Palladium-catalyzed c(sp2)-n bond cross-coupling with triaryl phosphates

Article abstract of DOI:10.1021/acs.joc.9b00703

The first general palladium-catalyzed amination of aryl phosphates is described. The combination of MorDalPhos with [Pd(-cinnamyl)Cl]₂ enables the amination of electron-rich, electron-neutral, and electron-poor aryl phosphates with a board range of aromatic, aliphatic, and heterocyclic amines. Common functional groups such as ether, keto, ester, and nitrile show an excellent compatibility in this reaction condition. The solvent-free amination reactions are also successful in both solid coupling partners. The gram-scale cross-coupling is achieved by this catalytic system.

Full text of DOI:10.1021/acs.joc.9b00703

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Palladium-Catalyzed C(sp2)−N Bond Cross-Coupling with Triaryl
Phosphates
Zicong Chen,† Xiangmeng Chen,† and Chau Ming So*,†,‡
†Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong
Kong
‡The Hong Kong Polytechnic University, Shenzhen Research Institute, Shenzhen 518057, People’s Republic of China
S
* Supporting Information
ABSTRACT: The first general palladium-catalyzed amination of aryl
phosphates is described. The combination of MorDalPhos with [Pd(π-
cinnamyl)Cl]2 enables the amination of electron-rich, electron-neutral,
and electron-poor aryl phosphates with a board range of aromatic,
aliphatic, and heterocyclic amines. Common functional groups such as
ether, keto, ester, and nitrile show an excellent compatibility in this
reaction condition. The solvent-free amination reactions are also
successful in both solid coupling partners. The gram-scale cross-coupling
is achieved by this catalytic system.
catalyzed N-arylation of amines with aryl phosphates are not
reported.
INTRODUCTION
■
Aryl amines constitute important building blocks in many
natural products, pharmaceutically active molecules, organic
materials, and useful catalysts.1 Considering their importance
and versatility, the development of efficient and diverse
synthetic methods is highly desirable. Nucleophilic substitu-
tion,2 addition to benzyne,3 electrophilic nitration,4 and
reductive amination5 are conventional routes for preparing
these valuable products through C(sp2)−N bond formation. In
the past two decades, many transition-metal catalysts have
been shown to efficiently perform the coupling reaction of
amines with aryl halides.6 Since the first report of palladium-
catalyzed N-arylation reactions,7 the continual development of
improved ligands/precatalysts, optimization studies, and
mechanistic studies have resulted in remarkable growth in
this aromatic C−N bond construction process.8
Aryl halides were commonly employed as electrophiles in
amination because of their easy oxidative addition (Scheme
1A).9 However, the halogenated compounds may not be
readily available in view of pharmaceutical chemistry. The
additional steps are required to synthesize aryl halides from
naturally occurring aromatic compounds. Indeed, aryl electro-
philes generating from phenolic moieties are highly desirable
because of their easy preparation, high stability towards air and
moisture, low cost, and unique substitution pattern.10 In recent
years, aryl sulfonates, such as triflates, tosylates, and mesylates,
have been successfully utilized in palladium-catalyzed C(sp2)−
N bond forming reactions (Scheme 1A).11 On the other hand,
aryl phosphates also derived from phenols have similar
advantages and have a common biologically functional group.
However, only one report by Yang has used the Ni(II)/NHC
catalyst system to demonstrate the amination of aryl phosphate
up-to-now (Scheme 1B).12 To our best knowledge, palladium-
We believe that the application of aryl phosphate was
obstructed by its inherently low reactivity towards palladium-
catalyzed oxidative addition and the competing hydrolysis
under harsh conditions (Scheme 2).10c Taking the afore-
mentioned points into account, palladium-catalyzed N-
arylation of amines with aryl phosphates is deemed a challenge.
To tackle this problematic issue, developing a general and
active catalyst system is highly desirable. In the past decade,
the development and selection of appropriate ligands have
effectively tackled the electrophiles considered extremely
difficult at that moment, such as aryl chlorides, tosylates and
mesylates, which have been applied in amination reactions as
well as other transformations.13 The past decades have also
seen the development of copper-catalyzed amination reac-
tions.14 As our research group’s interest focused on phosphine
ligands development15 and challenging electrophiles explora-
tion for cross-coupling reactions,11a we herein report the first
palladium-catalyzed N-arylation of aromatic amines, aliphatic
amines, and heterocyclic amines with aryl phosphates, and
even solvent-free reaction conditions (Scheme 1C).
RESULTS AND DISCUSSION
■
To initiate the study on unexplored aryl phosphates as the
electrophile, we first focused on the intensive screening of the
cutting-edge phosphine ligands, especially for those that are
commercially available and/or active toward C−O bond
activation reactions. A total of 40 ligands with diverse scaffolds
were attempted in this reaction. The selective results were
described as follows (see Supporting Information, Table S1 for
Received: March 12, 2019
© XXXX American Chemical Society
A
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Scheme 1. Palladium-Catalyzed N-Arylation of Amines
Scheme 2. Comparison on the Difficulty of Phenol
Derivatives in Cross-Coupling Reactions
screening results, we believed that the electron richness and
the steric effect provided by MorDalPhos might fulfil the
unique requirement of aryl phosphate activation.
Having identified the effective ligand, we next surveyed the
reaction conditions for this catalysis (Table 1). Several
common inorganic bases were tested. The triphenylphosphate
was subjected to moderate or complete hydrolysis to the
corresponding phenol if stronger bases such as NaOt-Bu,
Cs2CO3, and K3PO4 were used in the reaction (Table 1, entries
1−3). However, if the bases were too weak such as Na2CO3
and CsF, the reaction was very slow and significant amount of
starting triphenylphosphate was recovered (Table 1, entries 4−
5). It was worthy to note that the best result was found to be
mild inorganic base K2CO3 which allowed a better functional
group tolerance in the subsequent substrate scope exploration
(Table 1, entry 6). Then, the screening of solvents and
palladium sources were conducted in parallel. Highly polar
solvent DMF and protic solvent t-BuOH accelerated the
hydrolysis of triphenylphosphate while the amination reaction
proceeded slowly in the relatively non-polar toluene (Table 1,
entries 7−9). Ethereal solvents such as dioxane and CPME
gave better results, and CPME was the best solvent among
them (Table 1, entry 10). On the other hand, a series of
palladium source were screened (Table 1, entries 6, 11−14).
[Pd(π-cinnamyl)Cl]2 was found to be the best palladium
source in this reaction. Furthermore, the combination of
[Pd(π-cinnamyl)Cl]2 with CPME as the solvent gave 92%
yield of the desired product (Table 1, entry 15). Either
decreasing or increasing the metal to ligand ratio led to
decrease in the product yield (Table 1, entries 15−17). We
then attempted to reduce the catalyst loading from 2 to 1 mol
% of [Pd(π-cinnamyl)Cl]2 (Table 1, entry 18). However, the
desired product yield was decreased significantly. Efforts were
the full screening details). Classical phosphine ligands, such as
PPh3, PCy3, and dppf, were found inactive. Bidentate ligands,
such as XantPhos, PCy2-XantPhos, and dcype, which were
found active toward C−O bond activation reactions, were also
inactive toward amination of aryl phosphate reaction. The
Beller group ligands, such as cataCXiumA and cataCXiumABn,
bear a more electron-rich −PAd2 group, but could not realize
the conversion. Buchwald-type ligands were also screened.
DavePhos and SPhos gave zero or trace amount product yield.
