Iron-Catalyzed Regioselective α-C-H Alkylation of N-Methylanilines: Cross-Dehydrogenative Coupling between Unactivated C(sp3)-H and C(sp3)-H Bonds via a Radical Process

Article abstract of DOI:10.1021/acs.joc.9b00625

The iron-catalyzed α-C-H alkylation of N-methylanilines without any directing group by cross-dehydrogenative coupling between unactivated C(sp³)-H and C(sp³)-H bonds has been established for the first time, which provides a good complement to C(sp³)-H activation reactions and expands the field of Fe-catalyzed C-H functionalizations. Many different C(sp³)-H bonds in cyclic alkanes, cyclic ethers, and toluene derivatives can be used as coupling partners. Mechanistic investigations including the radical reaction process, the main role of various reagents, and the kinetic isotope effect experiment were also described.

Full text of DOI:10.1021/acs.joc.9b00625

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Iron-Catalyzed Regioselective α‑C−H Alkylation of N‑Methylanilines:
Cross-Dehydrogenative Coupling between Unactivated C(sp3)−H
and C(sp3)−H Bonds via a Radical Process
Ze-Lin Li,† Kang-Kang Sun,† Peng-Yu Wu,† and Chun Cai*,†,‡
†Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, People’s Republic of China
‡Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Lu, Shanghai 20032, People’s Republic of China
S
* Supporting Information
ABSTRACT: The iron-catalyzed α-C−H alkylation of N-
methylanilines without any directing group by cross-
dehydrogenative coupling between unactivated C(sp3)−H
and C(sp3)−H bonds has been established for the first time,
which provides a good complement to C(sp3)−H activation
reactions and expands the field of Fe-catalyzed C−H
functionalizations. Many different C(sp3)−H bonds in cyclic
alkanes, cyclic ethers, and toluene derivatives can be used as
coupling partners. Mechanistic investigations including the
radical reaction process, the main role of various reagents, and
the kinetic isotope effect experiment were also described.
workers;3d this catalytic system could be applied to the N-
nitrosation of aromatic amines and enabled the cleavage of the
INTRODUCTION
Aniline derivatives have found broad application in organic
synthesis and can be easily used for fundamental building
blocks of bioactive compounds.1 In addition, they also play
very important roles in numerous natural products, agro-
chemicals, dyestuff industry, and pharmaceuticals,2 for example
(Figure 1, 1−3), mabuterol 1 (treatment of tracheal
■
C−N bond of an aromatic tertiary amine. In 2016,
Kandasamy’s group3c developed an efficient synthesis of N-
nitrosamines using tert-butyl nitrite, featuring a broad substrate
scope, metal-free conditions, easy operation, and excellent
yields. On the other hand, a significant number of methods
have been described for the direct ortho C−H bond
functionalization of anilines.4 As a representative example, a
nickel-catalyzed direct C−H trifluoromethylation of free
anilines with Togni’s reagent by Wu et al.4a provides a concise
and efficient alternative protocol to synthesize trifluoromethy-
lated free anilines. Despite the breakthrough in the N−H bond
and ortho C−H bond functionalization of anilines, the research
in the field of α-C(sp3)−H activation of N-methylanilines is
still in its primary stage.
Figure 1. Representative examples of applications of aniline
derivatives.
In recent years, several transition metal complexes
containing Ir,5a Sc,5b Ti,5c Zr,5d Ta,5e and Nb5f have been
developed for α-C(sp3)−H activation of N-methylanilines
(Scheme 1). Examples include work in the direct C−H
alkylation adjacent to nitrogen in unprotected secondary
amines by using 2-pyridonate-Ta(NMe2)3Cl complex, which
does not require additives, protecting/directing groups,
terminal oxidants, or photoinitiators. In 2015, the first example
of a titanium-based catalyst for intermolecular hydroaminoal-
kylation reactions of alkenes and styrenes with secondary
amines was developed by Doye’s group,5c showing excellent
obstructive diseases), dephostatin 2 (potential inhibitor of
cysteine-containing enzymes such as protein tyrosine phos-
phatases, papain, and caspase) and propachlor 3 (highly
selective herbicide for rice field).
Due to the significance of this substructure in various fields,
the development of efficient synthetic methods that allow for
easy access to substituted anilines and their derivatives is of
great importance. Over the past decade, a significant number of
procedures have been established for the direct N−H bond
and ortho C−H bond functionalization of anilines.3,4 For
instance, the Cu(II)-catalyzed oxidative N-nitrosation of
secondary and tertiary amines with nitromethane under an
oxygen atmosphere was provided by Sakai and his co-
Received: March 3, 2019
Published: May 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 1. Representative Examples of Activation of the N−
H/C−H Bond in Anilines
Table 1. Optimization of the Reaction Conditions
regioselectivity. Furthermore, Nishibayashi and co-workers5a
demonstrated the addition of α-aminoalkyl radicals to electron-
deficient alkenes by visible-light-mediated electron transfer
using transition metal polypyridyl complexes as photocatalysts,
opening up a novel synthetic route for the direct functionaliza-
tion of the C(sp3)−H bond adjacent to the N atom of anilines.
However, previous works were all limited to the coupling of
C(sp3)−H with C(sp2)−H bonds in terminal alkenes or dienes
or internal alkenes, and the catalysts are very high-cost. The
catalytic cross-dehydrogenative coupling reaction between
C(sp3)−H bonds of N-methylaniline and C(sp3)−H bonds
has thus far remained elusive, especially in the area of
employing a cheap transition metal.
b
entry
cat.
FeCl2
ligand peroxide
base
yield (%) of 3a
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
TBPB
DCP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
DMAP
35
11
13
26
0
FeSO4
Fe(OAc)2
Fe(acac)3
NiCl2
CuCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
0
50
75
39
trace
trace
0
9
10
11
12
13
14
15
16
17
18
19
20
We herein demonstrate the first example of a cheap
transition metal iron-catalyzed cross-dehydrogenative coupling
of C(sp3)−H bonds in the N-methylanilines with C(sp3)−H
bonds of cyclic alkanes, cyclic ethers, and toluene derivatives
without any directing group (DG) via a radical process.
0
41
30
46
63
31
27
0
trace
0
0
RESULTS AND DISCUSSION
■
At first, we examined the reaction of N-methylaniline 1a with
cyclohexane 2a under various conditions, and the results are
summarized in Table 1. When the reaction of 1a with 2a was
carried out at 140 °C using FeCl2 as the catalyst, L1 as the
ligand, TBHP (tert-butyl hydroperoxide) as the oxidant, and in
the presence of Na2CO3 under air for 18 h, 3a was obtained in
35% total yield (entry 1). Next, a survey of different iron
catalysts such as FeSO4 and Fe(OAc)2, Fe(acac)3 was
investigated. The results showed that FeCl2 was the best
catalyst, and the anion bound to iron plays a crucial role in the
catalysis (entries 2−4). Other catalysts including NiCl2 and
CuCl2 all failed to give the desired product (entries 5−6).
