Metal-Free β-Amino Alcohol Synthesis: A Two-step Smiles Rearrangement

Article abstract of DOI:10.1021/acs.joc.0c01543

A novel method for the synthesis of β-amino alcohols has been demonstrated under mild reaction conditions with a broad scope via a two-step Smiles rearrangement. What is more, theoretical calculations have been performed to confirm the rationality of the mechanism. The method has been proved to be notably effective for N-arylated amino alcohols, which are difficult to synthesize by traditional methods.

Full text of DOI:10.1021/acs.joc.0c01543

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Article
Metal-Free β‑Amino Alcohol Synthesis: A Two-step Smiles
Rearrangement
Di Yang, Cai-Xia Xie, Xiao-Tian Wu, Luo-Ran Fei, Lei Feng, and Chen Ma*
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ABSTRACT: A novel method for the synthesis of β-amino
alcohols has been demonstrated under mild reaction conditions
with a broad scope via a two-step Smiles rearrangement. What is
more, theoretical calculations have been performed to confirm the
rationality of the mechanism. The method has been proved to be
notably effective for N-arylated amino alcohols, which are difficult
to synthesize by traditional methods.
an intramolecular nucleophilic aromatic substitution reaction
and can be easily incorporated in tandem reactions.16
In this work, we envisaged a cascade reaction that offered β-
amino alcohols starting from an alkyl sulfonamide and an
epoxide ring via benzene sulfonamide−styrene oxide addition,
ipso-substitution, SO2 extrusion, and the subsequent two-step
Smiles rearrangement (Scheme 2). What is more, the reaction
achieved an effective method to synthesize aromatic-
substituted amino alcohols which are tough to obtain by
traditional ways. All in all, it might broaden the sight of
designing multicomponent reactions for the Smiles rearrange-
ment.
1. INTRODUCTION
β-Amino alcohols have attracted tremendous interest among
natural product synthesis because of the wide existence of their
skeleton in drugs,1 including antihypertensives,2 antianginal
agents,3 antiasthmatic agents,4 antimalarial agents,5 anti-HBV
drugs,6 and so on (Scheme 1).7 β-amino alcohols are
considered as promising molecular structures which are widely
present in biologically active, natural, and unnatural amino
acids.8 As an intermediate, they can be candidates for
heterocyclic organic synthesis, such as indoles9 and benzox-
azines.10 In addition, they are widely used as chiral auxiliaries
in organic synthesis (Scheme 1).11
Because of their great value, the preparation of amino
alcohols has gained much attention.12 The classical method
was the opening of epoxides with an amine under heating.13
Among the investigated efforts, a lot of metal catalysts such as
Bi, In, and Fe were used to afford amino alcohols (Scheme 2a)
via opening the rings.14 The use of a Lewis acid catalyst
generally promoted the reaction of nitrogen-based nucleo-
philes with epoxides whose reactivity could be enhanced by
complexation with the Lewis acid. In addition, construction of
chiral amino alcohols also required the participation of chiral
metal catalysts. Recently, a cascade reaction to construct amino
alcohols was reported including a three-component reaction
(Scheme 2b).15 However, severe reaction conditions, such as
excess requirement of amines, high temperatures, long reaction
times, and the unavoidable use of metal catalysts would not
meet the concept of green chemistry. The discovery of a mild
and simple method to synthesize β-amino alcohols would,
therefore, be a worthy study in the field.
2. RESULTS AND DISCUSSION
2.1. Optimization for the Synthesis of β-Amino
Alcohols. As the Smiles rearrangement frequently required
strong electron-withdrawing groups to stabilize the Meisen-
heimer intermediate and enable the successful Smiles
rearrangement, we sought to use the readily available 4-
nitrobenzenesulfonamide. At the outset, our investigation
commenced with the reaction of 4-nitrobenzenesulfonamide
(1a, 0.5 mmol) and 2-phenyloxirane (2a, 1.5 mmol) in the
presence of Li2CO3 (1 mmol) at 70 °C in commercially
available dimethyl sulfoxide (DMSO) (2 mL) under an air
atmosphere, and the target product (3a) was obtained in 13%
yield after 4 h (Table 1, entry 1).
As shown in Table 1, other bases such as Na2CO3 could
catalyze the reaction, but no satisfactory results were acquired
(Table 1, entries 2−8). Delightfully, an excellent yield of 86%
Received: June 30, 2020
To solve the problem, we seek the readily available aryl
sulfonamides, which are widely present in pharmaceuticals and
agrochemicals. They not only exhibit desirable physicochem-
ical properties along with excellent stability but also can result
in reactivity that treats SO2 as the traceless linker in
sulfonamides to achieve the Smiles rearrangement, which is
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Scheme 1. Selected Example Compounds with the β-Amino Alcohol Skeleton
Scheme 2. Synthesis of N-Substituted β-Amino Alcohols via Ring Opening
was achieved when K2CO3 was employed as a base. Compared
with CH3COONa, the yield was sharply reduced when t-
BuONa was used (Table S1, entries 4−6). When we used an
organic base such as Et3N in the reaction, 3a was not obtained
(Table S1, entries 1−3). The next step optimized the
concentration of K2CO3 in the reaction without obvious
improvement in the product yield (Table 1, entries 9−10).
Neither the decrease nor the increase of temperature was
conducive to the reaction, and no product was obtained at
room temperature (Table 1, entries 11−12). After screening of
solvents, DMSO was identified as the solvent of choice (Table
1, entries 14−20). The other relevant reaction conditions are
summarized in the ESI (Tables S2−S4).
large steric hindrance or long chain were well tolerated with
satisfying yields (3ia−3ma). The extension of applicability was
subsequently performed on N-aryl. The aryl ring of the
sulfonamide includes electron-withdrawing or electron-donat-
ing substituents that were well tolerated, with the correspond-
ing products formed with moderate to excellent yields (3na−
3va). We delightedly found that alternative N-substituted
groups such as heterocycles were effective in the reaction
(3wa), but some attrition in yield was observed. We noticed
that the N-substituted sulfonamide with a heteroatom directly
presented a satisfactory reactivity, thus producing the target
product (3xa) in good yield.
Having established the scope of the reaction for substituted
sulfonamides, we were keen to develop a more general
procedure with a broad substrate scope for 2-phenyloxirane
under the optimized reaction conditions (Table 4). Despite the
weak nucleophilicity of sulfonamide, the scope of epoxy
compounds with a variety of primary and secondary alkyl- and
aryl-substituted alkynes was proved to be very broad,
producing β-amino alcohols in good to excellent yields
(3ab−3ak). Interestingly, considerable yields (3al−3am)
were obtained when polycyclic aromatic substrates were used.
To explore the practicality, a reaction of 1na on a 10 mmol
scale was performed. The target product 3na was isolated in
79% yield (Scheme 3a).
2.2. Synthesis. With these simple reaction conditions in
hand, we examined the scope of the reaction for a range of aryl
sulfonamides with different substituents (Table 2). We first
investigated compounds with electron-withdrawing groups
such as chlorine and heteroaryl sulfonamides, but there were
no target products (3ba−3ca). We realized that the existence
of a strong electron-deficient group was necessary, which could
be achieved by using other functional groups (3da−3ea).
