Tin Powder-Promoted One-Pot Construction of α-Methylene-γ-lactams and Spirolactams from Aldehydes or Ketones, Acylhydrazines, and 2-(Bromomethyl)acrylate

Article abstract of DOI:10.1021/acs.joc.5b02154

A concise and efficient method for the synthesis of α-methylene-γ-lactams is developed from multicomponent one-pot reactions of aldehydes or ketones, hydrazides, and ethyl 2-(bromomethyl)acrylate promoted by tin powder. The reaction proceeds smoothly under mild reaction conditions without using any catalyst to give the corresponding products in high yields. α-Methylene-γ-spirolactams can also be prepared from cyclic ketones.

Full text of DOI:10.1021/acs.joc.5b02154

Article
pubs.acs.org/joc
Tin Powder-Promoted One-Pot Construction of α‑Methylene-γ-
lactams and Spirolactams from Aldehydes or Ketones,
Acylhydrazines, and 2‑(Bromomethyl)acrylate
Yanli Xu,† Danfeng Huang,*,† Ke-Hu Wang,† Junyan Ma,† Yingpeng Su,† Ying Fu,† and Yulai Hu*,†,‡
†College of Chemistry and Chemical Engineering, Northwest Normal University, 967 Anning East Road, Lanzhou 730070, P. R.
China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: A concise and efficient method for the synthesis
of α-methylene-γ-lactams is developed from multicomponent
one-pot reactions of aldehydes or ketones, hydrazides, and
ethyl 2-(bromomethyl)acrylate promoted by tin powder. The
reaction proceeds smoothly under mild reaction conditions
without using any catalyst to give the corresponding products
in high yields. α-Methylene-γ-spirolactams can also be
prepared from cyclic ketones.
We found that one-pot reactions of aldehydes or ketones,
acylhydrazine, 2-(bromomethyl)acrylic esters, and tin powder
will give α-methylene-γ-lactams in good yields. In particular, α-
methylene-γ-spirolactams12 can be also obtained from cyclic
ketones. Herein, we report a concise method for the
construction of α-methylene-γ-lactams and α-methylene-γ-
spirolactams (Scheme 1).
INTRODUCTION
■
α-Methylene-γ-lactam units are important scaffolds found in
some biologically active molecules and natural products (Figure
1).1−3 Compared with their isosteric α-methylene-γ-lactones, α-
methylene-γ-lactams display much lower toxic side effects while
maintaining similar bioactivities in antibacterial, antiinflamma-
tory, antianaphylactic, and anticancer properties.2 They are also
versatile building blocks in organic synthesis. Thus, the
development of appropriate synthetic strategies for obtaining
these frameworks has received much attention over the past
several decades.3 For instance, intramolecular Baylis−Hillman
reactions,4 Baylis−Hillman alcohols and their derivatives as
precursors,5 addition of the allylic organometallic reagents to
the imines,6 Wittig or Horner−Wadsworth−Emmons reactions
of functionalized α-(dialkoxyphosphoryl)-substituted lactams
with carbonyl compounds,2f,g,7 and radical chemistry8 were the
major approaches to obtaining α-methylene-γ-lactam moieties.
Among these methodologies, addition of the allylic organo-
metallic reagents to the imines is a fascinating method for
producing α-methylene-γ-lactams. Metals such as zinc5c,6b−d,9
and indium6e successfully promoted the addition of 2-
(bromomethyl)acrylic acid or esters to aldimines to give the
desired products. The allylboration of aldimines with 2-
(alkoxycarbonyl)-allylboronates represents another facile route
to α-methylene-γ-lactams.10 However, additions of these
reagents to ketimines have never been reported. In our
research group, we are interested in metal tin-mediated organic
reactions recently because organotin compounds usually display
good stability toward heat, hydrolysis, and oxidation, tolerance
to functional groups, and high selectivity in organic reactions.11
RESULTS AND DISCUSSION
■
In our initial investigations, the reactivity of N-acylhydrazones
generated in situ was first examined (Table 1). Benzaldehyde
(1a, 1 equiv) and benzoylhydrazine (2a, 1 equiv) were stirred
at room temperature in ethanol for 3 h to form the
corresponding N-benzoylhydrazone (3a) first, and then 2-
(bromomethyl)acrylic ester (4, 1 equiv) and tin powder (1
equiv) were added. After the mixture had been stirred for an
additional 8 h at room temperature, there was no desired
product α-methylene-γ-lactam (5a) formed. Only N-benzoylhy-
drazone (3a) was recovered in 81% yield (Table 1, entry 1).
Considering the lower reactivity of metal tin, the reaction was
conducted again under reflux. To our delight, the reaction
occurred to afford the desired product 5a in 20% yield (Table
1, entry 2). To improve the yield, the reaction conditions were
optimized (Table 1). The molar ratio of the substrates was
examined first and found to influence the product yields greatly
(Table 1, entries 2−10). In particular, a slight excess of tin was
beneficial to the reaction. After careful optimization, 1 equiv of
Received: September 14, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.joc.5b02154
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Figure 1. Natural products and biologically active molecules with an α-methylene-γ-lactam moiety.
Scheme 1. Tin Powder-Promoted One-Pot Reactions for the Construction of α-Methylene-γ-lactams and α-Methylene-γ-
spirolactams
a
Table 1. Optimization of Reaction Conditions
5a could not be obtained in THF, which was usually the best
solvent in other reactions that include metal. This indicated the
different behavior of tin with other metals in organic reactions.
Under the optimized reaction conditions, the generality of
substrates was checked next. Different aldehydes or ketones
were reacted with benzoylhydrazine (Table 2). As shown in
Table 2, most of the aromatic and aliphatic aldehydes would
give the α-methylene-γ-lactams in good yields. However, the
substituents on the phenyl ring of aromatic aldehydes had some
influence on the yields. The aldehydes bearing an electron-
withdrawing group on their phenyl rings usually gave the
corresponding products in yields higher than that with electron-
donating groups (Table 2, 5a−c vs 5g, 5h, and 5j). The reason
was that the electron-withdrawing groups on the phenyl rings
of aromatic aldehydes could increase the eletrophilicity of
hydrazones (3) by an inductive effect. The position of
substituents on the phenyl ring also affected the results. For
instance, o-chlorobenzadehyde gave yields lower than that of
the p-chlorobenzaldehyde or m-chlorobenzaldehyde because of
steric hindrance (Table 2, 5e−g). The aromatic aldehydes
bearing amino, nitro, and hydroxyl groups on the phenyl ring
could not afford the products (Table 2, 5d, 5i, and 5l). Some
less sterically hindered aliphalic ketones such as acetone or
butan-2-one could produce the products in good yields (Table
2, 5r and 5s), but aromatic ketones or sterically hindered
aliphatic ketones did not afford the products (Table 2, 5t−v).
In the investigations described above, N-acylhydrazones were
generated in situ first and then reacted with 2-(bromomethyl)-
acrylic ester and metal tin to produce the products in a cascade
process. After the investigations mentioned above, it was clear
that N-acylhydrazones were active enough to react with 2-
(bromomethyl)acrylic ester and metal tin to give the desired
products. Following these results, we just wondered if the one-
pot reactions could also give the same results without
preformation of N-acylhydrazones. Thus, benzaldehyde 1a,
benzoylhydrazine 2a, 2-(bromomethyl)acrylic ester 4, and tin
powder were put into a flask simultaneously and then stirred
and refluxed in ethanol. To our delight, the reaction occurred,
and product 5a was obtained in 76% yield after 10 h (Scheme
entry
1a:2a:4:Sn mole ratio
solvent
EtOH
time (h)
yield (%)
b
1
1:1:1:1
11
6
6
6
7
6
6
7
6
6
7
9
9
8
7
8
0
2
1:1:1:1
EtOH
20
41
47
54
56
55
62
63
73
67
43
40
52
48
55
trace
3
1:1:1:1.5
EtOH
4
1:1:1:2
EtOH
5
1:1.2:1.5:1.5
1:1.2:1.5:2
1:1.2:2:2
EtOH
6
EtOH
7
EtOH
8
1:1.2:2:2.5
1:1.2:3:2.5
1:1.2:3:3.5
1:1.2:3:3.5
1:1.2:3:3.5
1:1.2:3:3.5
1:1.2:3:3.5
1:1.2:3:3.5
1:1.2:3:3.5
1:1.2:3:3.5
EtOH
9
EtOH
10
11
12
13
14
15
16
17
EtOH
MeOH
1,4-Dioxane
ethyl acetate
CHCl3
CH2Cl2
toluene
THF
10
a
b
The reaction was conducted under reflux. The reaction was
conducted at room temperature, and N-benzoylhydrazone (3a) was
obtained in 81% yield.
benzaldehyde, 1.2 equiv of benzoylhydrazine, 3.0 equiv of 2-
(bromomethyl)acrylic ester, and 3.5 equiv of tin were
determined to give the best molar ratio with an increase in
product yield to 73% (Table 1, entry 10). Next, effects of
solvent on the reaction were screened (Table 1, entries 10−17).
