strategy of Ketones
J . Org. Chem., Vol. 63, No. 9, 1998 2871
Hz), 6.7 (d, 2H, J ) 9.80 Hz), 3.75 (s, 3H), 2.55 (t, 2H, J ) 7.5
Hz), 2.40 (t, 2H, J ) 7.5 Hz), 2.10 (s, 3H), 1.85 (m, 2H).
5-(3,4-Dim eth oxyph en yl)pen tan -2-on e (21b). Yield: 80%.
Viscous liquid. IR (neat): 2900, 1710, 1515, 1580, 1515, 1420,
This strategy has provided an easy and novel approach
for constructing the five-, six-, seven-, and eight-
membered benzannulated products as well as ben-
zospiroannulated compounds.
1360, 1260, 1160, 1020 cm-1 1H NMR (200 MHz, CDCl3) δ:
.
6.60-6.75 (m, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 2.65 (t, 2H, J )
7.5 Hz), 2.45 (t, 2H, J ) 7.5 Hz), 2.20 (s, 3H), 1.90 (m, 2H).
13C NMR (50.32 MHz, CDCl3) δ: 208.54, 149.23, 147.63,
134.52, 120.54, 112.25, 111.78, 56.02, 42.89, 34.79, 29.95,
25.57.
Exp er im en ta l Section
Reactions were monitored by thin-layer chromatography
(TLC) or gas chromatography (GC). All yields reported refer
to isolated material. Temperatures above and below ambient
temperature refer to bath temperatures unless otherwise
stated. Solvents and anhydrous liquid reagents were dried
according to established procedures by distillation under argon
atmosphere from the appropriate drying agent. Reagents were
procured from Aldrich Chemical Co. and SD Fine Chemicals,
India. Column chromatography was performed using silica
gel (100-200 mesh, SD fine Chemicals, India) by standard
chromatographic techniques. All nuclear magnetic resonance
spectra were recorded on either 200 MHz FT NMR or 300 MHz
NMR spectrometers using CDCl3 as solvent. IR spectra were
taken on an FT-IR instrument. Mass spectra were obtained
at a voltage of 70 eV. Melting points (mp) were measured were
uncorrected.
5-(3,4,5-Tr im eth oxyp h en yl)p en ta n -2-on e (21c). Yield:
80%. Viscous liquid. IR (neat): 2945, 2262, 1700, 1612, 1510
1045, 950 cm-1 1H NMR (200 MHz, CDCl3) δ: 6.45 (s, 2H),
.
3.90 (s, 6H), 3.85 (s, 3H), 2.65 (t, 2H, J ) 7.42 Hz), 2.45 (t,
2H, J ) 7.42 Hz), 2.20 (s, 2H), 1.85 (m, 2H).
6-(3,4-Dim eth oxyph en yl)h exan -2-on e (21d). Yield: 82%.
Viscous liquid. IR (neat): 2920, 1710, 1590, 1500, 1440, 1420,
1355, 1260, 1160, 1030, 850, 800, 770, 740 cm-1 1H NMR (200
.
MHz, CDCl3) δ: 6.75 (m, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 2.55
(t, 2H, J ) 7.25 Hz), 2.45 (t, 2H, J ) 7.25 Hz), 2.10 (s, 3H),
1.50 (m, 4H). 13C NMR (50.32 MHz, CDCl3) δ: 208.38, 148.58,
146.89, 134.57, 119.91, 111.60, 111.15, 55.55, 55.45, 43.06,
34.94, 30,71, 29.36, 23.07. MS (m/e): 236 (M+), 178 (15), 163
(12), 151 (100), 137 (15), 121 (16), 107 (24), 91 (26), 77 (30).
P r ep a r a tion of 32. This is illustrated by taking 32a as
an example.
Gen er a l P r oced u r es for t h e Syn t h esis of St a r t in g
Keton es. Ketones 14 were prepared by the hydrogenation of
13 in 92-96% yields. A representative experimental detail
for 14a is described below.
2-[(4′-Meth oxyph en yl)eth yl]-1,3-cycloh exan edion e (31a).
