A Facile and Efficient Synthesis of Six-Membered Enol Carbocyclic Compounds

Article abstract of DOI:10.1055/s-0035-1560517

A facile and efficient method for the synthesis of six-membered enol carbocyclic compounds was realized by intermolecular cyclization reaction of 3-aryllidenepentane-2,4-diones with t-BuOK in CH₂Cl₂. The reaction is conducted under m

Full text of DOI:10.1055/s-0035-1560517

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2826–2830
2826
cluster
D.-S. Yang et al.
Cluster
Synlett
A Facile and Efficient Synthesis of Six-Membered Enol Carbocyclic
Compounds
De-Suo Yang*a
Sen Kea
Ming-Jin Fana
Hai-Tao Zhua
Xiao-Ling Wanga
Zheng-Hui Guan*b
O
R2
R1
t-BuOK(1.3 equiv)
CH2Cl2, r.t.
R1
O
R1
R2
R2
OH
a Shannxi Key Laboratory of Phytochemistry, Baoji University of Arts and
Sciences, Baoji 721013, P. R. of China
b Key Laboratory of Synthesis and Natural Functional Molecule Chemistry
of Ministry of Education, Department of Chemistry & Materials Science,
Northwest University, Xi’an 710069, P. R. of China
yangdesuo@163.com
Received: 30.07.2015
Accepted after revision: 13.10.2015
Published online: 28.10.2015
rather than the desired addition product (Scheme 1,B).7
Based on the previous studies and because of our interest in
the synthesis of enolates, we herein report a facile and effi-
cient synthesis of six-membered enol carbocyclic com-
pounds from double intermolecular cyclization of 2,4-dione
derivatives (Scheme 1,C).
DOI: 10.1055/s-0035-1560517; Art ID: st-2015-s0591-c
Abstract A facile and efficient method for the synthesis of six-mem-
bered enol carbocyclic compounds was realized by intermolecular cy-
clization reaction of 3-aryllidenepentane-2,4-diones with t-BuOK in
CH2Cl2. The reaction is conducted under mild conditions and shows
good functional group tolerance.
O
O
OH
O
HO
HO
Key words Michael addition, enol, dicarbonyl compounds, synthesis
R
O
OH
O
Enol carbocyclic compounds have drawn enormous at-
tention from both synthetic and biomechanistic points of
view and research in these areas continue to be actively
pursued. The enolate moiety is an important skeleton in
natural compounds such as humulinone, trineurone, and α-
acid(humulone) (Figure 1).1 It is also a versatile synthetic
intermediate in organic synthesis.2 Their outstanding phys-
iological and pharmaceutical activities, as well as their im-
portant position in synthetic chemistry means that the de-
velopment of versatile convenient and atom-economical
methods for the synthesis of enolates is highly desired. Al-
though a few methods for the synthesis of enolates have
been developed,3 harsh reaction conditions such as ul-
tralow temperature and expensive catalysts are usually re-
quired and the yields of the products are, in some cases,
very low.4,5 For example, Kuwajima and Nakamura used
lithium diisopropylamide (LDA) as base to selectively re-
move the proton on the methyl group of 2-methylcyclohex-
anone, then the resulting enolate could be transformed into
an enol silylether.6 It is not hard to see that the enol is an
intermediate in this transformation (Scheme 1,A). After
that, in 2012, Jahn and co-workers found that the Michael
addition reactions of tert-butyl- 4-pentenoate with 3-ben-
zylidene malonate using LDA as the base for deprotonation
in THF at –78 °C provided the enolate as the main product
trineurone
humulinone
OH
O
R
HO
HO
O
α-acid (humulone)
Figure 1 Enolates in natural products
The initial exploration started by employing compound
1a (0.2 mmol) as the model substrate and t-BuOK (2.0
equiv) as the base in anhydrous THF (2.0 mL) (Table 1, entry
4). To our delight, the expected product 2a was detected
and isolated in 48% yield. A brief survey of solvents indicat-
ed that CH2Cl2 was the most effective (entries 1–5). When
the effect of temperature of the reaction was explored, it is
found that room temperature was the most suitable
(entries 2, 9, and 10). When the amount of base was in-
creased from 2.0 to 2.5 equivalents (entries 2 and 11), the
yield of the product did not increase significantly. In con-
trast, when the amount of base was decreased from 2.0 to
1.3 equivalents, the yield of the product increased (entries
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2826–2830

