Oxa-Michael addition promoted by the aqueous sodium carbonate

Article abstract of DOI:10.1016/j.tetlet.2014.10.019

An efficient Michael addition of alcohols to activated alkenes promoted by sodium carbonate with water as reaction medium has been developed. The reaction provides a general, economical and environmentally friendly approach for the synthesis of β-alkoxycarbonyl compounds.

Full text of DOI:10.1016/j.tetlet.2014.10.019

Tetrahedron Letters 55 (2014) 6718–6720
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxa-Michael addition promoted by the aqueous sodium carbonate
⇑
Shi-Huan Guo , Sheng-Zhu Xing , Shuai Mao, Ya-Ru Gao, Wen-Liang Chen, Yong-Qiang Wang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an
710069, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2014
Revised 30 September 2014
Accepted 4 October 2014
Available online 29 October 2014
An efficient Michael addition of alcohols to activated alkenes promoted by sodium carbonate with water
as reaction medium has been developed. The reaction provides a general, economical and environmen-
tally friendly approach for the synthesis of b-alkoxycarbonyl compounds.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Sodium carbonate
Oxa-Michael addition
Alcohols
b-Alkoxycarbonyl compounds
The b-alkoxy carbonyl structural moiety is ubiquitous in natural
products and biologically active compounds.1 It is typically synthe-
sized via aldol reaction and the subsequent alkylation of the result-
ing hydroxyl group.2 Alternatively, Michael addition of alcohols to
enones provides a direct and versatile method for the moiety.3 But
the formation of the carbonAoxygen bond by the oxa-Michael
reaction remains challenging due to potential oligomerization of
the acceptor, reversibility and the inherent energetic aspects of this
process.4 In the past decades, some elegant intermolecular Michael
additions of alcohols to enones have been developed, in which cat-
alytic approach was the most attractive method.5,6 Recently,
Scheidt et al.7 have reported that N-heterocyclic carbene could also
promote Michael addition of alcohols to enones. Despite these
important advances, some challenging issues of the oxa-Michael
addition still remained; for example, (1) some cases employed
strong bases (e.g., n-BuLi)7 or acids (e.g., Tf2NH)5e in the reaction
system, resulting in the requirement of high practical operation
skills; (2) some cases used expensive transition metal (e.g., Pd,5a
Rh5h and Pt5o) or costly organic compounds5c as catalyst; (3)
almost all of reaction mediums were organic solvents8 or special
ionic liquids.5k,n Therefore, a facile, economical and environmen-
tally benign catalytic oxa-Michael addition remains highly desir-
able. Herein, we disclose an efficient sodium carbonate-promoted
Michael addition of alcohols to activated alkenes with water as
the reaction medium. The key advantages of the approach are gen-
erality, economy and green chemistry.
Initial studies were carried out with 1-phenyl-2-propylen-1-
one (1a) and ethanol as a model system. Considering unique reac-
tivity of organic compounds in aqueous suspension and the ‘on
water’ effect in reaction rate acceleration which has been evidently
observed by Sharpless et al.,9 we chose water as solvent. Pure
water provided no product (Table 1, entry 1). To our delight, when
sodium hydroxide (0.1 M, 0.2 mL) was introduced, the reaction
afforded the desired product (2a), albeit in only 34% yield (Table 1,
Table 1
Optimization of reaction conditionsa
O
O
base (aq.)
OEt
+ EtOH
2a
1a
Entry
Base
Concentration (M)
Yieldb (%)
1c
2
3
4
5
6
7
8
—
NaOH
LiOH
—
N.R.d
34
29
31
62
0.1
0.1
0.1
0.1
0.1
0.05
0.01
KOH
Na2CO3
NaHCO3
Na2CO3
