Ru(II)-Catalyzed C-H Activation: Amide-Directed 1,4-Addition of the Ortho C-H Bond to Maleimides

Article abstract of DOI:10.1021/acs.joc.6b01160

Maleimide has been used as a selective coupling partner to generate conjugate addition products exclusively. The typical Heck-type oxidative coupling that occurs when alkenes are used is avoided by choosing maleimide as an alkene, which cannot undergo β-hydride elimination due to the unavailability of a syn-periplanar β-hydrogen atom. The amide nitrogen, which is notorious for undergoing tandem reactions to generate spirocyclic or annulation products under cross-coupling conditions, remains innocent in this report. Along with the substrate scope, a robustness screen has been performed to analyze the performance of amide as a directing group in the presence of other directing groups and also to examine the tolerance of the reaction conditions for other frequently encountered functional groups.

Full text of DOI:10.1021/acs.joc.6b01160

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Article
Ru (II)-Catalyzed C-H Activation: Amide -Directed
1,4-Addition of Ortho C-H Bond to Maleimides
Puspam Keshri, Kiran R Bettadapur, Veeranjaneyulu Lanke, and Kandikere Ramaiah Prabhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01160 • Publication Date (Web): 17 Jun 2016
Downloaded from http://pubs.acs.org on June 17, 2016
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Ru(II)-Catalyzed C−H Activation: Amide -Directed
1,4-Addition of Ortho C−H Bond to Maleimides
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Puspam Keshri, Kiran R. Bettadapur, Veeranjaneyulu Lanke and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka,
India
*E-mail: prabhu@orgchem.iisc.ernet.in.
Abstract
Maleimide has been used as a selective coupling partner to generate conjugate addition
products exclusively. The typical Heck-type oxidative coupling that occurs, when alkenes are
used, is avoided by choosing maleimide as an alkene, which cannot undergo β-hydride
elimination, due to the unavailability of syn-periplanar β-hydrogen atom. The amide nitrogen
which is notorious to undergo tandem reactions to generate spirocyclic or annulation products
under cross-coupling conditions, remains innocent in this report. Along with the substrate scope,
a robustness screen has been performed to analyze the performance of amide as a directing group
in presence of other directing groups, and also to examine the tolerance of the reaction conditions
for other frequently encountered functional groups.
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Introduction
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Functionalization of arenes at the ortho–position by employing a directing group strategy
is well known.1 Various metal catalysts have been used to achieve such functionalization of
arenes, however, the Pd catalysts have, by and large, dominated this arena.2 Ruthenium, a much
cheaper metal than palladium,3 has been under-represented in this area.4 Nonetheless, the
pioneering work by Murai5 and others6 has resulted in an increased number of reports of ortho–
functionalization of arenes using Ru catalysts. In continuation of our work in this area,7 we
initiated studies towards the use of diverse coupling partners with traditional directing groups.
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The hydroarylation reaction is a useful method to add an arene, across an alkene or
alkyne.8 Ru (0) catalysts/precursors have been traditionally5,8 used for hydroarylation across an
alkene, wherein, the metal inserts into the C-H bond at the ortho–position. This oxidative
addition process generates a reactive C(sp2)–Ru–H species,9 which undergoes an insertion
reaction with an alkene. Further, the metal is ejected via a reductive elimination process to create
a new bond between the arene and the coupling partner (Scheme 1). Here, the metal goes through
a cycle of redox reactions, typically from Ru(0) to Ru(II) and back to Ru(0). Ru(0) catalysts are
often not stable to air and water, a property that limits the wide application of a method.10 There
have been some reports on generating Ru(0) catalysts in situ, using the more stable and easy to
handle Ru(II) or Ru(III) catalysts.10,11
An alternate pathway to obtain hydroarylated products using Ru(II) catalysts, is to choose
a substrate which undergoes protonation faster than beta-hydride elimination. This can be
achieved by ensuring that the β-hydrogen for β-hydride elimination is not available in a syn-
periplanar fashion and keeping the reaction medium rich in acid (Scheme 1). In view of this
difference in the mechanism, it would be more fitting to call this second pathway, as a 1,4-
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addition or conjugate addition. We have recently demonstrated the use of maleimide as an
effective coupling partner to yield conjugate addition products (Scheme 2) under Ru(II)
catalysis. 12
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Scheme 1. Mechanistic hypothesis for the work
Amide as a directing group has been fairly well explored,13 and several reactions yield
products in which amide (especially, the nitrogen atom) also undergoes transformations to
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eventually yield products that are bicyclic or spirocyclic (Scheme 2).14 Hence, amides are non-
innocent directing groups and to preserve them without undergoing any further transformations
in the reaction medium is a challenge and reports in this direction are scanty.
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Scheme 2: Comparison of previous reports and current report
Results and Discussion
Optimization of reaction conditions
We started our investigation with N-methylbenzamide (1a) and N-benzylmaleimide (2b) as
benchmark substrates. Our initial studies started with 5 mol% [RuCl2(p-cymene)]2 as the catalyst,
20 mol% AgSbF6 as the activator, 1 equiv of Cu(OAc)2.H2O as a source of acetate ions, and 10
equiv of AcOH as protonating source, which furnished 70% of the requisite product (3ab, entry
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1, Table 1). Without AcOH, the yield decreased to 41% (entry 2), which clearly revealed the
importance of acetic acid in the reaction. However, using a large excess of AcOH (30 equiv) did
not improve the yield (entry 3). Increasing the amount of maleimide, 2b (2 equiv), did not
enhance the yield of (3ab) (entry 4), and neither did decreasing the amount of 2b to 1.1 equiv
(entry 5, 63% yield). By replacing N-benzylmaleimide (2b) to N-ethylmaleimide (2a) we
observed a dramatic increase in yield (entry 6, 85%). Performing the reaction at either higher
temperature (120 C, entry 7, 57%) or lower temperature (80 °C, entry 8, 74%) did not bring any
improvement to the outcome of the reaction. When the reaction was performed in argon
atmosphere it gave same yield of 3aa as before (85%, entry 9). Decreasing the catalyst amount to
2.5 mol % of Ru, and 10 mol % of Ag, provided only 74% yield of the product (entry 10).
Varying the amount of Cu catalyst also did not help (entries 11 and 12). Changing the solvent to
acetonitrile or DMF was found to be detrimental to the yield of the product (entries 13 and 14).
Eventually, the silver activator was changed to AgNTf2 and it provided a marginal increase in the
yield of the expected product 3aa (87%, entry 15). To our surprise, changing the activator to
AgBF4, proved to be very helpful and the yield increased to 95% (entry 16). Hence, Ru (5 mol
%), AgBF4 (20 mol %), Cu(OAc)2.H2O (1.5 equiv), Acetic acid (10 equiv) in dichloroethane
solvent at 100 oC was established as the best condition to carry out the reaction.
