Highly stereoselective, one-pot synthesis of azetidines and 2,4-dioxo-1,3-diazabicyclo[3.2.0] compounds mediated by I2

Article abstract of DOI:10.1021/jo400181r

We report here a convenient method to construct polysubstituted azetidines and 2,4-dioxo-1,3-diazabicyclo[3.2.0] compounds with high stereoselectivities in a one-pot reaction mediated by I₂. The tetramethylguanidine (TMG)/I₂-mediated formal [2 + 2] cycloaddition reaction of α-amidomalonate 1 with enones 2 affords functionalized azetidine derivatives 4 in moderate to good yields with high diastereoselectivity. When the α-ureidomalonate 5 is used instead of 1, 2,4-dioxo-1,3-diazabicyclo[3. 2.0]heptanes 8 and 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptenes 9 can be prepared selectively through the control of solvent and temperature. 2,4-Dioxo-1,3- diazabicyclo[3.2.0]heptanes 8 can further undergo ring-opening reactions with different nucleophilic reagents to afford the corresponding polyfunctionalized azetidine derivatives 13-16 with high steroselectivities.

Full text of DOI:10.1021/jo400181r

Article
pubs.acs.org/joc
Highly Stereoselective, One-Pot Synthesis of Azetidines and 2,4-
Dioxo-1,3-diazabicyclo[3.2.0] Compounds Mediated by I2
Chun-Bao Miao,* Chun-Ping Dong, Min Zhang, Wen-Long Ren, Qi Meng, Xiao-Qiang Sun,*
and Hai-Tao Yang
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, People’s Republic of China
S
* Supporting Information
ABSTRACT: We report here a convenient method to
construct polysubstituted azetidines and 2,4-dioxo-1,3-diazabi-
cyclo[3.2.0] compounds with high stereoselectivities in a one-
pot reaction mediated by I2. The tetramethylguanidine
(TMG)/I2-mediated formal [2 + 2] cycloaddition reaction of
α-amidomalonate 1 with enones 2 affords functionalized
azetidine derivatives 4 in moderate to good yields with high
diastereoselectivity. When the α-ureidomalonate 5 is used
instead of 1, 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptanes 8 and
2,4-dioxo-1,3-diazabicyclo[3.2.0]heptenes 9 can be prepared
selectively through the control of solvent and temperature. 2,4-Dioxo-1,3-diazabicyclo[3.2.0]heptanes 8 can further undergo ring-
opening reactions with different nucleophilic reagents to afford the corresponding polyfunctionalized azetidine derivatives 13−16
with high steroselectivities.
I2 as an inexpensive and efficient reagent has been used
extensively in organic transformations.12 Most recently, we
reported 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 I2.13 During the investigation of the reaction
mechanism, we established that α-hydroxymalonate derivatives
could be converted to oxetane derivatives in the presence of I2
and base. Owing to the structural similarity of α-amidomalo-
nate and α-hydroxymalonate derivatives (Scheme 1), we
questioned whether the α-amidomalonate derivatives could
follow a similar reaction pathway to generate azetidines. Not
long ago, Fan and co-workers reported the PhIO/Bu4NI-
mediated oxidative cyclization of the Michael adducts of α-
amidomalonates with chalcones to afford azetidines.14 Although
in their research the I2/Bu4NOH system could not realize the
INTRODUCTION
■
Azetidines are an important class of four-membered con-
strained heterocyclic compounds and can be found as an
important building block in a number of drugs and bioactive
compounds,1 which makes them an interesting synthetic topic.
Azetidines can also undergo various transformations to
generate a variety of compounds with new molecular
skeletons.2 However, the strain associated with the azetidine
ring system leads to difficulties in its synthesis, functionaliza-
tions, and modifications.
Among the various general procedures available for the
synthesis of azetidines,2a,b,3 intramolecular nucleophilic sub-
stitution of 1,3-amino halides or 1,3-amino alcohol derivatives4
and reduction of β-lactams5 are the classical and commonly
used approaches. Over the past few years, numerous new
methods have been explored to synthesize azetidine derivatives
such as intramolecular nucleophilic reactions of carbanions6
and ring-opening reactions of epoxides and aziridines.7 The
Yadav group applied diethyl N-arylphosphoramidates as the
nitrogen source in the preparation of azetidines starting from
Morita−Baylis−Hillman adducts or chalcones.8 The metal-
catalyzed intramolecular NH insertion of diazo compounds has
also received considerable attention.9 Pd-catalyzed coupling−
cyclization of β-sulfonylamino allenes has been reported.10
Azetidines were also prepared from α- or β-aminoalkenes
through intramolecular opening of bromonium, iodonium, and
seleniranium intermediates.11 Their unique reactivity and
structural properties have prompted chemists to develop
more efficient methodologies for the preparation of such
strained cycles.
Scheme 1
Received: February 10, 2013
Published: April 10, 2013
© 2013 American Chemical Society
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cyclization of Michael adducts to azetidines, we still wanted to
attempt such a transformation in the presence of I2 and other
bases because I2 is far cheaper and more readily available than
hypervalent iodine reagents.
therefore shifted our further optimization efforts to the
examination of the range of solvents compatible with the
reactions (Table 1, entries 13−26). Although the 86% yield of
4aa in TMG/dioxane is adequate, THF has a lower boiling
point than dioxane and is easier to remove. Finally, I2/TMG/
THF was chosen as the optimal system for the conversion of
3aa to 4aa in 88% yield (Table 1, entry 22).
The Michael reaction is generally regarded as one of the
most efficient carbon−carbon bond forming reactions, which
can be catalyzed by various bases. Assuming that the Michael
addition reaction of 2-aminomalonate 1a with enone 2a could
be catalyzed by a base in THF, the final azetidines would be
constructed easily in one pot via a formal [2 + 2] cycloaddition
process involving a Michael addition and subsequent I2-
mediated cyclization. The Michael reaction of 2-aminomalonate
1a with enone 2a has been realized by a grind-promoted
solvent-free method.14 Nevertheless, 2 equiv of enone 2a, 1
equiv of K2CO3, and 1 equiv of PhEt3NCl were required. It was
not an atom-economical reaction. Moreover, before the next
step of cyclization with PhIO/Bu4NI the Michael adducts must
be preprocessed to remove the solid base. Therefore, we
thought about exploring a better method to realize the one-pot
synthesis of azetidines.
RESULTS AND DISCUSSION
The cyclization of the Michael adduct α-benzamidomalonate
3aa was then selected as a model reaction (Table 1). Although
■
Table 1. I2-Mediated Cyclization of Michael Adduct 3aa to
a
4aa
entry
base
solvent
time (h)
yield (%)
1
Na2CO3
DBU
DMF
24
6
6
6
6
6
6
6
6
6
6
6
6
4
4
4
4
6
6
4
4
4
4
4
4
4
0
49
0
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
toluene
CH2Cl2
THF
3
Na2CO3
piperidine
DMAP
TEA
4
20
0
5
6
0
The Michael addition reaction of enone 2a with α-
benzamidomalonate 1a was performed with different bases in
THF (Table 2). Several bases could catalyze the Michael
7
DABCO
NaOBut
KOH
0
8
0
9
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
NaOH
TMG
NaOAc
DBU
0
Table 2. Michael Addition of 2-Benzamidomalonate with
50
0
a
Chalcone
40
74
61
54
73
40
45
58
55
88
86
62
50
73
DBU
DBU
DBU
dioxane
CH3CN
DMSO
DMF
DBU
b
b
base
yield (%)
entry
base
yield (%)
DBU
DBU
1
2
3
4
5
6
7
Na2CO3
DMAP
80
8
NaHCO3
NaOH
NaOBut
NaOAc
TMG
30
80
70
35
82
80
36
TMG
TMG
TMG
TMG
TMG
TMG
TMG
toluene
CH2Cl2
THF
nr
9
DBU
81
10
11
12
piperidine
TEA
trace
nr
dioxane
CH3CN
DMSO
DMF
c
TEA, LiClO4
DABCO
75
13
TMG
d
trace
14
TMG
a
Unless otherwise noted, all the reactions were performed with 0.5
a
All the reactions were performed with 0.5 mmol of 3aa in 6 mL of
mmol of 1a, 0.5 mmol of 2a, and 0.05 mmol of base in 0.2 mL of THF
b
b
solvent for the designated time. Isolated yield based on substrate 3aa.
at 25 °C for 1 h. Isolated yield based on substrate 1a; nr = no
c
d
reaction. 2.4 equiv of TMG was used. Reacted for 24 h in 6 mL of
THF.
the α-hydroxymalonates could be transformed to oxetanes
under I2/Na2CO3/DMF conditions quantitatively,13 no reac-
tion occurred with 3aa under similar conditions (Table 1, entry
1). Thus, we attempted the use of a strong organic base. Under
I2/DBU/EtOH conditions the desired azetidine 4aa was
obtained in 49% yield after 6 h (Table 1, entry 2). Nevertheless,
the reaction seemed to achieve an equilibrium, because there
was no further increase in the yield by prolonging the reaction
time. The yield is not satisfactory, and so we tried the use of
various bases in this conversion using EtOH as the solvent
(Table 1, entries 3−12). The results summarized in Table 1
showed that only strong organic bases such as TMG
(tetramethylguanidine) and DBU were more efficient (Table
1, entries 2 and 11). When piperidine was used, the yield of 4aa
was only 20% (Table 1, entry 4). All of the inorganic bases and
other weak organic bases could not initiate the reaction. We
addition reaction and gave good yields of 3aa. Fortunately,
TMG was also an efficient base to catalyze the addition
reaction. It was worth noting that the concentration of reactants
had a great influence on the yield. When the enone 2a was
treated with α-benzamidomalonate 1a using 10% mol TMG as
the base in 6 mL of THF for 24 h, 3aa was obtained in only
36% yield. Decreasing the amount of THF to 0.2 mL
dramatically improved the yield of Michael adduct 3aa to
82% after stirring for only 1 h (Table 2, entry 12). The small
amount of THF plays a crucial role in keeping the reactants in
high concentration and being well stirred. If there is no solvent,
the mixture of the reactants cannot be well mixed and stirred
sufficiently.
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Next, we tested the one-pot formal [2 + 2] cycloaddition. A
mixture of 1a (0.5 mmol), 2a (0.5 mmol), and TMG (0.05
mmol) was stirred in 0.2 mL of THF for 1 h. Without any
workup procedure, 6 mL of THF, I2 (0.6 mmol), and TMG
(1.15 mmol) were added and the mixture was stirred for
another 4 h. The azetidine 4aa could be obtained in 76% yield.
We also attempted to use 2.4 equiv of TMG directly in the first
addition step. It also gave a similarly good yield of 4aa.
However, for some substrates, these conditions were
unfavorable. For example, when R was a tosyl or mesyl
group, the Michael adduct would transform quickly to other
byproducts under high concentration of base in neat conditions
and the next step of cyclization could not be realized.
