Base-promoted michael reaction concomitant with alkylation of cyclic-1,3-diones, an efficient approach to 2-substituted vinylogous esters

Article abstract of DOI:10.1055/s-0032-1317496

Vinylogous esters can be synthesized by a base-promoted Michael reaction concomitant with alkylation of the cyclic 1,3-dione substrate. The methodology provides a wide range of 2-substituted vinylogous esters in good to excellent yields. Copyright

Full text of DOI:10.1055/s-0032-1317496

LETTER
▌2785
letter
Base-Promoted Michael Reaction Concomitant with Alkylation of Cyclic-1,3-
diones, an Efficient Approach to 2-Substituted Vinylogous Esters
2-Substituted Vinylogous Esters
Subhadip De, Lakshmana K. Kinthada, Alakesh Bisai*
Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, ITI (Gas Rahat) Building, Govindpura, Bhopal,
MP 462 023, India
Fax +91(755)4092392; E-mail: alakesh@iiserb.ac.in
Received: 15.08.2012; Accepted after revision: 28.09.2012
Me
R
Me
Me
Abstract: Vinylogous esters can be synthesized by a base-promot-
ed Michael reaction concomitant with alkylation of the cyclic 1,3-
dione substrate. The methodology provides a wide range of 2-sub-
stituted vinylogous esters in good to excellent yields.
H
H
H
H
O
O
OMe
O
O
Key words: vinylogous esters, cyclohexenones, Michael reaction,
alkylation, diones
CN
COOMe
Me
1a R = H
1b R = Me
2a
2b
2c
Me
Me
H
Me
Functionalized vinylogous esters such as 1a and 1b (Fig-
ure 1) play an important role in the synthesis of several
natural products and drug molecules. Functionalized
cyclohexenones provide an attractive synthetic platform
to access various architecturally interesting natural prod-
ucts and drug molecules.1,2 Prevalent structures are 2-al-
kylated-2-cyclohexenones such as (R)-5-methyl-2-
alkylcyclohexen-2-ones 2b–f, which serve as precursors
for a wide range of naturally occurring terpenoids and al-
kaloids.3–9 Naturally occurring (R)-pulegone (4a) has
been exhaustively used for the synthesis of (R)-5-methyl-
2-alkylcyclohexen-2-ones.4a,6,9 Recently, enantioenriched
enones have been synthesized through organocatalytic di-
rect Michael reactions followed by aldol condensa-
tion.4a,10 However, one of the classical ways to synthesize
these compounds is through the Stork–Danheiser se-
quence with 2-substituted vinylogous esters such as 1a
and 1b using a hydride nucleophile.11
H
H
H
O
O
O
O
R
Me
Me
O
4b R = H
4c R = I
4a pulegone
N
OR
2d R = H
2e R = Bn
2f R = TBDPS
3 huperzine W
Figure 1 Important 2-alkyl-2-cyclohexenone intermediates
chael adduct 7a, which, upon subsequent treatment with
alkyl halides, could lead to the formation of a variety of
vinylogous esters 5 (Scheme 1).
Initially, 1,3-cyclohexanedione 6a was treated with ethyl
acrylate in the presence of bases such as NaH, K2CO3,
Na2CO3, Cs2CO3, t-BuOK in different solvents and at a
range of temperatures (first step) and then treated with 2-
bromoallyl bromide (second step); the results are summa-
rized in Table 1. It was found that the Michael reaction re-
quired elevated temperature (80 °C) to form adducts 7
selectively, without any double alkylation.14 Upon com-
plete conversion of starting material 6 into Michael
adducts 7, the reaction mixture was treated with 2-bromo-
The use of vinylogous esters has already been recognized
in various areas of organic synthesis.12,13 Prompted by this
synthetic potential, we decided to develop a base-promot-
ed methodology for the synthesis of a variety of 2-substi-
tuted vinylogous esters 5 from cycloalkane 1,3-diones 6,
ethyl acrylate, and alkyl halides. We proposed that treat-
ment of 1,3-cyclohexanedione 6 with acrylates in the
presence of a catalytic amount of base could afford a Mi-
Br
Br
Br
base, solvent
25–80 °C
O
O
O
O
O
O
60–80 °C
0.5–1 h
6a
3–4 h
+
OEt
O
OEt
O
OEt
O
7a
5a
Scheme 1 One-pot Michael reaction followed by alkylation
SYNLETT 2012, 23, 2785–2788
Advanced online publication: 31.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317496; Art ID: ST-2012-D0689-L
© Georg Thieme Verlag Stuttgart · New York

