Synthesis of Unsymmetrical Diaryl Acetamides, Benzofurans, Benzophenones, and Xanthenes by Transition-Metal-Free Oxidative Cross-Coupling of sp3 and sp2 C-H Bonds

Article abstract of DOI:10.1021/acs.joc.6b01771

A chemo- and regioselective intermolecular sp³ C-H and sp² C-H coupling reaction for C-C bond formation is described to access unsymmetrical diaryl acetamides under TM-free conditions from sec- and tert-arylacetamides and nitroarenes using tert-butoxide base in DMSO at room temperature. The coupling partners with sensitive functionalities such as chloro, bromo, hydroxy, and cyano were also amenable to the developed reaction. Synthesized α-(2/4-nitroaryl) phenylacetamides have been transformed into biologically important benzofurans, xanthenes, diaryl indoles, and unsymmetrical benzophenones by novel routes without applying a transition metal. Overall, an economical, yet efficient, strategy has been devised to access unsymmetrical diarylacetamides with the possibility of their further elaboration into a variety of biologically important heterocycles. Mechanistic understanding suggests that the reaction proceeds by a nucleophilic addition of a phenylacetamide carbanion, which is generated in the presence of tert-butoxide base, to the para or ortho (if para is substituted) position of nitrobenzene. The formed α-(4-nitrocyclohexa-2,4-dien-1-yl) phenylacetamide anion intermediate oxidized by a basic solution of DMSO or atmospheric oxygen led to the desired sp³ C-H and sp² C-H coupled α-(2/4-nitroaryl) phenylacetamides.

Full text of DOI:10.1021/acs.joc.6b01771

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Article
Synthesis of Unsymmetrical Diaryl Acetamides, Benzofurans,
Benzophenones, and Xanthenes by Transition-Metal-
Free Oxidative Cross Coupling of sp3 and sp2 C-H Bonds
Vandana Rathore, Moh. Sattar, Raushan Kumar, and Sangit Kumar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01771 • Publication Date (Web): 12 Sep 2016
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Synthesis of Unsymmetrical Diaryl Acetamides,
Benzofurans, Benzophenones, and Xanthenes by
Transition-Metal-Free Oxidative Cross Coupling of sp3
and sp2 C-H Bonds
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Vandana Rathore, Moh. Sattar, Raushan Kumar, Sangit Kumar*
Department of Chemistry, Indian Institute of Science Education and Research (IISER),
Bhopal, MP 462 066, India, E-mail: sangitkumar@iiserb.ac.in
Abstract
A chemo and regioselective intermolecular sp3 C-H and sp2 C-H coupling reaction for C-C
bond formation is described to access unsymmetrical diaryl acetamides under TM-free
conditions using sec- and tert-arylacetamides and nitroarenes using tert-butoxide base in
DMSO at room temperature. The coupling partners with sensitive functionalities such as
chloro, bromo, hydroxy, cyano were also amenable to the developed reaction. Synthesized α-
(2/4-nitroaryl) phenylacetamides have been transformed into biologically important
benzofurans, xanthenes, diaryl indoles, and unsymmetrical benzophenones by novel routes
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without applying transition metal. Overall an economical yet efficient strategy has been
devised to access unsymmetrical diarylacetamides with the possibility of their further
elaboration into a variety of biologically important heterocycles. Mechanistic understanding
suggests that the reaction proceeds by a nucleophilic addition of phenylacetamide carbanion,
which is generated in the presence of tert-butoxide base, to the para or ortho (if para is
substituted) position of nitrobenzene. The formed α-(4-nitrocyclohexa-2,4-dien-1-yl)
phenylacetamide anion intermediate oxidized by basic solution of DMSO or atmospheric
oxygen, led to the desirecd sp3 C-H and sp2 C-H coupled α-(2/4-nitroaryl) phenylacetamides.
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Introduction
The direct transition metal-free cross coupling of two C-H bonds to form a new C-C
bond is a sustainable approach to the synthesis of organic molecules as this strategy is
highly atom economical, avoid costly transition metals, ligands and generate water as
side product.1 Moreover, mild reaction conditions make this approach regio and
chemoselective and tolerate various groups such as halides, NO2, and OH which
provide an easy synthetic handle for later stage transformations.
Amides are common building blocks for the construction of fine chemicals, alkaloids,
herbicidal, pharmaceuticals (analgesic; BRL 37959 with low gastric irritancy and potential
anticancer agents), chromophores, and materials relevant molecules.2,3 C-H Functionalization
in amides, particularly for C-C bond formation is accomplished by metalation using
organolithium reagents followed by coupling with alkyl halides (Scheme 1).4a Light induced
base mediated intramolecular C-C coupling reactions in α,β-unsaturated amides or ortho-
halobenzamides are well documented by Rossi et al. involving electron transfer processes.4b
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Arylation of benzylic C-H bond in amide has also been realized with aryl halides coupling
partners using Pd-catalyst in the presence of strong base such as tert-butoxide or potassium
bis(trimethyl silyl) amide under heating conditions.5,6 In an alternative method; zinc-enolate
was prepared from amide by the reaction of sec-BuLi followed by the addition of ZnCl2. The
zinc-enolate which was generated in-situ, smoothly reacted with aryl bromides under Pd-
catalyzed conditions at 25 to 70 oC.6c
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Scheme 1. Synthetic routes to aryl acetamides
Ni-catalyzed reaction of α-haloamides with arylboronic acid substrates has also been
described for the α-arylation of amides.7 Nonetheless, the developed methodologies
require prefunctionalized coupling partners α-halo-acetamides, haloarenes or
phenylboronic acids and harsh reaction conditions. Prefunctionalized substrates not
only lower the economy and generate by-products but also restrict the substrate scope
due to incompatibility of other functional groups in the prefunctionalized substrates.
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The TM-free direct functionalization of sp3 C-H bond in acetamides under mild
reaction conditions has not been presented. A mild method may also enabled
chemoselective C-H arylation in sec-amides over N-H bond, which has not been
addressed till date due to nearly the similar reactivity of N-H bond (pKa ≤ 20 for N-H
and pKa ≥ 26 for C-H bond). On the other hand, sec-amides are better substrates for
further functionalizations due to their facile conversion into acid and are also viable
coupling partners for inter and intramolecular C-N or X-N (X = S, Se, P) bond
forming reactions.
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TM-Free approaches for the construction of C-C and C-N bonds are being explored by
many researchers in recent times.1,8-10 Particular interest is the coupling of C-H bond
with arenes for the synthesis of various organic molecules containing alkyl-aryl bond.
Nitroarenes are easily available aromatic substrates, moreover, many of the nitroarenes
are economical than other substituted benzenes. Also, the nitro group has wide scope
in organic synthesis and the chemical industry as this can be easily manipulated by
various methods into indole and carbazole heterocyclic rings and used as a leaving
group in biaryl cross-coupling.10 Our group has also studied C-C and C-N coupling
reactions for the synthesis and applications of heterocycles namely phenanthridiones,
isoindolinones, biaryls, aryl indoles, dihydropyridin-2(1H)-ones, and pyridin-2(1H)-
ones.11 Nonetheless, intermolecular cross coupling of sp3 C-H and sp2 C-H bonds have
not been studied by us. Here, we present tert-butoxide base-mediated oxidative
coupling of amides with nitroarenes for the synthesis of α-arylated amides at room
temperature. Synthesized α-arylated amides were further transformed into
unsymmetrical diaryl ketones, 3-aryl-benzofurans, 9H-xanthen-9-ylidene and α-indole
aryl amides.
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Results and discussion
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Optimization of reaction conditions were performed on phenyl ring substituted N,N-diethyl-
acetamide and nitrobenzene substrates and listed in Table 1. Weak bases sodium and
potassium carbonates were found ineffective for the promotion of sp3 and sp2 C-C coupling
reaction (Table 1, entries 1 and 2).