Protic solvents such as ethanol and methanol were found to be
the suitable solvents. The reactions in aprotic solvent such as
1,4-dioxane, ethyl acetate, chloroform, dichloromethane, and
toluene gave the products in low yields; in particular, product
B
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a
Table 2. Reaction of Different Aldehydes or Ketones for the Synthesis of α-Methylene-γ-lactam
a
Aldehydes 1a−q (0.5 mmol) and benzoyl hydrazine 2a (0.6 mmol) or ketones 1r−v (0.5 mmol) and benzoyl hydrazine 2a (0.75 mmol) were
refluxed in EtOH to generate hydrazone 3 monitored by analytical thin layer chromatography, and then tin powder (1.75 mmol) and ethyl 2-
(bromomethyl)acrylate 4 (1.5 mmol) were added under reflux. Isolated yields.
2). This result was almost the same as the result of the cascade
process described above. Therefore, the one-pot process was
checked again with different aldehydes and acylhydrazines. The
results are summarized in Table 3.
It was shown that both aromatic and aliphatic aldehydes
could react with different aromatic acylhydrazines to afford the
corresponding α-methylene-γ-lactams in good to excellent
yields. The electron-withdrawing groups on both of the phenyl
ring of aromatic aldehydes and acylhydrazines could increase
the yields of α-methylene-γ-lactams (Table 3, 5ad−f).
However, when the groups on aromatic rings of both aldehydes
and acylhydrazines were electron-donating groups, the yield of
the products would be lower (Table 3, 5ag). An acyclic
aliphatic ketone such as acetone could also be used in the
reaction to give γ,γ-disubstituted α-methylene-γ-lactams (Table
3, 5an and 5ao). Finally, it was found that the products could
C
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Scheme 2. One-Pot Reaction among 1a, 2a, 4, and Tin Powder
a
Table 3. One-Pot Reaction of Different Carbonyl Compounds with Hydrazides for the Synthesis of α-Methylene-γ-lactams
a
Aldehydes 1 (0.5 mmol) and acylhydrazines 2aa−m (0.6 mmol) or ketones 1 (0.5 mmol) and acylhydrazine 2an−p (0.75 mmol), tin powder (1.75
mmol), and ethyl 2-(bromomethyl)acrylate 4 (1.5 mmol) were refluxed in EtOH (5 mL) under one-pot conditions. Isolated yields.
not be obtained if acyclic aliphatic acylhydrazines were used
(Table 3, 5aj, 5ak, and 5ap).
In the investigation described above, we noticed that some
acyclic aliphatic ketones could be used as substrates to produce
the corresponding γ,γ-disubstituted α-methylene-γ-lactams. We
just wondered if the cyclic ketones could be used in the same
reactions to produce the α-methylene-γ-spirolactams. Thus,
cyclopentanone was tested as a substrate in the reaction
described above. To our delight, the reaction occurred to give
α-methylene-γ-spirolactam 7b in 90% yield (Table 4, 7b).
Afterward, different cyclic ketones were examined, and the
results are summarized in Table 4. It was shown that cyclic
D
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a
Table 4. One-Pot Reactions of Different Cyclic Ketones and Hydrazides for the Synthesis of α-Methylene-γ-spirolactams
a
Cyclic ketones 6 (0.5 mmol) and hydrazines 2 (0.75 mmol), tin powder (1.75 mmol), and ethyl 2-(bromomethyl)acrylate 4 (1.5 mmol) were
refluxed in EtOH (6 mL) under one-pot conditions. Isolated yields.
ketones from small ring cyclobutanone to middle ring
cycloheptanone could react with benzoyl hydrazine and 2-
(bromomethyl)acrylic ester in the presence of tin powder to
afford the corresponding α-methylene-γ-spirolactams 7 in high
yields (Table 4, 7a−d). With the growing size of the cyclic
ketone ring, the yield of the products decreased. For instance,
when cycloheptanone was used, the yield of product 7d was
decreased to 58% (Table 4, 7d). If cyclooctanone was used,
there was no product formed (Table 4, 7e). We also found the
position of substituents on cyclohexanone greatly influenced
the reaction. For example, 2-methylcyclohexanone did not
produce the product, but 3-methylcyclohexanone and 4-
methylcyclohexanone afforded the products in good yields
(Table 4, 7f−h). Furthermore, different kinds of hydrazides
also affected the reactions. All of the aromatic hydrazides,
including heteroaromatic hydrazides such as furan-2-carbohy-
drazide, could be used to give the products in good to excellent
yields. However, aliphatic hydrazides such as acetylhydrazide
could not produce the product (Table 4, 7o). In addition, 1,3-
cyclohexanedione or unsaturated cyclic ketones such as 2-
cyclohexenone, 1-indanone, and 1-tetralone could not produce
the α-methylene-γ-spirolactams (Table 4, 7p−t).
Finally, a possible mechanism was proposed on the basis of
the literature11 and experimental results (Scheme 3). First, N-
acylhydrazones 3 were formed from aldehydes 1 and hydrazides
2 because product 5a could also be obtained in 70% yield if N′-
benzylidenebenzohydrazide 3a was used as a substrate (Scheme
4). Intermediate 8, which is in equilibrium with intermediate
9,11a was generated from 2-(bromomethyl)acrylic ester 4 and
tin metal. Afterward, the intermediate 8 would react with N-
acylhydrazones 3 to give intermediate 10, which was then
cyclized to afford product 5. N-Acylhydrazones 3 were more
reactive than aldehydes 1 because the allylic alcohol products
from aldehydes 1 and intermidate 8 were not obtained in the
reaction. Furthermore, when an equal amount of benzaldehyde
1a and N′-benzylidenebenzohydrazide 3a were mixed together
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recorded as follows: chemical shift in parts per million from internal
tetramethylsilane on the δ scale, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad), coupling constant (hertz),
integration, and assignment. 13C NMR spectra were measured on 150
MHz (5n, 5aa−f, 5ai−o, 7a, 7g, 7i, 7j, and 7l−n) and 100 MHz (5a−
m, 5o−s, 5ag, 5ah, 7b−d, 7h, and 7k) spectrometers. Chemical shifts
were recorded in parts per million from the solvent resonance
employed as the internal standard (deuterochloroform at 77.0 ppm).
The solvents were distilled by standard methods. Reagents were
obtained from commercial suppliers and used without further
purification unless otherwise noted.