When But was employed as the substrate of R1, the Michael
addition reaction failed, perhaps due to the large steric
hindrance. It was fortunate that N-mesylazetidines 4ca and
N-tosylazetidines 4ba were also obtained in 55% and 33%
yields, respectively (Table 3, entries 18 and 19). The lower
yield of 4ba was mainly due to the lower reactivity in the
Michael addition step. All azetidines were formed with a trans
orientation of both R1 and R2 groups, because in this
conformation, the two groups are both in equatorial positions.
In the above cyclization reaction only one nucleophilic atom
existed in the Michael adducts 3; thus, only the azetidine
products 4 were formed. Presuming that two nucleophilic
atoms existed in the Michael addition adducts, the reaction
would yield two possible cyclization products. Therefore,
diethyl 2-(3-phenylureido)malonate (5a) was chosen as a
substrate to react with chalcone 2a. Contrary to our
expectations, no Michael adduct (A) was observed (Table 4).
Under the optimal reaction conditions, the scope and the
generality of one-pot synthesis of polysubstituted azetidines
were explored (Table 3). The reactions proceeded well when
Table 3. One-Pot Synthesis of Highly Functionalized
Azetidines
a
a
Table 4. Addition Reaction of 2a with 5a
entry
R
R1
R2
product yield (%)
1
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
Ts (1b)
Ms(1c)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4aa
4ab
4ac
4ad
4ae
4af
76
55
63
54
63
66
66
78
69
62
70
59
47
62
61
0
2
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
Ph
3
4
5
b
c
entry
solvent
base
TMG
time (h)
6a/7a
yield (%)
6
1
THF
1
1
85/15
67/33
67/33
56
54
52
nr
7
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-MeC6H4
pyridyl
4ag
4ah
4ai
2
THF
DBU
8
Ph
3
THF
DBN
1
9
Ph
4
THF
piperidine
TEA
5
10
11
12
13
14
15
16
17
18
19
Ph
4aj
5
THF
5
nr
4-ClC6H4
furyl
4ak
4al
6
EtOH
THF
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
KHCO3
Cs2CO3
K2CO3
3
96/4
99
20
39
93
86
90
99
99
99
7
43
43
43
43
43
4
80/20
78/22
72/28
70/30
82/18
95/5
4-MeOC6H4
4-NO2C6H4
Ph
4am
4an
4ao
4ap
4aq
4ba
4ca
8
CH2Cl2
CH3CN
acetone
DMF
EtOH
EtOH
EtOH
pyridyl
9
PhCHCH
10
11
12
13
14
Ph
But
CH3
Ph
0
Ph
Ph
33
55
3
96/4
Ph
Ph
1
96/4
a
The reactions were carried out in THF (0.2 mL) with 1 (0.5 mmol),
2 (0.5 mmol), and TMG (0.05 mmol) at 25 °C for 1 h. Then 6 mL of
THF, I2 (0.6 mmol), and TMG (1.15 mmol) were added and the
mixture was stirred for another 4−6 h.
a
The reactions were carried out with 5 (1 mmol), 2a (1.05 mmol),
b
and base (0.05 mmol) in 5 mL of solvent at 25 °C. The ratio of 6a
and 7a was determined by a H NMR analysis. Isolated yield of the
mixture of 6a and 7a; nr = no reaction.
c
1
R1 and R2 were both aryl groups and gave gratifying yields of
azetidines (Table 3, entries 1−11). The electronic effect of the
substituent groups on the phenyl ring had no significant impact
on the reaction. Heterocyclic substituted azetidines 4al, 4am,
and 4an could also be obtained in moderate yields (Table 3,
entries 12−14). When R1 was the phenyl group and R2 was the
styryl group, 4ao was constructed in 61% yield (Table 3, entry
15). Notably, 4aj, which could not be isolated using Fan’s
procedure,14 also was obtained in 62% yield (Table 3, entry
10). Unfortunately, this method has some limitations. If R1 or
R2 was an alkyl group, no azetidine was obtained (Table 3,
entries 16 and 17). When R1 was a phenyl group and R2 was a
methyl group, the second-step cyclization could not occur.
Instead, the follow-up intramolecular SN reaction gave the
mixed stereoisomers 6a and 7a (Table 4). Interestingly, the
base and solvent had a great influence on the yield and
diastereoselectivity. Under the same conditions (THF/TMG)
as Michael addition of 2a with 1a, only 56% of the products (6a
+ 7a) were isolated with a modest diastereoselectivity (6a/7a =
85/15; Table 4, entry 1). To optimize the reaction, we
investigated the use of more bases and solvents. DBU and DBN
gave lower yields and worse diastereoselectivities (Table 4,
entries 2 and 3). No reaction took place in the presence of
either Et3N or piperidine (Table 4, entries 4 and 5). We were
pleased to find that the reaction in EtOH using carbonate or
bicarbonate as the basic catalyst afforded the corresponding
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Table 5. I2-Mediated Cyclization of Michael Adduct 6a to 8a or 9a
b
yield (%)
8a
36
a
entry
conditions
solvent
base (amt (equiv))
amt of I2 (equiv)
T (°C)
time (h)
9a
1
A
A
A
A
A
A
A
A
B
B
B
B
THF
TMG (2.4)
TMG (2.4)
DBU (2.4)
DBN (2.4)
piperidine (2.4)
TEA (2.4)
DBN (2.4)
DBN (2.4)
DBN (2.4)
DBN (6.0)
DBN (6.0)
DBN (6.0)
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3.0
3.0
3.0
25
25
25
25
25
25
25
25
0
4
22
5
7
0
2
THF
0
3
THF
40
42
trace
0
5
4
THF
5
7
5
THF
5
0
6
THF
5
0
7
CH3CN
EtOH
THF
5
33
29
55
5
16
0
8
5
9
4.5
4.5
30
30
5
10
11
CH3CN
CH3CN
CH3CN
0
25
32
48
25
25−60
17
trace
c
12
a
Conditions A: a mixture of 6a (0.5 mmol), I2, and base was stirred in 7 mL of solvent at room temperature. Conditions B: a solution of base in 8
b
c
mL of solvent was added dropwise into a mixture of 6a (0.5 mmol) and I2 in 7 mL of solvent. Isolated yield. After addition of the base, the mixture
was further stirred at 60 °C until only a trace of 8a remained.
products (6a + 7a) in nearly quantitative yield and excellent
diastereoselectivity (6a/7a ≥ 95/5; Table 4, entries 6 and 12−
14). Using THF or CH2Cl2 as the solvent resulted in a dramatic
decrease in yield with no improvement on diastereoselectivity
(Table 4, entries 7 and 8). Dipolar solvents such as CH3CN,
acetone, and DMF also gave high yields but with poor
diastereoselectivities (Table 4, entries 9−11). Overall, an
efficient method to construct high yield of imidazolidine 6a
with high diastereoselectivity using a catalytic amount of
Na2CO3 in ethanol was developed (99% yield, dr = 96:4; Table
4, entry 6).
Since 6a also contained a nucleophilic nitrogen atom similar
to 3aa, we next considered the possibility of I2-mediated
cyclization of 6a to form a 1,3-diazabicyclic[3.2.0] heptane
compound. The synthesis and character of compounds with a
1,3-diazabicyclic[3.2.0] heptane nucleus have seldom been
reported in the literature.15
According to the previously developed conditions for
synthesis of azetidines 4, a mixture of 6a (0.5 mmol), I2 (1.2
equiv), and TMG (2.4 equiv) was stirred in 7 mL of THF. As
expected, 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptane (8a) was
isolated in 36% yield along with the minor product 2,4-dioxo-
1,3-diazabicyclo[3.2.0]heptene (9a) after 4 h (Table 5, entry
1). Surprisingly, by prolonging the reaction time, 8a
disappeared gradually on TLC (Table 5, entry 2). Afterward,
we proved that the base TMG, which possessed an N−H, could
further react with 8a and generate a highly polar byproduct.
Therefore, other strong organic bases such as DBU and DBN
without N−H bonds were under consideration. Comparatively,
DBN was superior to DBU and resulted in a better yield of 8a
(Table 5, entries 3 and 4). Furthermore, we observed that the
low yields were due to the incomplete conversion of 6a and
notable decomposition of 6a to chalcone 2a. Neither TEA nor
piperidine was effective in this conversion, probably due to their
relatively weak basicity (Table 5, entries 5 and 6). Other
solvents such as EtOH and CH3CN were also tried.
Interestingly, in CH3 CN more 2,4-dioxo-1,3-
diazabicyclo[3.2.0]heptene (9a) could be formed than in
THF (Table 5, entry 7 vs 4). It reminded us that CH3CN
was a good solvent for the selective synthesis of 9a and thus the
solvent-controlled selective synthesis of 1,3-diazabicyclic[3.2.0]
compounds 8a and 9a might be realized. Considering the
decomposition of 6a under these robust base conditions, we
performed the reaction of 6a with I2 in THF by the dropwise
addition of a solution of DBN in THF to decrease the basicity
of the reaction mixture. However, part of 6a inevitably
decomposed to 2a. Under similar conditions, decreasing the
temperature to 0 °C partially suppressed the decomposition of
6a and 8a was selectively obtained in a moderate yield of 55%
accompanied by 5% of 9a (Table 5, entry 9). It is a pity that no
further improvement in the yield was achieved by prolonging
the reaction time. Pleasingly, under these conditions the main
product 8a was easily isolated as almost a single product. As for
the formation of 9a, it was assumed to be generated through
iodination of 8a and subsequent elimination of HI. Thus, the
amounts of I2 and DBN were increased to 3 and 6 equiv,
respectively. When the reaction was performed in CH3CN at 0
°C for 4.5 h, 25% of 9a was produced with mostly unreacted 6a
(Table 5, entry 10). When the temperature was increased to 25
°C, the yield of 9a was increased to 32% along with 17% of 8a
(Table 5, entry 11). Further increases in the reaction time did
not lead to a noticeable transformation of 8a to 9a. When the
mixture was stirred at 60 °C for another 24 h after the addition
of the base, the yield of 9a could be increased to 48% with a
trace of 8a remaining (Table 5, entry 12). In addition, it should
be noted that the cyclization of 3aa under the same conditions
did not afford the azetine product at all.
