Synthesis of diaryl ketones through oxidative cleavage of the C-C double bonds in N -Sulfonyl enamides

Article abstract of DOI:10.1021/acs.joc.7b03068

An oxidative cleavage of a C-C double bond is developed from the photochemical [2+2]-cycloaddition of diaryl N-tosyl enamides, aryl heteroaryl N-tosyl enamides, and N-tosyl cyclic enamides with singlet molecular oxygen, followed by a ring-opening reaction mediated by Cs₂CO₃ under air and sunlight without the use of photosesitizer, producing symmetrical and unsymmetrical diaryl, heterodiaryl, and cyclic ketones in good to excellent yields. Moreover, the oxidative cleavage of C-C triple bonds from 1-alkynes is demonstrated for the synthesis of symmetrical and unsymmetrical ketones from the Cu-catalyzed [3+2]-cycloaddition, Rh-catalyzed alkoxyarylation, photooxygenation, and ring-opening reaction in one-pot. Because the synthesis of the symmetrical and unsymmetrical diaryl and/or heterodiaryl ketones bearing an electron-donating group is not easy, the present method is notable.

Full text of DOI:10.1021/acs.joc.7b03068

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Synthesis of Diaryl Ketones through Oxidative
Cleavage of C#C Double Bonds in N-Sulfonyl Enamides
Hyunseok Kim, Sangjune Park, Yonghyeon Baek, Kyusik Um,
Gi Uk Han, Da-Hye Jeon, Sang Hoon Han, and Phil Ho Lee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03068 • Publication Date (Web): 22 Mar 2018
Downloaded from http://pubs.acs.org on March 23, 2018
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Synthesis of Diaryl Ketones through Oxidative Cleavage of C‒C Double Bonds in N-Sulfonyl
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Enamides
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Hyunseok Kim,† Sangjune Park,† Yonghyeon Baek, Kyusik Um, Gi Uk Han, Da-Hye Jeon,
Sang Hoon Han, and Phil Ho Lee*
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Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea
E-mail: phlee@kangwon.ac.kr
Table of Contents
ABSTRACT: An oxidative cleavage of C‒C double bond is developed from photochemical [2 +
2]-cycloaddition of diaryl N-tosyl enamides, aryl heteroaryl N-tosyl enamides, and N-tosyl cyclic
enamides with singlet molecular oxygen followed by ring-opening reaction mediated by Cs2CO3
under air and sunlight without the use of photosesitizer, producing symmetrical and unsymmetrical
diaryl, heterodiaryl, and cyclic ketones in good to excellent yields. Moreover, the oxidative
cleavage of C‒C triple bonds from 1-alkynes is demonstrated for the synthesis of symmetrical and
unsymmetrical ketones from Cu-catalyzed [3 + 2]-cycloaddition, Rh-catalyzed alkoxyarylation,
photooxygenation, and ring-opening reaction in one-pot. Because synthesis of the symmetrical and
unsymmetrical diaryl and/or heterodiaryl ketones bearing an electron-donating group is not easy,
the present method is notable.
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INTRODUCTION
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Ketones have been recognized as one of the most significant and convertible functional groups in
organic chemistry.1 Moreover, diaryl ketones are an element of an ordinary structural motif that is
found in not only many natural products and biologically active compounds but also valuable
building blocks and intermediates (Scheme 1).2
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Scheme 1. Important Compounds Containing Diaryl Ketone Moiety
O
O
OH
O
OH
HO
O
O
OH
OH
Me
OH HO
OH
Morintrifolins A
Monodictyphenone
OH
O
OH
R
O
MeO
MeO
OH
R
N
Me
OMe
R =
N
OMe
Phenstatin
antineoplastic agent
Universal chirality sensor
for amino acids
Accordingly, the development of various synthetic approaches to prepare diaryl ketones has been
the important themes which have been investigated by many groups. To date, a number of synthetic
methods for diaryl ketones have been reported and these methods can be generally divided into
some categories (Scheme 2): Friedel-Crafts acylation of arenes with acid derivatives (eq 1),3
transition metal-catalyzed cross-coupling of organometallic species with carboxylic acid derivatives
(eq 2),4 carbonylative cross-coupling of organometallic species with aryl halides (eq 3),5 cross-
coupling of acyl anion equivalents with electrophiles (eq 4),6 oxidative cleavage of CðC double
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bond using oxidants7 and photooxygenation using singlet molecular oxygen (1O2) in the presence of
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photosensitizer (eq 5),8 oxidative CðC bond cleavage of aldehydes through visible light photoredox
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catalysis (eq 6),9 and metal-free oxidative CðC bond cleavage of aldehydes by O2 (10 atm) (eq 7).10
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Scheme 2. Previously Reported Synthetic Methods for Diaryl Ketone
Recently, we reported a synthetic method for aryl azulenyl ketones through oxidative cleavage
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of the CðC double bond by the reaction of N-sulfonyl enamides having azulene moiety, which is
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nonbenzenoid aromatic compound, with cesium carbonate (Cs2CO3) without use of photosensitizer
under air and natural sunlight (eq 8).11
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In this regards, expansion of the limited scope of substrates bearing azulene motif are highly
required. In our continuing efforts to develop the oxidative cleavage of CðC multiple bond, we
envisioned that if a wide range of aromatic, heteroaromatic, and cyclic N-sulfonyl enamides were
treated with base, the oxidative cleavage of the CðC double bond would take place to afford the
valuable diaryl, aryl heteroaryl, and cyclic ketones. In addition, because synthesis of the
symmetrical and unsymmetrical diaryl and/or heterodiaryl ketones bearing an electron-donating
group is not easy, the development of efficient method is still very attractive and a significant
challenge. Herein, we report an oxidative cleavage of C<C double bond through photochemical [2 +
2]-cycloaddition of diaryl N-tosyl enamides, aryl heteroaryl N-tosyl enamides, and N-tosyl cyclic
enamides with singlet molecular oxygen (1O2) followed by ring-opening reaction under air and
sunlight without the use of a photosesitizer, producing symmetrical and unsymmetrical diaryl and/or
heterodiaryl ketones. Moreover, the oxidative cleavage of C<C triple bonds from 1-alkynes and N-
tosyl azide is described for the synthesis of diaryl ketones from Cu-catalyzed [3 + 2]-cycloaddition,
Rh-catalyzed alkoxyarylation, photooxygenation, and ring-opening reaction in one-pot (Scheme 3).
