Revisiting [3 + 3] route to 1,3-cyclohexanedione frameworks: Hidden aspect of thermodynamically controlled enolates

Article abstract of DOI:10.1021/jo010325d

We have revisited the traditional consecutive Michael-Claisen [3 + 3] process (MC-[3+3]) promising the synthesis of a cyclohexane-1,3-dione derivatives from nonactivated simple ketones and enoates and evaluated its potential in modern organic synthesis. Twenty to thirty examples were demonstrated to be effective. The reactions exhibited remarkable regioselectivity with the Michael addition proceeding through nucleophilic attack by the more hindered site of the ketones without exception. The subsequent Claisen condensation resulted in the formation of carbon-carbon bonds between less hindered site of the ketones and acyl carbon of the enoates. The MC-[3+3] process described is useful for the synthesis of Taxol A-ring synthons in multigram quantities and for the synthesis of other six-membered carbocyclic compounds. A number of control experiments have been conducted to provide strong support for the mechanism of this MC-[3+3].

Full text of DOI:10.1021/jo010325d

8000
J . Org. Chem. 2001, 66, 8000-8009
Revisitin g [3 + 3] Rou te to 1,3-Cycloh exa n ed ion e F r a m ew or k s:
Hid d en Asp ect of Th er m od yn a m ica lly Con tr olled En ola tes
Teruhiko Ishikawa,* Ryuichiro Kadoya, Masaki Arai, Haruka Takahashi, Yumi Kaisi,
Tomohiro Mizuta, Kazusa Yoshikai, and Seiki Saito*
Department of Bioscience and Biotechnology, Faculty of Engineering, Okayama University, Tsushima,
Okayama 700-8530, J apan
seisaito@biotech.okayama-u.ac.jp
Received March 26, 2001
We have revisited the traditional consecutive Michael-Claisen [3 + 3] process (MC-[3 + 3])
promising the synthesis of a cyclohexane-1,3-dione derivatives from nonactivated simple ketones
and enoates and evaluated its potential in modern organic synthesis. Twenty to thirty examples
were demonstrated to be effective. The reactions exhibited remarkable regioselectivity with the
Michael addition proceeding through nucleophilic attack by the more hindered site of the ketones
without exception. The subsequent Claisen condensation resulted in the formation of carbon-carbon
bonds between less hindered site of the ketones and acyl carbon of the enoates. The MC-[3 + 3]
process described is useful for the synthesis of Taxol A-ring synthons in multigram quantities and
for the synthesis of other six-membered carbocyclic compounds. A number of control experiments
have been conducted to provide strong support for the mechanism of this MC-[3 + 3].
In tr od u ction
of this MC-[3 + 3] route to the 1,3-cyclohexanedione
framework. In this paper, we will describe the generality
of the MC-[3 + 3] in the synthesis of wide variety of
cyclohexane-1,3-dione derivatives from nonactivated simple
ketones and R,â-unsaturated esters and discuss the
mechanistic insight gained through our control experi-
ments.
About 60 years ago, Hurd and Kelso reported that they
obtained 1-undecene-3,5-dione (1) as a product of Claisen
reaction1 between ethyl acrylate and 2-octanone in the
presence of sodium ethoxide: the elemental analysis was
the only proof of the product structure. Seventeen years
later, Miller and Benneville2 correctly revised Hurd and
Kelso’s product to be 4-pentyl-1,3-cyclohexanedione (2)
(Scheme 1)
They also proposed the mechanism that Michael ad-
dition reaction of an enolate generated from the ketone
under thermodynamically controlled conditions toward
the R,â-unsaturated ester took place in the first place
followed by intramolecular Claisen condensation to give
a 1,3-cyclohexanedione framework of 2 (Michael-Claisen
[3 + 3] reaction ) MC-[3 + 3]). Although Michael addition
reactions of 1,3-dicarbonyl compounds toward R,â-
unsaturated ketones were also well-known to be followed
by intramolecular Claisen cyclizations,3 the combination
of Michael addition and Claisen condensation using
nonactivated simple ketones and R,â-unsaturated esters
as starting materials would provide an extremely simple
[3 + 3] route to 1,3-cyclohexanedione frameworks.4,5
However, little effort has been made in this context6 since
the first report of Hurd and Kelso.1 Such a situation has
given us strong incentive to further examine the potential
(4) It is well-known that 2-methyl-1,3-cyclohexanedione is a key
starting compound for the synthesis of Wieland-Mischer ketone; see:
(a) Hajos, Z. G.; Parrish, D. R. J . Org. Chem. 1974, 39, 1615-1621.
(b) Buchschcher, P.; Fu¨rst, A.; Gutzwiller, J . Organic Syntheses;
Wiley: New York, 1990; Collect. Vol. VII, pp 368-372.
(5) For total synthesis utilizing 1,3-cyclohexanedione derivatives,
see: (a) Stork, G.; Kretchmer, R. H.; Schlessinger, R. H. J . Am. Chem.
Soc. 1968, 90, 1647-1648. (b) Canonica, L.; Rindone, B.; Santaniello,
E.; Scolastico, C. Tetrahedron 1972, 28, 4395-4404. (c) Kieczykowski,
G. R.; Quesada, M. L.; Schlessinger, R. H. J . Am. Chem. Soc. 1980,
102, 782-790. (d) J ung, M. E.; McCombs, C. A.; Takeda, T.; Pan,
Y.-G. J . Am. Chem. Soc. 1981, 103, 6677-6685. (e) Magnus, P.;
Gopalan, A. J . Org. Chem. 1984, 49, 2317-2321. (f) Holton, R. A.;
Kennedy, R. M.; Kim, H.-B.; Krafft, M. E. J . Am. Chem. Soc. 1987,
109, 1597-1600. (g) Kraus, G. A.; J ohnston, B. E.; Applegate, J . M.
J . Org. Chem. 1991, 56, 5688-5691. (h) Myers, A. G.; Fraley, M. E.;
Tom, M. J .; Cohen, S. B.; Modar, D. J . Chem. Biol. 1995, 2, 33-43. (i)
Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.;
Kusama, H.; Kuwajima, I. J . Am. Chem. Soc. 1998, 120, 12980-12981.
(j) Hara, R.; Furukawa, T.; Kashima, H.; Kusama, H.; Horiguchi, Y.;
Kuwajima, I. J . Am. Chem. Soc. 1999, 121, 3072-3082. (k) Dudley,
G. B.; Takai, K. S.; Cha, D. D.; Danheiser, R. L. Org. Lett. 2000, 2,
3407-3410.
(6) This work is not concerned with MC-[3 + 3] using activated
ketones such as 1,3-dicarbonyl compounds, for which a large number
of papers have been published (see ref 3). As far as nonactivated simple
ketones and enoates are concerned, only one additional report is
available to the best of our knowledge; see: (a) Miller, M. L.; Ray, P.
S. Synth. Commun. 1997, 27, 3991-3996 in which MC-[3 + 3]
employing 3-pentanone and methyl acrylate (dropwise addition of a
mixture of the ketone and the enoate to NaOMe/xylene at 35 °C and
heating at 120 °C to remove the methanol) was described. For other
closely related work Zimmerman reported the synthesis of 4,4-
diphenylcyclohexane-1,3-dione through MC-[3 + 3] between moderately
activated 1,1-diphenylacetone and ethyl acrylate (t-BuOK/ether, 18 h
at room temperature) without discussion about regiochemical issue of
the reaction: (b) Zimmerman, H. E.; Pasteris, R. J . J . Org. Chem. 1980,
45, 4876-4891.