Switching the nitro group to the ortho or even meta position
was effective with satisfactory yields (3ea−3ga).
Turing to the N-substituted sulfonamide compounds, N-
alkyl sulfonamides were first investigated, all of them with good
yields (Table 3). Even the N-substituted sulfonamides with a
B
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a
Table 1. Optimization of the Reaction Conditions
b
entry
base
equiv
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
8
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K3PO4
LiOH
NaOH
CsOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2
2
2
2
2
2
2
2
1
3
2
2
2
2
2
2
2
2
2
2
DMSO
70
70
70
70
70
70
70
70
70
70
r.t
60
80
70
70
70
70
70
70
70
13b
20
86
84
85
76
74
58
73
80
n.p.
62
80
NR
78
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
None
DMF
CH3CN
NMP
1,4-dioxane
TBA
EtOH
9
10
11
12
13
14
15
16
17
18
19
20
c
d
51
64
13
trace
70
a
Reaction conditions: 4-nitrobenzenesulfonamide 1a (0.5 mmol), 2-phenyloxirane 2a (1.5 mmol), K2CO3 (1 mmol), DMSO (2 mL), 70 °C, 4 h.
b
c
d
Isolated yields. n.p. = no product. NR = no reaction.
ab
Table 2. Synthesis of Products 3ba−3ga
a
Unless specifically noted otherwise, reaction conditions: 1a (0.5 mmol), 2-phenyloxirane 2a (1.5 mmol), K2CO3 (1 mmol), DMSO (2 mL), 70
b
°C, 4 h. Isolated yields.
Furthermore, we assumed that the presence of an ortho-
amino group in 4-nitro-N-phenylbenzenesulfonamide was
nicely realized by the tandem of the Smiles rearrangement
and the Ullmann reaction to produce 3,4-dihydro-2H-1, 4-
benzoxazines (Scheme 3b). To our delight, we successfully
obtained the target product (4a) in 35% yield when using N-
(2-chlorophenyl)-4-nitrobenzenesulfonamide. Notably, both
−Br and −I as the N-(2)-substituent in 4-nitro-N-phenyl-
benzenesulfonamide gave good yields, while no desired
product was obtained when using −F as the N-(2)-substituent.
This phenomenon further illustrated the application prospect
of the method.
2.3. Mechanism Investigation. To elucidate the
mechanism of the reaction, several control experiments were
conducted. The first control used benzene sulfonamide
without an electron-withdrawing group as the raw material
that reacted with styrene oxide, and no product was collected
as expected (Scheme 4a). Next, amide with a nitro substitution
C
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ab
Table 3. Synthesis of Products 3ha−3ya
a
Unless specifically noted otherwise, reaction conditions: 1a (0.5 mmol.), 2-phenyloxirane 2a (1.5 mmol), K2CO3 (1 mmol), DMSO (2 mL), 70
b
°C, 4 h. Isolated yields.
in the ortho position was used as the raw material, and there
was no product either, which accounts for the necessity of
removing SO2 during the reaction (Scheme 4b). Finally,
tertiary sulfonamides turned out to be unreactive (Scheme 4c).
Based on the above control experiments and our previous
work17 on the Smiles rearrangement, a possible mechanism for
this reaction was proposed, as shown in Scheme 5. Starting
with the readily available aryl sulfonamides 1, addition of
styrene oxide should give the adduct b. This intermediate b
could then undergo an O/S Smiles-type ipso substitution with
SO2 extrusion from intramolecular cyclization, thus offering a
sulfonamide anion intermediate d. Subsequently, d formed the
intermediate e via the N/O Smiles rearrangement, by
undergoing another intramolecular cyclization and capturing
a proton from KHCO3, which led to the corresponding
product 3.
2.4. Theoretical Results. Because of the reliable accuracy
to evaluate structures and energetics, theoretical calculations
have been strongly confirmed as a convincing method for
many chemical processes. The methods were used to
rationalize the experimental process from the intermediate 2-
phenoxy-N-phenylaniline to product 3. First, the geometries of
minimal and transition states were optimized and calculated
using Gaussian 09, which are shown in Figure 1a. The free
energy barrier from 2-phenoxy-N-phenylaniline to compound
3 is 7.76 kcal/mol, indicating that the secondary rearrange-
ment product was more stable than the intermediate. Also, it
was in good agreement with the experiments that through the
D
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ab
Table 4. Synthesis of Products 3ab−3an
a
Unless specifically noted otherwise, reaction conditions: 1a (0.5 mmol), 2-phenyloxirane 2a (1.5 mmol), K2CO3 (1 mmol), DMSO (2 mL), 70
b
°C, 4 h. Isolated yields.
Scheme 3. Gram-Scale Experiment and Synthesis of 3,4-Dihydro-2H-1,4-Benzoxazines
Scheme 4. Control Experiments
E
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Scheme 5. Proposed Mechanism
Figure 1. (a) Optimized structures for transition states, intermediate, and products and (b) calculated relative free-energy profiles.
two-step Smiles rearrangement produced the target product β-
amino alcohols.
traditional methods. Applications of these β-amino alcohols
will be the subject of future investigations in our laboratory.
Figure 1b presents the calculated free-energy profiles. R′
denotes the most stable geometry of the anionic reactant, and
it was the common starting point of the results of intrinsic
reaction coordinate (IRC) calculations. TS1 corresponds to
the transition state and the negatively charged N1 atom was
ready to attack C1. The forward product from TS1 was the
precursor of the Smiles rearrangement product P′, a metastable
intermediate located on the potential energy surface, where the
C1−N bond had formed and the C1−O bond had broken.
Then, the Smiles rearrangement pathway was completed. From
Figure 1b, the free-energy barrier from R′ to P′ is calculated to
be 55.67 kcal/mol. The result also confirmed the rationality of
the speculation on the mechanism.
4. EXPERIMENTS
1
4.1. General Information. H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker AVANCE 400 MHz
spectrometer, with DMSO-d6 as a solvent and tetramethylsilane as an
internal standard. Melting points (mp) were measured on a Tektronix
XT-4 instrument. All reactions were carried out under an air
atmosphere. Thin-layer chromatography (TLC) was conducted on
silica gel 60 F254 plates (Yinlong) and column chromatography was
performed over silica gel (mesh 300−400). Melting points were
determined on an XD-4 digital micro melting point apparatus. High-
resolution mass spectra were obtained on a Q-TOF6510 spectrograph
(Agilent). Single-distilled water was used throughout all experiments;
other reagents were commercially available and were used without
further purification. DMSO was refluxed and distilled in the presence
of Na2SO4 in the system.
4.2. Compounds 1a−m Were Prepared According to the
Literature (Scheme S1).18 Amines (4.7 mmol) and sodium acetate
(7 mmol) were dissolved in water (6 mL). 4-Nitrobenzensulfonyl
chloride (4.5 mmol) was added rapidly to the above mixture. The
reaction was stirred and heated at 85 °C until the reaction was
finished (modified by TLC). A dark, viscous solid formed initially, but
continued heating and stirring converted the product to pale yellow.