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Table 1: Optimization table
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malemide
(eq)
AcOH Temp
entry
Solvent
activator
Yielda
(eq)
(°C)
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2
R= Bn(1.5) AgSbF6
R= Bn(1.5) AgSbF6
R= Bn(1.5) AgSbF6
R= Bn(2.0) AgSbF6
R= Bn(1.1) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgSbF6
R= Et(1.5) AgNTf2
10
0
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120
80
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
70%
41%
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44%
4
65%
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63%
6
85%
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57%
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74%
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100
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100
85% b
74% c
68% d
75% e
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100 CH3CN 42%
100
100
100
DMF
DCE
DCE
N.R
87%
16 R= Et(1.5) AgBF4
95% (91%)
Reaction conditions: 1a (0.3 mmol), 2a/b (1.5 equiv), [RuCl2(p-cymene)]2 (5 mol %), Ag salt (20 mol %),
a
Cu(OAc)2H2O (1.5 equiv), AcOH (10 equiv), DCE (2.0 mL), 100 °C. NMR yield of the product using
terephthaldehyde as the internal standard, isolated yield in parentheses b reaction was performed in Ar atmosphere
c 2.5 mol% of Ru and 10 mol% of Ag was used d reaction was performed with 2.0 equiv of Cu catalyst reaction
e
was performed with 1.0 equiv of Cu catalyst.
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Substrate scope
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With an optimized catalytic system in hand, we explored the scope of the reaction (Scheme 3).
For all the substrate scope reactions, neither the starting material nor the maleimide partner was
ever detected in significant amounts post-reaction, indicating that these components of the
reaction underwent decomposition. For this reason, the thin layer chromatograms would
generally be messy. Compounded with this problem, was the high polarity of the final product
due to the amide and succinimide groups in the same molecule. Due to this increased polarity of
the product, and decomposition of starting materials, purification was not easy and isolated
products were frequently found to be contaminated with uncharacterized impurities. Washing the
reaction mixture or the final isolated products with either, acid or base, or column purification
with different mesh sizes of silica, or alumina were not found to greatly enhance the product
purity. Wherever, extensive decomposition was observed lower yields of the product have been
reported.
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The electron rich benzamide derivatives such as 4-methoxy-N-methylbenzamide (1b)
with (2a) under the optimal reaction conditions gave 86% of the expected hydroarylated product
3ba when AgSbF6 was used instead of AgBF4 (Scheme 3). The 3- methoxy-N-methylbenzamide
derivative furnished low yield of the corresponding product (3ca, 40%). However, ortho
substituted derivatives like, 2-chloro-N-methylbenzamide (1d), 2-iodo-N-methylbenzamide (1e),
2-methyl-N-methylbenzamide (1f) and N-methyl-[1,1'-biphenyl]-2-carboxamide (1g), furnished
excellent yields of the corresponding products 3da, 3ea, and 3fa and 3ga, respectively (91, 68,
51 and 79%, respectively). To our surprise, the bulky substitution on the ortho-position of
benzamide derivative did not hamper the reaction and the reaction of ortho-styryl substitute
benzamide derivative (1h) with 2a furnished the expected hydroarylated product 3ha in 65%
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Scheme 3: Substrate Scope for benzamide a,b,c
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a Standard reaction conditions: 1 (0.3 mmol), 2 (1.5 equiv), [RuCl2(p-cymene)]2 (5 mol %), AgBF4 (20 mol %),
Cu(OAc)2.H2O (1.5 equiv), AcOH (10 equiv), DCE (2.0 mL), 100 °C. b Isolated yields c NMR yields in parentheses,
obtained by using terephthaldehyde as internal standard d Reaction was performed with AgSbF6, instead of AgBF4
e unreacted starting material = 55% f No internal standard added because of the same Rf with the product
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yield. Naphthalene derivatives such as N-methyl-1-naphthamide (1i), and N-methyl-2-
naphthamide, (1j) underwent a smooth reaction with N-ethylmaleimide (2a) under optimal
reaction conditions and produced the corresponding products 3ia and 3ja, respectively, in good
to excellent yields (65 and 83%, respectively). . On the other hand, the reaction of substrates with
different substituent on the nitrogen atom of amide such as N-cyclohexylbenzamide (1k), and N-
benzylbenzamide (1l) with N-ethylmaleimide (2a), the corresponding hydroarylated products
3ka and 3la were obtained excellent yields (95 and 86%, respectively). However, N-
phenylbenzamide (1m) under the similar reaction with N-ethylmaleimide (2a), gave only 31% of
the expected product (3ma) where around 40% of the starting material was left even after 2h.
Surprisingly, 4-methoxy-N-(4-methoxyphenyl)benzamide (1n) reacted smoothly with 2a to
provide 79% yield of 3na. The reactions of disubstituted amides such as, N,N-diethylbenzamide
(1o), N,N-dibenzylbenzamide (1p), furnished the corresponding hydroarylated products 3oa and
3pa in moderate to good yields (51 and 72%, respectively). Next we changed the maleimide
derivative to N-benzylmaleimide, and found that the reaction of the cyclohexyl derivative of
benzamide (1k) as a coupling partner furnished 96% yield of 3kb. Whereas the 4-OMe
derivative (1n) furnished only moderate yield of 3nb (48%). On reacting N-phenylmaleimide
(2c) with N-cyclohexylbenzamide (1k) the expected product 3kc was obtained in 47%.
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Acetanilide as substrate
After studying the benzamides as the directing group, we thought it is relevant to study the
reaction of acetanilide with maleimides. Under the optimized reaction conditions that was
employed for the reaction of benzamide with maleimides (entry 16, Table 1), the reaction of
acetanilide with maleimides furnished poor yields of the corresponding hydroarylated products
(6). Therefore, several conditions were examined to carry out this transformation effectively, and
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we were unable to optimize to obtain good yields. In these attempts, it was found that acetanilide
was decomposing rapidly under the reaction conditions. On reducing the temperature to 80 C,
and carrying out the reaction in the absence of AcOH, we were able to obtain the hydroarylated
prodcuts in moderate yields. Thus the reaction of acetanilide with N-ethylmaleimide afforded the
hydroarylated product 6aa in 38% isolated yield (Scheme 4). On changing to N-benzylmaleimde,
we obtained 41% of the expected product (6ab), and by using N-(4-methoxyphenyl)acetamide
we obtained only 38% of the corresponding product (6bb).
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Scheme 4: Substrate scope for acetanilide a,b,c
a
Reaction conditions: 4 (0.3 mmol), 2 (1.5 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %),
Cu(OAc)2.H2O (1.5 equiv), DCE (2.0 mL), 80 °C. b Isolated yields c NMR yields in parentheses, obtained by using
terephthaldehyde as internal standard.
