TEMPO-catalyzed aerobic oxygenation and nitrogenation of olefins via C=C double-bond cleavage

Article abstract of DOI:10.1021/ja403824y

A novel TEMPO-catalyzed aerobic oxygenation and nitrogenation of hydrocarbons via C=C double-bond cleavage has been disclosed. The reaction employs molecular oxygen as the terminal oxidant and oxygen-atom source by metal-free catalysis under mild conditions. This method can be used for the preparation of industrially and pharmaceutically important N- and O-containing motifs, directly from simple and readily available hydrocarbons.

Full text of DOI:10.1021/ja403824y

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TEMPO-catalyzed Aerobic Oxygenation and
Nitrogenation of Olefins via C=C Double Bond Cleavage
Teng Wang, and Ning Jiao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja403824y • Publication Date (Web): 31 Jul 2013
Downloaded from http://pubs.acs.org on August 1, 2013
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TEMPO-catalyzed Aerobic Oxygenation and Nitrogenation of
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Olefins via C=C Double Bond Cleavage
Teng Wang† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Xue Yuan Rd. 38, Beijing 100191,
China, State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China
Supporting Information Placeholder
terminal oxidant, and a useful reagent TMSN3 as the
ABSTRACT:
A
novel TEMPO-catalyzed aerobic
nitrogen source (Scheme 1).7 The current protocol has
many advantages and can be summarized as follows: 1)
Variant alkenes, including terminal, di- and
trisubstituted alkenes, are compatible. 2) A simple and
readily available TEMPO has emerged as an efficient
organocatalyst. 3) The incorporation of O- and N-atoms
into simple hydrocarbons is achieved to convert alkenes
to highly useful N- and O-containing building blocks for
synthesis. 4) The TEMPO-O2 system is inexpensive, mild
and easily handled with high catalytic efficiency and
safety.
oxygenation and nitrogenation of hydrocarbons via C=C
double bond cleavage has been disclosed. The reaction
employs molecular oxygen as the terminal oxidant and
oxygen-atom source by metal-free catalysis under mild
conditions. This method can be used for the preparation
of industrially and pharmaceutically important N- and
O-containing motifs, directly from simple and readily
available hydrocarbons.
Scheme 1. Our Strategy of Olefins Direct Oxidative
Nitrogenation via C−C Double Bond Cleavage.
The alkene functionalization is an essential functional
group inter-conversion for organic synthesis.1 The
resulting compounds from alkene functionalization take
a privileged position in the fields of pharmaceuticals,
agrochemicals and materials. Among intensive research
in olefin chemistry, transition metal-catalyzed C=C
double bond cleavage is a fundamental method in
building
complex
molecules
that
would
be
Recently, we developed several approaches to
unapproachable by other methods.2 For example, the
venerable ring-closing metathesis (RCM) processes offer
an efficient approach to various medium and large cyclic
hydrocarbons with transition-metal catalysts.3 Although
significant progresses have been made, some crucial
issues have remained fairly unaddressed: 1) there are
restrictions in terms of substrate scopes; 2) expensive
and toxic metals are often employed; and 3) for oxidative
transformation, unattractive stoichiometric oxidants are
sometimes utilized. Therefore, the development of a
promising access towards alkene functionalization
associated with these challenges is highly desired.
nitrogen-containing
compounds
via
oxidative
nitrogenation involving C−C bond cleavage.8 This is
conceived and of long-standing interest by us. Among a
number of failed attempts, an intriguing result attracted
our attention. When α-methylstyrene 1 was submitted to
catalytic amount of TEMPO in the presence of TMSN3
under oxygen, acetophenone 2 was detected by GC-MS.
This result indicates that the nitrogen source may play
an important role in C=C double bond cleavage, albeit
the nitrogenation products are not observed. Hence, 1H-
indene 3 was selected as the substrate for the model
reaction. As expected, even at ordinary pressure, the
reaction gave the nitrogenation product 3a in good yield
with high regioselectivity (entry 1, Table 1, for the
optimization details, see SI). The reaction of 3 in gram-
scale (1.16 g) afforded 3a in 76% yield (Table S4, SI).
Therefore, the present protocol concurrently realizes
oxygenation and nitrogenation of C=C double bonds
with high efficiency.
