'On water' direct vinylogous Henry (nitroaldol) reactions of 3,5-dimethyl-4-nitroisoxazole with aldehydes and trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tet.2016.03.072

An efficient 'on water'-promoted direct catalytic vinylogous addition of 3,5-dimethyl-4-nitroisoxazole to aldehydes and trifluoromethyl ketones was described, giving Henry (nitroaldol) adducts in excellent yields. The trifluoromethyl tertiary alcohol prod

Full text of DOI:10.1016/j.tet.2016.03.072

Accepted Manuscript
“On water” direct vinylogous Henry (nitroaldol) reactions of 3,5-dimethyl-4-
nitroisoxazole with aldehydes and trifluoromethyl ketones
Yong Zhang, Biao-Wen Wei, Li-Na Zou, Mei-Lian Kang, Hai-Qing Luo, Xiao-Lin Fan
PII:
S0040-4020(16)30203-4
10.1016/j.tet.2016.03.072
TET 27612
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 December 2015
Revised Date: 21 March 2016
Accepted Date: 22 March 2016
Please cite this article as: Zhang Y, Wei B-W, Zou L-N, Kang M-L, Luo H-Q, Fan X-L, “On water”
direct vinylogous Henry (nitroaldol) reactions of 3,5-dimethyl-4-nitroisoxazole with aldehydes and
trifluoromethyl ketones, Tetrahedron (2016), doi: 10.1016/j.tet.2016.03.072.
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ACCEPTED MANUSCRIPT
Graphical Abstract
“On water” direct vinylogous Henry
(nitroaldol) reactions of 3,5-dimethyl-4-
nitroisoxazole with aldehydes and
trifluoromethyl ketones
Yong Zhang a,*, Biao-Wen Wei a, Li-Na Zou a, Mei-Lian Kang a, Hai-Qing Luo a, and Xiao-Lin Fan a,b,
*

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
“On water” direct vinylogous Henry (nitroaldol) reactions of 3,5-dimethyl-4-
nitroisoxazole with aldehydes and trifluoromethyl ketones
Yong Zhang a,*, Biao-Wen Wei a, Li-Na Zou a, Mei-Lian Kang a, Hai-Qing Luo a, and Xiao-Lin Fan a,b,
*
a Key Laboratory of Organo-pharmaceutical Chemistry, Gannan Normal University, Ganzhou 341000, P. R. China
b Material and Chemical Engineering Department, Pingxiang University, Pingxiang 337055, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient “on water”-promoted direct catalytic vinylogous addition of 3,5-dimethyl-4-
nitroisoxazole to aldehydes and trifluoromethyl ketones was described, giving Henry (nitroaldol)
adducts in excellent yields. The trifluoromethyl tertiary alcohol product could be transformed to
the corresponding styrene derivative, which was demonstrated as a new type of Michael
acceptor in the vinylogous 1,6-Michael addition with nitromethane.
Available online
2015 Elsevier Ltd. All rights reserved
.
Keywords:
On water
Vinylogous Henry reactions
4-nitro-isoxazoles
The use of water as solvent for organic synthesis is regarded
as an important subject in green chemistry, because water is
cheap, nontoxic, nonflammable, and the most abundant liquid on
our planet.1 In addition, water has unique physical and chemical
properties, which allows us to realize reactivities that cannot be
achieved in conventional organic solvents. In the early 1980s,
Breslow and coworkers uncovered rate enhancement of Diels-
Alder reactions using water as the solvent.2 About 25 years later,
Sharpless and co-workers introduced the concept of “on water”
to explain the unusual reaction rate acceleration when the organic
reactants were insoluble in the aqueous phase.3 Since these two
seminal findings, many organic reactions have been tested under
on water conditions to improve synthetic efficiency.4 However,
developing new type of reaction in water is still highly desirable.
temperature for 15 h, the desired vinylogous adduct 3a was
obtained in high yield (92 %), together with 6% of dehydration
product 3a′. Some additional organic bases were then screened,
and the obtained results are summarized in Table 1. Significant
improvement in reaction efficiency was observed for DBU (1,8-
Diazabicyclo[5.4.0]undec-7-ene), but the selectivity is rather
poor. DMAP (4-dimethylaminopyridine), DABCO (1,4-
Diazabicyclo[2.2.2]octane), QD (qunidine) and diethylamine
were not suitable for such a reaction in term of both reaction
efficiency and selectivity. Inorganic bases such as NaOH and
K2CO3 can also catalyze the reaction, albeit in slightly lower
efficiency (entries 9 and 10).
Table 1 Screening of catalyst for the vinylogous addition of 2
to 1aa
With the exploitation of the vinylogy concept5, the
vinylogous-type reactions have emerged as effective strategies
for remote functionalizations and have been intensively studied
in recent years.6 However, so far, only a few examples of the
vinylogous-type reactions using pre-enolized reagents on water
have been reported.7 In the course of our studies on vinylogous-
type reactions8, we recently reported an “on water” promoted
direct vinylogous addition of 3,5-dialkyl-4-nitroisoxazoles to
isatins.9 Herein, we disclose an efficient vinylogous Henry
(nitroaldol) reaction between 3,5-dimethyl-4-nitroisoxazole and
aldehydes10 as well as trifluoromethyl ketones using water as the
solvent.
Entry
Catalyst
triethylamine
DBU
T (h)
15
3
3a/3a′Yieldb (%)
92/6
1
2
3
4
5
50/32
Using p-chlorobenzaldehyde (1a) and 3,5-dimethyl-4-
nitroisoxazole (2) as the model substrates and water as the
solvent, we initially screened NEt3 as the base catalyst to effect
the desired vinylogous Henry (nitroaldol) reaction between 1a
and 2. As shown by the data in Table 1 (entry 1), when the
reaction was carried out with 20 mol% of NEt3 at room
DMAP
36
48
48
57/30
DABCO
QD
36/19
31/37

