Base-controlled selective conversion of Michael adducts of malonates with enones in the presence of iodine

Article abstract of DOI:10.1021/jo201879t

An efficient base-controlled selective conversion of the Michael adducts of malonates with enones in the presence of iodine is reported. Highly functionalized cyclopropane, oxetane, and α-hydroxylmalonate derivatives are obtained selectively using DBU, Na₂CO₃, and NaOAc as the base, respectively. O₂ was identified to be crucial to the formation of oxetane and α-hydroxylmalonate derivatives.

Full text of DOI:10.1021/jo201879t

Article
pubs.acs.org/joc
Base-Controlled Selective Conversion of Michael Adducts of
Malonates with Enones in the Presence of Iodine
Chun-Bao Miao,* Min Zhang, Zong-Yong Tian, Hai-Tao Xi, Xiao-Qiang Sun, and Hai-Tao Yang*
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P.R. China
S
* Supporting Information
ABSTRACT: An efficient base-controlled selective conver-
sion of the Michael adducts of malonates with enones in the
presence of iodine is reported. Highly functionalized cyclo-
propane, oxetane, and α-hydroxylmalonate derivatives are
obtained selectively using DBU, Na2CO3, and NaOAc as the
base, respectively. O2 was identified to be crucial to the
formation of oxetane and α-hydroxylmalonate derivatives.
the other hand, I2 as an inexpensive and efficient reagent has
been used extensively in organic transformation.13 Recently, it
was reported that I2 mediated an oxidative addition reaction of
aldehydes with dimedone or 1,3-indandione to selectively
afford spiro dihydrofuran or cyclopropane derivatives.14
Inspired by their results,14 we attempted to construct the
cyclopropane and dihydrofuran structure selectively from the
Michael adducts of malonates with enones in the presence of I2
under basic condition.
INTRODUCTION
■
Highly strained cyclic compounds such as cyclopropanes and
oxetanes are important molecular architectures of a large
number of biologically and medicinally relevant substances.1
Moreover, the rigid scaffolds can undergo a variety of ring-
opening reactions to generate new molecular skeletons.2 Their
unique reactivity and structural properties have led chemists to
develop different methodologies for preparation of such
strained cycles. Compared to the diverse ways to construct
the cyclopropane skeleton,1g,i,3 fewer methods have been
explored in the synthesis of oxetane derivatives due mainly to
Dunitz−Schumaker strain.4 Oxetane rings can be prepared via
intramolecular nucleophilic substitution reactions.1d,2d,5 The
RESULTS AND DISCUSSION
■
An initial examination was carried out using the Michael adduct
of diethyl malonate with chalcone (1a) as a substrate (Table 1).
In the presence of I2, 1a was treated with different bases in
EtOH at 35 °C. The results summarized in Table 1 showed that
no dihydrofuran derivative was obtained as expected in all
cases. Under most of the organic bases such as DMAP, DBU,
piperidine, morpholine, Et3N, DABCO, pyridine (except N-
methylimidazole), NaOH, and NaOt-Bu, trans-cyclopropane 2a
was isolated as the main or single product (Table 1, entries 1−7
and 11−14). When Na2CO3 or NaHCO3 was used as the base,
it was surprising that compound 3a,7 which contains an oxetane
framework involving trans-orientation of both phenyl and
benzoyl groups, was a major product (Table 1, entries 9 and
10). More interestingly, the employment of NaOAc resulted in
the formation of undesired α-hydroxymalonate 4a as the
dominating product (Table 1, entry 15). It should be noted that
more oxetane 3a was generated while further prolonging the
reaction time (Table 1, entry 16 vs 15). Herein, the I2/NaOAc
system was discovered to be a novel system to realize the direct
α-hydroxylation of malonates.
Paternò−Buchi (PB) reaction is a versatile method for the
̈
construction of oxetane ring systems.2b,6 A new oxidative
cyclization of Michael adducts with iodosobenzene and
tetrabutylammonium iodide to oxetanes was reported recently.7
α-Hydroxymalonates and their equivalents are valuable class
of compounds utilized in organic transformation. The direct
introduction of a hydroxyl group at the α-position of malonates
has been developed using stoichiometric amounts of oxidants
such as CAN,8 N-sulfonyloxaziridine derivatives,9 and dime-
thyldioxirane.10 Oxygenation of α-substituted malonates has
also been achieved under oxygen atmosphere with CsF or
Cs2CO3 as base11 or with a catalytic amount of a transition-
metal reagent.12
We now present an interesting base-controlled selective
conversion of Michael adducts of malonates with enones to
cyclopropane, oxetane, and α-hydroxymalonate derivatives,
respectively, in the presence of I2.
The Michael reaction is generally regarded as one of the
most efficient carbon−carbon bond-forming reactions. Fur-
thermore, the Michael adducts afford synthetically useful
building blocks in organic synthesis as a result of their
possessing various functional groups for further elaboration. On
Received: September 15, 2011
Published: October 25, 2011
© 2011 American Chemical Society
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The Journal of Organic Chemistry
Article
influence on the reaction. EtOH was chosen as the best solvent
(Table 2, entry 2, condition A) because the use of a protic
solvent seemed to give a little higher yield than with other
solvents. Comparatively, it was another case for the preparation
of oxetane 3a and α-hydroxymalonate 4a. Although 85% yield
of 3a in EtOH was acceptable, the reaction sustained a long
time (48 h). Finally, DMF was deemed the optimal solvent for
the formation of oxetane 3a in 91% yield (Table 2, entry 7,
condition B). For the production of 4a, the selectivity and yield
were higher by performing the reaction in ether solvent, rather
than in protic solvent or dipolar solvent from which more
oxetane 3a was generated. Eventually, THF was chosen as the
optimal solvent in which 4a could be isolated with the best
yield (88%, Table 2, entry 12, condition C).
Table 1. Conversion of the Michael Adduct of Diethyl
Malonate with Chalcone (1a) in the Presence of I2 with
Different Bases
a
b
yield
entry
base
time (h)
2a (%)
3a (%)
4a (%)
Most puzzling of all was that the conversion of 1a to 4a and
3a only needed 1 equiv of NaOAc and 1 equiv of I2,
respectively. If it was just a simple iodination-substitution
process, the conversion of 1a to 4a would need 2 equiv of
NaOAc and conversion to 3a would need 2 equiv of I2.
Therefore, a major aim of ours was to achieve a better insight
into the mechanism of the selected conversion.
