NBu4NI-catalyzed intermolecular C-O cross-coupling reactions: Synthesis of alkyloxyamines

Article abstract of DOI:10.1039/c5ra12691f

A practical and simple nBu₄NI-catalyzed C-O bond formation for the synthesis of alkyloxyamines was achieved under metal-free conditions. The reaction is applicable to the coupling of a range of benzylic and allylic hydrocarbons with N-hydroxyphthalimide and is tolerant of various functional groups. The reaction mechanism was primarily investigated and a radical process was proposed.

Full text of DOI:10.1039/c5ra12691f

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DOI: 10.1039/C5RA12691F
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nBu4NI-Catalyzed Intermolecular C-O Cross-coupling Reactions:
Synthesis of Alkyloxyamines
Received 00th January 20xx,
Accepted 00th January 20xx
Yunhe Lv,*a Kai Sun,a Tingting Wang,a Gang Li,a Weiya Pu,a Nannan Chai,a Huihui Shen,a and
Yingtao Wua
DOI: 10.1039/x0xx00000x
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A practical and simple nBu4NI-catalyzed C-O bond formation for knowledge, an example of a direct transformation from readily
the synthesis of alkyloxyamines was achieved under metal-free available hydrocarbons and NHPI to alkyloxyamines via a formal
conditions. The reaction is applicable to the coupling of a range of C(sp3)-H functionalization under metal-free conditions has not been
benzylic and allylic hydrocarbons with N-hydroxyphthalimide and reported until this work.
is tolerant of various functional groups. The reaction mechanism
was primarily investigated and a radical process was proposed.
Previous work:
Selective direct C-H bond functionalization is emerging as a valuable
tool for the synthesis of natural products and medicinal
compounds.1 The formation of C-O bonds is of fundamental
importance in organic synthesis,2 and alkyloxyamines are widely
employed in the synthesis of pharmaceuticals and functional
materials.3 N-Hydroxyphthalimide (NHPI) is not only a cheap,
nontoxic catalyst for C-H bond functionalization by using an in situ
generated phthalimide N-oxyl (PINO) radical, but also a precursor of
oxime ethers.4 In recent years, NHPI has been also utilized as a
stoichiometric reactant for the construction of the C-O bond in
organic synthesis.5 In 2008, Chang and co-workers reported a highly
efficient protocol for the benzyl or allylic C-H functionalization of
simple hydrocarbons using stoichiometric amounts of N-
hydroxyphthalimide and PhI(OAc)2 in the presence of CuCl catalyst
(Scheme 1, equation a).5b Although the above-mentioned elegant
methods appear to be general and efficient, new synthetic methods
are still required.
This work:
Scheme 1 Different pathways for the synthesis of alkyloxyamines.
Initially, o-xylene 1a and NHPI 2 were selected as the model
substrates to optimize the reaction conditions (Table 1). To our
delight, the combination of nBu4NI (0.2 equiv) and tert-butyl
hydroperoxide (TBHP, 2 equiv) exhibited excellent catalytic activity
and gave the desired product 3a in 85% yield (entry 1). Ethyl
acetate and dichloromethane (DCM) were effective to provide 3a in
73% and 55% yield, respectively (Table 1, entries 2 and 3). Other
catalysts such as KI, NH4I, I2 and NIS gave unsatisfactory results
(Table 1, entries 4 - 7). TBHP was found to play an important role in
the process. As shown in Table 1, TBHP was the most effective
peroxide in the process. Other peroxides such as Na2S2O8, di-tert-
butylperoxide (TBP) and 30% H2O2 did not perform well (Table 1,
entries 8 - 10). In addition, the reaction in the absence of nBu4NI or
TBHP did not work (Table 1, entries 11 and 12). The best yield of 3a
(92%; entry 13) was obtained at 100 °C, whereas at higher