2827
D.-S. Yang et al.
Cluster
Synlett
(A) Nakamura's work
OLi
O
O
R
RX
LDA
Me4Si
Me3SiCl
MeLi
OSiMe3
(B) Jahn's work
O
O
O
O
O
O
O
LDA
+
+
O
–78 °C, 0.5 h
THF
O
O
O
OH
60%
secondary product
10%
desirable product
(C) this work
O
R2
R1
R1
O
t-BuOK (1.3 equiv)
R1
R2
CH2Cl2, r.t.
R2
OH
Scheme 1 Some examples of the synthesis of enolates
2, 12, and 13). Compared with K2CO3, Cs2CO3 and t-BuOLi,
t-BuOK was found to be most suitable and convenient for
this reaction (entries 6–8 and 13). After a series of detailed
investigations, the optimal reaction conditions were final-
ized as 1a (1.0 equiv) and t-BuOK (1.3 equiv) in CH2Cl2 (5.0
mL) at room temperature for 20 minutes.
mations, possibly due to the different reactivities of sub-
strates. Although substrates 1n–q were expected to be suit-
able for this transformation, the final results indicated that
the yield of the products was very low (entries 14–17).
When the two methyl groups on unsaturated ketones were
replaced by ethyl groups (1r), no desired product was ob-
served (Scheme 2). Finally, the structures of the products
were deduced from their IR, 1H NMR, 13C NMR spectroscop-
ic and HRMS spectrometric data. In addition, the NMR-
based structures were further confirmed by X-ray crystallo-
graphic analysis of 2l (Figure 2), the corresponding data for
which are presented in the Supporting Information.8
With the optimum reaction conditions established, the
scope of the reaction was investigated. As shown in Table 2,
substrates with electron-donating groups (methyl and me-
thoxy groups), or electron-withdrawing groups (nitro and
halogen groups) at the ortho-, para-, or meta-position of
phenyl ring (2b–k) were all suitable for use in this transfor-
mation. However, a detailed study on the electron influence
revealed that substrates with electron-withdrawing groups
(entries 2−8) are more suitable than those with electron-
donating groups (entries 9–11) for this transformation. It is
noteworthy that the halogen-substituted substrates 2b–f
and 2h are tolerated in this transformation, thereby, facili-
tating further modifications at the halo-substituted posi-
tion. When the steric hindrance of the ortho-substituent
was increased, the reaction was also found to proceed effec-
tively (entries 12 and 13). However, in the case of 1l and
1m, different bases were used to achieve efficient transfor-
Et Et
O
O
Et
O
t-BuOK (1.3 equiv)
Et
CH2Cl2, r.t.
O
Et
O
OH
2r, 0%
1r
Scheme 2 The reaction of substrate 1r
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2826–2830

