": A Jack of Trio "-robust one-pot metal free oxidative amination, azidation and peroxidation of phenols

Article abstract of DOI:10.1039/c7nj00169j

Herein we disclose a highly efficient methodology for the generation of nitrogen containing quaternary carbon centres via aminative and azidative oxidative dearomatization of phenols. The same protocol has also been successfully employed to achieve oxidative peroxidation of phenols. The simplest metal free reaction conditions delineate an easy breakthrough to the "Trio"- oxidative amination, azidation and peroxidation. An array of diverse polyfunctionalised heterocycles has been synthesized in one pot.

Full text of DOI:10.1039/c7nj00169j

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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DOI: 10.1039/C7NJ00169J
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“A Jack of Trio”- Robust One-pot Metal free Oxidative Amination,
Azidation and Peroxidation of Phenols
Received 00th January 20xx,
Accepted 00th January 20xx
*
Debayan Sarkar a, Manoj Kumar Ghosha, Nilendri Routa, and Puspendu Kuilaa
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here in we disclose a highly efficient methodology for generation Aminocyclohexadieneones, azido-napthaleneones and Peroxo-
of nitrogen containing quarternary carbon centres via aminative cyclohexadieneones constitute the central core for a vast set
and azidative oxidative dearomatization of phenols. The same of medicinally important molecules and thus create an
protocol has also been succesfully employed to achieve oxidative extreme focus of attention. Certainly, a generalised oxidative
peroxidation of Phenols. The simplest metal free reaction strategy which carefully aaccomplishes this “trio” of reactions
conditions delineates an easy break through to the “Trio”- of of aminative, azidative and peroxodative dearomatisations,
oxidative amination, azidation and peroxidation. An array of can be a reaction of tremendous synthetic importance5.
diverse polyfunctionalised heterocycles has been synthesized in Interestingly extensive literature survey has fetched us scanty
one pot
reports focussing on discrete aminative and peroxidative
dearomatization of naphthols6,7. Nevertheless, there has been
no reports on oxidative amination & azidation of phenols,
which possess elevated aromatic energy levels than naphthols.
Thus suitable design of a generalised straightforward and
sustainable synthetic methodology of this trio of conversions
demands for an appealing intervention into this area.
Cyclohexadieneones and naphthalenones are important
structural motifs which serve as effective molecules towards
complex natural product synthesis1,2. These important motifs
are normally achieved from the direct dearomatization of
arenes.
N
HO
H3
O
C
O
N
O
O
O
O
OH
(-)-n-methylguattescidine
CH3
CH3
OH
O
CH3
H3C
OH
Tetrapolone A
Aminative
O
H
HN
H
Oxidative
Dearomatisation
O
O
O
O
O
O
O
Artimisinin
Azidative
Peroxidative
(Trio)
Cl
Enilospirone
O
N
OH
H
HO
O
MeO
OH
MeO
MeO
N
O
O
Lacinilene C
3-demethoxyery thratidinone
Guatterine
Fig. 1: Biologically active natural products with amino-
naphthalenones, amino-cyclohexadieneone, peroxides and
azaspiro structural cores.
Scheme-1: Reaction “Trio”
There has been continued reports for accomplishing these
molecules via oxidative dearomatization reactions using varied
hypervalent iodine3 and transition metal complexes4. Notably,
the last decade has seen a tremendous urge to develop
sustainable versions of this atom-economic transformation
Herein, we report the first economic protocol for achieving the
“trio” - aminative, azidative and peroxidative dearomatization
of naphthols as well as phenol derivatives employing Phenyl
trimethyl ammonium tribromide (PTAB) as the effective
reagent. Initially, we began our study using 2,4,6-trimethyl
phenol as the model substrate and on reaction with
cyclohexylamine as the incoming nucleophile in presence of
PTAB at room temperature delivered 4-(cyclohexylamino)-
which
can
be
applied
to
a
wider
context.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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2,4,6-trimethylcyclohexa-2,5-dieneone (1) as the sole product
in overwhelming yields in 12 hrs.(Scheme-1).
The reactions on suitable optimisation required for
1
equivalent of PTAB for completion. Solvent Screening as listed
in Table 1 puts up an impression that THF fits as the best
solvent for this trio of reactions. (Table 1).
Scheme 2: Partially planar reactive intermediate8
To re-investigate this proposal further, several controlled
experiments were carried out. Secondary amines delivered better
yields compared to primary amines, thus highlighting nucleophilicity
to be a dominant factor in this reaction. Cyclic amines prompted
higher yields as compared to acyclic amines and the acyclic ones
