An efficient synthesis of alkyl substituted cyclic 1,3-diones

Article abstract of DOI:10.1055/s-2001-16787

An efficient method for the synthesis of cyclic α-alkyl β-dicarbonyl compounds of cyclopentane, cyclohexane, tetronic acid and α-pyrone series is described. The method consists of the selective transformation of the corresponding cyclic β,β′-tricarbonyl compounds by NaBH₃CN in a mixture of THF and 2N aqueous HCl.

Full text of DOI:10.1055/s-2001-16787

LETTER
1391
An Efficient Synthesis of Alkyl Substituted Cyclic 1,3-Diones
Felix S. Pashkovsky,* Igor P. Lokot, Fedor A. Lakhvich
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevicha str. 5/2, 220141 Minsk, Republic of Belarus
Fax 00375 (17) 2637132; E-mail: evk@ns.iboch.ac.by
Received 22 May 2001
terest to extend the scope of the method by Nutaitis et al.
Abstract: An efficient method for the synthesis of cyclic -alkyl
to , -tricarbonyl compounds of the cyclohexane, cyclo-
pentane and tetronic acid series. However, in our hands at-
tempted application of this protocol to some , -triones 1
-dicarbonyl compounds of cyclopentane, cyclohexane, tetronic
acid and -pyrone series is described. The method consists of the se-
lective transformation of the corresponding cyclic
-tricarbonyl
compounds by NaBH3CN in a mixture of THF and 2N aqueous showed that although the reduction proceeded regioselec-
HCl.
tively at the side chain the yields of the corresponding
-alkyl- -dicarbonyl compounds 2 in general were re-
markably lower as compared with the method of ionic hy-
drogenation. Probably, this is due to incomplete
crystallization of the reaction products from dilute aque-
ous solutions of AcOH during work-up of the reaction
mixtures. Another reason may be the drastic conditions
during removal of high boiling acidic solvent in the case
of the formation of oily materials.
Key words: cyclic
tive reduction, cyclic -alkyl -diones
-triones, sodium cyanoborohydride, selec-
2-Alkyl cycloalkane-1,3-diones as well as 3-alkyltetronic
acids, and 3-alkyl-3,4-dihydro-2H-pyran-2,4-diones have
found a widespread application in the synthesis of natural
and structurally related compounds.1 Earlier we have de-
veloped a method for obtaining 2-alkyl cycloalkane-1,3-
diones and their heterocyclic analogs starting from the
readily available 2-acylcyclohexane-1,3-diones, 2-acyl-
cyclopentane-1,3-diones, 3-acyltetronic acids, and 3-acyl-
3,4-dihydro-2H-pyran-2,4-diones.2 The method consists
of the regioselective hydrogenolysis of the carbonyl func-
tion at the side chain of the latter compounds under the ac-
tion of Et3SiH in CF3CO2H in the presence of catalytic
amounts of BF3 OEt2 or LiClO4 (ionic hydrogenation).3
The yields of the target -dicarbonyl compounds were in
the range of 66-98%. In the case of arylidene acyl deriva-
tives of cyclic -dicarbonyl compounds saturation of con-
jugated double bond of arylidene acyl fragment occurs
along with hydrogenolysis of the carbonyl function. Addi-
tionally, in furylidene acyl derivatives reduction of the fu-
ran ring takes place.
In the present communication we wish to report an effi-
cient method for the selective reduction of cyclic , -tri-
ones of cyclohexane, cyclopentane, tetronic acid and -
pyrone series. As a result of our research efforts it has
been established that the use of approximately equal vol-
umes of THF and 2 N aqueous HCl instead of organic acid
improved considerably the yields (comparable with those
when Et3SiH/CF3CO2H was employed) of the NaBH3CN
reduction of 1 to -dicarbonyl compounds 2 (75-96%).8
The excess of reducing agent does not cause further re-
duction of the cyclic -dicarbonyl system in the products
formed.
In the course of our investigations directed towards the
synthesis of natural products we searched for alternative
methods for selective reduction of cyclic , -triones. In
view of the similar mechanistic aspects of the carbonyl
function reductions by NaBH3CN in acidic medium4 to
those of reductions by organosilanes, we focused our at-
tention on the use of NaBH3CN for our synthetic purpose.
