Metal-Free Organocatalytic Oxidative Ugi Reaction Promoted by Hypervalent Iodine

Article abstract of DOI:10.1021/acs.joc.7b00594

We report here a novel IBX-promoted oxidative coupling of primary amines and its utilization to Ugi reaction. Advantageously, the reaction could be carried out in choline chloride urea as a natural deep eutectic solvent. A range of imines and bisamides fr

Full text of DOI:10.1021/acs.joc.7b00594

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Article
Metal-Free Organocatalytic Oxidative Ugi
Reaction Promoted by Hypervalent Iodine
Karandeep Singh, Amanpreet Kaur, Venus Singh Mithu, and Siddharth Sharma
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Apr 2017
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MetalꢀFree Organocatalytic Oxidative Ugi Reaction
Promoted by Hypervalent Iodine
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a,b
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a
Karandeep Singh, Amanpreet Kaur, Venus Singh Mithu, Siddharth Sharma ٭
a
Department of Chemistry, Mohanlal Sukhadia University, Udaipur, India, 313001
b
Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev
University, Amritsar, India 143005
c
Department of Chemistry, Indian Institute of Technology Delhi, New Delhi, India 110016
TOC/Abstract Graphics:
ABSTRACT:
We report here a novel IBX promoted oxidative coupling of primary amines and its utilization to
Ugi reaction. Advantageously, the reaction could be carried out in choline chlorideꢀurea as a
natural deep eutectic solvent. A range of imines and bisꢀamides from pseudoꢀfour component
oxidative Ugi reaction could be synthesized under mild and metalꢀfree conditions.
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Advantageously, the oxidant (IBX) and solvent could be recycled up to five times with only a
slight loss in activity.
INTRODUCTION
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Organocatalytic oxidations, the use of small organic molecules as catalysts for the oxidation
reactions, are considered to be the major branch of organic synthesis along with transition metal
catalysis. Despite their importance, oxidation reactions using organocatalysts have received
limited synthetic attention with respect to their site specific activity in asymmetric synthesis.
Seminal works by Dess, Martin, Moriarty, Koser and Varvoglis reignited the curiosity of organic
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chemist in the chemical reactivity of hypervalant iodine reagents under mild conditions.
Furthermore, the reactivity of phenyliodonium diacetate (PIDA, I), phenyliodine
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bis(trifluoroacetate), (PIFA, II) as λ iodanes while DessꢀMartin periodinane (DMP, III) and oꢀ
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iodoxybenzoic acid (IBX, IV) as λ iodanes have been extensively studied due to their low cost,
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mild reaction conditions, and excellent oxidizing abilities (Figure 1).
Figure 1. Hypervalent iodine reagents utilized in the reaction.
Recenly, Zhdankin et al. utilized hypervalent iodine reagents for the oxidation of aldoximes to
nitrile oxides, which on tandem reaction with alkenes and alkynes to give the corresponding
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isoxazolines and isoxazoles in moderate to good yields. More recently Goti et al. has developed
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the IBX promoted oxidation of N,Nꢀdisubstituted hydroxylamines to the corresponding nitrones.
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In particular, Nicolaou group have been utilized intrinsic qualities of DMP and IBX for the
number of widespread applications. Included in these methods are the selective oxidation of
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carbon adjacent to aromatic systems with IBX, cyclization of Nꢀaryl amides, oxidation of
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ketones and aldehydes to the corresponding α,βꢀunsaturated carbonyl compounds and IBX
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mediated methods for the generation of imines from secondary amines (Scheme 1). However,
when primary amines were subjected to IBX or DMP, afforded mixtures of corresponding
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nitriles and aldehydes or solely nitriles. We surmised that the oxidative process of amine could
be exploited for the synthesis of imines by altering the reaction conditions and/or using additive.
Scheme 1. Comparison of hypervalent iodine mediated oxidation of amines with this work.
Imines are the most versatile synthetic intermediates in the variety of organic transformations
from the synthesis of fine chemicals to pharmaceuticals. Therefore, the oxidation of primary
amines to secondary imines have attracted much interest in recent years using different
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catalysts. The reported methods of this transformation have their own drawbacks, involving the
metal catalyzed oxidations involving dioxygen. However, metal is not the first choice in the
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pharmaceutical industry due to the possible contamination in the final drug molecule. In contrast
to metalꢀmediated reactions for amine oxidation, recently several metalꢀfree and organocatalytic
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methods have been reported but most of these metalꢀfree catalysts are difficult to prepare, have
complex structure and of high price. Evidently, there is a strong demand for a general and
convenient approach to access the substituted imine derivatives that uses easily available
catalysts, mild reaction conditions and gives high yield of products. As a part of our interest
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towards the development of isocyanide chemistry herein, we report a mild and selective
oxidation of primary amines with IBX to access the corresponding imines in deep eutectic
solvents and the oxidation can be combined in one pot by the addition of isocyanides affording
oxidative Ugi reaction.
RESULTS AND DISCUSSION
Building upon the work of Nicolaou and coꢀworkers, we started investigating the feasibility of
the oxidation of benzylamine 1a with IBX. The results of control experiments for the oxidative
coupling of benzylamine are illustrated in table 1. Oxidation of 1 equiv. of 1a with 1 equiv. of
IBX was afforded mixtures of the corresponding aldehyde (18%) and nitrile (34%) in CH Cl2
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(Table 1, entry 1, yields are not shown in the table). Similarly 2 equiv. of 1a with 1 equiv. of
IBX was afforded desired product 2a in 17% yield (Table 1, entry 2). Further experiments were
revealed that the 2 equiv. of 1a and addition of 0.1 equiv. of benzoic acid to the reaction mixture
gave the 2a in 54% yield (Table 1, entry 3) in 12h. The latter was assigned as imine structure 2a
based on the standard spectroscopic analysis. Different hypervalent iodine reagents (Figure 1)
were screened for the oxidation of benzyl amine in order to compare the efficiency for the
desired transformation (Table 1, entry 4ꢀ6). IBX and DMP were highly selective oxidants for the
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oxidative coupling reaction, afforded the desired imine (2a) (Table 1, entry 3, 6). While the use
of organic solvent afforded the desired product in moderate yield, we sought to further improve
the yield of the reaction while avoiding the use of organic solvents.
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Table 1. Optimizations of oxidants and solvents for the synthesis of 2a from benzylamine
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(
1a).
Entry
Oxidant
IBX
IBX
IBX
PIDA
PIFA
DMP
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
IBX
Solvent
CH Cl
Additive
None
None
BA
Yield (%)
Trace
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b
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CH Cl
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CH Cl
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CH Cl
BA
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2
CH Cl
BA
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2
CH Cl
BA
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2
CH CN
BA
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3
Toluene
BA
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CH Cl /HFIP
BA
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Urea: ChCl
DMU: ChCl
Imidazole: ChCl
CA: ChCl
BA
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BA
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BA
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BA
NR
f
Urea: ChCl
Urea: ChCl
Urea: ChCl
Urea: ChCl
Urea: ChCl
Urea: ChCl
AcOH
PTSA
82
77
38
84
82
84
BF .OEt2
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d
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BA
BA
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Reaction conditions: a mixture of 1a (2.0 mmol), oxidant, additive (0.1 equiv.) and solvent (5
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ml) was stirred. 1 equiv. IBX and 1 mmol amine were used. ChClꢀcholine chloride, CAꢀcitric
acid, DMUꢀ1,3ꢀDimethyl urea, 1,1,1,3,3,3ꢀhexafluoroisopropanol (HFIP) and BAꢀBenzoic acid.
