Substituted (E)-2-methylene-3,4-cyclohexenones through direct and convenient synthesis from cyclohexenone-MBH alcohol in the presence of DMAP

Article abstract of DOI:10.1002/ejoc.201801301

An unexpected and effective DMAP catalyzed one-step construction of 3,4-cyclohexenone skeleton from simple and easily available cyclohexenone-MBH alcohol has been disclosed. A series of substituted (E)-2-methylene-3,4-cyclo-hexenones have been effectively prepared in excellent yields (up to 93 %) under convenient reaction conditions. Succesful scale-up preparation and synthetic transformations have demonstrated the potentials of this new protocol.

Full text of DOI:10.1002/ejoc.201801301

A Journal of
Accepted Article
Title: Direct and convenient construction of substituted (E)-2-
methylene-3,4-cyclohexenone skeleton from cyclohexenone-
MBH alcohol in the presence of DMAP
Authors: Hong-Xia Ren, Xiang-Jia Song, Lin Wu, Zhi-Cheng Huang,
Ying Zou, Xia Li, Xiao-Wen Chen, Fang Tian, and Li-Xin
Wang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801301
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801301
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10.1002/ejoc.201801301
European Journal of Organic Chemistry
COMMUNICATION
Direct and convenient construction of substituted (E)-2-
methylene-3,4-cyclohexenone skeleton from cyclohexenone-MBH
alcohol in the presence of DMAP
Hong-Xia Ren,[a], [b] Xiang-Jia Song,[a], [b] Lin Wu,[a], [b] Zhi-Cheng Huang,[a], [b] Ying Zou,[a], [b]
Xia Li,[a], [b] Xiao-Wen Chen,[a], [b] Fang Tian*[a] and Li-Xin Wang*[a]
Based on the applications of cyclohexenone-MBH
Abstract: An unexpected and effective DMAP catalyzed one-
step construction of 3,4-cyclohexenone skeleton from simple and
easily available cyclohexenone-MBH alcohol has been disclosed. A
series of substituted (E)-2-methylene-3,4-cyclohexenones have
been effectively prepared in excellent yields (up to 93%) under
convenient reaction conditions. Succesful scale-up preparation and
synthetic transformations have demonstrated the potentials of this
new protocol.
carbonates9-11 and our previous related w ork in MBH
carbonates12-13, w e attempted to fulfill some enantioselective
applications of cyclohexenone-MBH carbonates. Unexpectedly,
when w e tried to prepare cyclohexenone-MBH carbonates by
treating cyclohexenone-MBH alcohol[14] w ith di-tert-butyl
dicarbonate ester (Boc2O) in the presence of DMAP for 2 hours,
an unusual (E)-2-benzylidene-3,4-cyclohexenone 3a, w hich w as
difficultly available from common raw materials and synthetic
methods, w as formed except for some expected MBH t-
butyloxycarboryl ester 4 (Scheme 1). After prolonging reaction
time, more 3a and less 4 w as observed by monitoring.
Introduction
The 3,4-cyclohexenone skeleton, w idely existed in huge
numbers of bioactive natural products (Figure 1), is an important
structural motif w ith the multiple-drug-resistance reversing
activity, insecticidal and fungicidal activities, inhibition efficacy of
platelet activating factor.1-2 Those features made 3,4-
cyclohexenone and their derivatives unusual attractive synthetic
targets. Metal catalyzed approaches for 3,4-cyclohexenone
construction from unusual starting functional materials have
been successfully developed.3-8 Murakami3 and Yu7 groups
have reported a [5 + 1] reaction of vinylcyclopropanes w ith
carbon monoxide catalyzed by Ir or Rh complex for the
Scheme 1 The reaction between cyclohexenone MBH alcohol and Boc2O in
the presence of DMAP
Results and Discussion
Based on the preliminary results, w e attempted to further
understand the unexpected new reaction. Our studies w ere
conducted w ith MBH alcohol 1a and Boc2O 2a in CH2Cl2 in the
presence of 20 mol% catalyst for conditioning screenings as
show n in Table 1. Firstly, the reaction w as not detected w ithout
catalyst (Table 1, Entry 1). Amines, such as DMAP, DABCO,
DBU, Et3N, pyridine, pyrrole, piperidine and imidazole w ere
tested (Table 1, Entries 2-9). Only DMAP and DBU show
catalytic activities, giving the target product in 48% yield for 2 d
and 8% yield for 3 d respectively (Table 1, Entries 2, 4). For
analogus phosphines, Bu3P can smoothly catalyze the reaction
in 24% yield after 2 days, w hile Ph3P show n no catalytic activity,
possibly for its less nucleophilicity (Table 1, Entries 10, 11). For
inorganic bases, such as carbonates and hydroxides, no desired
product w as observed (Table 1, Entries 12-15). So, DMAP w as
chosen as the reaction promoter.
