Ruthenium-Catalyzed Direct Transformation of Alkenyl Oximes to 5-Cyanated Isoxazolines: A Cascade Approach Based on Non-Stabilized Radical Intermediate

Article abstract of DOI:10.1002/ejoc.201701651

A ruthenium-catalyzed ammoxidation of alkenyl oximes under mild and neutural condtions is described. In this method, tert-butyl nitrite plays a dual role, acting as an oxidant as well as a nitrogen source. This reaction avoids using any toxic radical initiators or cyanide reagents. This convenient and practical method offers an easy access to 5-cyanated isoxazolines in good to high yields, and shows good functional group tolerance and high efficiency. It is rather remarkable that this new reaction provides a strategically distinct approach based on non-stabilized radical intermediate and constructs C–O and C≡N triple bonds in a single-step. Moreover, the difunctionalization of unactivated olefins bearing oximes has been realized.

Full text of DOI:10.1002/ejoc.201701651

A Journal of
Accepted Article
Title: Ruthenium-catalyzed Direct Transformation of Alkenyl Oximes to
5-cyanated Isoxazolines: A Cascade Approach Based on Non-
stabilized Radical Intermediate
Authors: Dan-Jun Wang, Bei-Yi Chen, Yi-Qi Wang, and Xiao-Wei
Zhang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701651
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701651
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10.1002/ejoc.201701651
European Journal of Organic Chemistry
COMMUNICATION
Ruthenium-catalyzed Direct Transformation of Alkenyl Oximes to
5-cyanated Isoxazolines: A Cascade Approach Based on Non-
stabilized Radical Intermediate
Dan-Jun Wang, Bei-Yi Chen, Yi-Qi Wang, Xiao-Wei Zhang*[a]
Abstract: A ruthenium-catalyzed ammoxidation of alkenyl oximes
under mild and neutural condtions is described. In this method, tert-
butyl nitrite plays a dual role, acting as an oxidant as well as a
nitrogen source. This reaction avoids using any toxic radical initiators
or cyanide reagents. This convenient and practical method offers an
easy access to 5-cyanated isoxazolines in good to high yields and
shows good functional group tolerance and high efficiency. It is
rather remarkable that this new reaction provides a strategically
distinct approach based on non-stabilized radical intermediate and
constructs C–O and C≡N triple bonds in a single-step. Moreover,
the difunctionalization of unactivated olefins bearing oximes has
been realized.
isoxazoline skeletons are extensively found in molecules with
biological activity and also act as versatile intermediates in
organic synthesis.[15] A quick survey of the precedent work in this
filed shows that non-stabilized radical
B is a common
intermediate involved in radical reactions of alkenyl oximes, and
the existence of this functionalized alkyl radical B was proved
both experimentally[14] and computationally.[14a,16,17]
The nitrile group is of great importance in organic synthesis, as
on one hand it is ubiquitous in numerous marketed drugs and
bioactive compounds, on the other hand, it can be easily
transformed to other functional groups such as amine, aldehyde,
acid, amide and heterocycle.[1] Generally, the methods for the
synthesis of nitriles mainly include Sandmeyer reaction,[2]
Rosenmund-von Braun reaction,[3] transition-metal-catalyzed
cyanation,[4] direct cyanation of C-H bonds,[5] nucleophilic
aliphatic substitution,[6] and functional group transformation from
corresponding alcohols, amines, amides or oximes.[7] More
recently, the ammoxidation strategy for cyanation through a
radical intermediate has emerged as a more efficient and
economic tool for the introduction of nitrile group,[8,9,10] owing to
the mild conditions and avoiding of highly toxic cyanide source.
Despite great success has been made in this field by Jiao, Wang,
Kang and Togo et al., only substrates that can generate
stabilized radical intermediate, for example, benzylic[8], allylic[9]
or α-imino radicals[10], are viable for this strategy (schem 1, top).