(1) Hurd, C. D.; Kelso, C. D. J . Am. Chem. Soc. 1940, 62, 2184-
2187.
(2) Miller, J . J .; Benneville, P. L. J . Org. Chem. 1957, 22, 1268-
1269.
(3) See, for instance: (a) Hauser, C. R.; Swamer, F. W.; Adams, J .
T. Org. React. 1954, 8, 59-195. For Michael addition, see: (b) J ung,
M. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 1.1. For Claisen
condensation, see: (c) Davis, B. R.; Garratt, P. J . In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
1991; Vol. 2, Chapter 3.6.
10.1021/jo010325d CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/27/2001

[3 + 3] Route to 1,3-Cyclohexanedione Frameworks
J . Org. Chem., Vol. 66, No. 24, 2001 8001
Sch em e 1
of the ketones and acyl carbon of the enoates (Table 1,
entries 1-5 and 12-21). Therefore, no regioisomers were
isolated at all.
The proportions of homo coupling products under the
standard conditions were 2% at most as far as ethyl
methyl ketone, diethyl ketone, and isopropyl methyl
ketone were concerned: also we observed that acetone
was a special ketone to result in violent reaction giving
a complex dark mixture under the standard condi-
tions. As already mentioned above t-BuOK is the key to
the successful MC-[3 + 3] (see the EtONa example in
Scheme 2). The nature of the countercation, however,
seems unimportant in terms of reactivity or regioselec-
tivity: as far as three cations (t-BuO-M+; M ) Li, Na,
and K) were concerned, no difference was observed in
every respect.8
C. Mech a n ism of t h e MC-[3 + 3] in THF : (1)
P r op osa l. The plausible mechanism of MC-[3 + 3] is
illustrated in Scheme 3. The reaction reproduces t-BuOK
after the Michael addition, which plays the role of second-
stage deprotonation for Claisen cyclization, and an
enoate-based alkoxide was eventually produced. This
base was, however, destined to deprotonate from the final
products 1,3-diones. Therefore, the equimolar amount of
the base was strictly required for the completion of the
MC-[3 + 3].
Sch em e 2
(2) Con tr ol Exp er im en ts to Su p p or t th e Mech a -
n ism . When enediones such as 23 or 24 were treated
with t-BuOK, no intramolecular Michael adduct such as
15 or 17 was furnished at all as shown in eqs 1 and 2.
Therefore, there seems no chance of initial Claisen
reaction followed by intramolecular Michael addition.
Resu lts a n d Discu ssion
A. Reexa m in a tion of th e Or igin a l MC-[3 + 3].
Initially, the original MC-[3 + 3] between 2-octanone and
ethyl acrylate was carefully reexamined. In our hands,
the original conditions employing sodium ethoxide re-
sulted in a 58% yield of 2 and a considerable amount of
ethyl 3-ethoxypropanoate (30%) (Scheme 2). We found
that the combination of commercially available potassium
tert-butoxide (t-BuOK) as a base and THF as a solvent
can effect the expected MC-[3 + 3] to efficiently furnish
2 in high yield (88%).
B. Gen er a lity of th e MC-[3 + 3]: Syn th esis of
Va r iou s Cycloh exa n e-1,3-d ion es. To assess the gen-
erality of MC-[3 + 3] for the synthesis of various cyclo-
hexane-1,3-diones, we applied the conditions (t-BuOK/
THF) to various simple ketone7 and enoate combinations,
and the results are summarized in Table 1. Although
reactivities or product yields depended on the structures
of substrates and/or enoates, the expected MC-[3 + 3]
was effected for every case examined (21 entries). The
best choice of enoate alkyl group was a tert-butyl group,
the typical cases of which are shown in Table 1, entries
6 and 7 or 12 and 13. Interestingly, Michael addition
proceeded through nucleophilic attack by more hindered
site of the ketones without exception, which, in turn,
means that Claisen condensation resulted in the forma-
tion of carbon-carbon bond between less hindered site
The use of 10 mol % of t-BuOK for the reaction of
isopropyl methyl ketone with tert-butyl acrylate resulted
in the formation of 14 in 10% yield (eq 3). This result
clearly indicated that the regenerated t-BuOK was
trapped by highly acidic cyclohexane-1,3-dione deriva-
tives to give E5 (Scheme 3) as a final product before
quenching.
Kuwajima reported in 1976 that the kinetic generation
of enolate from methyl ketones became feasible when a
solution of the ketones in THF was treated with sterically
hindered bases even in the presence of aldehydes.9
Indeed, when isopropyl methyl ketone was treated with
t-BuOK in the presence of methyl benzoate, kinetically
controlled Claisen condensation took place to give a 1,3-
(8) The regioselectivity for aldol reaction of 2-methylcyclohexanone
enolate depended on the nature of countercations such as K+ or Li+;
see: Duhamel, P.; Cahard, D.; Quesnel Y.; Poirier J .-M. J . Org. Chem.
1996, 61, 2232-2235.
(9) Kuwajima, I.; Sato, T.; Arai, M.; Minami, N. Tetrahedron Lett.
1976, 1817-1820.
(7) These ketones were prepared by alkylation of ethyl methyl
ketone with requisite alkyl halides in the presence of t-BuOK. The
regioselective alkylation of simple ketones using alkoxide bases are
under active investigation in this laboratory.

8002 J . Org. Chem., Vol. 66, No. 24, 2001
Ishikawa et al.
Ta ble 1. Resu lts of MC-[3 + 3] betw een Sim p le Keton es a n d En oa tes Lea d in g to Cycloh exa n e-1,3-d ion es P r om oted by
t-Bu OK in THF a

[3 + 3] Route to 1,3-Cyclohexanedione Frameworks
J . Org. Chem., Vol. 66, No. 24, 2001 8003
Ta ble 1. (Con tin u ed )
a
Standard conditions:
d
b After the addition of t-BuOK. c Aqueous HCl as a better proton source than ammonium chloride. Diastereomer ratio were not determined
g
h
i
unless otherwise indicated. e Cis/trans ) 4:1. f Cis/trans ) 2:3. Trans only. Cis/trans ) 2:3. See ref 7.
addition to the aldehyde (eq 5).10 These two control
Sch em e 3
experiments clearly indicated the presence of kineti-
cally generated enolate of isopropyl methyl ketone (E1
in Scheme 3). Nevertheless, no Michael reaction between
E 1 and enoate was detected at all for the present
MC-[3 + 3].11
As shown in Table 1, the ketone enolates generated
from ethyl methyl ketone (entries 1-5), isopropyl methyl
diketone (d ion e 1: 75%) as shown in eq 4. Also treat-
ment of the same simple ketone with catalytic amount
of t-BuOK (10 mol %) in the presence of an aromatic
aldehyde such as furfural furnished aldol condensation
product as a result of kinetically generated enolate
(10) For review of aldol condensation, see: Heathcock, C. H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, Chapter 1.5.

8004 J . Org. Chem., Vol. 66, No. 24, 2001
Ishikawa et al.