Scheme 3. Proposed Mechanism
General Experimental Procedures for the Synthesis of
Compounds 5 and 7. Cascade Reactions of Carbonyl Compounds
for the Synthesis of α-Methylene-γ-lactams 5a−v Promoted by Tin
Powder. Aldehydes 1 (0.5 mmol, 1 equiv) and benzoyl hydrazine 2
(0.6 mmol, 1.2 equiv) or ketones 1 (0.5 mmol, 1 equiv) and benzoyl
hydrazine 2 (0.75 mmol, 1.5 equiv) were put into a dried round-
bottom flask (50 mL) fitted with a magnetic bar. Ethanol (3 mL) was
then added. The mixture was stirred under reflux, and the reaction
process was monitored by TLC. After formation of benzoyl hydrazone,
tin powder (1.75 mmol, 3.5 equiv) and ethyl 2-(bromomethyl)acrylate
4 (1.5 mmol, 3 equiv) in 2 mL of ethanol were added to the flask. The
resulting mixture was stirred under reflux for 6−13 h. The reaction
mixture was cooled to room temperature, and ethanol was removed
under vacuum. The saturated NH4Cl solution (10 mL) was poured
into the mixture and stirred for 10 min. The mixture was extracted
with EtOAc (3 × 10 mL). The combined organic phases were dried
(MgSO4) and concentrated. Purification of the residue by silica gel
column chromatography using hexane and EtOAc (1:1) as the eluent
furnished the pure products.
Scheme 4. Reaction Using Hydrazone as a Substrate
One-Pot Synthesis of α-Methylene-γ-lactams (5aa−m) from
Aldehydes Promoted by Tin Powder. Aldehydes 1 (0.5 mmol, 1
equiv), acylhydrazines 2 (0.6 mmol, 1.2 equiv), tin powder (1.75
mmol, 3.5 equiv), and ethyl 2-(bromomethyl)acrylate 4 (1.5 mmol, 3
equiv) were placed in a dried round-bottom flask (50 mL) fitted with a
magnetic bar. Ethanol (5 mL) was then added. The mixture was stirred
under reflux for 6−13 h. The reaction mixture was cooled to room
temperature, and ethanol was removed under vacuum. The saturated
NH4Cl solution (10 mL) was poured into the mixture and stirred for
10 min. The mixture was extracted with EtOAc (3 × 10 mL). The
combined organic phases were dried (MgSO4) and concentrated.
Purification of the residue by silica gel column chromatography using
hexane and EtOAc (1:1) as the eluent furnished the pure products.
One-Pot Synthesis of γ,γ-Disubstituted α-Methylene-γ-lactams
(5ao and 5ap) and α-Methylene-γ-spirolactams (7a−t) from
Ketones Promoted by Tin Powder. Ketones 1 (0.5 mmol, 1 equiv),
acylhydrazines 2 (0.75 mmol, 1.5 equiv), tin powder (1.75 mmol, 3.5
equiv), and ethyl 2-(bromomethyl)acrylate 4 (1.5 mmol, 3 equiv) were
placed in a dried round-bottom flask (50 mL) fitted with a magnetic
bar. Ethanol (6 mL) was then added. The mixture was stirred under
reflux for 6−13 h. The reaction mixture was cooled to room
temperature, and ethanol was removed under vacuum. The saturated
NH4Cl solution (10 mL) was poured into the mixture and stirred for
10 min. The mixture was extracted with EtOAc (3 × 10 mL). The
combined organic phases were dried (MgSO4) and concentrated.
Purification of the residue by silica gel column chromatography using
hexane and EtOAc (1:1) as the eluent furnished the pure products.
N-(3-Methylene-2-oxo-5-phenylpyrrolidin-1-yl)benzamide 5a.
White solid (115 mg, 73% yield): mp 118−120 °C; IR (KBr) ν
3188, 2992, 1713, 1677, 1525, 1402, 1272 cm−1; 1H NMR (400 MHz,
and then reacted with 2-(bromomethyl)acrylic ester 4 in the
presence of tin powder under standard conditions, only product
5a from N′-benzylidenebenzohydrazide 3a was obtained in 59%
yield, and no product from benzaldehyde 1a was detected
(Scheme 5).
In conclusion, a novel method for the construction of α-
methylene-γ-lactams is developed from multicomponent one-
pot reactions of aldehydes or ketones, hydrazides, and ethyl 2-
(bromomethyl)acrylate promoted by tin powder without using
any transition metal catalysts. In particular, α-methylene-γ-
spirolactams can also be obtained from cyclic ketones in good
yields. This strategy is highly efficient with easy operation.
EXPERIMENTAL SECTION
■
General Methods. Flash chromatography was performed using
silica gel 60 (230−400 mesh). Analytical thin layer chromatography
(TLC) was conducted using silica gel GF254. TLC plates were
analyzed by an exposure to ultraviolet (UV) light and/or submersion
in a phosphomolybdic acid solution or in I2. IR spectral absorption
frequencies are reported in reciprocal centimeters. High-resolution
mass spectra were recorded on a transform ion cyclotron resonance
1
mass spectrometer. H NMR spectra were measured on 600 MHz
(5aa−f, 5ah−m, 5ao, 7g, 7i, 7j, 7l, and 7m) and 400 MHz (5a−s, 5ag,
5an, 7a−d, 7h, 7k, and 7n) spectrometers. Chemical shifts were
Scheme 5. Competitive Reactions between 1a and 3a
F
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CDCl3) δ 10.08 (s, 1H), 7.60−7.58 (m, 2H), 7.36−7.24 (m, 6H),
7.18−7.15 (m, 2H), 6.20 (s, 1H), 5.53 (s, 1H), 5.22 (dd, J = 8.4, 4.8
Hz, 1H), 3.41 (dd, J = 17.2, 8.4 Hz, 1H), 2.76 (dt, J = 17.2, 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 167.7, 165.6, 140.0, 136.4,
132.0, 131.1, 129.1, 128.5, 128.4, 127.5, 126.8, 118.6, 60.5, 34.3;
HRMS (ESI) calcd for C18H16N2O2 [M + H]+ 293.1285, found
293.1294.
N-[3-Methylene-2-oxo-5-(p-tolyl)pyrrolidin-1-yl]benzamide 5b.
White solid (120 mg, 76% yield): mp 240−241 °C dec; IR (KBr) ν
3238, 2970, 2912, 1705, 1654, 1510, 1394, 1271 cm−1; 1H NMR (400
MHz, CDCl3) δ 9.93 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 8.0
Hz, 1H), 7.10−7.06 (m, 6H), 6.10 (s, 1H), 5.44 (s, 1H), 5.11−5.09
(m, 1H), 3.31 (dd, J = 17.2, 8.0 Hz, 1H), 2.66 (d, J = 17.2 Hz, 1H),
2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 165.6, 138.2,
136.9, 136.6, 132.0, 131.1, 129.7, 128.3, 127.5, 126.8, 118.4, 60.3, 34.3,
21.3; HRMS (ESI) calcd for C19H18N2O2 [M + H]+ 307.1441, found
307.1438.
J = 8.0 Hz, 2H), 7.33−7.26 (m, 3H), 7.12−7.08 (m, 2H), 6.15 (s, 1H),
5.53 (s, 1H), 5.25 (t, J = 4.0 Hz, 1H), 3.39 (dd, J = 17.2, 8.8 Hz, 1H),
2.63 (d, J = 17.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.8,
165.6, 145.3, 135.5, 132.9, 132.4, 130.6, 128.5, 127.6, 127.5, 119.4,
118.5, 112.5, 60.1, 33.9; HRMS (ESI) calcd for C19H15N3O2 [M + H]+
318.1237, found 318.1233.
N-[3-Methylene-2-oxo-5-(thiophen-3-yl)pyrrolidin-1-yl]-
benzamide 5k. White solid (110 mg, 74% yield): mp 141−143 °C; IR
(KBr) ν 3281, 3100, 2920, 1720, 1674, 1510, 1408, 1230, 1286 cm−1;
1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.61 (d, J = 8.0 Hz,
2H), 7.35−7.30 (m, 2H), 7.25 (s, 1H), 7.20 (t, J = 7.4 Hz, 2H), 6.98
(d, J = 4.0 Hz, 1H), 6.17 (s, 1H), 5.52 (s, 1H), 5.33 (dd, J = 8.4, 4.4
Hz, 1H), 3.37 (dd, J = 17.2, 8.4 Hz, 1H), 2.78 (dd, J = 17.2, 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 167.3, 165.6, 140.9, 136.2,
132.1, 131.0, 128.4, 127.5, 127.1, 125.5, 123.1, 118.7, 56.1, 33.5;
HRMS (ESI) calcd for C16H14N2O2S [M + H]+ 299.0849, found
299.0845.