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equiv. of additive used. Reaction was done under N . Reaction was done under O . Product
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was 2ꢀ(Nꢀbenzylacetamido)ꢀNꢀ(tertꢀbutyl)ꢀ2ꢀphenylacetamide.
DESs (deep eutectic solvents) are gaining importance as green and biodegradable solvents for
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the synthesis of a wide variety of useful and important compounds. Interestingly, IBX was
soluble in DES (ChCl:urea), which is otherwise sparingly soluble in organic solvents. Poor
solubility of IBX in organic solvents and high solubility in a DES (ChCl:urea) inspired us to use
DESs for the oxidation reaction under homogeneous conditions (Table 1, entry 7ꢀ13). A study on
different types of DESs, for example ChCl:CA (1:1), ChCl: Imidazole (3:7), ChCl: Urea (1:2)
and ChCl: DMU (1:2) (Table 1, entries 10ꢀ13) were demonstrated that the ChCl: Urea (1:2)
dramatically changes the results of this oxidation. Subsequently, various additives were
evaluated such as benzoic acid, acetic acid, PTSA, and BF .OEt (Table 1, entries 10, 14−16).
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Benzoic acid and acetic acid (Table 1, entries 10, 14) caused rapid and complete conversion to
afford a single, stable product. Increasing the amount of benzoic acid as additive did not alter the
reaction yields (Table 1, entry 17). Reaction was equally effective under N and O atmosphere
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indicates there is no involvement of O in the oxidation process (Table 1, entry 18, 19). All of
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these systematic studies indicated that the combination of IBX in ChCl: Urea (1:2) at room
temperature for 12 h with a catalytic amount of carboxylic acid was the most effective system for
the oxidative coupling of benzylamines to imines.
The efficiency of the pilot reaction prompted us to explore the scope of the method and
generality for the construction of the various imines. Under the optimized conditions, substituted
benzylamines undergo oxidation to their secondary imine dimmers (Table 2). Electonꢀrich
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amines, such as pꢀmethylbenzylamine (88%, entry 2) and oꢀmethoxybenzylamine (94%, entry 4)
and electronꢀdeficient amine such as mꢀfluorobenzylamine (81%, entry 3), were readily
converted to the secondary imines in high yields. The heterocycle amines (1e) proceeded
smoothly with good outcome of reaction yield (Entry 5, 84%). The hydrochloride salt of
benzylamine was unreactive towards oxidation, but good yield was obtained upon addition of 1
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equiv. of Brønsted base, such as Et N (entry 6). No reaction was found with amine lacking of αꢀ
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H, such as aniline (entry 7).
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Table 2. Oxidation of primary amines with IBX.
Entry
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Substrate
Product
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Reaction conditions: a mixture of 1a (2.0 mmol), IBX (1.0 mmol), additive (0.1 equiv.) and
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solvent (5 ml) was stirred. 1 equiv. of base (NEt ) was used.
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The successful synthesis of imine derivatives prompted us to apply this method to the more
practical interest such as Ugi fourꢀcomponent reactions. Ugi reaction involves the condensation
of a carbonyl and an amine, to generate imine as an intermediate followed the reaction of an
isocyanide, and a carboxylic acid to form bis(amide)s. Upon subjecting benzylamine (1a, 2.0
equiv.), benzoic acid (1.0 equiv.) and tertꢀbutylisonitrile (1.0 equiv.) to the conditions of IBXꢀ
promoted oxidation reaction, the Ugi reaction product (4a) was obtained in 82% yield. Evidently,
carboxylic acid in the reaction is not only involves in the catalyzing the reaction but also act as
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one of the component in the Ugi reaction. A range of diverse carboxylic acids and primary
amines were suitable reaction partners. Electronꢀdonating substituents, para-methoxy and paraꢀ
methyl present on the benzylamines could be reacted under standard conditions to give the Ugi
reaction products 4c and 4d in 80% and 85% yields respectively (Figure 2). Electronwithdrawing
substituents, meta and paraꢀtrifluoromethyl, meta and paraꢀfluoro, paraꢀchloro on the
benzylamines (4e, 4i, 4g, 4b and 4h) also smoothly coupled to yield the desired product in 78%,
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5%, 76%, 77%, 81% yields respectively. The electronic properties of the carboxylic acid
exerted some influence on this transformation; carboxylic acid bearing electron withdrawing
groups (4k, 4o) provided the corresponding bisꢀamides in better yields 81%, 87% respectively
than those with electron donating substituents (4lꢀ73%, 4pꢀ79%). More sterically hindered orthoꢀ
substituted benzyl amine and benzoic acids were also amenable to this protocol, and the
corresponding bisꢀamides (4f, 4n, 4q, 4r) were obtained in good yields 83%, 82, 64%, 74%
respectively. This protocol was further extended to heteroaromatic methanamine (4jꢀ4m) and the
desired products were obtained in moderate to good yields. Next, several isocyanide derivatives
were evaluated for this transformation (4a, 4t, 4v, 4w, 4x). Isonitriles including tert-
butylisonitrile (4aꢀ4s), cyclohexyl isonitrile (4t, 4u), 1ꢀpentyl isocyanide (4v), 1,1,3,3ꢀ
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tetramethylbutyl isocyanide (4w) and ethyl isocynoacetate (4x) were proved to be good
substrates for the reaction, giving the products in good yields. Complex mixture was obtained,
when aliphatic amine such as pentyl amine was used for the oxidation in place of substituted
benzyl amines.
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Figure 2. Scope of the oxidative three-component Ugi reaction.
a
Reaction conditions: a mixture of amines (2.0 mmol), IBX (1.0 mmol), acid (1.0 mmol),
isocyanide (1.0 mmol) and solvent (5 ml) was stirred for 24h.
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Figure. 3. Reusability chart for the DES.
In view of green chemistry, complete study was done to assess the reusability of DES (Urea:
ChCl). After completion of reaction, water was added to the reaction mixture. The DES was
soluble in water and solid crude was precipitated. The obtained solid was separated by filtration.
The DES was recovered from the filtrate by evaporating the water phase under vacuum. The
recovered DES was then successfully used for the next 5 batches and small losses in catalytic
activity were observed for the desired compound 4a (Figure 3). Product and Iodosylbenzoic acid
(
IBA, reduced form of IBX) were separated quantitatively by dissolving the Ugi reaction product
in EtOAc and filtration. Solid IBA obtained from filtration was oxidized with aqueous oxone,
precipitated by cooling, and isolated by filtration to obtained IBX. The recovered IBX was
further reused five times for the oxidative Ugi reaction (Figure 4). To our delight, catalytic
potential of regenerated IBX was identical to freshly prepared IBX from oꢀiodobenzoic acid up
to three cycles however yields were decreased for 4th and 5th cycles. Thus, the insolubility of
IBX and IBA were exploited for the recycling of oxidant and simultaneously, IBX was used
under homogeneous condition in DESs.