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Robustness Screening
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After exploring the substrate scope of the reaction, we thought it would be appropriate to explore
this reaction in the presence of other directing groups. Since constructing molecules which have
multiple similar functional groups requires multiple steps and cumbersome, we employed the
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strategy described by Glorius et al, for exploring the tolerance of the reaction in the presence
of other directing groups as well as functional groups. Accordingly, we setup a robustness screen
to evaluate two aspects of the reaction; (i) to identify a potential ‘strong directing group’, i.e. to
check if the metal component of the reaction can effectively bind to a different directing group
and hence, deter the formation of the expected product 3aa, and (ii) to check if other directing
groups ‘survive’ the standard reaction conditions. The robustness screen acts as an indirect
method to evaluate functional group tolerance and is operationally simple. However, it cannot
evaluate the effects of electronic factors which a functional group imposes on the directing
abilities of the amide group. Along with a robustness screen for directing group tolerance (Table
2) we also decided to include several random molecules (Table 3). The standard reaction with 1a
and 2a as the coupling partners in the standard reaction conditions furnishes 3aa, in 95% yield
(entry 16, Table 1). This reaction was then repeated in the presence of a variety of additives (1
equiv), and the yield of product 3aa, as well as the amount of additive (7 or 8) and starting
materials (1a and 2a) remaining after the reaction were determined. In all cases, amount of 2a
left was less than 10%, indicating that maleimide decomposes extensively and hence 1.5 equiv is
required for the reaction (Table 2 and 3).
Effect of other directing groups
Different directing groups like ketone, aldehyde, carboxylic acid, ester, amide, 2-phenylpyridine
and oxime were used in the form of simple compounds (7a – 7g). In the case of oxygen based
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directing groups such as ketone, aldehyde, carboxylic acid, and N-benzoylindole (7a – 7e), the
yield of 3aa was comparable to that obtained under additive free conditions (Table 2). However,
we observed extensive decomposition of acetophenone, aldehyde and ester (entries 1, 2 and 4,
respectively, Table 2), whereas, acid and N-benzoyl indole (entries 3 and 5) were found to be
more or less intact.
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Table 2: Robustness Screening – various directing groups a,b,c
a
Reaction conditions: 1a (0.3 mmol), 2a (1.5 equiv), 7 or 8 (1 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgBF4 (20
b
mol %), Cu(OAc)2.H2O (1.5 equiv), AcOH (10 equiv), DCE (2.0 mL), 100 °C. Yield values were obtained by
using terephthaldehye as an internal standard in 1H NMR. c In all the cases maleimide (2a) was less than 10%.
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In none of the cases, conjugate addition products with the additives was observed. It is
interesting to note that from our own lab, the conjugate additions with ketone and N-benzoyl
indole is reported.12 This indicates that aromatic amides are more reactive than aromatic ketones
and indole amides, as a directing group. In the case of nitrogen based directing groups (entries 6
and 7), the formation of the required product 3aa was not observed, which can be attributed to an
irreversible complexation of these molecules with the metal catalyst, but the starting material
(1a) was intact.
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Effect of other functionalities
When different functionalities were chosen to be evaluated in robustness screen for functional
groups (8a-8k), we obtained mixed results and no rationale could be pin-pointed for the decrease
in yield of 3aa (Table 3). Molecules bearing one or more the functional groups such as double
bond, triple bond, alcohol, enol, nitrile and halides (entries 1-8) were evaluated in this robustness
screen, along with some heterocycles like benzoxazole, indole and pyridine (entries 9-11). In
very few cases, such as styrene, butanol, coumarin and iodobenzene, the yield of 3aa was intact
(entries 1, 4 and 8, respectively). But the additives had underwent significant decomposition. In
the case of phenol and nitrile (entries 5 and 7, respectively), the yield of 3aa was significantly
reduced, while in the case of phenylacetylene, diphenylacetylene, benzoxazole, indole and
bromopyridine (entries 2, 3, 10 and 11, respectively), the product was observed in very low
yields. Based on the robustness study, we can see that amide is a powerful and strong directing
group, and the reaction is fairly tolerant towards the presence of other functional groups. Even in
the presence of other directing groups, we have observed only the products formed from the
control amide. However, the presence of heterocycles was found to be detrimental to the
formation of the product.
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Table 3: Robustness Screening – functional group tolerance a,b,c
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a
Reaction conditions: 1a (0.3 mmol), 2a (1.5 equiv), 7 or 8 (1 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), AgBF4 (20
b
mol %), Cu(OAc)2.H2O (1.5 equiv), AcOH (10 equiv), DCE (2.0 mL), 100 °C. Yield values were obtained by
using terephthaldehye as an internal standard in 1H NMR. c In all the cases maleimide (2a) was less than 10%.
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Conclusion
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In this article, we have presented a novel Ru(II)-catalyzed C−H functionalization of aromatic
amide with maleimide using N-substituted carboxamide as a directing group to obtain 3-arylated
succinimides. Succinimides are important molecules, which feature in several natural products
and commonly used medications. The succinimides can be easily reduced to pyrrolidines, lactims
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or lactams, all of which are important motifs in several intermediates or natural products.17
robustness screen has been employed to describe the robustness and tolerance of the reaction.
A
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Experimental Section
General experimental
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NMR spectra were recorded on a 400 MHz spectrometer in CDCl3 or DMSO-d6.
Tetramethylsilane (TMS; δ = 0.00 ppm) for 1H NMR in CDCl3, and residual non-deuterated
solvent peak (δ = 2.50 ppm) in DMSO-d6, served as an internal standard. The solvent signal
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(CDCl3, δ = 77.00 ppm; and DMSO-d6, δ = 39.5 ppm ) was used as internal standard for C
NMR. IR spectra were measured using an FT-IR spectrometer. Mass spectra were obtained with
a Q-TOF Mass Spectrometer (ESI-HRMS). Flash column chromatography was carried out by
packing glass columns with commercial silica gel 230-400 mesh (commercial suppliers) and
thin-layer chromatography was carried out using silica gel GF-254. All catalysts, reagents and
reactants were procured from commercial suppliers. Dichloroethane solvent was distilled over
calcium hydride and stored over molecular sieves and used for all procedures. Other solvents,
used for work up and chromatographic procedures were purchased from commercial suppliers
and used without any further purification.
NMR Yield calculation
After work up, 0.5 equiv of terephthaldehyde was added into the round bottom flask containing
the combined organic layers from the work up. Either an aliquot from the round bottom flask
was taken, evaporated and then submitted for NMR, or the organic layer was completely
evaporated and the residue was dissolved in an appropriate amount of solvent to submit for
NMR.
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Preparation of Amides
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To a solution of benzoyl chloride (2.0 g, 14.23mmol) in anhydrous Et2O (25 mL)
K2CO3was added (4.92 g, 35.57mmol) followed by MeNH3Cl (1.44 g, 21.34mmol). The mixture
was stirred at ambient temperature overnight, diluted with EtOAc (50 mL) and washed with H2O
(50 mL). The aqueous phase was extracted with EtOAc (2×30 mL), and the combined organic
phase was dried over Na2SO4, filtrated. The solvents were removed in vacuum to give a crude
product, which was purified by column chromatography on silica gel (n-hexane/EtOAc: 1/1) to
yield N-methylbenzamide as a colorless solid (1.84 g, 96 %).