Scheme 3. Synthesis of Diaryl Ketones via Oxidative Cleavage of C‒C Double and Triple Bond
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RESULTS AND DISCUSSION
To validate the strategy through the conversion of N-sulfonyl enamides to unsymmetrical diaryl
ketones, the oxidative cleavage of C‒C double bonds of N-(2-(4-(diethylamino)phenyl)-2-phenyl-
vinyl)-4-methylbenzenesulfonamide (1a) using base was examined as a model reaction under
various conditions (Table 1). N-Tosyl enamide 1a was easily prepared from Rh-catalyzed direct
arylation of 4-phenyl-N-sulfonyl-1,2,3-triazole with N,N-diethylaniline.12 Treatment of 1a with
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Li2CO3 and K2CO3 in toluene (80 C, 2 h) gratifyingly provided the desired oxidatively cleaved
compound, 4-diethylaminophenyl phenyl ketone (2a), in 78% and 85% yields, respectively (entries
1 and 2). Then, 2-(4-(diethylamino)phenyl)-2-phenylacetaldehyde (A) from hydrolysis of enamide
was not observed. However, Na2CO3 and K2PO4 were ineffective (entries 3 and 4). Next, we applied
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the optimum reaction conditions [Cs2CO3 (3.0 equiv), toluene, 80 C, 2 h] obtained from N-
sulfonylaminoalkenylation of azulenes to the oxidative cleavage of C‒C double bond in 1a,
resulting in the formation of 2a in quantitative yield (97% isolated yield) together with 4-
methylbenzenesulfonylformamide (3) in 35% yield (entry 5). However, this reaction did not
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proceed at 25 C (entry 9). These results indicate that the oxidative cleavage of C‒C double bonds
in N-sulfonyl enamide 1a smoothly took place at 80 oC and substrate scope of the present oxidative
cleavage reaction was not restricted to N-sulfonylaminoalkenyl azulenes.11,13 Screening of solvents
revealed that toluene was an optimum solvent, but other solvents such as THF, dioxane, and DMF
gave inferior results (entries 6, 7, and 8). Use of Cs2CO3 (1.0 and 2.0 equiv) provided 2a in 32%
and 74% yields, respectively (entries 10 and 11). The present reaction did not proceed without
Cs2CO3, indicating that the base was essential for successful oxidative cleavage of CðC double
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bond of N-sulfonyl enamide (entry 12).
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Table 1. Reaction Optimizationa
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entry
base
solvent temp (oC)
yield (%)b
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Li2CO3 toluene
K2CO3 toluene
Na2CO3 toluene
K2PO4 toluene
Cs2CO3 toluene
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99 (97)c (35)d
Cs2CO3
THF
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Cs2CO3 dioxane
Cs2CO3 DMF
Cs2CO3 toluene
10e Cs2CO3 toluene
11f Cs2CO3 toluene
80
80
32
74
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toluene
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0
aReactions were carried out with N-tosyl enamide 1a (0.2 mmol) in solvent (1.0 mL) at 80 oC for 2
b
h under air atmosphere and sunlight. NMR yield using dibromomethane as an internal standard.
cIsolated yield. dIsolated yield of 3. eCs2CO3 (1.0 equiv) was used. fCs2CO3 (2.0 equiv) was used.
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To demonstrate the synthetic utility of the present oxidative cleavage protocol, a reaction of
diaryl N-tosyl enamide (1a) with Cs2CO3 was performed on a 5 mmol scale of diaryl N-tosyl
enamide (eq 9). Gratifyingly, the efficiency of oxidative cleavage was found to be maintained at a
high level in this large scale to provide the desired ketone product 2a in 90% (1.1 g) yield.
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To establish the scope and efficiency of the present method, we applied the oxidative cleavage
of C‒C double bond to a wide range of unsymmetrical diaryl N-tosyl enamides (Scheme 4).
Electronic modification of substituents on the aryl group of N-2-aryl-2-(4-
diethylaminophenyl)vinyl-4-methylbenzenesulfonamides 1 slightly effected on the reaction
efficiency. For example, substrates bearing electron-donating groups such as 2-methyl, 4-methyl, 4-
tert-butyl, and 4-methoxy were smoothly converted to the corresponding diaryl ketones (2b-2e) in
good to excellent yields varying from 71% to 92%. Likewise, N-tosyl enamides bearing electron-
withdrawing groups such as 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, and 4-methoxycarbonyl
afforded the desired aryl 4-diethylaminophenyl ketones (2f, 2g, and 2i-2k) in high yields. However,
an oxidative cleavage of C‒C double bond of N-tosyl enamide having a 2-bromo group proceeded
to afford 2h in 62% yield as a result of steric effects. Treatment of 2-naphthyl-substituted N-tosyl
enamide with Cs2CO3 produced the cleaved product, 4-diethylaminophenyl 2-naphthyl ketone (2l),
in quantitative yield. N-Tosyl enamide with a 2-thienyl group was also cleaved to give the desired
ketone (2m) in 80% yield.