The solid was collected by reduced pressure filtration and washed
with water. The crude product was purified by recrystallization in
ether with 20% ethyl acetate, forming 1 g of white crystalline flakes
(Scheme S1).
3. CONCLUSIONS
To conclude, we have demonstrated that metal-free β-amino
alcohol synthesis is possible under mild reaction conditions
with a broad scope through a novel benzene sulfonamide−
styrene oxide addition, ipso-substitution, SO2 extrusion
sequence, and the subsequent two-step Smiles rearrangement,
which might give a new sight for designing multicomponent
reactions for the Smiles rearrangement. Moreover, we realized
the tandem of the Smiles rearrangement and the Ullmann
reaction to produce morpholine derivatives by a one-pot
method, further making it a promising candidate for improving
the value of the method. What is more, theoretical calculations
were performed to confirm the rationality of the speculation on
the mechanism. The reaction is notably effective for aromatic-
substituted amino alcohols, which are difficult to synthesize by
4.3. General Procedures. 4-Nitrobenzenesulfonamide (101 mg,
0.5 mmol) and 2-phenyloxirane (180 mg, 1.5 mmol) in DMSO (2
mL) with K2CO3 (1 mmol) were stirred at 70 °C. With the progress
of the reaction, the color of the solution gradually deepened and the
solution turned from pale yellow to dark brown yellow until the
reaction was completed (monitored by TLC). After cooling down to
F
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room temperature, brine (30 mL) was added to the mixture to
quench the reaction. The solution was extracted three times with
EtOAc (20 mL × 3). The organic phase was dried with anhydrous
magnesium sulfate overnight. After filtration, the solvent was removed
under reduced pressure to get a yellow product. The crude product
was purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate = 10:1, v/v) to obtain the desired product.
4.4. Gram-Scale Synthesis of 2-((4-Nitrophenyl)(phenyl)-
amino)-1-phenylethan-1-ol (3oa). 4-Nitro-N-phenylbenzenesulfo-
namide (2.78 g), K2CO3 (2.76 g), and 2-phenyloxirane (3.6 g) were
dissolved in DMSO (15 mL). The mixture was stirred and heated at
70 °C under the air conditions. Until the reaction completed in about
15 h (monitored by TLC), brine (200 mL) was poured to dilute the
mixture. After extraction with ethyl acetate (150 mL × 3), the organic
solvent was removed under reduced pressure. The crude product was
purified by flash column chromatography on silica gel using
petroleum ether/ethyl acetate (10:1, v/v) to obtain the desired
product.
4.5. Synthesis of 4-(4-Nitrophenyl)-2-phenyl-3,4-dihydro-
2H-benzo[b][1,4]oxazine (4a). 4-Nitro-N-phenylbenzenesulfona-
mide (139 mg, 0.5 mmol), 2-phenyloxirane (180 mg, 1.5 mmol),
K2CO3 (1 mmol), CH3COOK (0.25 mmol), and CuI (0.025 mmol)
with DMSO (2 mL) were stirred at 70 °C until the reaction was
completed (monitored by TLC). After cooling down to room
temperature, brine (50 mL) was added into the mixture to quench the
reaction. The solution was extracted three times with EtOAc (20 mL
× 3). The organic phase was dried with anhydrous magnesium sulfate.
After filtration, the solvent was removed under reduced pressure to
get a deep yellow product. The crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
= 15:1, v/v) to obtain the desired product.
5H), 7.30−7.26 (m, 1H), 7.77 (t, J = 8 Hz, 1H), 5.63 (s, 1H), 4.92−
4.88 (m, 1H), 3.85−3.73 (m, 2H); 13C NMR (101 MHz, DMSO-d6):
147.4, 146.6, 144.0, 140.9, 134.9, 131.3, 129.6, 128.7, 127.8, 126.6,
126.3, 126.0, 119.7, 115.8, 70.3, 61.0; HR-MS m/z: [M + H]+ calcd
+
for [C20H19N2O3 ], 335.1396; found, 335.1397.
4.6.5. 2-((3-Nitrophenyl)(phenyl)amino)-1-phenylethan-1-ol
(3ga). Purification on silica gel (petroleum ether/ethyl acetate =
10:1) afforded compound 3ga as a yellow solid (138 mg, 83% yield),
mp 133−135 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.73 (dd, J = 8
Hz, 2H), 7.68−7.67 (m, 1H), 7.53−7.47 (m, 3H), 7.41−7.35 (m,
3H), 7.33−7.30 (m, 1H), 7.10−7.07 (t, J = 8 Hz, 2H), 6.57−6.53 (m,
1H), 5.62−5.60 (m, 1H), 3.53−3.44 (m, 2H); 13C NMR (101 MHz,
DMSO-d6): 158.7, 149.0, 148.8, 139.1, 131.1, 129.4, 129.2, 126.9,
123.3, 116.6, 116.0, 112.7, 110.9, 79.0, 50.1; HR-MS m/z: [M + H]+
+
calcd for [C20H18N2O3 ], 335.1396; found, 335.1389.
4.6.6. 2-(Methyl(4-nitrophenyl)amino)-1-phenylethan-1-ol
(3ha). Purification on silica gel (petroleum ether/ethyl acetate =
15:1) afforded compound 3ha as a yellow oil (111 mg, 82% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.06−8.02 (m, 2H), 7.42 (d, J = 8
Hz, 2H), 7.37−7.34 (m, 2H), 7.30−7.25 (m, 1H), 6.83−6.79 (m,
2H), 5.61 (d, J = 4 Hz, 1H), 4.89−4.85 (m, 1H), 3.67−3.57 (m, 2H),
3.01 (s, 3H); 13C NMR (101 MHz, DMSO-d6): 154.3, 143.7, 136.0,
128.6, 127.8, 126.5, 126.2, 111.3, 70.7, 60.2; HR-MS m/z: [M + H]+
+
calcd for [C15H17N2O3 ], 273.1239; found, 273.1231.
4.6.7. 2-(Ethyl(4-nitrophenyl)amino)-1-phenylethan-1-ol (3ia).
Purification on silica gel (petroleum ether/ethyl acetate = 15:1)
afforded compound 3ia as a yellow oil (112 mg, 78% yield); 1H NMR
(400 MHz, DMSO-d6): δ 8.05−8.03 (m, 2H), 7.46−7.44 (m, 2H),
7.38−7.34 (m, 2H), 7.30−7.27 (m, 1H), 6.84−6.81 (m, 2H), 5.64 (s,
1H), 4.87 (m, 1H), 3.62−3.57 (m, 1H), 3.52−3.47 (m, 2H), 3.40−
3.35 (m, 1H), 1.06 (t, J = 8 Hz, 3H); 13C NMR (101 MHz, DMSO-
d6): 153.4, 143.5, 135.7, 128.6, 127.8, 126.6, 126.4, 111.3, 70.8, 58.3,
4.6. Theoretical Calculations. Theoretical calculations were
carried on a representative system in the framework of density
functional theory, introducing the popular B3LYP functional with the
standard 6-311+g (d, p) basis set, as implemented in the Gaussian 09
GaussView software package.