Next, we attempted the one-pot selective preparation of 8a
and 9a separately. A mixture of 2a (1.05 mmol), 5a (1 mmol),
and Na2CO3 (0.05 mmol) was stirred in 5 mL of EtOH at 25
°C. Upon completion of the addition reaction, the solvent was
removed in vacuo and I2 and 7 mL of dry THF or CH3CN
were added. Subsequently, the same procedure as for the
cyclization of 6a produced 8a and 9a in 50% and 46% yields,
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Table 6. One-Pot Construction of Highly Functionalized 1,3-Diazabicyclic[3.2.0] Azetidine Derivatives 8 and Azetine
Derivatives 9
product (yield (%))
entry
R1
R2
R3
8
9
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
8a (50)
8b (56)
8c (48)
8d (51)
8e (40)
8f (31)
8g (36)
8h (33)
8i (0)
8j (0)
8k (30)
8l (27)
8m(40)
8n(41)
0
9a (46)
9b (33)
9c (42)
9d (45)
9e (46)
9f (17)
9g (31)
9h (41)
9i (24)
9j (29)
9k (25)
9l (25)
9m (21)
9n (12)
0
2
4-MeOC6H4
3
4-MeC6H4
4
4-ClC6H4
5
4-NO2C6H4
6
Ph
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-NO2C6H4
3-NO2C6H4
pyridyl
7
Ph
8
Ph
9
Ph
10
11
12
13
14
15
16
Ph
4-MeOC6H4
2-furyl
Ph
4-MeC6H4
Ph
ClCH2CH2
Ph
Ph
n-Bu
Ts
Ph
Ph
Ph
CH3
Ph
0
0
Scheme 2. Ester Exchange Reaction in MeOH and Further Cyclization
respectively (Table 6, entry 1). To study the generality of the
current selective reaction, various α,β-unsaturated carbonyl
compounds were investigated (Table 6). The reaction was
found to tolerate a range of different groups with different
electronic demands on the aromatic ring. Most of the substrates
could give the 1,3-diazabicyclic[3.2.0] azetidine derivatives 8
and azetine derivatives 9 selectively (Table 6, entries 1−8). The
substituent on the phenyl ring of the enone, especially on the
benzoyl ring, had a great influence on the reaction. When a
strong electron-withdrawing group was linked with the benzoyl
ring, no azetidine derivatives 8i and 8j were generated (Table 6,
entries 9 and 10). However, bicyclic heptenes 9i,j could be
obtained normally. Heterocycle-substituted bicyclic compounds
8k,l and 9k,l could also be selectively constructed (Table 6,
entries 11 and 12). R3 had no notable influence on the reaction.
When R3 was a phenyl or an alkyl group, 1,3-diazabicy-
clic[3.2.0] compounds 8 and 9 could be formed (Table 6,
entries 13 and 14). The azetine derivatives 9m,n were
generated in lower yield than 8m,n. However, if R3 was a
tosyl group, the first step of addition could not be realized
(Table 6, entry 15). If the phenyl group of R2 was replaced by a
methyl group, no reaction occurred in the second cyclization
step (Table 6, entry 16). We are not very clear why the oxetane
could be obtained13 but the azetidine could not be generated
when R2 was a methyl group.
When the first step of Michael addition was performed in
methanol, a complete ester exchange reaction took place and
gave the addition product 10, which could be transformed to
bicyclic compounds 11 and 12, respectively, under those similar
conditions (Scheme 2).
All of the known products were confirmed by comparison of
their spectral data with those reported in the literature.14 The
identification of new compounds 4, 6a, 7a, and 8−12 was fully
1
confirmed by their HRMS, H NMR, 13C NMR, and FT-IR
spectra. The relative stereochemistry of the first-step addition
product 10 and the structure of 1,3-diazabicyclic[3.2.0]
azetidine derivatives 8d and azetine derivatives 9h were
unambiguously determined on the basis of their single-crystal
X-ray diffraction analysis (see the Supporting Information).
In the process of screening the cyclization reaction
conditions, an interesting phenomenon was observed. When
the reaction of 6a with I2 was conducted in EtOH using K2CO3
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as the base, compound 13 was formed as the main product in
35% yield and neither 8a nor 9a was formed (Scheme 3).
This kind of ring-opening reaction realized the migration of
the amine group from the carbonyl group of urea to the
carbonyl group of the ester and provided an easy approach to
construct azetidine derivatives containing various substituent
groups with high stereoselectivities (Figure 1).
Scheme 3. Cyclization of 6a under I2/K2CO3 Conditions in
EtOH and Ring-Opening Reaction of 8a Using Different
Nucleophilic Reagents
Figure 1. Comparison of the structure of azetidines 4 with those of
azetidines 13−16.
A plausible mechanism for the present reaction is described
in Scheme 4. The Michael addition reaction of 2 with 1 or 5
affords 3 or intermediate 17, respectively. Iodination of 318
generates 18, which undergoes an intramolecular SN reaction to
give the azetidine 4. Cyclization of intermediate 17 affords
adduct 6. Iodination of 6 generates 20, and a follow-up
intramolecular SN reaction produces 2,4-dioxo-1,3-
diazabicyclo[3.2.0]heptane 8. Further iodination of 8 and
subsequent elimination of HI forms the 2,4-dioxo-1,3-
diazabicyclo[3.2.0]heptene 9. However, a similar reaction
with azetidine 4 does not generate 19 in our hands.
Nucleophilic attack at the carbonyl group of the imidazolidine
ring of 8 leads to the formation of azetidines 13−16. Perhaps
the fused, highly strained four-membered ring in compound 8
leads to instability of the imidazolidine ring because 6 cannot
transform to 22 under similar conditions.
In conclusion, we have explored a convenient one-pot TMG/
I2-mediated formal [2 + 2] cycloaddition reaction of α-
amidomalonate with enones to efficiently synthesize azetidines.
Highly functionalized azetidine derivatives 4 are divergently
synthesized in moderate to good yields with high diaster-
eoselectivity. We also explored an efficient method to construct
imidazolidine derivatives with high yield and diastereoselectivity
using a catalytic amount of Na2CO3 and realized the one-pot
preparation of 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptanes and
2,4-dioxo-1,3-diazabicyclo[3.2.0]heptenes with high stereo-
selectivities. The influence of the base and solvent on those
reactions was investigated in detail. The ring-opening reaction
of 2,4-dioxo-1,3-diazabicyclo[3.2.0]heptane with different
nucleophilic reagents was also investigated. Our further
investigations on the construction of thietanes under similar
conditions are currently underway.
Compounds 13 may be generated from the nucleophilic attack
of ethanol at the carbonyl group of imidazolidine ring of 8a
under basic conditions. Further experiments confirmed this
conjecture. The bicyclic compound 8a could be converted to
13 in 72% yield using a catalytic amount of K2CO3 after stirring
in EtOH for 1 h (Scheme 3). It should be mentioned that no
ring-opening reaction took place for compound 6a under the
same conditions, even though it also contained a similar
imidazolidine ring. These results led us to envision other
nucleophilic reagents containing the nitrogen or sulfur atom
(Scheme 3). When 8a was treated with 5 equiv of n-butylamine
in THF, 14 was isolated as the single product through the
further ammonolysis of the ester group. Reducing the amount
of n-butylamine to 1 equiv could not prevent the formation of
the disubstituted product. Further reducing the temperature to
−20 °C resulted in a very low conversion. When morpholine
was used as the nucleophilic reagent, the monosubstituted
product 15 was obtained in 52% yield. No disubstituted
product was observed, due to the large steric hindrance. Using
n-butyl mercaptan as the nucleophilic reagent and K2CO3 as the
base produced 16 in 74% yield. The ring-opening reaction took
place on the urea group but not the amide group, as confirmed
by the 13C NMR spectrum of 16, which contained a clear signal
at 156.4 ppm for the thiocarbamate group (N−(CO)−S)16,
and the absence of a peak for the thioester group (C−(C
O)−S) at about 200 ppm.
EXPERIMENTAL SECTION
■
Synthesis of Diethyl 2-(4-Methylphenylsulfonamido)-
malonate (1b). p-Toluenesulfonyl chloride (1.9 g, 10 mmol) was
added in portions to a stirred solution of the diethyl aminomalonate
hydrochloride (2.11 g, 10 mmol) in 10 mL of pyridine at 0 °C. The
mixture was stirred at room temperature until the completion of
reaction (TLC analysis) and then was poured into 50 mL of ice-cold
water with stirring. The precipitate was gathered and washed with
water. Further recrystallization from ethyl acetate/petroleum ether
1
afforded the white solid 1b (2.7 g, 82%): mp 66−68 °C; H NMR
(500 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.1 Hz,
2H), 5.60 (d, J = 8.0 Hz, 1H), 4.65 (d, J = 8.3 Hz, 1H), 4.08−4.18 (m,
4H), 2.42 (s, 3H), 1.20 (t, J = 7.2 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ: 165.7, 144.1, 136.5, 129.8, 127.4, 63.0, 58.8, 21.7, 14.0; Q-
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Scheme 4. Plausible Mechanism
TOF-MS (+ESI) calcd for C14H19NNaO6S [M + Na]+ 352.0831,
found 352.0816.
191.5, 168.9, 166.6, 164.8, 150.3, 137.3, 134.3, 133.5, 131.1, 129.4,
128.7, 128.62, 128.57, 128.4, 127.3, 123.8, 73.9, 70.1, 61.7, 60.9, 46.8,
13.6, 13.3; IR (KBr) ν/cm−1 3070, 2982, 1754, 1724, 1688, 1642,
1598, 1580, 1532, 1450, 1402, 1353, 1307, 1293, 1276, 1214, 1177,
1160, 1039, 992, 846, 827, 192, 770, 734, 717, 685, 574; Q-TOF-MS
(+ESI) calcd for C29H26N2NaO8 [M + Na]+ C29H26N2NaO8 [M +
Na]+ 553.1587, found 553.1542.
Synthesis of Diethyl 2-(Methylsulfonamido)malonate (1c). A
solution of methanesulfonyl chloride (1.14g,10 mmol) in 15 mL of
dichloromethane was added dropwise to a stirred solution of diethyl 2-
aminomalonate hydrochloride (2.11 g, 10 mmol) and Et3N (4.3 mL,
30 mmol) in 25 mL of dichloromethane at 0 °C. After completion of
the addition the mixture was warmed to room temperature and stirred
for another 1 h. The reaction mixture was diluted with CH2Cl2 and
then washed with hydrochloric acid (1 N), saturated sodium
bicarbonate, and water in turn. The organic layer was dried over
MgSO4 and concentrated under reduced pressure. The crude product
was crystallized from ethyl acetate/petroleum ether to give the white
solid 1c (1.94 g, 77%): mp 74−75 °C; 1H NMR (500 MHz, CDCl3) δ
5.44 (d, J = 8.0 Hz, 1H), 4.86 (d, J = 8.2 Hz, 1H), 4.25−4.35 (m, 4H),
3.06 (s, 3H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR (125 MHz, CDCl3)
δ: 166.2, 63.1, 59.0, 42.3, 14.0; Q-TOF-MS (+ESI) calcd for
C8H15NNaO6S [M + Na]+ 276.0518, found 276.0531.