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Figure. 4. Reuse of regenerated IBX from IBA for oxidative Ugi reaction.
Scheme 2. Organocatalytic cross-coupling of amines for Ugi reaction.
The excellent selectivity for primary benzylic amines suggested that, selective heteroꢀcoupling
could be achieved through the IBX oxidation by combining two different benzylic amines. When
the reaction of paraꢀfluorobenzylamine (1h), benzylamine (1a, 1.5 equiv., slow addition),
benzoic acid, and tertꢀbutylisonitrile was performed in the presence of the IBX as the
organocatalyst, the desired Ugi reaction product was obtained in 82% yield (Scheme 2) in 48h.
This result indicating that the proposed methodology here is applicable for the production of a
wide diversity in Ugi reaction because heteroꢀcoupled imines are much less accessible by
traditional transitionꢀmetal catalysts with comparable chemoselectivity.
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Scheme 3. Mechanism for the oxidative Ugi reaction.
A tentative mechanistic rationalization for the oxidative imine synthesis and Ugi reaction can be
advanced as depicted in scheme 3. The initial stage is similar to that proposed by Nicolaou and
8
coꢀworkers for the IBX oxidation. IBX (IV) is undergoes a reaction with amine afford
intermediate 6. Further, 6 was hydrolyzed by the water leads to the formation of corresponding
aldehyde 7. Exposure to aromatic acid promotes dehydaration reaction with amine in the acidic
medium formed Schiff base 2a. Eventually, imine reacts with acid and isocyanide to generate the
desired Ugi reaction product.
CONCLUSION
In summary, we have developed a simple, efficient and organocatalyzed protocol for the direct
synthesis of useful imines using hypervalant iodine as an oxidant. The scope of the reaction was
studied by performing an expedient oneꢀpot protocol for oxidative threeꢀcomponent Ugi reaction.
The clean and mild synthetic procedure described herein is expected to have broader
implications for use in those syntheses where the metal has to be avoided, including isocyanide
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based multicomponent reactions in drug discovery and heterocyles synthesis where imine
involves as an intermediate.
EXPERIMENTAL SECTION
1
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Materials and Methods: All reactions were carried out in ovenꢀ or flameꢀdried glassware in an
open flask unless otherwise noted. Except as otherwise indicated, all reactions were magnetically
stirred and monitored by analytical thin layer chromatography (TLC) using preꢀcoated silica gel
glass plates (0.25 mm) with F254 indicator. Visualization was accomplished by UV light (254
nm). Flash column chromatography was performed using silica gel (100ꢀ200 mesh). Yields refer
to pure compounds, unless otherwise noted. Commercial grade reagents and solvents were used
1
13
without further purification. H and C NMR spectra were recorded on Bruker 500 MHz NMR
spectrometer using CDCl /DMSOꢀd as a solvent for deuterium locking, with temperature 298K.
3
6
Chemical shifts are given in ppm with TMS as an internal reference. J values are given in Hertz.
1
3
13
1
C NMR spectra were recorded as solutions in CDCl with complete proton decoupling C{ H
3
NMR}. Mass spectra were recorded on Bruker micrOTOF Q II Mass spectrometer. The solutions
were made/diluted in ACNꢀH O (3:7) and directly injected to the ESI source through pump. IBX
2
was synthesized in the laboratory. PIDA, PIFA and DMP were purchased and used directly.
1
5
General procedure for the preparation of Urea: ChCl: A mixture of choline chloride (6.98
g, 50 mmol) and urea (6.00 g, 100 mmol) in a 1:2 molar ratio, were taken in a round bottom task
and heated to 80°C for 30 min to give a colorless transparent liquid. The resulting eutectic
solvent was then allowed to cool at room temperature and was used for the synthesis without
further purification.
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6
General procedure for the imine synthesis: Benzyl amine 1a (214 mg, 2.0 mmol,), benzoic
acid (12 mg, 0.1 mmol), IBX (280 mg, 1.0 mmol) were taken in a 50 mL round bottom flask
containing 5 mL of DES. The reaction was stirred at room temperature for 12h. The reaction was
monitored by TLC. After completion of reaction water was added. The DES being soluble in
water comes in the water layer. The solid was separated by filtration. The crude product was
dissolved in ether and was filtered to remove IBA. Remaining filtrate was evaporated under
reduced pressure, the resulting crude was purified by column chromatography to obtain pure
product 2a.
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Procedure for the oxidatative Ugi reaction: Benzyl amine 1a (214 mg, 2.0 mmol), benzoic
acid (122 mg, 1.0 mmol), tert-butylisonitrile (83 mg, 1.0 mmol), IBX (280 mg, 1.0 mmol) were
taken in a 50 mL round bottom flask containing 5 mL of DES. The reaction was stirred at room
temperature for 24h. The reaction was monitored by TLC. After completion of reaction water
was added. The DES being soluble in water comes in the water layer. The solid was separated by
filtration. The crude product was dissolved in ethylacetate and residue was filtered to remove
IBA. Remaining filtrate was evaporated under reduced pressure, the resulting crude was washed
with cold ether to obtain pure product 4a.
Recycling studies of deep eutectic solvent Urea: ChCl: After completion of the reaction
(monitored by TLC), the reaction mixture was diluted with water (10 mL) The DES being
soluble in water comes in the water layer. Product was obtained by filtration. The DES was
recovered easily from filtrate by evaporating the water at 80°C under vacuum. The recovered
DES was then successfully used for the next batch and showing no significant loss of yield.
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Recycling studies of IBX: In a representative case, the IBX and IBX by products were
recovered essentially quantitatively by filtration from the oxidation of benzyl amine with 1.0
1
equiv of IBX in EtOAc. H NMR analysis of the crude mixture indicates the primary component
1
1
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to be iodosylbenzoic acid (IBA). The recovered solids were oxidized with aqueous oxone,
precipitated by cooling, and isolated by filtration and was reused without further purification.
Procedure for the hetero-coupled oxidatative Ugi reaction: para-Fluorobenzyl amine 1h (125
mg, 1.0 mmol), benzoic acid (122 mg, 1.0 mmol), and IBX (280 mg, 1.0 mmol) were taken in a
5
0 mL round bottom flask containing 3 mL of DES. The reaction was stirred at room
temperature for 5 min. Afterwards benzylamine (1a, 161 mg, 1.5 equiv) dissolved in 2 mL DES
was slowly added (15 min./mmol) to the reaction mixture followed by isocyanide (83 mg, 1.0
mmol). The reaction was further stirred for 48h. After completion of reaction water was added.
The DES being soluble in water comes in the water layer. The solid was separated by filtration.