N-(5-Isopropyl-3-methylene-2-oxopyrrolidin-1-yl)benzamide 5m.
White solid (108 mg, 84% yield): mp 136−139 °C; IR (KBr) ν 3216,
2596, 1720, 1654, 1516, 1416, 1278 cm−1; 1H NMR (400 MHz,
CDCl3) δ 10.77 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.36−7.33 (m, 1H),
7.22−7.19 (m, 2H), 6.05 (s, 1H), 5.43 (s, 1H), 4.10 (t, J = 4.0 Hz,
1H), 2.87 (dd, J = 17.2, 8.4 Hz, 1H), 2.58 (dd, J = 17.2, 2.0 Hz, 1H),
2.19−2.12 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 168.0, 165.6, 137.4, 132.0, 131.0,
128.4, 127.6, 117.6, 60.8. 28.7, 25.0, 18.1, 14.5; HRMS (ESI) calcd for
C15H18N2O2 [M + H]+ 259.1441, found 259.1441.
N-[5-(4-Methoxyphenyl)-3-methylene-2-oxopyrrolidin-1-yl]-
benzamide 5c. White solid (109 mg, 69% yield): mp 92−93 °C; IR
(KBr) ν 3230, 3006, 2839, 1712, 1668, 1610, 1509, 1401, 1235, 1183
1
cm−1; H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 7.60 (d, J = 8.0
Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.21−7.16 (m, 4H), 6.86 (d, J = 8.4
Hz, 2H), 6.18 (s, 1H), 5.52 (s, 1H), 5.16 (dd, J = 8.4, 4.8 Hz, 1H),
3.78 (s, 3H), 3.37 (dd, J = 17.2, 8.4 Hz, 1H), 2.77−2.72 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 167.4, 165.7, 159.8, 136.6, 132.1, 131.8,
131.2, 128.4, 128.2, 127.5, 118.4, 114.4, 60.0, 55.4, 34.3; HRMS (ESI)
calcd for C19H18N2O3 [M + H]+ 323.1390, found 323.1387.
N-(3-Methylene-2-oxo-5-propylpyrrolidin-1-yl)benzamide 5n.
Colorless syrup (102 mg, 79% yield): IR (neat) ν 3245, 2956, 2869,
2355, 1712, 1668, 1524, 1422, 1278 cm−1; 1H NMR (400 MHz,
CDCl3) δ 10.38 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.37 (dd,
J = 10.8, 4.0 Hz, 1H), 7.28−7.21 (m, 2H), 6.08 (s, 1H), 5.44 (s, 1H),
4.06 (s, 1H), 3.05 (dd, J = 17.2, 6.4 Hz, 1H), 2.50 (dd, J = 17.2, 2.0
Hz, 1H), 1.76 (dd, J = 15.6, 8.0 Hz, 1H), 1.44−1.25 (m, 3H), 0.92 (t, J
= 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 167.6, 165.7, 137.0,
132.1, 131.1, 128.5, 127.6, 117.9, 56.6, 35.4, 30.3, 17.7, 14.2; HRMS
(ESI) calcd for C15H18N2O2 [M + Na]+ 281.1266, found 281.1273.
N-(5-Butyl-3-methylene-2-oxopyrrolidin-1-yl)benzamide 5o. Col-
orless syrup (97 mg, 73% yield): IR (neat) ν 3224, 2927, 2854, 1726,
N-[5-(2-Chlorophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-
benzamide 5e. Colorless syrup (106 mg, 65% yield): IR (neat) ν
3238, 2999, 1705, 1668, 1516, 1278 cm−1; 1H NMR (400 MHz,
CDCl3) δ 10.56 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.43−7.20 (m, 5H),
7.17−7.14 (m, 2H), 6.24 (s, 1H), 5.65 (d, J = 4.4 Hz, 1H), 5.55 (s,
1H), 3.57 (dd, J = 16.8, 8.8 Hz, 1H), 2.70 (d, J = 16.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 168.4, 165.6, 137.6, 136.1, 133.3, 132.1,
130.9, 130.3, 129.3, 128.4, 127.6, 127.5, 119.0, 58.1, 32.7; HRMS
(ESI) calcd for C18H15ClN2O2 [M + H]+ 327.0895, found 327.0900.
N-[5-(3-Chlorophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-
benzamide 5f. White solid (162 mg, 71% yield): mp 153−155 °C; IR
1
(KBr) ν 3166, 2999, 1712, 1683, 1532, 1401, 1278 cm−1; H NMR
1
1647, 1516, 1278 cm−1; H NMR (400 MHz, CDCl3) δ 10.45 (d, J =
(400 MHz, CDCl3) δ 10.45 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.34−
7.24 (m, 4H), 7.17−7.13 (m, 3H), 6.29 (s, 1H), 5.56 (s, 1H), 5.23
(dd, J = 8.4, 4.4 Hz, 1H), 3.41 (dd, J = 17.2, 8.4 Hz, 1H), 2.75−2.69
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 167.8, 165.5, 142.2, 135.7,
135.0, 132.1, 130.7, 130.3, 128.7, 128.4, 127.5, 126.7, 125.2, 119.3,
59.9, 34.1; HRMS (ESI) calcd for C18H15ClN2O2 [M + H]+ 327.0895,
found 327.0899.
8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.23 (t,
J = 8.0 Hz, 2H), 6.08 (s, 1H), 5.43 (s, 1H), 4.05 (t, J = 4.0 Hz, 1H),
3.04 (dd, J = 16.8, 8.0 Hz, 1H), 2.50 (d, J = 16.8 Hz, 1H), 1.81−1.76
(m, 1H), 1.39−1.23 (m, 5H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 167.6, 165.6, 137.1, 132.0, 131.1, 128.4, 127.6, 117.9,
56.7, 32.9, 30.3, 26.5, 22.8, 14.1; HRMS (ESI) calcd for C16H20N2O2
[M + H]+ 273.1598, found 273.1595.
N-(3-Methylene-2-oxo-5-phenethylpyrrolidin-1-yl)benzamide 5p.
White solid (88 mg, 54% yield): mp 139−141 °C; IR (KBR) ν 3260,
3035, 2847, 1705, 1668, 1516, 1437, 1286 cm−1; 1H NMR (400 MHz,
CDCl3) δ 10.30 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.30−7.28 (m, 1H),
7.19−7.10 (m, 7H), 5.95 (s, 1H), 5.32 (s, 1H), 4.07 (d, J = 3.6 Hz,
1H), 3.00 (t, J = 8.0 Hz, 1H), 2.58−2.47 (m, 3H), 2.09−1.97 (m, 1H),
1.72 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 167.7, 165.6, 141.2,
136.7, 132.0, 130.9, 128.6, 128.4, 127.6, 126.2, 118.2, 56.4, 35.0, 30.6,
30.1; HRMS (ESI) calcd for C20H20N2O2 [M + H]+ 321.1598, found
321.1594.
(E)-N-(3-Methylene-2-oxo-5-styrylpyrrolidin-1-yl)benzamide 5q.
Colorless syrup (127 mg, 66% yield): IR (neat) ν 3252, 2978, 1712,
1662, 1510, 1401, 1278 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.98 (s,
1H), 7.68 (d, J = 8.0 Hz, 2H), 7.37−7.34 (m, 3H), 7.31−7.19 (m,
5H), 6.58 (d, J = 15.6 Hz, 1H), 6.14 (s, 1H), 6.08 (q, J = 8.0 Hz, 1H),
5.48 (s, 1H), 4.75−4.69 (m, 1H), 3.22 (dd, J = 17.2, 8.0 Hz, 1H), 2.67
(dd, J = 17.2, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.4,
165.8, 136.3, 136.1, 134.6, 132.1, 131.2, 128.7, 128.5, 128.3, 127.6,
127.5, 126.8, 118.4, 59.5, 31.8; HRMS (ESI) calcd for C20H18N2O2 [M
+ H]+ 319.1441, found 319.1437.