4am: colorless solid, 122 mg, 47%, mp 123−124 °C; 1H NMR (500
MHz, DMSO-d6) δ 8.34 (br, 1 H), 7.96 (br, 1 H), 7.88 (br, 1 H),
7.50−7.73 (m, 3 H), 7.32−7.50 (m, 5 H), 6.95 (d, J = 8.6 Hz, 2 H),
6.59 (d, J = 6.3 Hz, 1 H), 4.13−4.30 (m, 3 H), 3.60−3.81 (m, 5 H),
1.22 (br, 3 H), 0.80 (br, 3 H); 13C NMR (125 MHz, DMSO-d6) δ
193.3, 169.5, 166.9, 165.0, 158.9, 150.0, 149.0, 137.8, 133.8, 130.8,
129.5, 128.4, 127.4, 127.1, 122.3, 113.5, 74.2, 69.8, 61.5, 60.9, 55.1,
46.8, 13.6, 13.3; IR (KBr) ν/cm−1 3070, 2982, 1754, 1724, 1688, 1642,
1598, 1580, 1532, 1450, 1402, 1353, 1307, 1293, 1276, 1214, 1177,
1160, 1039, 992, 846, 827, 192, 770, 734, 717, 685, 574; Q-TOF-MS
(+ESI) calcd for C29H28N2NaO7 [M + Na]+ 539.1794, found
539.1789.
General Procedure for the Synthesis of Azetidines 4. A
mixture of diethyl 2-aminomalonate 1 (0.5 mmol), enone 2 (0.5
mmol), and TMG (0.05 mmol) was stirred in 0.2 mL of THF at 25 °C
for 1 h. Upon completion as shown by TLC, 6 mL of THF, I2 (152
mg, 0.6 mmol), and TMG (132 mg, 1.15 mmol) were added and the
mixture was stirred at 25 °C for 4−6 h. After completion of the
reaction detected by TLC, 20 mL of water and saturated Na2S2O3
were added until the disappearance of the umber color and 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 azetidines 4.
4an: colorless solid, 165 mg, 62%, mp 117−119 °C; 1H NMR (500
MHz, DMSO-d6) δ 8.26−8.32 (m, 3H), 7.97 (t, J = 7.4 Hz, 1 H),
7.83−7.93 (m, 3 H), 7.72 (br, 2 H), 7.58 (t, J = 5.7 Hz, 1 H), 7.46 (t, J
= 7.2 Hz, 1 H), 7.40 (t, J = 7.4 Hz, 2 H), 6.66 (d, J = 6.0 Hz, 1 H),
4.54 (br, 1 H), 4.16−4.31 (m, 2 H), 3.77 (br, 1 H), 3.67 (br, 1 H),
1.22 (t, J = 6.5 Hz, 2 H), 0.76 (br, 3 H); 13C NMR (125 MHz,
DMSO-d6) δ 192.5, 169.6, 166.6, 164.8, 149.7, 148.9, 147.0, 143.9,
137.9, 133.5, 131.0, 129.9, 128.5, 128.3, 127.3, 123.1, 122.3, 73.9, 70.0,
61.8, 61.2, 46.4, 13.6, 13.2; IR (KBr) ν/cm−1 3070, 2982, 1754, 1724,
1688, 1642, 1598, 1580, 1532, 1450, 1402, 1353, 1307, 1293, 1276,
1214, 1177, 1160, 1039, 992, 846, 827, 192, 770, 734, 717, 685, 574;
Q-TOF-MS (+ESI) calcd for C28H26N3O8 [M + H]+ 532.1714, found
532.1718.
1
4af: colorless solid, 175 mg, 66%, mp 91−93 °C; H NMR (500
MHz, DMSO-d6) δ 8.47 (br, 1 H), 8.28 (d, J = 7.9 Hz, 1 H), 8.11 (d, J
= 7.6 Hz, 1 H), 7.72−7.86 (m, 3 H), 7.50−7.62 (m, 3 H), 7.47 (t, J =
7.4 Hz, 1 H), 7.33−7.44 (m, 4 H), 6.85 (br, 1 H), 4.53 (br, 1 H),
4.12−4.30 (m, 2 H), 3.77 (br, 1 H), 3.64 (br, 1 H), 1.23 (br, 3 H),
0.75 (br, 3 H); 13C NMR (125 MHz, DMSO-d6) δ 191.6, 169.0, 166.2,
164.9, 147.9, 137.1, 135.3, 134.0, 133.6, 132.6, 131.1, 130.2, 128.8,
128.3, 128.0, 127.4, 123.9, 123.5, 73.8, 69.7, 61.7, 61.1, 45.9, 13.6, 13.2;
IR (KBr) ν/cm−1 3070, 2982, 1754, 1724, 1688, 1642, 1598, 1580,
1532, 1450, 1402, 1353, 1307, 1293, 1276, 1214, 1177, 1160, 1039,
992, 846, 827, 192, 770, 734, 717, 685, 574; Q-TOF-MS (+ESI) calcd
for C29H26N2NaO8 [M + Na]+ 553.1587, found 553.1571.
1
4ba: colorless solid, 88 mg, 33%, mp 108−109 °C; H NMR (500
MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H),
7.55 (t, J = 7.4 Hz, 1H), 7.44 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.8 Hz,
2H), 7.28−7.33 (m, 3H), 7.23 (d, J = 8.0 Hz, 2H), 6.49 (d, J = 8.4 Hz,
1H), 4.26−4.39 (m, 3H), 4.05 (dq, J = 10.7, 7.2 Hz, 1H), 3.98 (dq, J =
10.7, 7.2 Hz, 1H), 2.40 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.01 (t, J =
7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 195.1, 167.8, 166.2,
143.5, 138.5, 134.8, 134.1, 132.7, 129.1, 128.94, 128.89, 128.6, 128.4,
128.0, 64.4, 62.6, 62.5, 45.3, 21.7, 14.1, 13.7; IR (KBr) ν/cm−1 2989,
1749, 1732, 1695, 1599, 1497, 1450, 1372, 1338, 1299, 1278, 1211,
1165, 1152, 1092, 1054, 984, 946, 869, 813, 738, 697, 676; Q-TOF-
MS (+ESI) calcd for C29H29NNaO7S [M + Na]+ 558.1562, found
558.1594.
4aj: colorless solid, 164 mg, 62%, mp 133−135 °C; 1H NMR (500
MHz, DMSO-d6) δ 8.18 (br, 2 H), 7.79 (br, 3 H), 7.37−7.60 (m, 9
H), 6.81 (br, 1 H), 4.12−4.33 (m, 3 H), 3.76 (br, 1 H), 3.58 (br, 1 H),
1.23 (br, 3 H), 0.73 (br, 3 H); 13C NMR (125 MHz, DMSO-d6) δ
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4ca: colorless solid, 127 mg, 55%, mp 129−130 °C; 1H NMR (500
MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 2H), 7.49−7.55 (m, 3H), 7.31−
7.40 (m, 5H), 6.36 (d, J = 8.4 Hz, 1H), 4.35−4.48 (m, 2H), 4.23 (d, J
= 8.4 Hz, 1H), 3.92 (dq, J = 10.7, 7.2 Hz, 1H), 3.98 (dq, J = 10.7, 7.2
Hz, 1H), 3.40 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 195.5, 168.2, 165.9, 134.3,
133.7, 131.9, 129.3, 129.0, 128.9, 128.7, 66.0, 62.7, 62.6, 46.2, 44.0,
14.2, 13.7; IR(KBr) ν/cm−1 2979, 1750, 1735, 1595, 1452, 1373, 1331,
1293, 1224, 1173, 1145, 1050, 970, 862, 818, 798, 780, 737, 699, 567,
519; Q-TOF-MS (+ESI) calcd for C23H25NNaO7S [M + Na]+
482.1249, found 482.1205.
column (petroleum ether/ethyl acetate, 10/1) to afford the desired
products 8.
Synthesis of 9. I2 (381 mg, 1.5 mmol) and 7 mL of CH3CN were
added. To the mixture was added dropwise a solution of DBN (372
mg, 3.0 mmol) in 8 mL of CH3CN within 2 h at 25 °C. After that the
mixture was stirred at 60 °C for another 20−40 h until only a trace of
8 remained on TLC. The solvent was removed in vacuo, and the
residue was purified by flash chromatography on a silica gel column
(petroleum ether/ethyl acetate, 10/1) to afford the desired products 9.
1
8a: colorless solid, 113 mg, 50%, mp 133−134 °C; H NMR (300
MHz, CDCl3) δ 8.10 (d, J = 7.1 Hz, 2H), 7.63 (tt, J = 7.4, 1.3 Hz, 1H),
7.38−7.52 (m, 10H), 7.11−7.14 (m, 2H), 5.70 (d, J = 4.4 Hz, 1H),
5.06 (d, J = 4.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 192.8, 167.1, 165.6, 163.5,
134.5, 133.4, 132.9, 131.3, 129.7, 129.4, 129.3, 129.1, 129.0, 127.6,
125.6, 75.0, 68.9, 63.7, 50.3, 14.1; IR (KBr) ν/cm−1 3063, 2985, 2937,
1790, 1736, 1715, 1697, 1597, 1495, 1451, 1385, 1371, 1300, 1285,
1238, 1223, 1175, 1155, 1128, 1115, 1098, 1052, 1036, 1022, 1001,
954, 852, 842, 772, 751, 730, 698, 689, 644, 637, 510, 494; Q-TOF-MS
(+ESI) calcd for C27H22N2NaO5 [M + Na]+ 477.1426, found
477.1423.
General Procedure for the Synthesis of Ureidomalonates 5.
Triethylamine (2.42 g, 24 mmol) was added dropwise to diethyl 2-
aminomalonate hydrochloride (4.45 g, 21 mmol) in 30 mL of CH2Cl2
within 20 min. Then, a solution of phenyl isocyanate (2.38 g, 20
mmol) in 10 mL of CH2Cl2 was added dropwise to the mixture at 0
°C within 20 min. After that, the mixture was stirred at room
temperature for 2.5 h. Upon completion as shown by TLC, the
mixture was washed with 10% hydrochloride twice, saturated Na2CO3,
and NaCl solution. After drying with anhydrous Na2SO4 the solvent
was removed in vacuo. The residue was recrystallized from ethyl
acetate to give pure 5a (4.88 g, 83%).
1
8b: colorless solid, 136 mg, 56%, mp 112−113 °C; H NMR (400
1
MHz, CDCl3) δ 8.07 (d, J = 7.9 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.48
(t, J = 7.7 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.3 Hz, 1H),
7.32 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H), 6.98 (d, J = 8.5 Hz,
2H), 5.63 (d, J = 4.4 Hz, 1H), 4.97 (d, J = 4.4 Hz, 1H), 4.36 (q, J = 7.1
Hz, 2H), 3.84 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 192.8, 167.3, 165.7, 163.5, 160.2, 134.4, 133.5, 131.4, 129.4,
129.1, 129.0, 128.8, 125.7, 124.8, 115.0, 75.2, 69.6, 63.6, 55.5, 49.9,
14.1; IR (KBr) ν/cm−1 3056, 2987, 2939, 2829, 1789, 1736, 1713,
1694, 1612, 1597, 1583, 1512, 1494, 1463, 1450, 1385, 1371, 1302,
1286, 1247, 1223, 1183, 1172, 1156, 1116, 1042, 853, 844, 814, 770,
744, 699, 688, 644, 637, 553, 519; Q-TOF-MS (+ESI) calcd for
C28H24N2NaO6 [M + Na]+ 507.1532, found 507.1526.