1
DMAP
DBU
36
3
87
91
84
71
19
53
9
tr
0
tr
tr
6
2
3
piperidine
morpholine
TEA
24
36
48
48
48
48
48
48
6
tr
tr
0
4
7
5
0
6
DABCO
pyridine
0
0
7
0
0
The α-iodomalonate 5a was found to be a key intermediate,
which could be isolated under I2/NaOAc and I2/Na2CO3
conditions. However, under I2/DBU condition, 5a could not
be observed because the subsequent intramolecular SN2
reaction to form 2a was very fast. For the reaction of 1a with
I2/NaOAc in THF, it could be observed clearly that 5a
converted into 4a gradually until the complete conversion
along with the extension of reaction time (Table 3, entries 2
and 3). However, under nitrogen atmosphere, only α-
iodomalonate 5a was obtained in 59% yield (Table 3, entry
1). This proved that the O2 took a crucial role in the reaction.
The oxygen atom of the hydroxyl in 4a may be derived from O2
but not the water in solvent. Therefore, we further decreased
the quantity of I2. To our surprise, the reaction proceeded well
even using 0.2 equiv of I2 under air condition (Table 3, entry
4). Moreover, under anhydrous condition and O2 atmosphere,
4a was also obtained in high yield with a catalytic amount of I2
(96%, Table 3, entry 6). It should be noted that I2 also played
an essential role in the reaction because the absence of I2
resulted in no conversion under similar conditions. Com-
paratively, for the conversion of 1a to 3a under Na2CO3
condition, a catalytic amount of I2 was insufficient. The
reaction of 1a with 0.2 equiv of I2 and 2 equiv of Na2CO3 in
DMF for 48 h gave only 30% of 3a.
When 5a was treated with 1 equiv of DBU, 1 equiv of
Na2CO3, and 0.2 equiv of NaOAc, respectively, 2a, 3a, and 4a
could be formed in 96%, 95%, and 97% yields selectively (Table
4, entries 1, 7, and 9). However, under nitrogen atmosphere
only a trace of 3a and 4a was observed on TLC (Table 4,
entries 2 and 8). A catalytic amount of Na2CO3 could not
realize the total conversion of 5a to 3a (Table 4, entry 6),
which was different from the formation of 4a. To further
confirm the oxygen atom source in product 3a and 4a, the
reaction of 5a with 0.2 equiv of NaOAc was performed in dry
THF under O2 condition with addition of 5 Å molecular sieves
for 22 h; 4a also could be obtained in 95% yield (Table 4, entry
3). This revealed that the oxygen atom was derived from O2 but
not the water in solvent. It was further proved by the reaction
of 5a in the presence of 0.2 equiv of NaOAc in dry THF under
O2 condition with addition of 0.1 mL of isotope labeled H2O18,
which generated 4a with HRMS at 407.1477 (M + Na+) (Table
4, entry 4).
8
N-methylimidazole
Na2CO3
NaHCO3
NaOH
27
tr
4
52
0
9
85
67
0
10
11
12
13
14
15
16
tr
10
0
41
31
49
35
0
NaOH
24
6
0
0
NaOt-Bu
NaOt-Bu
NaOAc
0
0
24
20
48
0
0
10
43
61
39
NaOAc
0
a
All reactions were performed with 0.5 mmol of 1a, 0.5 mmol of I2,
and 1.0 mmol of base in 5 mL of EtOH at 35 °C for the designated
time. Isolated yield based on substrate 1a; tr = trace.
b
It is significant that the chemoselective conversion of 1a to
2a, 3a, or 4a in the presence of I2 is controlled by the base
(Table 1, entries 2, 9, and 15). As is known to all, selective
synthesis is a formidable challenge in organic synthesis,
especially controlled highly selective synthesis derived from
the same starting materials.15 Encouraged by these interesting
results, we further optimized the reaction conditions using
DBU, Na2CO3, and NaOAc as the base, respectively (Table 2).
The influence of molar ratio of 1a:I2:base on the reaction was
first investigated (Table 2, entries 1−4). Although 3 equiv of
DBU gave the best yield of 3a (92%), 2 equiv of DBU was
enough to give nearly identical yield (91%). For this reason, the
better molar ratio of 1a:I2:DBU for the formation of
cyclopropane 2a was determined to be 1:1:2 (Table 2, entry
2, condition A). For the generation of oxetane 3a, if it was
formed through iodination and then substitution by H2O in the
solvent, 2 equiv of I2 would be required. Instead, 1 equiv of I2
and 2 equiv of Na2CO3 was found to be sufficient to provide
the highest yield of 3a (85%, Table 2, entry 2, condition B). As
for the preparation of α-hydroxymalonate 4a, 1 equiv of I2 and
1 equiv of NaOAc was enough to give the highest yield (79%,
Table 2, entry 1, condition C). When the amount of NaOAc
was increased to 2−4 equiv, more oxetane derivative was
generated (Table 2, entries 2, 3, and 4, condition C).
Our further optimizing efforts were shifted to the
examination of the range of solvents compatible with the
three kinds of selective reactions (Table 2, entries 5−12). For
the conversion of 1a to 2a, the solvent had no dramatic
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a
Table 2. Screening of the Reaction Conditions
condition A
condition B
condition C
molar ratio time
b
b
b
yield (%)
yield (%)
yield (%)
molar ratio
[1a:I2:DBU]
time
(h)
molar ratio
time
(h)
entry
solvent
2a
4a
tr
[1a:I2:Na2CO3]
3a
4a
[1a:I2:NaOAc]
(h)
3a
4a
1
EtOH
EtOH
EtOH
EtOH
dioxane
DME
1:1:1
1:1:2
1:1:3
1:1:4
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
3
3
2
2
3
3
3
3
3
3
3
3
61
91
92
91
79
72
83
82
79
81
87
75
1:1:1
1:1:2
1:2:2
1:2:4
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
70
48
48
48
72
72
30
72
48
48
24
72
71
85
81
67
21
79
91
18
0
0
0
1:1:1
1:1:2
1:1:3
1:1:4
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
48
48
48
48
80
48
18
48
48
48
18
48
7
43
45
57
tr
79
39
34
25
69
82
45
53
tr
2
tr
tr
tr
8
3
0
4
0
5
55
10
0
6
9
0
7
DMF
4
30
tr
8
CH3CN
toluene
CH2Cl2
DMSO
THF
tr
0
49
tr
9
0
10
11
12
0
0
tr
0
tr
tr
10
80
59
0
43
0
36
88
26
a
All the reactions were performed with 0.5 mmol of 1a, 0.5 mmol of I2, and corresponding amount of base in 5 mL of solvent at 35 °C for designated
b
time; Isolated yield based on substrate 1a; tr = trace.