N-[5-(4-Chlorophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-
benzamide 5g. Colorless syrup (131 mg, 84% yield): IR (neat) ν
3238, 3064, 3020, 2984, 1712, 1668, 1532, 1480, 1401, 1271, 1083
1
cm−1; H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 7.57 (d, J = 8.0
Hz, 2H), 7.35−7.30 (m, 3H), 7.20−7.15 (m, 4H), 6.20 (s, 1H), 5.56
(s, 1H), 5.21 (dd, J = 8.0, 4.8 Hz, 1H), 3.41 (dd, J = 17.2, 8.4 Hz, 1H),
2.73−2.68 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 167.6, 165.6,
138.5, 136.1, 134.3, 132.2, 130.8, 129.3, 128.4, 128.3, 127.5, 118.9,
59.9, 34.2; HRMS (ESI) calcd for C18H15ClN2O2 [M + H]+ 327.0895,
found 327.0904.
N-{3-Methylene-2-oxo-5-[4-(trifluoromethyl)phenyl]pyrrolidin-1-
yl}benzamide 5h. Colorless syrup (160 mg, 86% yiled): IR (neat) ν
3252, 2999, 1720, 1654, 1532, 1329 cm−1; 1H NMR (400 MHz,
CDCl3) δ 10.33 (s, 1H), 7.62−7.56 (m, 4H), 7.41−7.31 (m, 3H), 7.17
(t, J = 7.6 Hz, 2H), 6.21 (s, 1H), 5.58 (s, 1H), 5.32 (dd, J = 8.0, 4.8
Hz, 1H), 3.46 (dd, J = 17.6, 8.0 Hz, 1H), 2.72 (dd, J = 17.6, 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 167.9, 165.7, 144.1, 135.8,
132.2, 130.8 (q, J = 33.0 Hz), 130.7, 128.4, 127.5, 127.2, 126.1 (q, JC,F
= 3.6 Hz), 124.1 (q, JC,F = 270.6 Hz), 119.2, 60.1, 34.1; HRMS (ESI)
calcd for C19H15F3N2O2 [M + H]+ 361.1158, found 361.1162.
N-[5-(4-Cyanophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-
benzamide 5j. White solid (148 mg, 82% yield): mp 181−183 °C; IR
N-(2,2-Dimethyl-4-methylene-5-oxopyrrolidin-1-yl)benzamide
5r. White solid (100 mg, 72% yield): mp 242−243 °C; IR (KBr) ν
3166, 2970, 1705, 1676, 1532, 1401, 1278 cm−1; 1H NMR (400 MHz,
1
(KBr) ν 3260, 3057, 2233, 1705, 1668, 1532, 1271 cm−1; H NMR
(400 MHz, CDCl3) δ 10.29 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.46 (d,
G
DOI: 10.1021/acs.joc.5b02154
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3) δ 10.06 (s, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.34−7.32 (m, 1H),
7.22−7.20 (m, 2H), 6.08 (s, 1H), 5.43 (s, 1H), 2.73 (s, 2H), 1.28 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 166.8, 166.5, 136.9, 132.0,
128.4, 127.7, 118.2, 109.9, 60.9, 40.0, 26.5; HRMS (ESI) calcd for
C14H16N2O2 [M + H]+ 245.1285, found 245.1288.
1278 cm−1; 1H NMR (600 MHz, CDCl3) δ 9.92 (br, 1H), 7.52 (d, J =
8.4 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 3.6 Hz, 2H), 7.13
(d, J = 7.8 Hz, 2H), 6.22 (s, 1H), 5.59 (s, 1H), 5.16 (dd, J = 8.4, 4.8
Hz, 1H), 3.42 (dd, J = 17.4, 8.4 Hz, 1H), 2.72 (dd, J = 17.4, 2.4 Hz,
1H); 13C NMR (150 MHz, CDCl3) δ 168.0, 164.4, 138.7, 135.9,
132.3, 128.9, 128.7, 128.5, 122.6, 119.3, 60.1, 34.2; HRMS (ESI) calcd
for C18H14BrClN2O2 [M + H]+ 405.0000, found 404.9997.
N-(2-Ethyl-2-methyl-4-methylene-5-oxopyrrolidin-1-yl)-
benzamide 5s. White solid (102 mg, 66% yield): mp >240 °C; IR
1
(KBr) ν 3158, 2970, 1705, 1683, 1538, 1408, 1278 cm−1; H NMR
4-Methyl-N-[3-methylene-2-oxo-5-(p-tolyl)pyrrolidin-1-yl]-
(400 MHz, CDCl3) δ 9.86 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.37 (t, J
= 6.8 Hz, 1H), 7.26−7.21 (m, 2H), 6.07 (s, 1H), 5.41 (s, 1H), 2.78 (d,
J = 16.8 Hz, 1H), 2.62 (d, J = 16.8 Hz, 1H), 1.66−1.60 (m, 2H), 1.27
(s, 3H), 0.83 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
167.1, 166.6, 137.2, 132.0, 131.1, 128.4, 127.7, 117.8, 63.8, 36.7, 31.8,
24.6, 8.4; HRMS (ESI) calcd for C15H18N2O2 [M + H]+ 259.1441,
found 259.1438.
benzamide 5ag. White solid (68 mg, 42% yield): mp 181−183 °C; IR
1
(KBr) ν 3288, 3028, 1705, 1676, 1495, 1394, 1264 cm−1; H NMR
(400 MHz, CDCl3) δ 9.80−9.73 (m, 1H), 7.50 (dd, J = 8.4 Hz, 2H),
7.16−7.11 (m, 4H), 6.98−6.95 (m, 2H), 6.18 (d, J = 2.4 Hz, 1H), 5.52
(s, 1H), 5.17 (dd, J = 8.4, 4.8 Hz, 1H), 3.42−3.35 (m, 1H), 2.76−2.70
(m, 1H), 2.33 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
167.6, 165.7, 142.5, 138.2, 137.0, 136.6, 129.7, 129.0, 128.4 127.5,
126.8, 118.3, 60.3, 34.3, 21.5, 21.3; HRMS (ESI) calcd for
C20H20N2O2 [M + Na]+ 343.1417, found 343.1415.
N-[5-(4-Cyanophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-2-
methylbenzamide 5aa. White solid (108 mg, 66% yield): mp 207−
209 °C; IR (KBr) ν 3166, 2970, 2225, 1740, 1676, 1524, 1408, 1271
4-Chloro-N-[5-(furan-2-yl)-3-methylene-2-oxopyrrolidin-1-yl]-
benzamide 5ah. White solid (110 mg, 71% yield): mp 190−191 °C;
IR (KBr) ν 3440, 3274, 2920, 1720, 1668, 1596, 1474, 1408, 1271
1
cm−1; H NMR (600 MHz, CDCl3) δ 8.40 (s, 1H), 7.67 (d, J = 6.0
Hz, 2H), 7.42 (d, J = 6.0 Hz, 2H), 7.30−7.27 (m, 1H), 7.20 (d, J = 7.8
Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.14 (d, J =
1.8 Hz, 1H), 5.51 (s, 1H), 5.28−5.26 (m, 1H), 3.39 (dd, J = 16.8, 7.8
Hz, 1H), 2.72−2.64 (m, 1H), 2.25 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 168.3, 167.1, 145.3, 137.3, 135.0, 133.0, 132.3, 131.4, 131.1,
127.8, 127.4, 125.9, 119.6, 118.4, 112.7, 60.1, 33.8, 19.9; HRMS (ESI)
calcd for C20H17N3O2 [M + Na]+ 354.1213, found 354.1207.