5a: colorless solid, 83%, mp 113−114 °C; H NMR (400 MHz,
CDCl3) δ 7.31 (t, J = 6.8 Hz, 2H), 7.27 (d, J = 6.5 Hz, 2H), 7.08 (s,
1H, NH), 7.06 (t, J = 7.1 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H, NH), 5.22
(d, J = 7.2 Hz, 1H), 4.21−4.34 (m, 4H), 1.30 (t, J = 7.1 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 167.5, 154.7, 138.2, 129.3, 124.0, 120.8,
62.8, 57.4, 14.1; IR (KBr) ν/cm−1 3336, 2985, 2940, 1746, 1736, 1645,
1598, 1566, 1444, 1374, 1346, 1281, 1223, 1182, 1025, 734, 694, 636,
590, 517; Q-TOF-MS (+ESI) calcd for C14H18N2NaO5 [M + Na]+
317.1113, found 317.1127.
5b: colorless solid, 88%, mp 83−84 °C; 1H NMR (300 MHz,
CDCl3) δ 5.73 (br, 1H, NH), 5.15 (d, J = 7.5 Hz, 1H), 5.04 (br, 1H,
NH), 4.18−4.34 (m, 4H), 3.18 (q, J = 6.5 Hz, 2H), 1.43−1.52 (m,
2H), 1.26−1.40 (m, 8H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 167.8, 157.0, 62.5, 57.4, 40.4, 32.2, 20.1, 14.1, 13.9; IR
(KBr) ν/cm−1 3335, 2957, 2935, 2873, 1747, 1736, 1633, 1581, 1371,
1343, 1282, 1225, 1179, 1162, 1117, 1105, 1024, 867, 672, 633, 601,
585; Q-TOF-MS (+ESI) calcd for C12H22N2NaO5 [M + Na]+
297.1426, found 297.1432.
1
8c: colorless solid, 112 mg, 48%, mp 136−137 °C; H NMR (300
MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz, 2H), 7.61 (tt, J = 7.4, 1.3 Hz, 1H),
7.48 (t, J = 7.8 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.41 (tt, J = 7.0, 1.6
Hz, 1H) 7.30 (d, J = 9.2 Hz, 2H), 7.26 (d, J = 9.2 Hz, 2H), 7.14−7.18
(m, 2H), 5.67 (d, J = 4.5 Hz, 1H), 4.98 (d, J = 4.4 Hz, 1H), 4.37 (q, J
= 7.1 Hz, 2H), 2.39 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 192.8, 167.3, 165.7, 163.5, 139.3, 134.4, 133.4, 131.4,
130.4, 129.9, 129.4, 129.1, 129.0, 127.5, 125.7, 75.1, 69.3, 63.6, 50.0,
21.3, 14.1; IR (KBr) ν/cm−1 3069, 2984, 2923, 1790, 1739, 1721,
1680, 1596, 1498, 1450, 1386, 1289, 1239, 1168, 1123, 1050, 1021,
842, 784, 738, 722, 687, 654, 628, 549, 497; Q-TOF-MS (+ESI) calcd
for C28H24N2NaO5 [M + Na]+ 491.1583, found 491.1577.
1
5c: colorless solid, 85%, mp 120−121 °C; H NMR (300 MHz,
CDCl3) δ 6.10 (d, J = 7.5 Hz, 1H, NH), 5.72 (t, J = 5.5 Hz, 1H, NH),
5.16 (d, J = 7.5 Hz, 1H), 4.19−4.35 (m, 4H), 3.52−3.63 (m, 4H), 1.30
(t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 167.7, 156.9, 62.6,
57.4, 44.8, 42.3, 14.1; IR (KBr) ν/cm−1 3360, 2984, 2950, 1748, 1731,
1629, 1581, 1372, 1348, 1282, 1226, 1180, 1118, 1025, 944, 865, 780,
731, 661, 606; Q-TOF-MS (+ESI) calcd for C10H17ClN2NaO5 [M +
Na]+ 303.0724, found 303.0741.
1
8d: colorless solid, 125 mg, 51%, mp 136−137 °C; H NMR (300
MHz, CDCl3) δ 8.12 (d, J = 7.3 Hz, 2H), 7.64 (tt, J = 7.4, 1.3 Hz, 1H),
7.40−7.53 (m, 7H), 7.34 (d, J = 8.5 Hz, 2H), 7.13−7.18 (m, 2H), 5.62
(d, J = 4.5 Hz, 1H), 5.07 (d, J = 4.4 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H),
1.33 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.5, 167.0,
165.4, 163.4, 135.3, 134.5, 133.4, 131.5, 131.2, 129.9, 129.5, 129.2,
129.1, 128.9, 125.5, 74.7, 68.8, 63.7, 49.3, 14.1; IR (KBr) ν/cm−1 3066,
2996, 2982, 2936, 1790, 1739, 1713, 1700, 1596, 1495, 1449, 1386,
1369, 1306, 1289, 1233, 1175, 1160, 1097, 854, 849, 767, 690, 644,
514; Q-TOF-MS (+ESI) calcd for C27H21ClN2NaO5 [M + Na]+
511.1037, found 511.1042.
5d: colorless solid, 89%, mp 92−93 °C; 1H NMR (300 MHz,
CDCl3) δ 7.92 (s, 1H, NH), 7.87 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 6.9
Hz, 1H, NH), 7.33 (d, J = 8.1 Hz, 2H), 5.04 (d, J = 6.9 Hz, 1H), 4.20−
4.36 (m, 4H), 2.44 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 165.9, 151.2, 145.0, 136.5, 130.0, 127.5, 63.0, 57.1,
21.8, 14.1; IR (KBr) ν/cm−1 3328, 3279, 2979, 2944, 2872, 1758,
1737, 1536, 1448, 1372, 1343, 1292, 1265, 1222, 1180, 1093, 1056,
1021, 982, 891, 868, 816, 670, 604, 590, 551, 521; Q-TOF-MS (+ESI)
calcd for C15H20N2NaO7S [M + Na]+ 395.0889, found 395.0897.
General Procedure for the One-Pot Synthesis of 1,3-
Diazabicyclic[3.2.0] Compounds 8 and 9. A mixture of chalcone
2 (0.525 mmol), 5 (0.5 mmol), and Na2CO3 (2.7 mg, 0.025 mmol)
was stirred in 3−5 mL of absolute EtOH at room temperature for 3−
12 h until the disappearance of 5a. The solvent was removed in vacuo,
and the adducts obtained were directly used for the next step rof the
eaction without further purification.
1
8e: colorless solid, 100 mg, 40%, mp 158−159 °C; H NMR (300
MHz, CDCl3) δ 8.33 (d, J = 8.8, 2H), 8.21 (d, J = 7.2 Hz, 2H), 7.66
(tt, J = 7.4, 1.3 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.53 (t, J = 7.5 Hz,
2H), 7.38−7.50 (m, 3H), 7.13−7.17 (m, 2H), 5.67 (d, J = 4.6 Hz,
1H), 5.31 (d, J = 4.6 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.3, 166.8, 165.2, 163.3,
148.2, 140.2, 134.7, 133.3, 131.0, 129.6, 129.4, 129.3, 129.2, 128.7,
125.4, 124.7, 74.4, 68.1, 64.0, 48.8, 14.1; IR (KBr) ν/cm−1 3075, 2987,
2947, 2926, 1791, 1744, 1720, 1676, 1597, 1518, 1495, 1387, 1347,
1285, 1264, 1240, 1181, 1166, 1126, 1111, 1056, 1019, 869, 825, 752,
742, 694, 672, 737, 622, 544; Q-TOF-MS (+ESI) calcd for
C27H21N3NaO7 [M + Na]+ 522.1277, found 522.1284.
Synthesis of 8. I2 (152.4 mg, 0.6 mmol) and 7 mL of dry THF were
added. To the mixture was added dropwise a solution of DBN (148.8
mg, 1.2 mmol) in 8 mL of dry THF within 2.5 h at 0 °C. After that the
mixture was stirred for another 2 h. The solvent was removed in vacuo,
and the residue was purified by flash chromatography on a silica gel
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Article
1
8f: colorless solid, 75 mg, 31%, mp 105−106 °C; H NMR (300
MHz, CDCl3) δ 8.10 (d, J = 9.0 Hz, 2H), 7.35−7.51 (m, 8H), 7.10−
7.14 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 5.65 (d, J = 4.4 Hz, 1H), 5.07
(d, J = 4.4 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.33 (t, J =
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 191.1, 167.2, 165.6, 164.5,
163.6, 133.1, 131.6, 131.4, 129.7, 129.4, 129.2, 129.0, 127.6, 126.5,
125.6, 114.3, 75.1, 68.7, 63.6, 55.7, 50.2, 14.1; IR (KBr) ν/cm−1 3060,
2988, 2937, 2840, 1790, 1736, 1715, 1683, 1598, 1574, 1515, 1494,
1385, 1301, 1243, 1224, 1171, 1157, 1035, 847, 782, 749, 694, 602,
581, 510; Q-TOF-MS (+ESI) calcd for C28H24N2NaO6 [M + Na]+
507.1532, found 507.1525.
1.38−1.58 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.12−1.26 (m, 2H), 0.87
(t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.0, 168.5, 166.0,
164.7, 134.4, 133.6, 133.0, 129.5, 129.2, 129.1, 129.0, 127.5, 74.8, 68.2,
63.4, 49.1, 40.2, 29.6, 19.9, 14.0, 13.6; IR (KBr) ν/cm−1 3064, 2960,
2936, 2873, 1786, 1747, 1720, 1597, 1449, 1399, 1369, 1272, 1231,
1181, 1071, 1038, 947, 757, 698, 659, 639, 570; Q-TOF-MS (+ESI)
calcd for C25H26N2NaO5 [M + Na]+ 457.1739, found 457.1731.
1
9a: yellow solid, 104 mg, 46%, mp 153−154 °C; H NMR (300
MHz, CDCl3) δ 8.28−8.32 (m, 2H), 8.00−8.04 (m, 2H), 7.65 (tt, J =
7.4, 1.3 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.39−7.48 (m, 6H), 7.33−
7.38 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 184.6, 164.6, 163.3, 158.9, 144.5, 140.0,
135.9, 134.3, 131.9, 131.1, 130.3, 129.34, 129.32, 129.1, 128.9, 128.7,
127.9, 126.0, 75.6, 63.9, 14.1; IR (KBr) ν/cm−1 3068, 2977, 2937,
1799, 1750, 1647, 1598, 1568, 1493, 1448, 1379, 1340, 1265, 1232,
1185, 1148, 1094, 1052, 962, 907, 752, 712, 690, 700, 631, 618, 595,
473; Q-TOF-MS (+ESI) calcd for C27H20N2NaO5 [M + Na]+
475.1270, found 475.1263.