2786
S. De et al.
LETTER
allyl bromide (1.2 equiv) and heating was continued for With the optimized conditions in hand, we then turned our
the time specified (Table 1). A survey of solvents led to attention to the substrate scope for the synthesis of 2-sub-
the observation that reactions performed in N,N-dimethyl- stituted vinylogous esters. A variety of primary halides
formamide (DMF; entries 4, 8, and 15) and dimethyl sulf- such as methyl iodide, benzyl bromide, propargyl bro-
oxide (DMSO; entries 6, 10, 12, and 16), worked mide, allyl bromide, and 2-bromoallyl bromide were
efficiently, whereas those conducted in tetrahydrofuran found to be suitable alkylating agents under the optimized
(THF) or acetonitrile (MeCN) were ineffective (Table 1). conditions (Figure 2). In most cases, 1,3-cyclohexane-
Among various conditions screened, it was found that dione (6a) afforded vinylogous esters 5a–e in good to
NaH in DMSO (entry 6) and Cs2CO3 in DMSO (entry 16) very high yields compared to those obtained with 1,3-cy-
were optimum for the Michael reactions (requiring nearly clopentadione (6b; see 5f–j in Figure 2). In the latter case
3 h for the first step) and alkylations (requiring typically the reactions were always associated with the formation of
0.5–1 h, second step).
unidentified materials.
Table 1 Optimization of Vinylogous Ester Synthesis
Br
Br
Br
base, solvent,
25–80 °C
60–80 °C
O
O
O
O
O
O
3–4 h
6a
0.5–1 h
+
OEt
O
OEt
O
OEt
O
5a
7a
Entry
Basea
Solvent
Temp (°C)
Time (h)b
Yield (%)c,d
1
2
NaH
NaH
NaH
NaH
NaH
NaH
THF
25
25
60
80
50
80
60
80
50
80
80
80
60
50
80
80
60
50
80
80
12/4
12/4
4/1
4/1
3/1.5
3/1
5/5
4/1
6/3
3/1
4/1
4/1
4/1
4/1
3/1
3/1
4/1
4/2
4/1
4/1
traces
52
DMF
3
THF
9
4
DMF
90
5
MeCN
DMSO
THF
79
6
93
7
K2CO3
75
8
K2CO3
DMF
82
9
K2CO3
MeCN
DMSO
DMF
57
10
11
12
13
14
15
16
17
18
19
20
K2CO3
84
Na2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
40e
63
DMSO
THF
dec.
74
MeCN
DMF
83
DMSO
THF
92
dec.
30
MeCN
DMSO
DMF
dec.
21
a Base (1.5 equiv) was used under an inert atmosphere.
b Times refer to the first Michael step followed by alkylation.
c Reaction conditions: 6a (0.5 mmol), ethyl acrylate (0.75 mmol), solvent (2 mL).
d Isolated yield.
e Decomposition accounts for the rest of the mass balance.
Synlett 2012, 23, 2785–2788
© Georg Thieme Verlag Stuttgart · New York