XPhos and BrettPhos, which were highly active in aryl tosylates
and mesylates reactions, also afforded trace amounts of the
product yield. Indole (CM-Phos), benzimidazole (PhMezole-
Phos), and carbazole (PhenCar-Phos)-based ligands all failed
in this transformation. In addition, commercially available
NHC-carbene ligand was tested and also inefficient in this
context. Interestingly, MorDalPhos introduced by Stradiotto’s
group found a unique ligand in this amination of aryl
phosphate reaction. In the previous reports of Stradiotto’s
group, MorDalPhos also demonstrated good capability in the
transformation of ammonia and other amines.16 With the
preliminary reaction condition, the Pd(OAc)2/MorDalPhos
system catalyzed the amination reaction to give the
corresponding product in 58% yield. In contrast, PCy2-
MorDalPhos failed to provide the desired product. From the
B
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a
Table 1. Initial Screening of Palladium-Catalyzed N-Arylation of Amine with Aryl Phosphate
b
entry
Pd source (mol %)
base
solvent
yield (%)
0%
1
2
3
4
5
6
7
8
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
Pd(TFA)2 (4)
PdCl2(CH3CN)2 (4)
[Pd(π-cinnamyl)Cl]2 (2)
Pd2dba3 (2)
[Pd(π-cinnamyl)Cl]2 (2)
[Pd(π-cinnamyl)Cl]2 (2)
[Pd(π-cinnamyl)Cl]2 (2)
[Pd(π-cinnamyl)Cl]2 (1)
[Pd(π-cinnamyl)Cl]2 (1)
[Pd(π-cinnamyl)Cl]2 (1)
[Pd(π-cinnamyl)Cl]2 (1)
[Pd(π-cinnamyl)Cl]2 (1)
[Pd(π-cinnamyl)Cl]2 (2)
NaOt-Bu
Cs2CO3
K3PO4
Na2CO3
CsF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
t-BuOH
toluene
CPME
dioxane
dioxane
dioxane
dioxane
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
13%
15%
12%
20%
59%
24%
54%
45%
77%
59%
67%
70%
3%
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
92%
85%
78%
64%
54%
85%
b
c
d
e
e f
,
95% (90%)
e g
,
39%
33%
h
a
Reaction conditions: aryl phosphate 1 (0.2 mmol), amine 2 (0.2 mmol), Pd source/MorDalPhos (mol % indicated), Pd/L = 1:2, base (0.6
mmol), and solvent (1 mL) were stirred at 130 °C for 3 h under N2. Calibrated GC yields were reported by using dodecane as an internal standard
b
c
d
e
and based on 1. Isolated yield was shown in parentheses. Pd/L = 1:1. Pd/L = 1:3. Arylphosphate (0.3 mmol) was used. Amine (0.3 mmol) was
used. Reaction time: 4 h. Reaction temperature: 120 °C. Arylphosphate (0.066 mmol) was used and the reaction was conducted for 16 h.
f
g
h
taken to change the substrate ratio, and increasing the use of
N-methylaniline to 1.5 equiv significantly increased the
product yield and 95% yield could be achieved by slightly
prolonging the reaction time to 4 h (Table 1, entries 19−21).
However, the reaction rate was largely reduced, if the reaction
temperature was reduced to 120 °C which might be resulted
from the high activation barrier of the aryl phosphates (Table
1, entry 22). After reducing the use of triphenyl phosphate to
0.067 mmol, the product yield decreased to 33%. This result
indicated that only one aryl group was utilized in the reaction
(Table 1, entry 23).
Encouraged by the promising Pd/MorDalPhos system, we
then turned our attention toward exploring the substrate scope.
In general, unactivated arenes with aromatic amines were
converted to the corresponding products in excellent yields
(Table 2, 3a−3e). Aliphatic primary, secondary cyclic,
spirocyclic, and heterocyclic primary amines were effective
coupling partners (Table 2, 3f−3l). Deactivated tris(4-
methoxyphenyl) phosphate was also transformed to the
corresponding product in quantitative yields (Table 2, 3m).
A slightly lower yield was observed with the activated tris(4-
(trifluoromethyl)phenyl) phosphate because the electron-
deficient substrates might be more easily subjected to the
hydrolysis reaction (Table 2, 3n). Sterically hindered aryl
phosphates and anilines were generally feasible substrates
under this reaction condition (Table 2, 3p, 3q, and 3s−3u).
With extended reaction time, good-to-excellent yields were
obtained. Highly sterically congested 2,6-diisopropylaniline
was also a capable substrate (Table 2, 3v). Furthermore, the
functional groups ketone, ester, and nitrile were compatible
under these reaction conditions (Table 2, 3w−3z, 3aa). The
relatively fast hydrolysis of tris(4-cyanophenyl) phosphate to
the 4-cyanophenol accounted for the moderate yield of the
desired product. It was noteworthy that heteroaryl amine was
also a good substrate in this reaction condition to give the
product quantitative yield (Table 2, 3ab). Heterocyclic
phosphate, for example, tri(pyridin-3-yl) phosphate, was
attempted to couple with N-methylaniline. However, only
trace amounts of the product yield was observed in gas
chromatography mass spectrometry (GCMS) spectrum due to
the decomposition of tri(pyridin-3-yl) phosphate.
To further explore the wide-ranging effectiveness of the
palladium system, aryl phosphates cross-coupling with a range
of nitrogen heterocycles were also investigated (Table 3).
Indole and substituted indoles were N-arylated smoothly in
good-to-excellent yields (Table 3, 3ac−3aj). Pyrrole, phenox-
azine, and phenothiazine were also effective substrates (Table
3, 3ak−3am). It was noteworthy that this was the first example
of N-arylation of heterocyclic compounds with aryl phos-
phates.
C
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a
Table 2. Palladium-Catalyzed N-Arylation of Aryl Amines and Aliphatic Amines with Aryl Phosphates
a
Reaction conditions: aryl phosphate 1 (0.2 mmol), aryl amine 2 (0.3 mmol), [Pd(π-cinnamyl)Cl]2 (2 mol %), MorDalPhos (8 mol %), K2CO3
b
(0.6 mmol), and CPME (1.0 mL) were stirred at 130 °C for 4 h under N2. Isolated yields were reported and based on 1. [Pd(π-cinnamyl)Cl]2 (1
mol %). Reaction time: 16 h. Reaction time: 18 h. Reaction time: 3 h. Reaction time: 6 h. Reaction time: 36 h. Reaction time 48 h.
c
d
e
f
g
h
Solvent-free reaction condition is an attractive operation,
especially in the industrial application, where it can reduce
solvent recovery costs and minimize organic waste. Herein, the
amination of aryl phosphates could generally proceed under
solvent-free reaction conditions with no obvious detrimental
effects (Table 4). We also attempted to reduce the use of
amines to prevent the generation of other organic waste forms.
By reducing the amines to 1.5 equiv, the product yields were
still essentially the same (Table 4, 3a, 3ao, and 3ap). It was
noteworthy that both solid aryl phosphates and amines also
worked well in this solventless condition (Table 4, 3ap).
To test the feasibility of scaling up the current reaction
condition, a gram-scale cross-coupling of triphenyl phosphate
with N-methylaniline was conducted (Scheme 3). It afforded
the desired coupling product in 87% yield.
CONCLUSIONS
■
In summary, we demonstrated the first palladium-catalyzed
N−H arylation of amines with aryl phosphates successfully.
The reaction conditions exhibited good functional group
tolerance and good reactivity toward a wide range of aryl, alkyl,
and heterocyclic amines, even without solvent. The gram-scale
cross-coupling was also feasible in this catalytic system. Further
application of aryl phosphates in other coupling reactions and
related mechanistic study is underway.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all reagents were
purchased from commercial suppliers and used without purification.
All Pd-catalyzed cross-coupling reactions were performed in a
resealable screw cap Schlenk tube (approx. 20 mL volume) in the
presence of a Teflon-coated magnetic stir bar (5 mm × 10 mm).
Solvents were distillated following the standard procedures under
nitrogen.17 K2CO3, Na2CO3, Cs2CO3, K3PO4, CsF, and NaOt-Bu
D
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a
Table 3. Palladium-Catalyzed N-Arylation of NH-
Heterocycles with Aryl Phosphates
Scheme 3. Gram-Scale Cross-Coupling Reaction
a
a
Reaction conditions: triphenyl phosphate 1 (10 mmol), N-
methlyaniline 2 (15 mmol), [Pd(π-cinnamyl)Cl]2 (1 mol %),
MorDalPhos (4 mol %), K2CO3 (30 mmol), and CPME (50 mL)
were stirred at 130 °C for 8 h under N2. Isolated yield was reported.
prepared according to the reported literature.19 Known aryl
phosphates were synthesized according to the reported procedure.20
Thin layer chromatography was performed on pre-coated silica gel 60
F254 plates. Silica gel (Merck, 70−230 and 230−400 mesh) was used
for column chromatography. Melting points were recorded on an
uncorrected Bu
were recorded on a Bru
̈
chi Melting Point B-545 instrument. NMR spectra
̈
ker spectrometer (400 MHz for 1H, 100 MHz
for 13C, 376 MHz for 19F and 162 MHz for 31P). Spectra were
referenced internally to the residual proton resonance in CDCl3 (δ
7.26 ppm) as the internal standard. Chemical shifts (δ) were reported
as part per million in δ scale downfield from TMS. 13C NMR spectra
were referenced to CDCl3 (δ 77.0 ppm, the middle peak). 19F NMR
chemical shifts were determined relative to CFCl3 as the external
standard and low field is positive. 31P NMR spectra were referenced to
85% H3PO4 externally. Coupling constants (J) were reported in hertz.