Table 3. Reaction of 1a with I2/NaOAc under Air or N2
Conditions
Table 4. Investigation on the Conversion of 5a to 2a, 3a, and
4a
a
a
yield (%)
entry
conditions
4a
5a
1
2
3
4
5
1a:I2:NaOAc = 1:1:1, THF, N2, 60 h
1a:I2:NaOAc = 1:1:1, THF, air, 7 h
1a:I2:NaOAc = 1:1:1, THF, air, 48 h
1a:I2:NaOAc = 1:0.2:0.2, THF, air, 48 h
tr
38
96
96
13
59
43
0
yield
entry
conditions
product
(%)
0
1a:I2:NaOAc = 1:0.2:0.2, with additive of 3 equiv of
TEMPO, THF, air, 50 h
7
1
2
3
NaOAc (0.2 equiv), THF, air, 24 h
NaOAc (0.2 equiv), THF, N2, 22 h
4a
4a
4a
97
tr
6
1a:I2:NaOAc = 1:0.2:0.2, dry THF, O2, 5 Å molecular
sieve, 48 h
96
0
NaOAc (0.2 equiv), dry THF, O2, 5 Å
molecular sieve, 22 h
NaOAc (0.2 equiv), dry THF, O2, H2O18, 24 h
95
a
All reactions were performed with 0.5 mmol of 1a in 5 mL of solvent
at 35 °C.
4
5
4a
4a
95
22
NaOAc (0.2 equiv), TEMPO (3 equiv), THF,
air, 24 h
The α-hydroxymalonate 4a could be cyclized to 3a in high
yield under either I2/Na2CO3/DMF or I2/DBU/EtOH
condition (Table 5, entries 1 and 4). This transformation
required at least 1 equiv of I2, and the O2 had no influence on
the reaction (Table 5, entries 2 and 3). However, under I2/
NaOAc/THF condition, the conversion of 4a to 3a was
difficult perhaps owing to the weak basicity of NaOAc (Table 5,
entry 5). It is interesting that under I2/DBU/EtOH condition
1a converted only to 2a because the transformation of
intermediate 5a to 4a was forbidden. Consequently, the base-
controlled selective conversion of Michael adducts of malonates
with enones was realized.
6
7
8
9
Na2CO3 (0.2 equiv), DMF, air, 48 h
Na2CO3 (1 equiv), DMF, air, 18 h
Na2CO3 (1 equiv), DMF, N2, 24 h
DBU (1 equiv), EtOH, 3 h
3a
3a
3a
2a
35
95
tr
96
a
All reactions were performed with 0.5 mmol of 5a in 5 mL of solvent
at 35 °C.
On the basis of these results and those reported radical
reactions of iodo-compounds,16 a possible reaction mechanism
is proposed in Scheme 1. The Michael adduct of diethyl
malonate with chalcone (1a) reacts with I2 to give the crucial
intermediate 5a. Under DBU condition, 5a converts to 2a
directly through intramolecular SN2 reaction. The first step
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Article
a
It is interesting that the transformation of 10 to 11 is difficult
when NaOAc is used as the base in THF. Therefore, under I2/
NaOAc/THF and I2/Na2CO3/DMF condition, α-hydroxymal-
onate 4a and oxetane 3a are the main products, respectively.
With the optimized conditions in hand, the scope of this
reaction was extended to various substrates. The results
presented in Table 6 demonstrate that the reactions proceeded
well when R1 and R2 were both aryl groups and gave gratifying
yields of cycopropanes 2, oxetanes 3, and α-hydroxylmalonates
4, respectively (Table 6, entries 1−10). The electronic effect of
the substituent group on the phenyl ring had no significant
impact on the reaction. The conversion of 1n with a bulky ester
group was relatively slower (Table 6, entry 14). When R1 was a
phenyl group and R2 was a pyridyl group, cycopropane 2k and
oxetane 3k were also obtained in good yield. However, under
NaOAc condition, a mixture of α-hydroxyl malonate 4k and
hemiketal 5k (in a ratio of 2.23:1, analysis of 1H NMR
spectrum), which was formed from 4k by intramolecular attack
of the hydroxyl on carbonyl, was yielded (Scheme 2). A similar
hemiketal also could be observed for 4i, 4j, and 4l. A trend
toward increasing ratio of hemiketal as electron-withdrawing
ability of R2 increased was also found. When R1 was phenyl
group and R2 was methyl group, only a trace of cyclopropane 2l
was detected. As for the Michael adduct of cyclic enone with
diethylmalonate (1o), only the α-hydroxyl malonate 4o was
obtained using either Na2CO3 or NaOAc as the base. It should
be noted that 1e, 1j, 1l, and 1n, which could not afford oxetane
poducts using the recently reported procedure,7 also gave
moderate to good yields of 3 under I2/Na2CO3/DMF
condition.
Table 5. Cyclization of 4a to 3a
entry
conditions
yield (%)
1
2
3
4
5
I2 (1 equiv), Na2CO3 (2 equiv), DMF, air, 24 h
I2 (1 equiv), Na2CO3 (2 equiv), DMF, N2, 24 h
I2 (0.2 equiv), Na2CO3 (2 equiv), DMF, air, 24 h
I2 (1 equiv), DBU (2 equiv), EtOH, air, 24 h
I2 (1 equiv), NaOAc (2 equiv), THF, air, 24 h
95
95
19
93
0
a
All reactions were performed with 0.5 mmol of 5a in 5 mL of solvent
at 35 °C.
iodination reaction needs 1 equiv of I2 and 1 equiv of DBU, and
the second step substitution reaction needs 1 equiv of DBU.