The crude product was dissolved in ethylacetate and residue was filtered to remove IBA.
Remaining filtrate was evaporated under reduced pressure, the resulting crude was washed with
cold ether to obtain pure product 4z.
Product characterization data
1
6a
(
E)-N-Benzyl-1-phenylmethanimine (2a). Yield: 164 mg, 84%; Yellow liquid; Rf = 0.56
1
(
hexanes/EtOAc, 9:1); H NMR (400 MHz, CDCl ) δ 4.82 (s, 2H), 7.24ꢀ7.27 (m, 1H), 7.37 (d, J
3
1
3
=
3.2 Hz, 4H), 7.40ꢀ7.41 (m, 3H), 7.77ꢀ7.79 (m, 2H), 8.39 (s, 1H); C NMR (400 MHz, CDCl )
3
δ 65.1, 127.1, 128.1, 128.4, 128.6, 128.7, 130.8, 136.3, 139.4, 162.1 ppm.
1
6a
(
E)-N-(4-Methylbenzyl)-1-(p-tolyl)methanimine (2b). Yield: 196 mg, 88%; White Solid; Rf
1
=
0.50 (hexanes/EtOAc, 9:1); H NMR (400 MHz, CDCl ) δ 2.33 (s, 3H), 2.37 (s, 3H), 4.76 (s,
3
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13
2
H), 7.13 (d, J = 6 Hz, 2H), 7.19ꢀ7.22 (m, 4H), 7.65 (d, J = 6 Hz, 2H), 8.33 (s, 1H); C NMR
(
400 MHz, CDCl ) δ 21.1, 21.5, 64.8, 127.9, 128.2, 129.1, 129.3, 133.7, 136.4, 136.5, 141.0
3
161.6 ppm.
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6b
(E)-N-(3-Fluorobenzyl)-1-(3-fluorophenyl)methanimine (2c). Yield: 187 mg, 81%; Yellow
1
liquid; Rf = 0.50 (hexanes/EtOAc, 9:1); H NMR (400 MHz, CDCl ) δ 4.75 (s, 2H), 6.91 (t, J =
3
6
.8 Hz, 1H), 7.03ꢀ7.09 (m, 3H), 7.24 (q, J = 6 Hz, J = 11.2 Hz, 1H), 7.31 (q, J = 6.4 Hz, J =
1 2 1 2
13
11.2 Hz, 1H), 7.47 (d, J = 6.4 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 8.29 (s, 1H); C NMR (400
2
2
2
MHz, CDCl ) δ 64.1, 113.8 (d, J = 80 HZ), 114.2 (d, J = 90 HZ), 114.7 (d, J = 85 HZ),
3
cꢀf
cꢀf
cꢀf
2
4
4
3
1
1
1
17.7 (d, J = 85 HZ), 123.4 (d, J = 10 HZ), 124.4 (d, J = 10 HZ), 129.9 (d, J = 35 HZ),
cꢀf
cꢀf
cꢀf
cꢀf
3
3
3
4
30.1 (d, J = 35 HZ) 138.4 (d, J = 30 HZ), 141.7 (d, J = 30 HZ), 160.9 (d, J = 10 HZ),
cꢀf
cꢀf
cꢀf
cꢀf
1
1
+
62.0 (d, J = 98 HZ), 162.1 (d, J = 98 HZ) ppm. HRMS (ESIꢀTOF) m/z: [M+H] calcd for
cꢀf
cꢀf
C H F N 232.0932; Found 232.0946.
14
11 2
1
6a
(
E)-N-(2-Methoxybenzyl)-1-(2-methoxyphenyl)methanimine (2d).
Yield: 240 mg, 94%;
1
Yellow liquid; Rf = 0.58 (hexanes/EtOAc, 9:1); H NMR (400 MHz, CDCl ) δ 3.89 (s, 6H), 4.94
3
(
s, 2H), 6.92 (t, J = 6 Hz, 2H), 7.01ꢀ7.07 (m, 2H), 7.29 (d, J = 6 Hz, 2H), 7.41ꢀ7.44 (m, 2H), 8.14
13
(
d, J = 6 Hz, 1H), 8.95 (s, 1H); C NMR (400 MHz, CDCl ) δ 55.3, 55.5, 59.7, 110.3, 111.1,
3
1
20.6, 120.8, 125.0, 127.5, 128.0, 128.2, 129.2, 131.8,157.1, 158.3, 158.8 ppm.
1
6a
(Z)-1-(Furan-3-yl)-N-(furan-3-ylmethyl)methanimine (2e). Yield: 147 mg, 84%; Oil; Rf =
1
0
.54 (hexanes/EtOAc, 9:1); H NMR (400 MHz, CDCl ) δ 4.74 (s, 2H), 6.26 (d, J = 2.4 Hz, 1H),
3
13
6
.32 (s, 1H), 6.45 (s, 1H), 6.77 (d, J = 2.8 Hz, 1H), 7.36 (s, 1H), 7.49 (s, 1H), 8.10 (s, 1H); C
NMR (400 MHz, CDCl ) δ 56.8, 107.8, 110.3, 111.6, 114.3, 142.2, 144.8, 151.2, 151.5, 151.8
3
ppm.
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N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)benzamide (4a).
Yield: 328 mg,
1
8
2%; White Solid; m.p. 112–114 °C; Rf = 0.6 (hexanes/EtOAc, 3:2); H NMR (500 MHz,
CDCl ) δ 1.28 (s, 9H), 4.47 (s, 1H), 4.73 (d, J = 15 Hz, 1H), 5.52 (s, 1H), 5.81 (s, 1H), 6.99 (s,
3
1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
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4
4
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0
1
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4
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8
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2
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0
2
H), 7.08ꢀ7.14 (m, 4H), 7.25ꢀ7.32 (m, 8H), 7.44 (d, J = 6.5 Hz, 2H); C NMR (500 MHz,
CDCl ) δ 28.5, 51.5, 126.6, 126.8, 127.0, 128.2, 128.4, 128.7, 129.6, 129.7, 135.2, 136.4, 137.5,
3
1
68.4, 173.2 ppm.
1
8
N-(2-(Tert-butylamino)-1-(4-fluorophenyl)-2-oxoethyl)-N-(4-fluorobenzyl)benzamide (4b).
1
Yield: 336 mg, 77%; White Solid; m.p. 112–114 °C; Rf = 0.54 (hexanes/EtOAc, 7:3); H NMR
(
500 MHz, CDCl ) δ 1.32 (s, 9H), 4.39 (d, J = 16.5 Hz, 1H), 4.74 (d, J = 10 Hz, 1H), 5.49 (s,
3
13
2
H), 6.80 (td, J = 2 Hz, J = 7.5 Hz, 2H), 6.94ꢀ6.97 (m, 4H), 7.26ꢀ7.43 (m, 7H); C NMR (500
1 2
2
2
MHz, CDCl ) δ 28.6, 51.9, 115.1 (d, J = 85 HZ), 115.7 (d, J = 85 HZ), 126.6, 128.7, 130.0,
3
cꢀf
cꢀf
3
1
1
1
1
31.1, 131.5 (d, J = 30 HZ), 136.2, 160.9 (d, J = 97 HZ), 161.8 (d, J = 99 HZ), 168.3,
cꢀf cꢀf cꢀf
19
73.2 ppm, F NMR (500 MHz, CDCl ) δ ꢀ112.6, ꢀ115.4.