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Table 1. Optimization of reaction conditionsa
Entry
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Base
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Time (h)
Yield 1 (%)
Na2CO3
K2CO3
Cs2CO3
LiOtBu
KOH
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NR
NR
NR
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NaOH
KH
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NaH
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KOtBu
NaOtBu
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KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
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(54)b (65)c
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16d
17e
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CH3CN
Benzene
DME
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NR
NR
trace
NR
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EtOH
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DMSO
DMSO
4
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a Reactions were carried out using amide (0.22 mmol) and nitrobenzene (0.27 mmol) and
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KOtBu (0.56 mmol) in inert atmosphere for indicated time. b Yield of 1 was obtained and was
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carried out in an open flask in the presence of air. Yield of 1 was obtained and was carried
out under nitrogen atmosphere. d Reaction was carried out in the presence of (NH4)2S2O8 (0.4
mmol). e Reaction was carried out in the presence of K2S2O8 (0.4 mmol) used.
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Caesium carbonate and lithium tert-butoxide also failed to yield coupled product
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(Table 1, entries 3 and 4). Strong protic bases NaOH and KOH were poorly effective
as provided 18 and 25% yields, respectively, in DMSO (Table 1, entries 5 and 6).
Sodium and potassium hydrides lead further improvement in the yields by 25% (Table
1, entries 7 and 8). Economical sodium and potassium tert-butoxides noticed to be
better base for the coupling of sp3 and sp2 C-H bonds (Table 1, entries 9 and 10).
Although, various other solvents; DMF, acetonitrile, and DME were screened, DMSO
found to be superior (Table 1, entries 11-15). Worth noticing, reaction provided
slightly better yield of
also screened external oxidants ammonium persulfate and potassium persulfate,
disappointingly, low yields of were realized.
1 under strict nitrogen atmosphere than under air in DMSO. We
1
After screening of various conditions, the scope with regards to phenylacetamide and
nitroarene substrates was explored and results are summarized in Table 2 and Scheme
2. Methoxy, chloro, dichloro and bromo substituents in the phenyl ring of acetamides
were well tolerated under the optimized mild reaction conditions and obtained
methoxy and halo substituted phenyl-(α-nitrophenyl)-acetamides 2-10 in nearly the
same yields. It seems that the addition of nucleophile in nitrobenzenes is favourable at
para or ortho-C-H bond over C-halogen bond at room temperature and therefore,
substitution of halogen in nitrobenzene was not observed.10f,i
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Table 2. Substrate scope with regards to tert-amide and nitroarenes
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Functional group tolerance in nitrobenzene was studied under the optimized reaction
conditions for the TM-free coupling of sp3 and sp2 C-H bonds. Functional groups such
as cyano, nitro, methyl, trifluoromethyl, and halogens (fluoro, chloro, dichloro,
bromo) in nitrobenzene tolerated well under the optimized reaction conditions and
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yielded variously substituted-α-nitrophenyl acetamides 2-4
, 6, 8-10, 13-16, 18-21, 24-
28 30-32. Interestingly, expected SNAr-coupling of halo-nitrobenzene with acetamide
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was not observed. Presence of halo substituent in the product is important for late-
stage transformation of molecules (vide infra). Here halogen substituents are well
tolerated in nitrobenzenes as well as in benzene and aniline rings of phenylacetamides
because of mild reaction conditions. When para-trifluoromethyl nitrobenzene was
employed under TM-free coupling of sp3 and sp2 C-H bonds, acetamide coupled at
ortho-position to nitro group leading ortho-nitro-substituted phenyl phenylacetamides
5, 12, and 17 in moderate (58, 59 and 57%) yields, respectively. Furthermore, different
aryls substrates such as 1-nitronaphthalene, heteroaryl thiophenyl and naphthyl
acetamides were amenable to the reaction conditions and provided nitronaphthyl
acetamides 22 and 29, α-(4-nitrophenyl) thiophenyl, naphthyls acetamide (30-32) in
good yields.
It is apparent from the Table 2 that variously N,N-dialkyl, N,N-unsymmetrical dialkyl,
N-alkyl-N-aryl, N,N-diaryl substituted phenyl acetamide substrates can be smoothly
reacted with nitroarenes under TM-free coupling reactions.
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Scheme 2. Synthesis of α-(4-nitrophenyl)phenyl-sec-acetamides
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Next, sec-acetamide substrates having acidic N-H bond were explored under the TM-
free reaction conditions (Scheme 2). N-nAlkyl, N-secalkyl, N-aryl, N-(halo)aryl and N-
benzyl substituted sec-acetamide substrates coupled with nitrobenzenes and 4-
nitrophenyl acetamides 33-39 were obtained chemoselectively despite the presence of
reactive NH functionality. This could be due to stabilization of amidate anion by
hydrogen bonding over carbanion nucleophile or alternatively, poor reactivity of
amidate nucleophile could be due to its hard nature.11c,13
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Scheme 3. Synthesis of α-(4-nitroso and nitrophenyl)-phenylacetamides
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a Nitroso compounds 41, 43 and 45 were obtained as a mixture of diastereomers
When ortho-chloro and fluoro substituted nitrobenzenes, lacking other substitution in
the ring, were treated with phenylacetamides under optimized reaction conditions, the
formation of nitroso products 41
,
43 and 45 also realized along with the desired
42, and 44, respectively (Scheme 3). It occurs
unsymmetrical diaryl acetamides 40
,
that the ortho-halonitrobenzene substrates act as an oxidant for the formation of
nitroso products (for mechanistic understanding, see, SI, page S2 and Scheme S1).
The structures of nitro and nitrosophenyl acetamides 12, 14, 41 and 43 and further
functionalized nitrophenyl acetamides 48 and 50 (vide infra) are established by single X-ray
crystal structure study (Figure 1, see SI, page S155-S211 for detail).
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Figure 1. ORTEP diagrams of 12 and 14. 14 shows strong N…O [2.886(2) Å] Van der
Waals radii of N+O = 3.07 Å. ORTEP views of 41, 43, 48 and 50 are presented in SI.
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Scheme 4. Synthesis of advanced heterocyclic molecules
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Next, synthesized α-(2/4-nitrophenyl) phenylacetamides were further investigated for the
synthesis of advanced heterocycles (Scheme 4).
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Reaction of 3-bromo-nitrobenzene with 2-hydroxyphenyl acetamide yielded xanthenes
46 and 47. Earlier methylene-9-xanthenes having chromophoric and plasticizing
properties2a were accessed by multi-steps, including ring closure step by TM-catalyst,
particularly, Pd.12 Here, cleavage of four bonds occurred by the KOtBu, which lead to
the formation of xanthenes 46 and 47 in 20 and 15% yields, respectively, in a single
pot.
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3-Phenyl benzofurans possess antimicrobial, antifungal activities and also act as
pharmacological molecular switches for K+ and Cl- channels.14 Synthesis of 3-
phenylbenzofurans involved multi-steps from ortho-hydroxy acetophenone involving
the use of PhMgBr followed by cyclization in the presence of CuI and Pd-
catalysts.14,15 Here 3-phenyl benzofurans 48 and 49 were obtained from 2-(2-bromo-4-
nitrophenyl)-acetamides
2
and 16 in 62 and 65% yields under TM-free conditions.
and 18 formed
Reaction of vinylmagnesium bromide with nitrophenylacetamides
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novel heterocyclic indoles 50 and 51 in 30 and 45% yields, respectively. Prolonged
34 and 36 with KOtBu resulted
heating of synthesized α-nitrophenyl acetamides 33
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into the formation of unsymmetrical benzofurans 52 and 53 via the cleavage of
unstrained C-C bond.
Mechanism
The tentative mechanism of the reaction is depicted in Scheme 5. We believe that reaction
promoted by abstraction of a proton from 2-phenyl acetamide substrate by KOtBu leads to
carbanion I which may add to para position of nitrobenzene chemoselectively.
