Organocatalytic amination of alkyl ethers via n-Bu4NI/t-BuOOH-mediated intermolecular oxidative C(sp3)-N bond formation: Novel synthesis of hemiaminal ethers

Article abstract of DOI:10.1039/c4cc05758a

A novel method for constructing the hemiaminal ether framework under metal-free conditions has been developed. It involves direct organocatalytic amination of alkyl ethers through intermolecular oxidative C(sp³)-N bond formation, with t-BuOOH being the oxidant and n-Bu₄NI as the catalyst.

Full text of DOI:10.1039/c4cc05758a

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Organocatalytic amination of alkyl ethers via
n-Bu4NI/t-BuOOH-mediated intermolecular
oxidative C(sp3)–N bond formation: novel
synthesis of hemiaminal ethers†
Cite this:DOI: 10.1039/c4cc05758a
Received 24th July 2014,
Accepted 12th August 2014
Longyang Dian,a Sisi Wang,a Daisy Zhang-Negrerie,a Yunfei Du*ab and Kang Zhaoa
DOI: 10.1039/c4cc05758a
www.rsc.org/chemcomm
A novel method for constructing the hemiaminal ether framework
under metal-free conditions has been developed. It involves direct
organocatalytic amination of alkyl ethers through intermolecular
oxidative C(sp3)–N bond formation, with t-BuOOH being the oxidant
and n-Bu4NI as the catalyst.
Hemiaminal ether is a commonly encountered functional
group present in many biologically active natural products as
well as some pharmaceutical agents.1 For example, natural
product aspidophylline A known to reverse drug resistance in
resistant KB cells,2a,b huperzine Q isolated from Huperzia
serrata,2c,d fendleridine isolated from vallesia dichotoma RUIZ et
PAV in peruandand,2e,f and the well-known anticancer pharma-
ceutical agent 5-fluorouridine2g all share the hemiaminal ether
moiety in their respective structures (Fig. 1).
The prevalence of the hemiaminal ether framework in bio-
logically important natural products and pharmaceuticals calls
for the development of efficient methods for the construction of
such a skeletal structure. Traditionally, the hemiaminal frame-
works were prepared from hydroamination of an enol ether3a or
substitution of a halide or the hydroxyl group in an a-substituted
ether by an amine.3b From the atom economy perspective, the
C(sp3)–H bond functionalization of alkyl ethers4 is the most
convenient and straightforward approach to access this class of
compounds. One of the most studied strategies is the transition-
metal catalyzed C(sp3)–H amination of alkyl ethers induced
by a nitrene precursor of either N-sulfonylimino-l3-iodane or
chloramine-T (Scheme 1, pathway a).5 An iron-catalyzed cross-
dehydrogenative-coupling (CDC) reaction6 between azoles and
alkyl ethers has also been reported to form the N-alkylated azoles
through the C(sp3)–H bond functionalization of alkyl ethers
Fig. 1 Biologically active molecules containing the hemiaminal ether skeleton.
(Scheme 1, pathway b).7a,b In 2012, Ochiai and co-workers reported
a metal-free direct amination of alkyl ethers with hyper-
valent sulfonylimino-l3-bromane serving as an active nitrenoid
(Scheme 1, pathway c).8
Although each of the above methodologies has its own merit
in preparing the corresponding hemiaminal ether compound,
the existing methods, however, all involve features of either the
participation of a transitional metal or the limited scope of the
a School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, China. E-mail: duyunfeier@tju.edu.cn; Fax: +86-22-27404031;
Tel: +86-22-27404031
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),
Tianjin 300072, China
Scheme 1 Different pathways for the synthesis of the hemiaminal ether
from alkyl ethers.
† Electronic supplementary information (ESI) available: NMR data. See DOI:
10.1039/c4cc05758a
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Table 1 Optimization of the reaction conditionsa
Entry
Oxidant (equiv.)