It should be noted that NaBH3CN has received extensive
application in organic reductions as versatile and remark-
ably selective reagent.5
Two decades ago Nutaitis et al.6 have demonstrated that
treatment of acyl derivatives of Meldrum’s acid, 5-acyl-
barbituric acids as well as dehydroacetic acid and 3-acyl-
4-hydroxycoumarins with 2 equivalents of NaBH3CN in
AcOH led to hydrogenolysis of the carbonyl group of the
acyl substituent to give the corresponding alkyl deriva-
tives in excellent yields. Kende et al. successfully applied
this protocol for selective reduction of some acyl couma-
rines and acyl pyrimidine triones.7 Therefore, it was of in-
Experimental results are summarized in the Table. Non-
conjugated double bonds without branching at the ethyl-
ene carbon9 (entry 4), triple bonds (entry 9) and ester
groups (entry 5) in the side chain are tolerant to reduction.
Hydrolysis of the ethyl ester was not observed and the tar-
get 3-(6-ethoxycarbonyl) tetronic acid 2f was isolated in
94% yield. In the case of the methyl ester the main com-
ponent in the reaction mixture was 3-carboxyhexyl tetron-
ic acid 2g (R = H). Nonconjugated ketones were reduced
to give the corresponding hydroxy derivatives. Thus, for
example, reduction of 1n led to lactone 2n arising from
the transformation of the C-4 oxo-function into a hydroxy
group followed by intramolecular re-esterification in
acidic medium (entry 10).
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1392
F. S. Pashkovsky et al.
LETTER
Table Reduction of cyclic -tricarbonyl compounds 1a-o by sodium cyanoborohydride in THF-2 N aq HCl
,
aAll new compounds gave satisfactory analytical and/ or spectral data.8 bIsolated yields. cThe yields when NaBH3CN/acetic acid was used
for reduction.
Synlett 2001, No. 9, 1391–1394 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Efficient Synthesis of Alkyl Substituted Cyclic 1,3-Diones
1393
Adlington, M.G.; Dittman, W.R.; Silverman, S.B.Jr.
J.Org.Chem. 1978, 43, 374; Olah, G.A.; Arvanaghi, M.;
Ohannesian, L. Synthesis 1986, 770 and references cited in
refs. 2 and 9.
Similar to the method of ionic hydrogenation in arylidene
acyl derivatives of cyclic -dicarbonyl compounds reduc-
tion of the enone fragment of the arylidene acyl substitu-
ent takes place. The nature of substituents on the aromatic
ring (compounds 1c,d,i) does not interfere with the reduc-
tion.
(4) Borch, R.F.; Bernstein, M.D.; Durst, H.D. J. Am. Chem. Soc.
1971, 93, 2897.
(5) For reviews on borohydride reductions, see:
Lane, C.F. Aldrichimica Acta 1975, 8, 3; Lane, C.F. Synthesis
1975, 135; Gribble, G.W. Chem. Soc. Rev. 1998, 27, 395.
(6) Nutaitis, C.F.; Schultz, R.A.; Obaza, J.; Smith, F.X.
J.Org.Chem. 1980, 45, 4606.
(7) Kende, A.S.; Koch, K.; Smith, C.A. J. Am. Chem. Soc. 1988,
110, 2210.
Surprisingly, we found that reduction of furylidene acyl
derivatives 1b,o by NaBH3CN under these conditions pro-
ceeded more selectively as compared to the method using
Et3SiH/CF3CO2H to furnish 2-furylalkyl derivatives 2b,o
(entries 2,11) even when a large excess of the reducing
agent was employed.
(8) General experimental procedure: To a stirred solution of 1
mmol of cyclic , -tricarbonyl compounds in 6 mL of THF 5
mL of 2 N aq HCl was added. In some cases partial pre-
cipitation of the reagents took place. To the resulting solution
(or suspension) NaBH3CN (see Table) was added portion-
wise. On addition of the reducing agent the dissolution of
precipitated starting materials was observed and in most cases
formation of two separate phases took place. The reaction
mixture was stirred until reduction was complete (TLC-
monitoring). After separation of the organic layer the desired
-dicarbonyl compounds obtained were extracted from the
water phase with Et2O or CHCl3. The combined organic layers
were dried over Na2SO4. After filtration and evaporation of
the solvents in vacuo the crude products were purified by
column chromatography on silica gel. In the case of hardly
soluble products, THF was evaporated under reduced
pressure. After cooling of the water phase the crystalline
materials were filtered off, washed with cold water and dried
in air. The products were purified by recrystallization.