Organocatalysis has attracted considerable attentions
and has been significantly developed.4 Organic radicals
have similar behavior to that of high-valent metals, but
the attractive features of these compounds have not been
identified as efficient catalysts due to instability issues.
Notably,
(2,2,6,6-Tetramethylpiperidine
a
representative stable radical, TEMPO
1-oxyl), has been
reported as a nonmetal catalyst in C−C bond formations5
with molecular oxygen as the terminal oxidant.6 Herein,
we report a TEMPO catalyzed C=C double bond cleavage
to produce oxo nitriles using molecular oxygen as the
Subsequently, the scope of this oxidative oxygenation
and nitrogenation transformation was investigated
(Table 1). Some benzocycloalkenes gave the desired
products in moderate yields (entries 1 to 3). The
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regioselectivity of these substrates is very high with
(Scheme 2). Benzophenone 21 was obtained in 92% yield
5
oxygenation occurring at the benzylic site. The reactivity
of aliphatic olefins is much lower than benzylic
substrates. Upon testing a number of different additives,
however, we found that inclusion of phenyliododiacetate
(PIDA) enabled formation of the oxo nitrile products in
moderate yield with simple cyclic olefins (entries 4 to 7).
Although the exact role of PIDA is not clear yet, the
presence of PIDA could improve the efficiency
significantly. For example, the reaction in the presence of
PIDA produced 7a in 60% yield (entry 6, Table 1).
However, only trace amount of 7a was obtained in the
absence of PIDA (entry 1, Table S3, see SI). Furthermore,
the reaction with PIDA in the absence of TEMPO catalyst
only afforded the desired product in 13% yield (entry 13,
Table S3, see SI). Interestingly, even a large ring like 8
gave the desired long-chain oxo nitriles 8a in 43% yield
(entry 6). It is noteworthy that (1z,5z)-cycloocta-1,5-
diene (COD) gave 9a in 34% yield with one double bond
retained (entry 7). Trisubstituted cyclic olefins, such as 1-
arylcycloalkenes, react smoothly under the standard
conditions (entries 8 to 15). The substitution effect is not
obvious among these substrates. However, 1-methyl
cyclohexene did work under the standard conditions.
Notably, 14a was obtained in 95% yield (entry 12), and
larger cyclic olefins were also tolerant in this
transformation (entries 14 and 15).
from 1,1-diphenylethylene. To investigate the possible
one carbon product, α-methyl styrene was carried out
under the standard conditions. After the reaction, HCN
as another product has been detected in the solvent by
GC-MS (see SI).
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This protocol of oxidative cleavage of olefins may have
profound implications of synthesis, since it offers facile
approaches to many valuable compounds (Scheme 3).
For instance, 2-arylacetonitriles such as 3a are versatile
building blocks in the synthesis of isoquinoline
derivatives.9 Benzonitrile derivatives such as 4a are
reported as synthetic precursors of isoquinolines.10
Scheme 2. TEMPO-catalyzed Oxidative Nitrogenation
of Some Terminal Alkenes.
In addition, oxo nitriles derived from 1-arylcyclic
olefins (such as 10 to 17) have been used to produce α-
hydroxyketones which are present in a multitude of
natural products.11,12 Furthermore, these oxo nitriles
(such as 10a to 17a) are utilized as key intermediates to
synthesize alkenenitriles.13
Terminal alkenes, such as styrenes, gave the
corresponding carbonyl compounds in good yields
Table 1. TEMPO-catalyzed Oxidative Nitrogenation of
Scheme 3. The Profound Implications of Oxo Nitriles in
Organic Synthesis.
Diverse Olefins.a
It should be mentioned that this protocol establishes
more efficient and concise synthetic methodologies. For
example, as common synthons, 6a is often produced
through multi-steps from pentane-1,5-diol.14 After
careful unilateral bromination, cyanation and oxidation,
the target product is isolated in 13% overall yield. In
contrast, it can be easily produced simply from
cyclohexene 6 by this present approach (i, Scheme 4).
