Copper-Catalyzed Intermolecular Hydroamination of Arylamines or Aza-Heterocycles with Nitrostyrene Derivatives

Article abstract of DOI:10.1002/adsc.201801582

A new copper-catalyzed protocol for the intermolecular anti-Markovnikov addition of arylamines or heterocycles to terminal and unsymmetrical 1,2-disubstituted vinylarenes has been developed. The direct hydroamination is catalyzed by a readily available N-

Full text of DOI:10.1002/adsc.201801582

Title: Copper-Catalyzed Intermolecular Hydroamination of Arylamines
or Aza-Heterocycles with Nitrostyrene Derivatives
Authors: Subin Park, Seongil Kang, and Yunmi Lee
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801582
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Intermolecular Hydroamination of
Arylamines or Aza-Heterocycles with Nitrostyrene Derivatives
Subin Park,a Seongil Kanga and Yunmi Leea*
a
Department of Chemistry, Kwangwoon University, Seoul 01897, Republic of Korea
E-mail: ymlee@kw.ac.kr
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A new copper-catalyzed protocol for the intermolecular anti-Markovnikov addition of arylamines or heterocycles
to terminal and unsymmetrical 1,2-disubstituted vinylarenes has been developed. The direct hydroamination is catalyzed by a
readily available N-heterocyclic carbene-based copper complex and KOt-Bu, and the use of MeOH as an additive enhances
the reactivity. The method provides a broad range of new and versatile amine compounds bearing various functional groups
in good to excellent yields.
Keywords: Copper catalysis; hydroamination; anti-Markovnikov selectivity; vinylarenes; N-heterocyclic carbene
reported,[3] and general approaches for accessing anti-
Markovnikov amine products remain rare. The
regioselectivity of Cu-catalyzed hydroaminations is
Introduction
Hydroamination of a carbon-carbon double bond known to be influenced by the catalytic system. For
or triple bond is one of the most atom efficient and example, Hii and coworkers explored the first
simple routes for synthesizing various amines.[1] Due intermolecular hydroamination of vinylarenes with
to the significance of nitrogen-containing compounds arylsulfonamides promoted by copper(II) triflate and a
in organic synthesis and medicinal chemistry, a phosphine ligand.[3c] The reaction was thought to be
number of efficient and selective catalytic systems for catalyzed by an acidic proton generated from the
the hydroamination of unsaturated compounds with copper triflate system, resulting in Markovnikov
nucleophilic
amines
such
amides,
as
carbamates,
alkylamines, selectivity (Scheme 1a).[7] On the other hand, Gunnoe
and and coworkers described the anti-Markovnikov
(hetero)arylamines,
sulfonamides have been intensively studied. In addition of aniline to styrene derivatives by using a
particular, early- and late-transition metal catalysts well-defined copper-amido catalyst[8] complexed with
have played an important role in promoting these an N-heterocyclic carbene (NHC) ligand.[3a] Although
transformations and controlling the chemo-, regio- and these two reported reactions are efficient and highly
stereoselectivities.[2]
Among the
regioselective, the methods still suffer from some
metal-catalyzed limitations: the NHC-Cu catalyst requires a multistep
numerous
hydroamination reactions, the copper-catalyzed direct synthesis, the substrate scope is limited to only
addition of amines to alkenes is an attractive and terminal styrenes, and the amine sources are limited to
practical method for the synthesis of aliphatic amines compounds such as tosyl or nosyl amides, aniline and
as it uses a relatively inexpensive, environmentally benzylamines. Therefore, the development of a new
benign and easy-to-handle copper catalyst and easily copper-catalyzed system with a broader substrate
accessible alkene substrates. In the past decade, a scope and improved operational simplicity is of
variety of copper catalysts have been utilized for practical and synthetic interest.
intramolecular and intermolecular hydroamination
As an alternative approach regarding the Cu-
reactions of alkenes,[3],[4] alkynes,[5] and allenes.[6] catalyzed amination reaction with unsymmetrical
Compared to the catalytic processes related to alkenes, Miura, Buchwald and coworkers[9]
intramolecular hydroaminations, the corresponding independently pioneered copper-hydride-catalyzed
intermolecular reactions have been less studied since formal
hydroaminations
using
O-
controlling the regioselectivity (Markovnikov vs. anti- benzoylhydroxylamines as electrophilic amine sources
Markovnikov selectivity) is challenging. To date, only and hydrosilanes as copper hydride sources (Scheme
a few examples of Cu-catalyzed direct intermolecular 1b).[10] This methodology allows the synthesis of
hydroaminations of unsymmetrical alkenes have been
1
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
Markovnikov amine products from vinylarenes with IPrCuCl species were more efficient (entries 3-6).
high regio- and enantioselectivity.[11]
Under these reaction conditions using imidazolium
In our previous studies, we demonstrated an aza- salts L1-L4, it was found that 11-49% of nitrostyrene
Michael addition of (hetero)aryl amines to α,β- 1a was decomposed presumably owing to
unsaturated carbonyls catalyzed by a copper complex polymerization. As the concentration of the reaction
generated in situ from the reaction of a phosphine or an solution increased, the amination proceeded more
imidazolinium salt with CuCl and KOt-Bu under mild effectively (entries 7-8). Complete conversion was
conditions.[12] As a continuation of our studies on the observed within 7 hours in the presence of 5 mol %
synthesis of amine compounds from alkenes using a IPrCuCl and the reaction generated only anti-
copper catalyst, we report herein an efficient and mild Markovnikov product 3aa (>98% yield, entry 8).
Cu-catalyzed
intermolecular
anti-Markovnikov When the amination was performed under non-inert
hydroamination of vinylarenes with arylamines or conditions, the efficiency was significantly reduced,
heterocycles (Scheme 1c). A readily prepared NHC- affording the desired amine 3aa in 41% yield along
CuCl species in the presence of KOt-Bu and MeOH with decomposition of 37% of nitrostyrene 1a (entry
promoted the addition of the amine to various mono- 9). As illustrated in entries 10-12 of Table 1, the NHC
and 1,2-disubstituted vinylarenes, providing various ligand, CuCl, and KOt-Bu were all essential for
novel arylamine and azole products in good to promoting the addition of the amine to nitrostyrene 1a.
excellent yields.
Based on these results, we assumed that the NHC-
copper amido complex A in Scheme 1,[8],[13] the key
catalytic species, might be generated from the reaction
of the in situ-formed NHC-CuOt-Bu species with
aniline. The copper-amido species A was selectively
inserted into nitrostyrene 1a to form a C-N bond at the
terminal carbon of the double bond, creating a C-Cu
bond on the internal carbon. Then, the alkylcopper
intermediate reacted with aniline to regenerate the Cu-
amido species with concomitant release of the
aminated product. As suggested by Sawamura and
coworkers,[4a] at this stage, the importance of methanol
can be explained by the assumption that MeOH reacts
more efficiently with the alkylcopper intermediate than
with the aniline substrate, facilitating the regeneration
of the catalytic species.
Table 1. Optimization of hydroamination of 4-
methoxyaniline (2a) to 4-nitrostyrene[a]
Scheme 1. Cu-catalyzed regioselective hydroamination
reactions
Cu catalyst
(mol %)
KOt-Bu
(mol %)
MeOH
(equiv)
conc.
(M)
time
(h)
conv
yield
entry
Results and Discussion
(%)[b]
(%)[b]
1
2
IPrCuCl (10)
IPrCuCl (10)
L1 + CuCl (10)
L2 + CuCl (10)
L3 + CuCl (10)
L4 + CuCl (10)
IPrCuCl (5)
IPrCuCl (5)
IPrCuCl (5)
IPrCuCl (5)
CuCl (5)
10
10
20
20
20
20
5
0
1
1
1
1
1
1
1
1
0
0
0
0.2
0.2
0.2
0.2
0.2
0.2
0.6
1.0
1.0
1.0
1.0
1.0
14
14
14
14
14
14
7
30
68
64
85
58
68
81
>98
78
<2
<2
58
30
63
53
36
32
43
80
>98
41
<2
<2
<2
We commenced our studies with 4-nitrostyrene
(1a) and 4-methoxyaniline (2a) as the model substrates,
as shown in Table 1. Guided by our previous studies
on aza-Michael reactions,[12] we initially attempted the
addition of amine 2a to 1a in the presence of IPrCuCl
and KOt-Bu in toluene at ambient temperature.
However, the reaction did not proceed (<2% of 3aa).
When the reaction temperature was increased to 80 °C,
desired aminated product 3aa was obtained in 30%
yield with >98% anti-Markovnikov selectivity (entry
1). The result shown in entry 2 indicated that the use of
MeOH as an additive promoted the amination and
improved the yield of 3aa (63%). It is noteworthy that
previous work on Cu-catalyzed intramolecular
hydroamination of aminoalkenes by Sawamura and
coworkers has shown that MeOH as a protic solvent
plays an significant role in enhancing yield due to the
rapid protonation of the copper-carbon bond generated
in situ.[4a] To optimize the catalytic system, various
imidazolium salts L1-L4 as NHC precursors were
examined, but reaction conditions using a preformed
3
4
5
6
7
8
5
7
9[c]
10
11
12
5
7
0
7
5
7
no
5
7
[a]Reaction conditions: nitrostyrene 1a (0.2 mmol), aniline
2a (0.24 mmol), toluene (0.2-1.0 M) under N2. 10 mol % of
L1-L4 was used. [b]Determined by H NMR analysis using
1
1,3,5-trimethoxybenzene as an internal standard. [c]The
reaction was carried out under open air conditions.
2
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
[a]Reaction conditions: nitrostyrene 1a (0.40 mmol), amine 2
(0.48 mmol), MeOH (0.40 mmol), IPrCuCl (5 mol %),
KOt-Bu (5 mol %), toluene (1.0 M) under N2. [b]Yields of
the isolated products. The reaction time was 7 h for 3aa-3ag
and 12 h for 3ah-3aq.
With the optimal conditions in hand, we explored
the generality of the amination. A range of arylamines
and heterocycles were efficiently and selectively added
to nitrostyrene 1a with a catalyst loading of 5 mol %
and 1 equiv MeOH, as depicted in Table 2. The Cu-
catalyzed hydroamination reactions with aniline
derivatives bearing methoxy, methyl, or halogen
groups at the para, meta, and ortho positions
proceeded well, affording corresponding amine
products 3aa-3aj in good to excellent yields (up to
>98%). Notably, sterically demanding anilines 2h-2j
with substituents at the ortho position required a longer
reaction time (7 h vs. 12 h). Substrates with
heterocyclic substituents including imidazole 2k,
methyl imidazoles 2l-2m, benzimidazoles 2n-2o,
pyrazole 2p, and triazole 2q, which have served as
valuable building blocks for biologically active
molecules, were also successfully transformed to the
desired amines (3ak-3aq) in 88 to >98% yields.