Na2CO3
None
73
S.R.e
a
Reaction conditions: 1a (0.5 mmol), EtOH (2 mmol), and catalyst (aqueous,
0.2 mL) at rt for 2 h.
b
Isolated yield.
0.2 mL water was used.
No reaction.
Slow reaction.
c
⇑
Corresponding author. Tel.: +86 29 88305966.
E-mail address: wangyq@nwu.edu.cn (Y.-Q. Wang).
d
e
Guo, S.-H. and Xing, S.-Z. contributed equally to this work.
http://dx.doi.org/10.1016/j.tetlet.2014.10.019
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S.-H. Guo et al. / Tetrahedron Letters 55 (2014) 6718–6720
6719
Table 2
Table 2 (continued)
Substrate scope for activated olefinsa
Entry
Substrate
ROH
Time (h)
Yieldb (%)
R2
R1
EWG
R2
R1
EWG
OR
ROH
Na2CO3 (aq.)
O
r.t.
MeOH
EtOH
2
2
81
78
14
1
2
1n
Entry
1
Substrate
ROH
Time (h)
Yieldb (%)
O
O
MeOH
EtOH
5
8
87
79
15
MeOH
EtOH
2
2
78
73
1o
1a
O
MeOH
EtOH
2
2
85
80
O
16
17
MeOH
EtOH
2
2
81
75
1p
O
2
3
4
5
6
1b
MeOH
EtOH
2
2
72
75
F
O
1q
MeOH
EtOH
2
2
73
69
O
MeOH
EtOH
8
8
87
83
18
19
20c
1c
Cl
1r
O
MeOH
EtOH
5
5
85
85
CN
MeOH
EtOH
2
2
75
70
1s
O
1d
Cl
MeOH
EtOH
5
5
90
88
OEt
O
1t
MeOH
EtOH
2
2
72
68
a
Reaction conditions: 1a (0.5 mmol), ROH (2 mmol), and base (0.05 M aq,
0.2 mL) at rt.
1e
1f
Br
b
Isolated yield.
O
c
Na2CO3 (1.1 mg, 0.04 equiv) as base without water.
MeOH
EtOH
2
2
72
67
entry 2). The result indicated that aqueous base solution was able
to realize oxa-Michael addition of alcohol to enone. Then we inves-
tigated other bases. Lithium hydroxide and potassium hydroxide
gave low yield (29% and 31%, respectively) because of material
decomposition (Table 1, entries 3 and 4). Sodium carbonate proved
to be an efficient catalyst, affording product 2a in 62% yield
(Table 1, entry 5), while sodium bicarbonate was not effective
(Table 1, entry 6). The great catalytic activity of sodium carbonate
probably attributes to proper basicity. Sodium bicarbonate could
not promote the reaction because of weak basicity, while alkali
hydroxides give low yields for their strong basicity leading to
material decomposition. Next, the amount of EtOH was examined.
It was found that the reaction obviously slowed down and could
not be complete within 12 h when the amount of EtOH was
reduced to 1.0 mmol. Finally we examined the amount of the cat-
alyst. Sodium carbonate (0.05 M, 0.2 mL) turned out to be the best
to afford the product in 73% isolated yield.
Under the optimized reaction conditions, we surveyed the sub-
strate scope with respect to conjugate acceptors in combination
with MeOH or EtOH. Results were summarized in Table 2. Na2CO3
(aq) promoted oxa-Michael reaction was found to be in general
with a wide range of substrates. Both electron-withdrawing and
electron-donating group substituted aromatic 2-propylen-1-ones
(1) were suitable substrates, yielding the desired products in good
to excellent yields (64–91%, Table 2, entries 1–12). All the halogens
(F, Cl, Br and I) were well-tolerated under the reaction conditions,
which could be easily transformed into other functionalities. Naph-
Br
O
MeOH
EtOH
2
2
68
64
7
1g
Br
O
MeOH
EtOH
2
2
70
67
8
1h
I
O
MeOH
EtOH
2
2
82
79
9
1i
Me
O
MeOH
EtOH
2
2
91
89
10
11
1j
MeO
O
MeOH
EtOH
2
2
71
68
O
O
1k
O
MeOH
EtOH
2
2
87
85
12
13
1l
thyl, a-substituted and non-terminal enones also obtained the cor-
O
responding products in 74–87% yields (Table 2, entries 13–15).
Gratifyingly, alkyl enones, which possess high reactivity and are
easily polymerized in base conditions, were accommodated under
the current conditions to provide the desired products in good
MeOH
EtOH
2
2
77
74
1m
yields (Table 2, entries 16–18). Furthermore,
a,b-unsaturated
nitrile was suitable substrate, despite its high tendency to poly-
merize, and afforded the corresponding hydroalkoxylated products

