Consecutive Michael-claisen process for cyclohexane-1,3-dione derivative (CDD) synthesis from unsubstituted and substituted acetone 1

Article abstract of DOI:10.1055/s-0031-1290900

A long-existing problem of cyclohexane-1,3-dione derivatives (CDD) synthesis from unreactive acetone through consecutive Michael-Claisen process was solved under this study. The practical applicability of this process was tested for a novel compound ethyl 3-(2,4-dioxocyclohexyl)propanoate for up to 20-gram scale. Furthermore, the scope of different acetone derivatives was investigated and resulted with similar consecutive Michael-Claisen process for CDD synthesis. The reaction exhibited remarkable regioselectivity in Michael addition followed by Claisen cyclization. In this process high substrate selectivity was observed for CDD synthesis following consecutive double-Michael-Claisen and Michael-Claisen cyclization. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290900

LETTER
▌1199
lCettoernsecutive Michael–Claisen Process for Cyclohexane-1,3-dione Derivative
(CDD) Synthesis from Unsubstituted and Substituted Acetone1
Michael–Claisen Strategy for Cyclohexane-1,3-dione Derivative Synthesis
Dharminder Sharma, Bandna, Arun K. Shil, Bikram Singh, Pralay Das*
Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur 176061, Himachel Pradesh, India
Fax +91(1894)230433; E-mail: pdas@ihbt.res.in
Received: 02.11.2011; Accepted after revision: 13.01.2012
O
O
O
NO2
Abstract: A long-existing problem of cyclohexane-1,3-dione de-
rivatives (CDD) synthesis from unreactive acetone through consec-
utive Michael–Claisen process was solved under this study. The
practical applicability of this process was tested for a novel com-
pound ethyl 3-(2,4-dioxocyclohexyl)propanoate for up to 20-gram
scale. Furthermore, the scope of different acetone derivatives was
investigated and resulted with similar consecutive Michael–Claisen
process for CDD synthesis. The reaction exhibited remarkable regi-
oselectivity in Michael addition followed by Claisen cyclization. In
this process high substrate selectivity was observed for CDD
synthesis following consecutive double-Michael–Claisen and
Michael–Claisen cyclization.
N3
O
O
CF3
DAz-2
NTBC
Figure 1 Bioactive compounds containing the CDD moiety
In recent years, Ishikawa et al. have improved the method
described by Miller and Benneville7a for CDD synthesis
using t-BuOK.9 In their processes, only substituted ace-
tone gave the corresponding CDD (Scheme 1). Also they
have demonstrated that acetone is not suitable substrate
for CDD synthesis and it reacts violently to give a com-
plex dark mixture. The undeveloped chemistry of acetone
has offered us the opportunity to describe a general meth-
od for CDD synthesis through consecutive Michael–
Claisen process.
Key words: cyclohexane-1,3-dione, Michael–Claisen, Claisen cy-
clization, acetone, acrylate
The cyclohexane-1,3-dione derivatives (CDD) are impor-
tant intermediates for several bioactive molecules synthe-
sis.2,3 Most of the triketo compounds contain
cyclohexane-1,3-dione as basic unit, are found to exhibit
herbicidal activity and some of them are potent against
Tyrosinemia type-I metabolic disorder disease4,5 (Figure
1). Leonard et al. have reported synthesis of DAz-2 from
cyclohexane-1,3-dione, a cell-permeable chemical probe
capable of detecting sulfenic acid modified proteins di-
rectly in living cells.6 While there is a huge demand for
CDD in pharmaceutical applications, the existing process-
es limit substrate scope for their wide synthesis.7,8
In this paper, we describe the versatility of our process for
wide variety of novel and known classes of CDD synthe-
sis from acetone and substituted acetone through one-pot
consecutive double Michael–Claisen cyclization (CD-
MCC) and consecutive Michael–Claisen cyclization
(CMCC) reaction.10
Double Michael reaction of acetone11 and double Mi-
chael–Claisen (DMC) process of substituted acetone for
O
O
C5H11
t-BuOk
THF, r.t., 15 min
CO2Et
C5H11
+
T. Ishikawa (2001)
O
O
O
R
CO2t-Bu
R
t-BuOk
+
t-BuOH–THF
0 °C to r.t.