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Scheme 4. Synthesis of Aryl 4-Diethylaminophenyl Ketones via Oxidative Cleavage of C‒C
Double Bond in N-Tosyl Enamidesa
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aReaction conditions: 1 (0.2 mmol) and Cs2CO3 (3.0 equiv) was heated in toluene (1.0 mL) at 80 °C
under air atmosphere and sunlight.
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Next, the scope of substituents on the aryl group of N-(2-(4-aminoaryl)-2-phenyl)-vinyl-4-
methylbenzenesulfonamides 1 was examined (Scheme 5). N-Sulfonyl enamides bearing
symmetrically N,N-disubstituted aniline derivatives afforded the corresponding aryl ketones 4a, 4b,
and 4c in 90%, 91%, and 98% yield, respectively. Also, N-sulfonyl enamides possessing
unsymmetrically N,N-disubstituted nitrogen in aniline gave the ketones 4d and 4e in excellent yield.
In addition, meta-methyl substituted N,N-diethylaniline provided the corresponding ketone 4f in
87% yield. However, meta-bromo substituted N,N-diethylaniline was less reactive and provided the
desired ketone 4g in 50% yield. Gratifyingly, the oxidative cleavage reaction of N-sulfonyl
enamides bearing N-based heterocyclic arenes such as indoline, tetrahydroquinoline, and
dibenzoazepine smoothly took place, producing the corresponding ketones (4h, 4i, and 4j) in good
yields varying from 50% to 76%.
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Scheme 5. Synthesis of Phenyl 4-Disubstituted Aminoaryl Ketones via Oxidative Cleavage of
C‒C Double Bond in N-Tosyl Enamidesa
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aReaction conditions: 1 (0.2 mmol) and Cs2CO3 (3.0 equiv) was heated in toluene (1.0 mL) at 80 °C
under air atmosphere and sunlight.
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On the basis of these results, the oxidative cleavage of a wide range of N-tosyl enamides having
aryl and 4-methoxyphenyl group was examined (Scheme 6). For instance, N-tosyl enamide14 having
phenyl and 4-methoxyphenyl was quantitatively converted to 4-methoxyphenyl phenyl ketone 5a.
Electronic variation of substituents on the aryl group of N-tosyl enamides 5b-5f effected on the
reaction efficiency. Although 3-methylphenyl-substituted enamide gave the corresponding ketone
5b in 67% yield, 4-methoxy-, 3-chloro-, and 4-trifluoromethylphenyl-substituted enamides were
transformed to the corresponding ketones (5c-5e) in quantitative yields. However, 4-nitrophenyl-
substituted enamide was less reactive and 4-methoxyphenyl 4-nitrophenyl ketone 5f was obtained in
43% yield. Thiophen-3-yl-substituted enamide was applied to the present method, providing 5g in
72% yield. The oxidative cleavage reaction was amenable with respect to 4-methoxynaphthalen-1-
yl and 2,4-dimethoxyphen-1-yl-substituted enamides to provide the corresponding ketones (5h and
5i) in good yields. When N-tosyl enamides bearing 4-ethoxy and 4-phenoxy group were employed,
the desired ketones 5j and 5k were obtained in excellent yields. In the case of substrate having triple
bond, C‒C double bond was selectively cleavaged and the desired ketone 5l was obtained in 63%
yield. N-Tosyl enamide having hydrobenzofuranyl and phenyl group took part in the oxidative
cleavage reaction to deliver 5m in 99% yield. Because the N-tosyl enamides used in the present
method were prepared from the Rh-catalyzed denitrogenative arylation reaction of triazoles with
aniline or anisole derivatives, the scope of substrates is limited to diaryl N-tosyl enamides bearing
an electron-donating group on the aryl group. However, because synthesis of the symmetrical and
unsymmetrical diaryl and/or heterodiaryl ketones bearing an electron-donating group is difficult, it
is noteworthy.
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Scheme 6. Synthesis of Alkoxyaryl Aryl Ketones via Oxidative Cleavage of C‒C Double Bond
in N-Tosyl Enamidesa
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aReaction conditions: 1 (0.2 mmol) and Cs2CO3 (3.0 equiv) was heated in toluene (1.0 mL) at 70 °C
under air atmosphere and sunlight.
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We next investigated synthesis of bi- and tri-cyclic ketones through the oxidative cleavage of
C‒C double bond in N-tosyl cyclic enamides (Table 2). N-Tosyl enamide 6a having dihydroindenyl
moiety underwent the oxidative cleavage with Cs2CO3 to give 2,3-dihydro-1H-inden-1-one 7a in
92% yield (entry 1). 9H-Fluorenyl-substituted N-tosyl enamide 6b was compatible with the reaction
conditions, leading to the formation of 3-methoxy-9H-fluoren-9-one 7b in 95% yield (entry 2).
When 4H-indeno[1,2-b]furanyl and 4H-indeno[1,2-b]thiophenyl-substituted enamides 6c and 6d
were employed, the desired ketones 7c and 7d were obtained in 66% and 88% yields (enties 3 and
4).