To a solution of t-BuLi (1.6 M in n-pentane, 9.7 mL, 1.11 equiv)
at -78 °C was added 1,5-dimethoxy-1,4-cyclohexadiene31 1.98
g (14 mmol) dissolved in THF (80 mL). The resultant solution
was stirred at -78 °C for 1 h. HMPA (1.2 equiv, freshly
distilled from LiAlH4) was added, and stirring was continued
for an additional 10 min. Addition of 2-(4-methoxyphenyl)-
ethyl bromide (3.87 g, 18 mmol, 1.31 equiv, freshly filtered
through a short column of neutral alumina) dissolved in THF
(10 mL) to the flask resulted in an immediate change in the
color of the reaction mixture (maroon to light brown). The
reaction mixture was allowed to warm to room temperature,
diluted with 5 mL of brine, and then extracted three times
with 50 mL portions of pentane. The combined pentane
extracts were washed twice with brine and dried over MgSO4.
Removal of the solvent followed by concentration at reduced
pressure gave a thick pale yellow oil product, which was
subsequently dissolved in acetone (20 mL of spectrograde,
previously purged with a stream of N2 for 15 min). To this
solution was added 1 N hydrochloric acid (4 mL) with vigorous
stirring, and the contents were allowed to stir for an additional
1 h. The acetone was removed under reduced pressure, the
residue was diluted with 10 mL of brine, and the mixture was
extracted four times with 10 mL portions of CH2Cl2. The
combined extracts were dried over anhydrous MgSO4. Re-
moval of the solvent afforded (2.82 g, 82%) of 2-[(4′-methoxy-
phenyl)ethyl]-1,3-cyclohexanedione as a white solid. Mp:
142-143.5 °C. IR (CHCl3): 2960, 2230, 1650, 1620, 1520,
4-(4-Meth oxyp h en yl)bu ta n -2-on e (14a ). Compound 13a
(5 g, 28 mmol) was quantitatively hydrogenated in anhydrous
ethanol using 10 mg of 10% Pd on activated carbon at rt at 60
psi of H2 pressure. Reaction was stopped when the consump-
tion of H2 ceased. The catalyst was filtered off, and the
solution was concentrated under reduced pressure. Flash
chromatography purification over silica gel with EtOAc/
petroleum ether (15:85) as eluent gave 14a as a pale yellow
oil. Yield: 4.8 g, 90%. IR (neat): 2935, 1716, 1612, 1514, 1247,
1035, 910 cm-1 1H NMR (200 MHz, CDCl3) δ: 7.15 (d, 2H, J
.
) 9.52 Hz), 6.85 (d, 2H, J ) 9.52 Hz), 3.75 (s, 3H), 2.70-2.85
(m, 4H), 2.20 (s, 3H). 13C NMR (50.32 MHz, CDCl3) δ: 207.73,
158.30, 133.32, 129.45, 114.15, 55.25, 45.41, 30.03, 29.10. MS
(m/e): 178 (M+), 163 (5), 135 (13), 121 (100), 108 (17), 91 (25),
77 (19), 65 (13).
4-(3,4-Dim eth oxyph en yl)bu tan -2-on e (14b). Yield: 84%.
IR (neat): 2937, 1716, 1591, 1456, 1236, 1028, 912 cm-1 1H
.
NMR (200 MHz, CDCl3) δ: 6.65-6.80 (m, 3H), 3.85 (s, 3H),
2.65-2.90 (m, 4H), 2.15 (s, 3H). 13C NMR (50.32 MHz, CDCl3)
δ: 208.01, 149.15, 147.64, 133.89, 120.30, 112.09, 111.72,
56.09, 55.99, 45.47, 30.16, 29.55. MS (m/e): 208 (M+), 193 (5),
165 (57), 151 (100), 135 (15), 119 (17), 107 (26), 91 (25), 77
(25), 65 (15).
Ketones 21 were prepared by the alkylation of acetone
dimethylhydrazone 19 using the corresponding phenyl alkyl
bromides 20. A representative experimental procedure for 21a
is described below.
1480, 1385, 1260, 1240, 1200, 1160, 930 cm-1 1H NMR (200
.