Methods that can convert other kind of radical intermediate,
especially non-stabilized radical, to nitrile group are expected to
extend the utility of this strategy substantially, and therefore
highly desirable.
Along with the significant development of radical chemistry,
radical reactions based on 1,2-difunctionalization of alkenes[11]
and nitrogen-centered radical scavengers[12] or C-N bond
formation with NO radical[13] have emerged as the most powerful
tools for the assembly of diverse useful molecules. Meanwhile,
β,γ-unsaturated ketoximes have been widely used to synthesize
the isoxazolines through radical cyclization strategy,[14] since the
Scheme 1. Ammoxidation strategies for cyanation based on radical
intermediate
We envisioned that, an efficient one-step cyanation method
could be developed if radical B could be selectively trapped by a
nitroso radical or related species, followed by a successive
tautomerization and dehydration (Scheme 1, bottom). Although
trapping radical B with nitroso radical (or related species) and
forming the dimeric compound of C has been reported,[14e]
tuning the reaction to the desired cascade reaction pathway is
still a difficult job, given the fact that the primary carbon radical B
is extreme reactive (react with air even at low temperature)[18]
and intermediate C is prior to dimerization.[14e] The identification
[a]
Dan-Jun Wang, Bei-Yi Chen, Yi-Qi Wang, Dr Xiao-Wei Zhang
National Engineering Research Center for Carbohydrate Synthesis
Jiangxi Normal University
Nanchang 330022, China
E-mail: xwzhang@jxnu.edu.cn
http://www.escience.cn/people/xwzhang/index.html
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701651
European Journal of Organic Chemistry
COMMUNICATION
of regent compatible with the radical conditions and capable of
were essential for this reaction (Entries 11-13, Table 1).
converting the oxime D to nitrile is another daunting task. Herein, Although the exact role of MgSO4 is unclear at this stage, it was
we report an efficient and practical ruthenium-catalyzed
transformation of alkenyl oximes to 5-cyanated isoxazoline
based on a non-stabilized radical intermediate.
probably more than a water absorbing reagent, as the 4Å
molecular sieve, a more effective dehydration reagent, gave
lower yield (Entry 14, Table 1). When the reaction was
conducted under oxygen atmosphere, the yield decreased
sharply and red-brown gas was observed on the surface of the
reaction solvent (Entry 15, Table 1).
Initially, β,γ-unsaturated ketoxime 1a was used as a model
substrate for reaction condition optimization. Interestingly, when
we chose t-BuONO as the oxidant and nitrogen source, oxime 3,
instead of the desired product 2a, was obtained in 65% yield in
the presence of 2 equivalents of LiCl in acetonitrile at 80 oC
(Entry 1, Table 1). This result was unexpected since analogous
Lewis acid AlCl3 gave chlorinated isoxazoline as the product.[19]
Encouraged by this exciting preliminary results, we subsequently
screened different catalysts capable of converting oxime to
nitrile, in conjunction with LiCl. When stannous chloride
dihydrate was added,[20] the desired product 2a was obtained in
49% yield (Entry 2, Table 1); however, the addition of Zn(OTf)2
gave a lower yield (Entry 3, Table 1). Gratifyingly, the yield
increased to 78% when 5 mol% of [RuCl2(p-cymene)]2 was used
as the catalyst (Entry 4, Table 1).[21] Other ruthenium catalysts,
such as Ru3(PPh3)2 and Ru3(CO)12, also worked for this
transformation (Entries 5-6, Table 1). Surprisingly, when the
reaction temperature was lowered to room temperature and the
reaction time was reduced to 4 h, the yield of 2a was almost
unchanged with [RuCl2(p-cymene)]2 as the catalyst (Entry 7,
Table 1). Next, various additives were screened based on this
mild conditions. We found many common inorganic salts were
effective in this transformation,[22] with magnesium sulfate
affording the best yield (Entries 8-10, Table 1). Control
experiments proved that the ruthenium catalyst and additive
Table 1. Optimization of the conditions[a]
Entry
Additives
Catalyst (mol%)
none
Yield[b]
0%[f]
1[c]
2[c]
LiCl
LiCl
.
