Iron-catalyzed N-alkylation using π-activated ethers as electrophiles

Article abstract of DOI:10.1039/c3ob27128e

A new method for the synthesis of diverse N-alkylation compounds was developed via an iron-catalyzed etheric Csp³-O cleavage with the C-N bond formation in the reaction of π-activated ethers with various nitrogen-based nucleophiles. In addition, the mechanism of this reaction was investigated. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27128e

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Iron-catalyzed N-alkylation using π-activated ethers as
electrophiles†
Cite this: Org. Biomol. Chem., 2013, 11,
2147
Xiaohui Fan,* Lin-An Fu, Na Li, Hao Lv, Xiao-Meng Cui and Yuan Qi
Received 31st October 2012,
Accepted 16th January 2013
A new method for the synthesis of diverse N-alkylation compounds was developed via an iron-catalyzed
etheric Csp3–O cleavage with the C–N bond formation in the reaction of π-activated ethers with various
nitrogen-based nucleophiles. In addition, the mechanism of this reaction was investigated.
DOI: 10.1039/c3ob27128e
www.rsc.org/obc
one of our continuous interests in nitrogen-containing com-
pound synthesis,9 herein we report a practical method for the
Introduction
The direct functionalization of etheric carbon–oxygen bonds is synthesis of diverse N-alkylation compounds via an iron-
an attractive strategy for construction of carbon–carbon and catalyzed etheric Csp3–O cleavage strategy, which serves as a
carbon–heteroatom bonds in organic synthesis,1 since ethers supplement to those existing methodologies.5–7,10
are stable and readily available building blocks in the natural
and synthetic world, and they have many apparent advantages
from environmental and economical viewpoints compared
with the corresponding halides. In the past decade, consider-
Results and discussion
able achievements have been made for the transition-metal
catalytic activation of etheric Csp2–O bonds in C–C and C–N
bond formation reactions,2 such as using aryl ethers instead of
aryl halides in Suzuki and Kumada couplings. However, com-
pared to the Csp2–O bond activation, far fewer methods exist
for the etheric Csp3–O bond cleavage due to its high bond dis-
sociation energy and difficulty in differentiating two different
Initial examinations were carried out on the reactions of
benzyl methyl ether (1a) and (1-methoxyethyl)benzene (1b)
with p-toluenesulfonamide (2a) in various solvents. FeCl3 was
chosen as the catalyst because iron is an abundant, economi-
cal, and environmentally friendly metal on earth and shows
increasing and promising catalytic abilities for the C–C and
C–N bond formations.11 The results are summarized in
Table 1. To our delight, primary and secondary benzylic
methyl ethers 1a and 1b can both serve as electrophiles in this
N-alkylation reaction. For primary ether 1a, a relatively high
reaction temperature was required (80 °C, Table 1, entries 1
and 17). Encouraged by these initial results, further investi-
gation of the solvent effect indicates that the nature of the
reaction media significantly affects the reaction (Table 1,
entries 4–11). DCE and DCM were found to be the more suit-
able solvents for the transformation of primary benzylic ether
1a and secondary benzylic ether 1b, respectively (Table 1,
entries 2 and 18). With respect to the catalyst loading, 20 mol
% of FeCl3 was found to be optimal (Table 1, entries 1–3 and
17–19). Under the optimized reaction conditions, the desired
amidation products 3a and 3b could be isolated in 61% and
75% yields, respectively (Table 1, entries 2 and 18). Note that
the reaction time and temperature are crucial to this trans-
formation due to the instability of the products under the reac-
tion conditions.12 Recently, the iron-catalyzed cleavage of the
C–N bond of benzylic sulfonamides has emerged as a useful
strategy in C–C bond formation reactions.13 Other iron and
copper salts, such as FeCl2, Fe(acac)3, and CuI, proved to be
ineffective for this reaction (Table 1, entries 12–14). Replacing
C
sp3–O bonds in unactivated ethers.1,3 Most reported examples
of Csp3–O cleavage are with strained cyclic ethers,3e,f alkyl C–O
bonds with good leaving groups such as OTs and OMs,4 or
relatively reactive Csp3–O bonds of allylic or benzylic acetates
and alcohols.5,6
In 2008, Shi and co-workers reported the first example of
Ni-catalyzed selective activation of benzylic Csp3–O etheric
bonds in C–C bond formations.3a However, up to now, only a
few examples of conversion of benzylic or allylic Csp3–O etheric
bonds to C–N bonds have been disclosed.7 Among them, the
reaction of allylic or benzylic ethers with chlorosulfonyl iso-
cyanate (CSI) was found to be a particularly useful methodo-
logy and has been applied to the total synthesis of biologically
active alkaloids.7g,h Given the importance of nitrogen-contain-
ing compounds in organic synthesis,8 further exploration of
new methods for this transformation is highly desirable. As
School of Chemical and Biological Engineering, Lanzhou Jiaotong University,
Lanzhou, 730070, China. E-mail: fanxh@mail.lzjtu.cn; Fax: +86 931 493 8755;
Tel: +86 931 493 8755
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/c3ob27128e
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2147–2153 | 2147

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization of reaction conditionsa
the electronic and steric properties of benzylic ethers and the
stability of the corresponding products.12,13 For example, with
the more sterically hindered tertiary benzylic methyl ether 1r
(Table 2, entry 16) as the reactant, the alkylation took place at
longer reaction time and the product 3r was obtained in lower
yield. With respect to the electronic effect, the substituents on
the phenyl ring of benzylic ethers had an obvious influence on
the product yields (Table 2, entries 3 and 6). Overall, the reac-
tion was facilitated with electron-rich benzylic methyl ethers
which bear an electron-donating group on the phenyl ring
(Table 2, entries 3, 9, and 10). The relatively lower yields of 3g
and 3m are presumably due to their lower stability under the
iron catalytic conditions (Table 2, entries 5 and 11).