1
cm−1; H NMR (600 MHz, CDCl3) δ 9.68 (s, 1H), 7.61 (d, J = 8.4
Hz, 2H), 7.38 (s, 1H), 7.26−7.23 (m, 2H), 6.33 (d, J = 1.2 Hz, 2H),
6.15 (s, 1H), 5.54 (s, 1H), 5.19 (dd, J = 8.4, 4.8 Hz, 1H), 3.28 (dd, J =
17.4, 8.4 Hz, 1H), 3.08−3.02 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 167.1, 164.3, 150.8, 143.1, 138.4, 135.5, 129.0, 128.9, 128.5, 118.8,
110.4, 109.2, 53.8, 30.0; HRMS (ESI) calcd for C16H13ClN2O3 [M +
H]+ 317.0687, found 317.0685.
N-[5-(4-Cyanophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-3-
methylbenzamide 5ab. Colorless syrup (107 mg, 65% yield): IR
N-[5-(Furan-2-yl)-3-methylene-2-oxopyrrolidin-1-yl]furan-2-car-
1
(neat) ν 3252, 2927, 2233, 1704, 1662, 1524, 1401, 1271 cm−1; H
boxamide 5ai. White solid (120 mg, 88% yield): mp 178−179 °C; IR
1
(KBr) ν 3216, 3144, 1712, 1668, 1582, 1502, 1394, 1155 cm−1; H
NMR (600 MHz, CDCl3) δ 9.97 (s, 1H), 7.67−7.63 (m, 2H), 7.41−
7.36 (m, 4H), 7.17−7.15 (m, 1H), 7.08−7.06 (m, 1H), 6.24 (d, J = 2.4
Hz, 1H), 5.60 (d, J = 2.4 Hz, 1H), 5.32−5.31 (m, 1H), 3.49−3.45 (m,
1H), 2.72−2.69 (m, 1H), 2.22 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 167.8, 165.7, 145.4, 138.3, 135.5, 133.1, 133.0, 130.4, 128.4, 128.1,
127.6, 124.4, 119.4, 118.5, 112.5, 60.1, 34.0, 21.3; HRMS (ESI) calcd
for C20H17N3O2 [M + H]+ 332.1394, found 332.1390.
N-[5-(4-Cyanophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-4-
methylbenzamide 5ac. White solid (111 mg, 70% yield): mp 202−
203 °C; IR (KBr) ν 3260, 3057, 2978, 2233, 1705, 1683, 1611, 1488,
1408, 1286 cm−1; 1H NMR (600 MHz, CDCl3) δ 10.18 (s, 1H), 7.64
(d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H),
6.96 (d, J = 7.8 Hz, 2H), 6.21 (s, 1H), 5.58 (s, 1H), 5.32−5.30 (m,
1H), 3.45 (dd, J = 17.4, 8.4 Hz, 1H), 2.68 (d, J = 17.4 Hz, 1H), 2.28 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 167.9, 165.6, 145.4, 142.9,
135.6, 132.9, 129.0, 127.7, 127.6, 127.4, 119.3, 118.5, 112.4, 60.2, 33.9,
21.5; HRMS (ESI) calcd for C20H17N3O2 [M + H]+ 332.1394, found
332.1390.
NMR (600 MHz, CDCl3) δ 9.49 (s, 1H), 7.38 (s, 1H), 7.36−7.35 (m,
1H), 7.05 (d, J = 3.6 Hz, 1H), 6.37−6.35 (m, 2H), 6.32−6.31 (m,
1H), 6.17 (s, 1H), 5.52 (s, 1H), 5.18 (dd, J = 8.4, 4.8 Hz, 1H), 3.29−
3.24 (m, 1H), 3.05−3.01 (m, 1H); 13C NMR (150 MHz, CDCl3) δ
166.7, 156.8, 151.1, 145.6, 145.1, 143.2, 135.6, 118.8, 116.0, 111.9,
110.6, 109.4, 54.1, 30.2; HRMS (ESI) calcd for C14H12N2O4 [M + H]+
273.0870, found 273.0870.
4-Chloro-N-(5-isopropyl-3-methylene-2-oxopyrrolidin-1-yl)-
benzamide 5al. White solid (131 mg, 90% yield): mp 159−160 °C;
IR (KBr) ν 3180, 2963, 1698, 1668., 1596, 1524, 1430, 1278 cm−1; 1H
NMR (600 MHz, CDCl3) δ 11.03 (br, 1H), 7.68−7.67 (m, 2H),
7.20−7.17 (m, 2H), 6.06 (d, J = 3.0 Hz, 1H), 5.45 (d, J = 1.8 Hz, 1H),
4.06 (dd, J = 8.4, 3.6 Hz, 1H), 2.91−2.86 (m, 1H), 2.57 (d, J = 17.4
Hz, 1H), 2.15−2.13 (m, 1H), 0.91−0.90 (m, 3H), 0.77−0.75 (m, 3H);
13C NMR (150 MHz, CDCl3) δ 168.2, 164.1, 138.3, 137.0, 129.0,
128.8, 128.4, 117.8, 60.9, 28.5, 24.8, 17.9, 14.2; HRMS (ESI) calcd for
C15H17ClN2O2 [M + H]+ 293.1051, found 293.1049.
4-Chloro-N-[5-(4-cyanophenyl)-3-methylene-2-oxopyrrolidin-1-
4-Chloro-N-(3-methylene-2-oxo-5-propylpyrrolidin-1-yl)-
benzamide 5am. White solid (107 mg, 73% yield): mp 122−124 °C;
IR (KBr) ν 3230, 2956, 1712, 1647, 1589, 1474, 1292 cm−1; 1H NMR
(600 MHz, CDCl3) δ 10.48 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.21 (d,
J = 7.2 Hz, 2H), 6.08 (t, J = 2.4 Hz, 1H), 5.46 (t, J = 2.4 Hz, 1H),
4.05−4.01 (m, 1H), 3.08−3.03 (m, 1H), 2.54−2.49 (m, 1H), 1.77−
1.71 (m, 1H), 1.42−1.37 (m, 1H), 1.33−1.26 (m, 2H), 0.92 (t, J = 7.2
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 167.9, 164.5, 138.6, 136.9,
129.3, 129.0, 128.7, 118.2, 56.8, 35.4, 30.3, 17.6, 14.2; HRMS (ESI)
calcd for C15H17ClN2O2 [M + H]+ 293.1051, found 293.1049.
4-Chloro-N-(2,2-dimethyl-4-methylene-5-oxopyrrolidin-1-yl)-
benzamide 5an. White solid (111 mg, 80% yield): mp 189−191 °C;
IR (KBr) ν 3252, 2970, 1698, 1676, 1596, 1516, 1474, 1401, 1264,
1090 cm−1; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 7.71 (d, J =
6.4 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H), 6.07 (s, 1H), 5.44 (s, 1H), 2.74
(d, J = 1.6 Hz, 2H), 1.27 (s, 6H); 13C NMR (150 MHz, CDCl3) δ
166.9, 165.2, 138.5, 136.7, 129.2, 129.1, 128.6, 118.5, 61.0, 40.0, 26.5;
HRMS (ESI) calcd for C14H15ClN2O2 [M + H]+ 279.0895, found
279.0892.
yl]benzamide 5ad. White solid (118 mg, 80% yield): mp 173−174
1
°C; IR (KBr) ν 3260, 2927, 2225, 1705, 1690, 1480, 1286 cm−1; H
NMR (600 MHz, CDCl3) δ 10.55 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H),
7.45 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz,
2H), 6.22 (t, J = 2.4 Hz, 1H), 5.62 (t, J = 2.4 Hz, 1H), 5.26 (dd, J =
8.4, 4.8 Hz, 1H), 3.48−3.44 (m, 1H), 2.71−2.67 (m, 1H); 13C NMR
(150 MHz, CDCl3) δ 168.2, 164.3, 145.1, 138.8, 135.4, 133.0, 128.8,
128.7, 128.5, 127.5, 119.8, 118.5, 112.6, 60.2, 34.0; HRMS (ESI) calcd
for C19H14ClN3O2 [M + H]+ 352.0847, found 352.0852.