construction of 3,4-cyclohexenone skeleton.
catalyzed 1,3-acyloxy migration and subsequent [5
A
Rhodium-
1]
+
cycloaddition of cyclopropyl substituted propargyl esters for
vinylidine-cyclohexenone rings has been reported by Tang.4,6
9
Shi 8 and Chen has also reported a special byproduct of (E)-2-
benzylidenecyclohex-3-enone 3a in 55% and 30
% yield
respectively. Considering the limited starting materials or the
low er efficiency of the mentioned preparations, concise and
effective methods for the construction of 3,4-cyclohexenone
skeleton are highly desirable.
With DMAP as catalyst, solvents w ere furtherly screened
(Table 2). Halogen hydrocarbon, such as CHCl3, gave poor yield
(Table 2, Entry 1). Ethers such as Et2O, THF and 1,4-dioxane,
all gave poor yields (Table 2, Entries 2-4). Other solvents, such
as CH3CN, EA, DMF, slightly higher yields w ere observed (Table
2, Entries 5-6) or no reaction occured (Table 2, Entry 7). MeOH
gave no product (Table 2, Entry 8). How ever, the best result
w as obtained in toluene (up to 80% yield) (Table 2, Entry 9)
and analogus aromatic solvents of m-xylene and mesitylene
gave slightly reduced yields of 76% and 65% respectively,
possible due to low er solubility of the substrate 1a.
Figure 1 Selected bioactive natural products with 3,4-cyclohexenone skeleton.
[a]
[b]
Dr. H.-X. Ren, Dr. X.-J. Song, L. Wu, Dr. Z.-C. Huang, Dr. Y. Zou,
Dr. X. Li, X.-W. Chen, Prof. F. Tian, Prof. L.-X. Wang. Key
Laboratory of Asymmetric Synthesis and Chirotechnology of
Sichuan Province, Chengdu Institute of Organic Chemitry, Chinese
Academy of Sciences, Chengdu 610041, China
E-mails: wlxioc@cioc.ac.cn; 452553462@qq.com
http://people.ucas.edu.cn/~wlxcioc
Dr. H.-X. Ren, Dr. X.-J. Song, L. Wu, Dr. Z.-C. Huang, Dr. Y. Zou,
Dr. X. Li, X.-W. Chen, University of Chinese Academy of Sciences,
Beijing 100049, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801301
European Journal of Organic Chemistry
COMMUNICATION
Table 1 Screenings of catalyst[a]
Table 3 Screenings of other parameters[a]
Entry
1
Catalyst
None
Reaction time
Yield[b] (%)
NR
3 d
2 d
3 d
3 d
3 d
3 d
3 d
3 d
3 d
2 d
2 d
3 d
3 d
3 d
3 d
Catalyst
(x mol%)
Reaction
Yield[b] (%)
time
Entry
T
1a:2a
2
DMAP[e]
DABCO[f]
DBU[g]
48
1
2
3
4
50
100
20
rt
1:1.1
1:1.1
1:1.1
1:1.1
72 h
48 h
48 h
7 h
77
78
82
87
3
Trace[c]
rt
50 oC
4
8
5
Et3N
NR
20
reflux
6
Pyridine
Pyrrole
Piperidine
Imidazole
Bu3P
NR
5
20
reflux
1:1
7 h
83
7
NR
6
7
8
9
20
20
20
20
reflux
reflux
reflux
reflux
1:2
1:3
2:1
3:1
7 h
7 h
7 h
7 h
85
81
74
76
8
NR
9
NR
10[d]
11
12
13
14
15
24
[a] Unless otherwise specified, the reaction was performed on a scale of 0.2
mmol MBH alcohol 1a, y mmol Boc2O 2a, x mmol% catalyst in 1 mL toluene.