Notably, 4-methyl-1H-imidazole (2m) was selectively
added to nitrostyrene 1a, affording only 4-
methylimidazole product 3am (vs. 5-methylimidazole)
presumably due to steric hindrance.[14] However, these
catalytic reaction conditions were not effective in the
hydroamination with halogen-substituted styrenes.
When the catalytic reaction was carried out with p-
chlorostyrene or p-bromostyrene using 2a, the reaction
did not proceed (2% conv).
Next, we investigated the addition of amines to
challenging unsymmetrical 1,2-disubstituted alkenes,
which are rarely studied as substrates for Cu-catalyzed
intermolecular hydroaminations, as illustrated in Table
3. To our delight, when p-nitro-(E)-β-ethyl styrene (4a)
was treated with 4-methoxyaniline under the
established reaction conditions, only desired
regioisomer 5aa was produced, albeit less efficiently
(81% yield of 5aa vs. >98% yield of 3aa) and more
slowly (12 h vs. 7 h) compared with the addition to
nitrostyrene 1a. Various anilines with fluoro, chloro,
and bromo substituents at the para or meta positions of
the phenyl group were employed in this catalytic
reaction, and desired amines 5ab-5af were obtained in
62-88% yields. In addition, the Cu-catalyzed reactions
of a variety of heterocycles including imidazoles,
pyrazole, and triazole with β-ethyl styrene 4a provided
corresponding amines 5ak-5aq in moderate to good
yields (60-92%). However, the reaction with a
sterically demanding ortho-nitrostyrene (4b) was not
effective using these catalytic reaction conditions,
affording amine product 5ba in only 23% yield.
Table 3. Cu-catalyzed hydroamination of 4a with anilines
and azoles [a],[b]
Table 2. Cu-catalyzed hydroamination of 4-nitrostyrene
with various anilines and azoles[a],[b]
[a]Reaction conditions: β-ethyl styrene 4a (0.40 mmol),
amine 2 (0.48 mmol), MeOH (0.40 mmol), IPrCuCl (5-7
mol %), KOt-Bu (5-7 mol %), toluene (1.0 M) under N2.
[b]Yields of the isolated products.
3
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
Encouraged by the successful Cu-catalyzed
regioselective hydroamination of unsymmetrical
alkene 4 with anilines and heterocycles, we extended
the substrate scope to a variety of β-substituted styrene
derivatives 6, as shown in Table 4. All transformations
were highly regioselective in that 4-methylimidazole
(2m) was added at the β-position of vinylarenes 6,
providing
only
the
anti-Markovnikov
4-
methylimidazole products (7am-7km). Alkenes 6a-6d,
with p-nitrophenyl and various alkyl substituents such
as propyl, pentyl, isopropyl, and phenethyl groups,
were successfully converted to corresponding amine
products 7am-7dm in 71%-83% yields. This copper-
catalyzed reaction is tolerant of functional groups such
as a chloro, benzyl ether, and alkene substituents on the
substrates, affording new and versatile functionalized
amine products 7em-7im in 70-87% yields. When p-
nitro-(E)-β-ethyl styrenes 6j-6k bearing a chloro or a
fluoro group at the ortho position of the phenyl moiety
were subjected to the catalytic reaction conditions,
aminations with 2m also proceeded well and gave
desired amines 7jm-7km, which could be utilized for
further organic transformations, in good yields (82-
85%).
Scheme 2. Synthesis of indoline 9
Conclusion
We have developed an efficient and anti-
Markovnikov-selective copper-catalyzed intermole-
cular hydroamination of nitrostyrene derivatives with
various arylamines and heterocycles. A readily
accessible NHC-based copper catalyst combined with
KOt-Bu plays a key role in promoting the addition of
relatively less nucleophilic arylamines or heterocycles
to monosubstituted and even unsymmetrical 1,2-
disubstituted vinylarenes with high anti-Markovnikov
selectivity (>99:1). The catalytic process enables the
synthesis of new and synthetically versatile amine
compounds, including aniline, imidazole, pyrazole,
and triazole derivatives, in good to excellent yields.
The use of inexpensive and easy-to-handle copper
catalysts, the good functional group tolerance, the high
efficiency, the excellent regioselectivity, the broad
substrate scope and the operational simplicity make the
developed methodology attractive and practical.
Further studies of the catalytic addition of amines to
other types of alkenes are ongoing in our laboratory.
Table 4. Cu-catalyzed hydroamination of various β-
substituted styrenes with 2m[a],[b]
Experimental Section
General: Infrared (IR) spectra were recorded on a ABB
MB3000 FT-IR spectrophotometer, max in cm-1. Bands are
1
characterized as strong (s), medium (m), and weak (w). H
NMR spectra were recorded a JEOL JNM-AL400 (400
MHz) spectrometer. Chemical shifts are reported in ppm
from tetramethylsilane, with the solvent resonance as the
internal standard (CDCl3: δ 7.27 ppm). Data are reported as
follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, quint = quintet, m = multiplet),
coupling constants (Hz), and integration. 13C NMR spectra
were recorded on a JEOL JNM-AL400 (100 MHz)
spectrometer with complete proton decoupling. Chemical
shifts are reported in ppm from tetramethylsilane with the
solvent resonance as the internal standard (CDCl3: δ 77.00
ppm). High-resolution mass spectra (HRMS) were
[a]Reaction conditions: styrene
6
(0.40 mmol),
methylimidazole 2m (0.48 mmol), MeOH (0.40 mmol),
IPrCuCl (7 mol %), KOt-Bu (7 mol %), toluene (1.0 M)
under N2. [b]Yields of the isolated products. [c]5 mol % of performed at the Korea Basic Science Institute for technical
assistance using an electrospray ionization (ESI) time-of-
flight mass spectrometer. Unless otherwise noted, all
reactions were carried out with distilled solvents under an
atmosphere of dry N2 in oven-dried (130 °C) glassware.
Toluene and 1,4-dioxane were purified by distillation from
sodium benzophenone ketyl immediately prior to use unless
otherwise specified. Acetonitrile was purified by distillation
from CaH2 immediately prior to use. Methyl alcohol was
purified by distillation from sodium immediately prior to use.
All work-up and purification procedures were carried out
with reagent grade solvents in air. An IPrCuCl complex was
IPrCuCl was used.
The utility of the amine products obtained from
newly developed hydroamination was
our
demonstrated in the synthesis of indoline 9, as shown
in Scheme 2.[15] The Cu-catalyzed hydroamination of
β-substituted styrene 6j (with 2-chloro and 4-nitro
substituents on the phenyl group) with p-anisidine (2a)
produced amine 8 in 78% yield, which underwent a Pd-
catalyzed cyclization to afford indoline 9 in 81% yield.
synthesized
according to
reported
experimental
procedures.[16] A variety of vinylarenes were prepared
according to reported experimental procedures.[17]
4
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
Representative experimental procedure for the synthesis HRMS (EI) m/z: [M+H]+ Calcd for C14H14FN2O2 261.1039,
of NO2-substituted styrenes
Found 261.1041.
(E)-1-(But-1-en-1-yl)-4-nitrobenzene
(4a).
4- 4-Chloro-N-(4-nitrophenethyl)aniline (3ac). Compound
Nitrobenzaldehyde (1.06 g, 6.42 mmol), butyraldehyde 3ac was synthesized from 4-chloroaniline (2c, 61.2 mg,
(0.720 mL, 8.03 mmol), malononitrile (1.06 g, 16.1 mmol) 0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
and acetonitrile (40 mL) were added into a 100 mL round- mmol) in 95% yield (105 mg, 0.380 mmol) as a light yellow
bottom flask, and then acetic acid (0.689 mL, 12.0 mmol) solid. The crude product was purified using silica gel column
was added. The reaction was allowed to stir for 10 min, and chromatography (EtOAc:hexanes = 1:3). This compound
then ammonium acetate (0.619 mg, 8.03 mmol) was added has been previously reported and spectra data match
to the mixture, which was allowed to stir at 80 °C for an described.[18] 1H NMR (CDCl3, 400 MHz): δ 8.17 (d, J = 8.7
additional 5 h. After that time, the reaction solution was Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.9 Hz, 2H),
allowed to cool to room temperature and filtered to remove 6.54 (d, J = 8.9 Hz, 2H), 3.74 (br s, 1H), 3.44 (t, J = 6.8 Hz,
the precipitate. The filtrate was concentrated in vacuo and 2H) 3.02 (t, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz):
partitioned between water (50 mL) and ethyl acetate (50 mL δ 147.0, 146.7, 146.0, 129.6, 129.1, 123.7, 122.2, 114.0, 44.5,
x 3). The organic layers were combined, dried over MgSO4, 35.1.
filtered and concentrated. The resulting residue was purified
using silica gel column chromatography (EtOAc:hexanes =
4-Bromo-N-(4-nitrophenethyl)aniline (3ad). Compound
1:10) to afford the desired (E)-1-(but-1-en-1-yl)-4-
3ad was synthesized from 4-bromoaniline (2d, 82.6 mg,
nitrobenzene (4a, 600 mg, 3.39 mmol, 53% yield) as light-
0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
yellow oil. This compound has been previously reported and
mmol) in 82% yield (105 mg, 0.328 mmol) as a light yellow
[17]
spectra data match described.
1H NMR (CDCl3, 400
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:3). mp 70-71 °C; IR
(neat): 3394 (m), 3078 (w), 2924 (m), 1589 (m), 1504 (s),
1404 (m), 1342 (s), 1296 (m), 1180 (m), 1111 (m), 849 (m),
818 (s), 725 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.19
(d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.7
MHz): δ 8.11 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H),
6.50-6.38 (m, 2H), 2.27 (quint, J = 7.5 Hz, 2H), 1.10 (t, J =
7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 146.2, 144.4,
137.8, 127.0, 126.2, 123.8, 26.1, 13.0.
Representative experimental procedure for Cu- Hz, 2H), 6.50 (d, J = 8.7 Hz, 2H), 3.70 (br s, 1H), 3.44 (t, J
catalyzed hydroamination of vinylarenes
= 6.9 Hz, 2H), 3.02 (t, J = 6.9 Hz, 2H); 13C NMR (CDCl3,
100 MHz): δ 147.0, 146.7, 146.4, 132.0, 129.6, 123.7, 114.4,
109.2, 44.4, 35.1; HRMS (ESI) m/z: [M+H]+ Calcd for
C14H14BrN2O2 321.0239, Found 321.0237.