Sch em e 4
Sch em e 5a
a
Key: (a) (1) t-BuOK/THF/0.5 h, rt, (2) CH3I/3 h, 50 °C; (b)
HO(CH2)2OH/THF/TsOH/HC(OEt)3/rt, 12 h; (c) (1) TMSCN/CH2Cl2/
TMSOTf/rt, 6 h, (2) pyrid/SOCl2/Et2O/rt, 12 h; (d) DIBAL/CH2Cl2/
-78 °C, 0.5 h.
was apparently introduced through Michael reaction
between the en on e 1 and the more substituted enolate
generated from B followed by intramolecular aldol con-
densation to give en on e-2 (28), which acted as a more
substituted Michael donor toward A, affording en on e-3.
Dion e 2 was apparently provided through self-double
Michael addition of en on e-1. Thus, neither aldol reaction
between furfural and more substituted enolates nor
Michael reaction between en on e-1 or tert-butyl acrylate
and less substituted enolates proceeded at all.
D. Ap p lica tion of th e MC-[3 + 3]: (1) A-Rin g
Segm en t of Ta xol. 2,2,4-Trimethylcyclohexane-1,3-
dione (30)6a is the well-known A-ring segment employed
recently in the total synthesis of Taxol by Danishefsky,13
and his route to 3014 was originally reported by Hickmott
et al.15 MC-[3 + 3] between 3-pentanone and ethyl
acrylate followed by iodomethane treatment furnished
this important intermediate (65% yield) in multigram
quantities (Scheme 5). All staff required in this trans-
formation are cheap and safe commercial products,
available in bulk quantities, and used as received with-
out any further purification. It also features high yield,
operational simplicity, short reaction time, and envi-
ronmental consciousness in terms of the coproducts of
the reaction (t-BuOH, EtOH, and KI). When tert-butyl
acrylate was used in place of ethyl acrylate, the yield of
30 was somewhat improved (71% yield).
ketone (entries 12-18), 5-(p-methoxybenzyl)oxy-3-meth-
yl-2-pentanone (entries 19 and 20), 4-methyl-1-phenyl-
(1E)-hexen-5-one (entry 21), and 2-octanone (Scheme 2)
exhibited perfect and clear-cut selectivity that the more
substituted site plays a role of a Michael donor: the
methyl group never did this. However, we found that,
for ethyl isopropyl ketone, both sites could serve as the
Michael donor to give a mixture of the MC-[3 + 3] product
(25: 71%) and the regioisomeric Michael product (26:
29%) (eq 6). Thus, the ring-closing Claisen reaction
suffered from structure limitations: diisopropyl ketone
did not afford cyclohexane-1,3-dione derivatives but led
only to Michael adduct 27 (40%) under the conditions (eq
7), which was the same trend as the fact that no ring-
closing Claisen reaction of 26 took place.
(3) Ad d ition a l Evid en ce Su p p or tin g th e In tr in sic
Ch em oselectivity of Equ ilibr a tin g En ola tes. When
isopropyl methyl ketone (B) was treated with t-BuOK in
THF in the presence of both tert-butyl acrylate (A) and
furfural (C: Fu-CHO), five identifiable products [14, 28
(en on e-2), en on e-3, d ion e-2, and 29 (d ien ol)] were
obtained.12 Aside from 14, we need a plausible mecha-
nism that can explain the formation of the remaining four
products. These results and the mechanism are shown
in Scheme 4. Those four products contain an en on e-1-
based segment with them. Interestingly, such a segment
To confirm the structure of 30 and also to prepare a
novel A-ring synthon (33) for taxane diterpenoids,16 the
following transformations were conducted. After the C(1)-
carbonyl group of 30 was protected as an acetal (31), the
remaining carbonyl group was converted to cyanohydrin
(TMSCN/TMSOTf)17 followed by dehydration (SOCl2) to
(13) Masters, J . J .; Link, J . T.; Snyder, L. B.; Young, W. B.;
Danishefsky, S. J . Angew. Chem., Int. Ed. Engl. 1995, 34, 1723-1726.
(14) (a) Queneau, Y.; Krol, W. J .; Bornmann, W. G.; Danishefsky,
S. J . J . Org. Chem. 1992, 57, 4043-4047. (b) Grandi, M. J . D.; J ung,
D. K.; Krol, W. J .; Danishefsky, S. J . J . Org. Chem. 1993, 58, 4989-
4992.
(11) The regioselectivity of this class has been fragmentary observed;
see: (a) Bruson, H. A.; Riener, T. W. J . Am. Chem. Soc. 1942, 64, 2850-
2858. (b) Barkley, L. B.; Levine, R. Ibid. 1950, 72, 3966-3701. (c) Ross,
N. C.; Levine, R. J . Org. Chem. 1964, 29, 2341-2346.
(12) Treatment of en on e-2 (28) with t-BuOK in THF afforded
tautomeric d ien ol (29), which was so stable that it could be isolated
by silica gel column chromatography.
(15) Hargreaves, J . R.; Hickmott, P. W.; Hopkins, B. J . J . Chem.
Soc. C 1968, 2599-2603.
(16) For the synthesis of A-ring synthon of Taxol by means of intra-
molecular Claisen condensation, see: Seto, M.; Morihira, K.; Horiguchi,
Y.; Kuwajima, I. J . Org. Chem. 1994, 59, 3165-3174.
(17) Noyori, R.; Murata, S.; Suzuki, M. Tetrahedron 1981, 37, 3899-
3910.

[3 + 3] Route to 1,3-Cyclohexanedione Frameworks
J . Org. Chem., Vol. 66, No. 24, 2001 8005
Sch em e 6
Sch em e 7
the reaction of 2-methylcyclohexanone (41) with tert-butyl
methacrylate led to 1,3-dimethylbicyclo[3.3.1]nonane-4,9-
dione (42: 55%) under the standard conditions (Scheme
7). Again, Michael addition was effected only between the
more substituted enolate and the enoate in marked
contrast to eq 6.19 The final treatment of the reaction with
allyl bromide resulted in allylation not at the bridgehead
carbon but at the carbon corresponding to the R-carbon
of tert-butyl methacrylate to furnish 43 (62%). Cyclohex-
anone itself was not amenable to the MC-[3 + 3]. This
was also the case for other cyclic ketones such as
cycloheptanone or cyclooctanone, and only R-substituted
versions (44 or 47) led to the MC-[3 + 3] product 45 (69%)
or 48 (41%), respectively. In addition, enoates were
requested to bear an R-substituent for the MC-[3 + 3] to
be effected under the standard conditions.20
Interestingly, the reaction of 2-methylcyclohexanone
with tert-butyl methacrylate using 10 mol % of t-BuOK
resulted in only Michael addition to give 50 (92%) in
marked contrast to the case of acyclic simple ketone
such as isopropyl methyl ketone in which MC-[3 + 3]
took place to the extent equal to the amount of the
base used (see eq 3). The use of over 10 mol % of the
base gave a mixture of 50 and 42, and the amount of
42 gradually increased with the increase in the amount
of the base.
furnish an R,â-unsaturated nitrile (32), which was led
to enal 33 via DIBALH reduction. The known iodoolefin
(35) was also prepared via the hydrazone (34) by means
of the Barton protocol.18 Spectroscopic data for 33 or 35
involving IR and NMR were fully consistent with the
expected structures.