Mass spectra (EI-MS and ESI-MS) were recorded on a HP 5989B
mass spectrometer. High-resolution mass spectra (HRMS) were
a
Reaction conditions: aryl phosphate 1 (0.2 mmol), aryl amine 2 (0.3
mmol), [Pd(π-cinnamyl)Cl]2 (2 mol %), MorDalPhos (8 mol %),
K2CO3 (0.6 mmol), and CPME (1.0 mL) were stirred at 130 °C for 4
b
h under N2. Isolated yields were reported and based on 1. Reaction
time: 24 h. Reaction time: 6 h.
c
obtained on a Bruker APEX 47e FTICR mass spectrometer (ESI-
̈
MS). GC−MS analysis was conducted on a HP 5973 GCD system
using a HP5MS column (30 m × 0.25 mm). The products described
in GC yield were accorded to the authentic samples/dodecane
calibration standard from the HP 6890 GC-FID system. All yields
reported refer to isolated yield of compounds estimated to be greater
than 95% purity as determined by capillary GC or 1H NMR.
Compounds described in the literature were characterized by
comparison of their 1H, 13C, and/or 19F NMR spectra to the
previously reported data. The procedures in this section are
were purchased from Dieckmann. Triphenyl phosphate was
purchased from commercial suppliers and used directly. Pd(OAc)2,
PdCl2(CH3CN)2, [Pd(π-cinnamyl)Cl]2, and Pd2(dba)3 were pur-
chased from Strem. Pd(TFA)2 was purchased from Aldrich.
Indolylphosphine ligand CM-Phos was prepared according to the
reported literature.15a PhMezole-Phos was prepared according to the
reported literature.18 PPh2-MorDalPhos and PCy2-MorDalPhos were
a
Table 4. Palladium-Catalyzed N-Arylation of Amines with Aryl Phosphates in Solvent-Free Condition
a
Reaction conditions: aryl phosphate 1 (0.2 mmol), aryl amine 2 (1.0 mmol), [Pd(π-cinnamyl)Cl]2 (2 mol %), MorDalPhos (8 mol %), and
b
c
K2CO3 (0.6 mmol) were stirred at 130 °C for 4 h under N2. Isolated yields were reported and based on 1. Amine (2.0 equiv) was used. Amine
(1.5 equiv) was used. Reaction time: 6 h. Reaction time: 13 h. Reaction time: 16 h.
d
e
f
E
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representative, and thus the yields may differ from those reported in
tables.
was purified by column chromatography on silica gel (230−400
mesh) to afford the desired product.
General Procedure for Initial Ligand Screenings. A stock
solution of Pd(OAc)2 (0.08 mmol) in freshly distilled dioxane (10.0
mL) was first prepared under N2. Ligands (16.0 mol % without
specific notice), triphenyl phosphate (0.20 mmol), and K2CO3 (0.60
mmol) were added into an array of Schlenk tubes that were charged
with a Teflon-coated magnetic stir bar (5 mm × 10 mm) and
equipped with a screw cap. The tubes were evacuated and flushed
with nitrogen (3 cycles). The Schlenk tubes were then added with N-
methyaniline (35.2 μL, 0.20 mmol) via syringe. The stock solutions
(1.0 mL, 4.0 mol % Pd) were added by syringe to the array of Schlenk
tubes. The reaction mixture was stirred for 1 min at room
temperature. The batch of Schlenk tubes were sealed and magnetically
stirred in a preheated 130 °C oil bath for 3 h. The reactions were
allowed to reach room temperature. Ethyl acetate (∼8 mL), dodecane
(45.2 μL, internal standard), and water (∼4 mL) were added. The
organic layer was subjected to GC analysis. The GC yield was
previously calibrated by an authentic sample/dodecane calibration
curve.
General Procedure for Reaction Condition Screening. An
array of Schlenk tubes were charged with a Teflon-coated magnetic
stir bar (5 mm × 10 mm), Pd sources (each loading was indicated in
the reaction condition screening Table 1), ligands (the Pd/Ligand
ratio were indicated in Table 1), triphenyl phosphate (0.20 mmol),
and base (0.60 mmol) and then were evacuated and flushed with
nitrogen (3 cycles). N-methyaniline (35.2 μL, 0.20 mmol) and the
freshly distilled solvents (noted in Table 1) were added by syringes to
the array of Schlenk tubes. The reaction mixture was stirred for 1 min
at room temperature. The batch of Schlenk tubes were sealed and
magnetically stirred in a preheated oil bath for the indicated reaction
temperature and time in Table 1. The reactions were allowed to reach
room temperature. Ethyl acetate (∼8 mL), dodecane (45.2 μL,
internal standard), and water (∼4 mL) were added. The organic layer
was subjected to GC analysis. The GC yield was previously calibrated
by an authentic sample/dodecane calibration curve.
General Procedure for Palladium-Catalyzed Amination of
Aryl Phosphates. Palladium(π-cinnamyl) chloride dimer (2.1 mg,
0.004 mmol), MorDalPhos (7.4 mg, 0.008 mmol), aryl phosphate
(0.20 mmol, if solid), amine (0.30 mmol, if solid), and K2CO3 (83
mg, 0.60 mmol) were added to the Schlenk tube that was charged
with a Teflon-coated magnetic stir bar (5 mm × 10 mm) and
equipped with a screw cap. The tube was carefully evacuated and
flushed with nitrogen (3 cycles). Aryl phosphate (0.20 mmol, if
liquid), amine (0.30 mmol, if liquid), and the freshly distilled CPME
(1.0 mL) were added via syringes (exception for the solvent-free
entries). The tube was sealed and magnetically stirred in a preheated
130 °C oil bath for the indicated time. After the completion of the
reaction, the Schlenk tube was allowed to reach room temperature.
Ethyl acetate (∼8 mL) and water (∼4 mL) were added. The organic
layer was subjected to GC analysis. The organic layer was then
separated, and the aqueous layer was washed with ethyl acetate. The
organic layers were combined and concentrated. The crude product
was purified by column chromatography on silica gel (230−400
mesh) to afford the desired product.
General Procedure for Gram-Scale Cross-Coupling Reac-
tion. Palladium(π-cinnamyl) chloride dimer (51.8 mg, 0.10 mmol),
MorDalPhos (185.5 mg, 0.40 mmol), triphenyl phosphate (3.26 g, 10
mmol), and K2CO3 (4.15 g, 30 mmol) were added to the Schlenk
flask (250 mL) that was charged with a Teflon-coated magnetic stir
bar (8 mm × 30 mm) and equipped with a screw cap. The flask was
carefully evacuated and flushed with nitrogen (3 cycles). N-
methyaniline (1.63 mL, 15 mmol) and the freshly distilled CPME
(50 mL) were added via syringes. The flask was sealed and
magnetically stirred in a preheated 130 °C oil bath for 8 h. After
the completion of the reaction, the Schlenk flask was allowed to reach
room temperature. Ethyl acetate and water were added. The organic
layer was subjected to GC analysis. The organic layer was then
separated, and the aqueous layer was extracted with ethyl acetate. The
organic layers were combined and concentrated. The crude product
Tris(3,4,5-trimethylphenyl) Phosphate. Tris(3,4,5-trimethylphen-
yl) phosphate was synthesized according to a general procedure.20 To
3,4,5-trimethylphenol (30.0 mmol) and NaH (100.0 mmol) in
toluene (50 mL) was slowly added POCl3 (11.0 mmol) at 0 °C under
vigorous stirring. Then, the reaction mixture was stirred at room
temperature for 3 h. A solution of NaOH (10.0 g) in water (30 mL)
was added to the reaction mixture. The organic layer was separated
and the aqueous layer was extracted with toluene (5 × 50 mL). The
combined organic layers were washed with saturated brine (3 × 15
mL) and dried over anhydrous Na2SO4. Solvent was removed under
the reduced pressure, and the final product was recrystallized from
methanol affording tris(3,4,5-trimethylphenyl) phosphate as a white
solid 4.08 g (82%). mp: 114.8−115.3 °C; 1H NMR (400 MHz,
CDCl3): δ 2.12 (s, 3H), 2.25 (s, 6H), 6.89 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 14.8, 20.6, 118.9 (d, J = 5.2 Hz), 132.1, 137.9,
147.8 (d, J = 7.3 Hz); 31P NMR (162 MHz, CDCl3): δ −16.70; MS
(EI) m/z (relative intensity): 452.3 (M+, 100), 221.2 (14), 135.1
(13), 91.1 (14); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C27H34O4P, 453.2189; found, 453.2181.