Further investigation of the generality and efficiency of this
reaction was also conducted by using non-π-activated ethers,
allylic methyl ethers, p-toluenesulfonamide, aniline, benz-
amide, 4-nitroaniline and trimethylsilyl azide as substrates
(Table 3). Various allylic methyl ethers can react smoothly with
p-toluenesulfonamide, 4-nitroaniline and trimethylsilyl azide17
under the optimized conditions, giving the corresponding pro-
ducts in moderate to good yields. Interestingly, for the allylic
methyl ether 1v, only the thermodynamically favored isomeric
product 3v was obtained (Table 3, entry 2). Similarly, the cata-
lytic system was also effective for the reaction of secondary
benzylic methyl ethers 1n and 1j with 4-nitroaniline (2b) and
trimethylsilyl azide (2e), affording aniline-based product 3nb
and azide product 3je in 85% and 87% yields respectively
(Table 3, entries 7 and 11). However, to our disappointment,
non-π-activated ethers, such as 2-phenylethyl methyl ether 1u,
could not undergo this transformation even under harsh reac-
tion conditions (Table 3, entry 1).18 Examination also revealed
that aniline (2c) and benzamide (2d) were not suitable nucleo-
philes for this transformation (Table 3, entries 8, 9 and 10).
Based on the above results, we can conclude that (1) the π-acti-
vated ethers, such as allylic methyl ethers and primary, sec-
ondary and tertiary benzylic methyl ethers, can serve as
electrophiles in this N-alkylation, (2) the benzylic methyl
ethers are more reactive than the allylic methyl ethers, and (3)
amines with higher nitrogen basicity lead to lower reactivity in
this iron-catalyzed reaction.
Entry R1 Catalyst (mol%)
Solvent T (°C)/t (h) Yieldb (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
FeCl3 (15)
FeCl3 (20)
FeCl3 (30)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl2 (20)
Fe(acac)3 (20)
Cul (10)
DCE
DCE
DCE
DCM
CH3NO2 75/0.5
DMF 90/1.5
Toluene 90/9
THF
EtOAc
Dioxane 90/7
None
DCE
DCE
DCE
DCE
DCE
DCM
DCM
DCM
DCM
DCM
90/6
90/1
90/0.5
40/24
45
61
42
9
41
0
0
65/6
65/5
Trace
Trace
0
47
0
Mess
0
0
18
49
75
55
60
21
2
9
10
11
12
13
14
15
16
17
18
19
20c
21
22
23
24c
90/1.5
90/6.5
90/2
90/2
90/3
90/1
rt/6
rt/1
rt/1
rt/6
rt/6
None
Me FeCl3 (20)
Me FeCl3 (10)
Me FeCl3 (20)
Me FeCl3 (30)
Me FeCl3 (20)
Me FeCl3·6H2O (20)
Me FeCl3 (20)/TMEDA (20) DCM
Me FeCl3 (20)/K2CO3 (20)
Me TfOH (20)
rt/11
rt/6
rt/2
DCM
DCM
36
48
a Reaction conditions: benzylic ether (0.35 mmol), TsNH2 (0.46 mmol),
solvent (4 mL), under argon. b Isolated yield. c In air.