4-Methoxyaniline (59.1 mg, 0.480 mmol), IPrCuCl (9.63
mg, 0.0200 mmol) and KOt-Bu (2.24 mg, 0.0200 mmol)
were added to a vial (4 mL) charged with a magnetic bar in
a glove box. The vial was sealed with a cap (phenolic open 3-Chloro-N-(4-nitrophenethyl)aniline (3ae). Compound
top cap with gray PTFE/silicone) and removed from the 3ae was synthesized from 3-chloroaniline (2e, 50.7 µL,
glove box. Then, the vial was purged with N2 gas for 5 min 0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
and toluene (0.2 mL) was added. After premixing for 30 min, mmol) in 86% yield (95.2 mg, 0.344 mmol) as a light yellow
a solution of (E)-1-(but-1-en-1-yl)-4-nitrobenzene (70.9 mg, solid. The crude product was purified using silica gel column
0.400 mmol) in toluene (0.2 mL) was added to the mixture, chromatography (EtOAc:hexanes = 1:3). mp 71-72 °C; IR
which was allowed to stir at 80 °C for 12 h. After that time, (neat): 3310 (m), 3070 (w), 2924 (m), 1597 (s), 1512 (m),
the reaction solution was quenched by adding saturated 1342 (s), 1265 (m), 1165 (s), 1088 (m), 849 (m), 741 (s) cm-
aqueous NH4Cl (1 mL) and washed with EtOAc (3 mL x 3). 1; 1H NMR (CDCl3, 400 MHz): δ 8.18 (d, J = 8.8 Hz, 2H),
The organic layers were combined, dried over MgSO4, 7.38 (d, J = 8.8 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 6.70 (dd, J
filtered, and concentrated in vacuo. The crude product was = 8.0, 1.5 Hz, 1H), 6.59 (dd, J = 1.5, 1.5 Hz, 1H), 6.48 (dd,
purified using silica gel column chromatography J = 8.0, 1.5 Hz, 1H), 3.79 (br s, 1H), 3.45 (t, J = 6.7 Hz, 2H)
(EtOAc:hexanes = 1:3) to afford the desired product, 4- 3.03 (t, J = 6.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ
methoxy-N-(1-(4-nitrophenyl)butan-2-yl)aniline (5aa, 97.3 148.6, 147.0, 146.8, 135.2, 130.4, 129.7, 123.9, 117.7, 112.4,
mg, 0.324 mmol, 81% yield), as a yellow solid.
111.3, 44.2, 35.1; HRMS (ESI) m/z: [M+H]+ Calcd for
C14H14ClN2O2 277.0744, Found 277.0744.
4-Methoxy-N-(4-nitrophenethyl)aniline
(3aa).
Compound 3aa was synthesized from 4-methoxyaniline (2a, 3-Bromo-N-(4-nitrophenethyl)aniline (3af). Compound
59.1 mg, 0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 3af was synthesized from 3-bromoaniline (2f, 82.6 mg,
µL, 0.400 mmol) in 99% yield (108 mg, 0.396 mmol) as a 0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
yellow solid. The crude product was purified using silica gel mmol) in 98% yield (126 mg, 0.392 mmol) as a light yellow
column chromatography (EtOAc:hexanes = 1:3). This solid. The crude product was purified using silica gel column
compound has been previously reported and spectra data chromatography (EtOAc:hexanes = 1:3). mp 77-78 °C; IR
match described.[18] 1H NMR (CDCl3, 400 MHz): δ 8.17 (d, (neat): 3402 (m), 3078 (w), 2924 (m), 1589 (s), 1512 (s),
J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1504 (s), 1404 (m), 1335 (s), 1304 (m), 1173 (m), 1111 (m),
1
2H), 6.61 (d, J = 8.8 Hz, 2H), 3.76 (s, 3H), 3.45 (br s, 1H), 1060 (m), 849 (s), 764 (m) cm-1; H NMR (CDCl3, 400
3.42 (t, J = 6.9 Hz, 2H), 3.01 (t, J = 6.9 Hz, 2H); 13C NMR MHz): δ 8.17 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H),
(CDCl3, 100 MHz): δ 152.4, 147.5, 146.7, 141.6, 129.6, 7.03 (t, J = 8.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.74 (s,
123.7, 114.9, 114.3, 55.6, 45.4, 35.4.
1H), 6.52 (dd, J = 8.2, 1.5 Hz, 1H), 3.80 (br s, 1H), 3.44 (t,
J = 6.8 Hz, 2H) 3.02 (t, J = 6.8 Hz, 2H); 13C NMR (CDCl3,
100 MHz): δ 148.8, 147.0, 146.8, 130.6, 129.6, 123.8, 123.4,
120.4, 115.3, 111.6, 44.1, 35.1; HRMS (ESI) m/z: [M+H]+
Calcd for C14H14BrN2O2 321.0239, Found 321.0240.
4-Fluoro-N-(4-nitrophenethyl)aniline (3ab). Compound
3ab was synthesized from 4-fluoroaniline (2b, 45.5 µL,
0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
mmol) in 94% yield (97.9 mg, 0.376 mmol) as a light yellow
solid. The crude product was purified using silica gel column 3-Iodo-N-(4-nitrophenethyl)aniline (3ag). Compound 3ag
chromatography (EtOAc:hexanes = 1:3). mp 66-67 °C; IR was synthesized from 3-iodoaniline (2g, 105 mg, 0.480
(neat): 3364 (m), 3078 (w), 2924 (m), 1605 (m), 1504 (s), mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
1404 (m), 1342 (s), 1281 (m), 1211 (s), 1111 (m), 825 (s), mmol) in 73% yield (108 mg, 0.293 mmol) as a light yellow
1
748 (m) cm-1; H NMR (CDCl3, 400 MHz): δ 8.20 (d, J = solid. The crude product was purified using silica gel column
8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 6.95 (t, J = 8.7 Hz, chromatography (EtOAc:hexanes = 1:3). mp 103-104 °C;
2H), 6.62-6.58 (m, 2H), 3.67 (br s, 1H), 3.47 (t, J = 6.8 Hz, IR (neat): 3394 (m), 3070 (w), 2924 (m), 1582 (s), 1512 (s),
2H) 3.06 (t, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): 1474 (m), 1335 (s), 1234 (m), 1168 (m), 1080 (m), 1034 (m),
δ 147.3, 146.7, 145.6, 143.9, 129.6, 123.7 (JC-F = 41.4 Hz), 980 (m), 849 (s), 764 (m) cm-1; 1H NMR (CDCl3, 400 MHz):
115.7 (JC-F = 22.3 Hz), 113.7 (JC-F = 7.5 Hz), 45.0, 35.2; δ 8.17 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.05 (d,
J = 7.7 Hz, 1H), 6.95 (s, 1H), 6.90 (t, J = 7.7 Hz, 1H), 6.56
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801582
Advanced Synthesis & Catalysis
(dt, J = 7.7, 1.2 Hz, 1H), 3.71 (br s, 1H), 3.43 (t, J = 6.8 Hz, mg, 0.360 mmol) as a light yellow solid. The crude product
2H), 3.02 (t, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): was purified using silica gel column chromatography (10%
δ 148.6, 146.8, 130.8, 129.6, 126.7, 123.9, 121.3, 112.3, 95.3, MeOH in EtOAc). mp 58-59°C; IR (neat): 3094 (m), 2924
44.2, 35.2; HRMS (ESI) m/z: [M+H]+ Calcd for (m), 2839 (m), 1936 (w), 1597 (m), 1504 (s), 1427 (m), 1335
C14H14IN2O2 369.0100, Found 369.0097.
(s), 1288 (m), 1149 (m), 1111 (m), 1034 (m), 840 (m), 733
(s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.13 (d, J = 8.5 Hz,
2H), 7.17 (d, J = 8.5 Hz, 2H), 6.90 (s, 1H), 6.71 (s, 1H), 4.12
(t, J = 6.8 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.13 (s, 3H);
13C NMR (CDCl3, 100 MHz): δ 147.1, 145.0, 144.4, 129.6,
127.6, 123.9, 118.7, 46.7, 37.2, 12.8; HRMS (ESI) m/z:
[M+H]+ Calcd for C12H14N3O2 232.1086, Found 232.1091.
2-Methyl-N-(4-nitrophenethyl)aniline (3ah). Compound
3ah was synthesized from o-toluidine (2h, 51.0 µL, 0.480
mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
mmol) in 99% yield (101.5 mg, 0.396 mmol) as a light
yellow solid. The crude product was purified using silica gel
column chromatography (EtOAc:hexanes = 1:3). mp 75-
76 °C; IR (neat): 3371 (m), 3063 (w), 2932 (m), 1597 (s), 4-Methyl-1-(4-nitrophenethyl)-1H-imidazole
(3am).
1512 (s), 1466 (m), 1342 (s), 1281 (m), 1149 (m), 1111 (m), Compound 3am was synthesized from 4-methyl-1H-
1049 (m), 849 (s), 748 (s), 702 (m) cm-1; 1H NMR (CDCl3, imidazole (2m, 39.4 mg, 0.480 mmol) and 1-nitro-4-
400 MHz): δ 8.20 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, vinylbenzene (1a, 51.0 µL, 0.400 mmol) in 92% yield (85.1
2H), 7.20 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H), 6.75- mg, 0.368 mmol) as an orange solid. The crude product was
6.70 (m, 2H), 3.58 (br s, 1H), 3.54 (t, J = 7.0 Hz, 2H), 3.10 purified using silica gel column chromatography (10%
(t, J = 7.0 Hz, 2H), 2.09 (s, 3H); 13C NMR (CDCl3, 100 MeOH in EtOAc). mp 52-53°C; IR (neat): 3094 (m), 2916
MHz): δ 147.4, 146.7, 145.3, 130.3, 129.6, 127.2, 123.7, (m), 2854 (m), 1605 (m), 1512 (s), 1450 (m), 1342 (s), 1227
122.0, 117.3, 109.6, 44.2, 35.1, 17.2; HRMS (ESI) m/z: (m), 1165 (m), 1111 (m), 1034 (m), 856 (m), 818 (m), 756
[M+H]+ Calcd for C15H17N2O2 257.1290, Found 257.1294.
(m) cm-1; 1H NMR (CDCl3,400 MHz): δ 8.16 (d, J = 8.4 Hz,
2H), 7.22-7.19 (m, 3H), 6.55 (s, 1H), 4.15 (t, J = 6.8 Hz, 2H),
3.14 (t, J = 6.8 Hz, 2H), 2.21 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ 147.2, 145.1, 139.0, 136.1, 129.5, 124.0, 115.0,
47.6, 37.6, 13.7; HRMS (ESI) m/z: [M+H]+ Calcd for
C12H14N3O2 232.1086, Found 232.1096.