T. Ishikawa (2008)
O
O
CO2t-Bu
O
KOt-Bu
O
CO2R
+
CO2R
or
THF, 0 °C to r.t.
O
O
T. Ishikawa (2001)
Scheme1 Consecutive Michael–Claisen reaction for CDD synthesis
SYNLETT 2012, 23, 1199–1204
Advanced online publication: 23.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290900; Art ID: ST-2011-B0720-L
© Georg Thieme Verlag Stuttgart · New York

1200
D. Sharma et al.
LETTER
CDD synthesis are reported in literature.9 But consecutive corresponding by-products (Table 1, entries 5 and 11). No
double Michael–Claisen cyclization (CDMCC) of ace- further significant improvement in product yield of 1 was
tone has not yet been reported by any group for CDD syn- observed with higher loadings of NaH (Table 1, entries 6
thesis. In the present method first enolate of acetone was and 12).
prepared at –10 °C to 0 °C in the presence of NaH in neat
4-Alkyl-substituted cyclohexane-1,3-dione synthesis was
and toluene. Under neat conditions the reaction was com-
reported as a tedious multistep process with poor yield12
plete within five minutes and the mixture got solidified.
(Scheme 3). To the best of our knowledge there is no re-
But, in solvent, the reaction performed slowly and was
port available for the synthesis of 1 from cyclohexane-
found to be suitable for large-scale process (Scheme 2).
1,3-dione.
The crude reaction mixture was treated with 1 N HCl and
extracted with ethyl acetate to give 1 in satisfactory yield.
Cyclohexane-1,3-dione (2) and ethyl 3-ethoxypropanoate
(3) were also observed as by-products (Table 1).
O
O
O
R
EtOH, I2
EtO
RI, LDA, HMPA
THF, –78 °C
O
EtO
O
CO2Et
CO2Et
, NaH
Scheme 3 4-Substituted cyclohexane-1,3-dione synthesis through
LDA chemistry
neat, –10 °C, 5 min
O
1 (66%)
O
As per our proposed mechanism, acetone first participates
in Michael reaction as a donor and ethyl acrylate as accep-
tor (steps i and ii; Scheme 4). Substituted carbon again
participates in second Michael reaction with ethyl acrylate
(step iii). The double Michael intermediate further gets in-
volved in intramolecular Claisen cyclization leading to
cyclohexane-1,3-dione 1 containing a stereogenic center
at the C-4 position (steps iv and v). Thus the reaction pro-
ceeds with remarkable regioselectivity of the Michael re-
action and subsequent Claisen cyclization between the
1 g scale
CO2Et
, NaH
1 (54%)
20 g scale
toluene, 0 °C to r.t., 2 h
Scheme 2 Acetone to CDD synthesis following CDMCC process
To find out the optimum reaction conditions, several
bases, solvents and neat processes were tried. NaH (2
equiv) gave best results in toluene/neat with minimum
Table 1 Method Optimization for CDD Synthesis
EtO2C
O
O
O
O
CO2Et
base
+
+
+
O
OEt
–10 °C to r.t.
solvent, neat
O
O
1
3
2
Yield (%)a
Entry
Base (equiv)
Solvent, time
1
2
3
1
2
K2CO3 (3)
KOH (3)
t-BuOK (3)
NaOMe (3)
NaH (2)
NaH (3)
NaH (2)
NaH (2)
NaH (2)
NaH (1)
NaH (2)
NaH (3)
toluene, 5 h
toluene, 5 h
toluene, 5 h
toluene, 5 h
toluene, 2 h
toluene, 2 h
dioxane, 2 h
THF, 2 h
–
–
–
–
–
3
3
5
4
4
5
9
4
4
–
–
–
3
4
4
26
54
55
41
45
43
39
66
64
5
8
5
6
14
10
9
7
8
9
MeCN, 2 h
neat, 5 min
neat, 5 min
neat, 5 min
10
6
10
11
12
7
12
a Isolated yields.
