Synthesis of 1 H-Pyrrol-3(2 H)-ones via Three-Component Reactions of 2,3-Diketo Esters, Amines, and Ketones

Article abstract of DOI:10.1021/acs.joc.8b01887

An efficient one-pot, three-component reaction of 2,3-diketo esters with amines and ketones has been developed for the synthesis of 1H-pyrrol-3(2H)-ones. By using trifluoroacetic acid (TFA) as the additive and acetonitrile (MeCN) as the solvent, this conv

Full text of DOI:10.1021/acs.joc.8b01887

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Article
Synthesis of 1H-Pyrrol-3(2H)-ones via Three Component
Reactions of 2,3-Diketo Esters, Amines, and Ketones
Qiang Sha, Junke Wang, and Michael P Doyle
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01887 • Publication Date (Web): 24 Aug 2018
Downloaded from http://pubs.acs.org on August 24, 2018
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Synthesis of 1H-Pyrrol-3(2H)-ones via Three Component
Reactions of 2,3-Diketo Esters, Amines, and Ketones
Qiang Shaa*, Junke Wanga and Michael P. Doyleb
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Department of Chemistry, College of Sciences, Nanjing Agricultural University, Nanjing
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210095, P. R. China. Email: qsha@njau.edu.cn
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b
Department of Chemistry, The University of Texas at San Antonio, San Antonio, Texas, 78249,
USA.
ABSTRCT: An efficient one-pot, three component reaction of 2,3-diketo esters with amines and
ketones has been developed for the synthesis of 1H-pyrrol-3(2H)-ones. By using trifluoroacetic
acid (TFA) as the additive and acetonitrile (MeCN) as the solvent, this convenient method
provides a library of 1H-pyrrol-3(2H)-ones in moderate to good yields. The simple protocol
features readily available starting materials, a straightforward process, good functional group
tolerance, and broad substrate scope.
 INTRODUCTION
1H-Pyrrol-3(2H)-one derivatives have received considerable attention because they widely exist in
natural products and biologically active compounds.1 Due to their importance, many efforts have
been undertaken for their syntheses and modifications.2 The main synthetic strategies occur by three
routes: (1) dimerization of enamines (mediated by hypervalent iodine(III) regent,3 TBHP/TBAI
system;4 catalyzed by p-TSOH,5 Cu(TFA)2 ); (2) cyclization of corresponding open-chain precursors
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(catalyzed by gold,7 platinum,8 copper9; treated with I2,10 TEMPO,11 thermal cyclization12); (3)
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transformations based on indolin-3-ones or indoles including Michael addition reaction,13 annulation
reaction,14 rearrangement reaction15 and oxidation reaction16. Although considerable progress has
been made in this field, the existing methods suffer from drawbacks such as narrow substrate scope
and low availability of the starting materials. Thus developing a facile, simple and metal-free method
to construct 1H-pyrrol-3(2H)-one derivatives with broad functional group tolerance starting from
easily available starting materials is highly desirable.
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Vicinal tricarbonyl compounds (VTCs) are important synthetic reagents because they are strongly
electrophilic aggregates with several reactive sites. The pioneering work by Rubin, Wasserman and
others demonstrated the wide applications of VTCs in the synthesis of natural products and synthetic
intermediates especially various heterocycles.17 Continuing investigations in recent years have
developed new methods for VTC synthesis18 and have explored their novel applications.19
In 1991, Wasserman disclosed a novel transformation that occurs between 2,3-diketo esters with
Schiff bases, affording 1H-pyrrol-3(2H)-one derivatives in moderate yields (Scheme 1, a).20
However, only aldehyde-derived Schiff bases were involved, and the Schiff bases were prepared in
advance. Despite its limitations, this strategy provides a promising way to synthesize
1H-pyrrol-3(2H)-ones. Inspired by this work, we reported a two-step reaction for asymmetric
synthesis of 1H-pyrrol-3(2H)-ones from 2,3-diketo esters by combination of aldol condensation with
subsequent benzilic acid rearrangement (Scheme 1, b).19d However, due to the narrow substrate
scope determined for the aldol condensation, only six-membered cyclic ketones could be effectively
used. In order to improve the universality and efficiency of this reaction, we searched for a suitable
and general one-pot, one-step reaction system to synthesize 1H-pyrrol-3(2H)-ones starting from
2,3-diketo esters, amines and the general class of ketones.
We have also reported a metal-free aldol/cyclization/aromatization cascade reaction of 2,3-diketo
esters with anilines and cyclic ketones from which a variety of 5-vinyl-pyrrole and 4-hydroxy-indole
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derivatives could be easily accessed (Scheme 1, c).21 In the mechanism for this reaction (Scheme 2)
acid promoted loss of water and aromatization produces the pyrrole products. We speculated that the
key intermediate B has the potential to circumvent dehydration and undergo the benzylic
rearrangement that was not realized in the reactions promoted by benzoic acid in toluene. Herein we
report a simple and general method to synthesize 1H-pyrrol-3(2H)-ones from 2,3-diketo esters,
ketones and anilines in one pot.
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Scheme 1. General routes toward 1H-pyrrol-3(2H)-ones or 5-vinyl-pyrroles from 2,3-diketo esters.
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Scheme 2. Mechanism of the 5-vinyl-pyrrole formation and our assumption.
 RESULTS AND DISCUSSION
At the outset, we chose benzyl 2,2-dihydroxy-3-oxobutanoate (1a),22 aniline (2a), and
cycloheptanone (3a) as the model substrates to explore reaction conditions favourable to
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1H-pyrrol-3(2H)-one formation. Reaction occurs smoothly at 60 C without catalyst by using
toluene as the solvent, but 1H-pyrrol-3(2H)-one 4m was obtained in 33% yield along with pyrrole
4m’ in 30% yield (Table 1, entry 1). To improve the yield of 4m, the reaction was performed in a
spectrum of solvents of different polarity, including THF, MeOH, DCE, CHCl3, MeCN and DCM
(Table 1, entries 2-7). The results reveal that polar solvents increase the relative yield of 4m and that
MeCN privides the highest yield, giving 4m and 4m’ in 76% and 14% yield, respectively (Table 1,
entry 6). Two additives were then tested of which TFA at 20 mol% produced 4m with near
exclusivity (Table 1, entries 8-9) in 89% yield (Table 1, entry 9). The reaction also occurred with
TFA catalysis at a lower temperature or under solvent-free conditions, but the yield of 4m decreased
dramatically (Table 1, entries 10-11).
When TFA was used as the additive, the ratio (4m and 4m’) and the yield of 4m increased
dramatically. This suggested further investigations to evaluate additives with different acidities.