Thereafter, we explored various ligands with L3 furnishing
particularly effective catalysis (entries 7−13). In addition, a
range of peroxides were also screened (Table 1, entries 14−
16), but none of them were found to be effective for the
reaction, and this might be due to the different half-life of
peroxides under high-temperature reaction conditions (cau-
tion: TBHP is unstable above 75 °C, and heating large
amounts of TBHP at 140 °C is potentially dangerous7c).
Among the additives tested, Na2CO3 was found to be the best
choice (entries 17−20). Moreover, decreasing the reaction
temperature reduced the yield (entries 21 and 22). Finally,
optimizations in other solvents were made (entries 23 and 24),
and cyclohexane was proved as the best for this reaction. One
possible reason is that cyclohexane (4 equiv) is transferred
from liquid to gas under a high-temperature procedure, thus
resulting in a decrease of yield.
tBuOK
TFA
c
21
Na2CO3
Na2CO3
Na2CO3
Na2CO3
d
22
23
e
f
24
0
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mL), cat. (0.075
mmol), ligand (0.1 mmol), peroxide (1.75 mmol), (0.55 mmol), 140
°C, 18 h. Isolated yield. 125 °C. 110 °C. 2a (4 equiv), DMF (2.0
b
c
d
e
f
mL). 2a (4 equiv), DMSO (2.0 mL).
With the optimized conditions in hand, we next explored the
scope of the substrates, and the results are summarized in
Scheme 2. In general, a variety of N-methylanilines were
applicable, and moderate to excellent isolated yields of the
products were achieved (3a−3l). Substrates bearing electron-
donating groups at the C-4 position afforded the alkylation
products 3b and 3c in 70 and 66% yields, respectively.
Meanwhile, a series of common electron-withdrawing groups,
such as halogen, cyano, trifluoromethyl, and phenyl, were all
well-tolerated (3d−3i). In addition, meta-substituted (3k−3l)
and ortho-substituted (3j) N-methylanilines gave the corre-
sponding products in moderate yields, which show the position
of substituents on the phenyl ring did not have a significant
effect on the reaction yields. When anisole was applied to the
reaction under standard conditions (3m), however, alkylation
B
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a
With the successful development of methods for the cross-
dehydrogenative coupling of C(sp3)−H bonds in N-methylani-
lines with C(sp3)−H bonds from cyclic alkanes and cyclic
ether, we then sought to investigate the tolerance of C(sp3)−H
bonds in toluene derivatives (Scheme 4). To our delight, this
Scheme 2. Substrate Scope of Aniline Derivatives
a
Scheme 4. Substrate Scope of Toluene Derivatives
a
Reaction condition: 1 (0.5 mmol), 2a (2.0 mL), FeCl2 (0.075
mmol), L3 (0.1 mmol), TBHP (1.75 mmol), Na2CO3 (0.55 mmol),
140 °C, 18 h.
reaction could not proceed smoothly. It is worth noting that
N,N-dimethylaniline was tolerated in this procedure (3n).
Next, we turned our attention to the scope of other cyclic
alkanes (Scheme 3). As expected, substrates possessing
a
Reaction conditions: 1a (0.5 mmol), 2′′’ (2.0 mL), FeCl2 (0.075
mmol), L3L3 (0.1 mmol), TBHP (1.75 mmol), Na2CO3 (0.55
mmol), 140 °C, 18 h.
Scheme 3. Substrate Scope of Other Cyclic Alkanes and
a
Cyclic Ethers
procedure is compatible with both electron-donating and
-withdrawing toluenes (5b−5f). Remarkably, N-methylanilines
bearing methyl, methoxy, and chloro groups at different
positions were well-tolerated too, and the corresponding
products were obtained in good yields (5g−5k).
To clarify the mechanism of the reaction, several control
experiments were carried out (Scheme 5). Upon the addition
of radical inhibitors 2,2,6,6-tetramethylpiperidinyloxy
(TEMPO, 4.0 equiv), butylated hydroxytoluene (BHT, 4.0
equiv), or 1,1-diphenylethene (4.0 equiv), the cross-dehydro-
genative coupling reaction (Scheme 5, D1−D3) of 1a with
cyclohexane 2a is completely suppressed (determined by GC−
MS and NMR 6a). On the other hand, when the radical
scavenger TEMPO was added to the cross-dehydrogenative
coupling reaction of 1a with toluene 2′a, no product 5a was
formed (determined by GC−MS). These results suggested
that the cross-dehydrogenative coupling reaction might involve
a radical process.
a
Reaction conditions: 1 (0.5 mmol), 2 (2.0 mL), FeCl2 (0.075
At the same time, only trace desired product was detected in
the absence of the iron catalyst, suggesting that the iron
catalyst plays a critical role in electron transfer (Scheme 6, E1).
In our procedure, the ligand might work as an activating
reagent of catalyst to facilitate the reaction (Scheme 6, E2).
When the reaction was run without TBHP, no product was
obtained (Scheme 6, E3). It might work as both oxidant and
radical initiator. Importantly, less than 20% yield of the
product 3a was observed without Na2CO3 (Scheme 6, E4),
showing that the deprotonation process is very dependent on
the base additive. Notably, the procedure under argon resulted
in no significant decrease of the yield (Scheme 6, E5),
indicating that additional oxygen is not required for the
mmol), L3L3 (0.1 mmol), TBHP (1.75 mmol), Na2CO3 (0.55
mmol), 140 °C, 18 h. 150 °C.
b
electron-donating (4b, 4e) or electron-withdrawing (4c, 4d)
substituents at the C-3 and C-2 positions afforded the desired
products in satisfactory yields (62−67%). Furthermore, this
method was compatible with cyclooctane (4f) when we
increased the temperature from 140 to 150 °C. Unfortunately,
cyclopentane (4g) could not be coupled with 1a under
standard conditions (detected by GC−MS). It is worth noting
that dioxane (4h) and tetrahydrofuran (4i) reacted with 1a to
afford corresponding products in good yields too.
C
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Scheme 5. Control Experiment
Scheme 6. Control Experiment
Scheme 8. Proposed Reaction Mechanism
reaction, and TBHP plays a major role in oxidation. It is worth
noting that the side product was 1,1′-bi(cyclohexane) from
homo-coupling of two cyclohexane radicals, and the yield of
the side product was 10% under our reaction conditions
(determined by GC−MS).