Synlett 2012, 23, 1199–1204
© Georg Thieme Verlag Stuttgart · New York

LETTER
Michael–Claisen Strategy for Cyclohexane-1,3-dione Derivative Synthesis
1201
less hindered side of the ketone and the acyl carbonyl of the reaction followed the same CDMCC mechanism to
the enolate. Interestingly single Michael–Claisen cycliza- produce 14 in 64% yield (Table 2, entry 1). To determine
tion afforded 2 (steps vi and vii) and ethyl-3-ethoxypro- the effect of functional group foremost, α-methyl-substi-
panoate 3 was formed as by-product (step vii).
tuted tert-butyl methacrylate 5 was chosen for the same
reaction. But no significant effect of α-methyl substituent
was observed for the formation of 15 following the same
CDMCC process (Table 2, entry 2). However, n-butyl,
methyl and cyclopropyl methacrylate esters (6, 7 and 8)
gave CDD 16 with satisfactory yield following the CMCC
strategy (Table 2, entries 3–5). The reaction of acetone
with tert-butyl, ethyl and methyl crotonate (9, 10 and 11)
also gave CMCC product 17 and no considerable effects
of ester functionalizations were observed (Table 2, entries
6–8). Cinnamates 12 and 13 also underwent the same re-
action to produce phenyl-substituted CDD (Table 2, en-
tries 9 and 10). Further substituted acetone homologues
were tried with ethyl acrylate and ethyl cinnamate for the
same reaction. The single Michael reaction at the highly
substituted position of the alkyl carbonyl followed by
Claisen cyclization afforded 16, 20, 21 and 22 (Table 2,
entries 11–14). Treatment of ethyl acetoacetate with ethyl
acrylate under the same basic conditions gave 23 follow-
ing the CDMCC process (Table 2, entry 15).
CO2Et
O
O
ONa
NaH
(i)
CO2Et
CO2Et
(ii)
(iii)
NaH
NaH
(vi)
slow
O
ONa
fast
cyclization
O
EtO2C
(vii)
O
CO2Et
2
EtO2C
(iv)
ONa
NaH
O
CO2Et
(v) cyclization
–OEt
CO2Et
–
EtO2C
O
1
O
CO2Et
(vii)
–OEt
EtO
OEt
+
3
Scheme 4 Proposed mechanism for CDMCC and CMCC reactions
1
4
O
CO2Et
3
NaH
CO2H
+
2
To observe the wide applicability of this process, acetone
and substituted acetones were tested with various acry-
lates, crotonates and cinnamates under the standard reac-
tion conditions (Table 2). When acetone was treated with
methyl acrylate 4 using NaH base under neat conditions,
neat, –10 °C to r.t.
40 min
25
24
Scheme 5 Condensation reaction of acetone and ethyl-3-methylbut-
2-enoate
Table 2 CDD Synthesis following CDMCC and CMCC Processes
Yield (%)a
Entry
Acetone derivatives
Unsaturated compounds
Product
Time (min)
CO2Me
O
CO2Me
O
1
5
64
4
O
14
CO2t-Bu
O
CO2t-Bu
O
2
3
60
60
57
64
O
5
15
O
CO2n-Bu
O
O
6
16
© Georg Thieme Verlag Stuttgart · New York
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D. Sharma et al.