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Typical procedure for synthesis of 3aa
In a 8-mL screw cap reaction vial, 11.7 mg (20 mol %) AgBF4 was weighed in and 9.2mg
(5 mol %) of [Ru(p-cymene)Cl2]2 was added to it followed by the addition of 2mL of DCE. Then
both the starting materials, 1a (40.5mg, 0.3 mmol) and 2a (56.3mg, 0.45 mmol) were added,
followed by the addition of Cu(OAc)2•H2O (90mg, 0.45 mmol). To this mixture 0.17mL (3.0
mmol) of AcOH was added and the reaction vial was sealed with the screw cap and placed into a
pre-heated metal block at 100°C. The progress of the reaction was monitored by TLC.
Typical procedure for synthesis of 6aa
In a 8-mL screw cap reaction vial, 20.6 mg (20 mol %) AgSbF6 was weighed in and 9.2
mg (5 mol %) of [Ru(p-cymene)Cl2]2 was added to it followed by the addition of 2mL of DCE.
Then both the starting materials, 4a (40.5mg, 0.3 mmol) and 5a (56.3mg, 0.45 mmol) were
added, followed by the addition of Cu(OAc)2•H2O (90mg, 0.45 mmol). The reaction vial was
sealed with the screw cap and placed into a pre-heated metal block at 80°C. The progress of the
reaction was monitored by TLC.
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Experimental Data
2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-methylbenzamide (3aa) :
Prepared as shown in general procedure. Crude reaction mixture
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was purified on a silica gel column (Hexane/EtOAc, 40:60) to
obtain the product as pale yellow solid (mp = 75-78 ºC); Yield=
71 mg (91%); Rf (50% EtOAc/Hexane) 0.2; IR (Neat, cm-1): 3356,
1
1696, 1651, 1600; H NMR (400 MHz, CDCl3): δ 7.50 (d, J= 7.8
Hz, 1H), 7.41 (t, J= 7.7 Hz, 1H), 7.33 (t, J= 7.7 Hz, 2H), 6.7 (s,
1H), 4.38 (dd, J= 4.6 Hz, J= 9.3 Hz, 1H), 3.62 (q, J= 7.3 Hz, 2H),
13
3.18 (dd, J= 9.13 Hz, J= 18.26 Hz, 1H), 2.92-2.87(m, 4H), 1.22 (t, J= 7.53 Hz, 3H); C{1H}
NMR (100 MHz, CDCl3): δ 178.5, 176.1, 169.7, 136.5, 135.3, 130.8, 128.2, 128.0, 128.0, 44.1,
37.7, 34.0, 26.7, 12.9; HRMS (ESI-TOF) (m/z): Calculated for C14H16N2O3Na (M + Na):
283.1059, found (M + Na): 283.1059.
2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-4-methoxy-N-methylbenzamide (3ba) :
Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 40:60) to
obtain the product as pale yellow liquid; Yield= 75 mg (86%); Rf
(40% EtOAc/Hexane) 0.2; IR (Neat, cm-1): 3366, 2940, 1772,
1
1696, 1652; H NMR (400 MHz, CDCl3): δ 7.44 (d, J= 8.6 Hz,
1H), 6.80 (dd, J = 4.6 Hz, J= 8.6 Hz, 1H), 6.69 (s, 1H), 6.62 (d,
J= 2.4 Hz, 1H), 4.38 (dd, J1= 4.6 Hz, J2= 9.4 Hz, 1H), 3.80 (s, 3H), 3.61 (q, J = 7.7 Hz, 2H),
3.16 (dd, J1= 9.1 Hz, J2= 18.2 Hz, 1H), 2.91-2.85(m, 4H), 1.22 (t, J= 7.6 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 178.3, 176.1, 169.4, 161.1, 137.5, 129.7, 128.4, 114.9, 112.2, 55.3, 44.3,
37.7, 33.9, 26.6, 12.8; HRMS (ESI-TOF) (m/z): Calculated for C15H18N2O4Na (M + Na):
313.1164, found (M + Na): 313.1169.
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2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-5-methoxy-N-methylbenzamide (3ca) :
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Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 70:30) to
obtain the product as colurless liquid; Yield= 35 mg (40%); Rf
(50% EtOAc/Hexane) 0.2; IR (Neat, cm-1): 3378, 1770, 1695,
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1652; H NMR (400 MHz, CDCl3):  ppm 1.22 (t, J= 7.20 Hz,
4 H) 2.88 (dd, J1= 18.44, J2= 4.80 Hz, 1 H) 2.96 (d, J= 4.80 Hz,
3 H) 3.17 (dd, J1= 18.44, J2= 9.35 Hz 1 H) 3.62 (q, J= 7.07 Hz, 2 H) 3.82 (s, 3 H) 4.31 (dd, J1=
13
9.47, J2= 4.93 Hz, 1 H) 6.78 (br. s., 1 H) 6.91 - 6.97 (m, 1 H) 6.98 - 7.06 (m, 2 H); C{1H}
NMR (100 MHz, CDCl3): δ 179.0, 176.2, 169.6, 159.0, 137.9, 129.0, 126.7, 116.6, 113.5, 55.5,
43.1, 37.6, 34.1, 26.8, 12.9; HRMS (ESI-TOF) (m/z): Calculated for C15H18N2O4Na (M + Na):
313.1164, found (M + Na): 313.1163.
2-chloro-6-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-methylbenzamide (3da) :
Prepared as shown in general procedure. Crude reaction mixture was
purified on a silica gel column (Hexane/EtOAc, 40:60) to obtain the
product as white solid (mp = 129-132 ºC); Yield= 81 mg (91%); Rf
(50% EtOAc/Hexane) 0.2; IR (Neat, cm-1): 3322, 1773, 1699, 1654;
1H NMR (400 MHz, CDCl3): δ 7.36 (d, J= 7.8 Hz, 1H), 7.31 (t, J= 7.7
Hz, 1H), 6.97 (d, J= 7.6 Hz, 1H), 6.58 (d, J= 3.8 Hz, 1H), 4.1 (dd, J1=
5.3 Hz, J2= 9.2 Hz, 1H), 3.60 (q, J = 7.8 Hz, 2H), 3.18 (dd, J1= 9.2 Hz, J2= 19.2 Hz, 1H), 3.0 (d,
J= 4.9 Hz, 3H), 2.82 (dd, J1= 4.90 Hz, J2= 18.64 Hz, 1H), 1.12 (t, J= 7.9 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 177.4, 175.4, 166.8, 137.3, 136.6, 131.8, 130.6, 129.2, 124.7, 43.6,
37.2, 34.2, 26.5, 12.9; HRMS (ESI-TOF) (m/z): Calculated for C14H15ClN2O3Na(M + Na):
317.0669, found (M + Na): 317.0665.