+
46.2, 12.0; HR-MS m/z: [M + H]+ calcd for [C19H16N2O3 ],
287.1396; found, 287.1391.
4.6.8. 2-(Isopropyl(4-nitrophenyl)amino)-1-phenylethan-1-ol
(3ja). Purification on silica gel (petroleum ether/ethyl acetate =
15:1) afforded compound 3ja as a yellow oil (121 mg, 81% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.04 (d, J = 8 Hz, 2H), 7.44−7.27
(m, 5H), 6.97 (d, J = 8 Hz, 2H), 5.59 (d, J = 4 Hz, 1H), 4.84−4.80
(m, 1H), 4.23−4.16 (m, 1H), 3.54−3.48 (m, 1H), 3.42−3.37 (m,
1H), 1.20 (d, J = 8 Hz, 3H), 1.04 (d, J = 8 Hz, 3H); 13C NMR (101
MHz, DMSO-d6): 154.4, 144.2, 136.1, 128.7, 127.8, 126.6, 126.1,
112.7, 71.0, 52.9, 50.0, 20.5, 20.1; HR-MS m/z: [M + H]+ calcd for
4.6.1. 2-((4-Nitrophenyl)amino)-1-phenylethan-1-ol (3a). Purifi-
cation on silica gel (petroleum ether/ethyl acetate = 10:1) afforded
1
compound 3a as a yellow oil (111 mg, 86% yield); H NMR (400
MHz, CDCl3-d6): δ 8.07−8.04 (m, 2H), 7.41−7.26 (m, 5H), 6.55 (d,
J = 1 Hz, 2H), 4.97−4.95 (m, 1H), 3.51−3.39 (m, 2H); 13C NMR
(101 MHz, CDCl-d6): 153.2, 141.3, 138.3, 128.9, 128.6, 126.5, 125.9,
+
111.5, 50.5, HR-MS m/z: [M + H]+ calcd for [C14H15N2O3 ],
+
[C17H20N2O3 ], 301.1552; found, 301.1555.
259.1083; found, 259.1086.
4.6.9. 2-((4-Nitrophenyl)(propyl)amino)-1-phenylethan-1-ol
(3ka). Purification on silica gel (petroleum ether/ethyl acetate =
15:1) afforded compound 3ka as a yellow oil (124 mg, 83% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.10 (d, J = 8 Hz, 2H), 7.42 (d, J = 4
Hz 4H), 7.29 (s, 1H), 6.70 (dd, J = 8 Hz, 2H), 5.03 (q, J = 4 Hz,1H),
3.75−3.69 (q, J = 8 Hz, 2H), 3.62−3.57 (dd, J = 4 Hz, 2H), 3.42−
3.38 (m, 1H), 3.33−3.29 (m, 1H), 1.67−1.60 (m, 2H), 0.91−0.93 (t,
J = 8 Hz, 3H); 13C NMR (101 MHz, DMSO-d6): 153.6, 143.8, 135.7,
128.6, 126.6, 126.4, 122.0, 111.3, 70.6, 58.8, 53.4, 19.6, 11.5; HR-MS
4.6.2. 4-((2-Hydroxy-2-phenylethyl)(phenyl)amino)benzonitrile
(3da). Purification on silica gel (petroleum ether/ethyl acetate =
10:1) afforded compound 3da as a white oil (122 mg, 78% yield); 1H
NMR (400 MHz, DMSO-d6): δ 7.65 (d, J = 8 Hz, 2H), 7.47 (d, J = 8
Hz, 2H), 7.40−7.36 (m, 2H), 7.32−7.28 (m, 1H), 7.10−7.03 (m,
4H), 6.66 (d, J = 8 Hz, 2H), 6.53 (t, J = 8 Hz, 1H), 5.89 (t, J = 8 Hz,
1H), 5.57 (dd, J = 8 Hz, 1H), 3.58−3.49 (m, 1H), 3.45−3.39 (m,
1H); 13C NMR (101 MHz, DMSO-d6): 161.7, 148.7, 139.2, 134.6,
129.4, 129.2, 128.6, 126.9, 119.4, 117.2, 116.5, 112.7, 103.4, 78.9,
50.4; HR-MS m/z: [M + H]+ calcd for [C21H19N2O+], 315.1497;
found, 315.1492.
+
m/z: [M + H]+ calcd for [C17H20N2O3 ], 301.1552; found, 301.1550.
4.6.10. 2-(Butyl(4-nitrophenyl)amino)-1-phenylethan-1-ol (3la).
Purification on silica gel (petroleum ether/ethyl acetate = 10:1)
afforded compound 3la as a yellow oil (136 mg, 87% yield); 1H NMR
(400 MHz, DMSO-d6): δ 8.05−8.01 (m, 2H), 7.44−7.41 (m, 2H),
7.37−7.34 (m, 2H), 7.30−7.26 (m, 1H), 6.80 (d, J = 8 Hz, 2H), 5.61
(d, J = 4 Hz, 1H), 4.87−4.83 (m, 1H), 3.62−3.50 (m, 2H), 1.55−1.43
(m, 2H), 1.40−1.35 (m, 2H), 1.32−1.23 (m, 2H), 0.93−0.80 (m,
3H); 13C NMR (101 MHz, DMSO-d6): 153.5, 143.8, 135.7, 128.6,
127.8, 126.6, 126.5, 111.3, 70.6, 58.8, 51.5, 28.5, 20.0, 14.2; HR-MS
4.6.3. 1-Phenyl-2-(phenyl(4-(trifluoromethyl)phenyl)amino)-
ethan-1-ol (3ea). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 3ea as a colorless oil (142 mg,
1
80% yield); H NMR (400 MHz, DMSO-d6): δ 7.52−7.45 (m, 3H),
7.41−7.37 (m, 2H), 7.33−7.28 (m, 2H), 7.26−7.15 (m, 4H), 6.97−
6.91 (m, 3H), 6.66 (t, J = 8 Hz, 1H), 5.72−5.69 (m, 1H), 5.03−4.91
(m, 1H), 4.04−3.97 (m, 1H), 3.61−3.56 (m, 1H); 13C NMR (101
MHz, DMSO-d6): 160.8, 149.5, 140.2, 139.5, 129.3, 128.7, 128.0,
127.2, 126.7, 117.6, 116.5, 115.0, 79.2, 65.3, 62.8, 54.5; HR-MS m/z:
[M + H]+ calcd for [C21H19F3N2O+], 358.1419; found, 358.1414.
4.6.4. 2-((2-Nitrophenyl)(phenyl)amino)-1-phenylethan-1-ol
(3fa). Purification on silica gel (petroleum ether/ethyl acetate =
8:1) afforded compound 3fa as a yellow solid (104 mg, 62% yield),
mp 122−124 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.88 (dd, J = 8
Hz, 1H), 7.72−7.67 (m, 1H), 7.49 (dd, J = 8 Hz, 1H), 7.42−7.33 (m,
+
m/z: [M + H]+ calcd for [C18H23N2O3 ], 315.1709; found, 315.1704.