4-Chloro-N-[5-(4-chlorophenyl)-3-methylene-2-oxopyrrolidin-1-
yl]benzamide 5ae. White solid (149 mg, 83% yield): mp 157−159
°C; IR (KBr) ν 3202, 2992, 1976, 1676, 1596, 1488, 1401, 1271, 1288
1
cm−1; H NMR (600 MHz, CDCl3) δ 10.43 (s, 1H), 7.51−7.49 (m,
2H), 7.33−7.31 (m, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.14−7.13 (m,
2H), 6.21 (t, J = 2.4 Hz, 1H), 5.59 (t, J = 1.8 Hz, 1H), 5.17 (dd, J =
8.4, 4.8 Hz, 1H), 3.45−3.40 (m, 1H), 2.74−2.70 (m, 1H); 13C NMR
(150 MHz, CDCl3) δ 168.0, 164.3, 138.6, 138.2, 136.0, 134.4, 129.3,
128.9, 128.8, 128.6, 128.2, 119.2, 60.0, 34.2; HRMS (ESI) calcd for
C18H14Cl2N2O2 [M + H]+ 361.0505, found 361.0506.
N-(2,2-Dimethyl-4-methylene-5-oxopyrrolidin-1-yl)furan-2-car-
boxamide 5ao. White solid (95 mg, 81% yield): mp 160−163 °C; IR
(neat) ν 3210, 2970, 1720, 1683, 1582, 1516, 1459, 1300, 1177 cm−1;
1H NMR (600 MHz, CDCl3) δ 9.39 (s, 1H), 7.41 (s, 1H), 7.12 (d, J =
N-[5-(4-Bromophenyl)-3-methylene-2-oxopyrrolidin-1-yl]-4-
chlorobenzamide 5af. White solid (156 mg, 79% yield): mp 164−
166 °C; IR (KBr) ν 3238, 3064, 2934, 2862, 1712, 1662, 1532, 1386,
H
DOI: 10.1021/acs.joc.5b02154
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Article
3.6 Hz, 1H), 6.39 (s, 1H), 6.10 (s, 1H), 5.43 (s, 1H), 2.75 (s, 2H),
1.31 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 166.3, 157.8, 145.9,
144.9, 136.5, 118.2, 115.7, 111.8, 60.5, 39.7, 26.3; HRMS (ESI) calcd
for C12H14N2O3 [M + H]+ 235.1077, found 235.1074.
N-(7-Methylene-6-oxo-5-azaspiro[3.4]octan-5-yl)benzamide 7a.
White solid (109 mg, 85% yield): mp 171−173 °C; IR (KBr) ν
3252, 2999, 1720, 1662, 1516, 1408, 1278, 1119 cm−1; 1H NMR (400
MHz, CDCl3) δ 10.01 (s, 1H), 7.83 (d, J = 7.6 Hz, 2H), 7.36−7.34
(m, 1H), 7.23 (t, J = 7.6 Hz, 2H), 6.05 (d, J = 2.4 Hz, 1H), 5.42 (s,
1H), 3.04 (s, 2H), 2.50−2.47 (m, 2H), 1.88−1.85 (m, 2H), 1.69−1.65
(m, 2H); 13C NMR (150 MHz, CDCl3) δ 166.8, 166.5, 136.5, 132.1,
131.1, 128.5, 127.7, 117.9, 63.5, 38.5, 33.1, 13.3; HRMS (ESI) calcd
for C15H16N2O2 [M + H]+ 257.1285, found 257.1283.
N-(3-Methylene-2-oxo-1-azaspiro[4.4]nonan-1-yl)benzamide 7b.
White solid (122 mg, 90% yield): mp 152−154 °C; IR (KBr) ν 3202,
2978, 2869, 1712, 1662, 1495, 1401, 1271 cm−1; 1H NMR (400 MHz,
CDCl3) δ 10.23 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.32−7.30 (m, 1H),
7.20−7.17 (m, 2H), 6.06 (s, 1H), 5.41 (s, 1H), 2.76 (s, 2H), 1.95 (s,
2H), 1.72 (s, 2H), 1.60 (s, 2H), 1.54 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 167.2, 166.3, 136.9, 131.9, 130.9, 128.3, 127.6, 117.8, 70.3,
39.6, 35.5, 22.8; HRMS (ESI) calcd for C16H18N2O2 [M + H]+
271.1441, found 271.1443.
22.8, 21.3; HRMS (ESI) calcd for C17H20N2O2 [M + H]+ 285.1598,
found 285.1595.
3-Methyl-N-(3-methylene-2-oxo-1-azaspiro[4.4]nonan-1-yl)-
benzamide 7j. White solid (101 mg, 61% yield): mp 120−122 °C; IR
(KBr) ν 3252, 2970, 2876, 1712, 1668, 1524, 1408, 1286, 1184 cm−1;
1H NMR (600 MHz, CDCl3) δ 9.99 (s, 1H), 7.64−7.59 (m, 2H), 7.12
(d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.07 (s, 1H), 5.41 (s,
1H), 2.77 (s, 2H), 2.24 (s, 3H), 1.96 (s, 2H), 1.72 (s, 2H), 1.60 (s,
2H), 1.53 (d, J = 11.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 167.0,
166.3, 137.9, 136.9, 132.5, 130.7, 128.2, 128.1, 124.5, 117.5, 70.2, 39.6,
35.4, 22.7, 21.2; HRMS (ESI) calcd for C17H20N2O2 [M + H]+
285.1598, found 285.1595.
4-Methyl-N-(3-methylene-2-oxo-1-azaspiro[4.4]nonan-1-yl)-
benzamide 7k. White solid (118 mg, 71% yield): mp 153−154 °C; IR
1
(KBr) ν 3238, 2947, 1712, 1668, 1524, 1416, 1292 cm−1; H NMR
(400 MHz, CDCl3) δ 10.08 (d, J = 13.2 Hz, 1H), 7.64−7.59 (m, 2H),
7.13−7.07 (m, 2H), 6.07 (s, 1H), 5.41 (s, 1H), 2.77 (s, 2H), 2.25 (s,
3H), 1.97−1.94 (m, 2H), 1.72 (s, 2H), 1.60 (d, J = 4.4 Hz, 2H), 1.54
(d, J = 11.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 166.9, 166.3,
142.3, 136.9, 128.8, 128.1, 127.5, 117.5, 70.1, 39.6, 35.5, 22.7, 21.4;
HRMS (ESI) calcd for C17H20N2O2 [M + H]+ 285.1598, found
285.1597.
N-(3-Methylene-2-oxo-1-azaspiro[4.5]decan-1-yl)benzamide 7c.
White solid (116 mg, 80% yield): mp 227−228 °C; IR (KBr) ν
3216, 2920, 2840, 1712, 1654, 1532, 1230 cm−1; 1H NMR (400 MHz,
CDCl3) δ 9.97 (s, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.24 (d, J = 6.8 Hz,
1H), 7.13 (d, J = 7.2 Hz, 2H), 6.00 (s, 1H), 5.36 (s, 1H), 2.67 (s, 2H),
1.62 (s, 2H), 1.57 (d, J = 14.0 Hz, 2H), 1.45 (s, 2H), 1.24 (d, J = 13.2
Hz, 2H), 1.18 (s, 1H), 1.02 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
166.8, 166.3, 136.8, 131.7, 130.9, 128.2, 127.5, 118.0, 63.8, 35.5, 34.5,
24.6, 22.9; HRMS (ESI) calcd for C17H20N2O2 [M + H]+ 285.1598,
found 285.1595.
4-Chloro-N-(3-methylene-2-oxo-1-azaspiro[4.4]nonan-1-yl)-
benzamide 7l. White solid (135 mg, 89% yield): mp 191−193 °C; IR
1
(KBr) ν 3180, 2956, 1712, 1668, 1589, 1394, 1264, 1083 cm−1; H
NMR (600 MHz, CDCl3) δ 10.28 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H),
7.18 (d, J = 8.4 Hz, 2H), 6.07 (s, 1H), 5.44 (s, 1H), 2.78 (s, 2H), 1.96
(s, 2H), 1.74 (d, J = 6.6 Hz, 2H), 1.63 (d, J = 4.8 Hz, 2H), 1.54 (s,
2H); 13C NMR (150 MHz, CDCl3) δ 167.2, 165.0, 138.4, 136.7,
129.0, 128.9, 128.5, 117.9, 70.3, 39.6, 35.5, 22.8; HRMS (ESI) calcd
for C16H17ClN2O2 [M + K]+ 343.0610, found 343.0606.
