1,2-Dioxo-3-isopropyloxy-4-methyl-3-cyclobutene as a nucleophilic synthon. Synthesis of Sq-containing cinnamic acid derivatives

Article abstract of DOI:10.1016/S0040-4039(02)01525-3

An enolate-like intermediate A derived from 1,2-dioxo-3-isopropyloxy-4-methyl-3-cyclobutene (6) has proven to be a novel nucleophilic synthon for an aldol condensation reaction with an arylaldehyde to give a variety of 4-hydroxy-2,3-dioxocyclobut-1-enyl group (Sq group)-containing cinnamic acid derivatives.

Full text of DOI:10.1016/S0040-4039(02)01525-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6755–6758
1,2-Dioxo-3-isopropyloxy-4-methyl-3-cyclobutene as a
nucleophilic synthon. Synthesis of Sq-containing cinnamic
acid derivatives
Tetsuro Shinada,* Yuuki Ooyama, Ken-ichi Hayashi and Yasufumi Ohfune*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Received 1 July 2002; revised 4 July 2002; accepted 19 July 2002
Abstract—An enolate-like intermediate A derived from 1,2-dioxo-3-isopropyloxy-4-methyl-3-cyclobutene (6) has proven to be a
novel nucleophilic synthon for an aldol condensation reaction with an arylaldehyde to give a variety of 4-hydroxy-2,3-dioxocy-
clobut-1-enyl group (Sq group)-containing cinnamic acid derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
The 4-hydroxy-2,3-dioxocyclobut-1-enyl group (squaryl
(Sq) group), has attracted much attention as an isostere
of carboxylic acid and phospholic acid in medicinal
Since the Sq group possesses a potent electron-with-
drawing property, we envisioned that an enolate-like
intermediate A derived from 3 would perform as a
nucleophilic synthon which reacts with an electrophile
to give 2 under mild reaction conditions (route B). We
herein report generation of the enolate A in an aprotic
media and its aldol condensation with aromatic alde-
hydes to afford novel Sq-containing cinnamic acid
analogs whose carboxyl group is replaced by a strongly
acidic Sq group. Although an example to form the
enolate has been demonstrated by deuteration of 4 with
NaOD in D2O (Scheme 2) in 1970,11 its synthetic
application to carbon–carbon bond forming reaction
has not been reported to date. We initially examined
the enolate formation 7 from methylcyclobutenedione
66d in THF using several bases (Table 1). Treatment of
6 with LDA at −78°C in THF followed by quenching
with excess amounts of AcOD gave mono-deuterated
compound 8 in 57% yield with 55% d-incorporation.
chemistry,1
a novel chromophore for developing
organic optical materials,2 and a synthon of quinones,3
triquinanes,4 cyclopentenone,5 and furanones5a–f in
organic synthesis. In order to extend the utility of
squaric acid which possesses intriguing physicochemical
properties such as strong acidity, chelating ability to
metal ions, and aromaticity, the carbon–carbon bond-
forming reaction to squaric acid becomes an important
subject in the above mentioned area. A typical method
to prepare Sq-containing molecules 2 in which the Sq
moiety was connected with a carbon–carbon bond was
based on the nucleophilic addition of alkyllithium or
Grignard reagent to dialkyl squarate 1 (route A,
Scheme 1).6 Route A is a practical and convenient
method for this purpose while the strong nucleophilicity
of organometallics was occasionally incompatible with
other unstable functional groups. To this problem, we
and other groups have demonstrated efficient methods
which involve an addition reaction of allylsi-
lane,4d,5c,5d,5f,7 silylenol ether,4b,5c,5d,7 ester enolate,1c,5f
organozinc reagent,8 or Wittig reagent,9 and transition
metal-catalyzed cross-coupling reactions.10 Comple-
mentary methods to route A for the preparation of a
variety of Sq-containing molecule 2 are still sought.