[b] Isolated yield.
Ph3P
NR
Cs2CO3
K2CO3
Trace[c]
NR
Unsatisfactorily, the reaction w as not completely finished
even after 4 days, so further catalyst loadings, temperature and
substrate ratio w ere optimized. When increasing the DMAP
loading to 50 mol% or 100 mol%, the reaction time w as reduced
to 3d and 2 d respectively w ith slightly decreased yields (Table 3,
Entries 1, 2). The yields w ere increased to 82% at 50 oC for 2 d
and 87% at refluxing temperature (110 oC) for 7 h (Table 3,
Entries 3, 4). Changing the molar ratio of substrate 1a and 2a,
how ever, no better result w as observed (Table 3, Entries 5-9).
Considering all the active parameters, the optimal reaction
conditions w ere established as 0.2 mmol of 1a and 0.22 mmol of
2a w ith 20 mol% of DMAP as catalyst in 1mL toluene at refluxing
terperature for 7 h (Table 3, Entry 4).
Na2CO3
KOH
NR
Trace[c]
[a] Unless otherwise specified, the reaction was performed on a scale of 0.2
mmol MBH alcohol 1a, 0.22 mmol Boc2O 2a, 20 mmol% catalyst in 1 mL
CH2Cl2 at room temperature. [b] Isolated yield. [c] Only 4 and trace of 3a were
detected. [d] Under N2 atmosphere. [e] DMAP was 4-dimethylaminopyridine.
[f]
[g]
DABCO was 1, 4-Diazabicyclo[2.2.2]octane.
Diazabicyclo[5,4,0]undec-7-ene.
DBU was 1, 8-
Table 2 Screenings of solvent[a]
Under the optimized reaction conditions, the generality for
substrates w as further investigated (Table 4). Generally, most
Entry
Solvent
Reaction time
Yield[b] (%)
MBH alcohols
1
and 2 w ere w ell tolerated, providing
corresponding products in acceptable to excellent yields. While
w ith electron-w ithdraw ing group of halogen atom on phenyl
group (R1) of MBH alcohols 1, slightly decreased yields w ere
observed (Table 4, Entries 2-6). Especially, for 4-NO2-phenyl 1g,
only 17% yield w as obtained, and w hen the reaction w as
conducted in CH2Cl2 at room temperature for 3 d, how ever, the
yield increased to 52%, probably attributed to the unstability of
3g at refluxing temperature for hours (Table 4, Entry 7). For
electron-donating groups, such as methyl or methoxyl
substituted on the aromatic ring, excellent yields (86-93%) w ere
obtained (Table 4, Entries 8-11). For hetereocyclic 2-furyl MBH
alcohol, good result w as still achieved (Table 4, Entry 12).
Changing aromatic group to hydrogen atom or methyl, only
mixture or poor yields observed, possibly due to the more
unstable target molecules w ith smaller π conjugated system
(Table 4, Entries 13, 14).15 Broadly, w hen chloroformate w as
used instead of Boc2O, the reaction still w orked w ell w ith up to
80% yields (Table 4, Entries 15-18). The configuration of the
product w as determined by X-ray crystal structural analysis of
the representative product 3h (Figure 2)(see the Supporting
Information for details).16
1
2
3
4
5
6
7
8
9
CHCl3
Et2O
5 d
5 d
2 d
3 d
2 d
2 d
5 d
5 d
4 d
Trace[c]
Trace[c]
20
THF[e]
1,4-Dioxane
CH3CN
EA[f]
21
52
46
DMF[g]
NR
MeOH
NR
Toluene
80
10[d]
11[d]
m-Xylene
3 d
5 d
76
65
Mesitylene
[a] Unless otherwise specified, the reaction was performed on a scale of 0.2
mmol MBH alcohol 1a, 0.22 mmol Boc2O 2a, 20 mmol% DMAP in 1 mL
solvent at room temperature. [b] Isolated yield. [c] Only 4 observed. [d] Poor
solubility. [e] THF was Tetrahydrofuran. EA was ethyl acetate. [g] DMF was N,
[f]
N-Dimethylformamide.