4.6.11. 2-(Cyclohexyl(4-nitrophenyl)amino)-1-phenylethan-1-ol
(3ma). Purification on silica gel (petroleum ether/ethyl acetate =
15:1) afforded compound 3ma as a yellow oil (148 mg, 87% yield);
1H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J = 8 Hz, 2H), 7.44−7.42
(m, 2H), 7.39−7.34 (m, 2H), 7.30−7.26 (m, 1H), 6.97 (d, J = 8 Hz,
2H), 5.58 (d, J = 4 Hz, 1H), 4.83−4.79 (m, 1H), 3.37−3.72 (m, 1H),
G
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3.36−3.39 (m, 3H), 1.82−1.71 (m, 3H), 1.64−1.54 (m, 3H), 1.42−
1.33 (n, 4H); 13C NMR (101 MHz, DMSO-d6): 154.4, 144.1, 136.1,
128.7, 127.8, 126.6, 126.2, 112.6, 71.4, 58.3, 53.3, 30.8, 30.0; HR-MS
(m, 1H), 3.07−3.85 (m, 2H); 13C NMR (101 MHz, DMSO-d6):
162.1, 159.6, 154.4, 143.5, 137.5, 130.4, 128.7, 127.9, 126.6, 126.1,
117.2, 113.5, 70.3, 60.7; HR-MS m/z: [M + H]+ calcd for
+
+
m/z: [M + H]+ calcd for [C20H25N2O3 ], 341.1856; found, 341.1853.
[C20H18FN2O3 ], 353.1301; found, 353.1299.
4.6.12. 2-((4-Nitrophenyl)(phenyl)amino)-1-phenylethan-1-ol
(3na). Purification on silica gel (petroleum ether/ethyl acetate =
10:1) afforded compound 3na as a yellow oil (142 mg, 85% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.04−8.00 (m, 2H), 7.45 (t, J = 8 Hz,
2H), 7.39−7.27 (m, 8H), 6.80−6.76 (m, 2H), 5.73 (d, J = 4 Hz, 1H),
4.89−4.84 (m, 1H), 4.01−3.95 (m, 1H), 3.92−3.87 (m, 1H); 13C
NMR (101 MHz, DMSO-d6): 154.3, 145.5, 143.5, 137.3, 130.6,
128.7, 128.0, 127.9, 127.2, 126.6, 126.0, 113.8, 70.3, 60.5; HR-MS m/
4.6.19. 2-((4-Bromophenyl)(4-nitrophenyl)amino)-1-phenyle-
than-1-ol (3ua). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 3ua as a pale yellow oil (161 mg,
78% yield), mp 125−128 °C; H NMR (400 MHz, DMSO-d6): δ
1
8.03 (d, J = 9.2 Hz, 2H), 7.65−7.63 (dd, J = 8 Hz, 2H), 7.39 (d, J = 8
Hz, 2H), 736−7.32 (t, J = 8 Hz, 2H), 7.29−7.27 (m, 3H), 5.75 (d, J =
4 Hz, 1H), 4.89−4.84 (m, 1H), 3.92 (d, J = 8 Hz, 2H); 13C NMR
(101 MHz, DMSO-d6): 154.0, 145.1, 143.4, 138.0, 133.4, 129.9,
128.7, 127.9, 126.6, 126.0, 119.4, 114.4, 70.3, 60.4; HR-MS m/z: [M
+
z: [M + H]+ calcd for [C20H18N2O3 ], 335.1396; found, 335.1513.
+
4.6.13. 2-((4-Nitrophenyl)(p-tolyl)amino)-1-phenylethan-1-ol
(3oa). Purification on silica gel (petroleum ether/ethyl acetate =
10:1) afforded compound 3oa as a yellow oil (141 mg, 81% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 8 Hz, 2H), 7.39−7.32
(m, 4H), 7.28 (d, J = 8 Hz, 3H), 7.17 (d, J = 8 Hz, 2H), 7.75 (d, J = 8
Hz, 2H), 4.88−4.86 (m, 1H), 3.96−3.85 (m, 2H), 2.35 (s, 2H); 13C
NMR (101 MHz, DMSO-d6): 154.7, 143.6, 143.0, 137.2, 136.7,
131.1, 128.7, 128.0, 127.8, 126.6, 126.0, 113.4, 70.4, 60.6, 21.1; HR-
+ H]+ calcd for [C20H18BrN2O3 ], 413.0501; found, 413.0499.
4.6.20. 2-((4-Iodophenyl)(4-nitrophenyl)amino)-1-phenylethan-
1-ol (3va). Purification on silica gel (petroleum ether/ethyl acetate
= 10:1) afforded compound 3va as a yellow oil (168 mg, 73% yield),
mp 145−148 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.04 (dd, J = 8
Hz, 2H), 7.80 (dd, J = 8 Hz, 2H), 7.40−7.32 (m, 4H), 7.29−7.29 (m,
1H), 7.13 (dd, J = 8 Hz, 2H) 5.26 (d, J = 4 Hz, 1H), 3.92 (d, J = 8
Hz, 2H); 13C NMR (101 MHz, DMSO-d6): 153.9, 145.5, 143.3,
139.4, 137.9, 130.0, 128.6, 126.4, 125.9, 114.5, 91.8, 70.3, 60.4; HR-
MS m/z: [M + H]+ calcd for [C20H18N2O3I+], 461.0362; found,
461.0364.
4.6.21. 2-((1H-Benzo[d]imidazole-2-yl)(4-nitrophenyl)amino)-1-
phenylethan-1-ol (3wa). Purification on silica gel (petroleum
ether/ethyl acetate = 10:1) afforded compound 3wa as an orange
solid (56 mg, 30% yield), mp 133−134 °C;1H NMR (400 MHz,
DMSO-d6): δ 9.60 (s, 1H), 8.23 (d, J = 8 Hz, 2H), 8.00−7.96 (m,
2H), 7.49−7.47 (m, 1H), 7.41 (d, J = 8 Hz, 2H), 7.39−7.37 (m, 1H),
7.33−7.28 (m, 2H), 7.21−7.18 (m, 1H), 7.14−7.08 (m, 2H), 6.00 (s,
1H), 4.99−4.96 (m, 1H), 4.56−4.50 (m, 1H), 4.46−4.42 (m, 1H);
13C NMR (101 MHz, DMSO-d6): 149.2, 147.8, 142.7, 141.6, 140.5,
+
MS m/z: [M + H]+ calcd for [C21H20N2O3 ], 349.1522; found,
349.1548.