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Table 2. Synthesis of Cyclic Ketones via Oxidative Cleavage of C‒C Double Bond in N-Tosyl
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Enamidesa
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aReaction conditions: 6 (0.2 mmol) and Cs2CO3 (3.0 equiv) was heated in toluene (1.0 mL) at 80 °C
under air and sunlight.
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It was noted that N-tosyl cyclic enamide 6e was applied to the present method, providing unique
heterocycle 7e in 56% yield through the oxidative cleavage reaction followed by intramolecular
addition and elimination of 4-methylbenzenesulfonic acid (eq 10).
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Under the optimimum reaction conditions, the generality of the present method was examined
with various aryl indol-3-yl enamides (Table 3). N-Tosyl enamide15 having phenyl and N-
methylindol-3-yl group was smoothly cleaved to produce indol-3-yl phenyl ketone (9a) in 98%
yield (entry 1). Futhermore, when N-tosyl enamides bearing 4-methyl or 4-methoxyphenyl and N-
methyl-2-methylindol-3yl were treated with Cs2CO3, the corresponding indol-3-yl 4-phenyl or 4-
methoxyphenyl ketones (9b and 9c) in 85% and 90% yields, respectively. But, substrate having 4-
trifluoromethylphenyl and N-methyl-2-methylindol-3yl was less reactive and gave the desired
ketone 9d in 68% yield.
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Table 3. Synthesis of Aryl Indol-3-yl Ketones via Oxidative Cleavage of C‒C Double Bond in
N-Tosyl Enamidesa
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aReaction conditions: 8 (0.2 mmol) and Cs2CO3 (3.0 equiv) was heated in toluene (1.0 mL) at 80 °C
under air and sunlight.
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In general, a wide range of N-tosyl enamides were prepared from the reaction of electron-rich
anisole with triazoles obtained from Cu-catalyzed [3 + 2]-cycloaddition of terminal alkyne with N-
tosyl azide in the presence of CuTC [copper(I)-thiophene-2-carboxylate].16 In this regard, we
envisioned that oxidative cleavage of C‒C triple bonds from 1-alkynes might occur in one-pot
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through tandem Cu-catalyzed [3
+
2]-cycloaddition, Rh-catalyzed alkoxyarylation,
photooxygenation, and ring-opening reaction, producing the corresponding ketone compounds
(Scheme 7). Thus, we attempted four-step transformations in one-pot. After 4-methoxy-
phenylacetylene (10) was reacted with N-tosyl azide in the presence of CuTC (10.0 mol %) in
toluene at 25 oC for 3 h, Rh2(esp)2 (1.0 mol %) and anisole was added to the reaction mixture. After
1 h at 100 oC, Cs2CO3 was added and the reaction mixture was stirred at 100 C for 0.5 h, resulting
o
in the formation of di(4-methoxyphenyl)ketone 5c in 55% yield (eq 11). Moreover, the present
oxidative cleavage of C‒C triple bond works equally well through intramolecular reaction. For
example, 2-ethynyl-4'-methoxybiphenyl (12) was smoothly transformed to 3-methoxy-9H-fluoren-
9-one 7b in 58 % yield (eq 12).
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Scheme 7. Oxidative Cleavage of C‒C Triple Bonds from 1-Alkynes in One-Pot
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To shed light on the details of the reaction pathway, a series of mechanistic studies were designed
(Scheme 8). First, two isotopic labeling experiments were conducted to investigate the origin of
oxygen in the oxidative cleavage protocol. Although diaryl N-sulfonyl enamide 1a was reacted with
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Cs2CO3 in toluene and H218O under air and natural sunlight, the corresponding O-inserted-ketone
2a was not detected (eq 13). But, when the same reaction was conducted under an 18O2 atmosphere,
the corresponding 18O-inserted-ketone 2a-[18O] was obtained in 85% yield (eq 14). These results
suggest that oxygen in the oxidative cleavage protocol was originated from molecular oxygen and
that the dioxetane intermediate was involved in the reaction. However, this intermidiate was not
observed. When TEMPO (1.0 equiv) was used in the current reaction under air, diaryl ketone 2a
was only produced in 5% yield. This result demonstrates that radical species were involved in the
oxidative cleavage reaction (eq 15). When the oxidative cleavage reaction was performed in dark
conditions under air, no diaryl ketone 2a was observed (entry 16) to imply that natural sunlight is
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essential for oxidative cleavage reaction (eq 16).
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Scheme 8. Isotopic Labeling Experiments
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A plausible mechanism is described in Scheme 9. First, photooxidation of N-sulfonyl enamides
(1) with singlet oxygen afford dioxetane intermediate I.17 Oxidative cleavage reaction is initiated by
deprotonation of dioxetane I having 2o-amine moiety by Cs2CO3, resulting in the production of N-
sulfonyl amide anion II. However, the reaction did not proceed in the case of 3o-amine, indicating
that initiation step of the reaction is deprotonation of amine.11 Then, anion dioxetane intermediate II
is converted to biradical anion III through intramolecular electron transfer (ETintra). This biradical
anion III provides either a radical pair (path A) or another biradical anion (path B) through C-C
bond cleavage.18 In the case of path A, the intermediate III is decomposed to form IV and V. After
the radical pair is generated, an intermolecular back electron transfer (BETinter) occur to afford the
diaryl ketone 2 and N-sulfonyl formamide 3, which is isolated. Next, path B provides the desired
ketone compound 2 and another biradical anion VI. Then, the radical anion VI provides N-sulfonyl
formamide through intramolecular back electron transfer (BETintra).
