Palladium-catalyzed intramolecular aminoiodination of alkenes using molecular oxygen as oxidant

Article abstract of DOI:10.1007/s00706-016-1819-2

Abstract: Molecular oxygen as oxidant to promote palladium-catalyzed intramolecular aminoiodination of alkenes has been described. The yields are excellent and show high exo-selectivities with various substrates. Graphical abstract: [Figure not available:

Full text of DOI:10.1007/s00706-016-1819-2

Monatsh Chem
DOI 10.1007/s00706-016-1819-2
ORIGINAL PAPER
Palladium-catalyzed intramolecular aminoiodination of alkenes
using molecular oxygen as oxidant
Lu Chen1 Xianglin Luo1 Yibiao Li1
•
•
Received: 27 May 2016 / Accepted: 11 July 2016
Ó Springer-Verlag Wien 2016
Abstract Molecular oxygen as oxidant to promote palla-
dium-catalyzed intramolecular aminoiodination of alkenes
has been described. The yields are excellent and show high
exo-selectivities with various substrates.
Transition-metal-catalyzed intramolecular aminohalo-
genation of alkenes remains relatively rare. Chemler
reported that sulfonamidoalkenes could be cyclized with
Pd(TFA)2, using CuCl2 (4 equiv) or CuBr2 (3 equiv) as the
halogen source and oxidant [11]. Lu described the
cyclization of acylsulfonamides with Pd(OAc)2 catalyst,
also using copper halides as the halogen sources and oxi-
dants [12]. Michael reported palladium-catalyzed
intramolecular chloroamination of inactivated alkenes,
using NCS as sources and oxidants [13]. Li described a
novel and highly regioselective palladium-catalyzed
intramolecular aminofluorination of alkenes using KI as the
fluorinating reagent in the presence of PhI(OPiv)2 [14]. On
the other hand, the utilization of molecular oxygen as
oxidant is one of the most important goals in oxidation
chemistry [15–17]. Selective aerobic oxidation reactions
constitute a broad class of important oxidative chemical
transformations. As the ‘‘green oxidant’’, oxygen is an
abundant, inexpensive, and thermodynamically potent
oxidant. It would be preferred because it is environmentally
benign and palladium-catalyzed aerobic oxidation reac-
tions have been shown to be highly versatile in preparing
fine chemicals [18–24]. Herein, we report molecular oxy-
gen as oxidant to promote palladium-catalyzed
intramolecular aminoiodination of alkenes.
Graphical abstract
Keywords Homogeneous catalysis Á Heterocycles Á
Aminoiodination Á Oxidations Á Alkenes
Introduction
The development of general and efficient methodologies
for the synthesis of complex molecular skeletons is the
central focus of modern organic chemistry. Nitrogen
heterocycles are common components of biologically
active compounds [1, 2]. The halogenated nitrogen hete-
rocycles have been applied as potential medicinal agents
[3], and are primarily utilized to versatile synthetic inter-
mediates [4–8]. Synthesis of nitrogen heterocycles via C–N
bond formation represents a widely applied synthetic pro-
tocol [9, 10]. Therefore, the importance of the research for
more direct and environmental friendly aminohalogenation
modes is evident.
Results and discussion
We firstly examined the intramolecular aminoiodination of
2-allyl-N-tosylaniline under different reaction conditions,
and the results are summarized in Table 1. In the presence
of the Pd(OAc)2 catalyst (2 mol%), the reaction of 2-allyl-
N-tosylaniline in HOAc at room temperature afforded 2a in
a 53 % yield and the b-hydride elimination product was not
& Yibiao Li
wyuchemlyb@126.com
1
School of Chemical and Environmental Engineering,
Wuyi University, Jiangmen, China
123