5-(4-Meth oxyp h en yl)p en ta n -2-on e (21a ). To a previ-
ously dried 250 mL round-bottom flask equipped with a
magnetic stirring bar and argon gas balloon was added 19 (1.5
g, 15 mmol) in 50 mL of anhydrous THF. The flask was cooled
to -78 °C, and n-butyllithium (2.20 M in hexane, 6.80 mL)
was added (the mixture turned red). After 30 min, 20a (3.23
g, 15 mmol) in THF (50 mL) was added. The reaction mixture
was warmed to ambient temperature, quenched with 20 mL
of aqueous NH4Cl solution, and diluted with ethyl acetate (50
mL). The organic layer was washed with water (3 × 100 mL)
and brine (100 mL), concentrated by rotatory evaporation, and
then taken into 50 mL of MeOH. To this solution were added
5 mL of phosphate buffer (pH ) 7) solution (Na2HPO4/
NaH2PO4) and NaIO4 (6.50 g, 31 mmol) in 10 mL of water and
stirred for 30 min at rt. The reaction mixture was concen-
trated and then dissolved in ethyl acetate, washed with water
(20 mL), dried, and concentrated. Column chromatography
(eluting with (10:80) ethyl acetate/petroleum ether) gave 2.54
g (84%) of 21a as pale yellow oil. IR (neat): 2945, 1720, 1610,
MHz, CDCl3) δ: 7.15 (d, 2H, J ) 9.47 Hz), 6.85 (d, 2H, J )
9.47 Hz), 5.35 (s, 1H), 4.00 (t, 2H, J ) 7.37 Hz), 3.80 (s, 3H),
3.00 (t, 2H, J ) 7.37 Hz), 2.35 (m, 4H), 1.95 (m, 2H). 13C NMR
(50.32 MHz, CDCl3) δ: 199.78, 177.88, 158.60, 129.99, 129.61,
114.15, 102.98, 69.29, 55.37, 36.88, 34.24, 29.12, 21.33.
2-[3′-(Met h oxyp h en yl)p r op yl]-1,3-cycloh exa n ed ion e
(31b). Yield: 78%. White solid. Mp: 154 °C. IR (CHCl3):
2960, 1650, 1500, 1460, 1440, 1380, 1260, 1240, 1190, 1050,
920 cm-1 1H NMR (200 MHz, CDCl3) δ: 7.25 (dd, J ) 9.75
.
Hz, 1H), 6.75 (m, 3H), 5.35 (s, 1H), 3.90 (t, J ) 7.31 Hz, 2H),
3.80 (s, 3H), 2.70 (t, J ) 7.31 Hz, 2H), 2.40 (m, 4H), 2.00 (m,
4H). 13C NMR (50.32 MHz, CDCl3) δ: 199.35, 177.88, 159.68,
142.30, 129.24, 120.54, 114.10, 111.20, 102.49, 67.42, 54.85,
36.48, 31.88, 29.71, 29.79, 21.01. MS (m/e): 260 (M+), 228 (3),
208 (4), 166 (26), 148 (10), 135 (9), 122 (100), 107 (14), 91 (41),
84 (25), 77 (28), 55 (56).
Gen er a l P r oced u r es for th e P r ep a r a tion of En ol Silyl
Eth er s of Keton es (24a a n d 22a ). Kin etic En oliza tion .
To a stirred solution of 15 mmol of LDA at -78 °C was added
dropwise a solution of ketone, for example, 21a (2.8 g, 15
1510 cm-1 1H NMR (200 MHz, CDCl3) δ: 7.1 (d, 2H, J ) 9.8
.

2872 J . Org. Chem., Vol. 63, No. 9, 1998
Pandey et al.
mmol) in 20 mL of anhydrous THF. After the addition of the
substrate was complete, the reaction mixture was stirred for
an additional 20 min at -78 °C. TBDMSCl (2.25 g, 15 mmol)
in 20 mL of THF was slowly introduced into the flask. The
reaction mixture was warmed to room temperature with
continued stirring for 3 h. Pentane (100 mL) was added, and
the precipitated LiCl was removed by filtration through Celite.
Concentration in vacuo followed by distillation under reduced
pressure (85 °C/4 mmHg) gave the kinetic silyl enol ether 24a
(93%) essentially as a single regioisomer.