However, under NaOAc and Na2CO3 condition, the homolytic
cleavage of the C−I bond of 5a generates the carbon radical 6,
which reacts with molecular oxygen to generate the peroxyl
radical 7, subsequently coupling with iodine radical to form
iodoperoxide 8. Homolytic cleavage of the O−O bond of 8
generates oxygen radical 9, which is then trapped by iodine
radical to form hypoiodite 10 that is a good electrophilic
reagent as I+. Hypoiodite 10 reacts with the Michal adduct 1a
to form α-hydroxymalonate 4a and the intermediate 5a, which
undergos the next cycle. Therefore, the conversion of 1a to 4a
needs only a catalytic amount of I2 and NaOAc. Under I2/
Na2CO3 condition, 4a continues to react with 1 equiv of I2 and
1 equiv of Na2CO3 to generate 11, with subsequent
intramolecular SN2 reaction with 1 equiv of Na2CO3 to afford
3a. Therefore, the conversion of 1a to 3a can be accomplished
by 1 equiv of I2 and 2 equiv of Na2CO3. When 5a is treated
with Na2CO3, the path A is blocked. Intramolecular electro-
philic reaction of hypoiodite 10 will generate 11 (path B), with
further intramolecular SN2 reaction to yield 3a. For this reason,
1 equiv of Na2CO3 is required for the conversion of 5a to 3a.
To prove this radical reaction mechanism, we introduced
TEMPO to the system to trap the radical intermediate.
Although we failed to capture the carbon radical with TEMPO,
the reaction became sluggish in the presence of TEMPO
(Table 3, entry 5 and Table 4, entry 5).
CONCLUSION
■
In summary, we report here an efficient base-controlled
selective conversion of Michael adducts of malonates with
enones in the presence of I2. Highly functionalized cyclo-
propane and oxetane derivatives are divergently synthesized in
moderate to good yields with high diastereoselectivity. The
high stereoselectivity in cyclopropane is due to thermodynamic
stability of the trans-product.3c Oxetane 3 with trans-orientation
of both phenyl and benzoyl groups are stable because the two
groups are both in the equatorial position. A novel strategy of
direct α-hydroxylation of malonate derevatives using a catalytic
Scheme 1. Possible Reaction Mechanism for the Selective Conversion
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a
Table 6. Base-Controlled Selective Conversion of Michael Adducts of Malonates with Enones
substrate
condition A
yield of 2 (%)
condition B
yield of 3 (%)
condition C
yield of 4 (%)
b
b
b
entry
R1
R2
R
time (h)
time (h)
time (h)
1
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
3
3
2a
2b
2c
2d
2e
2f
90
87
89
92
95
93
89
88
88
36
48
36
36
36
36
36
36
36
36
36
60
48
72
48
3a
3b
3c
3d
3e
3f
91
82
90
91
88
92
89
90
91
91
79
42
90
87
41
48
48
48
48
48
48
48
48
48
48
48
24
48
72
24
4a
4b
4c
4d
4e
4f
93
87
89
91
86
84
92
90
2
4-MeO-C6H5
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
t-Bu
Et
3
4-Me-C6H5
3
4
4-Cl-C6H5
3
5
4-NO2−C6H5
3-NO2-C6H5
3
6
3
7
1g
1h
1i
Ph
4-MeO-C6H5
4-Me-C6H5
4-Cl-C6H5
4-NO2-C6H5
2-pyridyl
CH3
3
2g
2h
2i
3g
3h
3i
4g
4h
4i
8
Ph
3
e
9
Ph
3
87 (95:5)
85 (85:15)
71 (69:31)
95 (86:14)
84
e
e
e
10
11
12
13
14
15
1j
Ph
3
2j
86
3j
4j
c
c
1k
1l
Ph
3
2k
2l
92
3k
3l
4k
4l
Ph
24
3
tr
97
80
0
1m
1n
1o
H
Ph
2m
2n
2o
3m
3n
4m
4n
4o
Ph
Ph
12
48
73
d
R1, R2 = -(CH2)3-
4o
88
a
b
c
All reactions were performed with 1.0 mmol of 1 in 10 mL of solvent at 35 °C for the designated time. Isolated yield based on 1. Contains little
d
e
cis-isomer. No oxetane product was observed in the reaction. Anlysis of the NMR showed that it is a mixture of the α-hydroxylated malonate and
hemiketal.
dichloromethane (15 mL × 3). The organic layer was dried over
MgSO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/petroleum ether)
to provide the corresponding cyclopropanes 2.
Scheme 2. Formation of Hemiketal 5k from 4k
Diethyl 2-phenyl-3-picolinoylcyclopropane-1,1-dicarboxylate
2k. 1H NMR (500 MHz, CDCl3) δ 8.81 (d, J = 4.6 Hz, 1H), 8.06
(d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7, 1.6 Hz, 1H), 7.52 (ddd, J = 7.6,
4.8, 1.0 Hz, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H),
7.25 (t, J = 7.3 Hz, 1H), 5.09 (d, J = 7.6 Hz, 1H), 4.23−4.33 (m, 2H),
3.92−4.02 (m, 2H), 3.78 (d, J = 7.6 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H),
0.96 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 195.6, 166.4,
165.6, 152.9, 149.4, 136.9, 133.9, 128.9, 128.2, 127.53, 127.50, 122.01,
61.73, 61.67, 46.6, 37.9, 33.0, 14.0, 13.7; IR (KBr) ν/cm−1 2983, 2937,
1736, 1692, 1584, 1442, 1300, 1284, 1250, 1215, 1184, 1108, 1025,
745, 698; TOF-MS (EI) calcd for C21H21NO5 [M+] 367.1420, found
367.1429.
amount of I2/NaOAc was also explored. O2 was found to be
crucial to the formation of oxetane and α-hydroxylated
malonate derevatives. The influence of the solvent and molar
ratio of reactants on the selective reaction was investigated in
detail. Our further investigations on the construction of
azetidines and thietanes under similar conditions are currently
underway.
General Procedure for the Preparation Derivatives 3. A
mixture of the Michael adducts of malonates with enones (1, 1 mmol),
I2 (254 mg, 1 mmol), and Na2CO3 (212 mg, 2 mmol) were stirred in
10 mL of DMF upon exposure to air at 35 °C for designated time. To
the mixture was added 40 mL of cold water and saturated Na2S2O3
until the disappearance of umber, and then the mixture was extracted
with dichloromethane (20 mL × 3). The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate/petroleum ether) to
provide the corresponding oxetanes 3.
EXPERIMENTAL SECTION
■
General Method. All reactions were performed under atmos-
phere. 1H NMR and 13C NMR spectra were recorded in CDCl3 at 500
and 125 MHz, respectively. FT-IR spectra were taken in KBr pellets
and were reported in cm−1. High-resolution mass spectra (HRMS)
were obtained with a positive EI or positive ESI mode. All of the
known products were confirmed by comparison of their 1H NMR
spectral data with those reported in literature. The identification of
new compounds was fully confirmed by their HRMS, H NMR, 13C
1
Diethyl 4-Benzoyl-3-(4-nitrophenyl)oxetane-2,2-dicarboxylate
NMR, and FTIR spectra.