FeCl3 with FeCl3·6H2O, the reaction proceeded in lower yield
(21%, Table 1, entry 21). No desired products were formed in
the absence of catalyst (Table 1, entry 15). Optimization also
revealed that the present reaction is more favored under an
argon atmosphere than in air (Table 1, entries 18 and 20). In
order to further improve the yield of this transformation, the
additives of K2CO3 and TMEDA were added to the optimized
reaction conditions separately, since it has been reported that
some basic and ligand additives can affect the yields of the
iron-catalyzed reactions.11,14 Unfortunately, no favorable effect
on the yields was observed (Table 1, entries 22 and 23). In
addition, several Brønsted acids were also examined as cata-
lysts for the reaction between 1b and 2a in DCM at room temp-
erature. It was found that only triflic acid (Table 1, entry 24)
exhibited catalytic activity in this transformation and a lower
yield of 3b was obtained.15
With the optimized reaction conditions in hand (Table 1,
entries 2 and 18), the generality of this N-alkylation reaction
was investigated on a series of secondary and tertiary benzylic
methyl ethers (Table 2).16 Functional groups, such as aromatic
chloro or methoxy groups, CvC double bond, cyclopropyl and
acetal, can tolerate the reaction conditions. In general, the
reaction proceeds efficiently for both electron-rich and -poor
benzylic methyl ethers within a very short period of time at
room temperature, and the yields are relatively consistent with
With respect to the reaction mechanism, an elimination–
hydroamidation pathway could be ruled out,12 since both
primary benzylic methyl ether and benzhydrylic methyl ethers
served as suitable reaction components in this transformation
(Table 1, entry 2, and Table 2, entries 1, 5, 8 and 11). The reac-
tion most likely proceeded via an SN1-type substitution
process. In order to verify this proposal, (R)-(1-methoxyethyl)-
benzene ((R)-1b, >97% ee) was prepared from commercially
available (R)-1-phenylethanol (>97% ee), and then treated with
toluenesulfonamide (2a) under the typical reaction conditions
(Scheme 1). After 1 h, the product 3b was isolated in 73% yield
in racemic form. This result suggests that a benzylic cation
intermediate was generated from (R)-1b through iron-catalyzed
Csp3–O etheric bond cleavage. Furthermore, considering that
the aniline 2c, which was more nucleophilic than 4-nitro-
aniline 2b, could not react as a nucleophile in this reaction
2148 | Org. Biomol. Chem., 2013, 11, 2147–2153
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Reaction of benzylic ethers with p-toluenesulfonamidea
Entry
1
Ether
Product
T (°C)/t (h)
Yieldb (%)
96
rt/2
2
3
rt/2
88
90
rt/0.5
4
5
6
7
rt/0.2
rt/1.5
40/12
40/12
70
71
52
61
8
40/3
rt/0.8
rt/0.8
rt/1
98
81
83
63
9
10
11c
12
13
14
rt/1
rt/1
rt/1
98
80
74
15
16
17
rt/0.25
40/7.5
rt/0.3
74
32
67
18
rt/0.3
62
a Reaction conditions: benzylic ether (0.35 mmol), TsNH2 (0.46 mmol), DCM (4 mL), FeCl3 (20 mol%), under argon. b Isolated yield. c 10 mol%
FeCl3.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2147–2153 | 2149

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 3 Reaction of p-toluenesulfonamide, aniline, 4-nitroaniline, benzamide and trimethylsilyl azide with various ethersa
Entry
1
Ether
Amine
Product
T (°C)/t (h)
Yieldb (%)
n.r.
TsNH2 2a
40/8
2c
3
2a
2a
2a
40/15
rt/1
55
61
63
4
rt/1
5
6
rt/1
71
47
2b
2b
rt/22
7
8
rt/8
85
40/8
n.r.
9
40/4
40/8
Trace
Trace
10
2d
11
12
TMSN3 2e
rt/3
87
82
2e
rt/2.5
a Reaction conditions: benzylic ether (0.35 mmol), TsNH2 (0.46 mmol), DCM (4 mL), FeCl3 (20 mol%), under argon. b Isolated yield. c In dioxane.
catalyzed N-alkylation reaction. In light of the above results, a
mechanism for this reaction was proposed in Scheme 2.
Conclusions
Scheme 1 N-Alkylation of 2a with (R)-1b.
In summary, we have developed a new iron-catalyzed N-alkyl-
ation reaction using π-activated benzylic and allylic ethers as
(Table 3, entries 7 and 8), we assume that an amino anion,
electrophiles, which provides an alternative method for the
rather than amine itself, acts as a nucleophile in this iron- synthesis of nitrogen-containing compounds. In addition, the
2150 | Org. Biomol. Chem., 2013, 11, 2147–2153
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
133.27, 132.94, 129.24, 129.07, 127.11, 126.96, 56.03, 29.42,
21.37, 10.19. HRMS (ESI): (M + NH4)+ C16H21Cl2N2O2S, Calcd
375.0701, found 375.0695. m.p. 153–154 °C.