CONCLUSIONS
■
A primary kinetic isotope effect (KIE) in competing KIE
1
In summary, we have developed the first example of a cheap
transition metal iron-catalyzed highly selective cross-dehydro-
genative coupling of C(sp3)−H bonds in the N-methylanilines
with C(sp3)−H bonds of cyclic alkanes, cyclic ethers, and
toluene derivatives without any directing group (DG) via a
radical process. This procedure provides a good complement
to C(sp3)−H activation reactions and expands the field of Fe-
catalyzed C−H functionalizations. Detailed exploration of the
mechanism has also been carried out.
experiments (the KIE was determined by H NMR spectros-
copy by analyzing the ratio of 3a vs 3a-D) was observed (KH/
KD = 7.69), suggesting that the cleavage of the C(sp3)−H
bond might be involved in the turnover-limiting step (Scheme
7).
On the basis of the above experiments and previous work,6 a
plausible reaction mechanism for this iron-catalyzed cross-
dehydrogenative coupling is described in Scheme 8. First,
Fe(II) is oxidized into Fe(III) species under aerobic
conditions, which then undergoes single-electron transfer
(SET) from 1a to give the radical cation intermediate I.6d
Meanwhile, the radical initiator TBHP undergoes a thermal
decomposition to generate the tert-butoxyl radical. Subse-
quently, the abstraction of a hydrogen atom from the
intermediate I with the help of Na2CO3 affords the radical
intermediate II. Finally, the tert-butoxyl radical grabs one of
the hydrogen atoms in cyclohexane to generate the respective
radical, which reacts with the radical intermediate II to
generate the corresponding product III.
EXPERIMENTAL SECTION
■
1
General Information. All compounds are characterized by H
NMR, 13C NMR, and MS. Analytical thin-layer chromatography is
performed on glass plates precoated with silica gel impregnated with a
fluorescent indicator (254 nm), and the plates are visualized by
exposure to ultraviolet light. 1H NMR and 13C NMR spectra are
recorded on an AVANCE 500 Bruker spectrometer operating at 500
and 125 MHz in CDCl3, respectively, and chemical shifts are reported
in ppm. GC analyses are performed on an Agilent 7890A instrument
(column: Agilent 19091J-413: 30 m × 320 μm × 0.25 μm, H, FID
Scheme 7. KIE Experiment
D
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detection). GC−MS data were recorded on a 5975C mass selective
detector, coupled with a 7890A gas chromatograph (Agilent
Technologies). High-resolution mass spectral data were acquired on
an Agilent Technologies Accurate-Mass Q-TQF LC/MS 6520
operated by China Pharmaceutical University.
1.80−1.77 (m, 1H), 1.74−1.70 (m, 1H), 1.61 (td, J = 7.4, 3.8 Hz,
1H), 1.29−1.21 (m, 3H), 1.03−0.99 (m, 1H), 0.91−0.88 (m, 2H).
13C{1H} NMR (126 MHz, chloroform-d, δ): 145.3, 128.7, 125.2,
112.0, 50.1, 36.6, 30.4, 25.7, 25.0, 19.4. GC−MS (EI) m/z: 203.
N-(Cyclohexylmethyl)-4-methoxyaniline (3c). To a mixture of 4-
methoxy-N-methylaniline (68.5 mg, 0.5 mmol) 1c, FeCl2 (9.5 mg,
0.075 mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %),
TBHP (157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3
mg, 0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3c was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (72.3 mg, 66%).8c 1H NMR (500
MHz, chloroform-d, δ): 6.81 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.9 Hz,
2H), 3.78 (s, 3H), 2.95 (d, J = 6.6 Hz, 2H), 1.89−1.82 (m, 2H),
1.80−1.77 (m, 1H), 1.74−1.70 (m, 1H), 1.60 (ddd, J = 11.1, 7.6, 4.1
Hz, 1H), 1.32−1.21 (m, 3H), 1.00 (td, J = 12.1, 3.4 Hz, 2H). 13C{1H}
NMR (126 MHz, chloroform-d, δ): 150.9, 141.8, 114.0, 113.1, 54.9,
50.8, 36.6, 30.4, 25.6, 25.0. GC−MS (EI) m/z: 219.
N-(Cyclohexylmethyl)-4-fluoroaniline (3d). To a mixture of 4-
fluoro-N-methylaniline (62.5 mg, 0.5 mmol) 1d, FeCl2 (9.5 mg, 0.075
mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP
(157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg,
0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3d was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (63.1 mg, 61%).8d 1H NMR (500
MHz, chloroform-d, δ): 6.96−6.85 (m, 2H), 6.60−6.52 (m, 2H), 2.94
(d, J = 6.7 Hz, 2H), 1.88−1.82 (m, 2H), 1.80−1.77 (m, 1H), 1.74−
1.71 (m, 1H), 1.59 (ddd, J = 7.8, 5.7, 3.2 Hz, 1H), 1.31−1.20 (m,
3H), 1.07−0.96 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d,
δ): 155.6, 143.9, 114.6 (d, J = 22 Hz), 112.5, 50.5, 36.6, 30.3, 25.6,
25.0. GC−MS (EI) m/z: 207.
4-Chloro-N-(cyclohexylmethyl)aniline (3e). To a mixture of 4-
chloro-N-methylaniline (79.2 mg, 0.5 mmol) 1e, FeCl2 (9.5 mg, 0.075
mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP
(157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg,
0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3e was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (63.1 mg, 71%).8e 1H NMR (500
MHz, chloroform-d, δ): 7.14 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz,
2H), 2.95 (d, J = 6.7 Hz, 2H), 1.87−1.80 (m, 2H), 1.79−1.76 (m,
1H), 1.74−1.70 (m, 1H), 1.63−1.58 (m, 1H), 1.27−1.22 (m, 3H),
1.03−1.00 (m, 1H), 0.92−0.90 (m, 1H). 13C{1H} NMR (126 MHz,
chloroform-d, δ): 146.0, 128.0, 129.6, 112.9, 49.8, 36.5, 30.3, 25.6,
25.0. GC−MS (EI) m/z: 223.
General Procedure for the Preparation of N-Methylani-
lines.7 Sodium metal (5 mmol) was added portionwise to dry MeOH
(20 mL) at 0 °C. After complete consumption of the sodium metal
were added aniline (1 mmol) and paraformaldehyde (5 mmol) at
room temperature (26 °C), and the mixture was stirred for 2 h at
reflux to give an imine intermediate. The mixture was then reacted
with NaBH4 (1.5 mmol) at 0 °C and then refluxed for an additional 2
h. The reaction mixture was then cooled to room temperature, and
the solvent was evaporated on a rotary evaporator to give a residue
that was diluted with CH2Cl2 (15 mL) then washed with water (5
mL). Drying (Na2SO4) and evaporation of the solvent gave a residue
that was purified on a silica gel column chromatography using hexane
as an eluent.
General Procedure for Cross-Dehydrogenative Coupling of
α-C(sp3)−H Bonds in N-Methylamides and C(sp3)−H Bonds
from Cyclic Alkanes. To a mixture of N-methylaniline (53.5 mg, 0.5
mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %), ligand L3 (23.6
mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75 mmol, 3.5 equiv),
and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1 equiv) in a sealed
reaction tube was added to the solvent (cyclohexane = 2.0 mL). The
reaction mixture was stirred at 140 °C in an oil bath for 18 h in air.