2828
D.-S. Yang et al.
Cluster
Synlett
Table 1 Optimization of the Base-Promoted Cyclization of 3-Ben-
zylidenepentane-2,4-dione (1a)a
Table 2 Scope of the Cyclization Reactiona
O
R2
O
O
R1
R1
O
t-BuOK (1.3 equiv)
R1
R2
O
base
CH2Cl2, r.t.
R2
solvent, T
O
OH
O
OH
1
2
1a
2a
Entry
Substrate
Product Yield (%)b
Entry
Base (equiv)
Solvent
T (°C)
Yield (%)b
1
R1
R2
COMe
2
1
2
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
K2CO3 (1.3)
CS2CO3 (1.3)
t-BuOLi (1.3)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.5)
t-BuOK (1.5)
t-BuOK (1.3)
t-BuOK (1.0)
CH3CN
CH2Cl2
DMF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
trace
54
1
2
1a
1b
1c
1d
1e
1f
H
2a
2b
2c
2d
2e
2f
80
4-Cl
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COMe
COOEt
Ph
64
3
0
3
2-Cl
83
4
THF
48
4
2-Br
84
5
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
5
3-Br
76
6
0
6
4-Br
79
7
0
7
1g
1h
1i
4-NO2
2g
2h
2i
32, 52c
70
8
trace
32
8
2,4-Cl
9
9
4-OMe
55c
60
10
11
12
13
14
50
r.t.
r.t.
r.t.
r.t.
mixture
42
10
11
12
13
14
15
16
17
1j
4-Me
2j
1k
1l
2-Me
2k
2l
70
65
2-OCH2CH2Cl
72
80
1m
1n
1o
1p
1q
2-OCH2CH2Br
2m
2n
2o
2p
2q
75c
45
59
2-OCH2CH2Cl
a Reaction conditions: 1a (0.5 mmol), 20 min.
H
H
H
tracec
mixtured
trace
b Isolated yield.
H
A noteworthy advantage of our method was that this re-
action could be easily scaled up; thus, 74% yield of 2a was
isolated on a gram scale starting from 15 mmol of 1a under
the optimal conditions. This result suggests that the ap-
proach may be suitable for application in industrial pro-
cesses (Scheme 3).
COOEt
a Reaction conditions: 1 (1 mmol), t-BuOK (1.3 equiv), CH2Cl2 (5.0 mL), r.t.,
20 min.
b Isolated yield.
c The base was t-BuOLi.
d A mixture of enol and ketone was obtained.
On the basis of previous reports and on the experiment
O
O
results reported above,9 a tentative mechanism is proposed
O
t-BuOK (1.3 equiv)
CH2Cl2, r.t.
O
O
OH
1a
15 mmol (2.836 g)
2a
74% (1.998 g)
Scheme 3 Scale-up of the reaction with 1a
(Scheme 4). Initially, deprotonation of 1a is realized by us-
ing t-BuOK or t-BuOLi as the base to give intermediate A.10
The latter intermediate acts as an electrophilic reagent to
attack a second molecule of 1a, generating intermediate B.
Subsequent intramolecular cyclization of B generates inter-
Figure 2 X-ray crystallographic analysis of 2l
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2826–2830

2829
D.-S. Yang et al.
Cluster
Synlett
base
–H+
O
O
O
O
O
O
A
1a
1a
O
O
O
O
O
Ph
O
O
+H+
O
O
O
O
OH
2a
Scheme 4 Possible reaction mechanism
C
B
mediate C, protonation of which gives the desired product
2a.
Chem. Biol. 2012, 7, 928. (d) Maskey, R. P.; Grün-Wollny, I. G.;
Laatsch, H. J. Nat. Prod. 2005, 68, 865. (e) Payton, F.; Sandusky,
P.; Alworth, W. L. J. Nat. Prod. 2007, 70, 145.
In summary, we have developed a novel approach to
synthesize six-membered enol carbocyclic compounds
from readily accessible α,β-unsaturated ketones under mild
reaction conditions.11 In contrast to traditional methods,
our reaction system could be scaled up to gram quantities
in satisfactory yields from easily prepared starting materi-
als and it avoids the use of toxic and expensive transition-
metal catalysts. Application of the enol carbocyclic com-
pounds to the synthesis of useful polycyclic compounds is
in progress.
(2) (a) Trost, B. M.; Xu, J. Y.; Schmidt, T. J. Am. Chem. Soc. 2009, 131,
18343. (b) Lawrence, A. J.; Hutchings, M. G.; Kennedy, A. R.;
McDoual, J. J. W. J. Org. Chem. 2010, 75, 690. (c) Lauer, M. G.;
Henderson, W. H.; Awad, A.; Stambuli, J. P. Org. Lett. 2012, 14,
6000.
(3) (a) Makeiff, D. A.; Vishnumurthy, K.; Sherman, J. C. J. Am. Chem.
Soc. 2003, 125, 9558. (b) DeBergh, J. R.; Spivey, K. M.; Ready, J.
M. J. Am. Chem. Soc. 2008, 130, 7828. (c) Lindner, P. E.; Correa, R.
A.; Gino, J.; Lemal, D. M. J. Am. Chem. Soc. 1996, 118, 2556.
(d) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett.
2005, 7, 979. (e) Basheer, A.; Rappoport, Z. Org. Lett. 2006, 8,
5931. (f) Babinski, D.; Soltani, O.; Frantz, D. E. Org. Lett. 2008, 10,
2901. (g) Lindner, P. E.; Lemal, D. M. J. Am. Chem. Soc. 1997, 119,
3259.
Acknowledgment
(4) (a) Scott, W. J.; McMurry, J. E. Acc. Chem. Res. 1988, 21, 54.
(b) Wenkert, E. Acc. Chem. Res. 1980, 13, 27.
(5) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447.
(6) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181.
(7) Holan, M.; Pohl, R.; Cisarova, I.; Jahn, U. Eur. J. Org. Chem. 2012,
3459.
(8) CCDC-1426187 (2l) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
(9) Shindo, M.; Kita, T.; Kumagai, T.; Matsumoto, K.; Shishido, K.
J. Am. Chem. Soc. 2006, 128, 1062.
The authors gratefully acknowledge the financial support of this work
by the research project of the Education Department of Shaanxi Prov-
ince Key Laboratory (13JS006), the PhD research startup foundation
of Baoji University of Arts and Sciences (ZK15047 and ZK15045) and
an open fund of the State Key Laboratory of Solid Lubrication, Lan-
zhou Institute of Chemical Physics, Chinese Academy of Sciences, P. R.
of China (LSL-1408).
Supporting Information
Supporting information for this article is available online at
(10) Argüello, J. E.; Peñéñory, A. B.; Rossi, R. A. J. Org. Chem. 1999, 64,
6115.
http://dx.doi.org/10.1055/s-0035-1560517.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(11) General Procedure: To a solution of α,β-unsaturated ketone
derivatives 1a (1 mmol) in CH2Cl2 (5.0 mL), t-BuOK (1.3 mmol)
was added at room temperature. Upon completion, the reaction
was quenched with H2O, the mixture was extracted with EtOAc
(3 × 15 mL), and the combined organic extract was washed with
H2O, saturated brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by chromatography
on silica gel to afford the corresponding enolate of 2a.
Data for 2a: 1H NMR (400 MHz, CDCl3): δ = 7.38 (t, J = 7.2 Hz,
2 H), 7.31 (dd, J = 14.6, 7.2 Hz, 2 H), 7.28–7.24 (m, 2 H), 7.23 (d,
References and Notes
(1) (a) Taniguchi, Y.; Taniguchi, H.; Matsukura, Y.; Kawachi, Y.;
Shindo, K. J. Nat. Prod. 2014, 77, 1252. (b) Ferreira, E. A.; Reigada,
J. B.; Correia, M. V.; Young, M. C. M.; Guimarães, E. F.; Franchi, G.
C. Jr.; Nowill, A. E.; Lago, J. H. G.; Yamaguchi, L. F. J. Nat. Prod.
2014, 77, 1377. (c) Klaić, L.; Morimoto, R. I.; Silverman, R. B. ACS
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2826–2830