Triethyl 3,3′,3″-(Phosphoryltris(oxy))tribenzoate. Triethyl 3,3′,3″-
(phosphoryltris(oxy))tribenzoate was synthesized according to a
general procedure.20 To ethyl 3-hydroxybenzoate (30.0 mmol) and
Et3N (100.0 mmol) in toluene (50 mL) was slowly added POCl3
(11.0 mmol) at 0 °C under vigorous stirring. Then, the reaction
mixture was stirred at room temperature for 3 h. A solution of NaOH
(10.0 g) in water (30 mL) was added to the reaction mixture. The
organic layer was separated, and the aqueous layer was extracted with
toluene (5 × 50 mL). The combined organic layers were washed with
saturated brine (3 × 15 mL) and dried over anhydrous Na2SO4. The
solvent was removed under the reduced pressure, and the final
product was recrystallized from methanol affording triethyl 3,3′,3″-
(phosphoryltris(oxy))tribenzoate as colorless viscous liquid 4.33 g
(80%). 1H NMR (400 MHz, CDCl3): δ 1.37 (t, J = 7.1 Hz, 3H), 4.35
(q, J = 7.1 Hz, 2H), 7.42−7.48 (m, 2H), 7.88−7.93 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 14.2, 61.4, 121.1 (d, J = 5.0
Hz), 124.4 (d, J = 4.6 Hz), 127.0, 130.0, 132.6, 150.1 (d, J = 7.3 Hz),
165.2; 31P NMR (162 MHz, CDCl3): δ −17.91; MS (EI) m/z
(relative intensity): 542.2 (M+, 100), 497.2 (70), 351.1 (24), 212.1
(20), 121.0 (15); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C27H28O10P, 543.1415; found, 543.1408.
N-Methyl-N-phenylaniline (Table 2, Compound 3a).21 Yield: 90%
(32.9 mg). Eluents (Rf = 0.4, hexane/DCM = 20:1) was used for flash
1
column chromatography. H NMR (400 MHz, CDCl3): δ 3.36 (s,
3H), 6.98−7.02 (m, 2H), 7.06−7.08 (m, 4H), 7.30−7.34 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 40.2, 120.4, 121.2, 129.2,
149.0; MS (EI) m/z (relative intensity): 183.1 (M+, 100), 167.1 (27),
104.0 (13), 77.1 (19), 51.1 (7).
N-Phenylnaphthalen-2-amine (Table 2, Compound 3b).22 Yield:
98% (42.9 mg). Eluents (Rf = 0.25, hexane/DCM = 9:1) was used for
1
flash column chromatography. H NMR (400 MHz, CDCl3): δ 5.87
(br, 1H), 7.00−7.04 (m, 1H), 7.18−7.20 (m, 2H), 7.23−7.26 (m,
1H), 7.32−7.37 (m, 3H), 7.42−7.46 (m, 2H), 7.67−7.69 (m, 1H),
7.76−7.79 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 111.6,
118.3, 120.0, 121.4, 123.5, 126.46, 126.5, 127.7, 129.2, 129.4, 134.6,
140.8, 142.9; MS (EI) m/z (relative intensity): 219.1 (M+, 100),
191.1 (5), 116.1 (10), 108.6 (15).
1-(4-(tert-Butyl)phenyl)-1,2,3,4-tetrahydroquinoline (Table 2,
Compound 3c).23 Yield: 95% (50.4 mg). Eluents (Rf = 0.50,
hexane/DCM = 20:1) was used for flash column chromatography. 1H
NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 2.04−2.14 (m, 2H), 2.90
(t, J = 6.4 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 6.70−6.74 (m, 1H),
6.77−6.79 (m, 1H), 6.95−7.00 (m, 1H), 7.07−7.09 (m, 1H), 7.21−
7.23 (m, 2H), 7.40−7.42 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3): δ 22.7, 27.8, 31.5, 34.4, 50.9, 115.4, 117.8, 124.1, 124.4,
126.2, 126.4, 129.3, 144.7, 145.6, 146.6; MS (EI) m/z (relative
intensity): 265.1 (M+, 55), 250.1 (100), 180.1 (10), 96.9 (8).
N-(p-Tolyl)-[1,1′-biphenyl]-4-amine (Table 2, Compound 3d).24
Yield: 98% (50.8 mg). Eluents (Rf = 0.40, hexane/DCM = 9:1) was
F
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The Journal of Organic Chemistry
Article
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 2.38 (s, 3H), 5.71 (br, 1H), 7.08−7.18 (m, 6H), 7.32−7.36 (m,
1H), 7.45−7.49 (m, 2H), 7.53−7.56 (m, 2H), 7.61−7.63 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 20.7, 116.8, 119.1, 126.4, 127.9,
128.7, 129.9, 131.1, 133.0, 140.0, 140.9, 143.3; MS (EI) m/z (relative
intensity): 259.1 (M+, 100), 243.1 (6), 152.0 (4), 115.0 (3), 77.1 (2).
N-(p-Tolyl)naphthalen-1-amine (Table 2, Compound 3e).25
Yield: 98% (45.7 mg). Eluents (Rf = 0.60, hexane/DCM = 9:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 2.39 (s, 3H), 5.92 (br, 1H), 7.00−7.03 (m, 2H), 7.15−7.17 (m,
2H), 7.35−7.37 (m, 1H), 7.41−7.46 (m, 1H), 7.50−7.59 (m, 3H),
7.91−7.93 (m, 1H), 8.06−8.08 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 20.6, 114.1, 118.4, 121.5, 122.0, 125.4, 125.98, 126.03,
127.0, 128.5, 129.8, 130.4, 134.6, 139.6, 141.7; MS (EI) m/z (relative
intensity): 233.1 (M+, 100), 217.1 (30), 127.0 (3), 115.3 (10), 77.0
(2).
δ 4.21 (br, 1H), 4.44 (s, 2H), 6.30−6.37 (m, 2H), 6.92−6.95 (m,
2H), 7.23−7.27 (m, 1H), 7.39−7.42 (m, 2H), 7.65−7.70 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 41.4, 105.0, 107.1, 110.1, 117.9,
122.2, 126.0, 126.3, 127.6, 127.7, 128.9, 135.0, 142.0, 145.2, 152.4;
MS (EI) m/z (relative intensity): 223.1 (M+, 100), 194.2 (15), 127.1
(14), 115.1 (39), 81.1 (89).
4-Methoxy-N-methyl-N-phenylaniline (Table 2, Compound
3m).32 Yield: 99% (42.2 mg). Eluents (Rf = 0.4, hexane/EA = 9:1)
1
was used for flash column chromatography. H NMR (400 MHz,
CDCl3): δ 3.28 (s, 3H), 3.83 (s, 3H), 6.79−6.83 (m, 3H), 6.90−6.94
(m, 2H), 7.10−7.14 (m, 2H), 7.20−7.24 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 40.4, 55.5, 114.7, 115.7, 118.3, 126.2, 128.9,
142.2, 149.7, 156.2; MS (EI) m/z (relative intensity): 213.1 (M+, 80),
198.1 (100), 154.1 (9), 129.0 (4), 77.0 (5).
N-Methyl-N-phenyl-4-(trifluoromethyl)aniline (Table 2, Com-
pound 3n).32 Yield: 77% (38.7 mg). Eluents (Rf = 0.5, hexane/EA
1
4-Phenylmorpholine (Table 2, Compound 3f).21 Yield: 85% (27.7
mg). Eluents (Rf = 0.30, hexane/EA = 9:1) was used for flash column
chromatography. 1H NMR (400 MHz, CDCl3): δ 3.16−3.18 (m,
4H), 3.86−3.89 (m, 4H), 6.88−6.94 (m, 3H), 7.27−7.30 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 49.3, 66.9, 115.7, 120.0, 129.1,
151.2; MS (EI) m/z (relative intensity): 163.1 (M+, 85), 132.1 (7),
106.1 (100), 77.1 (19), 51.0 (6).