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Scheme 5. KOtBu-Mediated coupling of phenylacetamide with nitroarene
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The resulted coupled carbanion II would be stabilized by nitro group forming 2-(4-
nitrocyclohexa-2,4-dien-1-yl)-2-phenylacetamide anion III. This intermediate III could
undergo oxidation by aerial oxygen via intermediates IV and V and furnish 4-nitrophenyl
phenyl acetamide 1 along with the concomitant generation of peroxide as a by-product10f
DMSO could also oxidize anion III into 4-nitrophenyl phenyl acetamide 1 via intermediates
VI and VII and reduced itself to dimethyl sulfide. The formation of dimethyl sulfide is
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established by GC-mass and H NMR analysis of the crude reaction mixture (for details, see
SI, page S153 and S154). In few cases as shown in Scheme 3 (vide supra), coupling partner
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nitrobenzene having electron withdrawing halogen substituent also serves as an oxidant and
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thus produced (4-nitrosophenyl) acetamides 41, 43 and 45 (for details, see SI, page S2).
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Conclusion
We have presented an elegant method to prepare unsymmetrically substituted diaryl
acetamides from readily accessible acetamides and nitroarenes under TM-free mild
conditions. The developed protocols tolerates sensitive functional groups namely
hydroxyl, chloride, cyanide, and bromide in the arene rings which enable to construct
several elaborated molecules such as benzofurans, xanthenes, indoles and
unsymmetrical benzophenones. Interestingly, sp3 C-H bond in sec-N-alkyl and aryl
arylacetamides has also been chemoselectively coupled with nitroarenes over N-H
bond. This method is simple, general, and practical and thus holds promise for the
preparation of structurally diverse arylated carbonyl compounds. The synthesis of
versatile nitrosoaryl acetamides and its reaction mechanism will be investigated in the
future.
Experimental Section
General experimental details
All reactions were carried out in oven-dried glassware with magnetic stirring. Nitroarenes
and phenyl acetic acid used in this study were obtained from commercial sources and used
without further purification. Solvents DMSO, DMF, acetonitrile, benzene, EtOH, and DME
were also obtained from commercial sources. Dichloromethane was dried over calcium
hydride, distilled and stored over molecular sieves. Silica gel (230-400 mesh size) was used
for column chromatography. TLC analysis of reaction mixtures was performed using silica
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gel plates. All NMR experiments were carried out on 400/500 MHz spectrometers in CDCl3
5
6
or DMSO-d6 and NMR chemical shifts are reported in ppm referenced to the solvent peaks of
7
8
9
1
13
CDCl3 (7.26 ppm for H and 77.16 (± 0.06) ppm for C, respectively) or DMSO-d6 (3.31
10
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17
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19
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1
ppm for H2O, 2.47 ppm for H and 39.50 ppm for 13C, respectively). The following
abbreviations were used to indicate multiplicity: s (singlet), d (doublet), t (triplet), q (quartet),
dd (doublet of doublet) td (triplet of doublet) and m (multiplet). High Resolution mass
analysis is performed on quadruple-time of flight (TOF-Q) equipped with an ESI and APCI
source. Single crystal X-ray data for compounds 12, 50, 14, 41, 43, and 48 (CCDC
No.1455187, 1455188, 1455189, 1455190, 1455191, and 1473220 respectively), were
collected using single crystal diffractometer equipped with CMOS Photon 100 detector and
Mo-Kα radiation (λ = 0.71073 Å) was used.
Preparation of N,N-diethyl-2-(2-methoxyphenyl)acetamide (substrate for 1,
2, 3, 4 and 5). General procedure for phenyl acetamides.
Substrates were prepared by following literature procedure with minor modifications. 11d To a
solution of 2-(2-methoxyphenyl)acetic acid (1.0 g, 6 mmol) in dichloromethane (8 mL) was
added thionyl chloride (0.7 mL, 9 mmol) and dimethylformamide (5μL, 0.06 mmol) under
nitrogen atmosphere. The resulted mixture stirred at room temperature for 1 h. The solvent
was removed in vacuo to give 2-(2-methoxyphenyl) acetyl chloride (1.13 g, 100%) as a liquid.
This liquid was used for amide preparation without further characterization. To a stirred
solution of 2-(2-methoxyphenyl)acetyl chloride in CH2Cl2 (25 mL), diethyl amine ( 1.9 ml,
18.0 mmol) in CH2Cl2 (15 mL) was added drop wise using a dropping funnel at 0 °C. After
o
complete addition, the reaction mixture was stirred for 4-5 h at 0 C to room temperature.
After completion of the reaction, 10% HCl aqueous solution (30 mL) was added to the
reaction mixture. The resulting solution was extracted with CH2Cl2 (30 mL × 3), organic
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layer was washed with brine (40 mL), dried over Na2SO4, and concentrated on a rotary
evaporator under vacuum. A brown liquid was obtained; compound was pure enough and
proceeded for next step. Brown liquid, Yield 1282 mg (95%); 1H NMR (400 MHz, CDCl3) δ
7.23 (t, J = 7.0 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 3.68
(s, 2H), 3.41 (q, J = 7.1 Hz, 2H), 3.33 (q, J = 7.1 Hz, 2H), 1.14 (q, J = 7.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 170.7, 156.8, 130.0, 127.9, 124.4, 120.7, 110.3, 55.4, 42.3, 40.2, 34.5,
14.2, 13.0; HRMS (ESI) m/z calcd for C13H19NO2 [M+H]+ 222.1489, found 222.1517. By
following this method, arylacetamide substrates for 6-47 were prepared. Arylacetamide
substrates for 11-14, 19, 40-43,16 23, 24,17 33,18 3819 are known.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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57
58
59
60
N-Isopropyl-N-methyl-2-phenylacetamide (substrate for 6). Yellow liquid, Yield 1292 mg
(92%); 1H NMR (400 MHz, CDCl3) δ 7.29 (t, J = 7.6 Hz, 4H), 7.22 (d, J = 7.8 Hz, 6H), 4.93-
4.86 (m, 1H), 4.11-4.03 (m, 1H), 3.74 (s, 2H), 3.68 (s, 2H), 2.77 (s, 3H), 2.75 (s, 3H), 1.05 (d,
J = 6.8 Hz, 6H), 1.01 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 170.4, 170.3, 135.5,
135.2, 128.6, 128.5, 126.63, 126.59, 48.4, 44.0, 41.8, 41.4, 28.6, 25.9, 20.2, 19.4; HRMS
(ESI) m/z calcd for C12H17NO [M+H]+ 192.1383, found 192.1407.
2-(2-Chlorophenyl)-N,N-diisopropylacetamide (substrate for 7 and 8). Cream crystalline
o
solid, Yield 1307 mg (88%), mp 31-33 C;1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 7.5,
1.6 Hz, 1H), 7.28 (dd, J = 7.4, 1.7 Hz, 1H), 7.22 – 7.14 (m, 2H), 3.95-3.88 (m, 1H), 3.74 (s,
13
2H), 3.47-3.35 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H), 1.10 (d, J = 6.7 Hz, 6H); C NMR (100
MHz, CDCl3) δ 169.0, 134.2, 133.9, 130.6, 129.4, 128.1, 126.9, 49.2, 45.9, 40.3, 20.7, 20.5;
HRMS (ESI) m/z calcd for C14H20ClNO [M+H]+ 254.1306, found 254.1315.