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2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-6-iodo-N-methylbenzamide (3ea) :
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Prepared as shown in general procedure. Crude reaction mixture was
purified on a silica gel column (Hexane/EtOAc, 60:40) to obtain the
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product as colourless liquid; Yield= 79 mg (68%); Rf (50%
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EtOAc/Hexane) 0.2; IR (Neat, cm-1): 3323, 1773, 1699, 1649; H
NMR (400 MHz, CDCl3): δ 7.79 (d, J= 7.6 Hz, 1H), 7.07 (t, J= 7.9
Hz, 1H), 7.02 (d, J= 7.6 Hz, 1H), 6.5 (d, J= 4.0 Hz, 1H), 4.11 (dd,
J1= 5.3 Hz, J2= 10.4 Hz, 1H), 3.6 (q, J= 7.5 Hz, 2H), 3.17 (dd, J1= 9.7 Hz, J2= 19.0 Hz, 1H),
3.01(d, J= 4.9 Hz, 3H), 2.79 (dd, J1= 4.81 Hz, J2= 18.66 Hz, 1H), 1.20 (t, J= 7.7 Hz, 3H);
13C{1H} NMR (100 MHz, Few drops of DMSO-D6 in CDCl3): δ 176.8, 175.0, 169.1, 143.4,
138.0, 136.0, 130.4, 125.9, 93.7, 43.8, 37.3, 33.6, 26.0, 12.5; HRMS (ESI-TOF) (m/z):
Calculated for C14H15IN2O3Na (M + Na): 409.0025, found (M + Na): 409.0023.
2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N,6-dimethylbenzamide (3fa) :
Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 70:30) to
obtain the product as pale yellow liquid; Yield= 42 mg (51%);
Rf (50% EtOAc/Hexane) 0.3; IR (Neat, cm-1): 3377, 1771, 1732,
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1689; H NMR (400 MHz, CDCl3):  1.20 (t, J= 7.17 Hz, 3 H)
2.33 - 2.45 (m, 3 H) 2.85 (dd, J1= 18.77, J2= 4.43 Hz, 1 H) 3.00
(d, J= 4.88 Hz, 3 H) 3.17 (dd, J1= 18.77, J2= 9.61 Hz, 1 H) 3.60 (q, J= 7.02 Hz, 2 H) 4.09 (dd,
J1= 9.46,J2= 4.58 Hz, 1 H) 6.85 (d, J= 7.63 Hz, 1 H) 7.16 (d, J= 7.63 Hz, 1 H) 7.22 - 7.32 (m, 1
H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.4, 176.0, 169.8, 138.1, 136.0, 133.7, 129.9, 129.6,
122.8, 77.3, 77.0, 76.7, 43.1, 37.1, 34.1, 26.4, 19.6, 12.9; HRMS (ESI-TOF) (m/z): Calculated
for C15H18N2O3Na (M + Na):297.1215, found (M + Na): 297.1216.
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3-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-methyl-[1,1'-biphenyl]-2-carboxamide (3ga) :
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Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 70:30) to
obtain the product as white solid (mp = 184-187 ºC); Yield= 80
mg (79%); Rf (50% EtOAc/Hexane) 0.4; IR (Neat, cm-1): 3376,
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1772, 1733, 1696; H NMR (400 MHz, CDCl3): δ 1.23 (t, J=
7.17 Hz, 4 H) 2.63 (d, J= 4.88 Hz, 3 H) 2.90 (dd, J1= 18.46, J2=
4.73 Hz, 1 H) 3.26 (dd, J= J1= 18.46, J2= 9.61 Hz, 1 H) 3.63 (q, J= 6.71 Hz, 2 H) 4.27 (dd, J1=
9.46, J2= 4.88 Hz 1 H) 5.70 (br. s., 1 H) 7.08 (d, J= 7.63 Hz, 1 H) 7.30 - 7.49 (m, 7 H); 13C{1H}
NMR (100 MHz, CDCl3): δ 178.0, 176.0, 169.5, 140.4, 140.0, 136.7, 135.6, 130.0, 129.6, 128.5,
128.3, 128.0, 125.8, 77.3, 77.0, 76.7, 43.9, 38.0, 34.1, 26.4, 13.0; HRMS (ESI-TOF) (m/z):
Calculated for C20H20N2O3Na (M + Na): 359.1372, found (M + Na): 359.1374.
(E)-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-methyl-6 styrylbenzamide (3ha) :
Prepared as shown in general procedure. Crude reaction
mixture was purified on
a
silica gel column
(Hexane/EtOAc, 40:60) to obtain the product as yellow
liquid; Yield= 71 mg (85%); Rf (50% EtOAc/Hexane) 0.5;
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IR (Neat, cm-1): 3275, 1727, 1673, 1626; H NMR (400
MHz, CDCl3): δ 1.18 - 1.25 (t, 3 H) 2.87 (dd, J= J1=
18.77, J2= 4.73 Hz, 1 H) 3.02 (d, J= 4.88 Hz, 3 H) 3.20
(dd, J1= 18.77, J2= 9.61 Hz 1 H) 3.62 (q, J= 7.12 Hz, 2 H) 4.15 (dd, J1= 9.46, J2= 4.58 Hz 1 H)
6.64 (d, J= 4.58 Hz, 1 H) 6.95 (d, J= 7.63 Hz, 1 H) 7.08 (d, J= 16.17 Hz, 1 H) 7.19 (d, J= 16.17
Hz, 1 H) 7.25 - 7.32 (m, 1 H) 7.37 (q, J= 7.73 Hz, 3 H) 7.49 (d, J= 7.32 Hz, 2 H) 7.65 (d, J= 7.93
Hz, 1 H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.2, 176.0, 169.35, 137.1, 136.8, 135.8, 134.6,
132.0, 130.0, 128.7, 128.1, 126.8, 125.2, 125.2, 124.8, 77.3, 77.0, 76.7, 43.3, 37.3, 34.2, 26.6,
13.00; HRMS (ESI-TOF) (m/z): Calculaed for C22H22N2O3Na (M + Na): 385.1528, found (M +
Na): 385.1530.
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2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-methyl-1-naphthamide (3ia) :
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Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 70:30) to
obtain the product as pale yellow solid (mp = 191-193 ºC);
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Yield= 61 mg (65%); Rf (50% EtOAc/Hexane) 0.3; IR (Neat,
cm-1): 3359, 1772, 1734, 16952; 1H NMR (400 MHz, CDCl3 ): δ
1.23 (t, J= 7.17 Hz, 3 H) 2.96 (dd, J J1= 18.92, J2= 4.27 Hz 1 H)
3.11 (d, J= 4.88 Hz, 3 H) 3.25 (dd, J1= 18.92, J2= 4.46 Hz, 1 H) 3.64 (q, J= 7.32 Hz, 2 H) 4.34
(dd, J1= 9.46, J2= 4.27 Hz Hz, 1 H) 6.97 (br. s., 1 H) 7.07 (d, J= 8.55 Hz, 1 H) 7.46 - 7.60 (m, 2
H) 7.87 (d, J= 8.85 Hz, 1 H) 7.82 (d, J= 7.93 Hz, 1 H) 7.96 (d, J= 8.24 Hz, 1 H); 13C{1H} NMR
(100 MHz, CDCl3): δ 178.3, 176.0, 169.3, 132.6, 130.6, 130.2, 128.0, 127.7, 126.8, 125.5, 77.3,
77.0, 76.7, 43.4, 36.8, 34.3, 26.7, 13.00; HRMS (ESI-TOF) (m/z): Calculated for C18H18N2O3Na
(M + Na): 333.1215, found (M + Na): 333.1213.