temperatures no appreciable increase in yield was obtained. Upon
decreasing the temperature to 90 oC or 70 oC, 3a was obtained in 81%
or 52% yield (Table 1, entries 14 and 15). It should be noted that
this coupling reaction was performed under environmentally benign
condition (with tert-butyl alcohol and water as by-products)
without utilizing metal or stoichiometric amount of hypervalent
iodine(III) species.5b-f
In our previous communication, nBu4NI-catalyzed C-N cross
coupling imidation reaction of C(sp3)-H bond of simple ketones and
N-H bond in imides with TBHP as an environmentally benign oxidant
was described.6 Taking the possible radical amination mechanism
for C-H functionalization into account, we envisaged that benzylic
and allylic C-H bond could be selectively oxygenated by using
appropriate oxygen-centered radicals. Herein, we report
a
straightforward and versatile method to obtain alkyloxyamines by
nBu4NI -catalyzed intermolecular highly selective benzylic and allylic
C-O bond formation from readily available benzylic and allylic
hydrocarbons with NHPI (Scheme 1, equation b). To the best of our
a.College of Chemistry and Chemical Engineering, Anyang Normal University,
Anyang, 455000, China. E-mail: lvyunhe0217@163.com
† Electronic Supplementary Information (ESI) available. See
DOI: 10.1039/x0xx00000x
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Table 2 Oxygenation of benzyl C-H substrates with NHVPieIw2aA,rbticle Online
Table 1 Optimization of the Reaction Conditionsa
DOI: 10.1039/C5RA12691F
Entry Oxidantb
Catalyst
nBu4NI
nBu4NI
nBu4NI
KI
Solvent
CH3CN
EtOAc
DCM
T (oC)
130
130
130
130
130
130
130
130
130
130
130
130
100
90
Yield(%)c
85
1
2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Na2S2O8
TBP
73
3
55
4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
25
5
NH4I
28
6
I2
0
7
NIS
trace
0
8
nBu4NI
nBu4NI
nBu4NI
nBu4NI
-
9
trace
0
d
10
11
12
13
14
15
H2O2
-
trace
trace
92
TBHP
TBHP
TBHP
TBHP
nBu4NI
nBu4NI
nBu4NI
81
70
52
a Reaction conditions: 1a (1.5 mmol), 2 (0.3 mmol), oxidant (0.6 mmol),
catalysts (0.06 mmol), solvent (3.0 mL), 2 h. b TBHP (70% in water).
c Yield of the isolated product. d H2O2 30% in water.
a
Standard reaction conditions: 1 (1.5 mmol), 2 (0.3 mmol), TBHP
(0.6 mmol, 70% in water), nBu4NI (0.06 mmol), CH3CN (3.0 mL), 100
The generality of the C-H functionalization reaction was next
examined. As described in Table 2, a broad range of toluene
derivatives were investigated. Both toluene and xylenes could be
successfully converted to the corresponding products in good to
excellent yields (3a-d). Remarkably, the benzylic oxidation was also
highly selective, affording only mono-oxidation products, and no
multi-oxidation or aromatic C-H oxidation products were detected.
Toluene substrates with various functional groups were effective. In
general, Toluene substrates bearing electron-donating substituents
provided higher yields than those containing electron-withdrawing
substituents on the aromatic ring (3d-i). Halo-substituted toluene
substrates (1h, 1j-m) were tolerated in the oxidation reaction, and
could be very useful for further transformations. In addition,
starting from ethylbenzene (1n), Indane (1o) and 1,2,3,4-
tetrahydronaphthalene (1p), 3n, 3o and 3p could be obtained in 70-
oC, 2 h. b Yield of the isolated products. c 0.9 mmol 1 was used.
derivatives 5a-d in good yields and with high regioselectivity. In
addition, cyclic alkenes such as cyclohexene 4e and cyclopentene 4f
gave the corresponding compounds in 88% and 70% yields. Notably,
under these conditions, the dioxygenation of alkenes products were
not obtained in the works of Woerpel, Punniyamurthy and Liang et
al.5c-e
Table 3 Oxygenation of allyl C-H substrates with NHPI 2a,b
90%
yields.