SnCl2 2H2O (50)
0%
3[c]
4[c]
5[c]
LiCl
Zn(OTf)2 (50)
[RuCl2(p-cymene)]2 (5)
Ru3(PPh3)2 (5)
0%
LiCl
0%
LiCl
0%
6[c]
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
13[d]
14[d]
15[d,g]
LiCl
Ru3(CO)12 (5)
43%
66%
52%
3%
89 (86)%[e]
77%
0%
LiCl
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (2.5)
none
CH3CO2Na
Na2SO4
MgSO4
MgSO4
MgSO4
none
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
0%
4Å MS
MgSO4
65%
14%
[a] Reaction conditions: 1a (0.25 mmol), t-BuONO (0.5 mmol), additive (0.5
mmol), CH3CN (2 mL), under argon atmosphere; [b] yield determined by 1H
NMR using MeOtBu as internal standard; [c] reaction at 80 oC for 8h; [d]
reaction at room temperature for 4h; [e] isolated yield was given in parenthesis.
[f] 3 was isolated in 65% yield while no 2a was obtained; [g] reaction under
oxygen atmosphere. For details, see SI.
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10.1002/ejoc.201701651
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COMMUNICATION
Scheme 2. Reaction scope. Reaction conditions: 1 (0.25 mmol), [RuCl2(p-
cymene)]2 (5 mol%), MgSO4 (0.5 mmol), CH3CN (2 mL), t-BuONO (0.5 mmol),
RT, 4 h, argon atmosphere. Isolated yield. For details, see SI.
2). This reaction implies that t-BuONO played the role of radical
initiator in both cyanation and trapping reactions. Furthermore,
radical clock experiment was also conducted to verify the
reaction mechanism. When cyclopropane-substituted oxime 6
was subjected to the standard conditions, the ring opening
products 7 was isolated in 44% yield (Eq 3). This result implies a
radical pathway for this reaction and also supports the
assumption that the C-N bond formation is not a fast process.[13a]
Finally, when oxime 3 was treated with ruthenium catalyst at
room temperature, nitrile 2a was isolated in 95% yield (Eq 4).
This result implies that oxime is probably the intermediate of this
reaction and the function of ruthenium catalyst may be
converting the oxime intermediate to nitrile.
With the optimized conditions in hand (Entry 10, Table 1), we
subsequently proceeded to explore the substrate scope of this
radical cascade reaction. To our delight, various substrates
containing aryl, heteroaryl, alkyl and other functional groups
were compatible in this transformation and gave the cyanated
isoxazoline in good to high yield (Scheme 2). For example,
substrates bearing halide (2b-2d), nitro (2e), alkoxy (2f),
trifluoromethyl (2g), methyl (2i) or cyano (2j) substituents on the
phenyl ring, underwent the reaction well to afford the
corresponding cyanation products in good to high yield (76-91%),
regardless of their different electronic properties or substitution
patterns. This reaction is not limited to simple benzene-based
substrates, heteroaryl-substituted β,γ-unsaturated ketoximes
also gave the desired products in good yields (2j-2l). Gratifyingly,
the current methodology could be successfully employed to build
a quaternary carbon center with specific regioselectivity (2m). To
further investigate the substrate scope, 1n with a quaternary
carbon at C2 was next tested in our conditions, and the desired
product 2n was obtained in 85% yield. We were pleased to find
that this system worked well with alkyl-substituted substrates,
giving 2o and 2p in 74% and 82% yield, respectively. Alkyl-
substituted substrates with protecting groups such as TBDPS
and phthalimidyl were also tolerable in this conditions, and the
desired product were obtained in high yields (2q, 2r). The high
yield of 2n, 2q, 2r probably benefits from the Thorpe-Ingold
effect.[23]
On the basis of these preliminary results, we proposed a
plausible mechanism for this transformation as depicted in
Scheme 5. First, t-BuONO oxidized alkenyl oxime
1 to
intermediate A, with the generation of nitroso radical and tert-
butanol. Second, oxime radical A underwent a 5-exo-trig
cyclization and generated the primary carbon radical B. Third,
intermediate B combined with the nitroso radical or related
species to afford the C. Finally, intermediate C tautomerized to
oxime D, which was transformed to product 2 with the aid of
ruthenium catalyst.