Acids with a range of acidities were used (pKa order: Phenol > Benzoic acid > TFA > CH3SO3H >
HCl (conc.) > CF3SO3H), and the results are shown in Table 2. After the analysis of Table 1 and
Table 2, we can conclude that the highest yields of 1H-pyrrol-3(2H)-one are obtained in polar media
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at moderate temperature using relatively strong acids as catalysts.
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Table 1. Optimization of the reaction conditions. a
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Yield (%)b
Entry
Solvent
Additive
Temperature
4m
4m’
1
Toluene
THF
---
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
60 oC
25 oC
60 oC
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22
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2
---
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MeOH
DCE
---
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---
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<5
trace
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CHCl3
MeCN
DCM
MeCN
MeCN
MeCN
---
---
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---
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---
8
Zn(OTf)2
TFAc
TFAd
TFA
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Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol), 3a (0.40 mmol), additive (0.040 mmol),
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solvent (2.0 mL), at indicated temperature for 48 h. Isolated yield. TFA refers to trifluoroacetic
acid. e 72 h.
Table 2. Evaluation of acid additives.a
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Ratio (4m:4m’)b
16:1
Yield of 4mc
72%
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Entry
Additive
Phenol
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Benzoic acid
TFA
9:1
75%
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>50:1
89%
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CH3SO3H
HCl (conc.)
CF3SO3H
49:1
85%
>50:1
86%
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>50:1
87%
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Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol), 3a (0.40 mmol), additive (0.040 mmol),
MeCN (2.0 mL), at 60 oC for 48 h; b The ratio was determined by 1H NMR; c Yields refer to isolated
yields.
Scheme 3. Investigation of the substrate scope with 2,3-diketo esters.
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a Reaction conditions: 1 (0.20 mmol), 2a (0.22 mmol), 3a (0.40 mmol), TFA (0.040 mmol), at 60 C
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for 48 h; yields refer to isolated yields.
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With the optimized reaction conditions in hand, we then investigated the scope of 2,3-diketo esters,
amines and ketones for this process. 2,3-Diketo esters with different ester groups were examined
first (Scheme 3, 4a-4e) which gave the desired products in good yields ranging from 60% to 83%.
Then various 2,3-diketo esters with different alkyl ketone chains were tested. As expected, those
with ethyl or n-propyl groups gave 4f and 4g in good yields, while those with isopropyl, cyclopropyl,
and phenyl substituents gave the products 4h, 4i, 4j in somewhat lower yields, which can probably
be ascribed to steric effects. The scope of vicinal tricarbonyl compounds was limited to 2,3-diketo
esters; when pentane-2,3,4-trione and N,N-dimethyl-2,3-dioxobutanamide were used, no desired
product was detected (4k, 4l). This means the ketone group or amide group cannot undergo the
rearrangement process similar as can the ester group.
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Aniline derivatives were then subjected to reactions with 2,2-dihydroxy-3-oxobutanoate and
cycloheptanone (Scheme 4). Both electron-donating and electron-withdrawing groups on the phenyl
ring gave the 1H-pyrrol-3(2H)-one products in similar yields. A series of substituents, including
halide (4n-4q), methyl (4r, 4s), methoxy (4t), nitro (4u), cyano (4v), and ethyl carboxylate group
(4w), were all tolerated thus providing broad space for further modifications or late-stage synthesis.
1H-Indazol-5-amine also participated in the reaction and gave 4x in 47% yield. Two aliphatic amines
were tested (Scheme 5), the reaction of benzylamine was messy but the desired product 4y can be
detected by LC-MS (< 10% yield, see SI). 2,2,2-Trifluoroethan-1-amine gave 4z in 50% yield.
Scheme 4. Investigation on the scope of aromatic amines. a
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Reaction conditions: 1a (0.20 mmol), 2 (0.22 mmol), 3a (0.40 mmol), TFA (0.040 mmol), MeCN
(2.0 mL), at 60 oC for 48 h; yields refer to isolated yields.
Scheme 5. Investigation on the reaction of aliphatic amines.
We were also attentive to structural variation of ketones since the scope of this modification
greatly determines the utility of this three-component transformation (Scheme 6). Cyclobutanone did
not give the desired product 4aa probably due to ring tension in the four-membered ring which made
the cyclization reaction too difficult. However, cyclopentanone did successfully participate in the
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reaction, although the yield of its product (4ab) was only 25%. Several six-membered cyclic ketones,
including aliphatic and heterocyclic substrates, were favored in this transformation, which give
corresponding 1H-pyrrol-3(2H)-one products in good yields (4ac-4af). Medium ring and
macrocyclic ketones, exemplified by cyclooctanone and cyclododecanone, gave the corresponding
products in 77% and 43% yields, respectively (4ag, 4ah). In order to further demonstrate the wide
substrate scope of ketones, 3-pentanone, a representative non-cyclic ketone, gave product 4ai in 31%
yield. Acetylacetone, N,N-dimethylacetoacetamide and methyl acetoacetate also afford
1H-pyrrol-3(2H)-one products in moderate yields (4aj-4al) (un-optimized). These results suggest an
extremely broad scope for this transformation.
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Scheme 6. Investigation on the scope of ketones. a
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a
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Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol), 3 (0.40 mmol), TFA (0.040 mmol), MeCN
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(2.0 mL), at 60 oC for 48 h; yields refer to isolated yields.
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Finally, we carried out gram-scale synthesis in order to further demonstrate that this method is
practically useful (Scheme 7). When performed on a 5 mmol scale, no obvious drop of the yield was
observed. Representative 2,3-diktoesters, one each with an aliphatic and aromatic ketone chain, gave
reacting with aniline and cycloheptanone to give products 4j and 4m, respectively, in 80% and 83%
yields. p-Bromoaniline was then used, and gave 4p in 75% yield. Tetrahydro-4H-thiopyran-4-one
was also tested, and 4af was obtained in moderate yield.
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Scheme 7. Gram-scale synthesis. a
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Reaction conditions: 1 (5.0 mmol), 2a (5.5 mmol), 3 (10.0 mmol), TFA (1.0 mmol), MeCN (30
mL), at 60 oC for 48 h; yields refer to isolated yields.
In order to look into the detail of reaction pathway, we tried to use LC-MS to detect possible
reaction intermediates. Fortunately, although the key intermediate, diol A (Scheme 2), was formed in
low concentration during the reaction, they were successfully detected (for details, see SI). The
above investigations suggest that the three component reactions of 2,3-diketo esters, amines and
ketones probably occur through the way that depicted in Scheme 2.
 CONCLUSION
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In conclusion, we have demonstrated that 2,3-diketo esters react with anilines and ketones in a
one-pot process to afford 1H-pyrrol-3(2H)-one derivatives in good yields. This method can be easily
scaled up and uses readily available starting materials. Its substrate scope allows easy access to a
broad diversity of novel 1H-pyrrol-3(2H)-one derivatives.