The reaction mixture was extracted with ethyl acetate (15 mL × 3).
The combined organic layers were washed with brine (30 mL × 1),
dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to afford the desired
product 3a.
General Procedure for Cross-Dehydrogenative Coupling of
α-C(sp3)−H Bonds in N-Methylamides and C(sp3)−H Bonds
from Toluene Derivatives. To a mixture of N-methylaniline (53.5
mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %), ligand L3
(23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75 mmol, 3.5
equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1 equiv) in a
sealed reaction was added to the solvent (toluene = 2.0 mL). The
reaction mixture was stirred at 140 °C in an oil bath for 18 h in air.
The reaction mixture was extracted with ethyl acetate (15 mL × 3).
The combined organic layers were washed with brine (30 mL × 1),
dried over MgSO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to afford the desired
product 5a.
N-(Cyclohexylmethyl)aniline (3a). To a mixture of N-methylani-
line (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (cyclohexane = 2.0
mL). The reaction mixture was stirred at 140 °C in an oil bath for 18
h in air. Following the general procedure, 3a was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 7:3) as
a white solid (70.9 mg, 75%).8a 1H NMR (500 MHz, chloroform-d,
δ): 7.24−7.15 (m, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.65 (dd, J = 8.3, 3.2
Hz, 2H), 3.81 (s, 1H), 3.10−2.86 (m, 2H), 1.89−1.81 (m, 2H),
1.81−1.71 (m, 3H), 1.65−1.56 (m, 1H), 1.33−1.20 (m, 3H), 1.07−
0.97 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 147.4,
128.3, 116.1, 111.8, 49.8, 36.6, 30.4, 25.6, 25.0. GC−MS (EI) m/z:
189.
4-Bromo-N-(cyclohexylmethyl)aniline (3f). To a mixture of 4-
bromo-N-methylaniline (92.5 mg, 0.5 mmol) 1f, FeCl2 (9.5 mg,
0.075 mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %),
TBHP (157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3
mg, 0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3f was
purified by column chromatography on silica gel (petroleum ether/
1
ethyl acetate = 7:3) as a white solid (92.1 mg, 69%). H NMR (500
MHz, chloroform-d, δ): 7.27 (td, J = 10.3, 9.0, 2.7 Hz, 2H), 6.54−
6.45 (m, 2H), 2.95 (d, J = 6.5 Hz, 2H), 1.87−1.80 (m, 2H), 1.79−
1.76 (m, 1H), 1.72 (d, J = 9.9 Hz, 1H), 1.63−1.57 (m, 1H), 1.28−
1.22 (m, 3H), 1.03−0.99 (m, 1H), 0.92−0.88 (m, 2H). 13C{1H}
NMR (126 MHz, chloroform-d, δ): 146.5, 130.9, 113.3, 107.5, 49.7,
36.5, 30.3, 25.6, 25.0. GC−MS (EI) m/z: 267. HRMS (ESI) m/z:
calcd for [C13H18BrN + H]+, 268.0701; found, 268.0705.
4-((Cyclohexylmethyl)amino)benzonitrile (3g). To a mixture of 4-
(methylamino)benzonitrile (66.0 mg, 0.5 mmol) 1g, FeCl2 (9.5 mg,
0.075 mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %),
TBHP (157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3
mg, 0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
N-(Cyclohexylmethyl)-4-methylaniline (3b). To a mixture of N,4-
dimethylaniline (60.5 mg, 0.5 mmol) 1b, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3b was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (71.1 mg, 70%).8b 1H NMR (500
MHz, chloroform-d, δ): 7.02 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 8.4 Hz,
2H), 2.97 (d, J = 6.7 Hz, 2H), 2.27 (s, 3H), 1.89−1.83 (m, 2H),
E
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(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3g was
purified by column chromatography on silica gel (petroleum ether/
2H), 1.74−1.70 (m, 1H), 1.63−1.57 (m, 2H), 1.27−1.23 (m, 3H),
1.04−1.01 (m, 1H), 0.93−0.90 (m, 2H). 13C{1H} NMR (126 MHz,
chloroform-d, δ): 134.0, 129.1, 115.8, 111.2, 110.1, 101.4, 49.5, 36.5,
30.3, 25.6, 24.9. GC−MS (EI) m/z: 223.
1
ethyl acetate = 7:3) as a white solid (66.3 mg, 62%). H NMR (500
MHz, chloroform-d, δ): 7.44 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 8.8 Hz,
2H), 3.02 (d, J = 6.7 Hz, 2H), 1.85−1.76 (m, 4H), 1.75−1.70 (m,
1H), 1.64−1.58 (m, 1H), 1.32−1.27 (m, 2H), 1.26−1.21 (m, 1H),
1.06−0.98 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ):
150.6, 132.7, 119.5, 111.1, 99.0, 48.8, 36.5, 30.2, 25.4, 24.9. GC−MS
(EI) m/z: 214. HRMS (ESI) m/z: calcd for [C14H18N2 + H]+,
215.1548; found, 215.1552.
N(Cyclohexylmethyl)-3-methylaniline (3l). To a mixture of N,3-
dimethylaniline (60.5 mg, 0.5 mmol) 1l, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3l was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (72.1 mg, 71%).8h 1H NMR (500
MHz, chloroform-d, δ): 7.09 (td, J = 7.5, 3.1 Hz, 1H), 6.60−6.51 (m,
1H), 6.50−6.40 (m, 2H), 3.03−2.94 (m, 2H), 2.31 (s, 3H), 1.85 (d, J
= 13.1 Hz, 2H), 1.79−1.76 (m, 1H), 1.72 (d, J = 10.2 Hz, 1H), 1.65−
1.58 (m, 1H), 1.28−1.21 (m, 3H), 1.04−1.00 (m, 1H), 0.91−0.88
(m, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 147.6, 138.0,
128.1, 117.0, 112.5, 108.9, 49.7, 36.6, 30.4, 25.6, 25.0, 20.7. GC−MS
(EI) m/z: 203.
N-(Cyclohexylmethyl)-N-methylaniline (3n). To a mixture of N,N-
dimethylaniline (60.5 mg, 0.5 mmol) 1n, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3n was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (73.1 mg, 72%).8i 1H NMR (500
MHz, chloroform-d, δ): 7.29 (td, J = 8.6, 7.2, 2.4 Hz, 2H), 6.74 (d, J =
8.2 Hz, 3H), 3.19 (d, J = 6.7 Hz, 2H), 3.02 (s, 3H), 1.87−1.70 (m,
6H), 1.33−1.22 (m, 3H), 1.06−0.96 (m, 2H). 13C{1H} NMR (126
MHz, chloroform-d, δ): 149.6, 129.1, 115.4, 111.7, 59.8, 39.6, 36.9,
31.4, 26.6, 26.1. GC−MS (EI) m/z: 203.