3
N-(2-(Tert-butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-N-(4-methoxybenzyl)benzamide
1
8
1
(
4c). Yield: 368 mg, 80%; White Solid; m.p. 130–132 °C; Rf = 0.54 (hexanes/EtOAc, 13:7); H
NMR (500 MHz, CDCl ) δ 1.30 (s, 9H), 3.75 (s, 3H), 3.79 (s, 3H), 4.37 (s, 1H), 4.61 (d, J = 16
3
Hz, 1H), 5.37 (s, 1H), 5.62 (s, 1H), 6.70 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.94 (s,
13
2H), 7.35ꢀ7.46 (m, 7H); C NMR (500 MHz, CDCl ) δ 28.7, 51.6, 55.3, 55.4, 113.8, 114.2,
3
1
14.4, 126.7, 127.5, 128.5, 129.7, 131.0, 136.7, 158.7, 159.7, 168.8, 173.2 ppm.
N-(2-(Tert-butylamino)-2-oxo-1-(p-tolyl)ethyl)-N-(4-methylbenzyl)benzamide (4d). Yield:
1
3
64 mg, 85%; White Solid; m.p. 114ꢀ116 °C; Rf = 0.54 (hexanes/EtOAc, 7:3); H NMR (500
MHz, CDCl ) δ 1.28 (s, 9H), 2.26 (s, 3H), 2.32 (s, 3H), 4.38 (s, 1H), 4.62 (s, 1H), 5.36 (s, 1H),
3
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.68 (s, 1H), 6.95ꢀ6.99 (m, 4H), 7.09 (d, J = 8 Hz, 3H), 7.25ꢀ7.37 (m, 4H), 7.45 (d, J = 9 Hz,
1
3
2
H); C NMR (500 MHz, CDCl ) δ 21.1, 21.2, 28.6, 51.6, 126.8, 127.1, 128.5, 129.1, 129.5,
3
+
129.6, 129.7, 132.4, 136.6, 136.7, 138.4, 168.6, 173.2 ppm. HRMS (ESIꢀTOF) m/z: [M+H]
calcd for C H N O 429.2537; Found 429.2542.
0
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32
2
2
N-(2-(Tert-butylamino)-2-oxo-1-(3-(trifluoromethyl)phenyl)ethyl)-N-(3-
(trifluoromethyl)benzyl)benzamide (4e). Yield: 418 mg, 78%; White Solid; m.p. 112ꢀ114 °C;
1
Rf = 0.64 (hexanes/EtOAc, 7:3); H NMR (500 MHz, CDCl ) δ 1.35 (s, 9H), 4.54 (s, 1H), 4.89
3
(s, 1H), 5.75 (s, 1H), 5.95 (s, 1H), 6.95 (s, 1H), 7.09ꢀ7.10 (m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.29
13
ꢀ7.44 (m, 9H), 7.54ꢀ7.56 (m, 1H); C NMR (500 MHz, CDCl ) δ 28.6, 52.2, 122.8, 123.7, 124.7,
3
1
1
25.0, 125.6, 126.5, 126.7, 128.7, 128.8, 129.4, 130.1, 130.4, 130.6, 131.1, 131.4, 133.0, 135.9,
1
9
68.0, 173.4 ppm; F NMR (500 MHz, CDCl ) δ ꢀ62.89, ꢀ62.96. HRMS (ESIꢀTOF) m/z:
3
+
[
M+H] calcd for C H F N O 537.1971; Found 537.1975.
2
8
26
6
2
2
N-(2-(Tert-butylamino)-1-(2-methoxyphenyl)-2-oxoethyl)-N-(2-methoxybenzyl)benzamide
1
(4f). Yield: 382 mg, 83%; White Solid; m.p. 112ꢀ114 °C; Rf = 0.50 (hexanes/EtOAc, 13:7); H
NMR (500 MHz, CDCl ) δ 1.26 (s, 9H), 3.60ꢀ3.73 (m, 6H), 4.59ꢀ4.74 (m, 2H), 5.37ꢀ6.00 (m,
3
13
2
H), 6.56 (d, J = 8 Hz, 2H), 6.80 (s, 2H),7.06 ꢀ7.53 (m, 9H); C NMR (500 MHz, CDCl ) δ
3
2
8.5, 51.2, 54.9, 109.6, 109.8, 120.0, 120.3, 126.9, 128.2, 129.5, 130.3, 156.5, 156.6, 157.6,
+
169.1, 173.4 ppm. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H N O 461.2435; Found
2
8
32
2
4
4
61.2428.
N-(2-(Tert-butylamino)-1-(3-fluorophenyl)-2-oxoethyl)-N-(3-fluorobenzyl)benzamide (4g).
1
Yield: 331 mg, 76%; White Solid; m.p. 112–114 °C; Rf = 0.58 (hexanes/EtOAc, 7:3); H NMR
(500 MHz, CDCl ) δ 1.33 (s, 9H), 4.45 (d, J = 16.5 Hz, 1H), 4.78 (d, J = 16 Hz, 1H), 5.60ꢀ5.79
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(
m, 2H), 6.66 (s, 1H), 6.78 (td, J = 8.5 Hz, J = 1 Hz, 2H), 6.95 (t, J = 7 Hz, 1H), 7.07ꢀ7.14 (m,
1
2
1
3
2
H), 7.24ꢀ7.25 (m, 2H), 7.36ꢀ7.43 (m, 5H); C NMR (500 MHz, CDCl ) δ 28.6, 51.9, 113.8 (d,
3
2
2
2
J = 85 HZ), 115.6 (d, J = 80 HZ), 116.6 (d, J = 90 HZ), 122.7, 125.3, 126.7, 128.7, 129.8
cꢀf
cꢀf
cꢀf
3
3
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(d, J = 30 HZ), 130.1, 130.4 (d, J = 30 HZ), 136.0, 137.6, 140.4, 161.8 (d, J = 98 HZ),
cꢀf cꢀf cꢀf
1
19
1
61.9 (d, J = 98 HZ), 167.9, 172.3 ppm; F NMR (500 MHz, CDCl ) δ ꢀ111.7, ꢀ113.0. HRMS
cꢀf 3
+
(ESIꢀTOF) m/z: [M+H] calcd for C H F N O 437.2035; Found 437.2037.
26 26 2 2 2
N-(2-(Tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-N-(4-chlorobenzyl)benzamide (4h).