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 EXPERIMENTAL SECTION
General Materials and Methods. Solvents and reagents (AR grade) were used without
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purification unless otherwise noted. H NMR and C NMR spectra were recorded in CDCl3 on a
Bruker-DMX 400 spectrometer. Chemical shifts are reported in ppm with the solvent signals as
reference, and coupling constants (J) are given in Hertz (Hz). Spectral splitting patterns are designated
as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; ddd, doublet of doublet of doublets and brs,
broad single. High resolution mass spectroscopic data of the products were collected on a Waters
Micromass GCT instrument using EI (70 eV) or an Agilent Technologies 6540 UHD Accurate-Mass
Q-TOF LC/MS using ESI. Melting points were obtained uncorrected from an Electrothermo Buchi
M-560 device.
General procedure for the synthesis of 2,3-diketo esters.
1. Preparation of α-Diazo-β-keto esters:23 A solution of β-keto ester (10 mmol, 1.0 equiv.) and
p-acetamidobenzenesulfonyl azide (p-ABSA) (2.8 g, 12 mmol, 1.2 equiv.) in 75 mL of CH3CN was
added triethylamine (2.1 mL, 1.5 mmol, 1.5 equiv.) at 0 °C, and the resulting solution was stirred at
room temperature for 8 hours during which time the corresponding sulfonamide precipitated as a
white solid. The white precipitate was filtered, and the resulting solution was concentrated under
reduced pressure. The residue was purified by flash column chromatography (SiO2), eluting with
petroleum and ethyl acetate to provide α-diazo-β-keto ester.
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2. General Procedure for the Synthesis of 2,3-Diketo esters:19f A solution of α-diazo-β-keto esters
(5.0 mmol, 1.0 equiv.) in 20 mL of solvent [CH3CN:H2O (9:1)] at 0 °C was added tert-butyl
hypochlorite (0.61 mL, 5.5 mmol) dropwise over 30 min via syringe pump. The reaction was stirred
for an additional 30 min at room temperature and then concentrated under reduced pressure. The
residue was purified by flash column chromatography (SiO2), eluting with petroleum and ethyl acetate
to provide 2,3-diketo esters as their monohydrates.
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General procedure for the synthesis of 1H-pyrrol-3(2H)-ones.
A Schlenk tube with a magnetic stir bar charged with 2,3-diketo esters 1 (0.20 mmol), amines 2
(0.22 mmol, 1.1 equiv.), ketones 3 (0.40 mmol, 2.0 equiv.), trifluoroacetic acid (0.04 mmol, 0.2
equiv.), and 2 mL acetonitrile. The reaction mixture was then heated to 60 oC and stirred for 48 hours.
The reaction mixture was then allowed to cool to ambient temperature and all of the volatiles were
removed under vacuum, the crude product was purified on flash chromatography, eluding with
petroleum/ethyl acetate, to provide 1H-pyrrol-3(2H)-ones.
General procedures for gram-scale reactions.
A Schlenk tube with a magnetic stir bar charged with 2,3-diketo esters 1 (5.0 mmol), amines 2 (5.5
mmol, 1.1 equiv.), ketones 3 (10.0 mmol, 2.0 equiv.), trifluoroacetic acid (1.0 mmol, 0.2 equiv.), and
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30 mL acetonitrile. The reaction mixture was then heated to 60 C and stirred for 48 hours. The
reaction mixture was then allowed to cool to ambient temperature and all of the volatiles were
removed under vacuum, the crude product was purified on flash chromatography, eluding with
petroleum/ethyl acetate, to provide 1H-pyrrol-3(2H)-ones.
Methyl-methyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-carboxylate (4a)
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45.4 mg (Brown solid, 76% yield); m.p. = 92.8-94.8 C; TLC Rf = 0.45 (PE/EtOAc = 2:1); 1H NMR
(400 MHz, CDCl3) δ 7.42-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.08-7.06 (m, 2H), 3.73 (s, 3H),
2.54-2.51 (m, 2H), 2.44-2.40 (m, 2H), 1.86-1.78 (m, 2H), 1.77-1.72 (m, 1H), 1.69-1.61 (m, 2H),
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1.59-1.53 (m, 1H), 1.50 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.3 , 179.8, 168.3, 137.7, 129.4,
128.2, 127.7, 112.6, 75.2, 53.0, 31.9, 29.8, 27.8, 26.0, 21.7, 19.4; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for -C18H21NO3Na 322.1414; Found 322.1414.
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Ethyl
(4b)
2-methyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-carboxylate
47.0 mg (Orange liquid, 75% yield); TLC Rf = 0.27 (PE/EtOAc = 3:1); 1H NMR (400 MHz, CDCl3) δ
7.40-7.38 (m, 3H), 7.06 (d, J = 8.0 Hz, 2H), 4.16 (q, J = 7.0 Hz, 2H), 2.56-2.45 (m, 2H), 2.43-2.39
(m, 2H), 1.83-1.79 (m, 2H), 1.69-1.64 (m, 2H), 1.58-1.57 (m, 2H), 1.48 (s, 3H), 1.23 (t, J = 7.0 Hz,
13
3H); C NMR (101 MHz, CDCl3) δ 195.4, 179.6, 167.7, 137.7, 129.4, 128.0, 127.5, 112.7, 75.2,
61.9, 31.9, 29.7, 27.8, 26.0, 21.7, 19.6, 19.2, 14.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C19H23NO3Na 336.1570; Found 336.1571.
Pentyl
2-methyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-carboxylate
1
(4c) 59.0 mg (Yellow liquid, 83% yield); TLC Rf = 0.35 (PE/EtOAc = 3:1); H NMR (400 MHz,
CDCl3) δ 7.41-7.37 (m, 2H), 7.33-7.29 (m, 1H), 7.06 (d, J = 7.3 Hz, 2H), 4.17-4.06 (m, 2H),
2.5-2.52 (m, 2H), 2.47 (ddd, J = 15.2 Hz, 7.4 Hz, 4.0 Hz, 1H), 1.86-1.79 (m, 2H), 1.69-1.59 (m, 6H),
13
1.48 (s, 3H), 1.31-1.27 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); C NMR (101 MHz, CDCl3) δ 195.4,
179.5, 167.8, 137.8, 129.4, 128.0, 127.4, 112.8, 75.2, 66.0, 32.0, 29.7, 28.1, 27.9, 27.8, 26.0, 22.2,
21.7, 19.1, 14.0; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H29NO3Na 378.2040; Found
378.2040.