N-(1-(2,4-Dichlorophenyl)but-3-enyl)-4-methylbenzenesulfon-
amide (3i). White solid. 1H NMR (400 MHz, CDCl3):
δ 7.61–7.56 (m, 2H), 7.24–7.12 (m, 4H), 7.06 (dd, J = 8.4,
2.1 Hz, 1H), 5.52–5.39 (m, 1H), 5.17–5.04 (m, 3H), 4.74 (dd, J =
13.8, 6.1 Hz, 1H), 2.45–2.34 (m, 5H). 13C NMR (100 MHz,
CDCl3): δ 143.51, 136.53, 133.46, 132.66, 132.27, 129.33,
129.12, 127.07, 119.77, 53.51, 40.09, 21.41. HRMS (ESI):
(M + Na)+ C17H17Cl2NNaO2S, Calcd 392.0255, found 392.0249.
m.p. 132–133 °C.
N-(1-(Benzo[d][1,3]dioxol-5-yl)propyl)-4-methylbenzenesulfon-
amide (3k). White solid. 1H NMR (400 MHz, CDCl3): δ 7.56 (d,
J = 8.1 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.62–6.41 (m, 3H), 5.85
(d, J = 7.3 Hz, 2H), 5.43 (d, J = 6.5 Hz, 1H), 4.08 (q, J = 7.1 Hz,
1H), 2.36 (s, 3H), 1.77 (dt, J = 14.1, 7.1 Hz, 1H), 1.68–1.59 (m,
1H), 0.76 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 147.45, 146.58, 142.75, 137.71, 134.64, 129.11, 127.01,
120.28, 107.79, 106.80, 100.85, 59.68, 30.42, 21.37, 10.44. m.
p. 91–92 °C.
Scheme 2 Proposed mechanism.
reaction pathway was also proposed based on the preliminary
mechanistic study and experimental results. Further explora-
tion of the oxygen-containing compounds as electrophiles in
organic synthesis is in progress in our laboratory.
Experimental
General
Reactions were monitored by analytical TLC using ultraviolet
light and phosphomolybdic acid for visualization. All organic
solvents were dried and freshly distilled before use. Purifi-
cation of products was accomplished by flash chromatography
on silica gel (200–300 mesh) and the purified compounds
show a single spot by analytical TLC. NMR spectra were
recorded on Bruker Avance-III 400 and Varian Mercury 400
(400 MHz for 1H and 100 MHz for 13C NMR) nuclear magnetic
resonance spectrometers. CDCl3 was used as the solvent with
TMS as an internal standard. Chemical shifts δ and coupling
constants J are given in ppm (parts per million) and Hz (hertz)
respectively. HRMS (ESI) analysis was measured on a Bruker
APEX II (ESI) mass spectrometer. Melting points were
measured on a micro melting apparatus and uncorrected.
N-(1-(Benzo[d][1,3]dioxol-5-yl)pentyl)-4-methylbenzenesulfon-
amide (3l). White solid. H NMR (400 MHz, CDCl3): δ 7.54 (d,
1
J = 8.1 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.54 (dd, J = 37.6, 7.9
Hz, 2H), 6.44 (s, 1H), 5.87 (d, J = 7.5 Hz, 2H), 4.93 (s, 1H), 4.16
(t, J = 7.2 Hz, 1H), 2.37 (s, 3H), 1.77–1.68 (m, 1H), 1.61 (dd, J =
7.5, 5.5 Hz, 1H), 1.22 (dt, J = 33.3, 14.5 Hz, 4H), 1.06 (dd, J =
12.1, 7.0 Hz, 1H), 0.80 (dd, J = 13.7, 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 147.52, 146.63, 142.81, 137.69, 134.89,
129.12, 127.04, 120.18, 107.85, 106.70, 100.89, 58.13, 37.17,
27.92, 22.12, 21.37, 13.77. HRMS (ESI): (M
+
Na)+
C19H23NNaO4S, Calcd 384.1245, found 384.1240. m.p.
97–98 °C.