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Scheme 9. A Plausible Mechanism
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CONCLUSIONS
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In conclusion, we have developed an oxidative cleavage of C‒C double bond from
photochemical [2 + 2]-cycloaddition of diaryl N-tosyl enamides, aryl heteroaryl N-tosyl enamides,
and N-tosyl cyclic enamides with singlet molecular oxygen (1O2) followed by ring-opening reaction
mediated by Cs2CO3 under air and sunlight without the use of a photosesitizer, producing
symmetrical and unsymmetrical diaryl, heterodiaryl, and cyclic ketones in good to excellent yields.
The oxidative cleavage of C‒C triple bonds from 1-alkynes is also demonstrated for the synthesis of
symmetrical and unsymmetrical ketones from Cu-catalyzed [3 + 2]-cycloaddition, Rh-catalyzed
alkoxyarylation, photooxygenation, and ring-opening reaction in one-pot. Because synthesis of the
symmetrical and unsymmetrical diaryl and/or heterodiaryl ketones bearing an electron-donating
group is not easy, the present method is notable.
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Experimental Section
General: Reactions were carried out in oven-dried glassware under nitrogen atmosphere. Cs2CO3
were purchased and was used as received. Commercial available reagents were used without
purification. Toluene and anisole were dried with CaH2. All reaction mixtures were stirred
magnetically and were monitored by thin-layer chromatography using silica gel pre-coated glass
plates, which were visualized with UV light and then developed using either iodine or a solution of
1
anisaldehyde. Flash column chromatography was carried out using silica gel (230-400 mesh). H
NMR (400 MHz), 13C{1H} NMR (100 MHz) and 19F NMR (377 MHz) spectra were recorded on
NMR spectrometer. Deuterated chloroform and benzene were used as the solvents, and chemical
shift values (δ) are reported in parts per million relative to the residual signals of solvent [δ 7.26 for
1H (chloroform-d3) and δ 77.2 for 13C{1H} (chloroform-d3)]. Infrared spectra were recorded on FT-
IR spectrometer as either a thin neat pressed between two sodium chloride plates or as a solid
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suspended in a potassium bromide disk. High resolution mass spectra (HRMS) were obtained by
fast atom bombardment (FAB) using a double focusing magnetic sector mass spectrometer and
electron impact (EI) ionization technique (magnetic sector - electric sector double focusing mass
analyzer) from the KBSI (Korea Basic Science Institute Daegu Center). Melting points were
determined in open capillary tube.
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General Procedure for the Oxidative Cleavage of C‒C Double Bond
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1) Oxidative Cleavage of C‒C Double Bond in Diaryl N-Tosyl Enamides12,14b
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N-(2-(4-(Diethylamino)phenyl)-2-phenylvinyl)-4-methylbenzenesulfonamide (0.2 mmol), Cs2CO3
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(0.6 mmol) and toluene (1.0 mL) were added to an oven-dried test tube equipped with a stirring bar
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under air. The mixture was stirred at 80 C for 2 h under air. To remove Cs2CO3, the residue was
passed through a pad of Cellite and eluted with CH2Cl2. The filtrate was concentrated under reduced
pressure and the residue was purified by Silica gel fresh column chromatography (EtOAc:Hexane).
The crude residue was purified by Silica gel column chromatography (EtOAc:Hexane) to give
compound of 2.
(4-(Diethylamino)phenyl)(phenyl)methanone (2a)19: Bright yellow oil (49.0 mg, 97%); Rf = 0.5
(EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 9.1 Hz, 2H), 7.73−7.71 (m, 2H),
7.53−7.49 (m, 1H), 7.46−7.42 (m, 2H), 6.64 (d, J = 9.1 Hz, 2H), 3.42 (q, J = 7.1 Hz, 4H), 1.21 (t, J
= 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.9, 151.1, 139.5, 133.1, 131.0, 129.4, 128.0,
124.0, 110.1, 44.6, 12.5; IR (film) 3056, 2973, 2930, 2900, 2871, 1643, 1589, 1523, 1408, 1271,
1199, 1144 cm-1; HRMS (EI) m/z: [M]+ Calcd for C17H19NO 253.1467; Found 253.1465.
(4-(Diethylamino)phenyl)(m-tolyl)methanone (2b)20: Yellow oil (44.6 mg, 75%); Rf = 0.5
(EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 9.1 Hz, 2H), 7.54 (s, 1H), 7.50-
7.49 (m, 1H), 7.32-7.31 (m, 2H), 6.64 (d, J = 9.1 Hz, 2H), 3.42 (q, J = 7.1 Hz, 4H), 2.40 (s, 3H),
1.21 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.1, 151.2, 139.6, 137.9, 133.2,
131.8, 130.0, 127.9, 126.7, 124.3, 110.1, 44.7, 21.5, 12.6; IR (film) 2971, 2341, 1637, 1590, 1271,
1185, 754, 596 cm-1; HRMS (EI) m/z: [M]+ Calcd for C18H21NO 267.1623; Found 267.1623.
(4-(Diethylamino)phenyl)(p-tolyl)methanone (2c)21: Ivory solid (38 mg, 71%); mp 77−79 °C; Rf
1
= 0.5 (EtOAc:Hexane = 1:4); H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.9 Hz, 2H), 7.55 (d, J =
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8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.53 (d, J – 9.0 Hz, 2H), 3.31 (q, J = 7.1 Hz, 4H), 2.31 (s, 3H),
1.10 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.6, 150.9, 141.4, 136.6, 132.9,
129.6, 128.6, 124.2, 110.0, 44.5, 21.5, 12.5; IR (film) 3025, 2971, 2244, 1922, 1432, 1144, 952, 709
cm-1; HRMS (EI) m/z: [M]+ Calcd for C18H21NO 267.1623; Found 267.1625.