2-(2,6-Dichlorophenyl)-N,N-diethylacetamide (substrate for 9 and 10). Light brown solid,
Yield 1153 mg (91%), mp 64-66 oC; 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H),
7.11 (t, J = 8.06 Hz, 1H), 3.99 (s, 2H), 3.48-3.38 (m, 4H), 1.29 (t, J = 7.1 Hz, 3H), 1.13 (t, J =
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7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ 167.3, 136.2, 133.1, 128.4, 127.9, 42.3, 40.7,
35.9, 14.3, 13.1; HRMS (ESI) m/z calcd for C12H15Cl2NO [M+H]+ 260.0603, found
260.0617.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N,N-Diisopropyl-2-phenylacetamide (substrate for 11, 12, 13, 14, 40, 41, 42 and 43).
Cream crystalline solid, Yield 1496 mg (93%); 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.25 (m,
2H), 7.24 – 7.17 (m, 3H), 3.99 – 3.87 (m, 1H), 3.66 (s, 2H), 3.34 (s, 1H), 1.39 (d, J = 6.8 Hz,
13
6H), 0.98 (d, J = 6.6 Hz, 6H); C NMR (100 MHz, CDCl3) δ 169.9, 135.9, 128.6, 128.4,
126.5, 49.4, 45.8, 43.5, 20.6, 20.5; GC-LRMS m/z calcd for C14H21NO [M]+ 219.2, found
219.1.
N,N-Diethyl-2-phenylacetamide (substrate for 15, 16, 17, 18, 44 and 45). Mustard liquid,
Yield 1347 mg (96%); 1H NMR (400 MHz, CDCl3) δ 7.32-7.17(m, 5H), 3.67 (s, 2H), 3.37 (q,
13
J = 7.1 Hz, 2H), 3.27 (q, J = 7.1 Hz, 2H), 1.08 (dt, J = 16.3, 7.1 Hz, 6H); C NMR (100
MHz, CDCl3) δ 170.0, 135.5, 128.61, 128.55, 126.6, 42.3, 40.9, 40.1, 14.1, 12.9; HRMS
(ESI) m/z calcd for C12H17NO [M+H]+ 192.1383, found 192.1363.
N-Ethyl-N-isopropyl-2-phenylacetamide (substrate for 19). Pale yellow liquid, Yield 1356
1
mg (90%); H NMR (400 MHz, CDCl3) δ 7.30 – 7.19 (m, 10H), 4.72 – 4.62 (m, 1H), 4.07-
3.97 (m, 1H), 3.72 (s, 2H), 3.67 (s, 2H), 3.26 – 3.18 (m, 4H), 1.19 – 1.11 (m, 12H), 1.01 (d, J
= 6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 170.5, 170.0, 135.7, 135.6, 28.7, 128.62,
128.57, 128.5, 126.6, 100.0, 48.9, 45.7, 41.8, 41.3, 37.8, 35.5, 21.0, 20.5, 16.7, 14.7; GC-
LRMS m/z calcd for C13H19NO [M]+ 205.1, found 205.1.
2-(2-Methoxyphenyl)-1-(piperidin-1-yl)ethan-1-one (substrate for 20, 21 and 22). Pale
1
yellow liquid, Yield 1147 mg (82%); H NMR (400 MHz, CDCl3) δ 7.22 – 7.17 (m, 2H),
6.92 – 6.82 (m, 2H), 3.81 (s, 3H), 3.67 (s, 2H), 3.58 – 3.54 (m, 2H), 3.37 – 3.33 (m, 2H), 1.59
– 1.47 (m, 4H), 1.39-1.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.8, 156.6, 129.8,
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127.9, 124.1, 120.7, 110.3, 55.4, 47.1, 42.9, 34.5, 26.3, 25.6, 24.6; HRMS (ESI) m/z calcd for
5
6
C14H19NO2 [M+H]+ 234.1489, found 234.1511.
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8
9
N-Cyclohexyl-N-methyl-2-phenylacetamide (substrate for 23, 24). Cream solid, Yield
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1459 mg (86%); H NMR (400 MHz, CDCl3) δ 7.31-7.16 (m, 10H), 4.50-4.39 (m, 1H), 3.71
(d, J = 17.0 Hz, 4H), 3.62-3.52 (m, 1H), 2.78 (d, J = 4.9 Hz, 6H), 1.78-1.69 (m, 4H), 1.65 –
1.56 (m, 4H), 1.45 – 1.02 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 170.6, 170.5, 135.7,
135.3, 128.63, 128.60, 126.7, 126.6, 57.2, 52.5, 41.9, 41.8, 30.7, 29.9, 29.8, 27.3; 25.8, 25.63,
25.60, 25.2; GC-LRMS m/z calcd for C15H21NO [M]+ 231.2, found 231.1.
N-Benzyl-N-ethyl-2-phenylacetamide (substrate for 25, 26 and 27). Mustard liquid, Yield
1
1561 mg (84%); H NMR (400 MHz, CDCl3) δ 7.35 – 7.20 (m, 18H), 7.11 (d, J = 7.3 Hz,
2H), 4.60 (s, 2H), 4.48 (s, 2H), 3.78 (s, 2H), 3.68 (s, 2H), 3.43 (q, J = 7.1 Hz, 2H), 3.27 (q, J
13
= 7.1 Hz, 2H), 1.07 (dt, J = 18.7, 7.1 Hz, 6H); C NMR (100 MHz, CDCl3) δ 171.1, 170.9,
137.8, 137.0, 135.3, 135.2, 128.9, 128.8, 128.75, 128.68, 128.5, 128.1, 128.0, 127.6, 127.3,
126.80, 126.77, 126.4, 50.9, 47.7, 41.9, 41.11, 41.07, 40.8, 13.6, 12.5.; HRMS (ESI) m/z
calcd for C17H19NO [M+H]+ 254.1539, found 254.1539.
N,N,2-Triphenylacetamide (substrate for 28 and 29). Green solid, Yield 1698 mg (80%),
mp 50-53 oC; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.14 (m, 13H), 7.13 – 7.08 (m, 2H), 3.65
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 171.1, 142.8, 135.1, 129.3, 129.1, 128.4, 126.7,
121.0, 117.8, 42.2; HRMS (ESI) m/z calcd for C20H17NO [M+H]+ 288.1383, found 288.1397.
1-Morpholino-2-(thiophen-3-yl)ethan-1-one (substrate for 30). Cream solid, Yield 1112
o
1
mg (75%), mp 71-73 C; H NMR (400 MHz, CDCl3) δ 7.28 (dd, J = 4.9, 3.0 Hz, 1H), 7.04
(d, J = 1.7 Hz, 1H), 6.99 – 6.96 (m, 1H), 3.70 (s, 2H), 3.62 (s, 4H), 3.50 – 3.47 (m, 2H), 3.44
– 3.40 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.3, 134.6, 128.0, 126.2, 122.0, 66.8, 66.5,
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46.6, 42.2, 35.7; HRMS (ESI) m/z calcd for C10H13NO2S [M+Na]+ 234.0559, found
234.0570.
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4
5
6
7
8
9
1-Morpholino-2-(naphthalen-1-yl)ethan-1-one (substrate for 31 and 32). White solid,
Yield 1266 mg (92%), mp 87-89 oC; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 1H),
7.89 – 7.83 (m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.56 – 7.47 (m, 2H), 7.44 – 7.39 (m, 1H), 7.32
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11
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41
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45
46
47
48
49
50
51
52
53
54
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56
57
58
59
60
13
(d, J = 7.0 Hz, 1H), 4.14 (s, 2H), 3.68 (s, 4H), 3.51 – 3.39 (m, 4H); C NMR (100 MHz,
CDCl3) δ 169.8, 133.9, 131.8, 131.0, 128.9, 127.9, 126.5, 126.2, 125.9, 125.5, 123.3, 66.9,
66.5, 46.5, 42.2, 38.2; HRMS (ESI) m/z calcd for C16H17NO2 [M+Na]+ 278.1151, found
278.1168.