4.6.14. 2-((4-Methoxyphenyl)(4-nitrophenyl)amino)-1-phenyle-
than-1-ol (3pa). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 3pa as a yellow oil (146 mg, 80%
1
yield); H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 8 Hz, 2H),
7.34−7.32 (m, 4H), 7.27 (d, J = 4 Hz, 1H), 7.21 (d, J = 8 Hz, 2H),
7.03 (d, J = 8 Hz, 2H), 6.71 (d, J = 8 Hz, 2H), 5.74 (d, J = 4 Hz, 1H),
4.88−4.87 (m, 1H), 3.95−3.93 (m, 2H), 3.80 (s, 3H), 3.39 (s, 1H);
13C NMR (101 MHz, DMSO-d6): 158.2, 154.9, 143.6, 129.6, 128.7,
128.6, 127.9, 126.0, 115.9, 113.3, 70.5, 60.8, 55.8; HR-MS m/z: [M +
+
H]+ calcd for [C21H20N2O4 ], 365.1501; found, 365.1496.
134.2, 128.5, 127.9, 126.6, 125.6, 121.8, 121.1, 117.3, 117.2, 109.9,
4.6.15. 2-((4-Butylphenyl)(4-nitrophenyl)amino)-1-phenylethan-
1-ol (3qa). Purification on silica gel (petroleum ether/ethyl acetate =
10:1) afforded compound 3qa as a yellow oil (156 mg, 80% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.02−8.00 (m, 2H), 7.37−7.32 (m,
4H), 7.31−7.26 (m, 3H), 7.19−7.17 (m, 2H), 6.75−6.73 (m, 2H),
5.70 (d, J = 4 Hz, 1H), 4.86−4.82 (m, 1H), 3.98−3.92 (m, 1H),
3.87−3.83 (m, 1H), 2.59 (t, J = 8 Hz, 2H), 1.61−1.55 (m, 2H),
1.37−1.32 (m, 2H), 0.91 (t, J = 8 Hz, 3H); 13C NMR (101 MHz,
DMSO-d6): 154.6, 143.6, 143.2, 141.5, 137.3, 130.4, 129.8, 128.7,
127.9, 126.6, 126.1, 121.8, 113.5, 70.4, 60.6, 34.8, 22.3, 14.3; HR-MS
+
71.5, 50.0; HR-MS m/z: [M + H]+ calcd for [C21H19N4O3 ],
375.1457; found, 375.1450.
4.6.22. 2-(Methoxy(4-nitrophenyl)amino)-1-phenylethan-1-ol
(3xa). Purification on silica gel (petroleum ether/ethyl acetate =
10:1) afforded compound 3xa as a yellow oil (104 mg, 72% yield); 1H
NMR (400 MHz, DMSO-d6): δ 7.99−7.97 (m, 2H), 7.44−7.42 (m,
2H), 7.38−7.33 (m, 3H), 6.73−6.71 (m, 2H), 5.62 (d, J = 4 Hz, 1H),
4.79−4.76 (m, 1H), 3.39−3.38 (m, 5H); 13C NMR (101 MHz,
DMSO-d6): 155.1, 143.9, 136.1, 129.2, 128.6, 127.7, 126.6, 126.6,
+
71.3, 51.0; HR-MS m/z: [M + H]+ calcd for [C15H17N2O4 ],
+
m/z: [M + H]+ calcd for [C24H27N2O3 ], 391.2022; found, 391.2021.
289.1188; found, 289.1185.
4.6.23. 1-((4-Nitrophenyl)amino)propan-2-ol (3ab). Purification
4.6.16. 2-((4-Nitrophenyl)(3,4,5-trimethoxyphenyl)amino)-1-
phenylethan-1-ol (3ra). Purification on silica gel (petroleum ether/
ethyl acetate = 10:1) afforded compound 3ra as a yellow oil (161 mg,
on silica gel (petroleum ether/ethyl acetate = 15:1) afforded
1
1
76% yield), mp 113−115 °C; H NMR (400 MHz, DMSO-d6): δ
compound 3ab as a yellow oil (75 mg, 76% yield); H NMR (400
8.03 (d, J = 8 Hz, 2H), 7.40−7.32 (m, 4H), 7.29−7.25 (m, 1H), 6.79
(d, J = 8 Hz, 2H), 6.25 (s, 2H), 5.74 (s, 1H), 4.89 (s, 1H), 4.05−3.99
(m, 1H), 3.86−3.83 (m, 1H), 3.70−3.69 (m, 9H), 3.36 (s, 1H); 13C
NMR (101 MHz, DMSO-d6): 154.6, 154.2, 143.6, 141.2, 137.3,
136.6, 128.7, 127.9, 126.8, 126.1, 113.5, 105.6, 70.3, 60.5, 56.4; HR-
MHz, DMSO-d6): δ 7.97 (d, J = 8 Hz, 2H), 7.27 (t, J = 8 Hz, 1H),
6.67 (d, J = 8 Hz, 2H), 4.81 (d, J = 4 Hz, 1H), 3.84−3.78 (m, 1H),
3.16−3.04 (m, 2H), 1.11 (d, J = 8 Hz, 3H); 13C NMR (101 MHz,
DMSO-d6): 155.3, 135.8, 126.7, 111.4, 65.2, 50.6, 21.7; HR-MS m/z:
+
[M + H]+ calcd for [C9H13N2O3 ], 197.0926; found, 197.0920.
+
MS m/z: [M + H]+ calcd for [C23H25N2O6 ], 425.1713; found,
4.6.24. 1-(tert-Butoxy)-3-((4-nitrophenyl)amino)propan-2-ol
(3ac). Purification on silica gel (petroleum ether/ethyl acetate =
15:1) afforded compound 3ac as a yellow oil (106 mg, 79% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.00−7.97 (m, 2H), 7.24 (t, J = 4 Hz,
1H), 6.71−6.68 (m, 2H), 4.93 (d, J = 4 Hz, 1H), 3.34−3.27 (m, 3H),
3.14−3.07 (m, 1H), 1.14 (s, 9H); 13C NMR (101 MHz, DMSO-d6):
155.4, 135.9, 126.6, 111.5, 72.9, 69.2, 64.3, 27.8; HR-MS m/z: [M +
425.1712.
4.6.17. 2-((2-Bromophenyl)(4-nitrophenyl)amino)-1-phenyle-
than-1-ol (3sa). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 3sa as a yellow oil (157 mg, 76%
1
yield), mp 121−123 °C; H NMR (400 MHz, DMSO-d6): δ 8.09−
8.04 (d, 2H), 7.82 (d, J = 8 Hz, 1H), 7.51 (s, 1H), 7.40−7.32 (m,
5H), 7.30−7.26 (m, 1H), 6.61 (d, J = 8 Hz, 2H), 5.74 (d, J = 4.4 Hz,
1H), 4.95 (s, 1H), 3.35 (s, 2H); 13C NMR (101 MHz, DMSO-d6):
143.5, 137.8, 134.7, 132.7, 130.4, 130.0, 129.8, 128.7, 128.0, 127.0,
126.7, 126.2, 123.6, 112.6, 70.7, 59.8; HR-MS m/z: [M + H]+ calcd
+
H]+ calcd for [C12H19N2O3 ], 269.1501; found, 269.1499.