1
3e. Mp 99−100 °C; H NMR (500 MHz, CDCl3) δ 8.25 (d, J =
General Procedure for the Synthesis of Cyclopropane
Derivatives 2. A mixture of the Michael adducts of malonates with
enones (1, 1 mmol), I2 (254 mg, 1 mmol), and DBU (305 mg, 2
mmol) was stirred in 10 mL of ethanol at 35 °C for designated time.
Most of the solvent was removed in vacuo, and 20 mL of cold water
was added. To the mixture was added saturated Na2S2O3 until the
disappearance of umber, and the mixture was then extracted with
8.7 Hz, 2H), 7.99 (d, J = 7.8 Hz, 2H), 7.58−7.65 (m, 3H), 7.48 (t, J =
7.8 Hz, 2H), 6.13 (d, J = 7.6 Hz, 1H), 5.17 (d, J = 7.6 Hz, 1H), 4.36
(dq, J = 10.7, 7.1 Hz, 1H), 4.28 (dq, J = 10.7, 7.1 Hz, 1H), 4.00 (dq, J
= 10.8, 7.1 Hz, 1H), 3.89 (dq, J = 10.7, 7.1 Hz, 1H), 1.29 (t, J = 7.1
Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
194.9, 167.0, 166.4, 147.9, 141.6, 134.5, 133.3, 129.3, 129.2, 129.0,
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123.9, 86.7, 81.9, 63.0, 62.4, 48.1, 14.0, 13.8; IR (KBr) ν/cm−1 1743,
1678, 1599, 1524, 1348, 1300, 1263, 1169, 1071, 1016, 975, 853, 693;
TOF-MS (EI) calcd for C22H21NO8 [M+] 427.1267, found 427.1271.
Diethyl 4-(4-Nitrobenzoyl)-3-phenyloxetane-2,2-dicarboxylate
Diethyl 2-Hydroxy-2-(1-(4-methoxyphenyl)-3-oxo-3-
phenylpropyl)malonate 4b. Mp 111−113 °C; 1H NMR (500
MHz, CDCl3) δ 7.90 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H),
7.41 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.7 Hz,
2H), 4.40 (dd, J = 10.4, 2.9 Hz, 1H), 4.24−4.32 (m, 2H), 4.07 (dq, J =
10.7, 7.1 Hz, 1H), 4.00 (dq, J = 10.7, 7.1 Hz, 1H), 3.99 (s, 1H), 3.73
(s, 3H), 3.68 (dd, J = 17.3, 10.4 Hz, 1H), 3.33 (dd, J = 17.3, 3.1 Hz,
1H), 1.29 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 197.7, 170.0, 169.6, 158.9, 137.1, 133.1, 130.60,
130.56, 128.6, 128.2, 113.6, 82.2, 63.0, 62.8, 55.2, 44.1, 40.3, 14.1, 14.0;
IR (KBr) ν/cm−1 3560, 2976, 2926, 1739, 1686, 1613, 1518, 1447,
1252, 1221, 1178, 1127, 1051, 818, 762, 690; TOF-MS (EI) calcd for
C23H26O7 [M+] 414.1679, found 414.1667.
Diethyl 2-Hydroxy-2-(1-(4-methylphenyl)-3-oxo-3-phenylpropyl)-
malonate 4c. Mp 107−108 °C; 1H NMR (500 MHz, CDCl3) δ 7.91
(d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H),
7.28 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 4.40 (dd, J = 10.2,
2.9 Hz, 1H), 4.24−4.32 (m, 2H), 4.07 (dq, J = 10.7, 7.1 Hz, 1H), 3.99
(s, 1H), 3.98 (dq, J = 10.7, 7.1 Hz, 1H), 3.70 (dd, J = 17.3, 10.3 Hz,
1H), 3.44 (dd, J = 17.3, 3.1 Hz, 1H), 2.24 (s, 3H), 1.29 (t, J = 7.1 Hz,
3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 197.7,
170.1, 169.6, 137.1, 137.0, 135.4, 133.1, 129.4, 128.9, 128.6, 128.2,
82.1, 63.0, 62.8, 44.5, 40.2, 21.2, 14.1, 14.0; IR (KBr) ν/cm−1 3562,
2976, 2927, 1740, 1688, 1595, 1446, 1251, 1220, 1126, 1048, 761, 689;
TOF-MS (EI) calcd for C23H26O6 [M+] 398.1729, found 398.1727.
Diethyl 2-Hydroxy-2-(1-(4-chlorophenyl)-3-oxo-3-phenylpropyl)-
malonate 4d. Mp 103−105 °C; 1H NMR (500 MHz, CDCl3) δ 7.89
(d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H),
7.37 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 4.43 (dd, J = 10.4,
2.9 Hz, 1H), 4.25−4.32 (m, 2H), 4.08 (dq, J = 10.7, 7.1 Hz, 1H), 4.01
(s, 1H), 4.00 (dq, J = 10.7, 7.1 Hz, 1H), 3.75 (dd, J = 17.9, 10.6 Hz,
1H), 3.44 (dd, J = 17.9, 2.9 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.15 (t, J
= 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 197.3, 169.8, 169.4,
137.3, 136.9, 133.4, 133.3, 131.0, 128.7, 128.4, 128.2, 81.9, 63.2, 63.0,
44.1, 40.2, 14.1, 14.0; IR (KBr) ν/cm−1 3560, 2978, 2929, 1740, 1688,
1596, 1446, 1252, 1220, 1126, 753, 691; TOF-MS (EI) calcd for
C22H23ClO6 [M+] 418.1183, found 418.1171.
1
3j. Mp 84−86 °C; H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.8
Hz, 2H), 8.12 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.41 (t, J =
7.2 Hz, 2H), 7.36 (t, J = 7.0 Hz, 1H), 6.09 (d, J = 7.4 Hz, 1H), 5.00 (d,
J = 7.4 Hz, 1H), 4.33 (dq, J = 10.7, 7.1 Hz, 1H), 4.26 (dq, J = 10.7, 7.1
Hz, 1H), 3.92 (dq, J = 10.7, 7.1 Hz, 1H), 3.85 (dq, J = 10.7, 7.1 Hz,
1H), 1.28 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H); NMR (125
MHz, CDCl3) δ 194.3, 167.1, 166.4, 150.9, 137.9, 133.7, 130.3, 129.1,
128.9, 128.2, 124.1, 87.4, 82.8, 62.85, 62.2, 49.0, 14.0, 13.6; IR (KBr)
ν/cm−1 2994, 2960, 2917, 1759, 1740, 1698, 1602, 1525, 1353, 1298,
1254, 1125, 1065, 1016, 983, 854, 839, 791, 751, 709, 566; TOF-MS
(EI) calcd for C22H21NO8 [M+] 427.1267, found 427.1264.