Moreover,
2-methylfuran
(1q)
and
1-
methylnaphthalene (1r) were also tolerated in this protocol,
furnishing the desired products in good yields (3q-r). Next, the
regioselectivity of the reaction was studied. 2-(1-(p-
tolyl)ethoxy)isoindoline-1,3-dione
(3s)
and
2-((4-
ethylbenzyl)oxy)isoindoline-1,3-dione (3s’) were obtained after 2
hours in 86% total yield in
a ratio of 3:1 from 1-ethyl-4-
methylbenzene (1s).
a
Standard reaction conditions: 4 (0.9 mmol), 2 (0.3 mmol), TBHP
To further explore the potential of this efficient C-H
functionalization reaction, several alkenes were examined as
substrates to react with NHPI (2) under the optimized reaction
conditions(Table 3). Alkenes 4a-d led to linear (E)-allyl-PINO
(0.6 mmol, 70% in water), nBu4NI (0.06 mmol), CH3CN (3.0 mL), 100
oC, 2 h. b Yield of the isolated products. c 1.5 mmol 4 was used.
2 | J. Name., 2012, 00, 1-3
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The protocol was further explored for the gram scale oxidation Scheme 2. Initially, the tert-butoxyl and tert-butylperoxyl radicals
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DOI: 10.1039/C5RA12691F
9
of ethylbenzene 1n as a representative example (equation 1). As form catalytically (Scheme 3a). tert-Butoxyl or tert-butylperoxyl
above, the reaction smoothly occurred with 72% yield. In addition, radicals then reacts with NHPI to generate NIPO radical, a fairly
The obtained PINO adducts could be readily converted to the stable but highly reactive free radical, which has been proposed as a
corresponding alcohols or hydroxylamine species (equation 2). 7 For key intermediate in NHPI mediated oxidations (Scheme 3b).4a,10
example, product 3b can be transformed into phenylmethanol 6a in Subsequently tert-butoxyl, tert-butylperoxyl or NIPO radical induces
70% yield by cleavage of the N−O bond with Mo(CO)6, while 3n the homolysis of a benzyl C-H bond to give the benzyl radical
underwent reaction to afford 1-phenylethanol 6b in 78% yield. The (Scheme 3c).11 Finally, the recombination of the benzyl radical and
reaction of 3b with hydrazine produced O-benzylhydroxylamine 7a PINO radical will lead to the PINO adducts 3b (Scheme 3d).
in 71% yield. Similar results were observed with 3n, furnishing O-(1-
phenylethyl)hydroxylamine 7b in 70% yield.
Several control experiments were performed to probe the
reaction mechanism. The competitive oxidation involving toluene
1b and its deuterated derivative 1b-d8 were performed (equation 3).
Scheme 2 Proposed mechanism
Obvious kinetic isotope effects (kH/kD=13/1) was observed,
indicating that the cleavage of benzyl C-H bond is involved in the
rate-determining step. When the radical scavenger 2,2,6,6-
tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv) was added to the
reaction of ethylbenzene (1n) under the optimal condition, after 2 h,
a TEMPO-captured product 8 was isolated (24%) and only a trace
amount of 3n was detected.The results indicates that the benzyl
radical was involved under the catalytic system.8
In summary, we have reported a novel nBu4NI catalyzed
operationally simple method for the C-H functionalization of
hydrocarbons. Various alkyloxyamines products were obtained in
good to excellent yields using TBHP (70% in water) as an
inexpensive and environmentally friendly oxidant. Importantly, This
metal-free catalyzed C-O bond formation makes use of simple,
inexpensive starting materials and demonstrates excellent
regioselectivity in all cases. Further investigations to gain a detailed
mechanistic understanding of this reaction and apply this strategy
in other oxidative coupling reactions are currently in progress.
We gratefully acknowledge the Foundation of Henan
Educational Committee (15A150029) for financial support.
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A table of contents entry
nBu4NI-catalyzed cross-coupling of benzyl and allylic compounds with N-Hydroxyphthalimide
for the synthesis of alkyloxyamines were realized for the first time.