1
8
1
Yield: 379 mg, 81%; White Solid; m.p. 164–166 °C; Rf = 0.59 (hexanes/EtOAc, 13:7); H
NMR (500 MHz, CDCl ) δ 1.32 (s, 9H), 4.37 (d, J = 16.5 Hz, 1H), 4.74 (d, J = 10.5 Hz, 1H),
3
1
3
5
.46 (s, 1H), 5.69 (s, 1H), 6.92 (s, 2H), 7.11 (d, J = 8.5 Hz, 2H), 7.26ꢀ7.43 (m, 9H); C NMR
(500 MHz, CDCl ) δ 28.7, 51.9, 126.7, 128.5, 128.7, 129.1, 130.1, 131.0, 132.9, 133.7, 134.8,
3
1
36.1, 168.1, 173.2 ppm.
N-(2-(Tert-butylamino)-2-oxo-1-(4-(trifluoromethyl)phenyl)ethyl)-N-(4-
(trifluoromethyl)benzyl)benzamide (4i). Yield: 402 mg, 75%; White Solid; m.p. 122–124°C;
1
Rf = 0.58 (hexanes/EtOAc, 7:3); H NMR (500 MHz, CDCl ) δ 1.34 (s, 9H), 4.49 (d, J = 16 Hz,
3
13
1
H), 4.91 (s, 1H), 5.72 (s, 2H), 7.05 (d, J = 6.5 Hz, 2H), 7.34ꢀ7.46 (m, 11H); C NMR (500
MHz, CDCl ) δ 28.7, 52.1, 122.7, 123.0, 124.8, 125.2, 125.7, 125.8, 126.7, 127.4, 128.8, 130.0,
3
19
130.3, 130.9, 131.2, 135.8, 139.0, 167.8, 173.3 ppm; F NMR (500 MHz, CDCl ) δ ꢀ62.70, ꢀ
3
+
6
2.98. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H F N O 537.1971; Found 537.1968.
2
8
26
6
2
2
N-(2-(Tert-butylamino)-1-(furan-2-yl)-2-oxoethyl)-N-(furan-2-ylmethyl)benzamide
(4j).
Yield: 288 mg, 76%; White Solid; m.p. 130–131 °C; Rf = 0.58 (hexanes/EtOAc, 7:3); H NMR
500 MHz, CDCl ) δ 1.33 (s, 9H), 4.44 (d, J = 16 Hz, 1H), 4.58 (d, J = 16.5 Hz, 1H), 5.91ꢀ6.03
1
(
3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
m, 3H), 6.19 (s, 1H), 6.32 (dd, 1H), 6.54 (s, 1H), 7.24 (s, 1H), 7.34ꢀ7.41 (m, 4H), 7.51ꢀ7.53 (d,
1
3
J = 7.5 HZ, 2H); C NMR (500 MHz, CDCl ) δ 28.6, 51.7, 108.2, 110.5, 110.8, 111.7, 127.1,
3
+
130.1, 135.7, 141.8, 143.0, 148.5, 150.5, 166.3, 172.9 ppm. HRMS (ESIꢀTOF) m/z: [M+H]
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
calcd for C H N O 381.1809; Found 381.1814.
2
2
24
2
4
N-(2-(Tert-butylamino)-1-(furan-2-yl)-2-oxoethyl)-4-fluoro-N-(furan-2-ylmethyl)benzamide
1
(4k). Yield: 322 mg, 81%; White Solid; m.p. 142–144 °C; Rf = 0.63 (hexanes/EtOAc, 7:3); H
NMR (500 MHz, CDCl ) δ 1.34 (s, 9H), 4.45 (d, J = 16.5 Hz, 1H), 4.56 (d, J = 16.5 Hz, 1H),
3
5
.80 (s, 1H), 5.91ꢀ5.97 (m, 2H), 6.20 (s, 1H), 6.33ꢀ6.34 (m, 1H), 6.52 (s, 1H), 7.05 (t, J = 8.5 Hz,
13
1
H), 7.24 (d, J = 1 Hz, 1H), 7.34 (d, J = 1 Hz, 1H), 7.54ꢀ7.57 (m, 2H); C NMR (500 MHz,
2
3
CDCl ) δ 28.7, 51.8, 108.2, 110.6, 110.8, 111.7, 115.6 (d, J = 85 HZ), 129.5 (d, J = 35 HZ),
3
cꢀf
cꢀf
4
1
1
31.7 (d, J = 15 HZ), 141.9, 143.1, 148.5, 150.4, 162.7 (d, J = 99 HZ), 166.3, 172.0 ppm;
cꢀf cꢀf
19
+
F NMR (500 MHz, CDCl ) δ ꢀ109.88. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H FN O
4
3
22 23
2
3
99.1715; Found 399.1719.
N-(2-(Tert-butylamino)-1-(furan-2-yl)-2-oxoethyl)-4-ethoxy-N-(furan-2-lmethyl)benzamide
1
(4l). Yield: 309 mg, 73%; White Solid; m.p. 133–135°C; Rf = 0.51 (hexanes/EtOAc, 7:3); H
NMR (500 MHz, CDCl ) δ 1.33 (s, 9H), 1.39 (t, J = 7 Hz, 3H), 4.02 (q, J = 7 Hz, J = 14 Hz,
3
1
2
2
H), 4.42 (d, J = 16.5 Hz, 1H), 4.60 (d, J = 16.5 Hz, 1H), 5.78 (s, 1H), 5.99 (s, 1H), 6.14 (s, 1H),
6.21 (t, J = 2 Hz, 1H), 6.32 (q, J = 1.5 Hz, J = 3 Hz, 1H), 6.52 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H),
1
2
13
7
.25 (d, J = 1 Hz, 1H), 7.34 (d, J = 1 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H); C NMR (500 MHz,
CDCl ) δ 14.8, 28.7, 51.7, 63.7, 108.3, 110.6, 110.7, 111.5, 114.4, 127.5, 129.2, 141.8, 142.9,
3
+
148.7, 150.8, 160.6, 166.5, 172.9 ppm. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H N O
2
4
28
2
5
4
25.2071; Found 425.2072.
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N-(2-(Tert-butylamino)-2-oxo-1-(thiophen-2-yl)ethyl)-N-(thiophen-2-ylmethyl)benzamide
1
(4m). Yield: 309 mg, 75%; White Solid; m.p. 123–125 °C; Rf = 0.62 (hexanes/EtOAc, 7:3); H
NMR (500 MHz, CDCl ) δ 1.30 (s, 9H), 4.75ꢀ4.78 (m, 2H), 5.71 (s, 1H), 6.00 (s, 1H), 6.74 (d, J
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
3 Hz, 1H), 6.81ꢀ6.83 (m, 1H), 6.97ꢀ6.99 (m, 1H), 7.10 (s, 1H), 7.13 (d, J = 5 Hz, 1H), 7.33 (d,
13
J = 5 Hz, 1H), 7.38ꢀ7.41 (m, 3H), 7.48ꢀ7.50 (m, 2H); C NMR (500 MHz, CDCl ) δ 28.6, 51.7,
3
1
25.5, 126.6, 126.8, 126.9, 127.7, 128.7, 129.4, 130.2, 135.7, 137.3, 140.3, 167.4, 172.6 ppm.
+
HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H N O S 413.1352; Found 413.1358.