Diethyl 3-Phenyl-4-picolinoyloxetane-2,2-dicarboxylate 3k. Mp
1
94−95 °C; H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 4.6 Hz, 1H),
8.08 (d, J = 7.8 Hz, 1H), 7.83 (td, J = 7.7, 1.5 Hz, 1H), 7.52 (d, J = 7.4
Hz, 2H), 7.39−7.42 (m, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.5
Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 4.85 (d, J = 7.5 Hz, 1H), 4.39 (dq, J
= 10.7, 7.1 Hz, 1H), 4.32 (dq, J = 10.7, 7.1 Hz, 1H), 3.87 (dq, J = 10.7,
7.1 Hz, 1H), 3.82 (dq, J = 10.7, 7.1 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H),
0.82 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 195.8, 167.8,
166.7, 150.9, 149.2, 137.1, 134.5, 128.6, 128.4, 128.1, 127.9, 122.6,
87.3, 82.1, 62.7, 61.8, 49.9, 14.1, 13.7; IR (KBr) ν/cm−1 2979, 2935,
1760, 1736, 1708, 1584, 1442, 1290, 1272, 1258, 1117, 1062, 1045,
962, 855, 801, 753, 701; TOF-MS (EI) calcd for C21H21NO6 [M+]
383.1369, found 383.1388.
Diethyl 4-Acetyl-3-phenyloxetane-2,2-dicarboxylate 3l. 1H NMR
(500 MHz, CDCl3) δ 7.28−7.38 (m, 5H), 5.38 (d, J = 7.9 Hz, 1H),
4.74 (d, J = 7.8 Hz, 1H), 4.29−4.41 (m, 2H), 3.89 (dq, J = 10.7, 7.1
Hz, 1H), 3.82 (dq, J = 10.7, 7.2 Hz, 1H), 2.31 (s, 3H), 1.33 (t, J = 7.2
Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
206.6, 167.5, 166.5, 133.8, 128.8, 128.5, 128.1, 87.1, 83.7, 62.7, 62.0,
49.2, 25.4, 14.0, 13.6; IR (KBr) ν/cm−1 2984, 2939, 1743, 1456, 1369,
1278, 1175, 1122, 1053, 1011, 856, 747, 700; TOF-MS (EI) calcd for
C17H20O6 [M+] 320.1260, found 320.1252.
Diethyl 2-Hydroxy-2-(1-(4-nitrophenyl)-3-oxo-3-phenylpropyl)-
Diethyl 4-Benzoyloxetane-2,2-dicarboxylate 3m. 1H NMR (500
MHz, CDCl3) δ 7.96 (d, J = 7.9 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48
(t, J = 7.8 Hz, 2H), 5.78 (dd, J = 8.5, 6.7 Hz, 1H), 4.35 (q, J = 7.1 Hz,
2H), 4.23 (q, 7.1 Hz, 2H), 3.43 (dd, J = 12.2, 6.7 Hz, 1H), 3.36 (dd, J
= 12.2, 8.6 Hz, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 195.6, 168.2, 167.5, 133.8, 133.3,
1
malonate 4e. Mp 76−78 °C; H NMR (500 MHz, CDCl3) δ 8.09
(d, J = 8.8 Hz, 2H), 7.89 (d, J = 7.9 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H),
7.54 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 4.58 (dd, J = 10.5, 2.8
Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.19 (s, 1H), 4.09 (dq, J = 10.7, 7.1
Hz, 1H), 4.02 (dq, J = 10.7, 7.1 Hz, 1H), 3.75 (dd, J = 17.9, 10.6 Hz,
1H), 3.44 (dd, J = 17.9, 2.9 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.15 (t, J
= 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 196.7. 169.1, 168.9,
147.0, 146.6, 136.3, 133.2, 130.5, 128.5, 127.9, 122.9, 81.4, 63.0, 62.9,
44.2, 39.9, 13.8, 13.7; IR (KBr) ν/cm−1 3550, 2983, 2933, 1746, 1686,
1598, 1520, 1449, 1344, 1243, 1217, 1133, 858, 748, 707, 692; TOF-
MS (EI) calcd for C22H23NO8 [M+] 429.1424, found 429.1421.
Diethyl 2-Hydroxy-2-(1-(3-nitrophenyl)-3-oxo-3-phenylpropyl)-
128.8, 128.7, 81.9, 77.8, 62.4, 62.2, 31.0, 13.9, 13.7; IR (KBr) ν/cm−1
2984, 2940, 1746, 1693, 1598, 1450, 1370, 1301, 1277, 1231, 1140,
1061, 857, 695; TOF-MS (EI) calcd for C16H18O6 [M+] 306.1103,
found 306.1095.
Di-tert-Butyl 4-Benzoyl-3-phenyloxetane-2,2-dicarboxylate 3n.
Mp 118−120 °C; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz,
2H), 7.56 (t, J = 7.4 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.41 (t, J = 7.7
Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 6.06 (d, J =
7.3 Hz, 1H), 4.91 (d, J = 7.4 Hz, 1H), 1.50 (s, 9H), 1.07 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 195.5, 166.4, 165.5, 134.4, 133.9, 133.6,
129.0, 128.8, 128.7, 128.6, 128.3, 87.3, 83.2, 82.9, 81.9, 48.5, 27.8, 27.4;
IR (KBr) ν/cm−1 2980, 2934, 1756, 1740, 1685, 1598, 1451, 1370,
1300, 1272, 1256, 1169, 1141, 1125, 976, 840, 705; TOF-MS (EI)
calcd for C26H30O6 [M+] 438.2042, found 438.2031.
General Procedure for the Conversion of Michael Adducts
of Malonates with Enones to α-Hydroxylmalonates 4. A
mixture of the Michael adducts of malonates with enones (1, 1
mmol), I2 (51 mg, 0.2 mmol), and NaOAc (17 mg, 0.2 mmol) were
stirred in 10 mL of THF upon exposure to air at 35 °C for designated
time. Most of the solvent was removed in vacuo, and 20 mL of water
was added. To the mixture was added saturated Na2S2O3 until the
disappearance of umber, and then the mixture was extracted with
dichloromethane (15 mL × 3). The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate/petroleum ether) to
provide the corresponding α-hydroxylmalonates 4.