(2) Mor e Com p lex a n d F u n ction a lized Cycloh ex-
a n e-1,3-d ion es. When isopropyl methyl ketone was
reacted with a highly functionalized Michael acceptor
such as diethyl furfurylidenemalonate (36) under the
standard conditions, the desired MC-[3 + 3] product (37)
was only a minor one (Scheme 6). This is probably
because retro-Michael reaction from malonate anion
intermediate would be very easy which, in turn, means
that the chance of subsequent Claisen cyclization must
be scarce. In addition, inevitable moisture involved in the
reaction system might serve as a Michael donor to attack
36 leading to furfural and diethyl malonate. Indeed,
although 37 was only in <10% yield, unreacted 36 was
not recovered at all.
The initial Michael reaction became the acceptable
level by employing protic solvent such as dry t-BuOH to
afford 38 in high yield (90%). In addition, Claisen
cyclization of 38 proceeded very efficiently under the
protic conditions to afford 37 (88%). It also turned out
that such conditions (b in Scheme 6) can be employed to
effect the one-pot MC-[3 + 3] between isopropyl methyl
ketone and 36 to give 37 in somewhat lower yield (48%).
This MC-[3 + 3] under protic conditions was also used
for the 4-methyl-1-phenyl-1-hexen-5-one (39)7 and 36
system to afford highly functionalized cyclohexane-1,3-
dione derivative 40 (58%).
(4) Cycloh exen on e Der iva tives: Ta n d em Ald ol
Con d en sa tion , Mich a el Ad d ition , a n d Ald ol Con -
d en sa tion . We were intrigued with the idea to take
advantage of above-mentioned regiochemical features to
realize three components coupling process consisted of
(19) The reaction between 2-methylcyclohexanone and tert-butyl
acrylate gave only Michael adducts (61%) as a mixture of regioisomers
in a ratio 93:7 (10 mol % of t-BuOK in t-BuOH); see: House, H. O.;
Roelofs, W. L.; Trost, B. M. J . Org. Chem. 1966, 31, 646-655.
(20) It should be noted that no reaction between 2-methylcyclo-
hexanone and tert-butyl methacrylate with 10 mol % of the base in
protic solvent such as t-BuOH took place; see ref 19.
(3) Bicyclic 1,3-Dion es. The present MC-[3 + 3]
strategy was applicable to bicyclic systems. For example,
(18) Barton, D. H. R.; Bashiardes, G.; Fourrey, J . Tetrahedron 1988,
44, 147-162.

8006 J . Org. Chem., Vol. 66, No. 24, 2001
Ta ble 2. En ol Eth er fr om Cycloh exa n e-1,3-d ion esa
Ishikawa et al.
enone
cyclohexane-1,3-dione
yield/% (R)
A/B
13, a ) d ) Me; b ) H; c ) Ph
86 (Me)
92 (Me)
82 (Et)
73 (Me)
78 (Me)
53/54 ) 5.6:1
55/56 ) 3:1
57/58 ) 3.6:1
59/60 ) 2.8:1
61/62 ) 2.4:1
17, a ) b ) Me; c ) Ph; d ) H
18, a ) b ) Me; c ) CO2Et; d ) H
19, a ) b ) Me; c ) 1-propenyl; d ) H
22, a ) PhCHdCHCH2; b ) Me; c ) d ) H
a
A (0.3 equiv), B (1 equiv), C (0.3 equiv)/t-BuOK (0.62 eq) /t-BuOH-THF (1:1), 0 °C rt, 12 h: the yields based on B.
Sch em e 8
Ch a r t 1
regioselectivities were summarized in Table 2, which
range from 70 to 85% in preference to less hindered
carbonyl groups (Table 2, Chart 1).
The kind of alcohol exhibited almost no effect on this
regioselection. These enol ethers were readily separated
by means of simple silica gel column chromatography. A
part of thus-obtained 3-alkoxy-2-cyclohexen-1-ones (53,
55-57, 59, 61, 62) led to 2-cyclohexen-1-one derivatives
(63-69 in 63-83% yield, Chart 1), respectively, through
LAH reduction and acid treatment.
tandem aldol condensation of ketones with aldehydes to
give enones, Michael addition of ketone enolates to thus-
generated enones furnishing 1,5-diketone frameworks,
and final intramolecular aldol condensation of the 1,5-
diketones to cyclohexenone derivatives (AMA-[3+1+2]).21
We have succeeded in realizing the idea by using two
parts of a simple ketone, one part of an aromatic
aldehyde, and one part of t-BuOK which is summarized
in Scheme 8. Three of these were uniformly regioselective
for carbon-carbon bond formations which occurred three
times in this three-component coupling process. Interest-
ingly, the initial one part of the base got involved in
generating the enolates three times because it was able
to be regenerated. Thus, the AMA-[3 + 1 + 2] process
might become a simple, efficient and highly convenient
way of synthesizing cyclohexenones bearing aromatic
substituent at C(5) such as en on e-2 (28), 51, or 52.
Con clu sion s
It needs to be economical, safe, environmentally con-
scious, and resource- and energy-saving for organic
synthesis to be practical.23 As a part of programs to be
as close to such ultimate goals as possible, we revisited
an already existing but forgotten organic reaction and
have succeeded in evaluating its high potential in modern
organic synthesis. A system consisting of nonactivated
simple ketones, enoates, and t-BuOK in THF as a
practical method for the synthesis of cyclohexane-1,3-
dione derivatives deserves consideration. It requires no
skill and no special equipment and leaves behind only
environmentally benign coproducts other than the de-
sired products. The clear-cut, fabulous reactivity trend
observed for the thermodynamically equilibrating eno-
lates generated from simple aliphatic ketones should be
the main thrust of the revisiting chemistry and be taken
up as synthetic strategy in myriad aspects.
(5) Con ven ien t Syn th esis of Su bstitu ted Cyclo-
h exen on e Der iva t ives fr om Cycloh exa n e-1,3-d i-
on es. The transformation of cyclohexane-1,3-diones to
2-cyclohexen-1-ones is well-known.22 Thus, we selected
several diones such as 13, 17-19, and 22, which were
converted to enol ethers in a usual way. The observed
(21) For review of aldol condensation, see: Heathcock, C. H. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, Chapter 1.5.
(22) (a) Gannon, W. F.; House, H. O. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, pp 294-296 and 539-544. (b) Stork, G.;
Danheiser. R. L. J . Org. Chem. 1973, 38, 1775-1776.
(23) For example, see: Sato, K.; Aoki, M.; Noyori, R. Science 1998,
281, 1646-1647.

[3 + 3] Route to 1,3-Cyclohexanedione Frameworks
J . Org. Chem., Vol. 66, No. 24, 2001 8007
(d, 1H, J ) 4.3 Hz), 6.22-6.28 (m, 2H), 7.24-7.27 (m, 2H);
13C NMR δ 17.1, 18.4, 22.7, 27.3, 35.4, 40.2, 41.0, 47.8, 49.5,
50.3, 106.3, 108.6, 109.8, 110.3, 141.0, 142.1, 152.0, 155.0; IR
(film) 1742 cm-1. Anal. Calcd for C20H24O4: C, 73.15; H, 7.37.
Found: C, 73.02; H, 7.49.