To demonstrate the utility of this reaction, transformation of 1a
was carried out on gram scale. To our delight, the desired
product could be isolated in 81% yield even with lower amounts
(2.5 mol%) of ruthenium catalyst. The nitrile group could be
easily transformed to other useful functional groups. In this work,
the carboxylic acid 4 could be prepared in 84% yield after
recrystallization. This carboxyl-substituted isoxazoline could be
viewed as the precursor of α-hydroxyl acid by the cleavage of
N-O bond under reduction conditions.[24]
Scheme 4. Control experiments
Scheme 3. Gram scale synthesis and synthetic application. [a] [RuCl2(p-
cymene)]2 (2.5 mol%), MgSO4 (2.0 equiv), CH3CN, t-BuONO (2.0 equiv), RT, 4
h; [b] 4 N HCl aqueous solution, reflux, 10 h, recrystallized yield.
To gain insight into the mechanism, several control experiments
were carried out as shown in Scheme 4. Initially, this reaction
was conducted in the presence of 3 equivalents of 2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO), the cascade reaction were
completely shut down and only TEMPO-trapped product 5 was
isolated in 83% yield (Eq 1). This result indicates that the
cyanation reaction may proceed through a radical intermediate.
Removing t-BuONO from above control experiment, the product
2a or 5 could not be obtained while 1a was totally recovered (Eq
Scheme 5. Proposed mechanism.
In conclusion, we have developed a radical based, mild and
efficient cyanation method which converts the alkenyl oxime to
the cyanated isoxazoline without using any highly toxic cyanide
reagents. Various substrates bearing aryl, heteroaryl, alkyl and
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10.1002/ejoc.201701651
European Journal of Organic Chemistry
COMMUNICATION
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Experimental Section
General Procedure for the synthesis of cyanated isoxazolines
To a 15 mL Schlenk tube charged with MgSO4 (2.0 equiv) and [RuCl2(p-
cymene)]2 (5 mol%), a solution of oxime 1 (0.25 mmol) in CH3CN (2 ml),
t-BuONO (2.0 equiv) were added sequentially under argon atmosphere.
The reaction mixture was stirred at room temperature for 4 h, then the
mixture was concentrated under reduced pressure and the resulting
residue was purified by flash column chromatography.
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Acknowledgements
[10] F. Chen, X. Huang, Y. Cui, N. Jiao, Chem. A Eur. J. 2013, 19,
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We gratefully acknowledge the funding support of a Start-up
Grant from Jiangxi Normal University.
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Keywords: cyanation • olefin difunctionalization • isoxazoline •
ammoxidation • radical cyclization
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10.1002/ejoc.201701651
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Radical ammoxidation
Dan-Jun Wang, Bei-Yi Chen, Yi-Qi
Wang, Xiao-Wei Zhang *
Page No. – Page No.
Ruthenium-catalyzed Direct
A convenient method offers an easy access to 5-cyanated isoxazolines in good to
high yields and shows good functional group tolerance and high efficiency. In this
protocol, tert-butyl nitrte plays a dual role, acting as an oxidant as well as a nitrogen
source. It is rather remarkable that this new reaction avoids using any toxic radical
initiator or cyanide reagents and constructs C–O and C≡N triple bonds in a single-
step.
Transformation of Alkenyl Oximes to
5-cyanated Isoxazolines: A Cascade
Approach Based on Non-stabilized
Radical Intermediate
This article is protected by copyright. All rights reserved.