3-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-methyl-2-naphthamide (3ja) :
Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 70:30) to
obtain the product as pale yellow solid (mp = 202 ºC); Yield=
77 mg (83%); Rf (50% EtOAc/Hexane) 0.3; IR (Neat, cm-1):
3409, 1730, 1677, 1618; 1H NMR (400 MHz, CDCl3): δ 1.26 (t,
J= 7.17 Hz, 3 H) 2.92 - 3.11 (m, 4 H) 3.24 (dd, J1= 18.16, J2=
9.31 Hz, 1 H) 3.66 (dd, J1= 7.17, J2= 1.97 Hz 2 H) 4.53 (dd, J1=
9.46, J2= 4.49 Hz 1 H) 7.49 - 7.59 (m, 2 H) 7.61 (s, 1 H) 7.75 - 7.81 (m, 1 H) 7.81 - 7.88 (m, 1
H) 8.01 (s, 1 H); C{1H} NMR (100 MHz, CDCl3): δ 178.5, 176.2, 170.0, 133.8, 133.7, 132.4,
13
131.9, 128.4, 128.2, 128.0, 127.8, 127.4, 127.1, 77.3, 77.0, 76.7, 44.6, 38.0, 34.1, 26.8, 12.9;
HRMS (ESI-TOF) (m/z): Calculated for C18H18N2O3Na (M + Na): 333.1215, found (M + Na):
333.1214.
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N-cyclohexyl-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)benzamide (3ka) :
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Prepared as shown in general procedure. Crude reaction mixture was
purified on a silica gel column (Hexane/EtOAc, 50:50) to obtain the
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product as white solid (mp = 121-124 ºC); Yield= 94 mg (95%); Rf
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(30% EtOAc/Hexane) 0.3; IR (Neat, cm-1):3326, 1774, 1698, 1645;
1H NMR (400 MHz, CDCl3): δ 7.49 (d, J= 7.7 Hz, 1H), 7.40 (t, J=
7.9 Hz, 1H), 7.32 (t, J= 8.0 Hz, 1H), 7.10 (d, J= 7.7 Hz, 1H), 6.60 (d,
J= 6.7 Hz, 1H), 4.38 (dd, J1= 4.8 Hz, J2= 9.5 Hz, 1H), 3.93-3.85 (m, 1H), 3.60 (q, J= 7.7 Hz,
2H), 3.17 (dd, J1= 8.9 Hz, J2= 18.2 Hz, 1H), 2.87 (dd, J1= 5.0 Hz, J2= 18.5 Hz, 1H), 2.01-1.98
(m, 2H), 1.75-1.73 (m, 2H), 1.65-1.62 (m, 1H), 1.40 (m, 2H), 1.23-1.12 (m, 6H); 13C{1H} NMR
(100 MHz, CDCl3): δ 178.2, 176.0, 168.0, 136.9, 135.1, 130.6, 128.0, 127.9, 127.8, 48.8, 43.8,
37.6, 33.9, 33.0, 32.8, 25.4, 24.8, 24.7, 12.9; HRMS (ESI-TOF) (m/z): Calculated for
C19H24N2O3Na (M + Na): 351.1685, found (M + Na): 351.1668.
N-benzyl-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)benzamide (3la) :
Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 40:60) to
obtain the product as white solid (mp = 112-115 ºC); Yield=
88 mg (86%); Rf (50% EtOAc/Hexane) 0.5; IR (Neat, cm-1):
3351, 1732, 1691, 1657; 1H NMR (400 MHz, CDCl3):  1.19 (t,
J= 7.32 Hz, 3 H) 2.85 (dd, J1= 18.31, J2= 5.49 Hz 1 H) 3.11 (dd,
J1= 18.31, J2= 9.46 Hz 1 H) 3.51 - 3.64 (m, 2 H) 4.33 (dd, J1= 9.46, J2= 5.49 Hz 1 H) 4.53 (d, J=
5.80 Hz, 2 H) 7.03 (br. s., 1 H) 7.11 (d, J= 7.63 Hz, 1 H) 7.25 - 7.36 (m, 6 H) 7.37 - 7.44 (m, 1
13
H) 7.51 (d, J= 7.63 Hz, 1 H); C{1H} NMR (100 MHz, CDCl3): δ 178.2, 176.0, 168.8, 137.9,
136.0, 135.5, 130.9, 128.7, 128.6, 128.0, 127.9, 127.7, 127.5, 77.3, 77.0, 76.7, 44.0, 43.9, 37.7,
33.9, 12.9; HRMS (ESI-TOF) (m/z): Calculated for C20H20N2O3Na (M + Na): 359.1372, found
(M + Na): 359.1372.
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2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-phenylbenzamide (3ma) :
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Prepared as shown in general procedure. Crude reaction mixture was
purified on a silica gel column (Hexane/EtOAc, 50:50) to obtain the
9
product as pale yellow liquid; Yield= 30 mg (31%); Rf (30%
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EtOAc/Hexane) 0.3; IR (Neat, cm-1): 3327, 1775, 1694, 1599; H
NMR (400 MHz, CDCl3): δ 8.8 (s, 1H), 7.68 (d, J= 8.0 Hz, 3H), 7.47
(t, J= 7.35 Hz, 1H), 7.41 (t, J= 7.35 Hz, 1H), 7.35(t, J= 7.5 Hz, 2H),
7.16-7.13(m, 2H), 4.47 (dd, J1= 4.65 Hz, J2= 9.5 Hz, 1H), 3.61 (q, J= 7.50 Hz, 2H), 3.19 (dd, J1=
8.44 Hz, J2= 18.83 Hz, 1H), 2.94 (dd, J1= 4.7 Hz, J2= 18.6 Hz, 1H), 1.18 (t, J= 7.7 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 178.9, 175.9, 167.0, 138.0, 137.5, 134.5, 131.2, 129.0,
128.7, 128.3, 127.2, 124.6, 119.8, 43.4, 37.3, 34.2, 12.9; HRMS (ESI-TOF) (m/z): Calculated
for C19H18N2O3Na (M + Na): 345.1215, found (M + Na): 345.1215.
2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)-N-(4-methoxyphenyl)benzamide (3na) :
Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 50:50) to
obtain the product as black solid (mp = 163-167 ºC); Yield= 84
mg (79%); Rf (50% EtOAc/Hexane) 0.3; IR (Neat, cm-1): 3320,
1
1773, 1697, 1601; H NMR (400 MHz, CDCl3): δ 8.84 (s,1H),
7.62 (d, J= 7.7 Hz,1H), 7.55 (d, J= 8.9 Hz, 2H), 7.42 (t, J= 8.0
Hz, 1H), 7.35 (t, J= 8.0 Hz, 1H), 7.17(d, J= 7.7 Hz, 1H), 6.85(d, J= 8.85 Hz, 2H), 4.41 (dd, J1=
4.75 Hz, J2= 9.56 Hz, 1H), 3.78(s,3H), 3.57 (q, J= 7.7 Hz, 2H), 3.13 (dd, J1= 9.15 Hz, J2= 18.30
Hz, 1H), 2.87 (dd, J1= 4.69 Hz, J2= 18.44 Hz, 1H), 1.16(t, J= 7.84 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 178.8, 176.0, 168.8, 156.5, 137.2, 134.8, 131.3, 131.0, 128.6, 128.1, 127.6,
121.6, 114.1, 55.5, 43.6, 37.4, 34.1, 12.9; HRMS (ESI-TOF) (m/z): Calculated for
C20H20N2O4Na (M + Na): 375.1321, found (M + Na): 375.1318.