LETTER
Table 2 CDD Synthesis following CDMCC and CMCC Processes (continued)
Yield (%)a
Entry
4
Acetone derivatives
Unsaturated compounds
Product
Time (min)
O
CO2Me
O
60
69
O
7
16
O
O
O
O
O
O
O
O
5
6
7
8
9
40
60
66
66
68
70
53
O
16
8
O
CO2t-Bu
O
9
17
O
CO2Et
60
O
10
17
O
CO2Me
60
O
11
17
O
CO2Et
100
Ph
O
Ph
12
18
O
CO2Et
Cl
O
10
100
46
O
Cl
13
19
O
O
O
CO2Et
11
12
40
74
60
O
16
O
CO2Et
100
Ph
O
Ph
12
20
Synlett 2012, 23, 1199–1204
© Georg Thieme Verlag Stuttgart · New York

LETTER
Michael–Claisen Strategy for Cyclohexane-1,3-dione Derivative Synthesis
1203
Table 2 CDD Synthesis following CDMCC and CMCC Processes (continued)
Yield (%)a
Entry
13
Acetone derivatives
Unsaturated compounds
Product
Time (min)
O
O
CO2Et
40
69
O
21
O
O
CO2Et
14
15
60
60
66
64
O
22
CO2Et
OEt
O
O
O
CO2Et
OEt
O
O
23
a Isolated yields; reaction conditions: NaH, neat, –10 °C → r.t.
Chem. 2009, 74, 3211. (c) Weng, B.; Liu, R.; Li, J. H.
The reaction of acetone with ethyl 3-methylbut-2-enoate
(24) gave the unusual product, 25, in 45% yield (Scheme
5). The product 25 is only possible when a highly conju-
gated carbanion is generated at the C4 position of 24; sub-
sequent nucleophilic attack on acetone followed by
dehydration of the corresponding hydroxy intermediate
and hydrolysis of the ester leads to conjugated acid 25.
Synthesis 2010, 2926. (d) Ramachary, D. B.; Kishor, M.
J. Org. Chem. 2007, 72, 5056. (e) Kraus, G. A.; Wan, Z.
Synlett 2000, 363.
(3) (a) Pool, W. F.; Woolf, T. F.; Reily, M. D.; Caprathe, B. W.;
Emmerling, M. R.; Jean, J. C. J. Med. Chem. 1996, 39,
3014. (b) Han, Y.; Hou, H.; Yao, R.; Fu, Q.; Yan, C. G.
Synthesis 2010, 4061. (c) Vanejevs, M.; Jatzke, C.; Renner,
S.; Müller, S.; Hechenberger, M.; Bauer, T.; Klochkova, A.;
Pyatkin, I.; Kazyulkin, D.; Aksenova, E.; Shulepin, S.;
Timonina, O.; Haasis, A.; Gutcaits, A.; Parsons, C. G.;
Kauss, V.; Weil, T. J. Med. Chem. 2008, 51, 634.
(4) Beaudegnies, R.; Edmunds, A. J. F.; Fraser, T. E. M.; Hall,
R. G.; Hawkes, T. R.; Mitchell, G.; Schaetzer, J.;
Wendeborn, S.; Wibley, J. Bioorg. Med. Chem. 2009, 17,
4134.
(5) Rubinov, D. B.; Rubinova, I. L.; Akhrem, A. A. Chem. Rev.
1999, 99, 1047.
(6) Leonard, S. E.; Reddie, K. G.; Carroll, K. S. ACS Chem.
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1268. (b) Celli, A. M.; Lampariello, L. R.; Chimichi, S.;
Nesi, R.; Scotton, M. Can. J. Chem. 1982, 60, 1327. (c) Im,
Y. J.; Lee, C. G.; Kim, H. R.; Kim, J. N. Tetrahedron Lett.
2003, 44, 2987.
In conclusion for the first time commercially available ac-
etone was used as starting material for CDD synthesis.
Through these studies, the existing problem of unreactive
acetone for CDD synthesis and scope of other ketones
were investigated successfully. Both solvent and neat
methods were developed for novel (1,13 14, 15 and 23) and
known classes of CDD synthesis following a highly re-
gioselective consecutive Michael–Claisen process. We
hope that, in the near future, this process will meet indus-
trial demand, and that novel molecules will attract more
interest for target-based design of natural and unnatural
bioactive molecules.