4-Methyl-N-(1-(naphthalen-1-yl)pentyl)benzenesulfonamide
(3o). White solid. 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J = 5.3
Hz, 1H), 7.78–7.71 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.42 (d, J =
7.1 Hz, 4H), 7.31–7.20 (m, 2H), 6.84 (d, J = 8.0 Hz, 2H), 5.75 (d,
J = 7.1 Hz, 1H), 5.12 (d, J = 6.9 Hz, 1H), 2.20 (s, 3H), 1.88 (dd,
J = 14.2, 7.0 Hz, 2H), 1.38–1.29 (m, 1H), 1.23 (dd, J = 13.4,
6.6 Hz, 3H), 0.77 (t, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 142.60, 137.28, 137.13, 133.63, 130.47, 128.85,
128.71, 127.60, 126.88, 126.05, 125.41, 125.21, 123.91, 122.57,
54.11, 37.24, 28.28, 22.27, 21.27, 13.86. HRMS (ESI): (M + Na)+
C22H25NNaO2S, Calcd 390.1504, found 390.1499. m.p.
131–132 °C.
4-Methyl-N-(1-(naphthalen-1-yl)but-3-en-1-yl)benzenesulfon-
amide (3p). White solid. 1H NMR (400 MHz, CDCl3): δ 7.91 (d,
J = 8.6 Hz, 1H), 7.82–7.72 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H),
7.51–7.40 (m, 4H), 7.34–7.21 (m, 2H), 6.94 (d, J = 7.9 Hz, 2H),
5.63–5.50 (m, 2H), 5.23 (dd, J = 13.3, 6.6 Hz, 1H), 5.06 (t, J =
14.6 Hz, 2H), 2.62 (t, J = 6.5 Hz, 2H), 2.25 (s, 3H). 13C NMR
General procedure for iron-catalyzed N-alkylation
To a stirred solution of (1-methoxyethyl)benzene 1b (47.7 mg,
0.35 mmol, 1 equiv.) in 4 mL anhydrous CH2Cl2 under argon
was added p-toluenesulfonamide 2a (77.9 mg, 0.455 mmol)
and FeCl3 (11.4 mg, 0.07 mmol, 20 mol%) successively at room
temperature. After stirring at room temperature for 1 h
(monitored by TLC), the reaction was quenched by addition of
H2O (3 mL) and then extracted with ethyl acetate (3 × 3 mL).
The combined organic layer was washed with brine, dried over
Na2SO4, and concentrated. The crude product was purified by
column chromatography on silica gel (petroleum ether–ethyl
acetate
= 6 : 1) to afford the corresponding amidation
product 3b.
Characterization data for all new compounds
N-(1-(2,4-Dichlorophenyl)propyl)-4-methylbenzenesulfonamide (100 MHz, CDCl3): δ 142.82, 137.10, 135.90, 133.62, 133.17,
1
(3h). White solid. H NMR (400 MHz, CDCl3): δ 7.58 (dd, J = 130.17, 128.95, 128.75, 127.75, 126.94, 126.11, 125.40, 125.03,
8.2, 1.5 Hz, 2H), 7.16–6.99 (m, 5H), 5.82–5.66 (m, 1H), 124.17, 122.36, 119.05, 53.23, 41.17, 21.28. HRMS (ESI):
4.67–4.60 (m, 1H), 2.37 (s, 3H), 1.74–1.68 (m, 2H), 0.83 (t, J = (M + NH4)+ C21H25N2O2S, Calcd 369.1637, found 369.1631.
7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 143.32, 136.99, m.p. 96–97 °C.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2147–2153 | 2151

View Article Online
Paper
4-Methyl-N-(2-phenylpent-4-en-2-yl)benzenesulfonamide (3r).
Organic & Biomolecular Chemistry
Acknowledgements
1
White solid. H NMR (400 MHz, CDCl3): δ 7.56 (d, J = 8.2 Hz,
2H), 7.28 (dd, J = 7.7, 1.5 Hz, 2H), 7.21–7.12 (m, 5H), 5.54–5.43 We thank the Natural Science Foundation of China (21162013)
(m, 1H), 5.26 (d, J = 4.0 Hz, 1H), 5.10 (dd, J = 13.3, 6.9 Hz, 2H), for financial support, Drs Yong Liang and Lei Jiao for helpful
2.69 (dd, J = 13.7, 7.1 Hz, 1H), 2.53 (dd, J = 13.6, 7.4 Hz, 1H), discussions, and Prof. Xiaoqian Han for assistance with HPLC
2.38 (s, 3H), 1.63 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 143.56, analysis.
142.55, 139.86, 132.60, 129.18, 128.00, 126.85, 125.94, 120.00,
60.60, 47.98, 25.59, 21.38. HRMS (ESI): (M
+
Na)+
C18H21NNaO2S, Calcd 338.1191, found 338.1185. m.p.
83–84 °C.