L. Chen et al.
Table 1 Optimization of reaction conditions
Entry
Atmosphere (1 bar)
Catalyst
Additive
Temp./°C
Yield/%a
1
O2
O2
O2
Air
N2
O2
O2
O2
O2
O2
O2
O2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
KI
KI
KI
KI
KI
NaI
ZnI2
KI
KI
KI
KI
KI
r.t.
50
70
50
50
50
50
50
50
50
50
50
53
98 (94)
98
2
3
4
72
5
\10
92
6
7
88
8
76
9
PdBr2
84
10
11
12
Pd2(dba)3
–
85
\5
0
FeCl3
All reactions were performed with 1a (0.25 mmol), catalyst (2 mol%), and additive (1.1 equiv) in 2 cm3 of HOAc for 18 h
a
Determined by GC. Number in parentheses is isolated yield
detected in this process (Table 1, entry 1) [25]. But high
Scheme 1
yield of b-hydride elimination product could be obtained if
using other solvents (e.g., CH3CN, DMF, DMSO, or 1,4-
dioxane). The activity of substrate 1a was improved sig-
nificantly by raising temperature to 50 °C. By comparison
with room temperature, higher temperature led to the same
result (Table 1, entries 1–3). Using air as the oxidant led to
an unsatisfactory yield (Table 1, entry 4). Only trace
amounts of the desired product 2a was obtained when
reaction in nitrogen atmosphere (Table 1, entry 5). Further
investigation on other iodide salts led to the inferior results,
which indicated that the KI is the best choice (Table 1,
entries 2 vs. 6, 7). Different palladium species were also
tested, such as PdCl2, Pd2(dba)3, PdBr2, but the reaction
did not proceed well (Table 1, entries 8–10). A Pd(0)
complex could also be employed, as it is presumably oxi-
dized to Pd(II) species under the oxidation reaction
condition (Table 1, entry 10). Moreover, trace product of
intramolecular aminoiodination was obtained without
Pd(OAc)2 (Table 1, entry 11). Under N2 atmosphere, when
FeCl3 is utilized as catalyst instead of palladium salts, the
intramolecular aminoiodination reaction did not give the
participation in reaction to give the corresponding
aminoiodination products in higher yields in contrast to the
case with electron-poor in the para position (2a-2 g). The
reaction tolerated a variety of substituents including –Me, –
MeO, –Cl, and –F groups. Substituents at the ortho position
of benzyl group did not affect the yield of the reaction (2b
and 2c). Except the aniline-derived substrates, the aliphatic
desired product at all (Table 1, entry 12).
With the optimized conditions in hand, various sub-
strates were examined, and the results are summarized in
Scheme 1. In all the cases tested, the aminoiodination went
smoothly, giving a good yield of the desired products. A
series of the aniline-derived substrates with electron-rich
substituents in the para, meta, or ortho position
123

Palladium-catalyzed intramolecular aminoiodination of alkenes using molecular oxygen as oxidant
Scheme 2
Scheme 3
alkenes were also found to be suitable substrates for the
standard conditions. The pyrrolidines were readily syn-
thesized from alkenylsulfonamides in high yields (2h and
2j). A six-membered ring, piperidine 2i, was also obtained
in good yield by this procedure. Herein, simple filtration
through a silica-gel plug was sufficient to remove the
residual catalyst and provide desired piperidine products.
The exact pathways remain unknown at the present
stage. In principle, intermediate A was formed from the
intramolecular trans-nucleopalladation to 1a activated by
the palladium(II) species [9, 12, 26, 27]. Then followed by
the cleavage of the carbon–palladium bond by I- and O2
result in 2a (Scheme 2).
Conclusion
In conclusion, we have successfully developed palladium-
catalyzed intramolecular aminoiodination of alkenes using
molecular oxygen as oxidant. This process utilized
molecular oxygen as sole oxidant to synthesis of various
nitrogen heterocyclic rings. Moreover, the reaction condi-
tion was extremely mild and tolerated various functional
groups, this will make this method of use to medicinal and
academic chemists. Further studies on the mechanism, the
scope of the reaction, and the potential for asymmetric
induction in the aminoiodination process are in progress.
We next pursued analogous palladium-catalyzed
intramolecular aminohalogenation of 1a using KBr, KCl,
and KF as halogen sources (Scheme 3). However, treat-
ment of 1a under the optimized conditions with KBr, KCl,
or KF did not afford the expect results. Instead, the cor-
responding of b-hydride elimination product was obtained
in high isolated yields. This result suggests that b-hydride
elimination is significantly faster than C–X (X = Br, Cl, F)
coupling in this system.
Experimental
Unless otherwise noted, all commercial materials and sol-
vents were used without further purification. 1H NMR
spectra were recorded in CDCl3 at 400 MHz (or BRUKER
DRX-600 spectrometer) and 13C NMR spectra were
recorded in CDCl3 at 100 MHz, respectively. GC–MS was
obtained using electron ionization. HRMS was carried out
123