Isobutyl 2-methyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2- carboxylate
1
(4d) 48.5 mg (Orange liquid, 71% yield); TLC Rf = 0.38 (PE/EtOAc = 3:1); H NMR (400 MHz,
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CDCl3) δ 7.40-7.36 (m, 2H), 7.33-7.29 (m, 1H), 7.05 (d, J = 7.4 Hz, 2H), 3.97 (dd, J = 10.5 Hz, 6.6
Hz, 1H), 3.84 (dd, J = 10.5 Hz, 6.6 Hz, 1H), 2.55-2.52 (m, 2H), 2.49 (ddd, J = 15.2 Hz, 9.0 Hz, 2.6
Hz, 1H), 2.34 (ddd, J = 15.2 Hz, 9.0 Hz, 2.6 Hz, 1H), 1.96-1.77 (m, 3H), 1.69-1.53 (m, 4H), 1.46 (s,
3H), 0.91 (d, J = 4.3 Hz, 3H), 0.90 (d, J = 4.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 195.4, 179.5,
167.8, 137.7, 129.4, 127.9, 127.4, 112.9, 75.2, 71.7, 32.0, 29.7, 27.8, 26.1, 21.7, 19.0, 19.0, 18.9;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C21H27NO3Na 364.1883; Found 364.1883.
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2-Methoxyethyl
2-methyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
1
carboxylate (4e) 41.2 mg (Orange liquid, 60% yield); TLC Rf = 0.30 (PE/EtOAc = 2:1); H NMR
(400 MHz, CDCl3) δ 7.40-7.37 (m, 2H), 7.34-7.29 (m, 1H), 7.13 (d, J = 7.3 Hz, 2H), 4.33-4.30 (m,
1H), 4.22-4.17 (m, 1H), 3.61-3.53 (m, 2H), 3.36 (s, 3H), 2.53-2.49 (m, 2H), 2.46-2.38 (m, 2H),
1.84-1.79 (m, 2H), 1.69-1.65 (m, 2H), 1.61-1.55 (m, 2H), 1.49 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 195.1, 179.9, 167.7, 137.6, 129.4, 128.3, 127.7, 112.4, 75.2, 70.2, 64.8, 58.9, 31.9, 29.7, 27.8, 25.9,
21.7, 19.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C20H25NO4Na 366.1676; Found 366.1676.
Methyl 2-ethyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-carboxylate (4f)
o
53.2 mg (Yellow solid, 85% yield); m.p. = 92.7-94.8 C; TLC Rf = 0.27 (PE/EtOAc = 3:1); 1H NMR
(400 MHz, CDCl3) δ 7.41-7.38 (m, 2H), 7.33-7.29 (m, 1H), 7.07 (d, J = 7.4 Hz, 2H), 3.67 (s, 3H),
2.62-2.60 (m, 2H), 2.50 (ddd, J = 15.3 Hz, 8.2 Hz, 2.2 Hz, 1H), 2.44-2.34 (m, 2H), 2.01-1.94 (m,
1H), 1.92-1.85 (m, 1H), 1.81-1.73 (m, 2H), 1.69-1.57 (m, 2H), 1.52-1.44 (m, 1H), 0.78 (t, J = 7.4 Hz,
13
3H); C NMR (101 MHz, CDCl3) δ 194.2, 181.0, 167.9, 137.7, 129.3, 127.4, 127.2, 114.9, 79.3,
52.7, 32.0, 29.7, 27.9, 26.4, 25.1, 21.7, 6.8; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C19H23NO3Na 336.1570; Found 336.1572.
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Ethyl 3-oxo-1-phenyl-2-propyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-carboxylate (4g)
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4
o
56.6 mg (Yellow solid, 83% yield); m.p. = 75.9-77.5 C; TLC Rf = 0.36 (PE/EtOAc = 3:1); 1H NMR
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(400 MHz, CDCl3) δ 7.40-7.29 (m, 2H), 7.32-7.29 (m, 1H), 7.06-7.04 (m, 2H), 4.11 (q, J = 11.6 Hz,
2H), 2.65-2.55 (m, 2H), 2.48-2.33 (m, 3H), 1.91-1.79 (m, 3H), 1.77-1.70 (m, 1H), 1.66-1.60 (m, 2H),
1.54-1.49 (m, 1H), 1.18 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
194.4, 180.6, 167.3, 137.7, 129.3, 127.3, 127.0, 114.7, 79.0, 61.9, 34.0, 32.0, 29.7, 27.9, 26.4, 21.7,
15.6, 14.0; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C21H27NO3Na 364.1883; Found 364.1883.
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Ethyl 2-isopropyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2- carboxylate
1
(4h) 45.7 mg (Yellow liquid, 67% yield); TLC Rf = 0.32 (PE/EtOAc = 3:1); H NMR (400 MHz,
CDCl3) δ 7.40-7.36 (m, 2H), 7.34-7.30 (m, 1H), 7.19 (d, J = 7.5 Hz, 2H), 4.24-4.16 (m 2H),
2.82-2.75 (m, 1H), 2.53-2.51 (m, 2H), 2.48-2.35 (m, 2H), 1.86-1.78 (m, 2H), 1.75-1.58 (m, 3H),
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1.54-1.46 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.72 (d, J = 7.0 Hz, 3H); C
NMR (101 MHz, CDCl3) δ 180.2, 167.3, 139.0, 129.2, 128.4, 127.4, 114.0, 82.0, 61.8, 32.7, 32.0,
29.6, 28.0, 26.2, 21.6, 17.5, 15.6, 14.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C21H27NO3Na
364.1883; Found 364.1884.
Methyl
2-cyclopropyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
o
carboxylate (4i) 45.4 mg (Yellow solid, 70% yield); m.p. = 101.6-103.3 C; TLC Rf = 0.27
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(PE/EtOAc = 3:1); H NMR (400 MHz, CDCl3) δ 7.42-7.33 (m, 3H), 7.16-7.14 (m, 2H), 3.78 (m,
3H), 2.56-2.48 (m, 2H), 2.40 (ddd, J = 15.5 Hz, 8.1 Hz, 2.4 Hz, 1H), 2.30 (ddd, J = 15.5 Hz, 8.1 Hz,
2.4 Hz, 1H), 1.88-1.82 (m, 1H), 1.79-1.71 (m, 2H), 1.68-1.59 (m, 2H), 1.47-1.39 (m, 2H), 1.18-1.11
(m, 1H), 0.67-0.59 (m, 1H), 0.34-0.26 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 192.1, 180.5, 168.5,
138.1, 129.3, 128.6, 127.7, 113.5, 77.3, 53.0, 31.9, 29.9, 27.9, 26.1, 21.6, 13.9, 1.9, 0.5; HRMS
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(ESI-TOF) m/z: [M+Na]+ Calcd for C20H23NO3Na 348.1570; Found 348.1571.