O
O
O
O
1)
2)
R
M
R
HO
RO
OR
H3O
1
2
route A
electrophilic synthon
2)
H3O
O
O
O
O
1) base,
R
RO
CH3
RO
CH2
Keywords: squaric acid; cinnamic acids; aldol condensation; nucle-
ophilic synthon.
* Corresponding authors. Tel.: +81-6-6605-2570; fax: +81-6-6605-
3153 (Y.O.); tel.: +81-6-6605-3193; fax: +81-6-6605-3153 (T.S.);
e-mail: shinada@sci.osaka-cu.ac.jp; ohfune@sci.osaka-cu.ac.jp
route B
3
nucleophilic synthon
enolate A
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01525-3

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T. Shinada et al. / Tetrahedron Letters 43 (2002) 6755–6758
suggest that a retro-aldol process from 11 to 6 via
O
O
O
O
NaOD
D2O
alkoxide 13 would predominate under these conditions.
In order to prevent the reversible equilibrium, we
attempted to trap the putative intermediate 13 with an
electrophile. Addition of a small amount of H2O in the
reaction gave a trace amount of the desired adduct 11
(2%) (entry 3), suggesting that certain equilibrium exists
between 7 and 13 while the yield was only 2%. We
considered that dehydration of 11 or trapping the
alkoxide 13 with an electrophile would improve the
yield. Thus, addition of Ac2O into the reaction condi-
tion was found to provide a,b-unsaturated olefin 1212 in
17% yield. Presumably, the reaction proceeded through
acetylation of 13 and subsequent b-elimination of acetic
acid from the resulting 14 (not isolated) gave 12 (entry
4). After several attempts to increase the yield, the
unsaturated olefin 12 was obtained in 36% upon treat-
ment with Ac2O and Et3N without any solvent (entry
5).13
HO
CH3
NaO
CD3
4
5
Scheme 2.
Table 1. Trapping of enolate 8 with D2O or i-Pr3SiCl
Entry
Conditions (equiv.)
Products (yield,
d-incorporation)
1
LDA (1), THF, −78 to 20°C
1 h, then AcOD (13), D2O
(43), −78 to 0°C, 1 h
8 (57%, 55%)
2
3
Et3N (1), D2O (15), THF, 0°C, 9 (87%, 89%)
1.5 h
LDA (1.05), THF, −78 to
20°C, 1 h, then TIPSCl (1),
−78 to 20°C, 3 h
10 (\90%)
A variety of aldehydes 16a–h were condensed with 6 or
15 to give E-squaryl styrene derivatives 12, 17b–h, 18a,
18c, and 18e in a range of 16–76% yields (Scheme 5,
Table 3).15,16 Similarly, the reaction of butylcy-
clobutenone 157c with 16a or 16e afforded E-trisubsti-
tuted olefin 18a or 18e in good yield, respectively
(entries 9 and 11). The presence of a methoxy group on
the aromatic ring led to lower yields of 17b and 18c
(entries 2 and 10). The isopropyl group of these adducts
was removed smoothly by treatment with 12N HCl in
dioxane to give the corresponding Sq-containing cin-
namic acid derivatives in quantitative yields. The pKa
value of the squaryl group is estimated to be less than
0 which is much stronger acidity than that of cinnamic
acid.17
The incorporation took place when 6 was subjected to
triethylamine and D2O to give tri-deuterated 9 (>90%
d-incorporation). Moreover, lithium enolate 7 was
trapped with TIPSCl to afford novel silyl enolate 10 in
90% yield. These results confirmed the presence of the
conjugated enolate 7 in organic solvent (Scheme 3).
Having the enolate 7 in hand, we next examined its
reaction with benzaldehyde (Scheme 4, Table 2). Initial
treatment of 6 with LDA in THF and subsequent
addition of benzaldehyde at −20°C did not give any
aldol product and the starting material 6 was recovered
(entry 1). Switching the base to triethylamine provided
the same result as entry 1 (entry 2). These results
In conclusion, the generation of enolate 7 derived from
3 in aprotic media is reported for the first time and its
synthetic utility has been demonstrated as an aldol
condensation reaction with various aromatic aldehydes.