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N,N-diethyl-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)benzamide (3oa) :
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Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 40:60) to
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obtain the product as pale yellow liquid; Yield= 42 mg (51%); Rf
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(50% EtOAc/Hexane) 0.2; IR (Neat, cm-1):2978, 2939, 1774, 1703,
1625; 1H NMR (400 MHz, CDCl3): δ 7.39 (t, J= 8.6 Hz, 1H), 7.32
(t, J= 7.3 Hz, 1H), 7.26 (t, J= 8.5 Hz, 1H), 7.11 (d, J= 7.5 Hz, 1H),
4.1 (dd, J= 4.9 Hz, J= 9.6 Hz, 1H), 3.63 (dd, J1= 8.6 Hz, J2= 16.7
Hz, 3H), 3.47 (m,1H), 3.29 (dd, J1= 8.5 Hz, J2= 16.9 Hz, 2H), 3.18 (dd, J1= 8.7 Hz, J2= 18.7 Hz,
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1H), 2.82 (d, J= 17.0 Hz, 1H), 1.24 (q, J= 8.4 Hz, 6H), 1.14 (t, J= 8.1 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3): δ 177.7, 176.1, 170.2, 135.1, 129.7, 127.5, 126.3, 43.4, 39.0, 38.0, 33.9,
13.8, 13.0, 12.8; HRMS (ESI-TOF) (m/z): Calculated for C17H22N2O3Na (M + Na): 325.1528,
found (M + Na): 325.1524.
N,N-dibenzyl-2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)benzamide (3pa) :
Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (Hexane/EtOAc,
30:70) to obtain the product as yellow liquid; Yield= 92 mg
(72%); Rf (50% EtOAc/Hexane) 0.6; IR (Neat, cm-1): 3436,
1776, 1702, 1630; 1H NMR (400 MHz, CDCl3): δ ppm 1.23 (t,
J= 7.17 Hz, 3 H) 2.75 (dd, J1= 18.46, J2= 5.34 Hz 1 H) 3.05 -
3.27 (m, 1 H) 3.56 - 3.68 (m, 2 H) 4.15 (dd, J1= 9.46, J2= 5.19
Hz 1 H) 4.36 - 4.57 (m, 3 H) 4.93 (d, J= 14.04 Hz, 1 H) 7.11 (d, J= 7.63 Hz, 1 H) 7.20 (d, J=
13
7.02 Hz, 2 H) 7.23 - 7.43 (m, 12 H); C{1H} NMR (100 MHz, CDCl3): δ 177.5, 175.9, 170.8,
136.7, 135.9, 135.7, 130.1, 128.8, 128.6, 128.4, 127.7, 127.6, 127.6, 127.4, 126.3, 77.3, 77.0,
76.7, 51.9, 46.9, 43.3, 38.0, 34.0, 13.0; HRMS (ESI-TOF) (m/z): Calculated for C27H26N2O3Na
(M + Na): 449.1841, found (M + Na): 449.1843.
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2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-N-cyclohexylbenzamide (3kb) :
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6
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Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (Hexane/EtOAc,
40:60) to obtain the product as white solid (mp = 156-159 ºC);
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Yield= 113 mg (96%); Rf (50% EtOAc/Hexane) 0.5; IR (Neat,
cm-1): 3348, 1760, 1688, 1629; 1H NMR (400 MHz, CDCl3): 
ppm 1.13 - 1.32 (m, 4 H) 1.32 - 1.49 (m, 2 H) 1.56 - 1.67 (m, 2
H) 1.67 - 1.79 (m, 2 H) 1.88 - 2.03 (m, 2 H) 2.91 (dd, J1=
18.44, J2= 5.05 Hz 1 H) 3.22 (dd, J1= 18.44, J2= 9.60 Hz 1 H) 3.77 - 3.99 (m, 1 H) 4.42 (dd, J1=
9.60, J2= 5.31 Hz, 1 H) 4.62 - 4.83 (m, 2 H) 6.50 (d, J= 7.58 Hz, 1 H) 6.97 - 7.09 (m, 1 H) 7.27 -
13
7.36 (m, 4 H) 7.36 - 7.42 (m, 3 H) 7.49 (dd, J1= 7.33, J2= 1.52 Hz, 1 H); C{1H} NMR (100
MHz, CDCl3): δ 178.1, 175.8, 168.0, 137.1, 135.7, 134.8, 130.7, 128.6, 128.0, 127.9, 127.8,
77.3, 77.0, 76.7, 48.9, 43.8, 42.7, 37.6, 33.0, 32.9, 25.5, 24.8, 24.7; HRMS (ESI-TOF) (m/z):
Calculated for C24H26N2O3Na (M + Na): 413.1841, found (M + Na): 413.1841.
2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-N-(4-methoxyphenyl)benzamide (3nb) :
Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 70:30) to
obtain the product as blackish liquid; Yield= 60 mg (48%); Rf
(40% EtOAc/Hexane) 0.7; IR (Neat, cm-1): 3322, 1774, 1699,
1
1664; H NMR (400 MHz, CDCl3): δ 8.75 (s,1H), 7.62 (d, J=
7.3 Hz,1H), 7.53 (d, J= 8.8 Hz, 2H), 7.40-7.25 (m, 7H), 7.04(d,
J= 7.5 Hz, 1H), 6.86(d, J= 8.9 Hz, 2H), 4.68 (q, J= 8.1 Hz, 2H), 4.46 (dd, J1= 4.7 Hz, J2= 9.5 Hz,
1H), 3.79(s,3H), 3.18 (dd, J1= 8.3 Hz, J2= 18.7 Hz, 1H), 2.90 (dd, J1= 4.84 Hz, J2= 18.58 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.6, 175.7, 165.5, 137.3, 135.5, 134.5, 131.2, 131.0,
128.6, 128.6, 128.5, 128.2, 128.0, 127.3, 121.6, 114.1, 55.4, 43.5, 42.8, 37.3, 29.6; HRMS (ESI-
TOF) (m/z): Calculated for C25H22N2O4Na (M + Na): 437.1477, found (M + Na): 437.1476.