N-(Cycloheptylmethyl)aniline (4a). To a mixture of N-methylani-
line (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (cycloheptane =
2.0 mL). The reaction mixture was stirred at 140 °C in an oil bath for
18 h in air. Following the general procedure, 4a was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate
= 7:3) as a white solid (71.1 mg, 70%).8j 1H NMR (500 MHz,
chloroform-d, δ): 7.18 (t, J = 7.8 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H),
6.61 (d, J = 7.9 Hz, 2H), 3.72 (s, 1H), 2.96 (d, J = 6.6 Hz, 2H), 1.89−
1.80 (m, 2H), 1.79−1.74 (m, 1H), 1.74−1.67 (m, 2H), 1.64−1.59
(m, 2H), 1.57−1.50 (m, 3H), 1.47−1.42 (m, 1H), 1.31−1.25 (m,
2H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 150.3, 128.2,
115.9, 111.6, 49.8, 38.2, 31.5, 27.6, 25.4. GC−MS (EI) m/z: 203.
N-(Cycloheptylmethyl)-4-methylaniline (4b). To a mixture of
N,4-dimethylaniline (60.5 mg, 0.5 mmol) 1b, FeCl2 (9.5 mg, 0.075
mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP
(157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg,
0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cycloheptane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 4b was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (69.4 mg, 64%).8h 1H NMR (500
MHz, chloroform-d, δ): 7.02 (d, J = 8.1 Hz, 2H), 6.58 (d, J = 8.1 Hz,
2H), 2.97 (d, J = 6.6 Hz, 2H), 2.28 (s, 3H), 1.88−1.81 (m, 2H),
1.75−1.69 (m, 2H), 1.64−1.62 (m, 1H), 1.56−1.48 (m, 3H), 1.31−
1.25 (m, 3H), 0.95−0.88 (m, 2H). 13C{1H} NMR (126 MHz,
chloroform-d, δ): 145.2, 128.7, 125.2, 111.9, 50.3, 38.1, 31.4, 27.6,
25.4, 19.4. GC−MS (EI) m/z: 217.
N-(Cyclohexylmethyl)-4-(trifluoromethyl)aniline (3h). To a mix-
ture of N-methyl-4-(trifluoromethyl)aniline (87.5 mg, 0.5 mmol) 1h,
FeCl2 (9.5 mg, 0.075 mmol, 15 mol %), ligand L3 (23.6 mg, 0.1
mmol, 20 mol %), TBHP (157.7 mg, 1.75 mmol, 3.5 equiv), and
additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1 equiv) in a reaction tube
was added to the solvent (cyclohexane = 2.0 mL). The reaction
mixture was stirred at 140 °C in an oil bath for 18 h in air. Following
the general procedure, 3h was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate = 7:3) as a white solid (73.2
1
mg, 57%). H NMR (500 MHz, DMSO-d6, δ): 7.32 (d, J = 8.5 Hz,
2H), 6.62 (d, J = 8.5 Hz, 2H), 2.87 (t, J = 6.2 Hz, 2H), 1.79−1.73 (m,
2H), 1.70−1.66 (m, 1H), 1.63−1.59 (m, 1H), 1.55−1.47 (m, 1H),
1.24−1.12 (m, 4H), 0.96−0.88 (m, 2H). 13C{1H} NMR (126 MHz,
DMSO-d6, δ): 151.5, 125.3 (q, J = 94 Hz), 113.9, 110.5, 99.0, 48.3,
36.2, 30.1, 25.6, 24.9. GC−MS (EI) m/z: 257. HRMS (ESI) m/z:
calcd for [C14H18F3N + H]+, 258.1470; found, 258.1463.
N-(Cyclohexylmethyl)-[1,1′-biphenyl]-4-amine (3i). To a mixture
of N-methyl-[1,1′-biphenyl]-4-amine (91.5 mg, 0.5 mmol) 1i, FeCl2
(9.5 mg, 0.075 mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20
mol %), TBHP (157.7 mg, 1.75 mmol, 3.5 equiv), and additive
Na2CO3 (58.3 mg, 0.55 mmol, 1.1 equiv) in a reaction tube was
added to the solvent (cyclohexane = 2.0 mL). The reaction mixture
was stirred at 140 °C in an oil bath for 18 h in air. Following the
general procedure, 3i was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate = 7:3) as a white solid (86.1
mg, 65%).8f 1H NMR (500 MHz, chloroform-d, δ): 7.60−7.51 (m,
2H), 7.45 (dt, J = 25.4, 7.7 Hz, 4H), 7.27 (dd, J = 18.6, 7.8 Hz, 2H),
6.76−6.62 (m, 2H), 4.12 (s, 1H), 3.04 (t, J = 6.2 Hz, 2H), 1.92−1.85
(m, 1H), 1.84−1.72 (m, 3H), 1.70−1.58 (m, 2H), 1.35−1.22 (m,
3H), 1.07−0.96 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d,
δ): 140.3, 129.1, 127.7, 127.0, 125.3, 125.0, 118.2, 112.1, 49.9, 36.6,
30.3, 25.6, 25.0. GC−MS (EI) m/z: 265.
N-(Cyclohexylmethyl)-2-methylaniline (3j). To a mixture of N,2-
dimethylaniline (60.5 mg, 0.5 mmol) 1j, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3j was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (70.0 mg, 69%).8g 1H NMR (500
MHz, chloroform-d, δ): 7.16 (td, J = 7.7, 1.6 Hz, 1H), 7.09 (d, J = 7.2
Hz, 1H), 6.69 (t, J = 7.8 Hz, 2H), 3.04 (d, J = 6.7 Hz, 2H), 2.19 (s,
3H), 1.92−1.84 (m, 2H), 1.82−1.76 (m, 2H), 1.74−1.64 (m, 2H),
1.31−1.22 (m, 3H), 1.08−1.01 (m, 2H). 13C{1H} NMR (126 MHz,
DMSO-d6, δ): 146.0, 129.1, 126.2, 120.8, 114.6, 108.3, 49.0, 35.8,
30.3, 25.7, 25.0, 17.1. GC−MS (EI) m/z: 203.