5-F u r yl-3-isop r op ylid en e-6,6-d im eth yl-1-cycloh exen -1-
ol (d ien ol 29): 1H NMR δ 1.06 (s, 3H), 1.14 (s, 3H), 1.42 (s,
3H), 1.44 (s, 3H), 2.54 (dd, 1H, J ) 4.7, 18.7 Hz), 2.79 (dd, 1H,
J ) 10.2, 18.7 Hz), 3.16 (dd, 1H, J ) 4.7, 10.2, Hz), 4.00-4.01
(b, 1H), 6.12 (d, 1H, J ) 3.1 Hz), 6.33 (dd, 1H, J ) 1.9, 3.1
Hz), 6.75 (s, 1H), 7.34 (m, 1H); 13C NMR δ 20.0, 23.1, 27.2,
27.6, 28.1, 43.7, 43.8, 73.0, 107.3, 110.1, 135.2, 140.0, 141.4,
154.5, 199.5; IR (film) 3395 cm-1. Anal. Calcd for C15H20O2:
C, 77.55; H, 8.68. Found: C, 77.42; H, 8.81.
Exp er im en ta l Section
Gen er a l Meth od s. For general remarks, see ref 24.
Ma ter ia ls. Unless otherwise noted, materials were obtained
from commercial suppliers, and reagent-grade materials were
used without further purification. Toluene, triethylamine
(Et3N), dichloromethane (CH2Cl2), acetonitrile, and benzene
were freshly distilled from CaH2 prior to use. Methanol
(MeOH) and ethanol (EtOH) were distilled from magnesium
turnings under argon. tert-Butyl alcohol (t-BuOH) was dried
over 4 Å molecular sieve prior to use. Tetrahydrofuran (THF)
purchased from Kanto Chemical Co., Inc. was dehydrated and
stabilizer-free grade and used as received.
4-P en t yl-1,3-cycloh exa n ed ion e (2). To a solution of 2-
octanone (1.50 g, 11.6 mmol) in THF (10 mL) was added
t-BuOK (1.24 g, 10.7 mmol) at room temperature, and the
mixture was stirred at 0 °C for 5 min. To the mixture was
introduced ethyl acrylate (0.92 g, 9.2 mmol) dropwise at 0 °C.
The reaction mixture was stirred at room temperature for 20
min and the reaction quenched with a saturated aqueous
solution of NH4Cl (5 mL) followed by the addition of anhydrous
MgSO4. The organic solutions were concentrated to give an
oil, which, on CC (1:1 hexane/AcOEt), afforded dione 2 (1.48
4-(5-F u r yl-4,4-d im eth yl-3-oxo-1-cycloh exen yl)-4-m eth -
ylp en ta n oic Acid (En on e-3). En on e-3 was obtained not as
tert-butyl ester but as a free carboxylic acid: 1H NMR δ 1.00
(s, 3H), 1.08 (s, 3H), 1.14 (s, 6H), 1.77-1.83 (m, 2H), 2.14-
2.19 (m, 2H), 2.54 (dd, 1H,J ) 5.0, 18.4 Hz), 2.67 (ddd, 1H, J
) 1.7, 9.9, 18.4 Hz), 3.14 (dd, 1H, J ) 5.0, 9.9 Hz), 5.93 (d,
1H, J ) 1.7 Hz), 6.09 (d, 1H, J ) 3.0 Hz), 6.31 (dd, 1H, J )
1.9, 3.0 Hz), 7.31-7.33 (m, 1H); 13C NMR δ 19.9, 23.1, 26.2,
26.3, 28.1, 29.7, 34.9, 39.3, 44.4, 44.5, 107.1, 110.0, 123.5, 141.2,
154.9, 166.8, 178.9, 204.2; IR (film) 3650-2400 (very broad
1
g, 88%) as a colorless solid: mp 62-64 °C; H NMR for keto
with shoulders at 3450, 3150, and 2700), 1709, 1664 cm-1
.
form δ 0.89 (t, 3H, J ) 6.6 Hz), 1.22-1.43 (m, 8H) 1.52-1.66
(m, 2H), 1.75-1.92 (m, 2H), 2.16 (dq, 2H, J ) 5.1, 14.0 Hz),
2.41-2.51 (m, 1H), 2.59 (dd, 1H, J ) 5.5, 11.5 Hz) 2.70 (dt,
2,2,4-Tr im eth ylcycloh exa n e-1,3-d ion e (30). To a solution
of 3-pentanone (30.0 g, 348 mmol) in THF (500 mL) was added
t-BuOK (45.9 g, 409 mmol) at room temperature, and the
mixture was stirred at 0 °C for 10 min. To the mixture was
added ethyl acrylate (34.1 g, 341 mmol) dropwise at 0 °C, and
the reaction was stirred at room temperature for 20 min
followed by the addition of iodomethane (142 g, 1.0 mol). The
mixture was warmed to 50 °C and stirred for 3 h. The reaction
was quenched by the addition of water and extracted with
AcOEt. The combined organic layers were dried with Na2SO4
and concentrated to give a crude oil, which was purified by
CC (5:1 hexane/AcOEt) to afford dione 30 (34.0 g, 65%) as a
colorless oil: 1H NMR δ 1.10 (d, 3H, J ) 6.6 Hz), 1.18 (s, 3H),
1.32 (s, 3H), 1.42 (dq, 1H, J ) 4.9, 13.4 Hz), 2.02-2.12 (m,
1H), 2.57 (ddd, 1H, J ) 3.0, 4.9, 15.9 Hz), 2.70-2.88 (m, 2H);
13C NMR δ 14.7, 18.8, 25.9, 26.3, 37.1, 40.6, 61.0, 210.6, 211.3;
1H, J ) 4.7, 16.2 Hz) 3.42 (s, 2H); IR (film) 1730, 2980 cm-1
;
13C NMR signals for this compound were difficult to assign
because of indistinguishable signals due to keto-enol tau-
tomers.
Con tr ol Exp er im en ts: Rea ction of Isop r op yl Meth yl
Keton e w ith ter t-Bu tyl Acr yla te in th e P r esen ce of
F u r fu r a l. To a solution of isopropyl methyl ketone (0.72 mL,
6.7 mmol), tert-butyl acrylate (0.3 mL, 2.0 mmol), and furfural
(0.17 mL, 2.0 mmol) in THF (5 mL)-t-BuOH (5 mL) mixed
solvent was slowly added t-BuOK (470 mg, 4.2 mmol) at 0 °C.
The mixture was stirred at room temperature for 12 h and
quenched with a saturated aqueous solution of NH4Cl (5 mL)
followed by the addition of anhydrous MgSO4. The organic
solutions were concentrated to give a crude oil, which was
purified by CC (10:1-1:1 hexane/AcOEt) to give en on e-2 (28)
(0.32 mmol, 10%), d ion e-2 (0.173 mmol, 5.4%), d ien ol (29)
(0.21 mmol, 6.2%), en on e-3 (0.91 mmol, 27%), and 14 (1.12
mmol, 17%): the yields were based on the ketone.
En on e-2 (28) was identified by comparing its NMR spectra
with those of an authentic sample prepared as described below.