The present method provides a facile entry to prepare a
novel class of cinnamate derivatives whose pKa value is
ꢀ0 and conjugate system is extended (UV umax=350
nm).18 Preliminary bioassays indicated that 17b and 17h
exhibited antibacterial activities against Rhizoctonia
solan at micro mole level.19 Further studies regarding
O
O
O
O
D2O or
Base
iPr3SiCl
i-PrO
CH3
i-PrO
CH2
6
8
7
TIPSO
O
O
O
O
O
i-PrO
CH2
i-PrO
CDH2
i-PrO
CD3
10
9
Table 2. Optimization of the condensation reaction
Scheme 3.
Entry
Conditions (equiv.)
Results
(yield, %)
1
LDA (1), THF, −78 to 20°C, 1 h,
then PhCHO (1), −78 to −20°C,
2.5 h
6 (34)
2
3
4
5
Et3N (1.05), PhCHO (1), THF, rt,
24 h
Et3N (1.05), PhCHO (1), few drops
of H2O, THF, rt, 5 h
Et3N (1.05), PhCHO (1), Ac2O (1.05), 12 (17), 6 (26)
THF, 0°C to reflux, 16 h
Et3N (5), Ac2O (1.5), PhCHO (10),
neat, rt, 5 days
6 (64)
11 (2), 6 (77)
12 (36)
Scheme 4.

T. Shinada et al. / Tetrahedron Letters 43 (2002) 6755–6758
6757
Scheme 5.
Table 3. Condensation of 6 or 15 and 16a–h
Entry
Substrate
Aldehyde
Time (days)
Product
Yield (%)
1
2
3
4
5
6
7
8
6
6
6
6
6
6
6
6
16a
16b
16c
16d
16e
16f
16g
16h
16a
16c
16e
6
5
5
5
5
1
12
7
6
6
12
17b
17c
17d
17e
17f
17g
17h
18a
18c
18e
36
32
42
45
43
46
40
37
76
15
58
9
10
11
15
15
15
6
biological significance of the synthetic compounds are
currently investigated in our laboratories.
(d) Ashwell, G. J.; Jefferies, G.; Hamilton, D. G.; Lynch,
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Nature 1995, 375, 385–388; (e) Law, K. Y. Chem. Rev.
1993, 93, 449–486.
3. (a) Moore, H. W.; Yerxa, B. R. Chemtracts: Org. Chem.
1992, 5, 273–313; (b) Liebeskind, L. S. Tetrahedron 1989,
45, 3053–3060.
Acknowledgements
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71–73; (b) ErgUden, J. K.; Moore, H. W. Org. Lett.
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This study was financially supported by the Research
for the Future Program from the Japan Society for the
Promotion of Science (JSPS). We thank Kyowa Hakko
Kogyo Co., Ltd. for a generous gift of squaric acid and
Shionogi and Co. Ltd., Aburabi Laboratories for pre-
liminary bioassays.
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6758
T. Shinada et al. / Tetrahedron Letters 43 (2002) 6755–6758
7. (a) Yamamoto, Y.; Nunokawa, K.; Okamoto, K.; Ohno,
filtered. The filtrate was concentrated in vacuo. The
residue was purified by flash column chromatography to
give E-12 (87 mg, 36%) as a pale yellow oil. IR (neat)
3413, 2988, 1784, 1760, 1744, 1610, 1580, 1568, 1400,
M.; Eguchi, S. Synthesis 1995, 571–576; (b) Ohno, M.;
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1094 cm−1 1H NMR (400 MHz, CDCl3) l 7.85 (d,
;