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Ethyl 3-oxo-1,2-diphenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-carboxylate (4j) 57.8
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9
1
mg (Yellow liquid, 77% yield); TLC Rf = 0.32 (PE/EtOAc = 3:1); H NMR (400 MHz, CDCl3) δ
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7.30-7.28 (m, 5H), 7.25-7.20 (m, 3H), 6.92-6.90 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 2.69-2.55 (m,
2H), 2.52-2.41 (m, 2H), 1.85-1.82 (m, 2H), 1.79-1.74 (m, 1H), 1.70-1.63 (m, 2H), 1.61-1.51 (m, 1H),
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1.13 (t, J = 7.1 Hz, 3H); C NMR (101 MHz, CDCl3) δ 193.9, 180.5, 166.6, 138.2, 135.3, 128.8,
128.5, 128.3, 127.9, 127.1, 113.6, 82.4, 62.2, 32.0, 30.1, 27.9, 26.2, 21.9, 14.0; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C24H25NO3Na 398.1727; Found 398.1729.
Benzyl 2-methyl-3-oxo-1-phenyl-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-carboxylate
(4m)
o
66.8 mg (Yellow solid, 89% yield); m.p. = 82.8-84.2 C; TLC Rf = 0.27 (PE/EtOAc = 3:1); 1H NMR
(400 MHz, CDCl3) δ 7.36-7.27 (m, 8H), 6.92-6.90 (m, 2H), 5.21 (d, J = 12.4 Hz, 1H), 5.12 (d, J =
12.4 Hz, 1H), 2.51-2.44 (m, 3H), 2.38 (ddd, J = 15.3 Hz, 7.6 Hz, 3.9 Hz, 1H), 1.85-1.77 (m, 2H),
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1.66-1.55 (m, 4H), 1.50 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.3, 179.7, 167.6, 137.5, 135.4,
129.3, 128.5, 128.3, 128.1, 128.0, 127.5, 112.8, 75.1, 67.4, 31.9, 29.7, 27.8, 26.0, 21.7, 19.1; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C24H25NO3Na 398.1727; Found 398.1726.
Benzyl
1-(4-fluorophenyl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
o
carboxylate (4n) 68.4 mg (Yellow solid, 87% yield); m.p. = 74.6-76.3 C; TLC Rf = 0.59
1
(PE/EtOAc = 2:1); H NMR (400 MHz, CDCl3) δ 7.36-7.30 (m, 5H), 6.97-6.93 (m, 2H), 6.90-6.88
(m, 2H), 5.22 (d, J = 12.3 Hz, 1H), 5.09 (d, J = 12.3 Hz, 1H), 2.49-2.33 (m, 4H), 1.83-1.77 (m, 2H),
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1.64-1.55 (m, 4H), 1.50 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.2, 179.5, 167.3, 161.6 (d, J =
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249.4 Hz), 135.3, 133.4 (d, J = 3.2 Hz), 130.2 (d, J = 8.7 Hz), 128.6, 128.4, 128.3, 116.3 (d, J = 22.7
Hz), 112.6, 75.1, 67.4, 31.8, 29.5, 27.7, 25.9, 21.7, 19.1; 19F NMR (376 MHz, CDCl3) δ -113.2;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H24NO3FNa 416.1632; Found 416.1631.
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Benzyl
1-(4-chlorophenyl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
1
carboxylate (4o) 68.7 mg (Yellow liquid, 84% yield); TLC Rf = 0.33 (PE/EtOAc = 3:1); H NMR
(400 MHz, CDCl3) δ 7.36-7.34 (m, 3H), 7.31-7.29 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6
Hz, 2H), 2.49-2.42 (m, 3H), 2.40-2.33 (m, 1H), 1.85-1.77 (m, 2H), 1.65-1.56 (m, 4H), 1.50 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 195.2, 179.2, 167.3, 136.1, 135.3, 133.2, 129.5, 129.3, 128.6, 128.4,
128.3, 113.4, 75.0, 67.5, 31.8, 29.6, 27.6, 25.9, 21.7, 19.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C24H24NO3ClNa 432.1337; Found 432.1335.
Benzyl
1-(4-bromophenyl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
1
carboxylate (4p) 71.6 mg (Brown liquid, 79% yield); TLC Rf = 0.33 (PE/EtOAc = 3:1); H NMR
(400 MHz, CDCl3) δ 7.37-7.34 (m, 5H), 7.30-7.27 (m, 2H), 6.76 (d, J = 8.7 Hz, 2H), 5.21 (d, J =
12.3 Hz, 1H), 5.07 (d, J = 12.3 Hz, 1H), 2.48-2.42 (m, 3H), 2.39-2.33 (m, 1H), 1.83-1.78 (m, 2H),
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1.65-1.55 (m, 4H), 1.50 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.2, 179.2, 167.3, 136.6, 135.2,
132.5, 129.5. 128.6, 128.4, 128.3, 121.1, 113.5, 75.0, 67.5, 31.8, 29.7, 27.6, 25.9, 21.7, 19.2; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C24H24NO3BrNa 476.0832; Found 476.0832.
Benzyl
1-(4-iodophenyl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
1
carboxylate (4q) 77.2 mg (Yellow liquid, 77% yield); TLC Rf = 0.37 (PE/EtOAc = 3:1); H NMR
(400 MHz, CDCl3) δ 7.56 (d, J = 8.6 Hz, 2H), 7.36-7.34 (m, 3H), 7.30-7.27 (m, 2H), 6.63 (d, J = 8.6
Hz, 2H), 5.21 (d, J = 12.3 Hz, 1H), 5.08 (d, J = 12.3 Hz, 1H), 2.49-2.42 (m, 3H), 2.40-2.33 (m, 1H),
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1.85-1.75 (m, 2H), 1.65-1.56 (m, 4H), 1.50 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.2, 179.1,
167.3, 138.5, 137.4, 135.3, 129.7, 128.6, 128.4, 128.3, 113.6, 92.4, 75.0, 67.5, 31.8, 29.7, 27.6, 25.9,
21.7, 19.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H24NO3INa 524.0693; Found 524.0692.
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Benzyl 2-methyl-3-oxo-1-(p-tolyl)-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2- carboxylate
1
(4r) 56.8 mg (Brown liquid, 73% yield); TLC Rf = 0.30 (PE/EtOAc = 3:1); H NMR (400 MHz,
CDCl3) δ 7.37-7.32 (m, 5H), 7.08 (d, J = 8.2 Hz, 2H), 5.21 (d, J = 12.4 Hz, 1H), 5.11 (d, J = 12.4 Hz,
1H), 2.50-2.44 (m, 3H), 2.41-2.37 (m, 1H), 2.35 (s, 3H), 1.85-1.77 (m, 2H), 1.64-1.57 (m, 4H), 0.50
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.2, 179.9, 167.6, 137.6, 135.4, 134.7, 129.9, 128.5, 128.2,
128.1, 128.0, 112.2, 75.1, 67.3, 31.9, 29.6, 27.8, 25.9, 21.7, 21.1, 19.0; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C25H27NO3Na 412.1883; Found 412.1883.