2
Tetrahedron
ACCEPTED MANUSCRIPT
6
7
8
diethylamine
NaOH
36
48
48
85/11
86/nd
K2CO3
82/nd
a All of the reactions were performed with 0.22 mmol of 1a, 0.2 mmol of
2 and 0.04 mmol of catalyst in 1 mL H2O.
b Isolated yield.
Subsequently, we investigated the effect of solvent on the
reaction between 1a and 2 using NEt3 as the catalyst (Table 2).
Poor conversions were observed using polar aprotic solvents
DMSO and DMF (entries 1 and 2), whereas no reaction took
place in Et2O, Toluene, DCM, MeCN and THF (entries 3-7). The
use of MeOH afforded only a small amount of 3a (entry 8). It is
noteworthy that both the reaction efficiency and the selectivity
rose dramatically with the increase of proportion of water in the
co-solvent of H2O–MeOH, despite the fact that the reaction
system became heterogeneous (entries 9 and 10). When pure
water was used as the solvent, the reaction proceeded effectively
to afford the desired product in excellent yield (up to 92%) (entry
11). Lowering down the reaction temperature to 15 oC will
reduce the yield of the dehydration product, and no obvious
effect on the reaction rate was observed.
Figure 1 Proposed transition state.
These observations prompted us to study the scope and
limitation of the direct vinylogous Henry reaction on a variety of
o
aldehydes, using water as the solvent at 15 C. The results are
presented in Table 3. This “on water” vinylogous Henry reaction
is compatible with a series of electon-deficient aromatic
aldehydes, affording the desired products 3a-3i in excellent
yields (93-97%). Both p-methyl benzaldehyde and 2-
naphthaldehyde displayed low activity, giving the addition
products 3j and 3m in moderate yields. No desired product was
obtained for p-methoxybenzaldehyde bearing a stronger electron
donating group. Heteroaromatic aldehydes such as 2-furaldehyde
gave exclusively the undesired dehydration product 3l′ in
moderate yield (70%). To our delight, α,β-unsaturated aldehyde
(4-nitrocinnamaldehyde as an example) was also applicable,
affording the 1,2 addition product 3n in 50% yield. Aliphatic
aldehyde11 (n-butanal as an example) was not suitable in such
reaction, gave no desired vinylogous product, presumably owing
to its water solubility, which may not suitable for the “on water”
reaction system.
Table 2 Solvent effect on the NEt3 catalyzed addition of 2 to
1aa
Entry
Solvent
T (h)
3a/3a′Yieldb
(%)
1
2
3
4
5
6
7
8
9
DMSO
DMF
24
24
24
24
24
24
24
24
24
7/-
3/-
Et2O
NRc
Table 3 Direct vinylogous Henry reactions of 3,5-dimethyl-4-
Toluene
DCM
NR
nitroisoxazole with aromatic aldehydesa
NR
N
NO2
OH O
CHO
TEA (20 mol%)
MeCN
THF
NR
+
R
R
NO2
H2O, 15 o
C
N
O
NR
3
2
1
CH3OH
30/-
48 /43
N
O
N
N
OH
OH
O
H2O-CH3OH
(1:3)
Cl OH
O
Cl
Cl
NO2
NO2
NO2
10
H2O-CH3OH
(3:1)
15
85/8
Cl
Cl
3c
3a
10 h
15 h
96% yield
3b
10 h
94% yield
95% yield
11
H2O
H2O
15
15
92/6
96/-
N
N
N
OH
O
Cl OH
O
OH
O
12d
a
NO2
NO2
NO2
Unless otherwise noted, the reaction was performed with 0.22 mmol of
F
Cl
3d
O2N
1a, 0.2 mmol of 2 and 0.04 mmol of NEt3 in 1 mL solvent at RT.
3e
8 h
6 h
3f
10 h
94% yield
96% yield
93% yield
b Isolated yield.
N
N
OH
O
OH
O
N
OH
O
c No reaction.
F
NO2
NO2
d The reaction was carried out at 15 oC.
NO2
Br
3i
10 h
93% yield
3g
3h
94% yield
10 h
95% yield
18 h
An oil–water interface between reactants and water was
assumed to explain the high efficiency of this process9. As
illustrated in Figure 1, through the interactions with hydrogen-
bond networks at the phase boundary, the nitro-group of the
nucleophile and the carbonyl group of the electrophile might be
organized at the periphery of the oil droplet, while the
hydrophobic part is positioned within the hydrophobic interior.
As a result, the free hydroxyl groups at the interface effectively
activated the reactants and stabilized the transition state through
hydrogen-bond. Moreover, the dehydration process could be
suppressed when water was used as the sole solvent.
N
N
N
OH
O
OH
O
O
NO2
NO2
NO2
O
Me
MeO
3kb
3l'
15 h
70% yield
72 h
3j
84 h
60% yield
trace
N
N
OH
O
OH
O
N
OH
O
NO2
NO2
NO2
O2N
3mb
72 h
3n
96h
50% yield
3o
96h
trace
34% yield