Notes and references
4-Methyl-N-(3-methyl-4-phenylbut-3-en-2-yl)benzenesulfon-
amide (3x). White solid. H NMR (400 MHz, CDCl3): δ 7.75 (d,
1 (a) D.-G. Yu, B.-J. Li and Z.-J. Shi, Acc. Chem. Res., 2010, 43,
1
1486, and references therein;
(b) B. M. Rosen,
J = 8.2 Hz, 2H), 7.30–7.15 (m, 5H), 7.01 (d, J = 7.4 Hz, 2H), 6.25
(s, 1H), 5.03 (d, J = 7.2 Hz, 1H), 4.10–4.00 (m, 1H), 2.36 (s, 3H),
1.56 (s, 3H), 1.28 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 143.09, 137.87, 137.23, 137.00, 129.40, 128.81,
127.91, 127.29, 126.79, 126.46, 57.26, 21.40, 20.71, 13.12.
HRMS (ESI): (M + Na)+ C18H21NNaO2S, Calcd 338.1191, found
338.1185. m.p. 101–102 °C.
N-(2-Methyl-3-phenylallyl)-4-nitroaniline (3y). Yellow solid.
1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 9.2 Hz, 2H), 7.35–7.32
(m, 2H), 7.25–7.21 (m, 3H), 6.60 (d, J = 9.2 Hz, 2H), 6.49 (s,
1H), 4.86 (s, 1H), 3.94 (d, J = 5.8 Hz, 2H), 1.92 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 153.39, 138.22, 137.09, 133.61, 128.80,
128.22, 126.71, 126.55, 126.39, 111.35, 51.44, 16.20. HRMS
(ESI): (M + H)+ C16H17N2O2, Calcd 269.1290, found 269.1285.
m.p. 114–115 °C.
N-(2-Benzylideneoctyl)-4-nitroaniline (3z). Yellow solid.
1H NMR (400 MHz, CDCl3): δ 8.10 (d, J = 9.1 Hz, 2H), 7.33 (t,
J = 7.4 Hz, 2H), 7.20 (d, J = 7.5 Hz, 2H), 6.59 (d, J = 9.1 Hz, 2H),
6.48 (s, 1H), 4.77 (s, 1H), 3.95 (d, J = 5.7 Hz, 2H), 2.31–2.26 (m,
2H), 1.29 (dd, J = 17.0, 7.8 Hz, 8H), 0.87 (t, J = 6.5 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 153.25, 138.10, 128.46, 128.16,
126.57, 126.29, 111.25, 49.14, 31.46, 29.52, 29.34, 28.30, 22.50,
13.96. HRMS (ESI): (M + H)+ C21H27N2O2, Calcd 339.2073,
found 339.2067. m.p. 74–75 °C.
K. W. Quasdorf, D. A. Wilson, N. Zhang, A. M. Resmerita,
N. K. Garg and V. Percec, Chem. Rev., 2011, 111, 1346.
2 (a) J. W. Dankwardt, Angew. Chem., Int. Ed., 2004, 43, 2428;
(b) S. Ueno, E. Mizushima, N. Chatani and F. Kakiuchi,
J. Am. Chem. Soc., 2006, 128, 16516; (c) B.-T. Guan,
S.-K. Xiang, T. Wu, Z.-P. Sun, B.-Q. Wang, K.-Q. Zhao and
Z.-J. Shi, Chem. Commun., 2008, 1437; (d) T. Shimasaki,
Y. Konno, M. Tobisu and N. Chatani, Org. Lett., 2009, 11,
4890; (e) J. M. Nichols, L. M. Bishop, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2010, 132, 12554;
(f) A. Iijima and H. Amii, Tetrahedron Lett., 2008, 49, 6013;
(g) G. A. Molander and F. Beaumard, Org. Lett., 2010, 12,
4022; (h) B.-J. Li, D.-G. Yu, C.-L. Sun and Z.-J. Shi,
Chem.–Eur. J., 2011, 17, 1728.
3 (a) B.-T. Guan, S.-K. Xiang, B.-Q. Wang, Z.-P. Sun, Y. Wang,
K.-Q. Zhao and Z.-J. Shi, J. Am. Chem. Soc., 2008, 130, 3268;
(b) H. T. Dao, U. Schneider and S. Kobayashi, Chem.
Commun., 2011, 47, 692; (c) C. Chen and S. H. Hong, Org.
Lett., 2012, 14, 2992; (d) S. Son and F. D. Toste, Angew.