Representative examples: 2b (entry 2) : mp dec., 1H NMR
(200 MHz, CDCl3,): 1.78 (2H, quint, J = 7.5 Hz,-CH2-CH2-
CH2furyl), 2.26 (2H, t, J = 7.5 Hz,-CH2-(CH2)2furyl), 2.56
(4H, s, 2CH2 carbocyclic), 2.61 (2H, t, J = 7.5 Hz, -CH2furyl),
5.98 (1H furan, d, J = 2.5 Hz), 6.24 (1H furan, m), 7.26 (1H
furan, d, J = 2.5 Hz), 9.36 (1H, broad, -OH enolic). IR (KBr):
1370 (br, max), 1440, 1460, 1565, 1600 (sh), 2060-2810 (br)
(cm-1). Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C,
69.77; H, 6.77.
The proposed method offers an advantage over the proto-
col by Nutaitis et al. in terms of simple separation of the
reaction products. Thus, the work-up of the reaction mix-
ture is reduced to removal of THF in vacuo followed by
crystallization of the target -dicarbonyl compounds from
the aqueous solution of inorganic components. More com-
plete isolation can be achieved by extraction from the wa-
ter phase with organic solvents. Oily materials can be
isolated by extraction without evaporation of THF.
It should be noted that in contrast to ionic hydrogenations
where water-free conditions are essential, the presence of
water in the sodium borohydride reduction does not cause
any interference.
In conclusion, the reduction by NaBH3CN in THF - aque-
ous HCl is a simple and versatile method for selective
transformation of cyclic , -tricarbonyl compounds of
cyclopentane, cyclohexane, tetronic acid and -pyrone se-
ries to the corresponding cyclic -alkyl- -dicarbonyl de-
rivatives. By using Et3SiH and NaBH3CN furylidene acyl
-dicarbonyl compounds can be converted to derivatives
with different extent of saturation of the furylidene acyl
fragment.
2e (entry 4): mp 80-82 °C (from diethyl ether), 1H NMR (200
MHz, CDCl3,): 1.10-1.57 (14H, m, 7CH2), 2.04 (2H, q,
J = 6.5 Hz, -CH2CH=CH2), 2.20 (2H, t, J = 7.5 Hz,
-CH2(CH2)7-CH=CH2), 4.68 (2H, s, -OCH2- heterocyclic),
4.88-5.08 (2H, m, -CH=CH2), 5.82 (1H, ddt, J = 17.5, 10.0,
6.5 Hz, -CH=CH2). IR (KBr): 1400, 1440, 1600 (br, max),
1645 (sh), 1710, 2680 (br) (cm-1). MS (m/z): 252 (M+). Anal.
Calcd for C15H24O3: C, 71.39; H, 9.59. Found: C, 71.47; H,
9.44.
Acknowledgement
Financial support provided by INTAS (grant 97-0084) and the Be-
lorussian Foundation for Basic Research (grant X98-143) is greatly
appreciated.
References and Notes
2h (entry 6): pale yellow oil, 1H NMR (200 MHz, CDCl3):
1.47 (3H, d, J = 7.0 Hz, CH3), 1.82 (2H, quint, J = 7.5 Hz,
-CH2-CH2-CH2Ph), 2.27 (2H, t, J = 7.5 Hz, -CH2-(CH2)2Ph),
2.62 (2H, t, J = 7.5 Hz, -CH2Ph,), 4.79 (1H, q, J = 7.0 Hz,
>CH- heterocyclic), 7.07-7.42 (5H aromatic, m). IR (film):
1350, 1405, 1460, 1660 (br, max), 1725, 2730 (br) (cm-1). MS
(m/z): 232 (M+). Anal. Calcd for C14H16O3: C, 72.39; H, 6.94.
Found: C, 72.29; H, 6.89.
(1) Akhrem, A.A.;Titov, Yu.A. Total Synthesis of Steroids;
Nauka: Moscow, 1967; p322; Szantay, Cs.; Novak, L.