Th er m od yn a m ic En oliza tion . To a 100 mL round-
bottom flask containing a stirring solution of ketone 21a (2.8
g, 15 mmol) in DMF (50 mL) and ImH (2.10 g, 31 mmol) was
introduced TBDMSCl (2.25 g, 15 mmol) dissolved in 20 mL of
DMF. The contents were refluxed for 48 h. On cooling, it was
diluted with ether (100 mL) and washed with cold saturated
NaHCO3 solution. The aqueous phase was reextrated with
ether, and the combined organic extracts were washed rapidly
and successively with dilute HCl (20 mL), saturated NaHCO3
solution (20 mL), and water. After drying and concentration,
distillation of the residue under reduced pressure gave the
thermodynamically stable enol silyl ether 22a in an overall
yield of 80%.
Gen er a l Ir r a d ia tion P r oced u r e. A typical photochemical
reaction involved the irradiation of a mixture of silyl enol
ethers (2 mmol) and DCN (0.06 g, 0.34 mmol) in 500 mL of
CH3CN/H2O (4:1) for 3-4 h through Pyrex-filtered light (>280
nm, all light absorbed by enol ether only) using a 450 W
Hanovia lamp without removing the dissolved oxygen. Re-
moval of the solvent and silica gel (60-120 mesh) column
chromatographic purification of the reaction mixture gave
carbocyclic and spirocyclic products. The chemical purity of
cyclized products was confirmed by GC analysis (methyl
silicone, 25 m, 0.53 mm). DCN was recovered quantitatively
(98%) at the end of the reaction.13 During the irradiation of
silyl enol ethers, a minor quantity (∼10-15%) of starting
ketones were also formed, which have been shown to be formed
by the thermal reversion of the enol silyl ethers by adequate
control experiments.
3H), 3.80 (s, 3H), 2.70 (t, J ) 7.32 Hz, 2H), 2.20 (m, 2H), 2.05
(s, 3H). 13C NMR (50.32 MHz, CDCl3) δ: 206.26, 148.35,
146.99, 136.33, 132.43, 110.18, 109.52, 62.04, 55.65, 54.78,
30.43, 26.95, 22.65. HRMS (EI): 220.1102, calcd for C13H16O3
220.1099. MS (m/e): 220 (M+), 204 (100), 189 (74), 173 (15),
161 (16), 146 (15), 121 (20), 115 (40), 91 (20), 77 (18).
3-Meth oxy-6,7,8,9-tetr ah ydr o-5H-ben zo[a ]cycloh epten -
6-on e (25a ). Yield: 65%. Viscous liquid. IR (neat): 2940,
2260, 1700, 1610, 1500, 1050, 940 cm-1 1H NMR (200 MHz,
.
CDCl3) δ: 7.05 (d, 1H, J ) 10 Hz), 6.70 (s, 1H), 6.65 (d, J ) 10
Hz, 1H) 3.75 (s, 3H), 3.65 (s, 2H), 2.90 (t, 2H, J ) 7.5 Hz),
2.55 (t, 2H, J ) 7.5 Hz), 2.05 (m, 2H). 13C NMR (50.32 MHz,
CDCl3) δ: 208.95, 159.01, 141.81, 130.39, 125.64, 115.35,
111.56, 55.21, 49.19, 43.54, 33.25, 26.23. HRMS (EI): 190.1017,
calcd for C12H14O2 190.0994. MS (m/e): 190 (M+), 176 (4), 162
(24), 147 (22), 134 (100), 115 (11), 105 (18), 91 (49), 77 (39).
2,3-Dim et h oxy-6,7,8,9-t et r a h yd r o-5H -b en zo[a ]cyclo-
h ep ten -6-on e (25b). Yield: 74%. Viscous liquid. IR (neat):
2950, 1700, 1615, 1520, 1460, 1360, 1270, 1120 cm-1 1H NMR
.
(200 MHz, CDCl3) δ: 6.75 (s, 1H), 6.70 (s, 1H), 3.90 (d, 6H, J
) 4 Hz), 3.65 (s, 2H), 2.90 (t, 2H, J ) 7.5 Hz), 2.55 (t, 2H, J )
7.5 Hz), 2.00 (m, 2H). 13C NMR (50.32 MHz, CDCl3) δ: 208.97,
148.12, 147.79, 132.93, 125.48, 113.51, 113.24, 56.21, 55.91,
49.81, 44.05, 32.95, 26.93. HRMS (EI): 220.1118, calcd for
C
13H16O3 220.1099. MS (m/e): 220 (M+), 192 (27), 177 (51),
164 (72), 149 (51), 121 (60), 107 (68), 91 (74), 77 (78).