2
2
24
2
2 2
1
8
N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-3-nitrobenzamide (4n). Yield: 365
1
mg, 82%; White Solid; m.p. 156–158 °C; Rf = 0.62 (hexanes/EtOAc, 7:3); H NMR (500 MHz,
CDCl ) δ 1.34 (s, 9H), 4.45 (d, J = 15 Hz, 1H), 4.65 (d, J = 15 Hz, 1H), 5.47 (s, 1H), 5.71 (s,
3
13
1
H), 6.86 (s, 2H), 7.10 (s, 3H), 7.33ꢀ7.47 (m, 6H), 7.74 (s, 1H), 8.19 (s, 2H); C NMR (500
MHz, CDCl ) δ 28.7, 29.8, 52.0, 122.1, 124.4, 126.9, 127.3, 128.5, 129.1, 129.2, 129.6, 129.9,
3
1
32.5, 134.9, 138.2, 148.0, 168.1, 170.8 ppm.
N-Benzyl-4-bromo-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)benzamide (4o). Yield: 415
1
mg, 87%; White Solid; m.p. 144–146 °C; Rf = 0.61 (hexanes/EtOAc, 7:3); H NMR (500 MHz,
CDCl ) δ 1.31 (s, 9H), 4.43 (d, J = 16Hz, 1H), 4.69 (d, J = 16 Hz, 1H), 5.50 (s, 2H), 6.97 (s, 2H),
3
13
7
.12ꢀ7.16 (m, 3H), 7.28ꢀ7.45 (m, 9H); C NMR (500 MHz, CDCl ) δ 28.7, 51.8, 124.2, 127.0,
3
128.4, 128.5, 128.8, 129.0, 129.8, 131.7, 135.1, 135.3, 168.3, 172.3 ppm. HRMS (ESIꢀTOF)
+
m/z: [M+H] calcd for C H BrN O 479.1329; Found 479.1336.
2
6
27
2
2
N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-3-methoxybenzamide (4p). Yield:
1
3
39 mg, 79%; White Solid; m.p. 135–137 °C; Rf = 0.53 (hexanes/EtOAc, 7:3); H NMR (500
MHz, CDCl ) δ 1.30 (s, 9H), 3.64 (s, 3H), 4.45 (s, 1H), 4.71 (d, J = 16.5 Hz, 1H), 5.46 (s, 1H),
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
.62 (s, 1H), 6.90 (d, J = 21 Hz, 2H), 7.04ꢀ7.08 (m, 3H), 7.12ꢀ7.18 (m, 3H), 7.26ꢀ7.39 (m, 6H);
1
3
C NMR (500 MHz, CDCl ) δ 28.7, 51.7, 55.3, 111.8, 116.3, 119.0, 127.0, 128.4, 128.6, 128.9,
3
+
129.7, 135.4, 137.6, 159.6, 168.4, 173.1 ppm. HRMS (ESIꢀTOF) m/z: [M+H] calcd for
C H N O 431.2329; Found 431.2330.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
27
30
2
3
N-Benzyl-2-(tert-butyl)-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)benzamide (4q). Yield:
1
2
92 mg, 64%; White Solid; m.p. 136–138 °C; Rf = 0.65 (hexanes/EtOAc, 7:3); H NMR (500
MHz, CDCl ) δ 1.29 (s, 18H), 4.46 (s, 1H), 4.76 (s, 1H), 5.45 (s, 1H), 5.71 (s, 1H), 7.06 (s, 2H),
3
1
3
7
.13ꢀ7.18 (m, 3H), 7.25ꢀ7.44 (m, 9H); C NMR (500 MHz, CDCl ) δ 28.6, 31.3, 34.9, 51.6,
3
1
25.5, 126.7, 127.0, 128.4, 128.5, 128.8, 129.6, 133.3, 135.4, 153.3, 168.6, 173.5 ppm. HRMS
+
(ESIꢀTOF) m/z: [M+H] calcd for C H N O 457.2850; Found 457.2863.
3
0
36
2
2
N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-2-fluorobenzamide (4r). Yield: 309
1
mg, 74%; White Solid; m.p. 125–127 °C; Rf = 0.60 (hexanes/EtOAc, 7:3); H NMR (500 MHz,
CDCl ) δ 1.35 (s, 9H), 4.38 (d, J = 16.5 Hz, 1H), 4.61 (d, J = 16 Hz, 1H), 5.69 (s, 1H), 5.86 (s,
3
1
3
1H), 6.84 (s, 1H), 7.04ꢀ7.08 (m, 4H), 7.18ꢀ7.29 (m, 7H), 7.42 (d, J = 6 Hz, 2H); C NMR (500
2
4
MHz, CDCl ) δ 28.6, 44.2, 51.6, 64.3, 115.7 (d, J = 85 HZ), 124.4 (d, J = 10 HZ), 124.6 (d,
3
cꢀf
cꢀf
2
3
J = 70 HZ), 127.0, 127.4, 127.7, 128.2, 128.4 (d, J = 40 HZ), 128.5, 128.7, 129.5, 131.1
cꢀf
cꢀf
3
1
3
19
(
d, J = 35 HZ), 135.0, 136.8, 157.2 (d, J = 97 HZ), 157.4, 168.1 (d, J = 16 HZ) ppm; F
cꢀf cꢀf cꢀf
+
NMR (500 MHz, CDCl ) δ ꢀ115.18. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H FN O
3
26 27
2
2
4
19.2129; Found 419.2143.
N-Benzyl-N-(2-(tert-butylamino)-2-oxo-1-phenylethyl)-3-methylbenzamide (4s). Yield: 364
1
mg, 88%; White Solid; m.p. 134–136 °C; Rf = 0.62 (hexanes/EtOAc, 7:3); H NMR (500 MHz,
CDCl ) δ 1.29 (s, 9H), 2.30 (s, 3H), 4.45 (s, 1H), 4.69 (d, J = 15 Hz, 1H), 5.47 (s, 1H), 5.67 (s,
3
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13
1
H), 7.00ꢀ7.04 (m, 2H), 7.11ꢀ7.21 (m, 5H), 7.22ꢀ7.34 (m, 7H); C NMR (500 MHz, CDCl ) δ
3
2
1.4, 28.6, 51.7, 123.6, 126.9, 127.3, 127.8, 128.3, 128.5, 128.8, 129.7, 130.5, 135.4, 136.4,
+
138.4, 168.5, 173.5 ppm. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H N O 415.2380;
27
30
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Found 415.2385.
18
N-Benzyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)benzamide (4t). Yield: 362 mg,
1
8
5%; White Solid; m.p. 128–130 °C; Rf = 0.53 (hexanes/EtOAc, 7:3); H NMR (400 MHz,
CDCl ) δ 1.03ꢀ1.13 (m, 3H), 1.25ꢀ1.37 (m, 2H), 1.55ꢀ1.65 (m, 3H), 1.80ꢀ1.90 (m, 2H), 3.78ꢀ3.84
3
(
m, 1H), 4.47 (s, 1H), 4.70 (s, 1H), 5.50 (s, 1H), 5.72 (s, 1H), 7.07 (d, J = 4.8 Hz, 2H), 7.12ꢀ7.19
13
(
m, 4H), 7.29 (m, 4H), 7.33ꢀ7.39 (m, 3H), 7.46 (d, J = 5.2 Hz, 2H); C NMR (400 MHz, CDCl )
3
δ 24.7, 24.8, 25.5, 32.7, 48.6, 126.7, 126.9, 127.1, 128.3, 128.4, 128.5, 128.8, 129.5, 129.7,
35.1, 136.3, 168.2, 173.2 ppm.