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(4-(tert-Butyl)phenyl)(4-(diethylamino)phenyl)methanone (2d)22: Green oil (57.0 mg, 92%); Rf =
0.4 (Acetone:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 9.0 Hz, 2H), 7.68 (t, J = 8.2
Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 9.0 Hz, 2H), 3.42 (q, J = 7.1 Hz, 4H), 1.36 (s, 9H),
1.20 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.7, 154.6, 151.0, 136.7, 133.1,
129.5, 125.0, 124.4, 110.1, 44.6, 35.0, 31.3, 12.6; IR (film) 2965, 1731, 1639, 1591, 1269, 1147,
771 cm-1; HRMS (EI) m/z: [M]+ Calcd for C21H27NO 309.2093; Found 309.2089.
(4-(Diethylamino)phenyl)(4-methoxyphenyl)methanone (2e)23: Green oil (44.8 mg, 79%); Rf =
0.4 (Acetone:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J =7.8 Hz, 4H), 6.95 (d, J =8.8
Hz, 2H), 6.65 (d, J =9.0 Hz, 2H), 3.88 (s, 3H), 3.44 (q, J = 7.1 Hz, 4H), 1.22 (t, J = 7.1 Hz, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 162.1, 150.8, 132.8, 131.9, 131.8, 124.5, 113.2, 110.0,
55.4, 44.5, 12.6; IR (film) 2970, 2359, 1730, 1592, 1253, 1170, 768 cm-1; HRMS (EI) m/z: [M]+
Calcd for C18H21NO2 283.1572; Found 283.1570.
(4-(Diethylamino)phenyl)(4-fluorophenyl)methanone (2f): Brown oil (45.0 mg, 83%); Rf = 0.4
1
(EtOAc:Hexane = 1:5); H NMR (400 MHz, CDCl3) δ 7.77.74 (m, 4H), 7.12 (t, J = 8.7 Hz, 2H),
6.64 (d, J = 9.1 Hz, 2H), 3.43 (q, J = 7.1 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 193.5, 164.6 (d, JCF = 251.4 Hz), 151.2, 135.7 (d, JCF = 3.1 Hz), 133.1, 131.9 (d,
JCF = 8.8 Hz), 123.9, 115.2 (d, JCF = 21.7 Hz), 110.2, 44.7, 12.6; 19F NMR (376 MHz, CDCl3) δ -
108.7; IR (film) 2972, 2360, 1770, 1638, 1598, 1269, 1143, 765 cm-1; HRMS (EI) m/z: [M]+ Calcd
for C17H18FNO 271.1372; Found 271.1373.
(4-Chlorophenyl)(4-(diethylamino)phenyl)methanone (2g)24: Brown oil (46.5 mg, 81%); Rf = 0.4
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(EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 9.1 Hz, 2H), 7.67 (d, J = 8.5 Hz,
2H), 7.42 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 9.1 Hz, 2H), 3.44 (q, J = 7.1 Hz, 4H), 1.22 (t, J = 7.1 Hz,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 151.4, 137.9, 137.3, 133.1, 131.9, 128.4, 123.8,
110.3, 44.7, 12.7; IR (film) 2971, 2359, 1788, 1588, 1270, 1146, 755, 593cm-1; HRMS (EI) m/z:
[M]+ Calcd for C17H18ClNO 287.1077; Found 287.1077.
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(2-Bromophenyl)(4-(diethylamino)phenyl)methanone (2h): Brown oil (41.4 mg, 62%); Rf = 0.4
(EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 8.2 Hz,
1H), 7.39-7.35 (m, 1H), 7.31-7.28 (m, 2H), 6.61 (d, J = 9.2 Hz, 2H), 3.42 (q, J = 7.1 Hz, 4H), 1.21
(t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6, 151.9, 142.2, 133.1, 133.0, 130.3,
128.8, 127.1, 123.3, 119.7, 110.4, 44.6, 12.6; IR (film) 2971, 2341, 1638, 1591, 1319, 1269, 1197,
557 cm-1; HRMS (EI) m/z: [M]+ Calcd for C17H1879BrNO 331.0572, C17H1881BrNO 333.0572;
Found 331.0569, 333.0555.
(4-Bromophenyl)(4-(diethylamino)phenyl)methanone (2i)25: Ivory solid (46.5 mg, 70%); mp
94−96 °C; Rf = 0.4 (EtOAc:Hexane = 1:4); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 9.1 Hz, 2H),
7.59 (s, 4H), 6.64 (d, J = 9.1 Hz, 2H), 3.44 (q, J = 7.1 Hz, 4H), 1.21 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.6, 151.2, 138.2, 133.0, 131.2, 131.0, 125.7, 123.5, 110.1, 44.6, 12.5;
IR (film) 2972, 2929, 2899, 1639, 1591, 1524, 1408, 1319, 1271, 1199, 1144, 1069, 1011, 926 cm-1;
HRMS (EI) m/z: [M]+ Calcd for C17H1879BrNO 331.0572, C17H1881BrNO 333.0572; Found
331.0569, 333.0557.