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10.1002/ejoc.201801301
European Journal of Organic Chemistry
COMMUNICATION
To understand the unexpected reaction, w e proposed a
plausible mechanism (Scheme 2). Firstly, MBH carbonate 4 w as
obtained via cyclohexenone-MBH alcohol 1a w ith di-tert-butyl
dicarbonate ester in the presence of DMAP. MBH carbonate 4
was attacked by DMAP to form quaternary ammonium salt 5 and
tert-butoxide anion after emission of CO2. Further deprotonation
of 5 by tert-butoxide anion, intermediate 6 w as formed. The
allylic hydrogen atom in 6 w as transfered to the neighboring
carbon to form 7. The leaving of catalyst driven by a negative
charge completed the catalytic cycle, yielding the product and
setting the catalyst free.
Scheme 2 Plausible Mechanism
To demonstrate the synthetic potential of this new protocol
(Scheme 3), scale-up experiment w as conducted on gram scale,
almost equal result (84% yield) w as still achieved, w hich may
lead to a further scale-up preparation. Treating 3a w ith NaBH4 in
THF, product 8 w as afforded in 83% yield for selective reduction
of carbonyl group. Under H2 atmosphere, 3a can be vinyl
selectively reducted to 9 in 94% yield catalysed by Pd/C (5%
w.t.). Carbonyl addition can be selectively occurred in the
presence of Grignard reagent and product 10 w as obtained in 89%
yield.
Table 4 Generality of substrates[a]
Entry
1/R1
3/Yield[b] (%)
2
1
2
1a/C6H5
1b/2-FC6H4
1c/4-FC6H4
1d/2-ClC6H4
1e/4-ClC6H4
1f/3-BrC6H4
1g/4-NO2C6H4
1h/4-CH3C6H4
1i/2-OCH3C6H4
1j/3-OCH3C6H4
1k/4-OCH3C6H4
1l/ Furyl
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2a/Boc2O
2b/ClCO2Bn
2c/ClCO2Ph
2d/ClCO2Et
2e/ClCO2i-Bu
3a/87
3b/70
3c/79
Scheme 3 Scale-up preparation and the synthetic transformations of 3a
3
4
3d/67
3e/58
Conclusions
5
6
3f/64
In summary, an unexpected new reaction of cyclohexenone-
MBH alcohol catalyzed by DMAP has been disclosed. A series
of substituted (E)-2-methylene-3,4-cyclohexenones have been
successfully prepared in excellent yields (up to 93%) under
convenient reaction conditions. After typical successful scale-up
preparation and synthetic transformations, our protocol is
potentially feasible for scale-up applications for concise and
effective constructions of 3,4-cyclohexenone skeleton.
7
3g/17(52)[c]
3h/86
3i/90
8
9
10
11
12[d]
13
14
15
16
17
18
3j/89
3k/93
3l/81
1m/H
3m/trace
1n/47[e]
3a/42
1n/Me
Experimental Section
1a/C6H5
General information
1a/C6H5
3a/80
1a/C6H5
3a/46
Commercial grade solvent was dried and purified by standard
procedures as specified in Purification of Laboratory Chemicals, 4th
Ed (Armarego, W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997).
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
(300 MHz for 1H NMR, 75 MHz for 13C NMR) instrument. Data for 1H
NMR are reported as chemical shift (ppm, tetramethylsilane as the
internal standard), integration, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m= multiplet), coupling constant (Hz). Data for 13C
NMR are reported as chemical shift. High resolution mass spectra
were obtained with the Q-TOF-Premier mass spectrometer. Flash
column chromatography was carried out using silica gel eluting with
ethyl acetate and petroleum ether. Reactions were monitored by TLC
and visualized with ultraviolet light.
1a/C6H5
3a/74
[a] Unless otherwise specified, the reaction was performed on a scale of 0.2
mmol MBH alcohol 1, 0.22 mmol ester 2, 20 mmol% DMAP in 1 mL toluene
refluxfor 7 h. [b] Isolated yield. [c] The reaction condition was 0.2 mmol 1g,
0.22 mmol 2a, 20 mmol% DMAP in 1 mL CH2Cl2 at room temperature for 3 d.