= 9:1) was used for flash column chromatography. H NMR (400
MHz, CDCl3): δ 3.36 (s, 3H), 6.86 (d, J = 8.5 Hz, 2H), 7.19−7.21
(m, 3H), 7.38−7.45 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ
40.2, 114.8, 120.0 (q, JCF = 32.7 Hz), 124.9 (q, JCF = 268.2 Hz),
125.0, 125.3, 126.2 (q, JCF = 3.7 Hz), 129.8, 147.8, 151.5; 19F NMR
(376 MHz, CDCl3): δ −61.2; MS (EI) m/z (relative intensity): 251.2
(M+, 100), 232.1 (9), 167.1 (13), 145.1 (11), 77.1 (10).
1-(4-Fluorophenyl)-1,2,3,4-tetrahydroquinoline (Table 2, Com-
pound 3o). Yield: 70% (31.8 mg). Eluents (Rf = 0.3, hexane) was
used for flash column chromatography to afford 3o as colorless liquid.
1H NMR (400 MHz, CDCl3) 2.04−2.11 (m, 2H), 2.88 (t, J = 6.4 Hz,
1-(3,5-Dimethylphenyl)pyrrolidine (Table 2, Compound 3g).26
Yield: 86% (30.1 mg). Eluents (Rf = 0.8, hexane/EA = 9:1) was used
1
for flash column chromatography. H NMR (400 MHz, CDCl3): δ
1.99−2.02 (m, 4H), 2.31 (s, 6H), 3.28−3.31 (m, 4H), 6.25 (s, 2H),
6.37 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 21.7, 25.4, 47.6,
109.6, 117.5, 138.6, 148.1; MS (EI) m/z (relative intensity): 175.1
(M+, 100), 132.1 (7), 119.1 (32), 105.1 (10), 77.0 (7).
2H), 3.59 (t, J = 5.6 Hz, 2H), 6.57−6.59 (m, 1H), 6.68−6.72 (m,
1H), 6.92−6.96 (m, 1H), 7.05−7.09 (m, 3H), 7.20−7.23 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 22.4, 27.7, 51.3, 114.8, 116.1
(d, JCF = 22.1 Hz), 117.9, 123.7, 126.4, 127.2 (d, JCF = 8.1 Hz), 129.3,
144.4 (d, JCF = 2.9 Hz), 144.8, 159.5 (d, JCF = 241.6 Hz); 19F NMR
(376 MHz, CDCl3): δ −118.3; MS (EI) m/z (relative intensity):
227.1 (M+, 100), 211.1 (9), 189.1 (12), 91.1 (7), 77.0 (7); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H15FN, 228.1183; found,
228.1181.
2-(Naphthalen-2-yl)-1,2,3,4-tetrahydroisoquinoline (Table 2,
Compound 3h).27 Yield: 74% (38.3 mg). Eluents (Rf = 0.35,
1
hexane/DCM = 9:1) was used for flash column chromatography. H
NMR (400 MHz, CDCl3): δ 3.06 (t, J = 5.7 Hz, 2H), 3.69 (t, J = 5.8
Hz, 2H), 4.53 (s, 2H), 7.19−7.23 (m, 5H), 7.27−7.31 (m, 1H),
7.36−7.39 (m, 1H), 7.40−7.44 (m, 1H), 7.71−7.78 (m, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 29.2, 47.1, 51.0, 109.3, 118.7,
122.9, 126.1, 126.2, 126.4, 126.52, 126.55, 127.4, 128.0, 128.6, 128.8,
134.3, 134.7, 148.4; MS (EI) m/z (relative intensity): 259.1 (M+,
100), 155.1 (23), 127.1 (24), 115.1 (10), 104.1 (25).
2-Methyl-N-phenylaniline (Table 2, Compound 3p).33 Yield: 86%
(31.5 mg). Eluents (Rf = 0.45, hexane/EA = 19:1) was used for flash
1
column chromatography. H NMR (400 MHz, CDCl3): δ 2.29 (s,
3H), 5.41 (s, 1H), 6.93−7.01 (m, 4H), 7.17−7.20 (m, 1H), 7.24−
7.26 (m, 1H), 7.28−7.32 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 17.9, 117.4, 118.7, 120.4, 121.9, 126.7, 128.2, 129.3, 130.9,
141.1, 143.9; MS (EI) m/z (relative intensity): 183.1 (M+, 100),
167.1 (28), 106.1 (19), 90.7 (11), 77.0 (10).
4-Methyl-1-(naphthalen-2-yl)piperidine (Table 2, Compound
3i).28 Yield: 68% (30.6 mg). Eluents (Rf = 0.5, hexane/EA = 4:1)
1
was used for flash column chromatography. H NMR (400 MHz,
CDCl3): δ 1.00−1.02 (m, 3H), 1.37−1.47 (m, 2H), 1.54−1.59 (m,
1H), 1.78−1.81 (m, 2H), 2.75−2.81 (m, 2H), 3.77−3.80 (m, 2H),
7.13−7.14 (m, 1H), 7.26−7.31 (m, 2H), 7.37−7.41 (m, 1H), 7.67−
7.72 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 21.9, 30.8, 34.1,
50.3, 110.3, 120.1, 123.0, 126.1, 126.6, 127.3, 128.2, 128.5, 134.7,
149.8; MS (EI) m/z (relative intensity): 225.1 (M+, 100), 182.1 (11),
155.1 (25), 127.1 (28), 115.1 (7).
N-Methyl-N-phenylnaphthalen-1-amine (Table 2, Compound
3q).34 Yield: 78% (36.4 mg). Eluents (Rf = 0.5, hexane/DCM = 20:1)
1
was used for flash column chromatography. H NMR (400 MHz,
CDCl3): δ 3.43 (s, 3H), 6.64−6.67 (m, 2H), 6.75−6.78 (m, 1H),
7.18−7.22 (m, 2H), 7.39−7.41 (m, 1H), 7.44−7.48 (m, 1H), 7.50−
7.55 (m, 2H), 7.81−7.83 (m, 1H), 7.90−7.95 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 40.2, 113.5, 117.2, 123.8, 125.2, 126.2,
126.3, 126.4, 126.6, 128.4, 128.9, 131.3, 135.1, 145.3, 150.1; MS (EI)
m/z (relative intensity): 233.1 (M+, 100), 217.1 (34), 115.4 (8),
104.0 (5), 77.0 (5).
8-Phenyl-1,4-dioxa-8-azaspiro[4.5]decane (Table 2, Compound
3j).29 Yield: 93% (40.7 mg). Eluents (Rf = 0.4, hexane/EA = 9:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 1.84−1.87 (m, 4H), 3.32−3.35 (m, 4H), 3.40 (s, 4H), 6.83−6.86
(m, 1H), 6.95−6.97 (m, 2H), 7.24−7.28 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 34.5, 47.7, 64.3, 107.1, 116.6, 119.4, 129.1,
150.9; MS (EI) m/z (relative intensity): 219.1 (M+, 100), 174.1 (24),
158.1 (19), 132.1 (50), 105.1 (78).
N-Methyl-N-phenylbenzo[d][1,3]dioxol-5-amine (Table 2, Com-
pound 3r).34 Yield: 55% (25.0 mg). Eluents (Rf = 0.5, hexane/EA =
9:1) was used for flash column chromatography. 1H NMR (400 MHz,
CDCl3): δ 3.28 (s, 3H), 5.99 (s, 2H), 6.62−6.64 (m, 1H), 6.68−6.69
(m, 1H), 6.80−6.87 (m, 4H), 7.23−7.27 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 40.6, 101.2, 106.1, 108.5, 116.5, 117.2, 118.9,
128.9, 143.7, 143.9, 148.2, 149.6; MS (EI) m/z (relative intensity):
227.1 (M+, 100), 196.0 (10), 168.0 (18), 154.1 (18), 77.0 (14).