Chem., Int. Ed., 2010, 49, 3791; (e) R. E. Mulvey, V. L. Blair,
W. Clegg, A. R. Kennedy, J. Klett and L. Russo, Nat. Chem.,
2010, 2, 588; (f) X. W. Guo, S. G. Pan, J. H. Liu and Z. P. Li,
J. Org. Chem., 2009, 74, 8848; (g) B.-Q. Wang, S.-K. Xiang,
Z.-P. Sun, B.-T. Guan, P. Hu, K.-Q. Zhao and Z.-J. Shi, Tetra-
hedron Lett., 2008, 49, 4310; (h) B. L. H. Taylor, E. C. Swift,
J. D. Waetzig and E. R. Jarvo, J. Am. Chem. Soc., 2011, 133,
389; (i) X. Han, Y. Zhang and J. Wu, J. Am. Chem. Soc., 2010,
132, 4104.
4 (a) M. R. Netherton and G. C. Fu, Angew. Chem., Int. Ed.,
2002, 41, 3910; (b) S. P. Y. Cutulic, N. J. Findlay, S. Z. Zhou,
E. J. T. Chrystal and J. A. Murphy, J. Org. Chem., 2009, 74,
8713.
5 (a) P. Rubenbauer and T. Bach, Adv. Synth. Catal., 2008,
350, 1125; (b) D. A. Powell and G. Pelletier, Tetrahedron
Lett., 2008, 49, 2498; (c) M. Feuerstein, D. Laurenti,
H. Doucet and M. Santelli, Tetrahedron Lett., 2001, 42,
2313; (d) H.-P. Deng, Y. Wei and M. Shi, Eur. J. Org. Chem.,
2011, 1956.
6 With only a few exceptions, the alcohols that were reported
previously for Lewis and Brønsted acids catalyzed N-alkyl-
ation are limited to secondary benzylic and allylic alcohols,
for the borrowing-hydrogen methodologies, the substrates
are limited to primary benzylic alcohols, see: (a) U. Jana,
S. Maiti and S. Biswas, Tetrahedron Lett., 2008, 49, 858;
N-(1-(Naphthalen-1-yl)propyl)-4-nitroaniline (3nb). 1H NMR
(400 MHz, CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 7.91 (t, J = 9.4 Hz,
3H), 7.74 (d, J = 8.1 Hz, 1H), 7.60–7.50 (m, 2H), 7.45 (d, J = 7.1
Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.40 (d, J = 9.0 Hz, 2H),
5.20–5.13 (m, 2H), 2.17–2.05 (m, 1H), 1.95–1.87 (m, 1H), 1.06
(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 152.74,
137.98, 137.16, 134.15, 130.78, 129.41, 128.08, 126.50, 126.29,
125.78, 125.61, 122.80, 122.10, 111.86, 55.36, 30.37, 11.11.
HRMS (ESI): (M + H)+ C19H19N2O2, Calcd 307.1447, found
307.1441.
1-(1-Azido-1-phenylmethyl)-2,4-dichlorobenzene
(3je). 1H
NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.4 Hz, 1H), 7.38 (d, J =
1.8 Hz, 1H), 7.36–7.26 (m, 6H), 6.09 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 137.68, 135.95, 134.43, 133.65, 129.62,
129.56, 128.79, 128.42, 127.51, 64.43.
4-Phenyl-3-methyl-3-buten-2-yl
azide
(3xe). 1H
NMR
(400 MHz, CDCl3): δ 7.35 (t, J = 7.5 Hz, 2H), 7.30–7.22 (m, 3H),
6.51 (s, 1H), 4.16 (q, J = 6.8 Hz, 1H), 1.89 (s, 3H), 1.37 (d, J =
6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 136.91, 136.73,
129.08, 128.37, 128.19, 127.79, 126.83, 65.47, 18.66, 13.64.
2152 | Org. Biomol. Chem., 2013, 11, 2147–2153
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
(b) M. Noji, T. Ohno, K. Fuji, N. Futaba, H. Tajima and
K. Ishii, J. Org. Chem., 2003, 68, 9340; (c) G.-W. Wang,
Y.-B. Shen and X.-L. Wu, Eur. J. Org. Chem., 2008, 4367;
(b) R. Fan, W. Li, D. Pu and L. Zhang, Org. Lett., 2009, 11,
1425; (c) Z. Wang, Y. Zhang, H. Fu, Y. Jiang and Y. Zhao,
Org. Lett., 2008, 10, 1863.
(d) X. Cui, Y. Zhang, F. Shi and Y. Deng, Chem.–Eur. J., 11 (a) C. Bolm, J. Legros, J. Le Paih and L. Zani, Chem. Rev.,
2011, 17, 1021, and references therein; (e) B. G. Das,
R. Nallagonda and P. Ghorai, J. Org. Chem., 2012, 77, 5577;
(f) F. Shi, M. K. Tse, S. L. Zhou, M. M. Pohl, J. Radnik,
S. Hubner, K. Jahnisch, A. Bruckner and M. Beller, J. Am.
Chem. Soc., 2009, 131, 1775; (g) C. R. Reddy and
2004, 104, 6217; (b) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem.