1
8g: colorless solid, 84 mg, 36%, mp 145−146 °C; H NMR (300
MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.35−7.51 (m, 8H), 7.28 (d,
J = 8.4 Hz, 2H), 7.10−7.14 (m, 2H), 5.68 (d, J = 4.4 Hz, 1H), 5.04 (d,
J = 4.4 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.33 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 192.3, 167.2, 165.6, 163.5,
145.5, 133.0, 131.4, 130.9, 129.8, 129.7, 129.4, 129.24, 129.21, 129.0,
127.6, 125.6, 75.0, 68.9, 63.6, 50.3, 21.9, 14.1; IR (KBr) ν/cm−1 3059,
2987, 2938, 1790, 1741, 1716, 1687, 1606, 1495, 1384, 1300, 1243,
1224, 1174, 1157, 1126, 1051, 853, 749, 727, 692, 605, 511; Q-TOF-
MS (+ESI) calcd for C28H24N2NaO5 [M + Na]+ 491.1583, found
491.1575.
1
9b: yellow solid, 80 mg, 33%, mp 189−190 °C; H NMR (300
MHz, CDCl3) δ 8.27−8.31 (m, 2H), 8.08 (d, J = 9.0, 2H), 7.63 (tt, J =
7.4, 1.3 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.38−7.47 (m, 3H), 7.33−
7.37 (m, 2H), 6.96 (d, J = 9.1 Hz, 2H), 4.42 (q, J = 7.0 Hz, 2H), 3.87
(s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 184.6,
164.9, 163.5, 162.6, 159.4, 142.2, 140.7, 136.3, 134.0, 131.5, 131.1,
130.2, 129.30, 129.25, 128.5, 126.0, 120.8, 114.4, 75.6, 63.8, 55.6, 14.1;
IR (KBr) ν/cm−1 3069, 2962, 2930, 2838, 1798, 1752, 1736, 1643,
1599, 1583, 1505, 1386, 1261, 1230, 1183, 1151, 1093, 1047, 1024,
965, 912, 843, 750, 706, 695, 631, 591, 513; Q-TOF-MS (+ESI) calcd
for C28H22N2NaO6 [M + Na]+ 505.1376, found 505.1381.
8h: colorless solid, 80.5 mg, 33%, mp 104−105 °C; 1H NMR (300
MHz, CDCl3) δ 8.12 (d, J = 8.8, 2H), 7.36−7.51 (m, 10H), 7.10−7.14
(m, 2H), 5.62 (d, J = 4.4 Hz, 1H), 5.09 (d, J = 4.4 Hz, 1H), 4.36 (q, J
= 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
191.8, 166.9, 165.5, 163.5, 141.0, 132.8, 131.8, 131.3, 130.7, 129.7,
129.5, 129.3, 129.1, 127.5, 125.6, 74.9, 68.8, 63.7, 50.0, 14.1; IR (KBr)
ν/cm−1 3059, 2988, 2939, 1791, 1744, 1716, 1691, 1589, 1494, 1386,
1282, 1239, 1225, 1173, 1159, 1092, 1013, 851, 771, 752, 735, 697,
690, 537, 501; Q-TOF-MS (+ESI) calcd for C27H21ClN2NaO5 [M +
Na]+ 511.1037, found 511.1042.
1
9c: yellow solid, 98 mg, 42%, mp 129−130 °C; H NMR (300
MHz, CDCl3) δ 8.27−8.31 (m, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.64 (tt,
J = 7.4, 1.3 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.38−7.47 (m, 3H),
7.33−7.37 (m, 2H), 7.24 (d, J = 8.3 Hz, 2H), 4.34−4.48 (m, 2H), 2.40
(s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 184.6,
164.7, 163.4, 159.1, 143.6, 142.8, 140.5, 136.1, 134.1, 131.1, 130.3,
129.7, 129.3, 129.32, 129.27, 129.2, 128.6, 126.0, 125.2, 75.6, 63.8,
22.0, 14.1; IR (KBr) ν/cm−1 3058, 2978, 2928, 1798, 1737, 1637,
1598, 1584, 1504, 1381, 1341, 1269, 1230, 1181, 1152, 1092, 960, 910,
751, 702, 480; Q-TOF-MS (+ESI) calcd for C28H22N2NaO5 [M +
Na]+ 489.1426, found 489.1434.
1
8k: yellow oil, 73 mg, 30%; H NMR (300 MHz, CDCl3) δ 8.46
(ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.17 (dt, J = 7.8, 1.1 Hz, 1H), 7.88 (td,
J = 7.8, 1.7 Hz, 1H), 7.46 (ddd, J = 7.7, 4.8, 1.2 Hz, 1H), 7.34−7.46
(m, 5H), 7.11−7.15 (m, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 4.8
Hz, 1H), 4.73 (d, J = 4.8 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.84 (s,
3H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.2,
167.9, 166.2, 163.4, 159.7, 150.6, 149.3, 137.3, 131.5, 129.3, 128.9,
128.7, 128.2, 125.7, 125.3, 122.9, 114.5, 75.2, 69.8, 63.5, 55.4, 50.7,
14.1; IR (KBr) ν/cm−1 3061, 2982, 2936, 2839, 1790, 1728, 1612,
1516, 1496, 1384, 1254, 1228, 1182, 1161, 1125, 1034, 995, 843, 743,
691, 650, 617; Q-TOF-MS (+ESI) calcd for C27H23N3NaO6 [M +
Na]+ 508.1485, found 508.1491.
1
9d: yellow solid, 109 mg, 45%, mp 172−173 °C; H NMR (300
MHz, CDCl3) δ 8.28−8.32 (m, 2H), 8.00 (d, J = 8.7 Hz, 2H), 7.64 (tt,
J = 7.4, 1.3 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.39−7.49 (m, 5H),
7.33−7.37 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 184.5, 164.5, 163.1, 158.6, 144.7, 138.9,
138.0, 135.8, 134.4, 131.0, 130.5, 130.4, 129.39, 129.37, 129.2, 128.7,
126.3, 126.0, 75.5, 64.0, 14.1; IR (KBr) ν/cm−1 3096, 2984, 2938,
1799, 1748, 1727, 1651, 1599, 1488, 1373, 1333, 1263, 1230, 1175,
1136, 1087, 1012, 962, 914, 835, 755, 725, 705, 689, 621, 503, 469; Q-
TOF-MS (+ESI) calcd for C27H19ClN2NaO5 [M + Na]+ 509.0880,
found 509.0889.
8l: yellow oil, 62 mg, 27%; 1H NMR (300 MHz, CDCl3) δ 8.02 (d,
J = 8.2 Hz, 2H), 7.41−7.55 (m, 4H), 7.35−7.39 (m, 2H), 7.30 (d, J =
8.1 Hz, 2H), 6.49 (dd, J = 3.3, 0.6 Hz, 1H), 6.44 (dd, J = 3.2, 1.9 Hz,
1H), 5.58 (d, J = 4.4 Hz, 1H), 5.06 (d, J = 4.4 Hz, 1H), 4.33 (q, J = 7.1
Hz, 2H), 2.42 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 191.9, 167.7, 165.3, 163.5, 147.0, 145.6, 143.9, 131.8, 130.9,
129.8, 129.5, 129.4, 129.0, 125.8, 111.5, 111.1, 73.9, 69.7, 63.6, 42.4,
21.9, 14.0; IR (KBr) ν/cm−1 3067, 2983, 2924, 1793, 1728, 1684,
1607, 1501, 1387, 1271, 1225, 1173, 1125, 1044, 1015, 841, 778, 747,
690, 597, 504; Q-TOF-MS (+ESI) calcd for C26H22N2NaO6 [M +
Na]+ 481.1376, found 481.1368.
1
9e: yellow solid, 114 mg, 46%, mp 207−208 °C; H NMR (300
MHz, CDCl3) δ 8.31−8.34 (m, 2H), 8.29 (d, J = 9.1 Hz, 2H), 8.18 (d,
J = 9.1 Hz, 2H), 7.69 (tt, J = 7.4, 1.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H),
7.40−7.50 (m, 3H), 7.34−7.38 (m, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.36
(t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 184.2, 164.2, 162.8,
157.9, 148.8, 147.4, 136.8, 135.4, 134.9, 133.3, 130.9, 130.5, 129.9,
129.6, 129.5, 128.8, 125.9, 124.0, 75.6, 64.3, 14.1; IR (KBr) ν/cm−1
3110, 3057, 2991, 2933, 1801, 1761, 1737, 1644, 1597, 1583, 1520,
1492, 1384, 1346, 1336, 1263, 1229, 1184, 1168, 1151, 1092, 966, 909,
860, 853, 751, 711, 697; Q-TOF-MS (+ESI) calcd for C27H19N3NaO7
[M + Na]+ 520.1121, found 520.1117.
8m: colorless oil, 88 mg, 40%; 1H NMR (300 MHz, CDCl3) δ 8.07
(d, J = 7.3 Hz, 2H)), 7.61 (tt, J = 7.4, 1.3 Hz, 1H), 7.38−7.50 (m, 5H),
7.31−7.34 (m, 2H), 5.59 (d, J = 4.7 Hz, 1H), 4.99 (d, J = 4.7 Hz, 1H),
4.34 (q, J = 7.1 Hz, 2H), 3.85 (dt, J = 14.0, 6.5 Hz, 1H), 3.79 (dt, J =
14.0, 6.2 Hz, 1H), 3.58 (dt, J = 11.3, 6.2 Hz, 1H), 3.54 (dt, J = 11.3,
6.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
192.7, 168.2, 165.6, 163.9, 134.4, 133.4, 132.8, 129.6, 129.13, 129.08,
129.06, 127.4, 74.9, 68.4, 63.6, 49.2, 41.7, 39.4, 14.0; IR (KBr) ν/cm−1
3064, 2983, 2938, 1790, 1747, 1724, 1597, 1498, 1397, 1231, 1169,
1100, 1025, 854, 756, 698, 658, 568; Q-TOF-MS (+ESI) calcd for
C23H21ClN2NaO5 [M + Na]+ 463.1037, found 463.1044.