2-Fluoro-N-(4-nitrophenethyl)aniline (3ai). Compound
3ai was synthesized from 2-fluoroaniline (2i, 44.7 µL, 0.480
mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
mmol) in 92% yield (95.8 mg, 0.368 mmol) as a light yellow
solid. The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:3). mp 73-74 °C; IR 1-(4-Nitrophenethyl)-1H-benzo[d]imidazole
(neat): 3379 (m), 3070 (w), 2924 (m), 1605 (m), 1512 (s), Compound 3an was synthesized
(3an).
from
1H-
1443 (m), 1335 (s), 1250 (m), 1188 (m), 1111 (m), 1034 (m), benzo[d]imidazole (2n, 56.7 mg, 0.480 mmol) and 1-nitro-
918 (m), 849 (m), 741 (s), 702 (m) cm-1; 1H NMR (CDCl3, 4-vinylbenzene (1a, 51.0 µL, 0.400 mmol) in 95% yield
400 MHz): δ 8.20 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, (102 mg, 0.380 mmol) as an ivory solid. The crude product
2H), 7.05-6-97 (m, 2H), 6.76-6.66 (m, 2H), 3.95 (br s, 1H), was purified using silica gel column chromatography (2%
3.50 (t, J = 7.0 Hz, 2H), 3.05 (t, J = 7.0 Hz, 2H); 13C NMR MeOH in EtOAc). mp 138-139 °C; IR (neat): 3078 (m),
(CDCl3, 100 MHz): δ 151.6 (JC-F = 239 Hz), 146.9, 146.8, 2924 (m), 2839 (m), 1597 (m), 1512 (s), 1404 (m), 1335 (s),
135.9 (JC-F = 11.6 Hz), 129.6, 124.7 (JC-F = 3.9 Hz), 123.9, 1281 (m), 1219 (m), 1111 (m), 1034 (m), 856 (m), 825 (w),
117.2 (JC-F = 6.8 Hz), 114.7 (JC-F = 18.3 Hz), 112.1 (JC-F
=
741 (s), 694 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.05
2.9 Hz), 44.2, 35.5; HRMS (ESI) m/z: [M+H]+ Calcd for (d, J = 8.3 Hz, 2H), 7.78 (br s, 1H), 7.56 (s, 1H), 7.33-7.27
C14H14FN2O2 261.1039, Found 261.1036.
(m, 3H), 7.10 (d, J = 8.3 Hz, 2H), 4.43 (t, J = 6.7 Hz, 2H),
3.23 (t, J = 6.7 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ
146.9, 145.1, 143.8, 142.8, 133.2, 129.5, 123.9, 123.1, 122.3,
120.5, 109.3, 45.7, 35.7; HRMS (ESI) m/z: [M+H]+ Calcd
for C15H14N3O2 268.1086, Found 268.1083.
2-Chloro-N-(4-nitrophenethyl)aniline (3aj). Compound
3aj was synthesized from 2-chloroaniline (2j, 50.5 µL,
0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
mmol) in 91% yield (101 mg, 0.366 mmol) as a light yellow
solid. The crude product was purified using silica gel column 2-Methyl-1-(4-nitrophenethyl)-1H-benzo[d]imidazole
chromatography (EtOAc:hexanes = 1:3). mp 84-85 °C; IR (3ao). Compound 3ao was synthesized from 2-methyl-1H-
(neat): 3394 (m), 3063 (w), 2924 (m), 1597 (m), 1512 (s), benzo[d]imidazole (2o, 63.4 mg, 0.480 mmol) and 1-nitro-
1458 (m), 1342 (s), 1296 (m), 1180 (m), 1095 (m), 1026 (m), 4-vinylbenzene (1a, 51.0 µL, 0.400 mmol) in 88% yield
926 (w), 849 (m), 741 (s) cm-1; 1H NMR (CDCl3, 400 MHz): (99.0 mg, 0.352 mmol) as an ivory solid. The crude product
δ 8.19 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.27 (dd, was purified using silica gel column chromatography (5%
J = 7.8, 1.4 Hz, 1H), 7.19 (td, J = 7.8, 1.2 Hz, 1H), 6.66-6.72 MeOH in EtOAc). mp 139-140 °C; IR (neat): 3086 (m),
(m, 2H), 4.35 (br s, 1H), 3.52 (t, J = 7.0 Hz, 2H), 3.06 (t, J 2916 (m), 2847 (m), 1605 (m), 1512 (s), 1458 (m), 1404 (m),
= 7.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 146.9, 146.8, 1335 (s), 1281 (m), 1149 (m), 1111 (m), 1011 (m), 841 (m),
1
143.3, 129.7, 129.3, 127.9, 123.9, 119.4, 117.7, 111.2, 44.2, 748 (m) cm-1; H NMR (CDCl3, 400 MHz): δ 8.11 (d, J =
35.1; HRMS (ESI) m/z: [M+H]+ Calcd for C14H14ClN2O2 8.3 Hz, 2H), 7.73 (d, J = 5.1 Hz, 1H), 7.27 (br s, 3H), 7.13
277.0744, Found 277.0748.
(d, J = 8.3 Hz, 2H), 4.38 (t, J = 6.7 Hz, 2H), 3.23 (t, J = 6.7
Hz, 2H), 2.25 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 151.3,
146.9, 145.2, 142.5, 134.3, 129.7, 123.8, 122.2, 122.0, 119.2,
108.8, 44.4, 35.2, 13.3; HRMS (ESI) m/z: [M+H]+ Calcd for
C16H16N3O2 282.1243, Found 282.1254.
1-(4-Nitrophenethyl)-1H-imidazole (3ak). Compound 3ak
was synthesized from 1H-imidazole (2k, 32.7 mg, 0.480
mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
mmol) in 93% yield (80.8 mg, 0.372 mmol) as a light yellow
solid. The crude product was purified using silica gel column 1-(4-Nitrophenethyl)-1H-pyrazole (3ap). Compound 3ap
chromatography (10% MeOH in EtOAc). mp 61-62 °C; IR was synthesized from 1H-pyrazole (2p, 32.7 mg, 0.480
(neat): 3109 (m), 2970 (m), 2924 (m), 1605 (m), 1504 (s), mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400
1412 (m), 1342 (s), 1234 (m), 1180 (m), 1103 (m), 1080 (m), mmol) in 99% yield (86.0 mg, 0.396 mmol) as a yellow solid.
918 (m), 841 (m), 741 (s) cm-1; 1H NMR (CDCl3, 400 MHz): The crude product was purified using silica gel column
δ 8.13 (d, J = 8.6 Hz, 2H), 7.29 (s, 1H), 7.19 (d, J = 8.6 Hz, chromatography (EtOAc:hexanes = 1:3). mp 82-83 °C; IR
2H), 7.03 (s, 1H), 6.82 (s, 1H), 4.23 (t, J = 6.8 Hz, 2H), 3.16 (neat): 3109 (m), 2932 (m), 2854 (m), 2847 (w), 1597 (m),
(t, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 147.1, 1512 (s), 1450 (w), 1396 (m), 1342 (s), 1281 (m), 1188 (w),
145.0, 137.0, 129.9, 129.5, 124.0, 118.6, 47.6, 37.5; HRMS 1157 (w), 1095 (m), 1041 (m), 964 (m), 918 (w), 856 (m),
(ESI) m/z: [M+H]+ Calcd for C11H12N3O2 218.0930, Found 733 (m) cm-1; H NMR (CDCl3, 400 MHz): δ 8.07 (d, J =
1
218.0935.
8.5 Hz, 2H), 7.51 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 7.13 (s,
1H), 6.15-6.14 (m, 1H), 4.37 (t, J = 6.8 Hz, 2H), 3.28 (t, J =
6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 146.9, 145.9,
139.8, 129.6, 129.5, 123.7, 105.3, 52.5, 36.4. HRMS (ESI)
m/z: [M+H]+ Calcd for C11H12N3O2 218.0930, Found
218.0933.
2-Methyl-1-(4-nitrophenethyl)-1H-imidazole
(3al).
Compound 3al was synthesized from 2-methyl-1H-
imidazole (2l, 39.4 mg, 0.480 mmol) and 1-nitro-4-
vinylbenzene (1a, 51.0 µL, 0.400 mmol) in 90% yield (83.3
6
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
1-(4-Nitrophenethyl)-1H-1,2,3-triazole (3aq). Compound column chromatography (EtOAc:hexanes = 1:3). IR (neat):
3aq was synthesized from 1H-1,2,3-triazole (2q, 27.8 µL, 3410 (m), 3325 (m), 2962 (m), 2870 (m), 1597 (m), 1512 (s),
0.480 mmol) and 1-nitro-4-vinylbenzene (1a, 51.0 µL, 0.400 1342 (s), 1180 (m), 1111 (m), 964 (w), 856 (m), 784 (m) cm-
mmol) in 90% yield (78.6 mg, 0.360 mmol) as an ivory solid. 1; 1H NMR (CDCl3, 400 MHz): δ 8.15 (d, J = 8.7 Hz, 2H),
The crude product was purified using silica gel column 7.34 (d, J = 8.7 Hz, 2H), 7.20 (td, J = 7.3, 0.9 Hz, 2H), 6.71
chromatography (EtOAc:hexanes = 1:3). mp 114-115 °C; (td, J = 7.3, 0.9 Hz, 1H), 6.61 (dd, J = 7.7, 0.9 Hz, 2H), 3.67-
IR (neat): 3016 (m), 2962 (m), 2854 (m), 1597 (m), 1512 (s), 3.61 (m, 1H), 3.44 (br s, 1H), 2.98 (dd, J = 13.7, 5.9 Hz, 1H),
1458 (m), 1342 (s), 1211 (m), 1111 (m), 1072 (m), 1026 (m), 2.93 (dd, J = 13.7, 6.0 Hz, 1H), 1.64-1.55 (m, 1H), 1.46-1.35
1
856 (m), 810 (m), 733 (m) cm-1; H NMR (CDCl3, 400 (m, 1H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100
MHz): δ 8.09 (d, J = 8.5 Hz, 2H), 7.61 (s, 1H), 7.36 (s, 1H), MHz): δ 147.1, 146.7, 146.6, 130.3, 129.5, 123.4, 117.4,
7.23 (d, J = 8.5 Hz, 2H), 4.67 (t, J = 7.0 Hz, 2H), 3.35 (t, J 113.1, 55.0, 39.8, 27.0, 10.5; HRMS (ESI) m/z: [M+H]+
= 7.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 147.2, 144.7, Calcd for C16H19N2O2 271.1447, Found 271.1452.
133.7, 129.6, 123.9, 123.7, 50.4, 36.2; HRMS (ESI) m/z:
[M+H]+ Calcd for C10H11N4O2 219.0882, Found 219.0886.
3-Fluoro-N-(1-(4-nitrophenyl)butan-2-yl)aniline (5as).