1
N,2-Diphenylacetamide (substrate for 33). Cream solid, Yield 1241 mg (80%); H NMR
(400 MHz, CDCl3) δ 7.39 (dd, J = 16.7, 7.5 Hz, 4H), 7.33 – 7.24 (m, 6H), 7.07 (t, J = 7.4 Hz,
13
1H), 3.71 (s, 2H); C NMR (125 MHz, CDCl3) δ 169.2, 137.7, 134.5, 129.5, 129.2, 129.0,
127.7, 124.5, 119.9, 44.8; GC-LRMS m/z calcd for C14H13NO [M]+ 211.0997, found 211.1.
N-(2-Fluorophenyl)-2-phenylacetamide (substrate for 34). Cream solid, Yield 1400 mg
(83%), mp 85-86 oC; 1H NMR (400 MHz, CDCl3) δ 8.28 (t, J = 8.0 Hz, 1H), 7.42 – 7.30 (m,
13
6H), 7.11 – 7.05 (m, 1H), 7.03 – 6.97 (m, 2H), 3.76 (s, 2H); C NMR (100 MHz, CDCl3) δ
169.1, 152.4 (d, J = 243.2 Hz), 134.1, 129.5, 129.3, 127.8, 126.2 (d, J = 10 Hz), 124.54 (d, J
= 3.7 Hz), 124.46 (d, J = 7.9 Hz) , 121.7, 114.7 (d, J = 19.1 Hz), 44.9; HRMS (ESI) m/z calcd
for C14H12FNO [M+H]+ 230.0976, found 230.0988.
N-(2-Bromophenyl)-2-phenylacetamide (substrate for 35 and 36). Cream solid, Yield
o
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1683 mg (79%), mp 97-98 C; H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.1 Hz, 1H), 7.63
(s, 1H), 7.41 (t, J = 7.2 Hz, 3H), 7.37 – 7.32 (m, 3H), 7.29 – 7.25 (m, 1H), 6.92 (td, J = 8.0,
13
1.3 Hz, 1H), 3.78 (s, 2H); C NMR (100 MHz, CDCl3) δ 169.2, 135.5, 133.9, 132.2, 129.9,
129.4, 128.3, 127.9, 125.2, 121.4, 113.2, 45.2; HRMS (ESI) m/z calcd for C14H12BrNO
[M+H]+ 290.0175, found 290.0174.
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N-Benzyl-2-(2-bromophenyl)acetamide (substrate for 37). White solid, Yield 781 mg
5
6
7
8
o
1
(79%), mp 120-122 C; H NMR (500 MHz, CDCl3) δ 7.61 (dd, J = 8.0, 1.1 Hz, 1H), 7.39
(dd, J = 7.6, 1.7 Hz, 1H), 7.33 (dd, J = 7.9, 6.6 Hz, 3H), 7.29-7.24 (m, 3H), 7.18 (td, J = 7.7,
1.7 Hz, 1H), 5.84 (s, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.79 (s, 2H); 13C NMR (125 MHz,
CDCl3) δ 169.5, 138.1, 134.8, 133.2, 131.8, 129.2, 128.7, 128.1, 127.6, 127.4, 125.0, 44.0,
43.7; HRMS (ESI) m/z calcd for C15H14BrNO [M+H]+ 304.0332, found 304.0334.
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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34
35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Isopropyl-2-phenylacetamide (substrate for 38). White solid, Yield 1180 mg (91%); 1H
NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.2 Hz, 2H), 7.27 – 7.21 (m, 3H), 5.27 (s, 1H), 4.07-
13
3.99 (m, 1H), 3.50 (s, 2H), 1.04 (d, J = 6.6 Hz, 6H); C NMR (100 MHz, CDCl3) δ 170.1,
135.2, 129.3, 128.9, 127.2, 44.0, 41.5, 22.6; GC-LRMS m/z calcd for C11H15NO [M]+ 177.1,
found 177.1.
2-(2-Bromophenyl)-N-butylacetamide (substrate for 39). White solid, Yield 1012 mg
o
1
(81%), mp 132-133 C; H NMR (400 MHz, CDCl3) δ 7.58 – 7.53 (m, 1H), 7.35 – 7.25 (m,
2H), 7.16-7.09 (m, 1H), 5.40 (s, 1H), 3.66 (s, 2H), 3.19 (dd, J = 13.1, 7.0 Hz, 2H), 1.44 –
13
1.36 (m, 2H), 1.29 – 1.20 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl3) δ
169.4, 135.1, 133.1, 131.7, 129.1, 128.0, 125.0, 44.1, 39.5, 31.5, 20.0, 13.7; HRMS (ESI) m/z
calcd for C12H16BrNO [M+H]+ 270.0488, found 270.0492.
N,N-Diethyl-2-(2-hydroxyphenyl)acetamide (substrate for 46). Brown liquid, Yield 772
mg (81%); 1H NMR (400 MHz, CDCl3) δ 10.43 (s, 1H), 7.18 – 7.13 (m, 1H), 7.02 – 6.99 (m,
1H), 6.96 (d, J = 7.5 Hz, 1H), 6.79 (td, J = 7.4, 0.9 Hz, 1H), 3.69 (s, 2H), 3.48 (q, J = 7.2 Hz,
13
2H), 3.37 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 172.7, 157.3, 130.4, 129.0, 121.2, 119.8, 118.2, 43.5, 41.3, 36.9, 14.8,
12.9; HRMS (ESI) m/z calcd for C12H17NO2 [M+H]+ 208.1332, found 208.1352.
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2-(2-Hydroxyphenyl)-1-(piperidin-1-yl)ethan-1-one (substrate for 47). Cream solid, Yield
1233 mg (85%), mp 79-81 oC; 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.15 (td, J = 8.1,
1.5 Hz, 1H), 7.02 – 6.98 (m, 1H), 6.95 (dd, J = 8.0, 0.6 Hz, 1H), 6.80 (td, J = 7.4, 1.0 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
1H), 3.72 (s, 2H), 3.63 – 3.59 (m, 2H), 3.57 – 3.53 (m, 2H), 1.64 – 1.51 (m, 6H); C NMR
(100 MHz, CDCl3) δ 171.2, 157.2, 130.1, 128.9, 121.0, 120.0, 118.1, 48.1, 43.4, 36.5, 26.5,
25.3, 24.2; HRMS (ESI) m/z calcd for C13H17NO2 [M+Na]+ 242.1151, found 242.1160.
General procedure for α-arylation of amide
N,N-Diethyl-2-(2-methoxyphenyl)-2-(4-nitrophenyl)acetamide (1). To a single neck flask,
KOtBu (280.5 mg, 2.5 mmol) was added in one portion to the solution of the N,N-diethyl-2-
(2-methoxyphenyl)acetamide (221.3 mg, 1 mmol) and nitroarene (148 mg, 1.2 mmol) in
DMSO (4 mL) at room temperature. The resulted reaction mixture was stirred at room
temperature for 4 h under N2. Next, saturated aqueous NaCl solution (15 mL) was added and
the resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were
combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography by using ethyl acetate/hexane (10/90). The
desired compound 1 was obtained as yellow solid. Yield 222 mg (65%), mp 102-103 oC; H
1
NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 – 7.24 (m,
1H), 7.17 (d, J = 7.3 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 5.62 (s, 1H),
3.77 (s, 3H), 3.50-3.41 (m, 1H), 3.38 – 3.17 (m, 3H), 1.12 (t, J = 7.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 170.1, 156.3, 147.3, 146.8, 130.3, 129.1, 128.9, 127.0, 123.3, 121.0, 110.6,
55.5, 47.3, 42.2, 40.7, 14.3, 12.8; HRMS (ESI) m/z calcd for C19H22N2O4 [M+Na]+ 365.1472,
found 365.1500.