2,6-Dimethyl-N-phenylaniline (Table 2, Compound 3s).35 Yield:
92% (36.3 mg). Eluents (Rf = 0.4, hexane/DCM = 20:1) was used for
N-Benzylnaphthalen-2-amine (Table 2, Compound 3k).30 Yield:
85% (39.6 mg). Eluents (Rf = 0.5, hexane/EA = 9:1) was used for
1
flash column chromatography. H NMR (400 MHz, CDCl3): δ 4.16
(s, 1H), 4.41 (s, 2H), 6.81−6.82 (m, 1H), 6.87−6.90 (m, 1H), 7.16−
7.21 (m, 1H), 7.26−7.41 (m, 6H), 7.56−7.67 (m, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 48.3, 104.6, 117.8, 122.0, 125.9, 126.3,
127.3, 127.53, 127.56, 127.59, 128.6, 128.9, 135.1, 139.1, 145.7; MS
(EI) m/z (relative intensity): 233.2 (M+, 100), 156.1 (13), 127.1
(13), 115.1 (21), 91.1 (50).
N-(Furan-2-ylmethyl)naphthalen-2-amine (Table 2, Compound
3l).31 Yield: 82% (36.6 mg). Eluents (Rf = 0.5, hexane/EA = 9:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
1
flash column chromatography. H NMR (400 MHz, CDCl3): δ 2.27
(s, 6H), 5.21 (s, 1H), 6.54−6.56 (m, 2H), 6.78−6.82 (m, 1H), 7.11−
7.25 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ 18.3, 113.5,
118.1, 125.7, 128.5, 129.2, 135.9, 138.2, 146.2; MS (EI) m/z (relative
intensity): 197.1 (M+, 100), 182.1 (34), 167.1 (12), 120.1 (13), 77.1
(7).
G
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The Journal of Organic Chemistry
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N-Phenyl-[1,1′-biphenyl]-2-amine (Table 2, Compound 3t).36
Yield: 99% (48.5 mg). Eluents (Rf = 0.3, hexane/DCM = 9:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 5.66 (s, 1H), 6.95−6.99 (m, 1H), 7.03−7.09 (m, 3H), 7.28−7.32
(m, 4H), 7.38−7.52 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ
117.4, 118.1, 121.00, 121.01, 127.4, 128.2, 128.8, 129.26, 129.27,
130.8, 131.4, 139.0, 140.1, 143.3; MS (EI) m/z (relative intensity):
245.1 (M+, 100), 167.1 (13), 152.0 (5), 115.0 (4), 77.1 (3).
flash column chromatography. H NMR (400 MHz, CDCl3): δ 6.21
(s, 1H), 7.01−7.05 (m, 1H), 7.19−7.21 (m, 2H), 7.28−7.36 (m, 4H),
7.40−7.41 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 9.0 Hz,
1H), 8.71 (dd, J = 4.2, 1.5 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 109.3, 119.0, 121.5, 122.1, 123.0, 129.45, 129.54, 130.5,
134.3, 141.7, 142.1, 144.2, 147.5; MS (EI) m/z (relative intensity):
220.1 (M+, 100), 191.0 (6), 109.6 (12), 95.5 (6).
1
1-Phenyl-1H-indole (Table 3, Compound 3ac).42 Yield: 98%
(37.8 mg). Eluents (Rf = 0.4, hexane) was used for flash column
chromatography. 1H NMR (400 MHz, CDCl3): δ 6.77−6.78 (m,
1H), 7.24−7.33 (m, 2H), 7.40−7.45 (m, 2H), 7.58−7.59 (m, 4H),
7.66 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 103.5, 110.5, 120.3, 121.1, 122.3, 124.3, 126.4,
127.9, 129.3, 129.6, 135.8, 139.8; MS (EI) m/z (relative intensity):
193.1 (M+, 100), 165.1 (22), 98.1 (10), 77.1 (4).
2,6-Diethyl-N-phenylaniline (Table 2, Compound 3u).33 Yield:
72% (32.4 mg). Eluents (Rf = 0.45, hexane/EA = 9:1) was used for
1
flash column chromatography. H NMR (400 MHz, CDCl3): δ 1.18
(t, J = 7.5 Hz, 6H), 2.62 (q, J = 7.5 Hz, 4H), 6.50−6.53 (m, 2H),
6.73−6.78 (m, 1H), 7.15−7.24 (m, 5H); 13C{1H} NMR (100 MHz,
CDCl3): δ 14.7, 24.7, 113.2, 117.9, 126.5, 126.6, 129.2, 136.9, 142.3,
147.2; MS (EI) m/z (relative intensity): 225.1 (M+, 85), 210.1 (100),
196.1 (12), 180.1 (65), 77.1 (9).
1-(Naphthalen-1-yl)-1H-indole (Table 3, Compound 3ad).43
Yield: 89% (43.1 mg). Eluents (Rf = 0.5, hexane/EA = 20:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 6.81−6.82 (m, 1H), 7.07−7.09 (m, 1H), 7.15−7.22 (m, 2H), 7.39−
7.45 (m, 2H), 7.49−7.51 (m, 1H), 7.55−7.64 (m, 3H), 7.80 (d, J =
7.7 Hz, 1H), 7.99−8.01 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3):
δ 102.9, 110.8, 120.1, 120.9, 122.1, 123.4, 125.1, 125.5, 126.6, 126.9,
128.2, 128.40, 128.43, 129.8, 130.5, 134.4, 136.0, 137.9; MS (EI) m/z
(relative intensity): 242.1 (M+, 100), 215.0 (6), 120.6 (12).
5-Methyl-1-(3,4,5-trimethylphenyl)-1H-indole (Table 3, Com-
pound 3ae). Yield: 98% (48.8 mg). Eluents (Rf = 0.4, hexane/
DCM = 20:1) was used for flash column chromatography to afford
3ae as colorless liquid. 1H NMR (400 MHz, CDCl3): δ 2.29 (s, 3H),
2.42 (s, 6H), 2.53 (s, 3H), 6.62 (d, J = 3.0 Hz, 1H), 7.08−7.10 (m,
1H), 7.20 (s, 2H), 7.32 (d, J = 3.1 Hz, 1H), 7.50−7.52 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 15.1, 20.7, 21.3, 102.4, 110.3,
2,6-Diisopropyl-N-phenylaniline (Table 2, Compound 3v).37
Yield: 44% (22.3 mg). Eluents (Rf = 0.5, hexane/EA = 19:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 1.17−1.19 (m, 12H), 3.19−3.29 (m, 2H), 5.13 (br, 1H), 6.52 (d, J
= 7.8 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 7.16−7.20 (m, 2H), 7.25−
7.28 (m, 2H), 7.31−7.35 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 23.8, 28.2, 112.9, 117.6, 123.8, 127.2, 129.2, 135.1, 147.5,
148.1; MS (EI) m/z (relative intensity): 253.2 (M+, 95), 238.1 (100),
196.1 (22), 180.1 (43).
(4-(Methyl(phenyl)amino)phenyl)(phenyl)methanone (Table 2,
Compound 3w).38 Yield: 90% (51.7 mg). Eluents (Rf = 0.5, hexane/
EA = 4:1) was used for flash column chromatography. 1H NMR (400
MHz, CDCl3): δ 3.39 (s, 3H), 6.79−6.81 (m, 2H), 7.22−7.25 (m,
3H), 7.40−7.47 (m, 4H), 7.51−7.55 (m, 1H), 7.74−7.76 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 40.2, 113.4, 125.7, 126.1, 126.7,
120.6, 123.2, 123.6, 128.0, 129.2, 129.4, 133.2, 134.3, 137.0, 137.7;
MS (EI) m/z (relative intensity): 249.1 (M+, 100), 234.1 (15), 218.1
(7); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H20N, 250.1590;
found, 250.1588.
128.0, 129.5, 129.9, 131.3, 132.3, 139.0, 147.2, 152.5, 195.1; MS (EI)
m/z (relative intensity): 287.1 (M+, 100), 210.1 (75), 167.1 (18),
105.0 (10), 77.1 (20).
Phenyl(4-(pyrrolidin-1-yl)phenyl)methanone (Table 2, Com-
pound 3x).11b Yield: 59% (29.6 mg). Eluents (Rf = 0.45, hexane/
EA = 4:1) was used for flash column chromatography. 1H NMR (400
MHz, CDCl3): δ 2.02−2.05 (m, 4H), 3.36−3.39 (m, 4H), 6.52−6.55
(m, 2H), 7.43−7.53 (m, 3H), 7.71−7.72 (m, 2H), 7.79−7.81 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 25.4, 47.5, 110.5, 124.1,
127.9, 129.4, 130.9, 132.9, 139.4, 150.8, 195.1; MS (EI) m/z (relative
intensity): 251.1 (M+, 100), 195.0 (8), 174.1 (51), 105.0 (14), 77.0
(18).