4.6.25. 1-(tert-Butoxy)-3-((4-nitrophenyl)(phenyl)amino)propan-
2-ol (3ad). Purification on silica gel (petroleum ether/ethyl acetate =
15:1) afforded compound 3ad as a yellow oil (138 mg, 80% yield); 1H
NMR (400 MHz, DMSO-d6): δ 8.02−8.00 (m, 2H), 7.52−7.49 (m,
2H), 7.40−7.34 (m, 3H), 6.79−6.77 (m, 2H), 5.06 (d, J = 4 Hz, 1H),
3.72−3.66 (m, 1H), 3.35−3.31 (m, 1H), 3.26−3.22 (m, 1H), 1.10 (s,
9H); 13C NMR (101 MHz, DMSO-d6): 154.6, 145.7, 137.3, 130.6,
128.1, 127.2, 126.0, 72.9, 68.2, 64.4, 56.5, 27.7; HR-MS m/z: [M +
+
for [C20H18BrN2O3 ], 413.0501; found, 413.0506.
4.6.18. 2-((4-Fluorophenyl)(4-nitrophenyl)amino)-1-phenyle-
than-1-ol (3ta). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 3ta as a yellow oil (141 mg, 80%
yield); 1H NMR (400 MHz, DMSO-d6): δ 8.05−8.02 (m, 2H), 7.40−
7.26 (m, 9H), 6.78−6.75 (m, 2H), 5.74 (d, J = 4 Hz, 1H), 4.89−4,85
+
H]+ calcd for [C18H23N2O3 ], 345.1814; found, 345.1818.
H
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Article
4.6.26. 1,1,1-Trifluoro-3-((4-nitrophenyl)(phenyl)amino)propan-
2-ol (3ae). Purification on silica gel (petroleum ether/ethyl acetate =
10:1) afforded compound 3ae as a yellow oil (122 mg, 75% yield), mp
105−107 °C; H NMR (400 MHz, DMSO-d6): δ 8.08−8.04 (m,
4.6.33. 1-(Naphthalen-2-yloxy)-3-((4-nitrophenyl)amino)-
propan-2-ol (3al). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 3al as a yellow oil (118 mg, 70%
yield); 1H NMR (400 MHz, DMSO-d6): δ 8.28−8.25 (m, 4H), 7.97−
7.94 (m, 2H), 7.87−7.84 (m, 1H), 7.52−7.45 (m, 3H), 7.41−7.34
(m, 2H), 6.93 (d, J = 8 Hz, 1H), 6.72 (dd, J = 8 Hz, 2H), 5.55 (d, J =
4 Hz, 1H), 4.20−4.14 (m, 3H), 3.55−3.50 (m, 1H), 3.41-3-38 (m,
1H); 13C NMR (101 MHz, DMSO-d6): 155.2, 154.4, 127.9, 127.0,
126.7, 126.6, 125.7, 122.2, 120.5, 105.7, 70.6, 68.0, 46.2; HR-MS m/z:
1
2H), 7.52 (t, J = 8 Hz, 2H), 7.42−7.36 (m, 3H), 6.85−6.76 (m, 3H),
4.28−4.22 (m, 1H), 4.12−4.07 (m, 1H), 4.03−3.97 (m, 1H); 13C
NMR (101 MHz, DMSO-d6): 154.2, 145.0, 138.1, 130.8, 128.1,
127.6, 126.0, 113.8, 67.5, 67.2, 66.9, 66.7, 52.6; HR-MS m/z: [M +
+
H]+ calcd for [C15H14F3N2O3 ], 327.0957; found, 327.0954.
+
[M + H]+ calcd for [C19H19N2O4 ], 339.1345; found, 339.1346.
4.6.27. 1-((4-Nitrophenyl)amino)but-3-en-2-ol (3af). Purification
on silica gel (petroleum ether/ethyl acetate = 10:1) afforded
4.6.34. 1-(Naphthalen-2-yloxy)-3-((4-nitrophenyl) (phenyl)-
amino)propan-2-ol (3am). Purification on silica gel (petroleum
ether/ethyl acetate = 10:1) afforded compound 3am as a yellow solid
(153 mg, 74% yield), mp 118−120 °C; 1H NMR (400 MHz, DMSO-
d6): δ 8.13 (d, J = 8 Hz, 1H), 7.99−7.97 (m, 2H), 7.85 (d, J = 8 Hz,
1H), 7.55−7.39 (m, 8H), 7.34−7.30 (m, 1H), 6.90 (d, J = 8 Hz, 1H),
6.86−6.82 (m, 2H), 5.60 (d, J = 4 Hz, 1H), 4.30−4.27 (m, 1H),
4.22−4.16 (m, 3H), 4.04−3.99 (m, 1H); 13C NMR (101 MHz,
DMSO-d6): 154.5, 154.3, 145.6, 137.5, 134.5, 130.7, 128.0, 127.9,
126.9, 126.6, 126.0, 125.7, 122.1, 120.6, 113.7, 105.7, 70.6, 67.2, 56.0;
1
compound 3af as a yellow oil (75 mg, 72% yield); H NMR (400
MHz, DMSO-d6): δ 7.97 (d, J = 8 Hz, 2H), 7.26 (t, J = 4 Hz, 1H),
6.69 (d, J = 8 Hz, 2H), 5.97−5.89 (m, 1H), 5.32−5.27 (m, 1H), 5.19
(d, J = 4 Hz, 1H), 5.13−5.11 (m, 1H), 4.20−4.17 (m, 1H), 3.28−3.22
(m, 1H), 3.16−3.10 (m, 1H); 13C NMR (101 MHz, DMSO-d6):
155.2, 140.2, 136.0, 126.6, 115.4, 111.2, 70.1, 49.0; HR-MS m/z: [M
+
+ H]+ calcd for [C10H13N2O3 ], 209.0926; found, 209.0925.
4.6.28. 1-((4-Nitrophenyl)(phenyl)amino)but-3-en-2-ol (3ag).
Purification on silica gel (petroleum ether/ethyl acetate = 10:1)
afforded compound 3ag as a yellow oil (105 mg, 74% yield), mp 94−
96 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.04−8.00 (m, 2H), 7.53−
7.49 (m, 2H), 7.40−7.33 (m, 3H), 6.75 (dd, J = 8 Hz, 2H), 5.96−
5.87 (m, 1H), 5.34 (d, J = 4 Hz, 1H), 5.31−5.26 (m, 1H), 5.12−5.09
(m, 1H), 4.29−4.25 (m, 1H), 3.87−3.73 (m, 2H); 13C NMR (101
MHz, DMSO-d6): 154.5, 145.5, 139.9, 137.4, 130.7, 128.2, 127.3,
126.1, 115.7, 113.6, 69.3, 58.5; HR-MS m/z: [M + H]+ calcd for
+
HR-MS m/z: [M + H]+ calcd for [C25H23N2O4 ], 415.1658; found,
415.1651.