Compound 5as was synthesized from 3-fluoroaniline (2s,
4-Methoxy-N-(1-(4-nitrophenyl)butan-2-yl)aniline (5aa). 46.0 µL, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4-
Compound 5aa was synthesized from 4-methoxyaniline (2a, nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 62% yield (71.5
59.1 mg, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4- mg, 0.248 mmol) as a yellow solid. The crude product was
nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 81% yield (97.3 purified using silica gel column chromatography
mg, 0.324 mmol) as a yellow solid. The crude product was (EtOAc:hexanes = 1:3). mp 54-55 °C; IR (neat): 3394 (m),
purified using silica gel column chromatography 3078 (w), 2924 (m), 2854 (m), 1620 (s), 1520 (s), 1481 (m),
(EtOAc:hexanes = 1:3). mp 63-64 °C; IR (neat): 3394 (m), 1335 (s), 1288 (m), 1142 (s), 1111 (m), 1018 (m), 856 (m),
3040 (w), 2955 (m), 2908 (m), 1597 (m), 1504 (s), 1342 (s), 810 (m), 748 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.15
1227 (s), 1180 (w), 1149 (m), 1111 (m), 1034 (s), 856 (m), (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.10 (td, J =
802 (s), 741 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.14 8.2, 6.6 Hz, 1H), 6.39 (td, J = 8.2, 2.3 Hz, 1H), 6.34 (ddd, J
(d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 6.80 (d, J = = 8.2, 2.3, 0.9 Hz, 1H), 6.28 (dt, J = 11.9, 2.3 Hz, 1H), 3.61-
8.7 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 3.76 (s, 3H), 3.57-3.51 3.56 (m, 1H), 3.55 (br s, 1H), 2.98 (dd, J = 13.7, 5.9 Hz, 1H),
(m, 1H), 3.17 (br s, 1H), 2.97-2.88 (m, 2H), 1.57-1.54 (m, 2.91 (dd, J = 13.7, 5.5 Hz, 1H), 1.65-1.56 (m, 1H), 1.47-1.36
1H), 1.43-1.38 (m, 1H), 0.99 (t, J = 7.5 Hz, 3H); 13C NMR (m, 1H), 1.00 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100
(CDCl3, 100 MHz): δ 152.0, 146.9, 146.5, 141.3, 130.2, MHz): δ 164.2 (JC-F = 243 Hz), 149.1, 149.0, 146.3, 130.5
123.4, 115.0, 114.6, 56.1, 55.7, 39.8, 27.0, 10.5; HRMS (JC-F = 10.6 Hz), 130.2, 123.5, 108.9, 103.8 (JC-F = 21.2 Hz),
(ESI) m/z: [M+H]+ Calcd for C17H21N2O3 301.1552, Found 99.7 (JC-F = 26.1 Hz), 55.1, 39.8, 27.1, 10.5; HRMS (ESI)
301.1557.
m/z: [M+H]+ Calcd for C16H18FN2O2 289.1352, Found
289.1352.
4-Fluoro-N-(1-(4-nitrophenyl)butan-2-yl)aniline (5ab).
Compound 5ab was synthesized from 4-fluoroaniline (2b, 3-Bromo-N-(1-(4-nitrophenyl)butan-2-yl)aniline (5af).
45.5 µL, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4- Compound 5af was synthesized from 3-bromoaniline (2f,
nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 85% yield (98.0 54.3 µL, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4-
mg, 0.340 mmol) as a yellow oil. The crude product was nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 85% yield (119
purified using silica gel column chromatography mg, 0.340 mmol) as a yellow oil. The crude product was
(EtOAc:hexanes = 1:3). IR (neat): 3410 (m), 3070 (w), 2962 purified using silica gel column chromatography
(m), 2870 (m), 1512 (s), 1404 (w), 1342 (s), 1219 (s), 1149 (EtOAc:hexanes = 1:3). IR (neat): 3402 (m), 3070 (w), 2970
(m), 1111 (m), 1011 (s), 856 (m), 818 (s), 748 (m), 702 (m) (m), 2916 (m), 1597 (m), 1512 (s), 1342 (s), 1281 (w), 1234
1
cm-1; H NMR (CDCl3, 400 MHz): δ 8.14 (d, J = 7.3 Hz, (m), 1142 (w), 1111 (m), 1011 (m), 849 (m), 764 (m) cm-1;
2H), 7.32 (d, J = 7.3 Hz, 2H), 6.9 (td, J = 8.6, 1.1 Hz, 2H), 1H NMR (CDCl3, 400 MHz): δ 8.14 (d, J = 8.7 Hz, 2H),
6.52 (ddd, J = 8.8, 4.2, 1.1 Hz, 2H), 3.58-3.52 (m, 1H), 3.32 7.32 (d, J = 8.7 Hz, 2H), 7.01 (dd, J = 7.8, 7.8 Hz, 1H), 6.80
(br s, 1H), 2.96 (dd, J = 13.7, 5.9 Hz, 1H), 2.90 (dd, J = 13.7, (d, J = 7.8 Hz, 1H), 6.71 (s, 1H), 6.49 (dd, J = 8.2, 2.3 Hz,
5.5 Hz, 1H), 1.64-1.54 (m, 1H), 1.41 (dquint, J = 14.2, 7.3 1H), 3.59 (br s, 1H), 3.53 (s, 1H), 2.98 (dd, J = 13.3, 5.5 Hz,
Hz, 1H), 1.00 (td, J = 7.3, 1.4 Hz, 3H); 13C NMR (CDCl3, 1H), 2.89 (dd, J = 13.3, 5.5 Hz, 1H), 1.66-1.56 (m, 1H), 2.98
100 MHz): δ 156.7 (JC-F = 235 Hz), 146.6, 146.6, 143.5, (dquint, J = 14.4, 7.3 Hz, 1H), 0.99 (t, J = 7.3 Hz, 3H); 13
C
130.2, 123.5, 115.8 (JC-F = 22.2 Hz), 114.0 (JC-F = 6.8 Hz), NMR (CDCl3, 100 MHz): δ 148.5, 146.6, 146.3, 130.7,
55.8, 39.7, 27.0, 10.5; HRMS (ESI) m/z: [M+H]+ Calcd for 130.3, 123.5, 123.4, 120.1, 115.5, 111.7, 54.9, 39.8, 27.1,
C16H18FN2O2 289.1352, Found 289.1353.
10.5; HRMS (ESI) m/z: [M+H]+ Calcd for C16H18BrN2O2
349.0552, Found 349.0552.
4-Chloro-N-(1-(4-nitrophenyl)butan-2-yl)aniline (5ac).
Compound 5ac was synthesized from 4-chloroaniline (2c, 1-(1-(4-Nitrophenyl)butan-2-yl)-1H-imidazole
(5ak).
42.8 µL, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4- Compound 5ak was synthesized from 1H-imidazole (2k,
nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 88% yield (107 32.7 mg, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4-
mg, 0.352 mmol) as an orange oil. The crude product was nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 72% yield (70.6
purified using silica gel column chromatography mg, 0.289 mmol) as a yellow solid. The crude product was
(EtOAc:hexanes = 1:3). IR (neat): 3402 (m), 3078 (w), 2962 purified using silica gel column chromatography (10%
(m), 2878 (m), 1597 (m), 1512 (s), 1404 (w), 1342 (s), 1180 MeOH in EtOAc). mp 49-50 °C; IR (neat): 3109 (m), 2967
(m), 1103 (m), 1011 (s), 856 (m), 818 (s), 748 (m), 702 (m) (m), 2924 (m), 1605 (m), 1512 (s), 1412 (m), 1342 (s), 1273
1
cm-1; H NMR (CDCl3, 400 MHz): δ 8.14 (d, J = 7.3 Hz, (m), 1180 (m), 1111 (m), 1080 (m), 918 (m), 856 (m), 802
2H), 7.32 (d, J = 7.3 Hz, 2H), 7.12 (td, J = 8.6, 3.2 Hz, 2H), (m), 741 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.07 (d, J
6.52 (ddd, J = 8.8, 4.2, 1.1 Hz, 2H), 3.58 (br s, 1H), 3.44 (s, = 8.6 Hz, 2H), 7.26 (s, 1H), 7.80-7.06 (m, 3H), 6.87 (s, 1H),
1H), 2.97 (dd, J = 13.7, 5.9 Hz, 1H), 2.90 (dd, J = 13.7, 5.5 4.09-4.01 (m, 1H), 3.18 (dd, J = 13.3, 4.5 Hz, 1H), 3.06 (dd,
Hz, 1H), 1.64-1.54 (m, 1H), 1.41 (dquint, J = 14.2, 7.3 Hz, J = 13.3, 10.5 Hz, 1H), 1.96-1.83 (m, 2H), 0.88 (t, J = 7.4
1H), 1.00 (td, J = 7.3, 1.4 Hz, 3H); 13C NMR (CDCl3, 100 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 146.9, 144.8,
MHz): δ 146.6, 146.4, 145.7, 130.2, 129.3, 123.5, 121.9, 136.4, 129.8, 129.5, 123.8, 116.2, 61.3, 42.7, 28.7, 10.6;
114.1, 55.2, 39.7, 27.0, 10.5; HRMS (ESI) m/z: [M+H]+ HRMS (ESI) m/z: [M+H]+ Calcd for C13H16N3O2 246.1243,
Calcd for C16H18ClN2O2 305.1057, Found 305.1057.
Found 246.1245.
N-(1-(4-Nitrophenyl)butan-2-yl)aniline (5ar). Compound 2-Methyl-1-(1-(4-nitrophenyl)butan-2-yl)-1H-imidazole
5ar was synthesized from aniline (2r, 44.0 µL, 0.480 mmol) (5al). Compound 5al was synthesized from 2-methyl-1H-
and (E)-1-(but-1-en-1-yl)-4-nitrobenzene (4a, 70.9 mg, imidazole (2l, 39.4 mg, 0.480 mmol) and (E)-1-(but-1-en-1-
0.400 mmol) in 75% yield (81.1 mg, 0.300 mmol) as a yl)-4-nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 82% yield
yellow oil. The crude product was purified using silica gel (85.1 mg, 0.328 mmol) as a yellow solid. The crude product
7
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
was purified using silica gel column chromatography (10% (m), 710 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.05 (d,
MeOH in EtOAc). mp 49-50 °C; IR (neat): 3109 (m), 2962 J = 8.7 Hz, 2H), 7.55 (s, 2H), 7.12 (d, J = 8.7 Hz, 2H), 4.76
(m), 2878 (m), 1605 (m), 1512 (s), 1458 (m), 1420 (m), 1342 (tt, J = 9.8, 4.9 Hz, 1H), 3.44 (dd, J = 14.0, 9.8 Hz, 1H), 3.24
(s), 1273 (m), 1157 (m), 1111 (m), 1011 (m), 987 (m), 941 (dd, J =14.0, 4.8 Hz, 1H), 2.19-2.11 (m, 1H), 1.96 (ddd, J =
1
(m), 856 (m), 802 (m), 741 (s), 702 (m) cm-1; H NMR 14.2, 7.3, 4.6 Hz, 1H), 0.80 (t, J = 7.3 Hz, 3H); 13C NMR
(CDCl3, 400 MHz): δ 8.06 (d, J = 8.6 Hz, 2H), 7.02 (d, J = (CDCl3, 100 MHz): δ 146.8, 145.3, 133.8, 129.6, 123.6, 68.5,
8.6 Hz, 2H), 6.97 (s, 1H), 6.91 (s, 1H), 4.03-3.96 (m, 1H), 41.2, 28.5, 10.5; HRMS (ESI) m/z: [M+H]+ Calcd for
3.13 (dd, J = 13.3, 4.5 Hz, 1H), 2.98 (dd, J = 13.3, 10.5 Hz, C12H15N4O2 247.1195, Found 247.1199.