Catalyst (mol%)
Time (h)
Yieldb
1
2
3
PIDA (2.0)
PIDA (2.0)
PIDA (2.0)
None
None
I2 (20)
12
12
5
NRc
5
20
4
5
6
7
8
9
10
11
m-CPBA (2.0)
H2O2 (2.0)
H2O2 (2.0)
t-BuOOH (3.0)
t-BuOOH (5.0)
t-BuOOH (5.0)
t-BuOOH (5.0)
t-BuOOH (5.0)
PhI (20)
PhI (20)
10
10
10
2
NR
NR
NR
85
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
CuBr (20)
FeCl3ꢀ6H2O (20)
None
1
92
10
10
10
Trace
5%
NR
a
Reaction conditions: 1a (1 mmol), 2a (20 mmol), catalyst (20 mol%,
0.2 mmol) and oxidant were heated in a sealed tube at 75 1C unless
b
c
otherwise stated. Isolated yields. RT.
Scheme 2 Scope of amines [reaction conditions: 1 (0.50 mmol), 2a
(10 mmol), anhydrous t-BuOOH (2.5 mmol), n-Bu4NI (0.10 mmol) at
75 1C unless otherwise stated, all the yields were isolated, yields in
parentheses were isolated yields based on the recovered starting material].
a Separable isomeric products, 3ha/3h0a = 3.4 : 1.
applicable amines. In this regard, the search for an environ-
mental friendly and efficient non-metallic oxidative system to
realize the target compound is still very much in demand.9
Herein, we report a novel procedure for metal-free amination of
alkyl ethers by using n-Bu4NI as the catalyst and t-BuOOH as THF (2a) was used as the ether reactant in the scope study of
the affordable and nontoxic oxidant.10
amines (Scheme 2). All phthalimide derivatives included in the
To begin our study, we chose the commercially available study reacted smoothly and afforded the desired products 3ba,
phthalimide 1a and tetrahydrofuran (THF) 2a as model substrates. 3ca, and 3da in moderate to great yields, except for 3ea in which
Initially, hypervalent iodine reagents were tried out as oxidants to the reaction was sluggish and only a 24% overall yield was
test the feasibility of this transformation.9b,11 However, no reaction obtained even though the yield based on the recovered starting
occurred at room temperature for 12 h or longer after 2 equiv. of material (brsm) was as high as 89%. The large difference between
PIDA has been added to the phthalimide 1a in THF 2a (Table 1, the overall and brsm in the case of 3ea seems to suggest that the
entry 1). When the reaction mixture was heated and maintained at strongly electron-withdrawing nitro group reduces the stability of
75 1C in a sealed tube overnight, the reaction afforded a meager the hemiaminal ether structure (therefore thermodynamically
yield of 5% of the desired product (Table 1, entry 2). The addition disfavored), but does not however affect the rate determining step
of a catalyst (20 mol% of I2) significantly improved the yield to a (kinetically favored). Succinimide afforded product 3fa in 90%
four-fold of 20% (Table 1, entry 3). Encouraged by this result, we yield, implying that the phenyl moiety in the amine substrate is
set out the search for an effective catalytic oxidative reaction not indispensable for the transformation. N-Benzoyl-benzamide
system, including m-CPBA/PhI12 (Table 1, entry 4), H2O2/PhI also gave the desired coupling product 3ga in moderate yield
(Table 1, entry 5), H2O2/n-Bu4NI (Table 1, entry 6) and n-Bu4NI/ under the optimal conditions, indicating that the lactam skeleton
t-BuOOH10 (Table 1, entry 7). The last combination led to a carried no importance in such a reaction. With benzotriazole, a
breakthrough result with the desired coupling product 3aa separable mixture of two regioisomeric products 3ha/3h0a
being formed in an excellent yield of 85%. Further optimization was obtained. Lastly, the method was shown to be also applic-
showed that an increased amount of the oxidant of 5 equiv. able to Ts-protected p-toluidine, with the desired product 3ia
improved the yield to 92% (Table 1, entry 8). We also checked being isolated in moderate yield. However, certain types of
out the transition-metal catalysts such as CuBr and FeCl3ꢀ6H2O amines including aniline and benzimidazole failed to give the
which have been reported to be effective in t-BuOOH-mediated desired products.