Rev., 2011, 111, 1293; (c) M. Johannsen and
K. A. Joergensen, J. Org. Chem., 1994, 59, 214; (d) W. P. Liu,
Y. M. Li, K. S. Liu and Z. P. Li, J. Am. Chem. Soc., 2011, 133,
10756.
E. Jithender, Tetrahedron Lett., 2009, 50, 5633; 12 J. Michaux, V. Terrasson, S. Marque, J. Wehbe, D. Prim and
(h) H. Yamamoto, E. Ho, K. Namba, H. Imagawa and J.-M. Campagne, Eur. J. Org. Chem., 2007, 2601.
M. Nishizawa, Chem.–Eur. J., 2010, 16, 11271; 13 C.-R. Liu, F.-L. Yang, Y.-Z. Jin, X.-T. Ma, D.-J. Cheng, N. Li
(i) S. Haubenreissera and M. Niggemann, Adv. Synth. and S.-K. Tian, Org. Lett., 2010, 12, 3832.
Catal., 2011, 353, 469; ( j) T. Ohshima, Y. Nakahara, 14 (a) S.-Y. Zhang, Y.-Q. Tu, C.-A. Fan, F.-M. Zhang and L. Shi,
J. Ipposhi, Y. Miyamotob and K. Mashima, Chem.
Commun., 2011, 47, 8322.
7 (a) T. Morita, Y. Okamoto and H. Sakurai, Synthesis, 1981,
Angew. Chem., Int. Ed., 2009, 48, 8761; (b) P.-F. Larsson,
A. Correa, M. Carril, P.-O. Norrby and C. Bolm, Angew.
Chem., Int. Ed., 2009, 48, 5691.
32; (b) J. Baran and H. Mayer, J. Org. Chem., 1989, 54, 5774; 15 Examined Brønsted acids include HCl, TfOH, and
(c) J. A. Donnelly and D. F. Farrell, J. Org. Chem., 1990, 55,
1757; (d) I. S. Kim, J. D. Kim, C. B. Ryu, O. P. Zee and
Y. H. Jung, Tetrahedron, 2006, 62, 9349; (e) J. Leonard,
J. Heterocycl. Chem., 1984, 21, 81; (f) S. H. Lee, I. S. Kim,
Q. R. Li, G. R. Dong and Y. H. Jung, Tetrahedron Lett., 2011,
TsOH·H2O. With respect to the catalyst loading, 20 mol%
TfOH give the best result. This indicates that the present
reaction is catalyzed by Fe(III), rather than the Bronsted
acid generated from hydrolysis of Fe(III) in the reaction
system.
52, 1901; (g) I. S. Kim, Q. R. Li, G. R. Dong, Y. C. Kim, 16 A control experiment was also conducted using alcohol 1d′
Y. J. Hong, M. Lee, K.-W. Chi, J. S. Oh and Y. H. Jung,
Eur. J. Org. Chem., 2010, 1569; (h) J. D. Kim, I. S. Kim,
C. H. Jin, O. P. Zee and Y. H. Jung, Org. Lett., 2005, 7, 4025.
8 (a) Modern Amination Reactions, ed. A. Ricci, Wiley-VCH,
Weinheim, Germany, 2000; (b) B. M. Trost and
M. L. Crawley, Chem. Rev., 2003, 103, 2921; (c) T. E. Müller,
K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem.
Rev., 2008, 108, 3795.
and p-toluenesulfonamide (2a) as substrates under the
optimized reaction conditions, the desired product 3d was
obtained in 41% yield. This experimental result suggests
that ethers are more suitable substrates for this transform-
ation (Table 2, entry 2).
9 (a) S. Gao, Y. Q. Tu, X. Hu, S. Wang, R. Hua, Y. Jiang,
Y. Zhao, X. Fan and S. Zhang, Org. Lett., 2006, 8, 2373; 17 With sodium azide as the nucleophile instead of trimethyl-
(b) F.-M. Zhang, Y. Q. Tu, J.-D. Liu, X. Fan, L. Shi, X. Hu,
S. Wang and Y.-Q. Zhang, Tetrahedron, 2006, 62, 9446.
10 For representative amination of benzylic C–H bonds, see:
(a) G. Pelletier and D. A. Powell, Org. Lett., 2006, 8, 6031;
silyl azide, the reaction could not occur.
18 Higher catalyst loading (30 mol% FeCl3) and reaction temp-
erature (90 °C) were used in this transformation, but no
product was obtained.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2147–2153 | 2153