3-Chloro-N-(cyclohexylmethyl)aniline (3k). To a mixture of 3-
chloro-N-methylaniline (70.5 mg, 0.5 mmol) 1k, FeCl2 (9.5 mg, 0.075
mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP
(157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg,
0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cyclohexane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 3k was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (75.8 mg, 68%).8h 1H NMR (500
MHz, chloroform-d, δ): 7.09 (t, J = 8.0 Hz, 1H), 6.66 (dd, J = 7.9, 1.9
Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.2, 2.3 Hz, 1H), 2.96
(d, J = 6.7 Hz, 2H), 2.73 (s, 1H), 1.86−1.83 (m, 1H), 1.80−1.75 (m,
4-Chloro-N-(cycloheptylmethyl)aniline (4c). To a mixture of 4-
chloro-N-methylaniline (70.5 mg, 0.5 mmol) 1e, FeCl2 (9.5 mg,
0.075 mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %),
TBHP (157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3
mg, 0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cycloheptane = 2.0 mL). The reaction mixture was stirred at 140 °C
F
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in an oil bath for 18 h in air. Following the general procedure, 4c was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (77.0 mg, 65%).8h 1H NMR (500
MHz, chloroform-d, δ): 7.14 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz,
2H), 2.95 (d, J = 6.6 Hz, 2H), 1.86−1.79 (m, 2H), 1.73−1.70 (m,
1H), 1.64−1.59 (m, 2H), 1.55−1.48 (m, 3H), 1.28−1.23 (m, 3H),
0.93−0.89 (m, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ):
145.9, 128.0, 112.9, 99.0, 50.1, 38.1, 31.4, 27.5, 25.4. GC−MS (EI)
m/z: 237.
Hz, 1H), 3.24 (dd, J = 12.7, 4.0 Hz, 1H), 3.14 (dd, J = 12.7, 7.4 Hz,
1H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 128.3, 116.9,
112.1, 111.6, 72.9, 68.4, 67.6, 65.6, 44.1. GC−MS (EI) m/z: 193.
HRMS (ESI) m/z: calcd for [C11H15NO2 + H]+, 194.1181; found,
194.1183.
(S)-N-((Tetrahydrofuran-2-yl)methyl)aniline (4i). To a mixture of
N-methylaniline (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent
(tetrahydrofuran = 2.0 mL). The reaction mixture was stirred at 140
°C in an oil bath for 18 h in air. Following the general procedure, 4i
was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate = 7:3) as a white solid (52.2 mg, 59%).8k 1H NMR
(500 MHz, chloroform-d, δ): 7.23 (q, J = 8.0 Hz, 2H), 6.76 (dd, J =
9.2, 6.5 Hz, 1H), 6.74−6.66 (m, 2H), 4.22−4.15 (m, 1H), 3.94 (t, J =
7.4 Hz, 1H), 3.84 (t, J = 7.2 Hz, 1H), 3.36−3.26 (m, 1H), 3.19−3.07
(m, 1H), 2.15−2.05 (m, 1H), 2.04−1.91 (m, 2H), 1.78−1.66 (m,
1H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 148.3, 129.2,
117.6, 113.2, 76.8, 68.1, 48.3, 29.2, 25.9. GC−MS (EI) m/z: 177.
N-Phenethylaniline (5a). To a mixture of N-methylaniline (53.5
mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %), ligand L3
(23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75 mmol, 3.5
equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1 equiv) in a
reaction tube was added to the solvent (toluene = 2.0 mL). The
reaction mixture was stirred at 140 °C in an oil bath for 18 h in air.
Following the general procedure, 5a was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 7:3)
as a white solid (68.0 mg, 69%).8l 1H NMR (500 MHz, chloroform-d,
δ): 7.38 (t, J = 7.4 Hz, 2H), 7.32−7.26 (m, 3H), 7.24 (dd, J = 8.6, 7.2
Hz, 2H), 6.80−6.74 (m, 1H), 6.71−6.66 (m, 2H), 3.46 (t, J = 7.1 Hz,
2H), 2.98 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-
d, δ): 146.9, 138.3, 128.3, 127.8, 127.7, 125.5, 116.7, 112.2, 44.2, 34.5.
GC−MS (EI) m/z: 197.
N-(4-Methylphenethyl)aniline (5b). To a mixture of N-methylani-
line (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (p-xylene = 2.0
mL). The reaction mixture was stirred at 140 °C in an oil bath for 18
h in air. Following the general procedure, 5b was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 7:3) as
a white solid (45.4 mg, 43%).8m 1H NMR (500 MHz, chloroform-d,
δ): 7.24 (t, J = 7.7 Hz, 2H), 6.78 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 8.0
Hz, 2H), 3.44 (t, J = 7.1 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.40 (s,
3H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 147.0, 135.2,
135.0, 128.4, 128.3, 127.7, 116.6, 112.1, 44.3, 34.1, 20.1. GC−MS
(EI) m/z: 211.
N-(4-Chlorophenethyl)aniline (5c). To a mixture of N-methylani-
line (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (1-chloro-4-
methylbenzene = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 5c was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (65.8 mg, 57%).8n 1H NMR (500
MHz, chloroform-d, δ): 7.36 (t, J = 7.5 Hz, 2H), 7.31−7.23 (m, 3H),
7.19−7.14 (m, 2H), 6.58 (d, J = 8.8 Hz, 2H), 3.41 (t, J = 7.0 Hz, 2H),
2.95 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ):
145.4, 138.0, 128.1, 127.8, 127.7, 125.6, 121.3, 113.3, 44.3, 34.3. GC−
MS (EI) m/z: 231.
N-(4-Bromophenethyl)aniline (5d). To a mixture of N-methylani-
line (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (1-bromo-4-
methylbenzene = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 5d was
purified by column chromatography on silica gel (petroleum ether/
3-Chloro-N-(cycloheptylmethyl)aniline (4d). To a mixture of 3-
chloro-N-methylaniline (70.5 mg, 0.5 mmol) 1k, FeCl2 (9.5 mg, 0.075
mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP
(157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg,
0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cycloheptane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 4d was
purified by column chromatography on silica gel (petroleum ether/
1
ethyl acetate = 7:3) as a white solid (79.4 mg, 67%). H NMR (500
MHz, chloroform-d, δ): 7.09 (t, J = 8.0 Hz, 1H), 6.67 (dd, J = 7.9, 1.9
Hz, 1H), 6.61 (s, 1H), 6.50 (dd, J = 8.2, 2.3 Hz, 1H), 2.96 (d, J = 6.6
Hz, 2H), 1.85−1.79 (m, 2H), 1.73−1.70 (m, 1H), 1.62 (dt, J = 9.2,
3.1 Hz, 2H), 1.55−1.48 (m, 3H), 1.28−1.21 (m, 3H), 0.93−0.88 (m,
2H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 134.1, 129.2,
116.0, 111.4, 110.2, 101.8, 49.8, 38.0, 31.4, 27.6, 25.4. GC−MS (EI)
m/z: 237. HRMS (ESI) m/z: calcd for [C14H20ClN + H]+, 238.1363;
found, 238.1358.