[d] Reacted for 2 h. [e] Detected by HPLC.
≡
Figure 2 Representative X-raycrystallographic structure of product 3h
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10.1002/ejoc.201801301
European Journal of Organic Chemistry
COMMUNICATION
(E)-2-(o-methoxybenzylidenecyclohex)-3-enone (3i). 90% yield,
pale yellow oil, Rf = 0.21 (silica gel, petroleum ether/ethyl acetate 20:1),
1H NMR (300 MHz, Chloroform-d) δ 7.63 (s, 1H), 7.34-7.28 (m, 2H),
6.97-6.88 (m, 2H), 6.82 (dd, J = 10.0, 0.8 Hz, 1H), 6.21-6.06 (m, 1H),
3.84 (s, 3H), 2.69-2.64 (m, 2H), 2.59-2.54 (m, 2H). 13C NMR (75 MHz,
Chloroform-d) δ 200.1, 158.3, 130.9, 130.4, 130.1, 130.1, 128.3, 125.5,
124.3, 120.0, 110.5, 55.4, 38.3, 24.5. HRMS (ESI) m/z calcd for
C14H15O2+ (M+H)+ 215.10666, found 215.10629.
General Procedures for the reaction of MBH alcohol 1 and 2.
A solution of 0.2 mmol MBH alcohol 1, 0.22 mmol 2, 20 mmol% DMAP in
1 mL toluene was stirred at reflux temperature for 7 h. After completion,
the crude product was directly purified by flash chromatography to obtain
the product.
(E)-2-benzylidenecyclohex-3-enone (3a). 87% yield, pale yellow oil,
Rf = 0.28 (silica gel, petroleum ether/ethyl acetate 20:1), 1H NMR (300
MHz, DMSO-d6) δ 7.54-7.30 (m, 5H), 7.27 (s, 1H), 6.90 (dq, J = 10.0, 1.4
Hz, 1H), 6.23 (dtd, J = 10.1, 4.4, 1.8 Hz, 1H), 2.68-2.44 (m, 4H). 13C NMR
(75 MHz, DMSO-d6) δ 199.0, 134.8, 132.3, 130.8, 130.5, 129.8, 128.7,
128.6, 124.2, 37.7, 24.0. HRMS (ESI) m/z calcd for C13H13O+ (M+H)+
185.09609, found 185.09572.
(E)-2-(m-methoxybenzylidenecyclohex)-3-enone (3j). 89% yield,
pale yellow oil, Rf = 0.20 (silica gel, petroleum ether/ethyl acetate 20:1),
1H NMR (300 MHz, Chloroform-d) δ 7.35 (s, 1H), 7.25 (t, J = 7.9 Hz, 1H),
7.63 (d, J = 7.6 Hz, 1H), 6.91-6.88 (m, 2H), 6.83 (dd, J = 8.2, 2.4 Hz, 1H),
6.13-6.07 (m, 1H), 3.76 (s, 3H), 2.65-2.60 (m, 2H), 2.56-2.50 (m, 2H). 13
C
(E)-2-(o-fluorobenzylidenecyclohex)-3-enone (3b). 70% yield, pale
yellow oil, Rf = 0.31 (silica gel, petroleum ether/ethyl acetate 20:1), 1H
NMR (300 MHz, Chloroform-d) δ 7.42 (s, 1H), 7.35-7.25 (m, 2H), 7.13-
7.02 (m, 2H), 6.73 (d, J = 10.0 Hz, 1H), 6.15-6.11 (m, 1H), 2.67-2.62 (m,
2H), 2.58-2.53 (m, 2H). 13C NMR (75 MHz, Chloroform-d) δ 199.4, 160.7
(J = 249.1 Hz), 132.4, 131.5, 130.6 (J = 2.7 Hz), 130.2 (J = 8.2 Hz),
124.9 (J = 0.9 Hz), 124.4 (J = 3.5 Hz), 123.7 (J = 3.6 Hz), 123.1 (J = 13.9
Hz), 115.5 (J = 21.6 Hz), 38.1, 24.5. HRMS (ESI) m/z calcd for
C13H12FO+ (M+H)+ 203.08667, found 203.08630.