5-(2-F u r yl)-3-isop r op yl-6,6-d im et h yl-2-cycloh exen -1-
on e (En on e-2: 28). To a solution of 3-methyl-2-butanone (2.59
mL, 24.2 mmol) in THF (50 mL) was added t-BuOK (1.40 g,
12.5 mmol) at 0 °C, and the mixture was stirred at 0 °C for 5
min. To the solution was added furfural (1.00 mL, 12.1 mmol)
dropwise at 0 °C, and the mixture was stirred at room
temperature for 6.5 h. The reaction was quenched by adding
saturated aqueous solution of NH4Cl and extracted with
AcOEt. The combined organic layers were dried over MgSO4
and concentrated to afford a crude oil, which was purified by
CC (10:1 hexane/AcOEt) to give 28 (1.39 g, 49%) as a colorless
oil: 1H NMR δ 1.00 (s, 3H), 1.08 (s, 3H), 1.12 (dd, 6H, J ) 1.4,
6.9 Hz), 2.35-2.50 (m, 2H), 2.73 (dq, 1H, J ) 2.2, 10.7 Hz),
3.17 (dd, 1H, J ) 4.7, 10.4 Hz), 5.87 (t, 1H, J ) 1.1 Hz), 6.09
(dd, 1H, J ) 0.8, 3.3 Hz), 6.31 (dd, 1H, J ) 1.9, 3.3 Hz), 7.32
(dd, 1H, J ) 0.8, 1.9 Hz); 13C NMR δ 20.0, 20.5, 20.8, 30.0,
35.4, 44.3, 44.7, 106.9, 110.0, 121.9, 141.1, 155.2, 168.0, 204.2;
IR (film) 1670 cm-1. Anal. Calcd for C14H20O2: C, 77.55; H,
8.68. Found: C, 77.42; H, 8.79.
IR (film) 1730 cm-1
.
3,3-(E t h ylen ed ioxy)-2,2,6-t r im et h yl-1-cycloh exa n on e
(31). To a solution of 30 (1.23 g, 7.97 mmol) in THF (15 mL)
were added ethylene glycol (0.67 mL, 12.0 mmol), p-toluene-
sulfonic acid monohydrate (150 mg, 0.80 mmol), and triethyl
orthoformate (1.60 mL, 9.56 mmol) at room temperature. The
mixture was stirred at room temperature for 8 h. The reaction
was quenched by the addition of Et3N (0.22 mL, 1.59 mmol).
The solution was concentrated to afford a crude oil, which was
purified by CC (20:1 hexane/AcOEt) to give 31 (1.43 g, 91%)
as a colorless oil: 1H NMR δ 0.98 (d, 3H, J ) 6.6 Hz), 0.98 (s,
3H), 1.22 (s, 3H), 1.35 (dq, 1H, J ) 4.1, 13.2 Hz), 1.71 (ddd,
1H, J ) 2.6, 4.3, 13.5 Hz), 1.78-1.87 (m, 1H), 2.03-2.2.15 (m,
1H), 2.55-2.70 (m, 1H), 3.80-4.00 (m, 4H); 13C NMR δ 14.6,
16.4, 24.0, 28.1, 30.0, 39.0, 54.6, 65.2, 65.3, 113.5, 213.5; IR
(film) 1709 cm-1; exact mass m/z 198.1243 (calcd for C11H18O3
m/z 198.1255). Anal. Calcd for C11H18O3: C, 66.64; H, 9.15.
Found: C, 66.55; H, 9.33.
5,5-(Eth ylen ed ioxy)-2,6,6-tr im eth yl-1-cycloh exen eca r -
bon it r ile (32). To a solution of 31 (1.07 g, 5.41 mmol)
and trimethylsilyl cyanide (2.72 mL, 21.6 mmol) in CH2Cl2
(15 mL) was added trimethylsilyl trifluoromethanesulfonate
(0.12 mL, 0.54 mmol) at room temperature. The mixture was
stirred at room temperature for 6 h, quenched by the addition
of water, and extracted with AcOEt-hexane (1:1) mixed
solvent. The combined extracts were dried with Na2SO4 and
concentrated to give an oil, which, on CC, gave a cyanohydrin
as a colorless oil (1.03 g, 85%). To a solution of the cyanohydrin
(241 mg, 1.07 mmol) and pyridine (0.86 mL, 10.7 mmol) in
ether (3 mL) was added thionyl chloride (0.38 mL, 5.35 mol)
at room temperature. The mixture was stirred at room
temperature for 8 h, quenched by the addition of water, and
extracted with AcOEt-hexane (1:1) mixed solvent. The com-
bined extracts were dried with Na2SO4 and concentrated to
3,5-Di(2-fu r yl)-4-isobu tyr yl-2,2-d im eth ylcycloh exa n -1-
on e (d ion e-2): 1H NMR δ 0.92 (d, 3H, J ) 6.9 Hz), 0.96 (d,
3H, J ) 6.9 Hz), 0.91 (s, 3H), 1.13 (s, 3H), 2.72 (dd, 1H, J )
6.0, 14.8 Hz), 2.72-2.82 (m, 1H), 3.06 (dd, 1H, J ) 6.0, 14.8
Hz), 3.51 (d, 1H, J ) 11.8 Hz), 3.88 (dt, 1H, J ) 4.7, 6.0 Hz),
4.00 (dd, 1H, J ) 4.7, 11.8 Hz), 5.95 (d, 1H, J ) 3.7 Hz), 6.01
(24) Ishikawa, T.; Okano, M.; Aikawa, T.; Saito, S. J . Org. Chem.
2001, 66, 4635-4642.

8008 J . Org. Chem., Vol. 66, No. 24, 2001
Ishikawa et al.
give an oil, which was purified by CC (10:1 hexane/AcOEt) to
give 32 (215 mg, 97%) as a colorless oil: 1H NMR δ 1.18 (s,
6H), 1.77 (t, 2H, J ) 6.6 Hz), 1.90 (t, 3H, J ) 0.6 Hz), 2.30 (dt,
2H, J ) 0.6, 6.6 Hz), 3.96-3.99 (m, 4H); 13C NMR δ 22.5, 23.0,
26.1, 30.5, 40.7, 64.9, 109.7, 115.9, 116.9, 151.0; IR (film) 2211
cm-1; exact mass m/z 207.1263 (calcd for C12H17NO2 m/z
207.1259). Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27.
Found: C, 69.67; H, 8.31.
and 50 (506 mg, 25%) as a colorless oil for each. Data for 42:
1H NMR δ 1.07 (d, 3H, J ) 6.3 Hz), 1.17 (s, 3H), 1.37-1.93
(m, 7H), 2.19-2.32 (m, 1H), 2.42-2.51 (m, 1H), 3.00 (t, 1H,
J ) 3.9 Hz); 13C NMR δ 13.0, 19.3, 24.3, 34.9, 38.3, 44.4, 44.8,
46.6, 60.9, 211.3, 213.3; IR (film) 1705 cm-1; exact mass m/z
180.1144 (calcd for C11H16O2 m/z 180.1150). Anal. Calcd for
C11H16O2: C, 73.30; H, 8.95. Found: C, 73.41; H, 8.86. Data
for 50: 1H NMR δ 1.05 (s, 3H), 1.13 (d, 3H, J ) 6.6 Hz), 1.40-
1.90 (m, 17H), 2.23-2.41 (m, 2H), 2.51-2.63 (m, 1H); 13C NMR
δ 20.8, 21.6, 23.0, 27.7, 36.4, 38.4, 39.9, 40.7, 41.0, 48.6, 79.7,
5,5-(Eth ylen ed ioxy)-2,6,6-tr im eth yl-1-cycloh exen eca r -
ba ld eh yd e (33). To a solution of 32 (1.85 g, 8.94 mmol) in
CH2Cl2 (20 mL) precooled at -78 °C was added dropwise
DIBAL-H (13.4 mL, 1.34 mmol) over 30 min, and the mixture
was stirred at 0 °C for an additional 30 min. The reaction was
quenched by the addition of water and filtered through a Celite
pad, the filter cake being thoroughly rinsed with ethyl acetate.