Acknowledgment
(8) (a) Foster, J. E.; Nicholson, J. M.; Butcher, R.; Stables, J. P.;
Edaogho, I. O.; Goodwin, A. M.; Henson, M. C.; Smith,
C. A.; Scott, K. R. Bioorg. Med. Chem. 1999, 7, 2415.
(b) Fadeyi, O. O.; Okoro, C. O. Tetrahedron Lett. 2008, 49,
4725.
Authors are grateful to Dr. P. S. Ahuja, Director IHBT (CSIR) for
providing necessary facilities during the course of the work. Finan-
cial assistance to D.S. (SRF), Bandna (SRF) and A.K.S. (JRF) from
CSIR, New Delhi, India is gratefully acknowledged.
(9) (a) Ishikawa, T.; Kadoya, R.; Arai, M.; Takahashi, H.; Kaisi,
Y.; Mizuta, T.; Yoshikai, K.; Saito, S. J. Org. Chem. 2001,
66, 8000. (b) Ishikawa, T.; Kudo, K.; Kuroyabu, K.; Uchida,
S.; Kudoh, T.; Saito, S. J. Org. Chem. 2008, 73, 7498.
(10) Das, P.; Sharma, D.; Singh, B. Int. Appl WO2011117881,
2011.
(11) Basu, B.; Das, P.; Hossain, I. Synlett 2004, 2224.
(12) (a) Juma, B.; Adeel, M.; Villinger, A.; Langer, P.; Reinke,
H.; Spannenberg, A.; Fischer, C.; Langera, P. Adv. Synth.
Catal. 2009, 351, 1073. (b) Poole, L. B.; Zeng, B. B.;
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
References and Notes
(1) IHBT communication no. 2181.
(2) (a) Takagi, R.; Miwa, Y.; Matsumura, S.; Ohkata, K. J. Org.
Chem. 2005, 70, 8587. (b) Zhao, Y. M.; Gu, P.; Zhang, H.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1199–1204

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D. Sharma et al.
LETTER
crude mixture afforded 1 as a light yellow gummy liquid
Knaggs, S. A.; Yakubu, M.; King, S. B. Bioconjugate Chem.
2005, 16, 1624.
(2412 mg, 66% yield) along with 2 as a light yellow solid (77
mg, 4%) and 3 as a light yellow liquid (176 mg, 7%). IR
(KBr): 1729, 1598, 1455, 1198, 1092, 1031, 851 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 6 H), 1.68–
1.75 (m, 4 H), 2.00–2.09 (m, 4 H), 2.28–2.58 (m, 10 H),
3.38–3.47 (m, 2 H), 4.04–4.12 (m, 4 H), 5.40 (s, 1 H), 6.67
(br, 1 H). 13C NMR (75 MHz, CDCl3): δ = 14.07, 24.26,
24.56, 25.41, 26.19, 29.76, 31.43, 31.94, 39.64, 41.27,
48.25, 58.26, 60.50, 104.01, 173.23, 173.67, 187.73, 195.15,
203.79, 204.06. HRMS (EI): m/z [M + H] calcd for
C11H17O4: 213.2503; found: 213.2519.
(13) Experimental Procedure for Ethyl 3-(2,4-
Dioxocyclohexyl)propanoate (1): A mixture of acetone
(1000 mg, 17.24 mmol) and NaH (1373 mg, 34.48 mmol)
was stirred with ethyl acrylate (3965 mg, 39.65 mmol) at
–10 °C for 5 min under nitrogen atmosphere. Progress of the
reaction was monitored by TLC. On completion of the
reaction, the reaction mixture was acidified with 1 M HCl,
extracted with EtOAc (3 × 5 mL) and washed with brine.
The combined organic layers were dried over anhyd Na2SO4
and concentrated under reduced pressure. Silica gel column
chromatographic purification (EtOAc–hexane, 7:3) of the
Synlett 2012, 23, 1199–1204
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