N-(Cycloheptylmethyl)-3-methylaniline (4e). To a mixture of N,3-
dimethylaniline (60.5 mg, 0.5 mmol) 1l, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent
(cycloheptane = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 4e was
purified by column chromatography on silica gel (petroleum ether/
1
ethyl acetate = 7:3) as a white solid (67.3 mg, 62%). H NMR (500
MHz, chloroform-d, δ): 7.09 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 7.4 Hz,
1H), 6.46 (s, 1H), 6.45 (d, J = 2.4 Hz, 1H), 2.97 (d, J = 6.5 Hz, 2H),
2.31 (s, 3H), 1.87−1.81 (m, 2H), 1.73−1.70 (m, 1H), 1.66−1.60 (m,
2H), 1.55−1.47 (m, 3H), 1.29−1.21 (m, 3H), 0.95−0.89 (m, 2H).
13C{1H} NMR (126 MHz, chloroform-d, δ): 147.6, 138.0, 128.1,
117.0, 112.5, 108.9, 49.9, 38.2, 31.5, 27.6, 25.4, 20.7. GC−MS (EI)
m/z: 217. HRMS (ESI) m/z: calcd for [C15H23N + H]+, 218.1909;
found, 218.1923.
N-(Cyclooctylmethyl)aniline (4f). To a mixture of N-methylaniline
(53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (cyclooctane = 2.0
mL). The reaction mixture was stirred at 150 °C in an oil bath for 18
h in air. Following the general procedure, 4f was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 7:3) as
a white solid (59.7 mg, 55%).8j 1H NMR (500 MHz, chloroform-d,
δ): 7.18 (dd, J = 8.6, 7.2 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.61 (d, J
= 8.0 Hz, 2H), 2.95 (d, J = 6.9 Hz, 2H), 1.85−1.79 (m, 1H), 1.77−
1.68 (m, 5H), 1.63−1.59 (m, 3H), 1.53−1.49 (m, 3H), 1.39−1.34
(m, 2H), 1.30−1.27 (m, 1H). 13C{1H} NMR (126 MHz, chloroform-
d, δ): 147.7, 128.2, 115.9, 111.6, 50.2, 36.5, 29.7, 26.1, 25.4, 24.6.
GC−MS (EI) m/z: 217.
(R)-N-((1,4-Dioxan-2-yl)methyl)aniline (4h). To a mixture of N-
methylaniline (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent (1,4-
dioxane = 2.0 mL). The reaction mixture was stirred at 140 °C in an
oil bath for 18 h in air. Following the general procedure, 4h was
purified by column chromatography on silica gel (petroleum ether/
1
ethyl acetate = 7:3) as a white solid (43.4 mg, 45%). H NMR (500
MHz, chloroform-d, δ): 7.23 (dd, J = 8.6, 7.2 Hz, 2H), 6.78 (dd, J =
7.9, 6.8 Hz, 1H), 6.69−6.65 (m, 2H), 4.05 (s, 1H), 3.89−3.85 (m,
2H), 3.82−3.76 (m, 2H), 3.74−3.65 (m, 2H), 3.51 (dd, J = 11.4, 9.7
G
DOI: 10.1021/acs.joc.9b00625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ethyl acetate = 7:3) as a white solid (86.6 mg, 63%).8o 1H NMR (500
MHz, chloroform-d, δ): 7.47 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 8.6, 7.2
Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.66 (d, J
= 7.9 Hz, 2H), 3.43 (t, J = 7.0 Hz, 2H), 2.91 (t, J = 7.0 Hz, 2H).
13C{1H} NMR (126 MHz, chloroform-d, δ): 146.7, 137.3, 130.7,
129.6, 128.4, 119.3, 116.8, 112.1, 44.0, 33.9. GC−MS (EI) m/z: 275.
N-(2-Chlorophenethyl)aniline (5e). To a mixture of N-methylani-
line (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (1-chloro-2-
methylbenzene = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 5e was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (69.3 mg, 60%).8p 1H NMR (500
MHz, chloroform-d, δ): 7.42 (dd, J = 7.2, 2.0 Hz, 1H), 7.28−7.20 (m,
5H), 6.77 (t, J = 7.3 Hz, 1H), 6.70 (d, J = 7.7 Hz, 2H), 3.47 (t, J = 7.2
Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H). 13C{1H} NMR (126 MHz,
chloroform-d, δ): 146.7, 136.0, 133.2, 130.0, 128.7, 128.4, 127.0,
126.0, 116.7, 112.1, 42.6, 32.5. GC−MS (EI) m/z: 231.
N-(3-Chlorophenethyl)aniline (5f). To a mixture of N-methylani-
line (53.5 mg, 0.5 mmol) 1a, FeCl2 (9.5 mg, 0.075 mmol, 15 mol %),
ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75
mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1
equiv) in a reaction tube was added to the solvent (1-chloro-3-
methylbenzene = 2.0 mL). The reaction mixture was stirred at 140 °C
in an oil bath for 18 h in air. Following the general procedure, 5f was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (71.6 mg, 62%).8q 1H NMR (500
MHz, chloroform-d, δ): 7.36 (dd, J = 8.1, 6.8 Hz, 2H), 7.30−7.24 (m,
3H), 7.11 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 8.0, 1.9 Hz, 1H), 6.65 (t, J
= 2.2 Hz, 1H), 6.53 (dd, J = 8.2, 2.3 Hz, 1H), 3.42 (t, J = 7.0 Hz, 2H),
2.96 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ):
138.7, 137.9, 134.1, 129.3, 127.8, 127.7, 125.6, 116.6, 111.8, 110.6,
44.1, 34.3. GC−MS (EI) m/z: 231.
4-Methoxy-N-phenethylaniline (5g). To a mixture of 4-methoxy-
N-methylaniline (68.5 mg, 0.5 mmol) 1c, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent (toluene
= 2.0 mL). The reaction mixture was stirred at 140 °C in an oil bath
for 18 h in air. Following the general procedure, 5g was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate
= 7:3) as a white solid (74.9 mg, 66%).8r 1H NMR (500 MHz,
chloroform-d, δ) 7.36 (t, J = 7.4 Hz, 2H), 7.27 (t, J = 8.9 Hz, 3H),
6.83 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 3.41
(t, J = 7.0 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126
MHz, chloroform-d, δ): 151.3, 141.1, 138.4, 127.8, 127.6, 125.4,
114.0, 113.6, 54.9, 45.2, 34.6. GC−MS (EI) m/z: 227.