2-(2-Bromo-4-nitrophenyl)-N,N-diethyl-2-(2-methoxyphenyl)acetamide (2). White solid,
o
1
Yield 153 mg (67%), mp 86-88 C; H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 2.3 Hz, 1H),
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8.00 (dd, J = 8.6, 2.3 Hz, 1H), 7.34 – 7.29 (m, 1H), 7.22 – 7.15 (m, 2H), 6.97 (t, J = 7.3 Hz,
1H), 6.89 (d, J = 8.2 Hz, 1H), 5.91 (s, 1H), 3.74 (s, 3H), 3.49-3.32 (m, 2H), 3.30-3.14 (m,
2H), 1.13 (td, J = 7.1, 3.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.3, 156.5, 147.2,
146.9, 131.8, 129.3, 129.2, 127.4, 125.7, 125.1, 121.9, 121.0, 110.8, 55.5, 48.2, 42.3, 40.7,
13.9, 12.7; HRMS (ESI) m/z calcd for C19H21BrN2O4 [M+H]+ 421.0757, found 421.0760.
2-(2,5-Dichloro-4-nitrophenyl)-N,N-diethyl-2-(2-methoxyphenyl)acetamide (3). Yellow
solid, Yield 118 mg (53%), mp 126-128 oC; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.37
– 7.32 (m, 1H), 7.23 (dd, J = 8.0, 1.8 Hz, 1H), 7.12 (s, 1H), 7.03 – 6.98 (m, 1H), 6.91 (d, J =
8.1 Hz, 1H), 5.86 (s, 1H), 3.75 (s, 3H), 3.53-3.44 (m, 1H), 3.36 – 3.28 (m, 1H), 3.27-3.19 (m,
1H), 3.18-3.09 (m, 1H), 1.12 (q, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 168.9,
156.4, 146.1, 144.7, 134.1, 133.0, 129.7, 129.1, 126.0, 125.4, 124.6, 121.2, 110.9, 55.6, 45.4,
42.3, 40.8, 13.8, 12.6; HRMS (ESI) m/z calcd for C19H20Cl2N2O4 [M+H]+ 411.0873, found
411.0897.
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2-(5-Chloro-2-methyl-4-nitrophenyl)-N,N-diethyl-2-(methoxyphenyl)acetamide
(4).
o
1
Orange solid, Yield mg (55%), mp 98-100 C; H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H),
7.33 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5 Hz,
1H), 6.92 (d, J = 8.2 Hz, 1H), 5.64 (s, 1H), 3.81 (s, 3H), 3.44 (q, J = 7.1 Hz, 2H), 3.28 – 3.12
(m, 2H), 2.34 (s, 3H), 1.16 (dd, J = 12.4, 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.6,
156.3, 145.9, 145.0, 136.5, 132.5, 129.4, 129.1, 126.8, 125.6, 124.5, 121.1, 110.6, 55.5, 44.5,
42.2, 40.8, 19.2, 14.0, 12.7; HRMS (ESI) m/z calcd for C20H23ClN2O4 [M+H]+ 391.1419,
found 391.1431.
N,N-Diethyl-2-(2-methoxyphenyl)-2-(2-nitro-5-(trifluoromethyl)phenyl)acetamide (5).
o
1
Light yellow solid, Yield 161 mg (58%), mp 77-78 C; H NMR (400 MHz, CDCl3) δ 7.95
(d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.5, 1.4 Hz, 1H), 7.38 (d, J = 10.1 Hz, 1H), 7.35 – 7.27 (m,
2H), 7.00 (td, J = 7.5, 0.7 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.06 (s, 1H), 3.69 (s, 3H), 3.52-
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3.43 (m, 1H), 3.39-3.30 (m, 1H), 3.25-3.10 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.2
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Hz, 3H); C NMR (100 MHz, CDCl3) δ 169.3, 156.3, 151.4, 136.3, 133.7 (q, J = 33.0 Hz),
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129.74 (q, J = 4.0 Hz), 129.68, 128.9, 125.2, 124.4 (q, J = 3.6 Hz), 124.3, 123.5 (q, J = 272.9
Hz), 121.3, 110.9, 55.4, 43.8, 42.1, 40.6, 13.5, 12.6; HRMS (ESI) m/z calcd for
C20H21F3N2O4 [M+H]+ 411.1526, found 411.1534.
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2-(2,5-Dichloro-4-nitrophenyl)-N-isopropyl-N-methyl-2-phenylacetamide (6). Yellow
solid, Yield 183 mg (48%), mp 120-122 oC; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 2H), 7.43
– 7.35 (m, 6H), 7.28 – 7.24 (m, 4H), 7.07 (d, J = 6.6 Hz, 2H), 5.64 (s, 1H), 5.52 (s, 1H), 4.93-
4.86 (m, 1H), 4.14-4.06 (m, 1H), 2.83 (s, 3H), 2.80 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H), 1.12 (d,
13
J = 6.8 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H), 0.79 (d, J = 6.5 Hz, 3H); C NMR (175 MHz,
CDCl3) δ 168.6, 168.3, 146.3, 145.2, 145.1, 135.9, 135.3, 134.7, 134.5, 132.5, 132.4, 129.57,
129.55, 129.0, 128.9, 128.39, 128.38, 126.0, 125.73, 125.68, 52.7, 52.3, 48.6, 44.9, 28.5,
26.4, 20.4, 19.8, 19.4, 19.3; HRMS (ESI) m/z calcd for C18H18Cl2N2O3 [M+H]+ 381.0767,
found 381.0780.
2-(2-Chlorophenyl)-N,N-diisopropyl-2-(4-nitrophenyl)acetamide (7). White solid, Yield
200 mg (68%), mp 131-133 oC; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.8 Hz, 2H), 7.41
– 7.37 (m, 3H), 7.26 – 7.23 (m, 2H), 7.22 – 7.19 (m, 1H), 5.63 (s, 1H), 3.94-3.87 (m, 1H),
3.43-3.36 (m, 1H), 1.42 (dd, J = 6.7, 4.4 Hz, 6H), 1.06 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4, 147.0, 145.8, 136.5, 133.8, 130.5, 130.1,
129.8, 129.0, 127.3, 123.6, 52.8, 49.3, 46.4, 20.8, 20.5, 20.1, 20.0; HRMS (ESI) m/z calcd for
C20H23ClN2O3 [M+H]+ 375.1470, found 375.1497.
2-(2-Chlorophenyl)-2-(2,4-dinitrophenyl)-N,N-diisopropylacetamide (8). Pale yellow
solid, Yield 100 mg (55%), mp 94-96 oC; 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 2.3 Hz,
1H), 8.22 (dd, J = 8.7, 2.3 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.41 – 7.36 (m, 2H), 7.00 (d, J = 8.7
Hz, 1H), 6.25 (s, 1H), 3.81-3.74 (m, 1H), 3.40-3.33 (m, 1H), 1.40 (dd, J = 6.7, 2.1 Hz, 6H),
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149.1, 146.7, 141.7, 134.4, 134.0, 133.0, 130.5, 130.4, 130.2, 127.8, 126.7, 120.2, 50.4, 49.8,
46.6, 20.4, 20.3, 19.9, 19.6; HRMS (ESI) m/z calcd for C20H22ClN3O5 [M+H]+ 420.1321,
found 420.1320.
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2-(2,6-Dichlorophenyl)-2-(2,4-dinitrophenyl)-N,N-diethylacetamide (9). Pale yellow semi
solid, Yield 100 mg (47%); 1H NMR (400 MHz, CDCl3) δ 8.90 (d, J = 2.4 Hz, 1H), 8.27 (dd,
J = 8.7, 2.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.37 – 7.30 (m, 1H), 7.07 (d, J = 8.67 Hz, 1H),
6.72 (s, 1H), 3.47-3.38 (m, 1H), 3.34-3.25 (m, 1H), 3.17 – 3.03 (m, 2H), 1.12 (t, J = 7.1 Hz,
3H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 149.9, 146.9, 139.1,
136.9, 132.6, 131.5, 130.5, 129.9, 126.7, 120.4, 50.0, 42.1, 41.3, 13.0, 12.5; HRMS (ESI) m/z
calcd for C18H17Cl2N3O5 [M+H]+ 426.0618, found 426.0635.