Benzyl 2-methyl-3-oxo-1-(m-tolyl)-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2- carboxylate
o
(4s) 52.9 mg (Yellow solid, 68% yield); m.p. = 93.3-94.8 C; TLC Rf = 0.33 (PE/EtOAc = 3:1); 1H
NMR (400 MHz, CDCl3) δ 7.36-7.34 (m, 5H), 7.18-7.14 (m, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.71-6.70
(m, 2H), 5.23 (d, J = 12.4 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 2.51-2.45 (m, 3H), 2.41-2.35 (m, 1H),
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2.24 (s, 3H), 1.86-1.78 (m, 2H), 1.66-1.59 (m, 4H), 1.49 (s, 3H); C NMR (101 MHz, CDCl3) δ
195.3, 179.8, 167.6, 139.4, 137.4, 135.4, 129.0, 128.5, 128.5, 128.3, 128.2, 125.0, 112.6, 75.1, 67.4,
31.9, 29.7, 27.8, 26.0, 21.8, 21.3, 19.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H27NO3Na
412.1883; Found 412.1883.
Benzyl
1-(4-methoxyphenyl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-
2-carboxylate (4t) 53.5 mg (Yellow liquid, 66% yield); TLC Rf = 0.48 (PE/EtOAc = 2:1); 1H NMR
(400 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 6.85 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 5.20 (d, J
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= 12.4 Hz, 1H), 5.09 (d, J = 12.4 Hz, 1H), 3.79 (s, 3H), 2.49-2.32 (m, 4H), 1.85-1.73 (m, 2H),
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1.63-1.56 (m, 4H), 1.50 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.1, 180.1, 167.5, 158.9, 135.4,
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129.8, 129.8, 128.5, 128.3, 128.2, 114.4, 111.7, 75.2, 67.3, 55.5, 31.9, 29.5, 27.9, 25.9, 21.7, 19.0;
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HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H27NO4Na 428.1832; Found 428.1834.
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Benzyl
2-methyl-1-(4-nitrophenyl)-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
1
carboxylate (4u) 62.2 mg (Yellow liquid, 74% yield); TLC Rf = 0.31 (PE/EtOAc = 3:1); H NMR
(400 MHz, CDCl3) δ 8.07 (d, J = 9.0 Hz, 2H), 7.34-7.32 (m, 3H), 7.28-7.25 (m, 2H), 6.93 (d, J = 9.0
Hz, 2H), 5.24 (d, J = 12.2 Hz, 1H), 5.06 (d, J = 12.2 Hz, 1H), 2.62 (t, J = 5.6 Hz, 2H), 2.48 (ddd, J =
15.4 Hz, 7.0 Hz, 4.1 Hz, 1H), 2.39 (ddd, J = 15.4 Hz, 7.0 Hz, 4.1 Hz, 1H), 1.91-1.82 (m, 2H),
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1.72-1.65 (m, 2H), 1.62-1.57 (m, 2H), 1.55 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.0, 177.7,
167.0, 145.1, 143.8, 135.0, 128.6, 128.6, 128.5, 126.1, 124.8, 117.0, 75.0, 67.8, 31.7, 30.1, 27.1, 26.1,
21.8, 19.6; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H24N2O5Na 443.1577; Found 443.1577.
Benzyl
1-(4-cyanophenyl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
1
carboxylate (4v) 56.8 mg (Yellow liquid, 71% yield); TLC Rf = 0.57 (PE/EtOAc = 2:1); H NMR
(400 MHz, CDCl3) δ 7.51 (d, J = 8.6 Hz, 2H), 7.36-7.33 (m, 3H), 7.28-7.26 (m, 2H), 6.90 (d, J = 8.6
Hz, 2H), 5.22 (d, J = 12.2 Hz, 1H), 5.07 (d, J = 12.2 Hz, 1H), 2.57 (t, J = 5.6 Hz, 2H), 2.47 (ddd, J =
15.4 Hz, 7.0 Hz, 3.8 Hz, 1H), 2.37 (ddd, J = 15.4 Hz, 7.0 Hz, 3.8 Hz, 1H), 1.87-1.80 (m, 2H),
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1.70-1.63 (m, 2H), 1.61-1.56 (m, 2H), 1.51 (s, 3H); C NMR (101 MHz, CDCl3) δ 195.1, 178.1,
167.1, 142.0, 135.0, 133.2, 128.6, 128.6, 128.4, 126.9, 118.2, 116.2, 109.8, 74.9, 67.8, 31.8, 30.0,
27.2, 26.0, 21.7, 19.5; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H24N2O3Na 423.1679; Found
423.1679.
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Benzyl
1-(4-(ethoxycarbonyl)phenyl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]
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pyrrole-2-carboxylate (4w) 58.1 mg (Yellow liquid, 65% yield); TLC Rf = 0.31 (PE/EtOAc = 3:1);
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.6 Hz, 2H), 7.35-7.28 (m 5H), 6.91 (d, J = 8.6 Hz, 2H),
5.20 (d, J = 12.3 Hz, 1H), 5.10 (d, J = 12.3 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.56 (t, J = 5.6 Hz,
2H), 2.47 (ddd, J = 15.4 Hz, 7.1 Hz, 3.6 Hz, 1H), 2.38 (ddd, J = 15.4 Hz, 7.1 Hz, 3.6 Hz, 1H),
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1.84-1.79 (m, 2H), 1.69-1.56 (m, 4H), 1.50 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); C NMR (101 MHz,
CDCl3) δ 195.2, 178.8, 167.3, 165.7, 141.8, 35., 130.7, 128.6, 128.6, 128.4, 128.2, 126.5, 114.9, 75.0,
67.6, 61.2, 31.9, 29.9, 27.4, 26.0, 21.8, 19.3, 14.4; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C27H29NO5Na 470.1938; Found 470.1938.
Benzyl
1-(1H-indazol-5-yl)-2-methyl-3-oxo-1,2,3,4,5,6,7,8-octahydrocyclohepta[b]pyrrole-2-
1
carboxylate (4x) 39.0 mg (Yellow solid, 47% yield); TLC Rf = 0.25 (PE/EtOAc = 1:1); H NMR
(400 MHz, CDCl3) δ 11.46 (brs, 1H), 7.97 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.33-7.30 (m, 6H), 6.95
(d, J = 8.8 Hz, 1H), 5.26 (d, J = 12.2 Hz, 1H), 5.09 (d, J = 12.2 Hz, 1H), 2.52-2.40 (m, 4H),
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1.82-1.81 (m, 2H), 1.64-1.57 (m, 7H); C NMR (101 MHz, CDCl3) δ 195.5, 180.8, 167.6, 139.1,
135.4, 134.8, 130.3, 128.6, 128.4, 127.5, 123.4, 121.0, 112.0, 110.9, 75.6, 67.5, 31.9, 29.6, 27.9, 25.9,
21.7, 19.1; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H25N3O3Na 438.1788; Found 438.1789.