LETTER
2-Substituted Vinylogous Esters
2787
Br
Me
Me
Me
Me
Me
Me
O
O
O
O
MeO
O
BnO
O
MeO
O
O
O
5c
5a
5b
O
OEt
O
OEt
O
OEt
5o
5n
5m
O
OEt
O
OEt
O
OEt
90%, 3 h/0.5 h, (A)
92%, 3 h/0.5 h, (B)
82%, 3 h/1 h, (A)
60%, 3 h/1 h, (B)
93%, 3 h/1 h, (A)
92%, 3 h/1 h, (B)
78%, 3 h/1 h, (A)
64%, 3 h/1 h, (B)
67%, 3 h/1 h, (A)
68%, 3 h/1 h, (B)
82%, 3 h/1 h, (A)
71%, 3 h/1 h, (B)
Me
Me
Me
BnO
O
O
O
O
O
Br
O
O
O
O
5d
5e
5f
O
OMe
O
OEt
O
OEt
O
OEt
70%, 3 h/0.5 h, (A)
92%, 3 h/0.5 h, (B)
90%, 3 h/0.5 h, (A)
88%, 3 h/0.5 h, (B)
55%, 3 h/1.5 h, (A)
60%, 3 h/1.5 h, (B)
5p
5q
5r
O
OEt
O
OEt
O
OEt
Br
70%, 3 h/1 h, (A)
74%, 3 h/1 h, (B)
61%, 3 h/1 h, (A)
68%, 3 h/1 h, (B)
46%, 3 h/1 h, (A)
64%, 3 h/1 h, (B)
O
O
MeO
O
BnO
O
Me
Me
conditions A:
NaH, DMSO
80 °C, 3 h/1 h
5g
5h
5i
O
OEt
O
OEt
O
OEt
BnO
O
O
O
46%, 3 h/1 h, (A)
49%, 3 h/1 h, (B)
59%, 3 h/1.5 h, (A)
62%, 3 h/1.5 h, (B)
48%, 3 h/1 h, (A)
60%, 3 h/1 h, (B)
conditions B:
Cs2CO3, DMSO
80 °C, 3 h/1 h
5s
5t
Me
Me
O
OEt
O
OEt
Me
Me
Br
56%, 3 h/1 h, (A)
68%, 3 h/1 h, (B)
57%, 3 h/1 h, (A)
66%, 3 h/1 h, (B)
O
O
O
O
O
O
Figure 3 Substrate scope for vinylogous ester synthesis
5l
5j
5k
O
OEt
O
OEt
O
OEt
Acknowledgment
50%, 3 h/1.5 h, (A)
55%, 3 h/1.5 h, (B)
91%, 3 h/0.5 h, (A)
90%, 3 h/0.5 h, (B)
42%, 3 h/1 h, (A)
68%, 3 h/1 h, (B)
We sincerely thank Professor Vinod K. Singh, Director, Indian In-
stitute of Science Education and Research (IISER) Bhopal for pro-
viding research facilities. A.B. thanks the BRNS, Department of
Atomic Energy (DAE), India, for a research grant through a Young
Scientist Award. S.D. and L.K.K. thank the Council of Scientific
and Industrial Research (CSIR), New Delhi, for doctoral fellow-
ships. Access to facilities at the Department of Chemistry, IISER
Bhopal is gratefully acknowledged.
Figure 2 Substrate scope for vinylogous ester synthesis
5,5-Dimethyl-1,3-cyclohexanedione (6c) has been widely
used in the synthesis of terpenoids and their ana-
logues.15,16 Thus, extending our methodology, we were
able to synthesize vinylogous esters 5k–o from 6c as well
as substrates 5p–t from 5-dimethyl-1,3-cyclohexanedione
(6d) under optimized conditions A and B, as shown in
Figure 3. Gratifyingly, in most cases, the reaction pro-
ceeded cleanly to afford vinylogous esters 5k–t in good to
high yields under both sets of conditions.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
(1) For examples of alkylative 1,3-carbonyl transpositions in
vinylogous esters, see: (a) Corey, E. J.; Crouse, D. J. Org.
Chem. 1968, 33, 298. (b) Stork, G.; Danheiser, R. L. J. Org.
Chem. 1973, 38, 1775. (c) Quesada, M. L.; Schlessinger, R.
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K.; Grosserade, R. S.; Wheeler, D. M. S. J. Org. Chem.
1980, 45, 1250. (e) For recent applications in total syntheses,
see: White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M.
J. Am. Chem. Soc. 2008, 130, 810. (f) Bisai, A.; West, S. P.;
Sarpong, R. J. Am. Chem. Soc. 2008, 130, 7222.
To conclude, we report a convenient procedure for the
preparation of cyclohexane/pentane based 2-substituted
vinylogous esters 5a–t through base-promoted Michael
reaction concomitant with alkylation of 1,3-cyclo-
hexane/pentane diones under mild conditions.17 Applying
this strategy, a wide variety of substrates has been synthe-
sized in good to high yields. Further efforts in this direc-
tion are in progress and will be reported in due course.
(2) (a) Smith, A. B. III. Evolution of a Synthetic Strategy: Total
Synthesis of (±)-Jatrophone, In Strategies and Tactics in
Organic Synthesis; Lindberg, T., Ed.; Academic: New York,
1984, 224–254, Chap. 9. (b) For numerous examples, see:
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2785–2788