1H), 1.96-1.83 (m, 5H), 0.84 (t, J = 7.4 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): δ 146.9, 145.1, 144.9, 129.6, 128.2,
4-Methoxy-N-(1-(2-nitrophenyl)butan-2-yl)aniline (5ba).
123.7, 114.3, 59.4, 42.7, 29.0, 12.9, 10.6; HRMS (ESI) m/z:
Compound 5ba was synthesized from 4-methoxyaniline (2a,
[M+H]+ Calcd for C14H18N3O2 260.1399, Found 260.1403.
59.1 mg, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-2-
nitrobenzene (4b, 70.9 mg, 0.400 mmol) in 23% yield (27.6
4-Methyl-1-(1-(4-nitrophenyl)butan-2-yl)-1H-imidazole
mg, 0.0920 mmol) as a yellow oil. The crude product was
(5am). Compound 5am was synthesized from 4-methyl-1H- purified using silica gel column chromatography
imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-1-(but-1-en- (EtOAc:hexanes = 1:3). IR (neat): 3402 (m), 2962 (m), 2932
1-yl)-4-nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 92% (m), 1612 (m), 1512 (s), 1458 (w), 1350 (m), 1242 (s), 1180
yield (95.4 mg, 0.368 mmol) as a yellow oil. The crude (w), 1142 (w), 1041 (m), 856 (w), 818 (m), 741 (s) cm-1; 1H
product was purified using silica gel column NMR (CDCl3, 400 MHz): δ 7.85 (dd, J = 7.8, 1.1 Hz, 1H),
chromatography (10% MeOH in EtOAc). IR (neat): 3101 7.47 (td, J = 7.7, 1.3 Hz, 1H), 7.38-7.30 (m, 2H), 6.70 (d, J
(m), 2970 (m), 2878 (m), 1605 (m), 1512 (s), 1458 (m), 1342 = 8.7 Hz, 2H), 6.44 (d, J = 8.7, 3.6 Hz, 2H), 3.72 (s, 3H),
(s), 1281 (m), 1157 (m), 1111 (m), 1057 (w), 972 (w), 910 3.57 (quint, J = 6.4 Hz, 1H), 3.27 (br s, 1H), 3.13-3.11 (m,
(m), 856 (m), 810 (m), 733 (s) cm-1; 1H NMR (CDCl3, 400 2H), 1.67-1.48 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H); 13C NMR
MHz): δ 8.02 (d, J = 8.7 Hz, 2H), 7.05-7.03 (m, 3H), 6.59 (CDCl3, 100 MHz): δ 151.8, 150.0, 141.8, 134.4, 132.8,
(s, 1H), 3.92 (tt, J = 9.5, 4.9 Hz, 1H), 3.10 (dd, J = 13.7, 4.5 132.5, 127.2, 124.6, 114.8, 114.3, 56.6, 55.7, 37.8, 28.0,
Hz, 1H), 2.99 (dd, J = 13.7, 9.6 Hz, 1H), 2.14 (s, 3H), 1.88- 10.3; HRMS (ESI) m/z: [M+H]+ Calcd for C17H21N2O3
1.76 (m, 2H) 0.81 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 301.1552, Found 301.1560.
100 MHz): δ 146.8, 145.6, 145.1, 129.5, 124.1, 123.6, 123.0,
61.2, 42.5, 28.6, 13.8, 10.5; HRMS (ESI) m/z: [M+H]+
4-Methyl-1-(1-(4-nitrophenyl)pentan-2-yl)-1H-
Calcd for C14H18N3O2 260.1399, Found 260.1401.
imidazole (7am). Compound 7am was synthesized from 4-
methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-
1-(1-(4-Nitrophenyl)butan-2-yl)-1H-benzo[d]imidazole
1-nitro-4-(pent-1-en-1-yl)benzene (6a, 76.5 mg, 0.400
(5an). Compound 5an was synthesized from 1H- mmol) in 75% yield (82.0 mg, 0.300 mmol) as a yellow oil.
benzo[d]imidazole (2n, 56.7 mg, 0.480 mmol) and (E)-1- The crude product was purified using silica gel column
(but-1-en-1-yl)-4-nitrobenzene (4a, 70.9 mg, 0.400 mmol) chromatography (10% MeOH in EtOAc). IR (neat): 2947
in 70% yield (82.7 mg, 0.280 mmol) as a yellow solid. The (m), 2870 (m), 2800 (w), 1605 (m), 1520 (s), 1450 (m), 1420
crude product was purified using silica gel column (w), 1342 (s), 1281 (w), 1219 (m), 1157 (m), 1111 (m), 1018
chromatography (10% MeOH in EtOAc). mp 103-104 °C; (m), 856 (m), 818 (s), 748 (m) cm-1; 1H NMR (CDCl3, 400
IR (neat): 3070 (m), 2962 (m), 2870 (m), 2361 (m), 1605 MHz): δ 8.06 (dd, J = 8.5, 2.1 Hz, 2H), 7.09 (s, 1H), 7.06 (d,
(m), 1512 (s), 1404 (m), 1342 (s), 1281 (m), 1203 (m), 1111 J = 8.5 Hz, 2H), 6.59 (s, 1H), 4.03 (quint, J = 4.5 Hz, 1H),
(m), 1072 (w), 1011 (m), 856 (m), 741 (s), 710 (m) cm-1; 1H 3.10 (dd, J = 13.7, 5.0 Hz, 1H), 3.02 (dd, J = 13.7, 9.3 Hz,
NMR (CDCl3, 400 MHz): δ 7.93 (d, J = 8.5 Hz, 2H), 7.77- 1H), 2.18 (s, 3H), 1.84-1.76 (m, 2H), 1.22 (dq, J = 14.8, 7.4
7.74 (m, 1H), 7.68 (s, 1H), 7.36-7.33 (m, 1H), 7.25-7.20 (m, Hz, 2H), 0.88 (td, J = 7.4, 1.4 Hz, 3H); 13C NMR (CDCl3,
2H), 6.98 (d, J = 8.5 Hz, 2H), 4.42-4.37 (m, 1H), 3.32 (dd, 100 MHz): δ 146.8, 145.1, 138.9, 135.5, 129.5, 123.7, 112.4,
J = 14.2, 7.8 Hz, 1H), 3.27 (dd, J = 13.7, 8.2 Hz, 1H), 2.15- 59.3, 42.8, 37.5, 19.2, 13.8, 13.5; HRMS (ESI) m/z: [M+H]+
2.01 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, Calcd for C15H20N3O2 274.1556, Found 274.1559.
100 MHz): δ 146.7, 144.8, 143.9, 141.5, 132.9, 129.5, 123.5,
122.8, 122.1, 120.5, 110.0, 60.0, 40.6, 27.1, 10.6; HRMS
4-Methyl-1-(1-(4-nitrophenyl)heptan-2-yl)-1H-
(ESI) m/z: [M+H]+ Calcd for C17H18N3O2 296.1399, Found
imidazole (7bm). Compound 7bm was synthesized from 4-
296.1397.
methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-
1-(hept-1-en-1-yl)-4-nitrobenzene (6b, 87.7 mg, 0.400
1-(1-(4-Nitrophenyl)butan-2-yl)-1H-pyrazole
(5ap). mmol) in 82% yield (98.9 mg, 0.328 mmol) as a yellow oil.
Compound 5ap was synthesized from 1H-pyrazole (2p, 32.7 The crude product was purified using silica gel column
mg, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4-nitrobenzene chromatography (10% MeOH in EtOAc). IR (neat): 2932
(4a, 70.9 mg, 0.400 mmol) in 81% yield (80.0 mg, 0.326 (m), 2862 (m), 1605 (m), 1520 (s), 1458 (m), 1342 (s), 1288
mmol) as a light yellow oil. The crude product was purified (w), 1157 (m), 1111 (m), 1003 (m), 972 (w), 858 (m), 818
using silica gel column chromatography (EtOAc:hexanes = (s), 702 (m), 741 (m) cm-1; 1H NMR (CDCl3, 400 MHz): δ
1:3). IR (neat): 2962 (m), 2924 (m), 2870 (m), 1605 (m), 8.09 (d, J = 8.7 Hz, 2H), 7.11 (s, 1H), 7.07 (d, J = 8.7 Hz,
1520 (s), 1466 (m), 1404 (m), 1342 (s), 1281 (m), 1103 (m), 2H), 6.59 (s, 1H), 4.06-3.99 (m, 1H), 3.12 (dd, J = 13.7, 5.0
1049 (m), 933 (w), 856 (m), 802 (m), 748 (s), 702 (m) cm-1; Hz, 1H), 3.03 (dd, J = 13.7, 9.6 Hz, 1H), 2.20 (s, 3H), 1.85-
1H NMR (CDCl3, 400 MHz): δ 8.01 (d, J = 8.7 Hz, 2H), 1.80 (m, 2H), 1.26-1.25 (m, 6H), 0.86 (t, J = 6.6 Hz, 3H);
7.54 (s, 1H), 7.05 (s, 1H), 7.02 (d, J = 8.7 Hz, 2H), 6.09 (s, 13C NMR (CDCl3, 100 MHz): δ 147.0, 145.1, 139.1, 135.5,
1H), 4.18-4.11 (m, 1H), 3.36 (dd, J = 13.7, 10.1 Hz, 1H), 129.6, 123.8, 112.5, 59.6, 43.0, 35.5, 31.3, 25.7, 22.4, 13.9,
3.13 (dd, J = 13.7, 4.1 Hz, 1H), 2.11-2.07 (m, 1H), 1.91-1.88 13.8; HRMS (ESI) m/z: [M+H]+ Calcd for C17H24N3O2
(m, 1H), 0.79 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 302.1869, Found 302.1871.