1
malonate 4f. Mp 81−82 °C; H NMR (500 MHz, CDCl3) δ 8.34
(t, J = 1.8 Hz, 1H), 8.06 (dd, J = 8.3, 2.1 Hz, 1H), 7.90 (d, J = 7.9 Hz,
2H), 7.81 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8
Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 4.57 (dd, J = 10.4, 2.8 Hz, 1H), 4.31
(q, J = 7.1 Hz, 2H), 4.09 (dq, J = 10.7, 7.1 Hz, 1H), 4.06 (s, 1H), 4.03
(dq, J = 10.7, 7.1 Hz, 1H), 3.77 (dd, J = 17.9, 10.6 Hz, 1H), 3.44 (dd, J
= 17.9, 2.9 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 196.9, 169.5, 169.1, 148.1, 141.0,
136.6, 136.1, 133.5, 129.0, 128.8, 128.2, 124.8, 122.6, 81.6, 63.4, 63.2,
44.2, 40.1, 14.1, 14.0; IR (KBr) ν/cm−1 3435, 2991, 2906, 1748, 1679,
1529, 1449, 1350, 1292, 1259, 1222, 1136, 1033, 978, 752, 706, 685;
TOF-MS (EI) calcd for C22H23NO8 [M+] 429.1424, found 429.1415.
Diethyl 2-Hydroxy-2-(3-(4-methoxyphenyl)-3-oxo-1-
1
phenylpropyl)malonate 4g. Mp 64−65 °C; H NMR (500 MHz,
CDCl3) δ 7.89 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 7.2 Hz, 2H), 7.20 (t, J
= 7.3 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 4.44
(dd, J = 10.2, 3.1 Hz, 1H), 4.24−4.31 (m, 2H), 4.06 (s, 1H), 4.05 (dq,
J = 10.7, 7.1 Hz, 1H), 3.97 (dq, J = 10.7, 7.1 Hz, 1H), 3.82 (s, 3H),
3.67 (dd, J = 17.1, 10.3 Hz, 1H), 3.31 (dd, J = 17.1, 3.2 Hz, 1H), 1.29
(t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
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CDCl3) δ 196.1, 169.9, 169.6, 163.5, 138.7, 130.5, 130.2, 129.5, 128.1,
127.4, 113.7, 82.1, 63.0, 62.8, 55.5, 45.0, 39.8, 14.1, 13.9; IR (KBr) ν/
cm−1 3479, 2982, 2937, 1739, 1678, 1601, 1455, 1303, 1257, 1223,
1171, 1134, 1208, 703; TOF-MS (EI) calcd for C23H26O7 [M+]
414.1679, found 414.1672.
859, 745, 691; TOF-MS (EI) calcd for C16H20O6 [M+] 308.1260,
found 308.1271.
Di-tert-butyl 2-Hydroxy-2-(3-oxo-1,3-diphenylpropyl)malonate
4n. 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 7.9 Hz, 2H), 7.50
(t, J = 7.4 Hz, 1H), 7.45 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H),
7.20 (t, J = 7.4 Hz, 2H), 7.14 (t, J = 7.3 Hz, 1H), 4.37 (dd, J = 10.4, 2.6
Hz, 1H), 4.03 (s, 1H), 3.70 (dd, J = 17.4, 10.5 Hz, 1H), 3.34 (dd, J =
17.4, 2.7 Hz, 1H), 1.49 (s, 9H), 1.24 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 197.8, 169.1, 168.8, 139.5, 137.2, 133.0, 129.8, 128.5, 128.2,
128.0, 127.2, 83.8, 83.2, 82.3, 44.3, 40.9, 27.9, 27.6; IR (KBr) ν/cm−1
3492, 2978, 2934, 1739, 1688, 1596, 1452, 1370, 1316, 1260, 1242,
1144, 841, 753, 706, 691; TOF-MS (EI) calcd for C26H32O6 [M+]
440.2199, found 440.2187.
Diethyl 2-Hydroxy-2-(3-oxocyclohexyl)malonate 4o. Mp 93−96
°C; 1H NMR (500 MHz, CDCl3) δ 4.25−4.31 (m, 4H), 3.81 (s, 1H),
2.77−2.85 (m, 1H), 2.35−2.44 (m, 2H), 2.18−2.30 (m, 2H), 2.05−
2.14 (m, 1H), 1.62−1.77 (m, 3H), 1.30 (t, J = 7.0 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 210.6, 169.7, 169.6, 81.2, 63.2, 62.9, 42.6, 41.8,
41.0, 25.0, 24.5, 14.2, 14.1; IR (KBr) ν/cm−1 2983, 2960, 2909, 1750,
1732, 1698, 1262, 1220, 1192, 1151, 1024, 862, 668, 519; TOF-MS
(EI) calcd for C13H20O6 [M+] 272.1260, found 272.1251.
Diethyl 2-Hydroxy-2-(3-(4-methylphenyl)-3-oxo-1-phenylpropyl)-
1
malonate 4h. Mp 83−84 °C; H NMR (500 MHz, CDCl3) δ 7.81
(d, J = 8.2 Hz, 2H), 7.41 (d, J = 7.2 Hz, 2H), 7.18−7.23 (m, 4H), 7.20
(t, J = 7.2 Hz, 1H), 4.44 (dd, J = 10.2, 3.0 Hz, 1H), 4.25−4.31 (m,
2H), 4.05 (dq, J = 10.7, 7.1 Hz, 1H), 4.00 (s, 1H), 3.98 (dq, J = 10.7,
7.1 Hz, 1H), 3.70 (dd, J = 17.3, 10.2 Hz, 1H), 3.33 (dd, J = 17.3, 3.1
Hz, 1H), 2.37 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 196.8, 169.7, 169.3, 143.5,
138.6, 134.3, 129.4, 129.0, 128.0, 127.8, 127.2, 81.9, 62.6, 62.5, 44.7,
39.9, 21.4, 13.8, 13.6; IR (KBr) ν/cm−1 3540, 2984, 2941, 1748, 1718,
1674, 1608, 1458, 1301, 1261, 1227, 1132, 1095, 1028, 702; TOF-MS
(EI) calcd for C23H26O6 [M+] 398.1729, found 398.1731.