(4-(Diethylamino)phenyl)(4-(trifluoromethyl)phenyl)methanone (2j): Green oil (67.1 mg, 99%);
Rf = 0.4 (EtOAc:Hexane = 1:7); 1H NMR (400 MHz, CDCl3) δ 7.81-7.70 (m, 6H), 6.65 (d, J = 9.2
Hz, 2H), 3.45 (q, J = 7.1 Hz, 4H), 1.22 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ
193.4, 151.6, 143.0, 133.2, 132.4 (q, JCF = 32.6 Hz), 129.5, 125.1 (q, JCF = 3.6 Hz), 124.0 (q, JCF
=
272.5 Hz), 123.3, 110.3, 44.7, 12.6; 19F NMR (376 MHz, CDCl3) δ -62.7; IR (film) 2974, 1590,
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1321, 1144, 1064, 929, 770, 597cm-1; HRMS (EI) m/z: [M]+ Calcd for C18H18F3NO 321.1340;
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Found 321.1342.
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Methyl 4-(4-(diethylamino)benzoyl)benzoate (2k)26: Green oil (47.3 mg, 76%); Rf = 0.4
(EtOAc:Hexane = 1:2); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.2 Hz, 2H), 7.77-7.74 (m, 4H),
6.65 (d, J = 9.1 Hz, 2H), 3.96 (s, 3H), 3.44 (q, J = 7.1 Hz, 4H), 1.22 (t, J = 7.1 Hz, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 194.0, 166.7, 151.5, 143.7, 133.2, 132.1, 129.4, 129.2, 123.6, 110.3,
52.4, 44.7, 12.6; IR (film) 2972, 2341, 1821, 1725, 1590, 1271, 1143, 711cm-1; HRMS (EI) m/z:
[M]+ Calcd for C19H21NO3 311.1521; Found 311.1524.
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(4-(Diethylamino)phenyl)(naphthalen-2-yl)methanone (2l)27: Yellow oil (61.0 mg, 99%); Rf =
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0.3 (EtOAc:Hexane = 1:7); H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.93-7.83 (m, 6H), 7.59-
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7.51 (m, 2H), 6.67 (d, J = 9.0 Hz, 2H), 3.45 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); C{1H}
NMR (100 MHz, CDCl3) δ 194.9, 151.2, 136.8, 134.8, 133.3, 132.5, 130.3, 129.2, 128.0, 127.9,
127.6, 126.6, 126.3, 124.4, 110.3, 44.7, 12.7; IR (film) 2869, 2341, 1712, 1589, 1318, 1186, 761,
570 cm-1; HRMS (EI) m/z: [M]+ Calcd for C21H21NO 303.1623; Found 303.1621.
(4-(Diethylamino)phenyl)(thiophen-2-yl)methanone (2m)28: Yellow solid (41.4 mg, 80%); mp
54−56 °C; Rf = 0.4 (EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 9.0 Hz, 2H),
7.65 (dd, J = 3.6 Hz, J = 0.9 Hz, 1H), 7.61 (dd, J = 4.9 Hz, J = 0.8 Hz, 1H), 7.14-7.12 (m, 1H), 6.67
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(d, J = 9.0 Hz, 2H), 3.43 (q, J = 7.1 Hz, 4H), 1.22 (t, J = 7.1 Hz, 6H); C{1H} NMR (100 MHz,
CDCl3) δ 186.0, 151.2, 144.7, 132.8, 132.3, 132.0, 127.5, 124.7, 110.3, 44.6, 12.6; IR (film) 2970,
2359, 1587, 1269, 1194, 1127, 841, 729 cm-1; HRMS (EI) m/z: [M]+ Calcd for C15H17NOS
259.1031; Found 259.1028.
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N-Tosylformamide (3)29: Colorless oil; Rf = 0.1 (EtOAc:Hexane = 1:2); H NMR (400 MHz,
CDCl3) δ 8.66 (brs, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 161.8, 145.7, 136.2, 130.3, 127.0, 21.7.
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(4-(Dipropylamino)phenyl)(phenyl)methanone (4a)30: Green oil (51.3 mg, 90%); Rf = 0.4
(EtOAc:Hexane = 1:10); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 9.1 Hz, 2H), 7.73-7.70 (m, 2H),
7.53-7.49 (m, 1H), 7.46-7.42 (m, 2H), 6.61 (d, J = 9.0 Hz, 2H), 3.32 (t, J = 7.8 Hz, 4H), 1.7-1.6 (m,
4H), 0.95 (t, J = 7.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.0, 151.7, 139.6, 133.1, 131.1,
129.5, 128.1, 124.1, 110.4, 52.9, 20.6, 11.5; IR (film) 2961, 2360, 1771, 1639, 1590, 1144, 700, 608
cm-1; HRMS (EI) m/z: [M]+ Calcd for C19H23NO 281.1780; Found 281.1783.
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(4-(Dibutylamino)phenyl)(phenyl)methanone (4b)31: Yellow oil (56.4 mg, 91%); Rf = 0.5
(EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 9.1 Hz, 2H), 7.73-7.70 (m, 2H),
7.53-7.49 (m, 1H), 7.46-7.42 (m, 2H), 6.61 (d, J = 9.1 Hz, 2H), 3.34 (t, J = 7.7 Hz, 4H), 1.64-1.56
(m, 4H), 1.41-1.32 (m, 4H), 0.97 (t, J = 7.3 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.9,
151.6, 139.6, 133.1, 131.0, 129.5, 128.1, 124.1, 110.3, 50.9, 29.5, 20.4, 14.1; IR (film) 2956, 2341,
1693, 1282, 1144, 700, 607, 505 cm-1; HRMS (EI) m/z: [M]+ Calcd for C21H27NO 309.2093; Found
309.2093.