MHz): δ 146.6, 146.1, 139.6, 129.6, 129.4, 123.4, 104.5,
65.8, 41.7, 28.4, 10.6; HRMS (ESI) m/z: [M+H]+ Calcd for
4-Methyl-1-(3-methyl-1-(4-nitrophenyl)butan-2-yl)-1H-
C13H16N3O2 246.1243, Found 246.1245.
imidazole (7cm). Compound 7cm was synthesized from 4-
methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-
1-(1-(4-Nitrophenyl)butan-2-yl)-1H-1,2,3-triazole (5aq). 1-(3-methylbut-1-en-1-yl)-4-nitrobenzene (6c, 76.5 mg,
Compound 5aq was synthesized from 1H-1,2,3-triazole (2q, 0.400 mmol) in 71% yield (77.6 mg, 0.284 mmol) as a
33.2 mg, 0.480 mmol) and (E)-1-(but-1-en-1-yl)-4- yellow oil. The crude product was purified using silica gel
nitrobenzene (4a, 70.9 mg, 0.400 mmol) in 60% yield (59.2 column chromatography (10% MeOH in EtOAc). IR (neat):
mg, 0.240 mmol) as a yellow solid. The crude product was 2978 (m), 2878 (m), 2824 (w), 1605 (m), 1512 (s), 1412 (w),
purified using silica gel column chromatography 1342 (s), 1281 (m), 1165 (m), 1111 (m), 1011 (w), 972 (m),
(EtOAc:hexanes = 1:3). mp 58-59 °C; IR (neat): 2962 (m), 941 (w), 849 (m), 725 (s) cm-1; 1H NMR (CDCl3,400 MHz):
2924 (m), 2854 (m), 1605 (m), 1512 (s), 1458 (m), 1420 (m), δ 8.06 (d, J = 8.7 Hz, 2H), 7.07-7.05 (m, 3H), 6.59 (s, 1H),
1342 (s), 1149 (m), 1111 (m), 957 (m), 864 (m), 810 (s), 741 3.73-3.67 (m, 1H), 3.28 (dd, J = 13.7, 3.7 Hz, 1H), 2.98 (dd,
8
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
J = 13.7, 11.0 Hz, 1H), 2.19 (s, 3H), 2.12-2.03 (m, 1H), 1.12 J = 13.7, 5.0 Hz, 1H), 3.05 (dd, J = 13.7, 9.1 Hz, 1H), 2.22
(d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H); 13C NMR (s, 3H), 1.88 (q, J = 7.6 Hz, 2H), 1.44-1.25 (m, 4H); 13C
(CDCl3, 100 MHz): δ 146.9, 145.6, 138.8, 136.0, 129.4, NMR (CDCl3, 100 MHz): δ 147.0, 144.8, 139.3, 135.5,
123.8, 113.2, 66.1, 39.6, 33.5, 20.2, 19.0, 13.8; HRMS (ESI) 129.6, 123.8, 112.4, 59.5, 44.4, 42.9, 34.8, 31.9, 23.4, 13.8;
m/z: [M+H]+ Calcd for C15H20N3O2 274.1556, Found HRMS (ESI) m/z: [M+H]+ Calcd for C16H21ClN3O2
274.1557.
322.1322, Found 322.1331.
4-methyl-1-(1-(4-nitrophenyl)-4-phenylbutan-2-yl)-1H-
4-Methyl-1-(1-(4-nitrophenyl)undec-10-en-2-yl)-1H-
imidazole (7dm). Compound 7dm was synthesized from 4- imidazole (7hm). Compound 7hm was synthesized from 4-
methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)- methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-
1-nitro-4-(4-phenylbut-1-en-1-yl)benzene (6d, 101 mg, 1-nitro-4-(undeca-1,10-dien-1-yl)benzene (6h, 109 mg,
0.400 mmol) in 83% yield (111 mg, 0.332 mmol) as a yellow 0.400 mmol) in 87% yield (124 mg, 0.349 mmol) as a yellow
oil. The crude product was purified using silica gel column oil. The crude product was purified using silica gel column
chromatography (10% MeOH in EtOAc). IR (neat): 2908 chromatography (10% MeOH in EtOAc). IR (neat): 2932
(m), 2862 (m), 1605 (m), 1566 (w), 1512 (s), 1450 (w), 1412 (m), 2862 (m), 1605 (m), 1597 (s), 1520 (s), 1481 (m), 1342
(w), 1342 (s), 1281 (m), 1157 (m), 1111 (m), 1003 (w), 918 (s), 1250 (m), 1203 (s), 1149 (s), 1111 (m), 1065 (m), 972
1
1
(w), 856 (m), 818 (w), 748 (m), 702 (m) cm-1; H NMR (m), 941 (m), 702 (s), 856 (m), 818 (s), 741 (m) cm-1; H
(CDCl3, 400 MHz): δ 8.06 (d, J = 8.7 Hz, 2H), 7.31-7.27 (m, NMR (CDCl3, 400 MHz): δ 8.08 (d, J = 8.7 Hz, 2H), 7.12
2H), 7.24-7.20 (m, 1H), 7.10-7.09 (m, 2H), 7.07 (s, 1H), (s, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.60 (s, 1H), 5.79 (ddt, J =
7.03 (d, J = 8.7 Hz, 2H), 6.64 (s, 1H), 4.05-3.98 (m, 1H), 17.0, 10.2, 6.7 Hz, 1H), 4.98 (dd, J = 17.0, 2.3 Hz, 1H), 4.93
3.11 (dd, J = 13.7, 5.0 Hz, 1H), 3.05 (dd, J = 13.7, 9.2 Hz, (dd, J = 10.2, 2.3 Hz, 1H), 4.03 (tt, J = 8.9, 5.5 Hz, 1H), 3.12
1H), 2.63-2.56 (m, 1H), 2.50-2.42 (m, 1H), 2.24 (s, 3H), (dd, J = 13.8, 4.6 Hz, 1H), 3.03 (dd, J = 13.8, 9.1 Hz, 1H),
2.21-2.15 (m, 2H); 13C NMR (CDCl3, 100 MHz): δ 147.0, 2.21 (s, 3H), 2.02 (q, J = 7.2 Hz, 2H), 1.84-1.80 (m, 2H),
144.8, 140.0, 139.4, 135.7, 129.5, 128.6, 128.3, 126.4, 123.7, 1.36-1.12 (m, 10H); 13C NMR (CDCl3, 100 MHz): δ 146.9,
112.3, 58.4, 43.0, 36.7, 31.9, 13.9; HRMS (ESI) m/z: 145.1, 139.0, 135.5, 129.6, 123.8, 123.8, 114.2, 112.4, 59.6,
[M+H]+ Calcd for C20H22N3O2 336.1712, Found 336.1710.
42.9, 35.5, 33.7, 29.1, 29.0, 28.9, 28.7, 26.0, 13.8; HRMS
(ESI) m/z: [M+H]+ Calcd for C21H30N3O2 356.2338, Found
356.2331.
1-(4-(Benzyloxy)-1-(4-nitrophenyl)butan-2-yl)-4-methyl-
1H-imidazole (7em). Compound 7em was synthesized from
4-methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-
(Z)-4-Methyl-1-(1-(4-nitrophenyl)dec-7-en-2-yl)-1H-
1-(4-(benzyloxy)but-1-en-1-yl)-4-nitrobenzene (6e, 113 mg, imidazole (7im). Compound 7im was synthesized from 4-
0.400 mmol) in 78% yield (114 mg, 0.312 mmol) as a yellow methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and 1-
oil. The crude product was purified using silica gel column ((1E,7Z)-deca-1,7-dien-1-yl)-4-nitrobenzene (6i, 104 mg,
chromatography (10% MeOH in EtOAc). IR (neat): 2862 0.400 mmol) in 85% yield (116 mg, 0.340 mmol) as a yellow
(m), 2800 (w), 1605 (m), 1512 (s), 1443 (m), 1342 (s), 1281 oil. The crude product was purified using silica gel column
(m), 1157 (m), 1111 (m), 1011 (m), 926 (m), 856 (m), 733 chromatography (10% MeOH in EtOAc). IR (neat): 2939
(s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, J = 8.7 Hz, (m), 2862 (m), 1605 (m), 1520 (s), 1450 (m), 1342 (s), 1288
2H), 7.37-7.26 (m, 5H), 7.09 (s, 1H), 7.07 (d, J = 8.7 Hz, (m), 1157 (m), 1111 (m), 1072 (w), 1003 (w), 972 (w), 856
1
2H), 6.57 (s, 1H), 4.40 (s, 2H), 4.40-4.34 (m, 2H), 3.47 (dt, (s), 810 (m), 741 (s), 702 (s) cm-1; H NMR (CDCl3, 400
J = 9.5, 4.6 Hz, 1H), 3.13 (dd, J = 14.2, 5.1 Hz, 1H), 3.04 MHz): δ 8.08 (d, J = 8.7 Hz, 2H), 7.09 (s, 1H), 7.06 (d, J =
(dd, J = 14.2, 9.6 Hz, 1H), 2.21-2.13 (m, 5H); 13C NMR 8.7 Hz, 2H), 6.59 (s, 1H), 5.36-5.32 (m, 1H), 5.27-5.22 (m,
(CDCl3, 100 MHz): δ 147.0, 144.9, 139.1, 137.8, 135.8, 1H), 4.05-3.98 (m, 1H), 3.11 (dd, J = 13.8, 5.1 Hz, 1H), 3.03
129.6, 128.4, 127.9, 127.8, 123.7, 112.5, 73.3, 65.6, 56.0, (dd, J = 13.8, 9.1 Hz, 1H), 2.20 (s, 3H), 2.02-1.94 (m, 4H),
42.4, 35.8, 13.8; HRMS (ESI) m/z: [M+H]+ Calcd for 1.85-1.80 (m, 2H), 1.33-1.20 (m, 4H), 0.92 (t, 7.5 Hz, 3H);
C21H24N3O3 366.1818, Found 366.1816.
13C NMR (CDCl3, 100 MHz): δ 146.9, 145.1, 139.1, 135.5,
132.1, 129.6, 128.3, 123.8, 112.4, 59.5, 42.9, 35.4, 29.1, 26.7,
25.6, 20.5, 14.3, 13.9; HRMS (ESI) m/z: [M+H]+ Calcd for
C20H28N3O2 342.2182, Found 342.2186.