4-Chloro-N-(3-methylene-2-oxo-1-azaspiro[4.5]decan-1-yl)-
benzamide 7m. White solid (121 mg, 76% yield): mp 185−186 °C;
IR (KBr) ν 3180, 2941, 2840, 1705, 1668, 1589, 1524, 1401, 1271,
1162 cm−1; 1H NMR (600 MHz, CDCl3) δ 10.00 (s, 1H), 7.73 (d, J =
8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 6.07 (s, 1H), 5.45 (s, 1H), 2.75
(s, 2H), 1.72 (d, J = 12.0 Hz, 2H), 1.63−1.61 (m, 3H), 1.50 (d, J =
12.0 Hz, 2H), 1.32 (d, J = 13.2 Hz, 2H), 1.09 (d, J = 12.6 Hz, 1H); 13C
NMR (150 MHz, CDCl3) δ 167.0, 165.3, 138.5, 136.7, 129.3, 129.1,
128.6, 118.5, 64.1, 35.7, 34.7, 24.8, 23.0; HRMS (ESI) calcd for
C17H19ClN2O2 [M + H]+ 319.1208, found 319.1204.
N-(3-Methylene-2-oxo-1-azaspiro[4.4]nonan-1-yl)furan-2-car-
boxamide 7n. White solid (133 mg, 88% yield): mp 215−216 °C; IR
(KBr) ν 3224, 3035, 2970, 1720, 1668, 1574, 1459, 1394, 1314, 1170
cm−1; 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.38 (s, 1H), 7.09
(d, J = 2.4 Hz, 1H), 6.35 (dd, J = 3.2, 1.6 Hz, 1H), 6.08 (s, 1H), 5.41
(s, 1H), 2.77 (s, 2H), 1.96 (dd, J = 11.2, 7.6 Hz, 2H), 1.73 (s, 2H),
1.66−1.54 (m, 4H); 13C NMR (150 MHz, CDCl3) δ 166.8, 157.8,
145.8, 145.0, 136.6, 117.7, 115.5, 111.7, 70.1, 39.5, 35.4, 22.7; HRMS
(ESI) calcd for C14H16N2O3 [M + H]+ 261.1234, found 261.1233.
N-(3-Methylene-2-oxo-1-azaspiro[4.6]undecan-1-yl)benzamide
7d. White solid (74 mg, 58% yield): mp 201−202 °C; IR (KBr) ν
3245, 3064, 2927, 2854, 1712, 1654, 1532, 1401, 1278, 1191, 1097
1
cm−1; H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.77 (d, J = 8.0
Hz, 2H), 7.33 (s, 1H), 7.20 (s, 2H), 6.04 (s, 1H), 5.42 (s, 1H), 2.71 (s,
2H), 2.04 (s, 2H), 1.60 (d, J = 11.2 Hz, 4H), 1.53 (s, 4H), 1.38 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 166.8, 166.4, 137.1, 131.9,
131.0, 128.4, 127.6, 118.0, 66.8, 38.5, 38.2, 29.5, 22.5; HRMS (ESI)
calcd for C18H22N2O2 [M + H]+ 299.1754, found 299.1751.
N-(7-Methyl-3-methylene-2-oxo-1-azaspiro[4.5]decan-1-yl)-
benzamide 7g. Colorless syrup (109 mg, 73% yield): IR (neat) ν
3238, 2927, 2370, 1712, 1668, 1516, 1408, 1278 cm−1; 1H NMR (600
MHz, CDCl3) δ 10.07 (s, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.30 (t, J = 7.2
Hz, 1H), 7.17 (t, J = 7.8 Hz, 2H), 6.03 (s, 1H), 5.38 (s, 1H), 2.69 (q, J
= 16.2 Hz, 2H), 2.02−1.96 (m, 2H), 1.90 (d, J = 12.6 Hz, 1H), 1.67
(d, J = 6.0 Hz, 1H), 1.56 (s, 2H), 1.36 (t, J = 12.0 Hz, 1H), 1.23 (dd, J
= 8.4, 6.0 Hz, 1H), 0.99 (d, J = 9.0 Hz, 1H), 0.89 (d, J = 6.6 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 167.2, 166.4, 137.1, 131.9, 131.1,
128.4, 127.6, 117.6, 62.9, 44.1, 41.2, 36.4, 32.5, 28.1, 22.1, 21.0; HRMS
(ESI) calcd for C18H22N2O2 [M + H]+ 299.1754, found 299.1750.
N-(8-Methyl-3-methylene-2-oxo-1-azaspiro[4.5]decan-1-yl)-
benzamide 7h. White solid (112 mg, 77% yield): mp 187−188 °C; IR
(KBr) ν 3245, 3065, 2934, 2862, 1726, 1662, 1532, 1401, 1278 cm−1;
1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.78 (d, J = 7.6 Hz,
2H), 7.33 (s, 1H), 7.20 (s, 2H), 6.06 (s, 1H), 5.41 (s, 1H), 2.73 (s,
2H), 1.95 (t, J = 12.4 Hz, 2H), 1.81 (s, 1H), 1.60 (s, 2H), 1.51 (s, 2H),
1.32 (d, J = 12.4 Hz, 2H), 0.91 (d, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 166.9, 166.5, 136.9, 131.9, 131.1, 128.4, 127.6, 118.0,
63.8, 36.4, 30.2, 28.7, 26.4, 17.7; HRMS (ESI) calcd for C18H22N2O2
[M + H]+ 299.1754, found 299.1768.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02154.
1
Copies of the IR, H NMR, 13C NMR and HRMS
spectra of 5 and 7 (PDF)
2-Methyl-N-(3-methylene-2-oxo-1-azaspiro[4.4]nonan-1-yl)-
AUTHOR INFORMATION
■
benzamide 7i. White solid (74 mg, 52% yield): mp 181−182 °C; IR
1
(KBr) ν 3166, 2963, 1678, 1668, 1524, 1401, 1278 cm−1; H NMR
Corresponding Authors
(600 MHz, CDCl3) δ 8.27 (s, 1H), 7.49 (d, J = 3.0 Hz, 1H), 7.32−
7.31 (m, 1H), 7.18 (s, 2H), 5.95 (s, 1H), 5.32 (s, 1H), 2.71 (s, 2H),
2.38 (s, 3H), 1.94 (s, 2H), 1.77 (s, 2H), 1.65 (s, 1H), 1.56 (s, 2H),
1.31 (d, J = 3.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 167.2, 166.4,
137.9, 137.0, 132.6, 130.7, 128.3, 128.2, 124.6, 117.7, 70.3, 39.7, 35.5,
*E-mail: huangdf@nwnu.edu.cn.
*E-mail: huyl@nwnu.edu.cn.
Notes
The authors declare no competing financial interest.
I
DOI: 10.1021/acs.joc.5b02154
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The Journal of Organic Chemistry
Article
J.; Villier
́
as, J. Tetrahedron 2008, 64, 2441. (c) Elford, T. G.; Hall, D. G.
ACKNOWLEDGMENTS
■
Tetrahedron Lett. 2008, 49, 6995. (d) Elford, T. G.; Ulaczyk-Lesanko,
A.; De Pascale, G.; Wright, G. D.; Hall, D. G. J. Comb. Chem. 2009, 11,
155.
We are thankful for financial support from the National Natural
Science Foundation of China (Grant 21462037), the Key
Laboratory of Polymer Materials of Gansu Province (North-
west Normal University), the Bioactive Product Engineering
Research Center for Gansu Distinctive Plants, and the State
Key Laboratory of Applied Organic Chemistry of Lanzhou
University.
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