The combined organic solutions were dried with Na2SO4 and
concentrated to give an oil, which was purified by CC (5:1
hexane/AcOEt) to afford 33 (873 mg, 46%) as a colorless oil
and recovered 32 (437 mg, 24%): 1H NMR δ 1.26 (s, 6H), 1.80
(dt, 2H, J ) 4.1, 6.8 Hz), 2.00 (s, 3H), 2.40 (t, 2H, J ) 6.6 Hz),
3.97-4.00 (m, 4H), 10.08 (s, 1H); 13C NMR δ 18.9, 21.8, 26.2,
176.4, 215.3; IR (film) 1735, 1710 cm-1
.
3-Allyl-3,5-dim eth ylbicyclo[3.3.1]n on an e-2,9-dion e (43).
To a solution of 2-methylcyclohexanone (1.00 mL, 7.96 mmol)
in THF (20 mL) was added t-BuOK (983 mg, 8.76 mmol) at
room temperature. The mixture was stirred at 0 °C for 5 min.
To the mixture was added tert-butyl methacrylate (1.29 mL,
7.96 mmol) dropwise at 0 °C, and stirring was continued at
room temperature for 1 h followed by the addition of allyl
bromide (2.00 mL, 23.9 mmol). The mixture was stirred at
room temperature for 15 h followed by the addition of water.
The resulting mixture was extracted with AcOEt, and the
combined organic layers were dried over MgSO4 and concen-
trated to afford a crude oil, which was purified by CC (10:1
hexane/AcOEt) to give 43 (1.08 g, 62%) as a colorless oil: 1H
NMR δ 1.10 (s, 3H), 1.18 (s, 3H), 1.39-2.10 (m, 9H), 2.43-
2.52 (m, 1H), 3.00 (t, 1H, J ) 4.0 Hz), 4.95-5.07 (m, 2H), 5.52
(ddt, 1H, J ) 7.4, 10.2, 16.8 Hz); 13C NMR δ 19.3, 20.6, 25.0,
36.7, 41.4, 44.0, 45.9, 46.1, 50.1, 59.8, 119.3, 131.7, 213.2, 214.8;
IR (film) 1712 cm-1. Anal. Calcd for C14H20O2: C, 76.33; H,
9.15. Found: C, 76.21; H, 9.31.
33.6, 41.4, 65.7, 111.5, 139.3, 153.9, 192.0; IR (film) 1726 cm-1
.
Anal. Calcd for C12H18O3: C, 68.55; H, 8.63. Found: C, 68.39;
H, 8.72.
[3,3-(Eth ylen ed ioxy)-2,2,6-tr im eth ylcycloh exylid en e]-
h yd r a zin e (34) a n d 4,4-(Eth ylen ed ioxy)-2-iod o-1,3,3-tr i-
m eth yl-1-cycloh exen e (35). These compounds were prepared
after the reported procedure by Danishefsky et al. (ref 14b).
Dieth yl 2-[1-(2-Fu r yl)-2,2-dim eth yl-3-oxobu tyl]m alon ate
(38). To a solution of t-BuOH (10 mL) in THF (10 mL) was
added butyllithium in hexane (3.75 mL, 5.63 mmol) at 0 °C
followed by the addition of isopropyl methyl ketone (0.72 mL,
6.75 mmol). To the mixture was added a solution of diethyl
furfurylidenemalonate 36 (536 mg, 2.25 mmol) in THF (2 mL),
and stirring was continued at 0 °C for 5 min. The reaction
was quenched by addition of a saturated aqueous solution of
NH4Cl and extracted with AcOEt. The combined organic layers
were dried over MgSO4 and concentrated to afforded a crude
oil, which was purified by CC (3:1 hexane/AcOEt) to give 38
(657 mg, 90%) as a colorless oil. 1H NMR δ 1.20 (t, 3H, J )
7.1 Hz), 1.20 (s, 3H), 1.33 (s, 3H), 2.73 (ddd, 1H, J ) 1.4, 2.8,
16.2 Hz), 2.81 (dd, 1H, J ) 2.8, 5.5, Hz), 2.90 (dd, 1H, J ) 5.5,
16.2 Hz), 3.45 (m, 2H), 4.11 (dq, 2H, J ) 2.2, 7.1 Hz); 13C NMR
δ 13.9, 21.6, 24.3, 39.7, 45.9, 49.2, 53.8, 61.6, 172.8, 202.3,
1-Allyl-9-m eth ylbicyclo[5.3.1]u n d eca n e-8,11-d ion e (45)
a n d ter t-Bu tyl 3-(1-Allyl-2-oxocyclooctyl)-2-m eth ylp r o-
p a n oa te (46). To a solution of 2-allylcyclooctanone 44 (548
mg, 3.30 mmol) in THF (15 mL) was added t-BuOK (382 mg,
3.40 mmol) at room temperature. The mixture was stirred at
0 °C for 5 min. To the mixture was added tert-butyl meth-
acrylate (0.53 mL, 3.30 mmol) dropwise at 0 °C, and the
mixture was stirred at room temperature for 5.5 h. The
reaction was quenched by adding saturated aqueous solution
of NH4Cl and extracted with AcOEt. The combined organic
layers were dried over MgSO4 and concentrated to afford a
crude oil, which was purified by CC (20:1 hexane/AcOEt) to
give 45 (529 mg, 69%) and 46 (123 mg, 12%) as a colorless oil,
respectively. Data for 45: 1H NMR δ 1.14 (d, 3H, J ) 6.6 Hz),
1.31-1.75 (m, 9H), 1.87-2.13 (m, 3H), 2.26-2.53 (m, 2H),
2.93-3.07 (m, 1H), 3.19 (t, 1H, J ) 8.5 Hz), 5.02-5.14 (m, 2H),
5.66-5.84 (m, 1H); 13C NMR δ 16.0, 22.4, 23.1, 28.6, 31.9, 32.4,
37.6, 38.8, 40.6, 50.3, 62.1, 118.8, 133.8, 210.3, 212.8; IR (film)
1715 cm-1. Anal. Calcd for C15H22O2: C, 76.88; H, 9.46.
Found: C, 76.71; H, 9.57. Data for 46: 1H NMR δ 1.08 (d, 3H,
J ) 6.9 Hz), 1.27-1.87 (m, 19H), 2.01-2.22 (m, 4H), 2.27-
2.38 (m, 1H), 2.54 (dd, 1H, J ) 8.5, 15.1 Hz), 2.72 (dt, 1H, J )
3.3, 11.5 Hz), 5.04 (m, 2H), 5.60-5.74 (m, 1H); 13C NMR δ 20.4,
24.4, 24.8, 26.0, 27.9, 30.4, 31.4, 34.0, 35.6, 37.5, 52.7, 80.3,
205.8; IR (film) 2981, 1732 cm-1
.