Benzyl 2-methyl-3-oxo-1-(2,2,2-trifluoroethyl)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate
(4z)
36.8 mg (Yellow liquid, 50% yield); TLC Rf = 0.42 (PE/EtOAc = 3:1); 1H NMR (400 MHz, CDCl3) δ
7.40-7.32 (m, 5H), 5.17 (q, J = 12.5 Hz, 2H), 3.99-3.88 (m, 1H), 3.67-3.57 (m, 1H), 2.48 (t, J = 5.8
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Hz, 2H), 2.23 (t, J = 5.7 Hz, 2H), 1.88-1.78 (m, 2H), 1.73-1.61 (m, 5H); 13C NMR (101 MHz,
CDCl3) δ 194.1, 175.5, 167.2, 135.3, 128.6, 128.3, 127.7, 123.6 (q, J = 281.0 Hz), 108.7, 74.8, 67.8,
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45.8 (q, J = 35.5 Hz), 24.2, 22.0, 21.6, 18.9, 18.5; F NMR (376 MHz, CDCl3) δ -69.95; HRMS
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(ESI-TOF) m/z: [M+Na]+ Calcd for C19H20NO3F3Na 390.1293; Found 390.1296.
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Benzyl
(4ab)
2-methyl-3-oxo-1-phenyl-1,2,3,4,5,6-hexahydrocyclopenta[b]pyrrole-2-carboxylate
17.4 mg (Brown liquid, 25% yield); TLC Rf = 0.52 (PE/EtOAc = 2:1); 1H NMR (400 MHz, CDCl3) δ
7.40-7.33 (m, 4H), 7.31-7.24 (m, 3H), 7.18-7.15 (m, 1H), 6.91-6.89 (m, 2H), 5.26 (d, J = 12.4 Hz,
1H), 5.18 (d, J = 12.4 Hz, 1H), 2.92-2.72 (m, 2H), 2.60-2.50 (m, 2H), 2.47-2.39 (m, 2H), 1.67 (s,
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3H); C NMR (101 MHz, CDCl3) δ 189.0, 185.3, 167.5, 138.0, 135.3, 129.5, 128.5, 128.3, 128.2,
125.5, 122.4, 116.6, 82.2, 67.7, 28.8, 27.6, 22.2, 19.2; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C22H21NO3Na 370.1414; Found 370.1415.
Benzyl 2-methyl-3-oxo-1-phenyl-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate (4ac)19d 57.8
1
mg (Yellow liquid, 80% yield); TLC Rf = 0.27 (PE/EtOAc = 3:1); H NMR (400 MHz, CDCl3) δ
7.36-7.27 (m, 9H), 7.00-6.98 (m, 2H), 5.22 (d, J = 12.4 Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H), 2.37-2.27
(m, 4H), 1.79-1.67 (m, 4H), 1.55 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 195.6, 175.2, 167.6, 137.1,
135.4, 129.3, 128.2, 128.1, 128.0, 127.6, 107.5, 75.0, 67.4, 25.5, 22.2, 22.1, 19.0, 19.0.
Benzyl 2,5,5-trimethyl-3-oxo-1-phenyl-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate (4ad)
63.8 mg (Yellow solid, 82% yield); m..p. = 60.2-62.0 oC; TLC Rf = 0.35 (PE/EtOAc = 3:1); 1H NMR
(400 MHz, CDCl3) δ 7.36-7.28 (m, 8H), 7.00-6.97 (m, 2H), 5.20 (d, J = 12.4 Hz, 1H), 5.13 (d, J =
12.4 Hz, 1H), 2.34-2.31 (m, 2H), 2.17 (d, J = 15.7 Hz, 1H), 2.09 (d, J = 15.7 Hz, 1H), 1.56 (s, 3H),
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1.53 (t, J = 6.5 Hz, 2H), 1.02 (s, 3H), 1.00 (s, 3H); C NMR (101 MHz, CDCl3) δ 196.0, 174.3,
167.6, 137.3, 135.3, 129.4, 128.5, 128.3, 128.2, 128.1, 127.6, 107.3, 75.5, 67.4, 35.0, 32.8, 29.5,
28.0, 27.6, 22.7, 18.9; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H27NO3Na 412.1883; Found
412.1885.
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Benzyl 2-methyl-3-oxo-1-phenyl-1,2,3,4,6,7-hexahydropyrano[4,3-b]pyrrole-2-carboxylate (4ae)
47.2 mg (Yellow liquid, 65% yield); TLC Rf = 0.32 (PE/EtOAc = 2:1); 1H NMR (400 MHz, CDCl3) δ
7.37-7.28 (m, 8H), 7.00-6.98 (m, 2H), 5.25 (d, J = 12.3 Hz, 1H), 5.13 (d, J = 12.3 Hz, 1H), 4.52 (s,
2H), 3.96-3.90 (m, 1H), 3.83-3.77 (m, 1H), 2.53 (dt, J = 17.9 Hz, 6.0 Hz, 1H), 2.45 (dt, J = 17.9 Hz,
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6.0 Hz, 1H), 1.58 (s, 3H); C NMR (101 MHz, CDCl3) δ 192.7, 171.9, 167.1, 136.4, 135.2, 129.5,
126, 128.4, 128.3, 127.9, 127.6, 105.4, 75.4, 67.7, 63.2, 62.5, 261, 18.8; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C22H21NO4Na 386.1363; Found 386.1362.
Benzyl 2-methyl-3-oxo-1-phenyl-1,2,3,4,6,7-hexahydrothiopyrano[4,3-b]pyrrole-2- carboxylate
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(4af)19d 45.5 mg (Orange liquid, 60% yield); TLC Rf = 0.27 (PE/EtOAc = 3:1); H NMR (400 MHz,
CDCl3) δ 7.39-7.27 (m, 8H), 7.00 (dd, J = 7.9 Hz, 1.6 Hz, 2H), 5.25 (d, J = 12.3 Hz, 1H), 5.12 (d, J
= 12.3 Hz, 1H), 3.52 (d, J = 15.6 Hz, 1H), 3.41 (d, J = 15.6 Hz, 1H), 2.89-2.72 (m, 2H), 2.58 (t, J =
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5.7 Hz, 2H), 1.56 (s, 3H); C NMR (101 MHz, CDCl3) δ 194.3, 173.7, 167.1, 136.4, 135.2, 129.6,
128.6, 128.6, 128.4, 128.3, 128.3, 104.4, 74.3, 67.6, 27.6, 24.8, 21.2, 18.9.