Synthesis of prostaglandins; Academiai Kiado: Budapest,
1978; p267; Damon, R.E.; Luo, T.; Schlessinger, R.H.
Tetrahedron Lett. 1976, 2749; Nishide, K.; Aramata, A.;
Kamanaka, T.; Node, M. Heterocycles 1993, 36, 2237.
(2) Akhrem, A.A.; Lakhvich, F.A.; Liss, L.G.; Khripach, V.A.;
Filchenkov, N.A.; Koziniets, V.A.; Pashkovsky, F.S. Doklady
Acad. Nauk SSSR 1990, 311, 1381; Lakhvich, F.A.;
Pashkovsky, F.S.; Liss, L.G. J.Org.Chem. Russia 1992, 28,
1626; Chem. Abstr. 1993, 119, 49087z; Pashkovsky, F.S.;
Lokot, I.P.; Lakhvich, F.A. Vesti Acad. Navuk Belarusi, ser.
khim. navuk 1993, 81.
2m (entry 9): mp 147-148 °C (from ethyl acetate), 1H NMR
(200 MHz, CDCl3): 1.78 (2H, quint, J = 7.0 Hz,
-CH2CH2C CH), 2.04 (1H, t, J = 2.5 Hz, -C CH), 2.24 (5H,
m, CH3+-CH2C CH), 2.58 (2H, t, J = 7.0 Hz,
-CH2(CH2)2C CH), 6.10 (1H heterocyclic, s), 9.02 (1H,
broad, -OH enolic). IR (KBr): 1415 (max), 1590, 1640,
1680, 2660 (br), 3085 (br), 3310 (cm-1). MS (m/z): 192 (M+).
Anal. Calcd for C11 H12 O3: C, 68.73; H, 6.30. Found: C, 68.59;
H, 6.21.
(3) For ionic hydrogenation reactions, see: Kursanov, D.N.;
Parnes, Z.N.; Bassova, G.I.; Loim, N.M.; Zdanovich, V.I.
Tetrahedron 1967, 23, 2235; Carey, F.A.; Tremper, H.S. J.
Am. Chem. Soc. 1968, 90, 2578; Fry, J.L.; Orfanopoulos, M.;
Synlett 2001, No. 9, 1391–1394 ISSN 0936-5214 © Thieme Stuttgart · New York

1394
F. S. Pashkovsky et al.
LETTER
(11) Germicidin, an autoregulative germination inhibitor of
(9) During ionic hydrogenation with silane hydrides in CF3CO2H,
reduction of the double bond in alkenes or cycloalkenes
occurs only in the case when branching at the ethylene carbon
is present, i.e. when the tertiary carbocation is formed in acidic
medium: Kursanov, D.N.; Parnes, Z.N.; Lojm, N.M. Synthesis
1974, 633.
(10) Initial , -triones (1a,j) were synthesized according to the
protocol: Merenyi, F., Nilsson, M. Acta Chem. Scand. 1963,
17, 1801. Furylidene- and arylidene acyl derivatives (1b-
d,h,i,o) were obtained as a result of Claisen-Schmidt
condensation of the readily available 2-acetylcyclopentane-
1,3-dione, 3-acetyltetronic acids and dehydroacetic acid with
furfural or aromatic aldehydes, see ref.2. , -Tricarbonyl
compounds (1e-g,k,m,n) were synthesized according to the
protocol described in: Nomura, K.; Hori, K.; Arai, M.; Yoshii,
E. Chem.Pharm.Bull. 1986, 34, 5188 and ref. 2.
Streptomyces viridochromogenes NRRl B-1551. Isolation,
biological properties and structure elucidation: Petersen, F.;
Zahner, H.; Metzger, J.W.; Freund, S.; Hummel, R.-P. J.
Antibiot. 1993, 46, 1126. Synthesis of rac-germicidin and
spectroscopic data: Lokot, I.P.; Pashkovsky, F.S.; Lakhvich,
F.A. Mendeleev Commun. 1999, 22; Lokot, I.P.; Pashkovsky,
F.S.; Lakhvich, F.A. Tetrahedron 1999, 55, 4783.
Article Identifier:
1437-2096,E;2001,0,09,1391,1394,ftx,en;G09401ST.pdf
Synlett 2001, No. 9, 1391–1394 ISSN 0936-5214 © Thieme Stuttgart · New York