Moreover, the current method is also attractive due to its
mild conditions and convenient operations. Another
convincing example is the synthesis of previously
mentioned aliphatic oxo nitriles (such as 10a, ii, Scheme
4). Traditional condensations need strict inert gas
protection for the sake of moist-sensitive bases with
cumbersome operations.15 Conversely, under the present
conditions, these compounds have been smoothly
produced in 50-95% yields starting from simple and
readily available 1-arylcyclic alkenes.
a Reaction conditions: olefin (0.3 mmol), TMSN3 (0.45 mmol), TEMPO
(0.045 mmol) in MeCN (2.0 mL) at 80 ℃ for 36 h under oxygen (1 atm). b
c
d
Isolated yields. Reation was carried out for 24 h. 10 mol % PIDA was
e
f
added. With cis and trans mixture. 10 mol % TBHP (5.5 M in decane)
was added.
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Scheme 4. A Concise Approach to Synthetic Important
Oxo Nitriles.
Scheme 5. Proposed Mechanism of This Oxidative
Nitrogenaion of Olefins.
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The regioselectivity of this transformation may be
interpreted by the stability of the possible α-azido radical
intermediates. This hypothesis was further confirmed by
parallels between 2-phenyl-1H-indene 4 (entry 2, Table 1)
and its analogue 22 (Eq. 4). When phenyl was replaced
by ethyl, the regioselectivity led to a Wacker-type
oxidation product 22a in 90% yield. tert-Butyl
hydroperoxide (TBHP) was identified as an essential
additive in this reaction; low efficiency was observed in
its absence.
Many control experiments have been investigated to
probe the mechanism of this TEMPO-catalyzed
oxygenation and nitrogenation chemistry. The results
indicate that TEMPO is required for this transformation
(Eq. 1). The result of 18O labeling experiment proves the
dual functions of molecular oxygen as both an oxidant to
reoxidize the catalyst, and an oxygen source for the
oxygenation process (Eq. 2). The reaction is not sensitive
to water, and the isolated yield of product insensitive to
the presence of two equivalents of water. No product was
observed in the presence of water under argon (Eq. 3).
The current method provides many opportunities to
synthesize useful intermediates. For instance, the widely
used anesthetic and analgesic medicine, the (S)-
Ketamine, was enantiomerically prepared from oxo
nitrile 23a for many steps.17 As previously mentioned, it
is inevitable to undergo trivial manipulations to obtain
23a. Alternatively, with our concise strategy, this
compound has been prepared in 86% yield with readily
available alkenes (Scheme 6).
Scheme 6. The Synthesis of Key Intermediate of
Ketamine.
On the basis of the preliminary results, a plausible
pathway is proposed for this oxygenation and
nitrogenation reaction (Scheme 5). Initially, TMSN3
generates azido free radical associated with the
formation of intermediate A16 (i, Scheme 5) which is
detected by GC-MS (see SI). The azido free radical
subsequently attacks the alkene and terminates with
molecular oxygen to form peroxide radical B (ii, Scheme
5). Subsequently, the peroxyl radical B reacts directly
To our delight, this kind of TEMPO-TMSN3 system
could be executed in the oxidation of steroids (Eq. 5).
Ergosterol is a vital steroid as the precursor of vitamin D.
In this case, the α-oxo azide product 24a was obtained in
64% yield without further Schmidt rearrangement due to
the polysubstituents (Eq. 5). Despite rarely reported in
preparation,18 many studies in steroid chemistry have
shown that α-azido steroidal ketones like 24a are key
intermediates to α-aminoalcohols,19 α-aminoketones20
and bis-steroidal pyrazines.21
with the TEMPO-TMS species A, followed by
a
continuous rearrangement and heterolysis of the O-O
bond to form the desired oxo nitrile product, with the
regeneration of the catalyst, the release of N2 and the
formation of TMSOH (GC-MS detected, see SI) (iii,
Scheme 5). Although the precise process from B to
product is not completely clear yet, α-azido ketone and
β-hydroxyl azide were excluded as the intermediates
involved in this process by the control experiments (see
SI).
In conclusion, selective C–C bond functionalization
has been considered as one of the most challenging and
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synthesis of various oxo nitriles, which can be used for
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oxidation under mild conditions could make it
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ASSOCIATED CONTENT
Experimental details and NMR spectra. This material is
available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jiaoning@bjmu.edu.cn
Present Addresses
† Peking University
‡ Chinese Academy of Sciences
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Financial support from National Basic Research Program of
China (973 Program) (Grant No. 2009CB825300) and
National Science Foundation of China (No. 21172006) are
greatly appreciated. We thank Zejun Xu and Yufeng Liang
in this group for reproducing the results of 8a, 14a, and 6a,
17a respectively.
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