1
9f: yellow solid, 41 mg, 17%, mp 154−155 °C; H NMR (300
MHz, CDCl3) δ 8.35 (d, J = 9.0 Hz, 2H), 7.98−8.03 (m, 2H), 7.38−
7.48 (m, 6H), 7.34−7.38 (m, 2H), 7.00 (d, J = 9.0 Hz, 2H), 4.41 (q, J
= 7.1 Hz, 2H), 3.90 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 182.7, 164.8, 164.7, 163.4, 158.9, 145.0, 139.1, 133.0,
131.5, 131.1, 129.32, 129.28, 129.0, 128.9, 128.8, 127.9, 126.0, 114.0,
75.6, 63.8, 55.7, 14.1; IR (KBr) ν/cm−1 3065, 2960, 2931, 2835, 1797,
1740, 1648, 1601, 1491, 1378, 1339, 1263, 1239, 1170, 1143, 1093,
8n: colorless oil, 89 mg, 41%; 1H NMR (300 MHz, CDCl3) δ 8.08
(d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H),
7.36−7.42 (m, 3H), 7.30 (d, J = 7.3 Hz, 2H), 5.56 (d, J = 4.7 Hz, 1H),
4.98 (d, J = 4.7 Hz, 1H), 4.26−4.41 (m, 2H), 3.39−3.54 (m, 2H),
4337
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Article
1025, 962, 907, 829, 756, 750, 692, 611, 591, 571, 508; Q-TOF-MS
(+ESI) calcd for C28H22N2NaO6 [M + Na]+ 505.1376, found
505.1368.
7.4, 1.3 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.38−7.48 (m, 3H), 4.38 (q,
J = 7.1 Hz, 2H), 3.80−3.99 (m, 2H), 3.65−3.78 (m, 2H), 1.31 (t, J =
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 184.5, 165.5, 163.1, 159.7,
144.6, 139.6, 135.8, 134.4, 131.8, 130.3, 129.0, 128.9, 128.7, 127.7,
75.7, 63.8, 41.8, 39.5, 14.0; IR (KBr) ν/cm−1 3064, 2982, 2937, 1798,
1751, 1731, 1653, 1598, 1494, 1448, 1391, 1336, 1265, 1229, 1179,
1123, 959, 760, 711, 687, 595; Q-TOF-MS (+ESI) calcd for
C23H19ClN2NaO5 [M + Na]+ 461.0880, found 461.0877.
1
9g: yellow solid, 72 mg, 31%, mp 155−156 °C; H NMR (300
MHz, CDCl3) δ 8.22 (d, J = 8.3 Hz, 2H), 7.98−8.04 (m, 2H), 7.38−
7.48 (m, 6H), 7.34−7.38 (m, 2H), 7.32 (d, J = 8.3 Hz, 2H), 4.41 (q, J
= 7.1 Hz, 2H), 2.44 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 184.1, 164.7, 163.3, 158.9, 145.5, 144.8, 139.5, 133.4,
131.7, 131.1, 130.5, 129.4, 129.30, 129.27, 129.0, 128.9, 127.9, 126.0,
75.6, 63.8, 22.1, 14.1; IR (KBr) ν/cm−1 3068, 2984, 1799, 1750, 1724,
1645, 1607, 1491, 1381, 1337, 1299, 1273, 1234, 1182, 1145, 1093,
907, 751, 743, 689, 609, 480; Q-TOF-MS (+ESI) calcd for
C28H22N2NaO5 [M + Na]+ 489.1426, found 489.1433.
9n: colorless oil, 26 mg, 12%; 1H NMR (300 MHz, CDCl3) δ 8.25−
8.30 (m, 2H), 7.92−7.96 (m, 2H), 7.65 (tt, J = 7.4, 1.3 Hz, 1H), 7.53
(t, J = 7.6 Hz, 2H), 7.38−7.46 (m, 3H), 4.37 (q, J = 7.1 Hz, 2H), 3.59
(dt, J = 13.5, 7.3 Hz, 1H), 3.47 (dt, J = 13.5, 7.0 Hz, 1H), 1.55−1.65
(m, 2H), 1.26−1.36 (m, 5H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 184.6, 165.8, 163.4, 160.2, 144.6, 139.7, 135.9, 134.3,
131.7, 130.3, 129.0, 128.8, 128.7, 127.9, 75.6, 63.7, 40.4, 29.3, 19.8,
14.0, 13.6; IR (KBr) ν/cm−1 3066, 2960, 2934, 2874, 1794, 1751,
1728, 1654, 1599, 1494, 1448, 1393, 1338, 1265, 1229, 1180, 1113,
1071, 955, 762, 712, 688, 596; Q-TOF-MS (+ESI) calcd for
C25H24N2NaO5 [M + Na]+ 455.1583, found 455.1591.
1
9h: yellow solid, 100 mg, 41%, mp 151−152 °C; H NMR (300
MHz, CDCl3) δ 8.28 (d, J = 8.6 Hz, 2H), 8.03−8.07 (m, 2H), 7.50 (d,
J = 8.6 Hz, 2H), 7.38−7.48 (m, 6H), 7.33−7.37 (m, 2H), 4.42 (q, J =
7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
183.2, 164.4, 163.2, 158.9, 144.0, 140.9, 140.7, 134.3, 132.1, 131.8,
131.0, 129.4, 129.2, 129.0, 128.9, 127.7, 125.9, 75.7, 64.0, 14.1; IR
(KBr) ν/cm−1 3068, 2984, 1798, 1751, 1649, 1590, 1569, 1491, 1379,
1336, 1267, 1234, 1186, 1145, 1094, 1014, 964, 908, 758, 744, 689,
619, 510, 477; Q-TOF-MS (+ESI) calcd for C27H19ClN2NaO5 [M +
Na]+ 509.0880, found 509.0876.
Ester Exchange Reaction for the Preparation of 10−12. The
operation was the same as that of the one-pot reaction for the
preparation of 8 and 9, except for changing the solvent from EtOH to
MeOH in the first addition step.
1
1
9i: yellow solid, 60 mg, 24%, mp 93−94 °C; H NMR (300 MHz,
10: colorless solid, 212 mg, 96%, mp 202−203 °C; H NMR (400
CDCl3) δ 8.46 (d, J = 9.1 Hz, 2H), 8.36 (d, J = 9.1 Hz, 2H), 8.11−8.15
(m, 2H), 7.40−7.54 (m, 6H), 7.31−7.35 (m, 2H), 4.44 (q, J = 7.1 Hz,
2H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 183.0,
164.1, 163.0, 159.1, 150.6, 143.2, 142.5, 140.7, 132.7, 131.3, 130.9,
129.5, 129.43, 129.42, 129.1, 127.5, 125.9, 123.7, 75.9, 64.2, 14.1; IR
(KBr) ν/cm−1 3067, 2985, 2938, 1797, 1735, 1663, 1603, 1526, 1495,
1375, 1345, 1265, 1229, 1142, 1093, 1049, 964, 850, 775, 748, 717,
688, 505; Q-TOF-MS (+ESI) calcd for C27H19N3NaO7 [M + Na]+
520.1121, found 520.1113.
MHz, CDCl3) δ 7.87 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.42
(dd, J = 8.0, 1.7 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.28−7.33 (m, 6H),
7.21 (s, 1H, NH), 6.71−6.76 (m, 2H), 4.57 (dd, J = 8.9, 5.2 Hz, 1H),
3.88 (s, 3H), 3.78 (dd, J = 16.8, 8.9 Hz, 1H), 3.32 (dd, J = 16.8, 5.2
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 196.1, 167.3, 166.9, 156.6,
136.5, 136.3, 133.6, 130.8, 129.4, 129.2, 128.80, 128.77, 128.5, 128.3,
126.5, 72.1, 54.3, 45.8, 39.1; IR (KBr) ν/cm−1 3316, 3060, 2960, 2898,
2359, 2337, 1798, 1787, 1748, 1727, 1686, 1596, 1496, 1453, 1405,
1376, 1349, 1265, 1224, 1191, 1149, 1108, 1088, 1073, 1041, 1000,
983, 945, 839, 808, 792, 772, 705, 669, 610; Q-TOF-MS (+ESI) calcd
for C26H22N2NaO5 [M + Na]+ 465.1426, found 465.1433.
9j: yellow solid, 72 mg, 29%, mp 154−155 °C; 1H NMR (300 MHz,
CDCl3) δ 9.20 (t, J = 1.8 Hz, 1H), 8.63 (dt, J = 7.8, 1.4 Hz, 1H), 8.50
(ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.11−8.15 (m, 2H), 7.74 (t, J = 8.0 Hz,
1H), 7.38−7.55 (m, 6H), 7.32−7.37 (m, 2H), 4.38−4.53 (m, 2H),
1.37 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 182.3, 164.0,
162.9, 159.1, 148.2, 143.1, 142.4, 137.3, 135.7, 132.7, 130.9, 129.8,
129.5, 129.43, 129.37, 129.1, 128.2, 127.5, 125.9, 125.4, 75.9, 64.2,
14.1; IR (KBr) ν/cm−1 3130, 3093, 2987, 1798, 1739, 1642, 1613,
1585, 1562, 1532, 1491, 1382, 1352, 1339, 1267, 1230, 1186, 1167,
1097, 1050, 975, 906, 848, 764, 745, 714, 689, 620; Q-TOF-MS
(+ESI) calcd for C27H19N3NaO7 [M + Na]+ 520.1121, found
520.1130.
1
11: colorless solid, 99 mg, 45%, mp 127−128 °C; H NMR (300
MHz, CDCl3) δ 8.09 (dd, J = 7.6 Hz, 2H), 7.63 (tt, J = 7.4, 1.3 Hz,
1H), 7.35−7.52 (m, 10H), 7.10−7.1414 (m, 2H), 5.71 (d, J = 4.4 Hz,
1H), 5.06 (d, J = 4.4 Hz, 1H), 3.92 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 192.7, 167.0, 166.1, 163.4, 134.5, 133.4, 132.8, 131.3, 129.7,
129.44, 129.36, 129.13, 129.06, 127.6, 125.6, 74.9, 68.9, 54.3, 50.2; IR
(KBr) ν/cm−1 3064, 2960, 1791, 1743, 1722, 1594, 1494, 1449, 1385,
1290, 1234, 1166, 1118, 1050, 1019, 928, 832, 769, 721, 705, 687, 665,
640, 581, 542 485; Q-TOF-MS (+ESI) calcd for C26H20N2NaO5 [M +
Na]+ 463.1270, found 463.1264.
1
1
9k: yellow solid, 61 mg, 25%, mp 211−212 °C; H NMR (300
12: yellow solid, 101 mg, 46%, mp 196−197 °C; H NMR (300
MHz, CDCl3) δ 8.75 (ddd, J = 4.7, 1.6, 0.9 Hz, 1H), 8.14 (dt, J = 7.8,
1.0 Hz, 1H), 7.97 (d, J = 9.1 Hz, 2H), 7.90 (td, J = 7.2, 1.7 Hz, 1H),
7.50 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.38−7.48 (m, 3H), 7.33−7.37
(m, 2H), 6.93 (d, J = 9.1, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H),
1.31 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 183.8, 165.1,
163.2, 162.6, 159.5, 153.4, 149.5, 142.0, 141.1, 137.0, 131.8, 131.2,
129.3, 129.2, 127.3, 126.0, 124.7, 121.1, 114.3, 75.8, 63.8, 55.6, 14.0; IR
(KBr) ν/cm−1 3069, 2982, 2937, 1793, 1753, 1724, 1651, 1600, 1510,
1384, 1266, 1187, 1144, 1097, 1050, 1018, 940, 844, 746, 717, 695,
666, 630, 500; Q-TOF-MS (+ESI) calcd for C27H21N3NaO6 [M +
Na]+ 506.1328, found 506.1319.