4.6.35. 4-(4-Nitrophenyl)-2-phenyl-3,4-dihydro-2H-benzo[b]-
[1,4]oxazine (4a). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 4a as a yellow solid, mp 135−137
1
°C; H NMR (400 MHz, DMSO-d6): δ 8.16−8.12 (m, 2H), 7.46−
7.44 (m, 2H), 7.41−7.35 (m, 5H), 7.32−7.29 (m, 2H), 7.10−7.01
(m, 2H), 6.94−6.90 (m, 1H), 5.30 (dd, J = 8 Hz, 1H), 4.21−4.17 (m,
1H), 3.79−3.74 (m, 1H); 13C NMR (101 MHz, DMSO-d6): 152.1,
147.1, 140.4, 138.3, 128.9, 128.3, 127.0, 125.9, 124.3, 121.1, 120.3,
119.0, 118.2, 75.8, 52.4; HR-MS m/z: [M + H]+ calcd for
+
[C17H17N2O3 ], 285.1239; found, 285.1259.
4.6.29. 1-((4-Nitrophenyl)(phenyl)amino)hexan-2-ol (3ah). Puri-
fication on silica gel (petroleum ether/ethyl acetate = 10:1) afforded
1
compound 3ah as a pale yellow oil (120 mg, 76% yield); H NMR
+
[C20H17N2O3 ], 333.1239; found, 333.1231.
(400 MHz, DMSO-d6): δ 8.03−7.99 (m, 2H), 7.49 (t, J = 8 Hz, 2H),
7.40−7.33 (m, 3H), 6.77−6.73 (m, 2H), 4.97 (d, J = 4 Hz, 1H),
3.78−3.70 (m, 3H), 1.42−1.28 (m, 4H), 1.26−1.20 (m, 2H), 0.81 (t,
J = 8 Hz, 3H); 13C NMR (101 MHz, DMSO-d6): 154.7, 145.7, 137.2,
130.7, 128.2, 127.3, 126.1, 113.4, 67.9, 59.1, 34.7, 27.7, 22.7, 14.4;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01543.
■
sı
+
HR-MS m/z: [M + H]+ calcd for [C18H23N2O3 ], 315.1709; found,
315.1701.
Reaction conditions, calculation of quantity, character-
ization, 1H NMR and 13C NMR spectra of all
compounds, and Cartesian coordinates and absolute
energies for all structures involved in theoretical
calculations (PDF)
4.6.30. 1-((4-Nitrophenyl)(phenyl)amino)-3-phenoxypropan-2-ol
(3ai). Purification on silica gel (petroleum ether/ethyl acetate = 10:1)
afforded compound 3ai as a yellow solid (144 mg, 79% yield), mp
100−102 °C 1H NMR (400 MHz, DMSO-d6): δ 8.03−7.99 (m, 2H),
7.50−7.48 (m, 2H), 7.43−7.40 (m, 2H), 7.36−7.32 (m, 1H), 7.30−
7.25 (m, 2H), 6.93−6.90 (m, 3H), 6.82−6.78 (m, 2H), 5.48 (d, J = 4
Hz, 1H), 4.13−4.05 (m, 2H), 3.99−3.96 (m, 2H), 3.92−3.87 (m,
1H); 13C NMR (101 MHz, DMSO-d6): 158.8, 154.6, 145.6, 137.5,
130.8, 129.9, 128.1, 127.3, 126.0, 121.2, 115.0, 113.6, 70.3, 67.0, 55.9;
AUTHOR INFORMATION
Corresponding Author
■
+
HR-MS m/z: [M + H]+ calcd for [C21H21N2O4 ], 365.1501; found,
Chen Ma − School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, P. R. China; orcid.org/
0000-0001-8908-4658; Email: chenma@sdu.edu.cn
365.1459.
4.6.31. 1-(4-(tert-Butyl)phenoxy)-3-((4-nitrophenyl)amino)-
propan-2-ol (3aj). Purification on silica gel (petroleum ether/ethyl
acetate = 10:1) afforded compound 3aj as a yellow oil (110 mg, 64%
yield); 1H NMR (400 MHz, DMSO-d6): δ 7.99−7.95 (m, 2H), 7.36−
7.27 (m, 3H), 6.89−6.85 (m, 3H), 6.71−6.69 (m, 1H), 5.41−5.30
(m, 1H), 4.13−4.07 (m, 1H), 3.94−3.92 (m, 2H), 3.84−3.80 (m,
1H), 3.61−3.55 (m, 1H), 1.25 (s, 9H); 13C NMR (101 MHz,
DMSO-d6): 156.7, 155.3, 153.8, 143.4, 136.0, 126.5, 114.5, 111.5,
70.3, 68.0, 67.0, 34.2, 31.8; HR-MS m/z: [M + H]+ calcd for
Authors
Di Yang − School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, P. R. China
Cai-Xia Xie − School of Chemistry and Chemical Engineering,
Shandong University of Technology, Zibo 255049, P. R. China
Xiao-Tian Wu − School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, P. R. China
Luo-Ran Fei − School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, P. R. China
Lei Feng − School of Chemistry and Chemical Engineering,
Shandong University, Jinan 250100, P. R. China; orcid.org/
0000-0002-5309-1298
+
[C19H25N2O4 ], 345.1814; found, 345.1818.
4.6.32. 1-(4-(tert-Butyl)phenoxy)-3-((4-nitrophenyl) (phenyl)-
amino)propan-2-ol (3ak). Purification on silica gel (petroleum
ether/ethyl acetate = 10:1) afforded compound 3ak as a yellow oil
1
(151 mg, 72% yield); H NMR (400 MHz, DMSO-d6): δ 8.01−7.97
(m, 2H), 7.51−7.47 (m, 2H), 7.41−7.30 (m, 2H), 7.34−7.31 (m,
1H), 7.27−7.25 (m, 2H), 6.84−6.77 (m, 4H), 5.45 (d, J = 4 Hz, 1H),
4.10−4.08 (m, 1H), 3.96−3.94 (m, 1H), 3.90−3.84 (m, 1H), 1,24 (s,
9H); 13C NMR (101 MHz, DMSO-d6): 161.4, 159.2, 150.4, 148.1,
142.2, 135.4, 132.8, 132.0, 131.2, 130.7, 119.3, 118.3, 75.2, 71.8, 60.7,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01543
+
39.0, 36.5; HR-MS m/z: [M + H]+ calcd for [C25H29N2O4 ],
Notes
421.2127; found, 421.2129.
The authors declare no competing financial interest.
I
https://dx.doi.org/10.1021/acs.joc.0c01543
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(11) Nishiyama, H.; Sakaguchi, H.; Nakamura, T.; Horihata, M.;
Kondo, M.; Itoh, K. Chiral and C2-Symmetrical Bis-
(oxazolinylpyridine)rhodium(III) Complexes: Effective Catalysts for
Asymmetric Hydrosilylation of Ketones. Organometallics 1989, 8,
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ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation of China
(no. 21572117) and the Shandong Key Research Program
(nos. 2019JZZY021015 and 2019GHY112053) for their
financial support. We are also grateful to the Analytical Center
for Structural Constituent and Physical Property of Core
Facilities Sharing Platform, Shandong University for their
technology and service support.
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