1-(5-(Benzyloxy)-1-(4-nitrophenyl)pentan-2-yl)-4-
methyl-1H-imidazole (7fm). Compound 7fm was
synthesized from 4-methyl-1H-imidazole (2m, 39.4 mg,
0.480 mmol) and (E)-1-(5-(benzyloxy)pent-1-en-1-yl)-4- 1-(1-(2-Chloro-4-nitrophenyl)butan-2-yl)-4-methyl-1H-
nitrobenzene (6f, 119 mg, 0.400 mmol) in 72% yield (110 imidazole (7jm). Compound 7jm was synthesized from 4-
mg, 0.290 mmol) as a yellow oil. The crude product was methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-
purified using silica gel column chromatography (10% 1-(but-1-en-1-yl)-2-chloro-4-nitrobenzene (6j, 84.7 mg,
MeOH in EtOAc). IR (neat): 2862 (m), 2800 (w), 1605 (m), 0.400 mmol) in 85% yield (100 mg, 0.340 mmol) as a yellow
1512 (s), 1443 (m), 1342 (s), 1281 (m), 1157 (m), 1111 (m), oil. The crude product was purified using silica gel column
1011 (m), 926 (m), 856 (m), 733 (s) cm-1; 1H NMR (CDCl3, chromatography (10% MeOH in EtOAc). IR (neat): 2970
400 MHz): δ 8.06 (d, J = 8.5 Hz, 2H), 7.38-7.29 (m, 5H), (m), 2878 (m), 1589 (m), 1520 (s), 1350 (s), 1242 (s), 1157
7.08 (s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.59 (s, 1H), 4.46 (s, (m), 1119 (m), 1041 (m), 895 (m), 810 (s), 733 (s) cm-1; 1H
2H), 4.09-4.07 (m, 1H), 3.48-3.40 (m, 2H), 3.11 (dd, J = NMR (CDCl3, 400 MHz): δ 8.23 (d, J = 2.3 Hz, 1H), 7.91
13.9, 4.9 Hz, 1H), 3.00 (dd, J = 13.7, 9.3Hz, 1H), 2.19 (s, (dd, J = 8.2, 2.3 Hz, 1H), 7.11 (s, 1H), 6.94 (d, J = 8.2 Hz,
3H), 2.02-1.90 (m, 2H), 1.53-1.50 (m, 2H); 13C NMR 1H), 6.62 (s, 1H), 4.07 (dq, J = 9.4, 4.7 Hz, 1H), 3.37 (dd, J
(CDCl3, 100 MHz): δ 146.9, 145.1, 139.1, 138.2, 135.7, = 13.7, 4.6 Hz, 1H), 3.02 (dd, J = 13.5, 9.8 Hz, 1H), 2.19 (s,
129.6, 128.5, 127.8, 127.7, 123.8, 112.4, 73.0, 69.2, 59.3, 3H), 1.95-1.90 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR
42.8, 32.5, 26.0, 13.7; HRMS (ESI) m/z: [M+H]+ Calcd for (CDCl3, 100 MHz): δ 147.3, 142.6, 139.1, 135.6, 134.6,
C22H26N3O3 380.1974, Found 380.1970.
131.4, 124.7, 121.8, 112.3, 59.1, 40.7, 28.8, 13.8, 10.6;
HRMS (ESI) m/z: [M+H]+ Calcd for C14H17ClN3O2
294.1009, Found 294.1013.
1-(6-Chloro-1-(4-nitrophenyl)hexan-2-yl)-4-methyl-1H-
imidazole (7gm). Compound 7gm was synthesized from 4-
methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)- 1-(1-(2-Fluoro-4-nitrophenyl)butan-2-yl)-4-methyl-1H-
1-(6-chlorohex-1-en-1-yl)-4-nitrobenzene (6g, 95.9 mg, imidazole (7km). Compound 7km was synthesized from 4-
0.400 mmol) in 70% yield (90.1 mg, 0.280 mmol) as a methyl-1H-imidazole (2m, 39.4 mg, 0.480 mmol) and (E)-
yellow oil. The crude product was purified using silica gel 1-(but-1-en-1-yl)-2-fluoro-4-nitrobenzene (6k, 78.0 mg,
column chromatography (10% MeOH in EtOAc). IR (neat): 0.400 mmol) in 82% yield (91.0 mg, 0.328 mmol) as a
2947 (m), 2870 (m), 1605 (m), 1558 (w), 1520 (s), 1450 (w), yellow oil. The crude product was purified using silica gel
1342 (s), 1265 (s), 1157 (m), 1111 (m), 1065 (w), 856 (m), column chromatography (10% MeOH in EtOAc). IR (neat):
818 (m), 733 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ 8.10 2970 (m), 2878 (m), 1605 (m), 1528 (s), 1435 (w), 1420 (w),
(d, J = 8.7 Hz, 2H), 7.16 (s, 1H), 7.08 (d, J = 8.2 Hz, 2H), 1350 (s), 1234 (m), 1165 (m), 1072 (m), 1003 (m), 949 (m),
6.61 (s, 1H), 4.08-4.03 (m, 1H), 3.51-3.47 (m, 2H), 3.15 (dd, 879 (m), 810 (s), 742 (s) cm-1; 1H NMR (CDCl3, 400 MHz):
9
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10.1002/adsc.201801582
Advanced Synthesis & Catalysis
δ 7.88 (dd, J = 9.6, 2.3 Hz, 1H), 7.84 (dd, J = 8.7, 2.3 Hz,
1H), 7.14 (s, 1H), 6.97 (t, J = 8.2 Hz, 1H), 6.62 (s, 1H), 4.02
(tt, J = 9.5, 4.9 Hz, 1H), 3.24 (dd, J = 14.0, 4.3 Hz, 1H), 2.97
(dd, J = 14.4, 9.8 Hz, 1H), 2.17 (s, 3H), 1.93-1.81 (m, 2H),
0.86 (t, J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ
160.2 (JC-F = 250 Hz), 147.8 (JC-F = 9.6 Hz), 138.9, 135.5,
References
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132.2 (JC-F = 16.4 Hz), 131.5 (JC-F = 5.8 Hz), 119.3 (JC-F
=
3.9 Hz), 112.4, 111.2 (JC-F = 27.9 Hz), 59.8, 36.3, 28.7, 13.7,
10.6; HRMS (ESI) m/z: [M+H]+ Calcd for C14H17FN3O2
278.1305, Found 278.1298.
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N-(1-(2-Chloro-4-nitrophenyl)butan-2-yl)-4-
methoxyaniline (8). Compound 8 was synthesized from 4-
methoxyaniline (2a, 59.1 mg, 0.480 mmol) and (E)-1-(but-
1-en-1-yl)-2-chloro-4-nitrobenzene (6j, 84.7 mg, 0.400
mmol) in 78% yield (104 mg, 0.311 mmol) as a yellow solid.
The crude product was purified using silica gel column
chromatography (EtOAc:hexanes = 1:3). mp 55-56 °C; IR
(neat): 3394 (w), 2970 (m), 2932 (m), 2862 (w), 1682 (w),
1512 (s), 1466 (w), 1350 (s), 1242 (m), 1180 (w), 1119 (m),
1041 (m), 895 (m), 818 (s), 741 (m), cm-1; 1H NMR (CDCl3,
400 MHz): δ 8.24 (d, J = 2.3 Hz, 1H), 8.01 (dd, J = 8.5, 2.3
Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H),
6.52 (d, J = 8.7 Hz, 2H), 3.73 (s, 3H), 3.63 (quint, J = 6.4
Hz, 1H), 3.23 (br s, 1H), 3.07-2.98 (m, 2H), 1.69-1.59 (m,
1H), 1.52 (dquint, J = 14.1, 7.2 Hz, 1H), 1.00 (t, J = 7.5 Hz,
3H); 13C NMR (CDCl3, 100 MHz): δ 152.1, 146.7, 145.1,
141.4, 135.0, 132.0, 124.5, 121.5, 114.9, 114.6, 55.7, 55.6,
38.9, 27.8, 10.7; HRMS (ESI) m/z: [M+H]+ Calcd for
C17H20ClN2O3 335.1162, Found 335.1158.
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Experimental procedure for Pd-catalyzed cyclization of
8
2-Ethyl-1-(4-methoxyphenyl)-6-nitroindoline (9). In a
glove box, tris(dibenzylideneacetone) dipalladium (0) (2.70
mg,
2.98
x
10-3
mmol),
1,3-bis(2,4,6-
trimethylphenyl)imidazolium chloride (2.0 mg, 5.97 x 10-3
mmol) and NaOt-Bu (8.6 mg, 0.0896 mmol) were added into
a vial (8 mL) charged with a magnetic bar, and the vial was
sealed with a cap (phenolic open top cap with gray
PTFE/silicone). After being removed from the glove box,
the vial was purged with N2 gas for 10 min, and 1,4-dioxane
(0.2 mL) was added. And then a solution of aminated
product 8 (20.0 mg, 0.0597 mmol) in 1,4-dioxane (0.2 mL)
was added at 0 °C. The phenolic open-top cap was changed
to a closed cap and the reaction mixture was heated at 110 °C
and stirred for 12 h. The mixture was filtered through a plug
of silica gel and washed with CH2Cl2. The organic filtrate
was concentrated in vacuo. The crude product was purified
using silica gel column chromatography (EtOAc:hexanes =
1:3) to afford 2-ethyl-1-(4-methoxyphenyl)-6-nitroindoline
(9, 14.3 mg, 0.0479 mmol, 81% yield) as a yellow solid. mp
59-60 °C; IR (neat): 2978 (m), 2870 (m), 2839 (w), 1620
(w), 1512 (s), 1443 (w), 1381 (w), 1342 (s), 1288 (m), 1242
(m), 1180 (w), 1119 (m), 1072 (w), 1034 (m), 949 (w), 849
(m), 810 (m), 741 (s) cm-1; 1H NMR (CDCl3, 400 MHz): δ
7.54 (dd, J = 8.0, 2.3 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.16-
7.13 (m, 2H), 6.98 (d, J = 9.1 Hz, 2H), 4.22 (qd, J = 9.2, 3.2
Hz, 1H), 3.86 (s, 3H), 3.30 (dd, J = 16.7, 8.9 Hz, 1H), 2.90
(ddd, J = 16.9, 9.6, 1.4 Hz, 1H), 1.76 (ddd, J = 13.7, 7.3, 3.2
Hz, 1H), 1.61-1.53 (m, 1H), 0.91 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3, 100 MHz): δ 157.4, 152.5, 148.4, 136.6,
134.8, 126.4. 124.1, 115.1, 113.6, 100.8, 67.3, 55.5, 33.8,
26.2, 9.1; HRMS (EI) m/z: [M+Na]+ Calcd for
C17H18N2NaO3 321.1215, Found 321.1215.
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Acknowledgements
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) (NRF-2017R1A2B4008310). This work was also partially
supported by the Bio & Medical Technology Development
Program of the National Research Foundation (NRF) and was
funded by the Korean government (MSIP&MOHW) (NRF-
2015M3A9E6029594).
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Advanced Synthesis & Catalysis
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FULL PAPER
Copper-Catalyzed Intermolecular Hydroamination
of Arylamines or Aza-Heterocycles with
Nitrostyrene Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Subin Park, Seongil Kang and Yunmi Lee*
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