(E)-2-(p-fluorobenzylidenecyclohex)-3-enone (3c). 79% yield, pale
yellow oil, Rf = 0.23 (silica gel, petroleum ether/ethyl acetate 20:1), 1H
NMR (300 MHz, Chloroform-d) δ 7.50-7.36 (m, 3H), 7.16-7.05 (m, 2H),
6.89 (dq, J = 10.0, 1.4 Hz, 1H), 6.20 (dtd, J = 8.7, 4.4, 1.7 Hz, 1H), 2.76-
2.66 (m, 2H), 2.66-2.54 (m, 2H). 13C NMR (75 MHz, Chloroform-d) δ
200.0, 162.6 (J = 248.4 Hz), 131.8, 131.7, 131.5, 131.4, 131.2, 130.9,
130.7, 124.8, 115.6 (J = 21.5 Hz), 38.1, 24.5. HRMS (ESI) m/z calcd for
C13H12FO+ (M+H)+ 203.08667, found 203.08620.
NMR (75 MHz, Chloroform-d) δ 199.8, 159.3, 136.4, 131.6, 131.1, 130.9,
129.2, 124.9, 122.2, 115.1, 114.0, 55.0, 38.0, 24.3. HRMS (ESI) m/z
calcd for C14H15O2+ (M+H)+ 215.10666, found 215.10645.
(E)-2-(p-methoxybenzylidenecyclohex)-3-enone (3k). 93% yield,
pale yellow solid, m. p. 55.8-56.7 oC, Rf = 0.16 (silica gel, petroleum
ether/ethyl acetate 20:1), 1H NMR (300 MHz, Chloroform-d) δ 7.38-7.35
(m, 3H), 6.92-6.86 (m, 3H), 6.11-6.07 (m, 1H), 3.78 (s, 3H), 2.63-2.59 (m,
2H), 2.55-2.51 (m, 2H). 13C NMR (75 MHz, Chloroform-d) δ 200.0, 159.8,
131.8, 131.6, 130.0, 129.4, 127.7, 125.1, 113.8, 55.1, 38.0, 24.2. HRMS
(ESI) m/z calcd for C14H15O2+ (M+H)+ 215.10666, found 215.10622.
(E)-2-(furan-2-ylmethylene)cyclohex-3-en-1-one (3l). 81% yield,
pale yellow oil, Rf = 0.23 (silica gel, petroleum ether/ethyl acetate 20:1),
1H NMR (300 MHz, Chloroform-d) δ 7.59 (d, J = 1.4 Hz, 1H), 7.45 (d, J =
10.1 Hz, 1H), 7.10 (s, 1H), 6.70 (d, J = 3.4 Hz, 1H), 6.52-6.50 (m, 1H),
6.22-6.16 (m, 1H), 2.71-2.66 (m, 2H), 2.63-2.60 (m, 2H). 13C NMR (75
MHz, Chloroform-d) δ 199.5, 152.3, 144.9, 130.4, 127.2, 125.9, 117.3,
+
116.9, 112.2, 38.0, 24.4. HRMS (ESI) m/z calcd for C11H11O2 (M+H)+
(E)-2-(o-chlorobenzylidenecyclohex)-3-enone (3d). 67% yield, pale
yellow oil, Rf = 0.27 (silica gel, petroleum ether/ethyl acetate 20:1), 1H
NMR (300 MHz, Chloroform-d) δ 7.50 (s, 1H), 7.40-7.31 (m, 2H), 7.24-
7.21 (m, 2H), 6.65 (dd, J = 10.0, 0.9 Hz, 1H), 6.14-6.11 (m, 1H), 2.69-
2.64 (m, 2H), 2.59-2.55 (m, 2H). 13C NMR (75 MHz, Chloroform-d) δ
199.5, 134.7, 133.6, 132.1, 131.7, 130.6, 129.6, 129.5, 128.7, 126.2,
124.6, 38.1, 24.6. HRMS (ESI) m/z calcd for C13H12ClO+ (M+H)+
219.05712, found 219.05673.
175.07536, found 175.07564.