1,2,3-Tr im eth oxy-6,7,8,9-tetr a h yd r o-5H-ben zo[a ]cyclo-
h ep ten -6-on e (25c). Yield: 72%. IR (neat): 2938, 1706,
1492, 1410, 1120 cm-1 1H NMR (200 MHz, CDCl3) δ: 1.9-
.
2.05 (m, 2H), 2.5-2.6 (t, 2H, J ) 7.5 Hz), 2.8-2.9 (t, 2H, J )
7.5 Hz), 3.75 (s, 2H), 3.8-3.9 (m, 9H), 6.5 (s, 1H). 13C NMR
(50.32 MHz, CDCl3) δ: 209.69, 152.35, 151.59, 141.21, 136.49,
119.90, 108.96, 61.57, 61.05, 56.23, 43.40, 41.47, 33.34, 26.67.
HRMS (EI) 250.1198, calcd for C14H18O4 250.1205. MS (m/e):
250 (M+), 219 (7), 190 (43), 161 (27), 147 (22), 134 (100), 105
(57), 91 (70), 77 (72).
2,3-Dim et h oxy-6,7,8,9,10-p en t a h yd r o-5H -b en zo[a ]cy-
cloocten -7-on e (27). Yield: 70%. Mp: 86 °C. IR (CHCl3):
3040, 2960, 1700, 1620, 1530, 1450, 1230, 1120 cm-1 1H NMR
.
7-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -2-on e (18a ).
Yield: 72%. Viscous liquid. IR (neat): 2949, 1716, 1612, 1504,
(200 MHz, CDCl3) δ: 6.65 (s, 1H), 6.70 (s, 1H), 3.85 (d, 6H),
3.70 (s, 2H), 2.80 (t, 2H, J ) 5.5 Hz), 2.35 (t, 2H, J ) 5.5 Hz),
1.80 (m, 4H). 13C NMR (50.32 MHz, CDCl3) δ: 211.76, 148.68,
147.69, 133.13, 125.63, 113.38, 113.15, 56.03, 48.20, 41.12,
32.95, 31.33, 24.71. HRMS (EI): 234.1229, calcd for C14H18O3
234.1255. MS (m/e): 234 (100, M+), 206 (63), 191 (54), 175
(68), 165 (46), 151 (24), 131 (24), 121 (44), 107 (37), 91 (49).
6′-Meth oxyspir o[cycloh exan e-1,1′-(2′,3′-dih ydr oin den e)]-
2,6-d ion e (34a ). Yield: 71%. IR (neat): 3020, 2940, 1700,
1261, 1037, 732 cm-1 1H NMR (200 MHz, CDCl3) δ: 7.05 (d,
.
1H, J ) 9.75 Hz), 6.75 (dd, J 1 ) 9.75 Hz, J 2 ) 2.53 Hz, 1H),
6.60 (bs, 1H), 3.75 (s, 3H), 3.50 (s, 2H), 2.90 (t, J ) 7.31 Hz,
2H), 2.45 (t, J ) 7.31 Hz, 2H). 13C NMR (50.32 MHz, CDCl3)
δ: 210.23, 158.39, 134.24, 128.46, 128.20, 113.37, 112.16,
54.98, 44.76, 38.23, 27.20. HRMS (EI): 176.0836, (calcd for
C
11H12O2 176.0837. MS (m/e): 176 (M+), 161 (5), 147 (10), 134
(100), 103 (17), 91 (25), 77 (17).
1600, 1430, 1320, 1250, 1210, 1080, 1020 cm-1 1H NMR (200
.
6,7-Dim e t h oxy-1,2,3,4-t e t r a h yd r on a p h t h a le n -2-on e
(18b). Yield: 74%. Viscous liquid. IR (CHCl3): 2939, 1716,
MHz, CDCl3) δ: 7.10 (d, J ) 9.80 Hz, 1H), 6.75 (m, 2H), 3.80
(s, 3H), 3.05 (t, J ) 7.50 Hz, 2H), 2.85 (m, 4H), 2.60 (t, J ) 7.5
Hz, 2H), 2.15 (m, 2H). 13C NMR (50.32 MHz, CDCl3) δ:
207.34, 160.19, 146.70, 132.52, 125.21, 112.89, 110.48, 77.89,
55.47, 38.38, 31.66, 17.85. HRMS (EI): 244.1068, calcd for
1510, 1514, 1465, 1338, 1247, 912 cm-1 1H NMR (200 MHz,
.