3
a Unless otherwise noted, the reaction was performed with 0.22 mmol of 1,
Scheme 1 Gram-scale synthesis of 5a
ACCEPTED MANUSCRIPT
0.2 mmol of 2 and 20 mol% of NEt3 in 1 mL water. The yield refers to the
isolated yield.
b 30 mol% of the catalyst was used.
Table 4 Direct vinylogous Henry reactions of 3,5-dimethyl-4-
nitroisoxazole with trifluoroacetophenone a
Scheme 2 Transformations of the corresponding Henry product 5a
In summary, we demonstrated an “on water” direct vinylogous
nitroadol (Henry) addition of 3,5-dimethyl-4-nitroisoxazole to
aldehydes and trifluoromethyl ketones. The reaction rate was
greatly enhanced under “on water” conditions. The process
provided a highly efficient and environmentally benign approach
for the synthesis of isoxazole-substituted alkanol products.
Moreover, the trifluoromethyl tertiary alcohol product could be
transformed to the corresponding styrene derivative, which was
demonstrated as a new type of Michael acceptor in the
vinylogous 1,6-Michael addition with nitromethane.
Acknowledgments
Financial support from the Jiangxi Provincial Department of
Science and Technology Fund (20144BAB2130003), and
National Natural Science Foundation of China (Nos.51478123,
21463003, 21502021) is gratefully acknowledged.
a Unless otherwise noted, the reaction was performed with 0.22 mmol of 4,
0.2 mmol of 2 and 20 mol% of NEt3 in 1 mL water. The yield refers to the
isolated yield.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at
The synthetic flexibility of this “on water” reaction using 3,5-
dimethyl-4-nitroisoxazole (2) was also expanded to various
trifluoroacetophenone (4). Under the similar condition as
mentioned in table 3, the desired vinylogous products 5 with a
unique CF3-bearing tertiary center were obtained in good to
excellent yields. The electronic nature and the position of the
substituents attached to the phenyl ring have no obvious impact
on the efficiencies of the processes (Table 4). 3,5-diethyl-4-
nitroisoxazole was also applicable in such reaction, affording the
corresponding vinylogous Henry adduct 5i in excellent
diastereoselectivity (>99%), albeit with moderate yield (51%).
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