6720
S.-H. Guo et al. / Tetrahedron Letters 55 (2014) 6718–6720
Table 3
tally friendly method for the synthesis of b-alkoxycarbonyl com-
Survey of alcohola
pounds which are ubiquitous in nature. The reaction conditions
are so mild that the method should have many applications in
organic and medical chemistry. Detailed mechanistic investiga-
tions and applications to the synthesis of biologically active molec-
ular complexes are currently underway.
O
O
ROH
Na2CO3 (aq.)
R'
R'
OR
r.t.
1a or 1p
2
Entry
Alcohol
R0
Time (h)
Yieldb (%)
Acknowledgments
Et
Ph
Et
4
8
4
8
70
69
68
70
OH
OH
1
2
This research was supported by the National Natural Science
Foundation of China (NSFC-20972126, 21272185) and the Program
for New Century Excellent Talents in the University of the Ministry
of Education China (NCET-10-0937).
Ph
Et
Ph
4
8
60
56
3
4
OH
OH
Et
Ph
4
8
73
71
Supplementary data
OH
Et
Ph
24
8
75
90
5c
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
019.
OH
6c,d
Ph
24
16
60 (>99% ee)
CO2Me
References and notes
O
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85
OH
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a
Reaction conditions: 1a or 1p (0.5 mmol), ROH (2 mmol), and Na2CO3 (0.05 M
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aq, 0.2 mL) at rt.
b
Isolated yield.
ROH (0.5 mmol) was used.
Na2CO3 (0.2 M aq, 0.5 mL) was used.
c
d
5. For select examples of intermolecular Michael reaction of alcohols to enones: (a)
Miller, K. J.; Kitagawa, T. T.; Abu-Omar, M. M. Organometallics 2001, 20, 4403; (b)
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in excellent yields (Table 2, entry 19). Additionally, Na2CO3 can
also efficiently promote Michael addition of alcohols to a,b-unsat-
urated ester, but the reaction was run under non-water conditions
because of ester hydrolysis in aqueous solution (Table 2, entry 20).
Using ethyl vinyl ketone and phenyl vinyl ketone as Michael
acceptors, the scope of alcohols was investigated (Table 3). Pri-
mary, secondary, and benzyl alcohols were competent nucleo-
philes (Table 3, entries 1–4), while tertiary alcohols did not
undergo the Michael addition because of huge steric hindrance
(not shown). Phenol was also found to serve as suitable nucleo-
phile for the aqueous sodium carbonate solution promoted
Michael additions and afforded good yields (Table 3, entry 5). It
was noteworthy to mention that chiral alcohol could be used as
substrate to afford the corresponding oxa-Michael adduct in good
yield with the chirality of the stereocenter intact (product ee
>99%, see Supplementary data) (Table 3, entry 6). For intramolecu-
lar oxa-Michael addition, the reaction system could also provide
excellent result (Table 3, entry 7).
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a,b-unsaturated
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8. Some cases used Michael donor, alcohol as solvent. Although Venkateswarlu
et al. reported a La(NO3)3ꢀ6H2O catalyzed oxa-Michael addition of phenols to
a,b-unsaturated carbonyl compounds under solvent-free conditions, aliphatic
alcohols could not react under the reaction conditions. See, Prabhakar, P.;
Suryakiran, N.; Narasimhulu, M.; Venkateswarlu, Y. J. Mol. Catal. A: Chem. 2007,
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In summary, we have shown that sodium carbonate is able to
promote Michael addition of alcohols to activated olefins with
water as solvent. With unprecedented reaction in water at room
temperature, well-common catalyst and broad substrate scope,
the catalytic approach provides a facile, economical, environmen-