5-Methoxy-1-(p-tolyl)-1H-indole (Table 3, Compound 3af).44
Yield: 93% (44.1 mg). Eluents (Rf = 0.6, hexane/EA = 9:1) was used
1
for flash column chromatography. H NMR (400 MHz, CDCl3): δ
2.46 (s, 3H), 3.91 (s, 3H), 6.63 (d, J = 3.1 Hz, 1H), 6.92 (dd, J = 8.9,
2.5 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.32−7.34 (m, 3H), 7.39−7.41
(m, 2H), 7.47 (d, J = 8.9 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 21.0, 55.8, 102.6, 102.8, 111.3, 112.4, 124.0, 128.4, 129.7,
130.1, 131.2, 136.1, 137.4, 154.4; MS (EI) m/z (relative intensity):
237.1 (M+, 100), 221.1 (67), 194.1 (30), 152.0 (7), 118.6 (6).
1-(4-(1H-Indol-1-yl)phenyl)ethanone (Table 3, Compound
3ag).45 Yield: 86% (40.4 mg). Eluents (Rf = 0.35, hexane/EA =
9:1) was used for flash column chromatography. 1H NMR (400 MHz,
CDCl3): δ 2.64 (s, 3H), 6.72 (d, J = 3.2 Hz, 1H), 7.18−7.28 (m, 2H),
7.36 (d, J = 3.3 Hz, 1H), 7.58−7.60 (m, 2H), 7.63 (d, J = 8.1 Hz,
1H), 7.69 (d, J = 7.5 Hz, 1H), 8.09−8.11 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 26.5, 105.0, 110.5, 121.0, 121.4, 122.9, 123.2,
127.3, 129.8, 130.0, 134.4, 135.3, 143.7, 196.8; MS (EI) m/z (relative
intensity): 235.1 (M+, 100), 220.1 (58), 191.1 (48), 110.0 (7), 95.5
(9).
1-(4-(Phenylamino)phenyl)ethanone (Table 2, Compound 3y).39
Yield: 92% (41.4 mg). Eluents (Rf = 0.45, hexane/EA = 2:1) was used
1
for flash column chromatography. H NMR (400 MHz, CDCl3): δ
2.34 (s, 3H), 2.52 (s, 3H), 6.13 (br, 1H), 6.91−6.93 (m, 2H), 7.08−
7.10 (m, 2H), 7.15−7.17 (m, 2H), 7.83−7.86 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 20.8, 26.1, 113.8, 121.4, 128.4, 130.0,
130.6, 133.3, 137.8, 149.1, 196.4; MS (EI) m/z (relative intensity):
225.1 (M+, 70), 210.1 (100), 180.1 (11), 98.8 (4), 167.1 (19).
Ethyl 4-(Methyl(phenyl)amino)benzoate (Table 2, Compound
3z).40 Yield: 97% (49.5 mg). Eluents (Rf = 0.4, hexane/EA = 9:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 1.34 (t, J = 7.2 Hz, 3H), 3.34 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H), 6.76
(d, J = 8.9 Hz, 2H), 7.18−7.19 (m, 3H), 7.35−7.39 (m, 2H), 7.86 (d,
J = 8.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 14.4, 40.2,
60.2, 113.8, 119.5, 125.2, 125.7, 129.7, 130.9, 147.5, 152.4, 166.7; MS
(EI) m/z (relative intensity): 255.1 (M+, 100), 227.1 (29), 210.1
(45), 180.1 (7), 167.1 (19).
Methyl 4-(5-Fluoro-1H-indol-1-yl)benzoate (Table 3, Compound
3ah). Yield: 72% (38.7 mg). Eluents (Rf = 0.2, hexane/DCM = 19:1)
was used for flash column chromatography to afford 3ah as white
solid. mp: 119.3−121.2 °C; 1H NMR (400 MHz, CDCl3): δ 3.97 (s,
3H), 6.68 (d, J = 3.2 Hz, 1H), 6.95−7.03 (m, 1H), 7.33 (dd, J = 9.1,
2.4 Hz, 1H), 7.40 (d, J = 3.3 Hz, 1H), 7.50−7.59 (m, 3H), 8.18−8.21
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 52.2, 104.6 (d, JCF
=
4-(Methyl(phenyl)amino)benzonitrile (Table 2, Compound
3aa).34 Yield: 55% (22.9 mg). Eluents (Rf = 0.6, hexane/EA = 4:1)
4.4 Hz), 106.2 (d, JCF = 23.5 Hz), 111.1 (d, JCF = 26.1 Hz), 111.3 (d,
JCF = 9.7 Hz), 123.1, 127.8, 128.9, 130.2 (d, JCF = 10.0 Hz), 131.3,
132.0, 143.4, 158.3 (d, JCF = 237.0 Hz), 166.3; 19F NMR (376 MHz,
CDCl3): δ −123.3; MS (EI) m/z (relative intensity): 269.1 (M+,
100), 238.0 (37), 209.1 (32), 119.0 (7), 104.6 (8); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C16H13FNO2, 270.0925; found,
270.0923.
1
was used for flash column chromatography. H NMR (400 MHz,
CDCl3): δ 3.32 (s, 3H), 6.68−6.71 (m, 2H), 7.17−7.18 (m, 2H),
7.22−7.25 (m, 1H), 7.38−7.42 (m, 4H); 13C{1H} NMR (100 MHz,
CDCl3): δ 40.1, 99.2, 113.8, 120.3, 126.1, 126.4, 130.0, 133.2, 146.7,
151.9; MS (EI) m/z (relative intensity): 208.1 (M+, 100), 192.1 (12),
102.0 (6), 77.0 (8).
N-Phenylquinolin-6-amine (Table 2, Compound 3ab).41 Yield:
99% (43.6 mg). Eluents (Rf = 0.5, hexane/EA = 2:1) was used for
Ethyl 3-(1H-Indol-1-yl)benzoate (Table 3, Compound 3ai).46
Yield: 88% (46.7 mg). Eluents (Rf = 0.55, hexane/EA = 9:1) was used
H
DOI: 10.1021/acs.joc.9b00703
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
for flash column chromatography. H NMR (400 MHz, CDCl3): δ
m/z (relative intensity): 223.1 (M+, 100), 208.1 (71), 180.1 (43),
152.1 (16), 77.1 (9).
1.46 (t, J = 7.2 Hz, 3H), 4.47 (q, J = 7.2 Hz, 2H), 6.77 (d, J = 3.1 Hz,
1H), 7.23−7.32 (m, 2H), 7.41−7.42 (m, 1H), 7.60−7.65 (m, 2H),
7.74−7.68 (m, 2H), 8.09 (d, J = 7.7 Hz, 1H), 8.24−8.25 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 14.3, 61.3, 104.1, 110.2, 120.6,
121.2, 122.6, 125.1, 127.3, 127.7, 128.3, 129.4, 129.6, 132.1, 135.7,
139.9, 165.8; MS (EI) m/z (relative intensity): 265.1 (M+, 100),
237.1 (57), 220.1 (7), 191.1 (27), 165.1 (8).
1-(3,5-Dimethylphenyl)-1H-pyrrole (Table 4, Compound 3aq).50
Yield: 80% (27.3 mg). Eluents (Rf = 0.5, hexane/DCM = 20:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 2.40 (s, 6H), 6.36−6.37 (m, 2H), 6.92 (s, 1H), 7.05 (s, 2H), 7.10−
7.11 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 21.4, 110.0,
118.5, 119.4, 127.3, 139.3, 140.7; MS (EI) m/z (relative intensity):
171.1 (M+, 100), 156.0 (23), 129.0 (22), 77.1 (11), 51.0 (4).