Phenyl(4-(pyrrolidin-1-yl)phenyl)methanone (4c)32: Yellow solid (51.2 mg, 98%); mp
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142−144 °C; Rf = 0.3 (EtOAc:Hexane = 1:10); H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.8 Hz,
2H), 7.72-7.70 (m, 2H), 7.53-7.50 (m, 1H), 7.46-7.43 (m, 2H), 6.54 (d, J = 8.8 Hz, 2H), 3.40-3.36
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(m, 4H), 2.06-2.03 (m, 4H); C{1H} NMR (100 MHz, CDCl3) δ 195.2, 151.0, 139.7, 133.1, 131.1,
129.5, 128.1, 124.4, 110.7, 47.7, 25.6; IR (film) 2931, 2341, 1637, 1448, 1276, 1092, 704, 579 cm-1;
HRMS (EI) m/z: [M]+ Calcd for C17H17NO 251.1310; Found 251.1312.
(4-(Ethyl(methyl)amino)phenyl)(phenyl)methanonemethanone (4d)33: Yellow oil (43.6 mg,
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91%); Rf = 0.4 (EtOAc:Hexane = 1:10); H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 9.0 Hz, 2H),
7.72-7.70 (m, 2H), 7.53-7.49 (m, 1H), 7.46-7.42 (m, 2H), 6.67 (d, J = 9.0 Hz, 2H), 3.48 (q, J = 7.1
Hz, 2H), 3.02 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.1, 152.3,
139.5, 133.0, 131.1, 129.5, 128.1, 124.6, 110.5, 46.7, 37.6, 11.7; IR (film) 3024, 2341, 1709, 1590,
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1319, 1145, 740, 593 cm-1; HRMS (EI) m/z: [M]+ Calcd for C16H17NO 239.1310; Found 239.1311.
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(4-(Ethyl(phenyl)amino)phenyl)(phenyl)methanone (4e)34: Yellow oil (58.7 mg, 98%); Rf = 0.4
(EtOAc:Hexane = 1:5); 1H NMR (400 MHz, CDCl3) δ 7.73-7.70 (m, 4H), 7.52-7.49 (m, 1H), 7.46-
7.40 (m, 4H), 3-7.xx (m, 4H), 7.27-7.21 (m, 2H), 6.71 (d, J = 8.9 Hz, 2H), 3.83 (q, J = 7.1 Hz, 2H),
1.27 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.1, 151.9, 145.8, 139.2, 132.6,
131.3, 130.1, 129.6, 128.1, 127.4, 126.3, 126.1, 113.3, 46.9, 12.6; IR (film) 2973, 2067, 1643, 1585,
1318, 1271, 937, 699 cm-1; HRMS (EI) m/z: [M]+ Calcd for C21H19NO 301.1467; Found 301.1465.
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(4-(Diethylamino)-2-methylphenyl)(phenyl)methanone (4f)35: Yellow oil (47.8 mg, 87%); Rf =
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0.4 (Actone:Hexane = 1:7); H NMR (400 MHz, CDCl3) δ 7.74-7.72 (m, 2H), 7.53-7.48 (m, 1H),
7.42 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.42 (dd, J = 8.8 Hz, 2.6
Hz, 1H), 3.41 (q, J = 7.1 Hz, 4H), 2.52 (s, 3H), 1.21 (t, J = 7.1 Hz, 6H); 13C{1H} NMR (100 MHz,
CDCl3) δ 197.0, 149.9, 142.3, 140.6, 134.7, 131.5, 129.9, 128.1, 124.3, 113.8, 107.1, 44.5, 22.3,
12.8; IR (film) 2970, 1771, 1598, 1257, 1106, 913, 700, 537 cm-1; HRMS (EI) m/z: [M]+ Calcd for
C18H21NO 267.1623; Found 267.1620.
(2-Bromo-4-(diethylamino)phenyl)(phenyl)methanone (4g): Yellow oil (35.4 mg, 50%); Rf =
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0.3 (Actone:Hexane = 1:7); H NMR (400 MHz, CDCl3) δ 7.81-7.79 (m, 2H), 7.56-7.52 (m, 1H),
7.45-7.41 (m, 2H), 7.30 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 6.56 (dd, J = 8.8 Hz, 2.5 Hz,
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1H), 3.39 (q, J = 7.1 Hz, 4H) 1.20 (t, J = 7.1 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) δ 195.4,
150.3, 138.5, 133.1, 132.5, 130.3, 128.3, 125.7, 123.4, 115.9, 109.1, 44.6, 12.6; IR (film) 2971,
1716, 1652, 1590, 1250, 1023, 730 cm-1; HRMS (EI) m/z: [M]+ Calcd for C17H1879BrNO 331.0572,
C17H1881BrNO 333.0572; Found 331.0573, 333.0556.
(1-Ethylindolin-5-yl)(phenyl)methanone (4h): Green solid (36.1 mg, 70%); mp 92−94 °C; Rf =
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0.5 (EtOAc:Hexane = 1:5); H NMR (400 MHz, CDCl3) δ 7.71-7.68 (m, 2H), 7.63-7.60 (m, 2H),
7.53-7.49 (m, 1H), 7.46-7.42 (m, 2H), 6.34 (d, J = 8.2 Hz, 1H), 3.55 (t, J = 8.6 Hz, 2H), 3.27 (q, J =
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