1
N-(2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-N-(4-methoxybenzyl)benzamide
1
(
4u). Yield: 427 mg, 88%; White Solid; m.p. 156–158 °C; Rf = 0.53 (hexanes/EtOAc, 7:3); H
NMR (500 MHz, CDCl ) δ 1.02ꢀ1.09 (m, 3H), 1.25ꢀ1.35 (m, 2H), 1.54ꢀ1.63 (m, 3H), 1.80ꢀ1.89
3
(
m, 2H), 2.27 (s, 3H), 3.77 (s, 4H), 4.36 (s, 1H), 4.63 (s, 1H), 5.38 (s, 1H), 5.75 (s, 1H), 6.81 (d,
13
J = 8.5 Hz, 2H), 7.00 (s, 4H), 7.26ꢀ7.33 (m, 5H), 7.45 (d, J = 7 Hz, 2H); C NMR (500 MHz,
CDCl ) δ 21.0, 24.7, 24.8, 25.5, 32.7, 48.5, 55.3, 114.2, 126.7, 127.2, 128.4, 129.0, 129.7, 131.0,
3
+
136.4, 136.6, 159.7, 168.5, 173.1 ppm. HRMS (ESIꢀTOF) m/z: [M+H] calcd for C H N O
3
0
34
2
4
4
87.2591; Found 487.2597.
N-Benzyl-N-(2-oxo-2-(pentylamino)-1-phenylethyl)benzamide (4v). Yield: 269 mg, 65%;
1
White Solid; m.p. 138–140 °C; Rf = 0.50 (hexanes/EtOAc, 7:3); H NMR (400 MHz, CDCl ) δ
3
0
.85 (d, J = 6 HZ, 3H), 1.22 (d, J = 18 Hz, 4H), 1.43 (s, 2H), 3.20 (s, 2H), 4.45 (d, J = 15.2 Hz,
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H), 4.77 (d, J = 13.6 Hz, 1H), 5.62 (s, 1H), 6.40 (s, 1H), 6.98 (s, 2H), 7.11 (s, 3H), 7.26ꢀ7.44
13
(m, 10H); C NMR (400 MHz, CDCl ) δ 14.0, 22.2, 28.9, 29.0, 39.6, 126.6, 127.0, 128.1, 128.5,
3
+
128.6, 128.7, 129.6, 129.7, 135.2, 136.4, 169.3, 173.1 ppm. HRMS (ESIꢀTOF) m/z: [M+H]
calcd for C H N O 415.2380; Found 415.2383.
0
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0
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N-Benzyl-4-bromo-N-(2-oxo-1-phenyl-2-((2,4,4-trimethylpentan-2-
yl)amino)ethyl)benzamide (4w). Yield: 416 mg, 78%; White Solid; m.p. 153–155 °C; Rf = 0.60
1
(hexanes/EtOAc, 4:1); H NMR (500 MHz, CDCl ) δ 0.86 (s, 9H), 1.38 (s, 3H), 1.43 (s, 3H),
3
1
.48 (d, J = 15 Hz, 1H), 1.67 (d, J = 15 Hz, 1H), 4.41 (d, J = 17 Hz, 1H), 4.71 (s, 1H), 5.36 (s,
1
H), 5.56 (s, 1H), 3.75ꢀ3.85 (m, 4H), 4.38 (s, 1H), 4.63 (s, 1H), 5.38 (s, 1H), 5.75 (s, 1H), 7.01
1
3
(d, J = 6.5 Hz, 2H), 7.12ꢀ7.17 (m, 3H), 7.28ꢀ7.42 (m, 9H); C NMR (500 MHz, CDCl ) δ 28.3,
3
2
1
8.6, 31.4, 31.7, 53.0, 55.8, 65.0, 124.0, 127.0, 128.2, 128.3, 128.4, 128.5, 128.5, 128.7, 128.9,
+
29.8, 130.7, 131.6, 135.2, 162.0, 167.7, 172.1 ppm. HRMS (ESIꢀTOF) m/z: [M+H] calcd for
C H BrN O 535.1955; Found 535.1954.
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2
2
Ethyl(2-(N-(4-fluorobenzyl)benzamido)-2-(4-fluorophenyl)acetyl)glycinate (4x). Yield: 386
1
mg, 83%; White Solid; m.p. 127–129 °C; Rf = 0.50 (hexanes/EtOAc, 7:13); H NMR (500 MHz,
CDCl ) δ 1.26 (t, J = 7 Hz, 3H), 4.01ꢀ4.03 (m, 2H), 4.17 (q, J = 7 Hz, J = 14 Hz, 2H), 4.40 (d,
3
1
2
J = 16 Hz, 1H), 4.73 (d, J = 15 HZ, 1H), 5.58 (s, 1H), 6.37 (s, 1H), 6.83 (t, J = 8.5 HZ, 2H),
1
3
6.97ꢀ7.00 (m, 4H), 7.35ꢀ7.39 (m, 5H), 7.45 (d, J = 7 Hz, 2H); C NMR (500 MHz, CDCl ) δ
3
2
2
3
1
4.1, 41.7, 61.7, 115.1 (d, J = 85 HZ), 115.8 (d, J = 85 HZ), 126.8, 128.7 (d, J = 30 HZ),
cꢀf cꢀf cꢀf
4
3
1
1
30.1, 130.3 (d, J = 15 HZ), 131.6 (d, J = 30 HZ), 135.8, 160.9 (d, J = 97 HZ), 161.8 (d,
cꢀf cꢀf cꢀf
1
19
J = 99 HZ), 169.2, 169.5, 173.1 ppm; F NMR (500 MHz, CDCl ) δ ꢀ112.32, ꢀ115.15. HRMS
cꢀf
3
+
(ESIꢀTOF) m/z: [M+H] calcd for C H F N O 467.1777; Found 467.1786.
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
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Eꢀmail: sidcdri@gmail.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by grant from the DSTꢀIndia in the form of INSPIRE Faculty (IFAꢀ13,
CHꢀ116) to SS. Authors acknowledges MLSUꢀUdaipur, Rajasthan for giving infrastructure
support. Authors also acknowledge Prof. S.S. Chimni, Prof. Palwinder Singh, from GNDUꢀ
Amritsar for scientific guidance. K.S. is registered Ph.D. scholar in GNDU, Amritsar.
Supporting Information
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Copy of H NMR and C NMR of all the synthesized compounds are contained in the
Supporting Information. This material is available free of charge via the Internet at
http://pubs.acs.org
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