Benzyl
2-methyl-3-oxo-1-phenyl-2,3,4,5,6,7,8,9-octahydro-1H-cycloocta[b]pyrrole-2-
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carboxylate (4ag) 59.9 mg (Orange liquid, 77% yield); TLC Rf = 0.27 (PE/EtOAc = 3:1); H NMR
(400 MHz, CDCl3) δ 7.40-7.26 (m, 8H), 6.97 (dd, J = 7.9 Hz, 1.5 Hz, 2H), 5.24 (d, J = 12.2 Hz, 1H),
5.12 (d, J = 12.2 Hz, 1H), 2.59-2.48 (m, 2H), 2.48-2.39 (m, 1H), 2.29-2.18 (m, 1H), 1.70-1.46 (m,
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10H), 1.42-1.33 (m, 1H); C NMR (101 MHz, CDCl3) δ 195.7, 177.5, 167.6, 137.2, 135.2, 129.4,
129.2, 128.6, 128.5, 128.4, 128.1, 110.2, 74.8, 67.52, 29.82, 28.1, 26.2, 25.3, 25.2, 20.8, 18.7;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25H27NO3Na 412.1883; Found 412.1884.
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Benzyl
2-methyl-3-oxo-1-phenyl-2,3,4,5,6,7,8,9,10,11,12,13-dodecahydro-1H-cyclododeca[b]
pyrrole-2-carboxylate (4ah) 38.3 mg (Orange liquid, 43% yield); TLC Rf = 0.54 (PE/EtOAc = 3:1);
1H NMR (400 MHz, CDCl3) δ 7.41-7.38 (m, 1H), 7.36-7.30 (m, 7H), 7.02-6.91 (m, 2H), 5.23 (d, J =
12.2 Hz, 1H), 5.14 (d, J = 12.2 Hz, 1H), 2.67-2.55 (m, 1H), 2.44-2.31 (m, 2H), 2.27-2.18 (m, 1H),
1.77-1.70 (m, 1H), 1.65-1.48 (m, 2H), 1.40 (s, 3H), 1.39-1.12 (m, 13H); 13C NMR (101 MHz, CDCl3)
δ 197.8, 176.9, 167.9, 138.2, 135.2, 129.4, 128.6, 128.5, 128.3, 127.6, 127.0, 111.0, 74.0, 67.5, 26.0,
25.9, 25.6, 24.2, 24.1, 23.7, 23.5, 23.2, 21.8, 20.2, 18.5; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C29H35NO3Na 468.2509; Found 468.2512.
Benzyl 5-ethyl-2,4-dimethyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrole-2-carboxylate (4ai) 21.6
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mg (Orange liquid, 31% yield); TLC Rf = 0.27 (PE/EtOAc = 3:1); H NMR (400 MHz, CDCl3) δ
7.37-7.28 (m, 8H), 6.97 (dd, J = 7.8 Hz, 1.7 Hz, 2H), 5.26 (d, J = 12.3 Hz, 1H), 5.08 (d, J = 12.4 Hz,
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1H), 2.51-2.36 (m, 2H), 1.82 (s, 3H), 1.50 (s, 3H), 1.02 (t, J = 7.6 Hz, 3H); C NMR (101 MHz,
CDCl3) δ 197.1, 178.3, 167.6, 137.4, 135.4, 129.4, 128.9, 128.5, 128.3, 128.0, 104.9, 74.6, 67.4, 20.4,
18.9, 11.7, 6.7; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H23NO3Na 372.1570; Found 372.1571.
Benzyl 4-acetyl-2,5-dimethyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrole-2-carboxylate (4aj) 39.9
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mg (Orange liquid, 55% yield); TLC Rf = 0.23 (PE/EtOAc = 3:1); H NMR (400 MHz, CDCl3) δ
7.44-7.32 (m, 8H), 6.99 (d, J = 7.3 Hz, 2H), 5.31 (d, J = 12.2 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H),
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2.51 (s, 3H), 2.45 (s, 3H), 1.61 (s, 3H); C NMR (101 MHz, CDCl3) δ 194.2, 192.9, 182.0, 165.7,
135.0, 134.8, 129.9, 129.7, 128.7, 128.6, 109.9, 76.9, 68.1, 30.2, 18.8, 16.7; HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C22H21NO4Na 386.1363; Found 386.1363.
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Benzyl
4-(dimethylcarbamoyl)-2,5-dimethyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrole-2-
o
carboxylate (4ak) 39.2 mg (Yellow liquid, 50% yield); m.p. = 120.2-122.2 C; TLC Rf = 0.26
(PE/EtOAc/MeOH = 15:15:1); 1H NMR (400 MHz, CDCl3) δ 7.46-7.29 (m, 8H), 7.02 (d, J = 7.3 Hz,
2H), 5.19 (s, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.24 (s, 3H), 1.58 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 190.4, 179.5, 166.4, 165.0, 135.8, 134.8, 129.8, 129.2, 128.7, 128.7, 128.6, 106.7, 75.9, 67.9, 38.5,
35.2, 18.5, 15.3; HRMS (ESI-TOF) m/z: [M+Na]+Calcd for C23H24N2O4Na 415.1628; Found
415.1628.
2-Benzyl 4-methyl 2,5-dimethyl-3-oxo-1-phenyl-2,3-dihydro-1H-pyrrole-2,4-dicarboxylate (4al)
44.0 mg (Yellow liquid, 58% yield); TLC Rf = 0.31 (PE/EtOAc = 2:1); 1H NMR (400 MHz, CDCl3) δ
7.44-7.30 (m, 8H), 6.99 (d, J = 7.4 Hz, 2H), 5.32 (d, J = 12.1 Hz, 1H), 5.06 (d, J = 12.1 Hz, 1H),
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3.86 (s, 3H), 2.44 (s, 3H), 1.61 (s, 3H); C NMR (101 MHz, CDCl3) δ 191.2, 182.0, 165.7, 164.7,
135.2, 134.8, 129.9, 129.6, 128.8, 128.7, 128.7, 128.7, 101.1, 76.7, 68.1, 51.2, 18.9, 16.1; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C22H21NO5Na 402.1312; Found 402.1312.
 ASSOCIATED CONTENT
Supproting Imformation
Proton, carbon, HRMS data and NMR spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
 AUTHOR IMFORMATION
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Corresponding Author
*E-mail: qsha@njau.edu.cn.
Notes
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The authors declare no competing financial interest.
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 ACKNOWLEDGEMENTS
The project was supported by the Fundamental Research Funds for the Central Universities
(KYZ201751) and Nanjing Agricultural University.
 REFERENCES
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