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S. De et al.
LETTER
Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis,
1st ed; Wiley-VCH: New York, 1996. (c) Nicolaou, K. C.;
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with acrylates, for example, see: Konno, M.; Nakae, T.;
Sakuyama, S.; Imaki, K.; Nakai, H.; Hamanaka, N. Synlett
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A. J. Org. Chem. 1984, 49, 2647. (b) For the use of 2-iodo-
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cited therein.
(17) Synthesis of Vinylogous Esters; General Procedure: A
flame-dried, round-bottomed flask was charged with cyclic
1,3-dione (1 mmol) and ethyl acrylate (1.3 mmol) in DMSO
(5 mL). To this solution was added NaH or Cs2CO3 (1.2
mmol) and the reaction mixture was stirred at 80 °C for the
indicated time. Upon completion of the Michael reaction
(typically, TLC showed complete conversion of starting
materials after 3 h of reaction), alkyl halide (1.2 mmol) was
added and the reaction mixture was heated at 80 °C for the
indicated time (typically 1 h). Upon completion of the
alkylation (TLC), the reaction mixture was acidified with
2 M HCl. The resulting mixture was extracted with EtOAc
(4 × 20 mL) and the combined organic layers were dried
over MgSO4 and concentrated under vacuum. The crude
product was purified by flash chromatography (petroleum
ether–EtOAc) to give the pure product.
Ethyl 3-{2-[(2-Bromoallyl)oxy]-6-oxocyclohex-1-en-1-
yl}propanoate (5a): Rf = 0.54 (EtOAc–hexane, 50%); 1H
NMR (400 MHz, CDCl3): δ = 5.95 (m, 1 H), 5.69 (m, 1 H),
4.63 (t, J = 1.44 Hz, 2 H), 4.10 (q, J = 7.12 Hz, 2 H), 2.65 (m,
2 H), 2.55 (t, J = 6.2 Hz, 2 H), 2.34–2.38 (m, 4 H), 1.99 (m,
2 H), 1.24 (t, J = 7.16 Hz, 3 H); 13C NMR (100 MHz,
CDCl3): δ = 197.9, 173.4, 170.2, 126.5, 119.0, 117.9, 70.4,
60.1, 36.3, 33.0, 25.1, 20.9, 18.0, 14.2; IR (film): 2939,
1728, 1628, 1589, 1446, 1385, 1354, 1277, 1169, 1072,
1041, 856 cm–1; HRMS (ESI): m/z [M + Na]+ calcd for
[C14H19BrO4+Na]+: 353.0359; found: 353.0342.
(13) (a) For synthesis of bicyclic vinylogous esters, see: Smith,
A. B. III.; Dorsey, B. D.; Ohba, M.; Lupo, A. T. Jr.;
Malamas, M. S. J. Org. Chem. 1988, 53, 4314. (b) For use of
vinylogous esters in organic synthesis, see: Masalov, N.;
Feng, W.; Cha, J. K. Org. Lett. 2004, 6, 2365. (c) Nicolaou,
K. C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C.
J. N. J. Am. Chem. Soc. 2005, 127, 8872. (d) Grundl, M. A.;
Trauner, D. Org. Lett. 2006, 8, 23. (e) For a review, see:
Rubinov, D. B.; Rubinova, I. L.; Akhrem, A. A. Chem. Rev.
1999, 99, 1047.
Ethyl 3-[2-(Allyloxy)-6-oxocyclohex-1-en-1-yl]propanoate
(5b): Rf = 0.59 (EtOAc–hexane, 50%); 1H NMR (400 MHz,
CDCl3): δ = 5.88–5.98 (m, 1 H), 5.31–5.36 (m, 1 H), 5.24–
5.28 (m, 1 H), 4.55 (m, 2 H), 4.08 (q, J = 7.12 Hz, 2 H),
2.59–2.64 (m, 2 H), 2.55 (t, J = 6.24 Hz, 2 H), 2.33 (m, 4 H),
1.95 (m, 2 H), 1.22 (t, J = 7.16 Hz, 3 H); 13C NMR (100
MHz, CDCl3): δ = 198.0, 173.6, 171.8, 132.8, 118.2, 117.5,
68.1, 60.1, 36.3, 33.1, 25.3, 20.9, 17.9, 14.2 cm–1; IR (film):
2931, 1724, 1597, 1438, 1385, 1265, 1184, 1076, 1030, 930,
860 cm–1; HRMS (ESI): m/z [M + H]+ calcd for
[C19H21O4+Na]+: 313.1434; found: 313.1273.
Synlett 2012, 23, 2785–2788
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