Diethyl 2-(3-(4-Chlorophenyl)-3-oxo-1-phenylpropyl)-2-hydroxy-
malonate 4i. 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.6 Hz,
2H), 7.39 (d, J = 7.4 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.21 (t, J = 7.2
Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 4.41 (dd, J = 10.2, 3.0 Hz, 1H),
4.23−4.33 (m, 2H), 4.05 (dq, J = 10.7, 7.1 Hz, 1H), 4.03 (s, 1H), 3.98
(dq, J = 10.7, 7.1 Hz, 1H), 3.66 (dd, J = 17.3, 10.3 Hz, 1H), 3.36 (dd, J
= 17.3, 3.1 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 196.4, 169.8, 169.4, 139.4, 138.4,
135.2, 129.5, 129.4, 128.8, 128.1, 127.5, 81.8, 62.9, 62.7, 44.8, 40.2,
14.0, 13.8; IR (KBr) ν/cm−1 3479, 2983, 2938, 1739, 1688, 1590,
1300, 1260, 1221, 1134, 1093, 1032, 1051, 702; TOF-MS (EI) calcd
for C22H23ClO6 [M+] 418.1183, found 418.1171.
Diethyl 2-Hydroxy-2-(3-(4-nitrophenyl)-3-oxo-1-phenylpropyl)-
malonate 4j. 1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 8.8 Hz,
2H), 8.04 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 7.0 Hz, 2H), 7.22 (t, J = 7.2
Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 4.39 (dd, J = 10.2, 3.0 Hz, 1H),
4.24−4.35 (m, 2H), 4.07 (s, 1H), 4.06 (dq, J = 10.7, 7.1 Hz, 1H), 3.98
(dq, J = 10.7, 7.1 Hz, 1H), 3.71 (dd, J = 17.3, 10.3 Hz, 1H), 3.48 (dd, J
= 17.3, 3.1 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 196.4, 169.8, 169.4, 150.4, 141.4,
138.1, 129.4, 129.3, 128.3, 127.8, 123.9, 81.7, 63.2, 62.9, 44.8, 41.0,
14.1, 13.9; IR (KBr) ν/cm−1 3476, 2983, 2938, 1739, 1697, 1604,
1526, 1455, 1348, 1260, 1221, 1134, 856, 745, 711; TOF-MS (EI)
calcd for C22H23NO8 [M+] 429.1424, found 429.1419.
Synthesis of Diethyl 2-Iodo-2-(3-oxo-1,3-diphenylpropyl)-
malonate 5a. Method A. A mixture of the Michael adduct of
diethyl malonate with chalcone (1a, 368 mg, 1 mmol), I2 (254 mg, 1
mmol), and NaOAc (82 mg, 1 mmol) was stirred in 10 mL of THF
upon exposure to air at 35 °C for 7 h (detected by TLC). The similar
operation process as above provides 5a (212 mg, 43%), unreacted 1a,
and 4a (146 mg, 38%).
Method B. A mixture of the Michael adduct of diethyl malonate
with chalcone (1a, 368 mg, 1 mmol), I2 (254 mg, 1 mmol), and
NaOAc (82 mg, 1 mmol) was stirred in 10 mL of THF under N2
atmosphere at 35 °C for 60 h. The similar operation process as above
1
provides 5a (291 mg, 59%) and unreacted 1a. 5a: H NMR (500
MHz, CDCl3) δ 7.92 (d, J = 8.1 Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H),
7.39−7.44 (m, 4H), 7.20−7.25 (m, 3H), 4.18−4.28 (m, 2H), 4.01−
4.15 (m, 3H), 3.84−3.86 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.16 (t, J =
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 196.5, 168.1, 166.8,
138.3, 136.6, 132.9, 129.3, 128.4, 127.90, 127.88, 127.76, 63.1, 62.8,
52.7, 47.1, 45.5, 13.54, 13.51; HRMS (+ESI) calcd for C22H23INaO5
[M + Na+] 517.0488, found 517.0475.
ASSOCIATED CONTENT
* Supporting Information
Diethyl 2-Hydroxy-2-(3-oxo-1-phenyl-3-(pyridin-2-yl)propyl)-
malonate 4k. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J = 4.7 Hz,
1H), 7.89 (d, J = 7.9 Hz, 1H), 7.74 (td, J = 7.7, 1.7 Hz, 1H), 7.45 (d, J
= 7.2 Hz, 2H), 7.41 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.31 (t, J = 7.4 Hz,
1H), 7.21 (t, J = 7.3 Hz, 2H), 4.46 (dd, J = 10.2, 3.2 Hz, 1H), 4.23−
4.30 (m, 2H), 4.14 (dd, J = 18.4, 10.3 Hz, 1H), 4.06 (dq, J = 10.7, 7.2
Hz, 1H), 4.05 (s, 1H), 3.99 (dq, J = 10.7, 7.2 Hz, 1H), 3.52 (dd, J =
18.3, 3.3 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 199.2, 169.9, 169.6, 153.3, 148.9,
■
S
General method and NMR spectra of all the products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: estally898@yahoo.com.cn; yanght898@yahoo.com.cn.
■
138.9, 136.8, 129.7, 127.9, 127.2, 127.1, 121.7, 82.1, 62.7, 62.6, 44.6,
39.5, 14.0, 13.8.
Diethyl 2-Hydroxy-2-(3-oxo-1-phenylbutyl)malonate 4l. 1H
NMR (500 MHz, CDCl3) δ 7.37 (d, J = 7.0 Hz, 2H), 7.17−7.26
(m, 3H), 4.25−4.33 (m, 2H), 4.21 (dd, J = 10.1, 3.2 Hz, 1H), 4.04
(dq, J = 10.7, 7.1 Hz, 1H), 3.96 (dq, J = 10.7, 7.1 Hz, 1H), 3.93 (s,
1H), 3.11 (dd, J = 17.1, 10.2 Hz, 1H), 2.85 (dd, J = 17.1, 3.2 Hz, 1H),
2.01 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 206.2, 169.8, 169.4, 138.4, 129.4, 128.2,
127.5, 81.7, 62.9, 62.7, 45.0, 44.6, 30.5, 14.0, 13.8; IR (KBr) ν/cm−1
3484, 2984, 2939, 1739, 1455, 1367, 1255, 1220, 1135, 1096, 1023,
860, 702; TOF-MS (EI) calcd for C17H22O6 [M+] 322.1416, found
322.1429.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the National
Natural Science Foundation of China (Nos. 20902039 and
20872051), Natural Science Foundation of Jiangsu Province
(BK2009543), and the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions.
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