CDC reactions,6 but neither of them was shown to be effective for
Similar scope studies were also carried out on the ether sub-
this transformation (Table 1, entries 9 and 10). The control experi- strates, with phthalimide 1a used as the amine. Results are listed in
ment showed that no 3aa was detected when n-Bu4NI was absent in Scheme 3. Cyclic ether compounds such as tetrahydropyran and
the reaction system (Table 1, entry 11). Other hypervalent iodine dioxolane were found to react smoothly to generate the coupling
reagents including PIFA and PhIO have also been tested out, products 3ab and 3ac with moderate yields. Straight chain ethers
however, only negative results of either no reaction at all or forming were also well tolerated and afforded the corresponding products
a complex mixture as a product were observed (see ESI†).
3ad, 3ae and 3af in good to excellent yields although the reaction
Under the most optimal reaction conditions (Table 1, entry 8), time was prolonged for 3ae and 3af containing the longer-
we proceeded to explore the generality of this methodology. chained alkyl substituent. Reaction of 2-methyltetrahydrofuran
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Scheme 4 The proposed mechanism.
Initially, active iodine species, ammonium hypoiodite A and
iodite B were generated by oxidation of n-Bu4NI with t-BuOOH.
After that, hemolytic cleavage of the alkyl C–H bond was
induced by A or B and gave the alkyl radical C, which could
be trapped by TEMPO to form the coupling product 4.13 The
alkyl radical C was further oxidized by active iodine species A or
B to form the oxonium D, with a hydroxide ion being released.
In the final step, the amine is deprotonated by the hydroxide ion
to generate the anionic specie E, nucleophilic addition of species
E with the oxonium D formed the title product 3. The proposed
mechanism is in complete agreement with the observation of the
nitro group effect on the reaction yields.
Scheme 3 Scope of alkyl ethers [reaction conditions: 1a (0.50 mmol), 2
(10 mmol), anhydrous t-BuOOH (2.5 mmol), n-Bu4NI (0.10 mmol) at 75 1C
unless otherwise stated, all the yields were isolated yields after silica
a
gel chromatography]. Separable isomeric products, 3ag/3ag0 = 2.5 : 1.
b Separable isomeric products, 3ah/3ah0=1.5 : 1. c Separable products, 3ai/
3ai0 = 1 : 1.2.
In summary, we have demonstrated a novel n-Bu4NI/t-BuOOH
mediated direct amination of various alkyl ethers with different
amines in forming the important hemiaminal ether skeletons.
The hypervalent iodine reagent was generated in situ by using
t-butyl hydrogen peroxide (t-BuOOH) as a very affordable and also
nontoxic terminal oxidant. The beneficial features of the present
approach are metal-free, organic catalytic and mild reaction condi-
tions. Further studies on the application of the hemiaminal ether
skeleton and the other oxidative coupling reactions are ongoing in
our laboratory (Scheme 4).
gave the coupling products in a separable regioisomeric mixture in
a total yield of 63%, with the less steric 3ag being the major
product. To confirm the outcome with unsymmetrical substitution,
we applied the reaction on another alkyl ether containing two
active sites, namely, ethylene glycol dimethyl ether. Expected
results were observed – a mixture of two regioisomeric products
of 3ah/3ah0 (1.5 : 1) separable by silica gel chromatography. For
the bulkier methyl tert-butyl ether, the yield of 3ag was only
29%, with the major product being the oxidative hydrolysis
product 3ag0 in 36% yield.
We carried out additional experiments in order to elucidate the
reaction mechanism (see ESI†). One control experiment showed
that no desired product was obtained if the catalyst was switched to
KI or I2, but with a combination of I2 and n-Bu4NOH, the desired
product was formed in 30% yield. This result suggests that the
active hypoiodite ([IO]ꢁ) or/and iodite ([IO2]ꢁ) were not only
generated during the process but also played an important role
in this transformation.10e Another control experiment was the
We acknowledge the Foundation (B) for the Peiyang Scholar-
Young Core Faculty of Tianjin University (2013XR-0144), the Innova-
tion Foundation of Tianjin University (2013XJ-0005) and the National
Basic Research Project (2014CB932201) for financial support.
Notes and references
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see ESI†.
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