Keywords: Cyclohexenone-MBH alcohol • Organocatalysis •
Substituted (E)-2-methylene-3,4-cyclohexenone skeleton •
Unexpected new reaction
(E)-2-(p-chlorobenzylidenecyclohex)-3-enone (3e). 58% yield, pale
yellow solid, m. p. 79.8-81.2 oC, Rf = 0.28 (silica gel, petroleum
ether/ethyl acetate 20:1), 1H NMR (300 MHz, Chloroform-d) δ 7.29-7.25
(m, 5H), 6.80 (dd, J = 10.0, 0.8 Hz, 1H), 6.16-6.09 (m, 1H), 2.64-2.59 (m,
2H), 2.56-2.50 (m, 2H). 13C NMR (75 MHz, Chloroform-d) δ 199.6, 134.2,
133.6, 131.6, 131.2, 131.0, 130.2, 128.5, 124.5, 37.9, 24.3. HRMS (ESI)
m/z calcd for C13H12ClO+ (M+H)+ 219.05712, found 219.05667.
(E)-2-(m-bromobenzylidenecyclohex)-3-enone (3f). 64% yield, pale
yellow oil, Rf = 0.21 (silica gel, petroleum ether/ethyl acetate 20:1), 1H
NMR (300 MHz, Chloroform-d) δ 7.53 (t, J = 1.8 Hz, 1H), 7.49-7.39 (m,
1H), 7.3-7.27 (m, 2H), 7.23 (t, J = 7.8 Hz, 1H), 6.84 (dq, J = 10.1, 1.5 Hz,
1H), 6.19 (dtd, J = 10.4, 4.4, 1.7 Hz, 1H), 2.73-2.63 (m, 2H), 2.61-2.55 (m,
2H). 13C NMR (75 MHz, Chloroform-d) δ 199.8, 137.4, 132.3, 132.1,
131.9, 131.2, 130.0, 129.9, 128.4, 124.5, 122.4, 38.1, 24.5. HRMS (ESI)
m/z calcd for C13H12BrO+ (M+H)+ 263.00660, found 263.00616.
(E)-2-(p-nitrobenzylidenecyclohex)-3-enone (3g). 52% yield, pale
yellow solid, m. p. 138.5-139.6 oC, Rf = 0.10 (silica gel, petroleum
ether/ethyl acetate 20:1), 1H NMR (300 MHz, Chloroform-d) δ 8.20 (d, J =
8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.35 (s, 1H), 6.82 (dd, J = 10.0, 0.8
Hz, 1H), 6.31-6.25 (m, 1H), 2.72-2.67 (m, 2H), 2.65-2.61 (m, 2H). 13C
NMR (75 MHz, Chloroform-d) δ 199.3, 147.1, 142.1, 133.9, 133.3, 130.4,
128.6, 124.2, 123.6, 38.0, 24.7. HRMS (ESI) m/z calcd for C13H12NO3+
(M+H)+ 230.08117, found 230.08183.
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(E)-2-(p-methylbenzylidenecyclohex)-3-enone (3h). 86% yield,
pale yellow solid, m. p. 86.1-87.4 oC, Rf = 0.29 (silica gel, petroleum
ether/ethyl acetate 20:1), 1H NMR (300 MHz, Chloroform-d) δ 7.41 (s,
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10.1002/ejoc.201801301
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Text for Table of Contents
Synthetic methods
Author(s), Corresponding Author(s)*
Hong-Xia Ren, Xiang-Jia Song, Lin Wu, Zhi-Cheng Huang,
Ying Zou, Xia Li, Xiao-Wen Chen, Fang Tian* and Li-Xin
Wang*
Page No. – Page No.
Title
Direct and convenient construction of substituted (E)-2-
methylene-3,4-cyclohexenone skeleton from cyclohexenone-
MBH alcohol in the presence of DMAP
An unexpected new reaction of cyclohexenone-MBH alcohol catalyzed by
DMAP has been successfully disclosed to prepare a series of substituted
(E)-2-methylene-3,4-cyclohexenones in excellent yields (up to 93%) under
convenient reaction conditions. Scale-up preparation and synthetic
transformations have been conducted.
This article is protected by copyright. All rights reserved.