2-(2-Bromo-4-nitrophenyl)-2-(2,6-dichlorophenyl)-N,N-diethylacetamide (10). Buff
solid, Yield 162 mg (52%), mp 97-98 oC; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.3 Hz,
1H), 8.05 (dd, J = 8.6, 2.3 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.28 – 7.24 (m, 1H), 7.19 (d, J =
8.6 Hz, 1H), 6.06 (s, 1H), 3.53-3.44 (m, 1H), 3.41 – 3.31 (m, 1H), 3.18 – 3.01 (m, 2H), 1.17
13
(t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3) δ 166.7, 147.2,
144.5, 136.5, 133.8, 131.0, 129.84, 129.77, 127.7, 126.1, 122.2, 53.3, 42.1, 40.9, 13.4, 12.6;
HRMS (ESI) m/z calcd for C18H17BrCl2N2O3 [M+H]+ 458.9872, found 458.9900.
N,N-Diisopropyl-2-(4-nitrophenyl)-2-phenylacetamide (11). Pale yellow solid, Yield 145
mg (62%), mp 128-130 oC; 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.9 Hz, 2H), 7.61 (d, J
= 8.9 Hz, 2H), 7.43 – 7.34 (m, 5H), 6.50 (s, 1H), 3.68-3.61 (m, 1H), 3.41-3.34 (m, 1H), 1.47
(dd, J = 10.0, 6.8 Hz, 6H), 0.60 (d, J = 6.4 Hz, 3H), 0.52 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 170.6, 149.3, 147.2, 140.7, 129.6, 128.6, 128.3, 128.1, 123.4, 80.3, 49.7,
47.5, 19.9, 19.8, 19.1, 19.0; HRMS (ESI) m/z calcd for C20H24N2O3 [M+H]+ 341.1860, found
341.1889.
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N,N-Diisopropyl-2-(2-nitro-5-(trifluoromethyl)phenyl)-2-phenylacetamide (12). Pale
Yellow solid, Yield 134 mg (48%), mp 114-116 oC; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J
= 8.4 Hz, 1H), 7.63 – 7.57 (m, 1H), 7.46 – 7.36 (m, 3H), 7.31 – 7.26 (m, 2H), 7.05 (s, 1H),
5.85 (s, 1H), 4.08-4.01 (m, 1H), 3.35-3.29 (m, 1H), 1.38 (dd, J = 11.5, 6.8 Hz, 6H), 1.29 (d, J
= 6.7 Hz, 3H), 0.62 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.4, 150.8, 137.9,
136.0, 134.1 (q, J = 33.1 Hz), 129.53, 129.47, 129.1 (q, J = 3.9 Hz), 128.3, 125.0, 124.6 (q, J
= 3.6 Hz), 122.9 (q, J = 273.2 Hz), 53.3, 49.6, 46.5, 20.4, 20.3, 19.9, 19.5; HRMS (ESI) m/z
calcd for C21H23F3N2O3 [M+H]+ 409.1734, found 409.1732.
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2-(2,5-Dichloro-4-nitrophenyl)-N,N-diisopropyl-2-phenylacetamide (13). Pale yellow
solid, Yield 182 mg (65%), mp 132-133 oC; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.45
– 7.35 (m, 3H), 7.30 – 7.25 (m, 2H), 6.94 (s, 1H), 5.52 (s, 1H), 4.08 – 3.98 (m, 1H), 3.41-
3.31 (m, 1H), 1.42 (d, J = 6.8 Hz, 6H), 1.24 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 167.7, 146.1, 145.7, 135.9, 134.5, 132.6, 129.6, 129.0, 128.4,
126.0, 125.6, 53.9, 49.7, 46.5, 20.7, 20.4, 20.1, 19.8; HRMS (ESI) m/z calcd for
C20H22Cl2N2O3 [M+H]+ 409.1080, found 409.1085.
2-(2,4-Dinitrophenyl)-N,N-diisopropyl-2-phenylacetamide (14). Buff solid, Yield 158 mg
(41%), mp 123-125 oC; 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.4 Hz, 1H), 8.20 (dd, J =
8.7, 2.4 Hz, 1H), 7.47 – 7.38 (m, 3H), 7.i31 – 7.27 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 5.92 (s,
1H), 4.06-3.99 (m, 1H), 3.37-3.30 (m, 1H), 1.38 (t, J = 6.7 Hz, 6H), 1.31 (d, J = 6.7 Hz, 3H),
13
0.63 (d, J = 6.5 Hz, 3H); C NMR (100 MHz, CDCl3) δ 168.1, 148.8, 146.5, 143.6, 135.9,
133.7, 129.7, 129.4, 128.5, 126.5, 120.0, 53.7, 49.8, 46.6, 20.4, 20.3, 19.9, 19.5; HRMS (ESI)
m/z calcd for C20H23N3O5 [M+H]+ 386.1710, found 386.1739.
N,N-Diethyl-2-(4-nitrophenyl)-2-phenylacetamide (15). Cream solid, Yield 156 mg (64%),
o
1
mp 69-70 C; H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.7 Hz, 2H), 7.40 – 7.25 (m, 7H),
5.23 (s, 1H), 3.54-3.46 (m, 1H), 3.40-3.29 (m, 2H), 3.28 – 3.19 (m, 1H), 1.14 (td, J = 7.1, 1.2
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Hz, 6H); C NMR (100 MHz, CDCl3) δ 169.5, 147.7, 146.9, 138.2, 130.2, 129.1, 128.6,
127.7, 123.5, 54.4, 42.3, 40.9, 14.7, 12.8; HRMS (ESI) m/z calcd for C18H20N2O3 [M+Na]+
335.1366, found 335.1346.
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2-(2-Bromo-4-nitrophenyl)-N,N-diethyl-2-phenylacetamide (16). Cream solid, Yield mg
o
1
(71%), mp 85-86 C; H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 2.2 Hz, 1H), 8.06 (dd, J =
8.7, 2.2 Hz, 1H), 7.43-7.34 (m, 3H), 7.31 – 7.25 (m, 3H), 5.68 (s, 1H), 3.54-3.46 (m, 1H),
3.44 – 3.34 (m, 2H), 3.32 – 3.23 (m, 1H), 1.17 (q, J = 7.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 168.5, 147.4, 147.0, 137.1, 132.5, 129.3, 128.9, 128.0, 127.4, 124.6, 122.0, 54.4,
42.4, 40.8, 14.0, 12.6; HRMS (ESI) m/z calcd for C18H19BrN2O3 [M+H]+ 391.0652, found
391.0651.
N,N-Diethyl-2-(2-nitro-5-(trifluoromethyl)phenyl)-2-phenylacetamide
(17).
Yellow
1
Liquid, Yield 160 mg (42%); H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.61
(dd, J = 8.4, 1.2 Hz, 1H), 7.43 – 7.34 (m, 3H), 7.29 – 7.25 (m, 2H), 7.21 (s, 1H), 5.81 (s, 1H),
3.46 – 3.28 (m, 3H), 3.24 – 3.15 (m, 1H), 1.12 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 168.7, 150.8, 137.1, 136.3, 134.1 (q, J = 33.5 Hz), 129.7 (q, J
= 4.0 Hz), 129.5, 129.2, 128.3, 124.8 (q, J = 3.3 Hz), 122.9 (q, J = 273.1 Hz), 120.7, 51.2,
42.3, 40.7, 13.5, 12.5; HRMS (ESI) m/z calcd for C19H19F3N2O3 [M+Na]+ 403.1240, found
403.1267.