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N-cyclohexyl-2-(2,5-dioxo-1-phenylpyrrolidin-3-yl)benzamide (3kc) :
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6
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Prepared as shown in general procedure. Crude reaction
mixture was purified on a silica gel column (Hexane/EtOAc,
30:70) to obtain the product as colourless liquid; Yield= 53 mg
(47%); Rf (50% EtOAc/Hexane) 0.6; IR (Neat, cm-1): 3357,
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1777, 1709, 1643; H NMR (400 MHz, CDCl3):  ppm 1.11 -
1.29 (m, 4 H) 1.31 - 1.41 (m, 2 H) 1.54 - 1.79 (m, 4 H) 1.88 (d,
J= 11.12 Hz, 1 H) 1.94 - 2.03 (m, 1 H) 3.11 (dd, J1= 18.32, J2=
5.68 Hz 1 H) 3.32 (dd, J1= 18.32, J2= 9.73 Hz, 1 H) 3.89 (d, J= 8.34 Hz, 1 H) 4.47 (dd, 1 H J1=
13
9.60, J2= 5.81 Hz) 6.34 (d, J= 8.08 Hz, 1 H) 7.17 - 7.30 (m, 1 H) 7.30 - 7.54 (m, 8 H); C{1H}
NMR (100 MHz, CDCl3): δ 177.3, 175.3, 168.3, 136.3, 135.3, 132.2, 130.8, 129.5, 129.1, 128.6,
128.1, 128.0, 126.8, 77.3, 77.0, 76.7, 48.9, 44.9, 38.0, 33.0, 32.9, 25.4, 24.9, 24.8; HRMS (ESI-
TOF) (m/z): Calculated for C23H24N2O3Na (M + Na): 399.1685, found (M + Na): 399.1685.
N-(2-(1-ethyl-2,5-dioxopyrrolidin-3-yl)phenyl)acetamide (6aa) :
Prepared as shown in general procedure. Crude reaction mixture was
purified on a silica gel column (Hexane/EtOAc, 30:70) to obtain the
product as pale colourless liquid; Yield= 30 mg (38%); Rf (50%
1
EtOAc/Hexane) 0.1; IR (Neat, cm-1): 3281, 1773, 1698, 1523; H
NMR (400 MHz, CDCl3): δ 8.64 (s, 1H), 7.52 (d, J= 7.5 Hz, 1H),
7.30 (t, J= 7.55 Hz, 1H), 7.21 (t, J= 7.7 Hz, 1H), 7.10 (d, J= 7.7 Hz,
1H), 4.29 (dd, J1= 4.7 Hz, J2= 9.4 Hz, 1H), 3.57 (q, J= 7.8 Hz, 2H),
3.09 (dd, J1= 9.44 Hz, J2= 18.76 Hz, 1H), 2.94(dd, J1= 4.4 Hz, J2= 18.65 Hz, 1H), 2.17 (s, 3H),
1.17 (t, J= 7.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 178.9, 175.8, 169.4, 136.1, 130.7,
13
128.4, 127.3, 126.6, 125.7, 41.2, 34.6, 34., 23.6, 12.8; HRMS (ESI-TOF) (m/z): Calculated for
C14H16N2O3Na (M + Na): 283.1059, found (M + Na): 283.1059.
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N-(2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)phenyl)acetamide (6ab) :
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6
7
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Prepared as shown in general procedure. Crude reaction mixture was
purified on a silica gel column (Hexane/EtOAc, 40:60) to obtain the
9
product as pale yellow liquid; Yield= 40 mg (41%); Rf (50%
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EtOAc/Hexane) 0.2; IR (Neat, cm-1): 3281, 1774, 1701, 1586; H
NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 7.51 (d, J= 7.9 Hz, 1H),
7.35 (d, J= 7.0 Hz, 2H), 7.32-7.29 (m,4H), 7.18 (t, J= 7.7 Hz, 1H),
7.06 (d, J= 7.7 Hz, 1H), 4.66(q, J= 15.2 Hz, 2H), 4.27 (dd, J1= 4.9
Hz, J2= 9.5 Hz, 1H), 3.09 (dd, J1= 4.4 Hz, J2= 18.8 Hz, 1H), 2.97(dd, J1= 97 Hz, J2= 18.9 Hz,
1H), 2.07 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.8, 175.6, 169.4, 136.1, 135.3, 130.3,
128.7, 128.7, 128.6,128.1, 128.1, 127.6, 126.7, 125.9, 42.7, 41.5, 34.5, 23.7; HRMS (ESI-TOF)
(m/z): Calculated for C19H19N2O3 (M + H): 323.1396, found (M + H): 323.1396.
N-(2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-4-methoxyphenyl)acetamide (6bb) :
Prepared as shown in general procedure. Crude reaction mixture
was purified on a silica gel column (Hexane/EtOAc, 70:30) to
obtain the product as colourless liquid; Yield= 40 mg (38%); Rf
(50% EtOAc/Hexane) 0.2; IR (Neat, cm-1): 3271, 1774, 1701,
1
1657; H NMR (400 MHz, CDCl3): δ ppm 2.01 (s, 3 H) 2.98
(dd, J J1= 18.69, J2= 4.80 Hz 1 H) 3.12 (dd, J1= 18.69, J2= 9.35
Hz, 1 H) 3.74 (s, 3 H) 4.22 (dd, J1= 9.35, J2= 4.80 Hz, 1 H) 4.68
(q, J= 14.06 Hz, 2 H) 6.60 (d, J= 2.78 Hz, 1 H) 6.85 (dd, J=
8.84, 2.78 Hz, 1 H) 7.28 - 7.43 (m, 6 H) 7.79 (s, 1 H); 13C{1H} NMR (100 MHz, CDCl3): δ
178.5, 175.5, 169.6, 158.3, 135.5, 132.7, 129.5, 128.9, 128.8, 128.6, 128.2, 113.4, 112.5, 55.5,
42.8, 42.1, 34.6, 23.5; HRMS (ESI-TOF) (m/z): Calculated for C20H20N2O4Na (M + Na):
375.1321, found (M + H): 375.1321.
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AUTHOR INFORMATION
Corresponding Author
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* E-mail: prabhu@orgchem.iisc.ernet.in
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The financial supports from IISc, SERB (NO.SB/S1/OC-56/2013), New Delhi, and CSIR (No.
02(0226)15/EMR-II), New Delhi are gratefully acknowledged. Authors thank Dr. Ramesha, A.
R. (RL Fine Chem) for useful discussion. KRB and VL Thank CSIR for senior fellowships.
SUPPORTING INFORMATION: 1H, and 13C NMR spectral data of all compounds.
REFERENCES
(1)
(a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731. (b) Colby, D.; Tsai, A.;
Bergman, R.; Ellman, J. Acc. Chem. Res. 2011, 45, 814.(c) Hartwig, J. F. Nature 2008, 455, 314.
(d) Godula, K.; Sames, D. Science 2006, 312, 67. (e) Zheng, Q.-Z.; Jiao, N. Tetrahedron Lett.
2014, 55, 1121.
(2)
(3)
(a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2011, 45, 788.
Based on industrial bullion prices of the metals in both American and Asian markets. Ruthenium
metal ($42 /troy ounce) is about 14 times cheaper than Pd ($596 /troy ounce). BASF Engelhard
Industrial Bullion (EIB) Prices. http://apps.catalysts.basf.com/apps/eibprices/mp/. (Accessed 17th
May, 2016).
(4)
Keyword search on Google Scholar, "Ruthenium catalyzed ortho" and "Palladium catalyzed
ortho" yields 29,400 and 89,100 hits respectively. (Accessed 17th, May, 2016).
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