Eth yl [6-(2-F u r yl)-2-h yd r oxy-5,5-d im eth yl-4-oxo-1-cy-
cloh exen e]ca r boxyla te (37). To a solution of 38 (160 mg,
0.50 mmol) in t-BuOH (5 mL) and THF (5 mL) was added
t-BuOK (160 mg, 1.50 mmol) at 0 °C. The mixture was stirred
at room temperature for 1.5 h and quenched with 6 N HCl
(0.25 mL) followed by the addition of anhydrous MgSO4. The
organic solutions were concentrated to give a crude oil, which
was purified by CC (1:1 hexane/AcOEt) to afford 37 (121 mg,
88%) as a colorless oil: 1H NMR δ 0.89 (s, 3H), 1.24 (s, 3H),
1.26 (t, 3H, J ) 7.1 Hz), 3.26 and 3.38 (ABq, 2H, J ) 22.4 Hz),
4.11-4.28 (m, 2H), 5.95 (d, 1H, J ) 3.0 Hz), 6.17 (dd, 1H, J )
1.8, 3.0, Hz), 7.17 (d, 1H, J ) 1.8 Hz), 12.25 (s, 1H); 13C NMR
δ 14.1, 21.0, 25.7, 40.7, 44.5, 48.0, 60.9, 99.0, 106.6, 109.9,
118.0, 134.1, 175.8, 219.6; IR (film) 1727, 1697 cm-1
.
3-Eth oxy-5-(eth oxycar bon yl)-6,6-dim eth yl-2-cycloh exen -
1-on e (57) an d 3-Eth oxy-5-(eth oxycar bon yl)-4,4-dim eth yl-
2-cycloh exen -1-on e (58). To a solution of 18 (294 mg, 1.39
mmol) in EtOH (7 mL) was added chlorotrimethylsilane (0.3
mL, 1.6 equiv) at room temperature. The mixture was stirred
at room temperature for 4 h, quenched by the addition of Et3N
(0.35 mL), and concentrated to give a crude residue, which
was subjected to CC (10:1 hexane/AcOEt) to afford 57 (213
mg, 64%) and 58 (60 mg, 18%) as a colorless oil for each. Data
141.5, 154.4, 168.4, 171.1, 208.4; IR (film) 1724, 1656 cm-1
;
exact mass, m/z 278.1167 (calcd for C15H18O5 m/z 278.1154).
Anal. Calcd for C15H18O5: C, 64.74; H, 6.52. Found: C, 64.61;
H, 6.82.
3,5-Dim eth ylbicyclo[3.3.1]n on a n e-2,9-d ion e (42) a n d
ter t-Bu t yl 3-(1-Met h yl-2-oxocycloh exyl)-2-m et h ylp r o-
p a n oa te (50). To a solution of 2-methylcyclohexanone (1.00
mL, 7.96 mmol) in THF (20 mL) was added t-BuOK (921 mg,
8.21 mmol) at room temperature, and the mixture was stirred
at 0 °C for 5 min. To the mixture was added tert-butyl meth-
acrylate (1.29 mL, 7.96 mmol) dropwise at 0 °C, and the
resulting mixture was stirred at room temperature for 1 h.
The reaction was quenched by addition of a saturated aqueous
solution of NH4Cl, and the resulting mixture was extracted
with AcOEt. The combined organic layers were dried over
MgSO4 and concentrated to afford a crude oil, which was
purified by CC (20:1 hexane/AcOEt) to give 42 (588 mg, 41%)
1
for 57: H NMR δ 1.10 (s, 3H), 1.18 (s, 3H), 1.24 (t, 3H, J )
7.1 Hz), 1.33 (t, 3H, J ) 7.1 Hz), 2.42-2.53 (m, 1H), 2.75-
2.86 (m, 2H), 3.88 (q, 2H, J ) 7.1 Hz), 4.05-4.22 (m, 2H), 5.25
(s, 1H); 13C NMR δ 14.1, 14.2, 20.5, 23.5, 29.1, 42.5, 48.8, 60.6,
64.3, 100.4, 172.1, 173.1, 201.8; IR (film) 1615 cm-1. Data for
1
58: H NMR δ 1.20 (s, 3H), 1.24 (t, 3H, J ) 7.1 Hz), 1.29 (s,
1H), 1.34 (t, 3H, J ) 7.1 Hz), 2.48 (dd, 1H, J ) 4.7, 17.3 Hz),
2.69 (dd, 1H, J ) 11.1, 17.3 Hz), 2.87 (dd, 1H, J ) 4.7, 11.1
Hz), 3.82-3.90 (m, 2H), 4.08-4.19 (m, 2H), 5.25 (s, 1H); 13C
NMR δ 13.9, 14.1, 21.5, 25.0, 36.3, 38.2, 49.5, 60.7, 74.7, 100.9,
172.0, 181.0, 196.6; IR (film) 1615 cm-1
.

[3 + 3] Route to 1,3-Cyclohexanedione Frameworks
J . Org. Chem., Vol. 66, No. 24, 2001 8009
4,4-Dim eth yl-5-p h en yl-2-cycloh exen -1-on e (64). To a
suspension of LiAlH4 (49.4 mg, 1.3 mmol) in THF (5 mL) was
added a solution of 55 (1.00 g) in THF (10 mL) at 0 °C. The
mixture was stirred at 0 °C to room temperature for 12 h. The
reaction was quenched by the addition of water and filtered
through a Celite pad, the pad being rinsed with AcOEt. The
combined organic solutions were concentrated to give a crude
solid, which was subjected to the next reaction without further
purification. This solid was dissolved in MeOH (10 mL), and
to this mixture was added p-toluenesulfonic acid monohydrate
(165 mg, 0.87 mmol) at room temperature. The resulting
mixture was stirred at room temperature for 2 h and quenched
by the addition of Et3N (0.15 mL, 1.09 mmol). The resulting
mixture was concentrated to give a crude oil, which was
purified by CC (15:1 hexane/AcOEt) to afford 64 (0.70 g, 80%)
as a colorless oil: 1H NMR δ 0.98 (s, 3H), 1.08 (s, 3H), 2.51
(ddd, 1H, J ) 1.1, 3.6, 16.7 Hz), 2.96 (dd, 1H, J ) 14.3, 16.7
Hz), 3.20 (dd, 1H, J ) 3.6, 14.3 Hz), 5.96 (dd, 1H, J ) 1.1, 9.9
Hz), 6.75 (d, 1H, J ) 9.9 Hz), 7.16-7.38 (m, 5H); 13C NMR δ
20.8, 28.1, 37.1, 40.0, 50.0, 126.3, 127.0, 128.0, 129.1, 139.9,
160.6, 200.1; IR (film) 2960, 1683 cm-1. Anal. Calcd for
C14H16O: C, 83.96; H, 8.05. Found: C, 83.79; H, 8.21.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research on Priority Areas
from the Ministry of Education, Science, Sports, and
Culture, J apan. We are also grateful to the SC-NMR
Laboratory of Okayama University for high-field NMR
experiments.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and/
or 13C NMR spectra for compounds en on e-2 (28), d ion e-2,
en on e-3, d ien ol (29), 32, 33, 37, 40, 42, 43, 52, 55, 56, 64,
and 65 and spectral data for compounds 4-12, 14-22, 40, 48,
49, 51-56, 59, 60-63, and 65-69. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O010325D