2-(2,5-Dichloro-4-nitrophenyl)-N,N-diethyl-2-phenylacetamide (18). Yellow solid, Yield
o
1
mg (56%), mp 91-92 C; H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.43 – 7.35 (m, 3H),
7.26 (d, J = 6.9 Hz, 2H), 7.16 (s, 1H), 5.56 (s, 1H), 3.53 – 3.45 (m, 1H), 3.38 – 3.29 (m, 2H),
13
3.24 – 3.14 (m, 1H), 1.13 (q, J = 7.0 Hz, 6H); C NMR (100 MHz, CDCl3) δ 168.1, 146.3,
144.9, 136.2, 134.8, 132.4, 129.5, 128.8, 128.3, 126.0, 125.6, 51.8, 42.4, 40.9, 14.0, 12.6;
HRMS (APCI) m/z calcd for C18H18Cl2N2O3 [M+H]+ 381.0767, found 381.0782.
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2-(2-Bromo-4-nitrophenyl)-N-ethyl-N-isopropyl-2-phenylacetamide (19). Buff solid,
5
6
7
8
o
1
Yield 216 mg (73%), mp 68-70 C; H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 1.9 Hz, 2H),
8.04-7.98 (m, 2H), 7.41-7.31 (m, 6H), 7.28 – 7.23 (m, 5H), 7.09 (d, J = 8.7 Hz, 1H), 5.69 (s,
1H), 5.59 (s, 1H), 4.59 – 4.48 (m, 1H), 4.14-4.07 (m, 1H), 3.29 (q, J = 6.9 Hz, 2H), 3.25-3.15
(m, 2H), 1.27 – 1.15 (m, 15H), 0.81 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.9, 168.2, 147.8, 147.5, 146.95, 146.92, 137.3, 136.9, 132.6, 132.4, 129.3, 129.2, 129.0,
128.9, 128.1, 127.9, 127.5, 127.4, 124.8, 124.6, 122.04, 122.02, 55.2, 55.1, 49.0, 47.3, 38.7,
36.1, 21.3, 20.5, 20.3, 20.2, 16.2, 14.3; HRMS (ESI) m/z calcd for C19H21BrN2O3 [M+Na]+
427.0628, found 427.0613.
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5-(1-(2-Methoxyphenyl)-2-oxo-2-(piperidin-1-yl)ethyl)-2-nitrobenzonitrile (20). Yellow
liquid, Yield 127 mg (52%); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.6 Hz, 1H), 7.70 (d,
J = 1.8 Hz, 1H), 7.62 (dd, J = 8.6, 1.8 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.01 (t, J = 7.3 Hz, 1H),
6.89 (d, J = 8.2 Hz, 1H), 5.62 (s, 1H), 3.76 (s, 3H), 3.41 – 3.35 (m, 1H), 3.26-3.22 (m, 2H) ,
1.61 – 1.46 (m, 5H), 1.41 – 1.35 (m, 1H), 1.10 – 1.03 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 168.4, 155.9, 147.9, 146.8, 136.8,134.9, 129.8, 128.5, 125.0, 124.9, 121.4, 115.4, 111.0,
107.3, 55.6, 47.4, 46.9, 43.5, 25.9, 25.5, 24.3; HRMS (ESI) m/z calcd for C21H21N3O4
[M+H]+ 380.1605, found 380.1629.
2-(2-Methoxyphenyl)-2-(2-methyl-4-nitrophenyl)-1-(piperidin-1-yl)ethan-1-one
(21).
Mustard solid, Yield 149 mg (55%), mp 79-80 oC; 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J =
2.1 Hz, 1H), 7.93 (dd, J = 8.6, 2.2 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.17 (d, J = 8.6 Hz, 1H),
7.09 (dd, J = 7.6, 1.3 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.72 (s, 1H),
3.75 (s, 3H), 3.69 – 3.63 (m, 1H), 3.59 – 3.52 (m, 1H), 3.27 (t, J = 5.1 Hz, 2H), 2.37 (s, 3H),
1.59 – 1.52 (m, 4H), 1.41 – 1.29 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.2, 156.3, 146.6,
145.9, 137.8, 130.1, 129.7, 128.9, 125.9, 124.8, 120.92, 120.90, 110.7, 55.6, 46.9, 44.6, 43.4,
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The Journal of Organic Chemistry
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26.1, 25.7, 24.5, 19.7; HRMS (ESI) m/z calcd for C21H24N2O4 [M+H]+ 369.1809, found
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369.1831.
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2-(2-Methoxyphenyl)-2-(4-nitronaphthalen-1-yl)-1-(piperidin-1-yl)ethan-1-one
(22).
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Brown liquid, Yield 145 mg (56%); 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.6 Hz, 1H),
8.08 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.66 (dd, J = 11.5, 4.0 Hz, 1H), 7.62 – 7.57
(m, 1H), 7.33 – 7.26 (m, 2H), 7.04 (dd, J = 7.5, 1.4 Hz, 1H), 6.92 (dd, J = 7.9, 4.5 Hz, 2H),
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6.33 (s, 1H), 3.81 (s, 3H), 3.55 – 3.23 (m, 4H), 1.63 – 1.46 (m, 6H); C NMR (100 MHz,
CDCl3) δ 169.6, 156.1, 146.2 , 142.9, 132.5,130.4, 128.9, 128.7, 127.7, 126.2, 125.5, 125.2,
123.9, 123.8, 123.3, 120.9, 110.6, 55.7, 47.1, 44.4, 43.5, 26.2, 25.7, 24.5; HRMS (ESI) m/z
calcd for C24H24N2O4 [M+H]+ 405.1809, found 405.1831.
N-Cyclohexyl-N-methyl-2-(4-nitrophenyl)-2-phenylacetamide (23). Yellow semisolid,
1
Yield 124 mg (54%); H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 8.8, 1.9 Hz, 4H), 7.38 –
7.35 (m, 4H), 7.34 – 7.23 (m, 10H), 5.26 (d, J = 15.0 Hz, 2H), 4.50-4.44 (m, 1H), 3.66 – 3.56
(m, 1H), 2.85 (s, 3H), 2.81 (s, 3H), 1.83 – 1.75 (m, 3H), 1.64 (d, J = 15.7 Hz, 6H), 1.39 –
1.14 (m, 11H); 13C NMR (175 MHz, CDCl3) δ 170.0, 169.9, 147.71, 147.65, 146.83, 146.82,
138.2, 137.9, 130.3, 130.2, 129.13, 129.11, 128.7, 128.6, 127.74, 127.66, 123.4, 57.2, 55.3,
55.1, 53.3, 31.1, 30.6, 29.92, 29.90, 29.73, 29.71, 25.9, 25.8, 25.7, 25.6, 25.5, 25.1; HRMS
(ESI) m/z calcd for C21H24N2O3 [M+H]+ 353.1860, found 353.1865.
2-(5-Chloro-2-methyl-4-nitrophenyl)-N-cyclohexyl-N-methyl-2-phenylacetamide
(24).
Pale yellow solid, Yield 148 mg (57%), mp 170-171 oC; 1H NMR (400 MHz, CDCl3) δ 7.70
(d, J = 6.3 Hz, 2H), 7.40 – 7.30 (m, 6H), 7.23-7.16 (m, 4H), 7.07 (d, J = 6.3 Hz, 2H), 5.26 (d,
J = 14.6 Hz, 2H), 4.51 – 4.44 (m, 1H), 3.60-3.44 (m, 1H), 2.85 (s, 3H), 2.78 (s, 3H), 2.32 (d,
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J = 2.9 Hz, 6H), 1.85 – 1.61 (m, 8H), 1.50 – 1.27 (m, 7H), 1.21 – 0.89 (m, 5H); C NMR
(175 MHz, CDCl3) δ 169.5, 169.4, 145.93, 145.90, 145.55, 145.51, 136.6, 136.2, 136.1,
136.0, 132.7, 129.24, 129.23, 129.17, 129.16, 128.0, 127.9, 127.02, 126.96, 124.69, 124.68,
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