MHz, CDCl3) δ 8.30 (d, J = 7.3 Hz, 2H), 7.99−8.04 (m, 2H), 7.65 (tt,
J = 7.4, 1.3 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.39−7.49 (m, 6H),
7.33−7.38 (m, 2H), 3.96 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
184.5, 164.5, 163.8, 158.8, 144.6, 140.0, 135.9, 134.3, 131.9, 131.0,
130.3, 129.3, 129.1, 129.0, 128.8, 128.7, 127.8, 126.0, 75.5, 54.4; IR
(KBr) ν/cm−1 3066, 2956, 1797, 1756, 1736, 1642, 1598, 1569, 1491,
1448, 1380, 1342, 1272, 1230, 1185, 1148, 1094, 1043, 971, 898, 784,
751, 708, 687, 630, 595, 468; Q-TOF-MS (+ESI) calcd for
C26H18N2NaO5 [M + Na]+ 461.1113, found 461.1120.
Ring-Opening Reaction of 8a with EtOH. A mixture of 8a (45.4
mg, 0.1 mmol) and K2CO3 (2.8 mg, 0.02 mmol) was stirred in 2 mL of
EtOH until the disappearance of 8a. A 15 mL portion of water was
added, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The
organic layers were combined, dried (MgSO4), and concentrated. The
residue was purified on a silica gel column (petroleum ether/ethyl
acetate, 10/1) to afford the desired product 13 (36 mg, 72%): white
9l: yellow solid, 57 mg, 25%, mp 171−172 °C; 1H NMR (300 MHz,
CDCl3) δ 8.24 (d, J = 8.3 Hz, 2H), 7.65 (dd, J = 1.8, 0.7 Hz, 1H), 7.56
(dd, J = 3.6, 0.7 Hz, 1H), 7.38−7.48 (m, 3H), 7.34−7.38 (m, 2H),
7.31 (d, J = 8.2 Hz, 2H), 6.60 (dd, J = 3.6, 1.7 Hz, 1H), 4.36−4.51 (m,
2H), 2.43 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 182.7, 164.1, 162.9, 159.2, 146.8, 145.3, 144.2, 140.6, 133.1,
131.1, 130.4, 129.31, 129.30, 128.5, 126.0, 118.8, 113.2, 74.5, 63.9,
22.1, 14.1; IR (KBr) ν/cm−1 3148, 3070, 2980, 2925, 1795, 1758,
1733, 1651, 1609, 1499, 1375, 1323, 1271, 1183, 1140, 1051, 961, 754,
746, 691, 590, 553, 477; Q-TOF-MS (+ESI) calcd for C26H20N2NaO6
[M + Na]+ 479.1219, found 479.1226.
1
solid, mp 86−87 °C; H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H,
NH), 7.97 (d, J = 7.3 Hz, 2H), 7.53 (tt, J = 7.4, 1.3 Hz, 1H), 7.32−
7.46 (m, 9H), 7.27 (t, J = 7.5 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.16
(d, J = 7.9 Hz, 1H), 4.43−4.59 (m, 3H), 3.82 (q, J = 7.1 Hz, 2H), 1.47
(t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 195.6, 170.0, 165.9, 155.8, 138.6, 134.9, 133.9, 133.1, 129.0,
128.92, 128.89, 128.84, 128.78, 123.1, 119.4, 77.0, 63.7, 62.8, 61.4,
46.3, 14.2, 13.7; IR (KBr) ν/cm−1 3328, 3064, 2972, 2938, 2869, 1750,
1
9m: yellow solid, 46 mg, 21%, mp 100−101 °C; H NMR (300
MHz, CDCl3) δ 8.23−8.27 (m, 2H), 7.90−7.94 (m, 2H), 7.65 (tt, J =
4338
dx.doi.org/10.1021/jo400181r | J. Org. Chem. 2013, 78, 4329−4340

The Journal of Organic Chemistry
Article
1718, 1700, 1690, 1598, 1549, 1499, 1447, 1369, 1330, 1317, 1302,
1255, 1219, 1181, 1166, 1048, 1013, 849, 760, 696, 663, 632, 522, 504;
Q-TOF-MS (+ESI) calcd for C29H28N2NaO6 [M + Na]+ 523.1845,
found 523.1836.
with anhydrous Na2SO4. Removing the solvent and then purifying on a
silica gel column gave the product 13 (175 mg, 35%).
ASSOCIATED CONTENT
* Supporting Information
■
Ring-Opening Reaction of 8a with n-Butylamine. A mixture of
8a (45.4 mg, 0.1 mmol) and BunNH2 (36.5 mg, 0.5 mmol) was stirred
in 1 mL of dry THF for 4.5 h. The solvent was removed in vacuo, and
the residue was purified on a silica gel column (petroleum ether/ethyl
acetate, 6/1) to afford the desired product 14 (48 mg, 86%): white
S
Figures giving NMR spectra of the products and figures and
CIF files giving the structures and crystallgraphic data for 8d,
9h, and 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
solid, mp 64−65 °C; H NMR (300 MHz, CDCl3) δ 9.03 (br, 1H,
NH), 8.42 (t, J = 5.6 Hz, 1H, NH), 7.72 (d, J = 7.8 Hz, 2H), 7.50 (t, J
= 7.3 Hz, 1H), 7.47 (d, J = 7.0 Hz, 2H), 7.20−7.31 (m, 5H), 7.14 (t, J
= 7.7 Hz, 2H), 7.06 (d, J = 7.6 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 5.93
(d, J = 8.3 Hz, 1H), 4.82 (br, 1H, NH), 4.00 (d, J = 8.2 Hz, 1H),
3.21−3.46 (m, 4H), 1.48−1.66 (m, 4H), 1.30−1.44 (m, 4H), 0.95 (t, J
= 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
196.8, 171.5, 162.5, 158.9, 136.7, 134.3, 133.3, 132.7, 129.1, 128.9,
128.8, 128.7, 128.5, 124.5, 120.5, 76.1, 65.5, 50.2, 40.5, 39.6, 32.1, 31.3,
20.10, 20.06, 13.9, 13.8; IR (KBr) ν/cm−1 3344, 3062, 2958, 2931,
2872, 1697, 1654, 1597, 1539, 1499, 1447, 1368, 1313, 1223, 1178,
1079, 970, 754, 692, 506; Q-TOF-MS (+ESI) calcd for
C33H38N4NaO4 [M + Na]+ 577.2791, found 577.2785.
Ring-Opening Reaction of 8a with Morpholine. A mixture of
8a (45.4 mg, 0.1 mmol) and morpholine (43.5 mg, 0.5 mmol) was
stirred in 1 mL of dry THF at room temperature for 13 h. The solvent
was removed in vacuo, and the residue was purified on a silica gel
column (petroleum ether/ethyl acetate, 3/1) to afford the desired
product 15 (28 mg, 52%): white solid, mp 85−86 °C; 1H NMR (300
MHz, CDCl3) δ 8.94 (br, 1H, NH), 7.80 (d, J = 7.3 Hz, 2H), 7.54 (t, J
= 7.4 Hz, 1H), 7.30−7.45 (m, 7H), 7.20 (t, J = 7.8 Hz, 2H), 7.06 (d, J
= 7.4 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.00 (d, J = 6.2 Hz, 1H),
4.32−4.48 (m, 2H), 4.07 (d, J = 6.3 Hz, 1H), 3.62−3.74 (m, 4H),
3.45−3.52 (m, 2H), 3.34−3.42 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 194.3, 171.4, 163.3, 158.6, 137.0, 134.6,
134.0, 133.7, 129.0, 129.02, 128.97, 128.91, 128.8, 128.7, 128.6, 124.7,
120.6, 76.0, 69.5, 66.5, 63.1, 49.9, 44.6, 14.0; IR (KBr) ν/cm−1 3327,
3060, 2964, 2922, 2857, 1738, 1698, 1634, 1597, 1541, 1499, 1445,
1430, 1304, 1282, 1226, 1116, 1050, 968, 851, 756, 694, 560, 507; Q-
TOF-MS (+ESI) calcd for C31H31N3NaO6 [M + Na]+ 564.2111,
found 564.2120.
AUTHOR INFORMATION
Corresponding Author
*E-mail: estally898@yahoo.com.cn (C.-B.M.); chemsxq@
yahoo.com.cn (X.-Q.S.),
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 20902039 and 21202011)
and the Priority Academic Program Development of Jiangsu
Higher Education Institutions.
REFERENCES
■
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64 h. A 15 mL portion of water was added, and the mixture was
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1
product 16 (40 mg, 74%): white solid, mp 179−180 °C; H NMR
(300 MHz, CDCl3) δ 7.97 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.3 Hz,
1H), 7.32−7.49 (m, 7H), 7.26−7.31 (m, 3H), 6.73 (br, 1H, NH),
6.67−6.70 (m, 2H), 4.88 (d, J = 10.0 Hz, 1H), 4.60 (d, J = 10.0 Hz,
1H), 4.11−4.26 (m, 2H), 2.25 (t, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz,
3H), 1.07−1.26 (m, 4H), 0.73 (t, J = 7.1 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 191.5, 166.8, 166.0, 156.4, 135.7, 134.6, 133.2, 130.8,
130.7, 129.1, 128.8, 128.7, 128.6, 128.4, 126.5, 70.9, 63.9, 50.3, 47.8,
30.3, 29.3, 21.9, 13.8, 13.6; IR (KBr) ν/cm−1 3235, 3120, 2960, 2928,
2856, 1790, 1724, 1673, 1596, 1495, 1421, 1262, 1250, 1224, 1195,
1113, 1041, 977, 881, 754, 694, 660, 573, 511; Q-TOF-MS (+ESI)
calcd for C31H32N2NaO5S [M + Na]+ 567.1930, found 567.1937.
Cyclization of 6a with I2/K2CO3 in EtOH for the Preparation
of 13. A mixture of chalcone 2a (218.4 mg, 1.05 mmol), 5a (294 mg,
1.0 mmol), and K2CO3 (6.9 mg, 0.05 mmol) was stirred in 6 mL of
absolute EtOH at room temperature until the disappearance of 5a.
Then K2CO3 (552 mg, 4 mmol) and 10 mL of EtOH were added. The
mixture was cooled to 0 °C, and a solution of I2 (508 mg, 2 mmol) in
10 mL of EtOH was added dropwise over 1 h. After that, the mixture
was stirred for another 5.5 h. Most of the solvent was removed in
vacuo, and 20 mL of water was added. The mixture was extracted with
CH2Cl2 (3 × 15 mL), and the combined organic layers were dried
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4339
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