L. Chen et al.
Scheme 4
Scheme 5
3H), 2.71–2.83 (m, 2H), 3.24 (t, J = 12.4 Hz, 1H),
3.59–3.67 (m, 1H), 4.26–4.36 (m, 1 H), 7.00 (d,
J = 8.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.35 (d,
J = 8.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H) ppm; 13C
NMR (CDCl3, 100 MHz): d = 11.4, 15.7, 19.5, 21.5, 34.4,
62.4, 117.8, 126.9, 127.7, 129.3, 129.6, 133.2, 134.4,
136.3, 139.0, 144.0 ppm; HRMS (EI): m/z calcd for
C18H20INO2S 441.0259, found 441.0252.
on a MAT 95XP (Thermo). TLC was performed using
commercially prepared 100–400 mesh silica gel plates
(GF254), and visualization was effected at 254 nm. All the
other chemicals were purchased from Alfa or Aldrich
Chemicals. Commercial reagents were used without further
purification. A typical procedure for the synthesis of
amides [28] is shown in Scheme 4, a procedure for the
synthesis of 2-allylanilines [29] in Scheme 5.
2-(Iodomethyl)-5-methoxy-1-tosylindoline (2d)
Yield 93 %; m.p.: 149–150 °C (Ref. [14]).
General procedure for aminoiodination of alkenes
The mixture of 2-allyl-N-tosylaniline (1a, 0.25 mmol),
46 mg KI (0.275 mmol), 1.1 mg Pd(OAc)2 (0.005 mmol),
and 2 cm3 AcOH were mixed in a glass vial or round-
bottom flask equipped with a magnetic stirring bar. The
vial was flushed with oxygen and then connected to a
balloon filled with oxygen. After rapid stirring at 50 °C for
18 h, the resulting crude oil was dissolved in 8 cm3 ethyl
acetate and washed with water (2 9 5 cm3) and saturated
aqueous NaHCO3 (2 9 10 cm3). The organic layer was
dried over MgSO4, filtered, and concentrated to afford a
crude product, which was purified by chromatography on a
silica gel column using light petroleum ether/ethyl acetate
as eluent.
2-(Iodomethyl)-5-phenoxy-1-tosylindoline
(2e, C22H20INO3S)
Yield 94 %; colorless crystalline solid; m.p.: 148–149 °C;
1H NMR (CDCl3, 400 MHz): d = 2.38 (s, 3 H), 2.72–2.84
(m, 2H), 3.27 (t, 1H), 3.60 (dd, J = 3.6, 3.6 Hz, 1H),
4.38–4.57 (m, 1H), 6.56 (d, 1H), 6.85–6.87 (m, 1H),
6.94–6.98 (m, 1H), 7.00–7.08 (m, 1H), 7.20 (d, 2H),
7.22–7.24 (m, 2H), 7.55–7.61 (m, 4H) ppm; 13C NMR
(CDCl3, 100 MHz): d = 11.5, 21.7, 34.9, 62.9, 116.0,
118.0, 118.6, 118.7, 123.4, 127.2, 129.9, 132.6, 134.2,
136.8, 144.4, 154.8, 157.3 ppm; HRMS (EI): m/z calcd for
C22H20INO3S 505.0209, found 505.0201.
2-(Iodomethyl)-1-tosylindoline (2a)
Yield 94 %; m.p.: 154–156 °C (Ref. [14]).
5-Chloro-2-Iodomethyl-1-(p-toluenesulfonyl)-2,3-dihyro-
1H-indole (2f)
2-(Iodomethyl)-7-methyl-1-tosylindoline (2b)
Yield 92 %; m.p.: 102–104 °C (Ref. [14]).
Yield 86 %; m.p.: 108–110 °C (Ref. [14]).
5-Fluoro-2-(iodomethyl)-1-tosylindoline (2g)
Yield 85 %; m.p.: 113–114 °C (Ref. [14]).
2-(Iodomethyl)-6,7-dimethyl-1-tosylindoline
(2c, C18H20INO2S)
Yield 89 %; pale yellow solid; m.p.: 128–130 °C; 1H NMR
(CDCl3, 400 MHz): d = 2.00 (s, 3H), 2.27 (s, 3H), 2.35 (s,
2-(Iodomethyl)-1-tosylpyrrolidine (2h)
Yield 92 %; m.p.: 92–93 °C (Ref. [7]).
123

Palladium-catalyzed intramolecular aminoiodination of alkenes using molecular oxygen as oxidant
11. Manzoni MR, Zabawa TP, Kasi D, Chemler SR (2014) Orga-
nometallics 23:5618
2-(Iodomethyl)-1-tosylpiperidine (2i)
Yield 95 %; m.p.: 92–93 °C (Ref. [7]).
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2-(1-Iodoethyl)-1-tosylpyrrolidine (2j)
Yield 95 %; m.p.: 112–114 °C (Ref. [7]).
Acknowledgments We thank the National Natural Science Founda-
tion of China (21302146) and Science Foundation for Young
Teachers of Wuyi University (2015td01).
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