CDCl3) δ: 6.75 (s, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 3.80 (s, 3H),
3.50 (s, 2H), 3.00 (t, J ) 7.32 Hz, 2H), 2.55 (t, J ) 7.32 Hz,
2H). 13C NMR (50.32 MHz, CDCl3) δ: 209.92, 148.19, 147.99,
128.57, 125.26, 111.96, 111.67, 56.08, 44.03, 38.41, 28.09.
HRMS (EI): 206.0937, calcd for C12H14O3 206.0942. MS (m/
e): 206 (M+), 191 (5), 178 (13), 164 (55), 147 (13), 135 (17),
121 (25), 107 (40), 91 (34).
C
15H16O3 244.1099. MS (m/e): 244 (M+), 162 (15), 141 (3), 127
(4), 111 (7), 97 (13), 91 (15), 85 (36), 71 (60), 57 (100).
6′-Met h oxysp ir o[cycloh exa n e-1,1′-(3′,4′-d ih yd r o-2′H -
n a p h th a len e)]-2,6-d ion e (34b). Yield: 69%. IR (neat):
2950, 1720, 1700, 1620, 1510, 1480, 1250, 1180, 1120, 920, 740.
1-(6-Met h oxy-2,3-d ih yd r o-1H -1-in d en yl)-1-et h a n on e
(23a ). Yield: 70%. Viscous liquid. IR (neat): 2950, 1710,
cm-1 1H NMR (200 MHz, CDCl3) δ: 6.70 (m, 2H), 6.50 (d, J
.
) 8.4 Hz, 1H), 3.80 (s, 3H), 3.05-2.85 (m, 2H), 2.80-2.65 (m,
4H), 2.30-2.15 (m, 2H), 2.10-1.90 (m, 2H), 1.70-1.85 (m, 2H).
13C NMR (50.32 MHz, CDCl3) δ: 209.85, 158.38, 139.64,
131.30, 125.31, 113.41, 112.59, 70.66, 55.04, 38.06, 34.14,
29.47, 18.88, 17.55. HRMS (EI): 258.1208, calcd for C16H18O3
258.1256. MS (m/e): 258 (M+), 174 (100), 159 (28), 126 (15),
115 (22), 91 (15), 84 (86), 71 (22), 55 (61).
1610, 1500, 1160 cm-1
.
1H NMR (200 MHz, CDCl3) δ: 7.20
(d, J ) 9.75 Hz, 1H), 6.80 (dd, J 1 ) 9.75 Hz, J 2 ) 2.80 Hz,
1H), 6.75 (s, 1H), 5.75 (t, J ) 6.94 Hz, 1H), 3.80 (s, 3H), 2.75
(t, J ) 7.31 Hz, 2H), 2.30-2.20 (m, 2H), 2.05 (s, 3H). 13C NMR
(50.32 MHz, CDCl3) δ: 206.23, 158.07, 137.66, 128.23, 112.56,
109.97, 62.04, 55.20, 31.45, 28.18, 25.82. HRMS (EI): 190.0996,
calcd for C12H14O2 190.0994. MS (m/e): 190 (M+), 174 (68),
159 (100), 144 (38), 128 (46), 115 (51), 103 (13), 91 (23), 77
(19).
Ack n ow led gm en t. M.K. and A.M. thank CSIR,
New Delhi, for the award of research fellowships. We
are grateful to Dr. K. R. Agnihotri, RSIC, Punjab
University, Chandigarh, for providing HRMS data.
1-(5,6-Dim et h oxy-2,3-d ih yd r o-1H -1-in d en yl)-1-et h a n -
on e (23b). Yield: 70%. Viscous liquid. IR (neat): 2930, 1710,
1590, 1495, 1250, 1150 cm-1 1H NMR (200 MHz, CDCl3) δ:
.
6.80 (s, 1H), 6.70 (s, 1H), 5.75 (t, J ) 6.94 Hz, 1H), 3.85 (s,
J O9718612