4-Chloro-N-phenethylaniline (5h). To a mixture of 4-chloro-N-
methylaniline (70.5 mg, 0.5 mmol) 1e, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent (toluene
= 2.0 mL). The reaction mixture was stirred at 140 °C in an oil bath
for 18 h in air. Following the general procedure, 5h was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate
= 7:3) as a white solid (77.4 mg, 67%).8s 1H NMR (500 MHz,
chloroform-d, δ): 7.32 (d, J = 8.3 Hz, 2H), 7.25−7.16 (m, 4H), 6.77
(t, J = 7.3 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 3.43 (t, J = 7.0 Hz, 2H),
2.93 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ):
146.6, 136.7, 131.3, 129.1, 128.4, 127.7, 116.9, 112.2, 44.1, 33.8. GC−
MS (EI) m/z: 231.
chromatography on silica gel (petroleum ether/ethyl acetate = 7:3) as
a white solid (58.9 mg, 51%).8t 1H NMR (500 MHz, chloroform-d,
δ): 7.42 (dd, J = 7.2, 2.0 Hz, 1H), 7.29−7.20 (m, 5H), 6.77 (d, J = 7.3
Hz, 1H), 6.70 (d, J = 7.6 Hz, 2H), 3.47 (t, J = 7.2 Hz, 2H), 3.10 (t, J =
7.2 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ): 146.8,
136.0, 130.0, 128.7, 128.4, 127.0, 125.9, 116.6, 112.1, 42.5, 32.5. GC−
MS (EI) m/z: 231.
3-Chloro-N-phenethylaniline (5j). To a mixture of 3-chloro-N-
methylaniline (70.5 mg, 0.5 mmol) 1k, FeCl2 (9.5 mg, 0.075 mmol,
15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7
mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55
mmol, 1.1 equiv) in a reaction tube was added to the solvent (toluene
= 2.0 mL). The reaction mixture was stirred at 140 °C in an oil bath
for 18 h in air. Following the general procedure, 5j was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate
= 7:3) as a white solid (67.0 mg, 58%).8u 1H NMR (500 MHz,
chloroform-d, δ): 7.32−7.20 (m, 5H), 7.14 (d, J = 7.0 Hz, 1H), 6.78
(t, J = 7.4 Hz, 1H), 6.67 (d, J = 7.9 Hz, 2H), 3.45 (t, J = 7.0 Hz, 2H),
2.94 (t, J = 7.0 Hz, 2H). 13C{1H} NMR (126 MHz, chloroform-d, δ):
146.6, 140.4, 133.4, 128.9, 128.4, 127.9, 126.0, 125.7, 116.8, 112.1,
43.9, 34.2. GC−MS (EI) m/z: 231.
3-Methyl-N-phenethylaniline (5k). To a mixture of N,3-
dimethylaniline (60.5 mg, 0.5 mmol) 1l, FeCl2 (9.5 mg, 0.075
mmol, 15 mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP
(157.7 mg, 1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg,
0.55 mmol, 1.1 equiv) in a reaction tube was added to the solvent
(toluene = 2.0 mL). The reaction mixture was stirred at 140 °C in an
oil bath for 18 h in air. Following the general procedure, 5k was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate = 7:3) as a white solid (55.9 mg, 53%).8v 1H NMR (500
MHz, chloroform-d, δ): 7.36 (dd, J = 8.6, 6.5 Hz, 2H), 7.28 (dd, J =
8.2, 6.6 Hz, 3H), 7.12 (dd, J = 9.0, 7.3 Hz, 1H), 6.59 (d, J = 7.5 Hz,
1H), 6.49 (d, J = 6.4 Hz, 2H), 3.44 (t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.0
Hz, 2H), 2.32 (s, 3H). 13C{1H} NMR (126 MHz, chloroform-d, δ):
147.0, 138.1, 128.2, 127.8, 127.6, 125.4, 117.6, 112.9, 109.3, 44.2,
34.6, 20.7. GC−MS (EI) m/z: 211.
(2-Cyclohexylethene-1,1-diyl)dibenzene (6a). To a mixture of N-
methylaniline (53.5 mg, 0.5 mmol) 1a, ethene-1,1-diyldibenzene
(360.0 mg, 2.0 mmol), FeCl2 (9.5 mg, 0.075 mmol, 15 mol %), ligand
L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg, 1.75 mmol, 3.5
equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol, 1.1 equiv) in a
reaction tube was added to the solvent (cyclohexane = 2.0 mL). The
reaction mixture was stirred at 140 °C in an oil bath for 18 h in air.
Following the general procedure, 6a was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 3:1)
as a white solid (267.2 mg, 51%).8w 1H NMR (500 MHz, chloroform-
d, δ): 7.38 (t, J = 7.2 Hz, 2H), 7.33 (dd, J = 6.9, 1.9 Hz, 1H), 7.29−
7.23 (m, 3H), 7.22−7.17 (m, 4H), 5.92 (d, J = 10.0 Hz, 1H), 2.14
(dd, J = 10.3, 3.2 Hz, 1H), 1.71−1.67 (m, 3H), 1.61 (d, J = 4.9 Hz,
1H), 1.23−1.13 (m, 5H), 0.91−0.84 (m, 1H). 13C{1H} NMR (126
MHz, chloroform-d, δ): 143.0, 140.6, 139.6, 136.0, 129.8, 128.2,
128.1, 127.2, 126.8, 126.7, 38.3, 33.4, 26.0, 25.6. GC−MS (EI) m/z:
262.
Scale-Up Experiment. To a mixture of N-methylaniline (535 mg,
5 mmol) 1a, FeCl2 (95 mg, 0.75 mmol, 15 mol %), ligand L3 (236
mg, 1 mmol, 20 mol %), TBHP (1.577 g, 17.5 mmol, 3.5 equiv), and
additive Na2CO3 (583 mg, 5.5 mmol, 1.1 equiv) in a reaction tube
was added to the solvent (cyclohexane = 20 mL). The reaction
mixture was stirred at 140 °C in an oil bath for 18 h in air. Following
the general procedure, 3a was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate = 7:3) as a white solid (652.1
mg, 69%) (caution: TBHP is unstable above 75 °C, and heating large
amounts of TBHP at 140 °C is potentially dangerous7c).
2-Chloro-N-phenethylaniline (5i). To a mixture of 2-chloro-N-
methylaniline (70.5 mg, 0.5 mmol) 1′, FeCl2 (9.5 mg, 0.075 mmol, 15
mol %), ligand L3 (23.6 mg, 0.1 mmol, 20 mol %), TBHP (157.7 mg,
1.75 mmol, 3.5 equiv), and additive Na2CO3 (58.3 mg, 0.55 mmol,
1.1 equiv) in a reaction tube was added to the solvent (toluene = 2.0
mL). The reaction mixture was stirred at 140 °C in an oil bath for 18
h in air. Following the general procedure, 5i was purified by column
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00625.
■
S
NMR spectra of the obtained compounds (ZIP)
H
DOI: 10.1021/acs.joc.9b00625
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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AUTHOR INFORMATION
Corresponding Author
*E-mail: c.cai@njust.edu.cn.
ORCID
Chun Cai: 0000-0002-5755-9361
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
Jiangsu Province (BK 20131346, BK 20140776) for the
financial support. This work was also supported by the
National Natural Science Foundation of China (21476116,
21402093) and the Chinese Postdoctoral Science Foundation
(2015M571761, 2016T90465).
̈
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