J=16.0 Hz, 1H), 7.61–7.56 (m, 2H), 7.45–7.35 (m, 3H),
6.98 (d, J=16.0 Hz, 1H), 5.52 (sept, J=6.2 Hz, 1H), 1.53
(d, J=6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) l
193.2, 193.1, 192.0, 173.8, 142.1, 135.3, 130.5, 129.0,
128.1, 112.9, 79.1, 22.9; HRMS (EI) m/z calcd for
C15H14O3 (M+ 242.0943, found 242.0936; UV umax=350
nm (CHCl3), mmax=32 500 (CHCl3). A solution of 12 (100
mg, 0.41 mmol), in dioxane (2 mL) and concd HCl (0.5
mL) was stirred for 4 h. The mixture was evaporated in
vacuo to give 19a as pale yellow crystals. mp>250°C
(dec.) (from H2O/THF); IR (neat) 1793, 1707, 1612,
8. Sidduri, A. R.; Budries, N.; Laine, R. M.; Knochel, P.
Tetrahedron Lett. 1992, 33, 7515–7518.
9. Hayashi, K.; Shinada, T.; Sakaguchi, K.; Horikawa, M.;
Ohfune, Y. Tetrahedron Lett. 1997, 38, 7091–7094.
10. (a) Shi, X.; Amin, S. R.; Liebeskind, L. S. J. Org. Chem.
2000, 65, 1650–1664; (b) Hinkle, R. J.; Poulter, G. T.;
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12. Configuration of 12 was confirmed by NOE experiments.
13. The starting material 6 was not recovered at all from the
reaction mixture due probably to a decomposition of 6
1497, 1473, 1330, 1155, 1038, 970 cm−1 1H NMR (300
;
MHz, D2O+NaOD) l 7.40–7.35 (m, 2H), 7.30–7.17 (m,
3H), 2.23 (d, J=16.3 Hz, 1H), 6.73 (d, J=16.3 Hz, 1H);
13C NMR (75 MHz, D2O+NaOD) l 208.5, 199.0, 178.7,
136.9. 136.1, 130.0, 129.0, 127.5, 114.2; HRMS (FAB)
m/z calcd for C12H8O3 (M−H) 199.0412, found 199.0429;
UV umax=354 nm (CHCl3), mmax=19 000 (CH3OH).
16. Other aldehydes such as n-octanal and pivalaldehyde did
not condense with 6 under the same reaction conditions.
It would be necessary to employ more reactive enolate
species such as silyl enolate from 6 to perform the
coupling with these aldehyde. Such attempts are currently
being investigated.
17. pKa Values of 4, 3-hydroxy-4-phenyl-1,2-dioxo-3-
cyclobutene, and cinnamic acid are −0.22, 0.24, and 4.2,
respectively; see Ref. 6e.
18. The Z-isomer of 12 has been reported as an intermediate
of quinone synthesis. All the E-analogs described in this
paper are new compounds. See: Turnbull, P.; Meileman,
M. J.; Moore, H. W. J. Org. Chem. 1996, 61, 2584–2585.
19. Squaric acid and diisopropyl squarates did not show any
antibacterial activity.
under the alkaline condition to give
a substituted
product.14 Moreover, lithium diiospropylamide (LDA)
adds to the carbonyl group of 6 under prolonged reaction
time to give 1,2-addition product of diisopropylamine
(unpublished result). These results suggest that triethyl-
amine adds to 6 followed by uncertain decomposition of
the resulting adducts competes with the desired aldol
process.
14. Tietze, L. F.; Arlt, M.; Beller, M.; Glusenkamp, K.;
Jahde, E.; Rajewsky, M. F. Chem. Ber. 1991, 124, 1215–
1221.
15. Typical experimental procedure: To a mixture of 6 (156
mg, 1 mmol), benzaldehyde (1.01 mL, 10 mmol), and
triethylamine (0.7 mL, 5 mmol) was added dropwise
acetic anhydride (0.14 mL 1.5 mmol). The mixture was
stirred for 5 days at room temperature, diluted with H2O,
and extracted with AcOEt (×2). The combined organic
layers were washed with brine, dried over MgSO4, and