4-(tert-Butyl)-N-phenylaniline (Table 4, Compound 3ar).24 Yield:
99% (44.6 mg). Eluents (Rf = 0.5, hexane/DCM = 20:1) was used for
4-(m-Tolyl)-1,2,3,4-tetrahydrocyclopenta[b]indole (Table 3,
Compound 3aj). Yield: 83% (41.0 mg). Eluents (Rf = 0.4, hexane/
DCM = 19:1) was used for flash column chromatography to afford
3aj as white solid. mp: 102.9−103.0 °C; 1H NMR (400 MHz,
CDCl3): δ 2.49 (s, 3H), 2.59−2.64 (m, 2H), 2.94−2.99 (m, 4H),
7.18−7.21 (m, 3H), 7.29−7.32 (m, 2H), 7.41−7.45 (m, 1H), 7.50−
7.52 (m, 1H), 7.55−7.57 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 21.4, 24.6, 26.2, 28.3, 110.8, 118.6, 120.0, 120.2, 120.7,
121.8, 124.9, 125.4, 126.9, 129.2, 138.9, 139.3, 140.9, 145.7; MS (EI)
m/z (relative intensity): 247.1 (M+, 100), 232.1 (19), 217.1 (11),
204.1 (6). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H18N,
248.1434; found, 248.1431.
1
flash column chromatography. H NMR (400 MHz, CDCl3): δ 1.38
(s, 9H), 5.67 (s, 1H), 6.93−6.97 (m, 1H), 7.08−7.10 (m, 4H), 7.26−
7.37 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 31.4, 34.1,
117.1, 118.1, 120.4, 126.1, 129.3, 140.3, 143.7, 144.1; MS (EI) m/z
(relative intensity): 225.1 (M+, 38), 210.1 (100), 195.1 (7), 180.0
(6), 167.0 (6).
N-(3-Methoxyphenyl)-2,6-dimethylaniline (Table 4, Compound
3as).51 Yield: 80% (36.3 mg). Eluents (Rf = 0.3, hexane/DCM =
20:1) was used for flash column chromatography. 1H NMR (400
MHz, CDCl3): δ 2.22 (s, 6H), 3.73 (s, 3H), 5.18 (br, 1H), 6.03−6.05
(m, 1H), 6.15 (dd, J = 8.0, 1.6 Hz, 1H), 6.32 (dd, J = 8.1, 1.9 Hz,
1H), 7.05−7.12 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3): δ 18.3,
55.0, 99.5, 103.1, 106.6, 125.9, 128.5, 129.9, 136.1, 138.0, 147.8,
160.8; MS (EI) m/z (relative intensity): 227.1 (M+, 100), 212.1 (43),
196.1 (13), 120.1 (7), 77.1 (5).
1-(3-Methoxyphenyl)-1H-pyrrole (Table 3, Compound 3ak).47
Yield: 93% (32.2 mg). Eluents (Rf = 0.4, hexane/EA = 9:1) was used
1
for flash column chromatography. H NMR (400 MHz, CDCl3): δ
3.86 (s, 3H), 6.36−6.37 (m, 2H), 6.80−6.82 (m, 1H), 6.95−6.97 (m,
1H), 7.00−7.02 (m, 1H), 7.10−7.12 (m, 2H), 7.34 (t, J = 8.2 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 55.4, 106.7, 110.3, 110.8,
112.8, 119.3, 130.3, 141.9, 160.5; MS (EI) m/z (relative intensity):
173.1 (M+, 100), 144.1 (15), 130.1 (26), 103.0 (18), 77.0 (18).
10-(4-(tert-Butyl)phenyl)-10H-phenoxazine (Table 3, Compound
3al).48 Yield: 94% (59.3 mg). Eluents (Rf = 0.5, hexane/DCM =
19:1) was used for flash column chromatography. 1H NMR (400
MHz, CDCl3): δ 1.44 (s, 9H), 5.97 (dd, J = 7.6, 1.4 Hz, 2H), 6.63−
6.72 (m, 6H), 7.26−7.29 (m, 2H), 7.61−7.63 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 31.4, 34.8, 113.2, 115.2, 121.0, 123.2,
127.9, 130.0, 134.6, 136.0, 143.9, 151.4; MS (EI) m/z (relative
intensity): 315.2 (M+, 100), 300.1 (45), 285.1 (14), 182.1 (39), 136.1
(9).
10-(3,5-Dimethylphenyl)-10H-phenothiazine (Table 3, Com-
pound 3am).11e Yield: 66% (40.0 mg). Eluents (Rf = 0.8, hexane/
EA = 9:1) was used for flash column chromatography. 1H NMR (400
MHz, CDCl3): δ 2.41 (s, 6H), 6.26 (dd, J = 8.0, 0.7 Hz, 2H), 6.79−
6.88 (m, 4H), 7.00−7.03 (m, 4H), 7.11−7.14 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 21.3, 115.8, 119.8, 122.2, 126.5, 126.7,
128.3, 129.8, 140.5, 140.6, 144.3; MS (EI) m/z (relative intensity):
303.1 (M+, 100), 287.0 (5), 271.1 (15), 254.1 (6), 198.0 (19).
1-(m-Tolyl)-1H-indole (Table 4, Compound 3an).49 Yield: 88%
(36.4 mg). Eluents (Rf = 0.6, hexane/EA = 20:1) was used for flash
N-Methyl-N-phenylaniline (Scheme 3, Compound 3a).21 Yield:
87% (1.60 g). Eluents (Rf = 0.4, hexane/DCM = 20:1) was used for
1
flash column chromatography. H NMR (400 MHz, CDCl3): δ 3.34
(s, 3H), 6.96−7.00 (m, 2H), 7.04−7.06 (m, 4H), 7.28−7.32 (m, 4H);
13C{1H} NMR (100 MHz, CDCl3): δ 40.2, 120.4, 121.2, 129.2,
149.0; MS (EI) m/z (relative intensity): 183.1 (M+, 100), 167.1 (45),
104.0 (20), 77.1 (25), 51.0 (9).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00703.
■
S
Copies of 1H NMR, 13C NMR, 19F NMR, 31P NMR and
HRMS spectra of synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: chau.ming.so@polyu.edu.hk.
■
1
ORCID
column chromatography. H NMR (400 MHz, CDCl3): δ 2.47 (s,
Chau Ming So: 0000-0001-6268-651X
Notes
The authors declare no competing financial interest.
3H), 6.71 (d, J = 3.0 Hz, 1H), 7.18−7.28 (m, 3H), 7.33−7.36 (m,
3H), 7.40−7.44 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 7.7
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 21.4, 103.3, 110.6,
120.2, 121.0, 121.4, 122.2, 125.0, 127.2, 127.9, 129.2, 129.3, 135.8,
139.6, 139.7; MS (EI) m/z (relative intensity): 207.1 (M+, 100),
191.0 (6), 165.0 (7), 102.4 (6), 89.0 (6).
ACKNOWLEDGMENTS
■
1-(3,5-Dimethylphenyl)-1H-indole (Table 4, Compound 3ao).44
Yield: 92% (40.7 mg). Eluents (Rf = 0.5, hexane/DCM = 19:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 2.48 (s, 6H), 6.74 (d, J = 3.1 Hz, 1H), 7.07 (s, 1H), 7.20−7.32 (m,
4H), 7.39 (d, J = 3.2 Hz, 1H), 7.64−7.66 (m, 1H), 7.75−7.77 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 21.3, 103.1, 110.6, 120.1,
121.0, 122.06, 122.1, 128.0, 128.1, 129.2, 135.9, 139.3, 139.7; MS
(EI) m/z (relative intensity): 221.1 (M+, 100), 204.1 (12), 178.1 (7),
102.2 (6), 89.1 (6).
We thank The Hong Kong Polytechnic University Start-up
Fund (1-BE0Z) and the Shenzhen Strategic New Industry
Development Research Fund of Shenzhen Science, Technol-
o g y a n d I n n o v a t i o n C o m m i s s i o n ( S Z S T I )
(JCYJ20180306173843318) for its financial support. We are
thankful to Wai-Hang Pang for preparing some of the aryl
phosphates.
5-Methoxy-1-phenyl-1H-indole (Table 4, Compound 3ap).45
Yield: 95% (42.4 mg). Eluents (Rf = 0.5, hexane/EA = 9:1) was
used for flash column chromatography. 1H NMR (400 MHz, CDCl3):
δ 3.91 (s, 3H), 6.65 (d, J = 3.1 Hz, 1H), 6.93 (dd, J = 9.0, 2.4 Hz,
1H), 7.19 (d, J = 2.4 Hz, 1H), 7.34−7.39 (m, 2H), 7.50−7.53 (m,
5H); 13C{1H} NMR (100 MHz, CDCl3): δ 55.8, 102.6, 103.2, 111.3,
112.4, 124.0, 126.2, 128.3, 129.6, 129.8, 131.0, 139.9, 154.5; MS (EI)
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