2830
D.-S. Yang et al.
Cluster
Synlett
J = 4.8 Hz, 2 H), 7.19 (t, J = 6.5 Hz, 2 H), 4.69 (s, 1 H), 3.88 (t,
J = 8.9 Hz, 1 H), 3.01 (d, J = 8.7 Hz, 2 H), 2.44 (s, 3 H), 1.95 (s,
3 H), 1.15 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 208.7, 205.8,
200.2, 180.2, 140.3, 139.0, 130.0, 129.2, 129.0, 128.3, 128.1,
127.0, 108.6, 71.8, 48.3, 39.2, 36.9, 30.3, 30.0, 25.6. IR (neat):
2 H), 7.21 (d, J = 8.5 Hz, 2 H), 7.16 (d, J = 8.5 Hz, 2 H), 7.13 (d,
J = 8.7 Hz, 2 H), 4.66 (s, 1 H), 3.75 (t, J = 9.0 Hz, 1 H), 2.95 (d,
J = 9.0 Hz, 2 H), 2.41 (s, 3 H), 1.95 (s, 3 H), 1.28 (s, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 207.3, 205.4, 200.1, 180.0, 138.4, 137.5,
134.4, 133.1, 131.1, 130.8, 129.2, 128.5, 108.4, 72.0, 47.4, 38.9,
36.6, 30.5, 29.9, 25.6. IR (neat): 3076, 2919, 2850, 1720, 1689,
1490, 1413, 1352, 775 cm–1. HRMS (ESI): m/z [M – H] calcd for
3060, 2918, 2850, 1724, 1683, 1496, 1414, 1350, 768 cm–1
.
HRMS (ESI): m/z [M – H] calcd for C24H23O4: 375.1597; found:
375.1603.
C
24H21Cl2O4: 443.0817; found: 443.0825.
Data for 2b: 1H NMR (400 MHz, CDCl3): δ = 7.36 (d, J = 8.4 Hz,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2826–2830