were found to be better than the aromatic amines. Exposure of a
wide range of amines with 2, 4, 6-trimethyl phenol in similar
conditions delivered the corresponding aminocyclohexadieneones
in good yields. A wide range of phenols delivered the desired
products in fantastic yields. Satisfactory functional group tolerance
(Table-2, entry- 4, 11, 13) like unsaturated esters is also revealed.
Not only phenols, the substituted naphthols derivatives also
delivered the corresponding α-amminonaphthalones in appreciable
yields. Labile functionalities like cyclopropanes, esters are left intact
in the reaction (Table-3, entry- 18, 19, 27) making this protocol for
aminative dearomatisation best of the available lot. The reaction
proceeds impressively well with unprotected alcohols (Table-2,
entry-10, Table-3, entry-28,).
Sl. No.
Solvent
Base/
Nucleophile
Cyclohexyl
amine
Yield(%)
1
Dioxane
40
2
3
4
5
6
7
8
DCM
Toluene
Benzene
DCE
„
45
35
40
40
30
75
25
„
„
„
„
„
„
DMF
THF
DMSO
9
Et2O
„
„
35
10
MeOH
No
reaction
No
reaction
No
reaction
No
reaction
No
11
12
13
14
H2O
„
„
„
„
EtOH
THF :
MeOH(1:1)
H2O
reaction
Table 1: Optimization of aminative dearomatization.
The reaction mechanism8 is perceived to be a straight forward
one and proceeds with the initial generation of phenoxide
which inturn activates the ammonium counterpart of PTAB
with the concomitant attack of the nucleophile maintaining a
perpendicular trajectory towards the partially planar reactive
intermediate (R1) with minimal stereo electronic interaction.
(Scheme-2). Presence of a moderately tight ion-pair in the
reactive intermediate in the reaction mixture is perceived, as
repeated reaction batches in polar solvents like DMSO and
DMF
delivered
reduced
yields
of
the
aminocyclohexadieneones. (Scheme 2)
.
Table-2: Substrate scope for the synthesis of
aminocyclohexadieneones
2 | J. Name., 2012, 00, 1-3
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The naphthols delivered oxidative etherification in presence of
other non-nucleophilic co-oxidants like m-CPBA, and
hydrogen-peroxide which interestingly delivered the tert-
butylperoxy- naphthalene-2-one in good yields on treatment
with TBHP (42).
NH
Me
O
94 %
19
Table-3: Substrate scope for the synthesis of α-aminonaphthalones
To evaluate further applicability of this methodology, azides and
peroxides were treated as potential nucleophiles with the above
phenolics under similar reaction conditions. To our delight, both the
azidative and peroxidative dearomatisations turned out to be
fruitful with enhanced yields further attesting our proposal for
dominant nucleophilicity in this reaction. No external base was
required during the amination and azidation reactions.
Table-6: Substrate scope for oxidative-etherification
The products obtained from this generalised methodology can be
diverted towards important synthetic transformations. For e.g. the
aminative dearomation of phenols with ester functionalities directly
delivered aza-spiranones9 whereas the peroxo-naphthalones can be
easily hydrolysed to α-ketols.
Table-4: Substrate scope for azidative dearomatization
Table-7: Substrate scope for spirolactamization
Conclusions
In summary, we have realized an unique and simplest “trio” of
aminative, azidative and peroxidative dearomatisation of
Phenols. The generalisability, substrate scope and the
associated simplicity of the reaction conditions makes this
methodology first of its kind. The facile generation of a
quaternary centre with amine, azide and the peroxide
substitutions from easily available phenolics, labile functional
group tolerance has given a special attention to this synthetic
protocol. Above all, it supersedes all the existing discrete
methodologies being not limited only to naphthols rather is
Table-5: Substrate scope for peroxidative dearomatisation
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functionalities. The diverse range of amino, azido and peroxo-
cyclohexadieneones as well as naphthalones synthesised in
one pot can be easily extended towards generation of
synthetically important heterocyclic motifs, thus solving
molecular intricacy to greater extents.
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We sincerely acknowledge Department of Science and
Technology (DST), Govt. of India (Grant no. SB/FT/CS-
076/2012), Board of Research in Nuclear Sciences (BRNS)
(2013/20/37C/2/BRNS/2651) and INSPIRE-DST, Govt. of India
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for research fellowship. NR thanks DST for research fellowship
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New Journal of Chemistry
“A Jack of Trio”- Robust One-pot Metal free Oxidative Amination,
Azidation and Peroxidation of Phenols
Debayan Sarkar*, Manoj Kumar Ghosh, Nilendri Rout, and Puspendu Kuila
Department of chemistry, National Institute of Technology, Rourkela, Odisha
Facile generation of quartenary carbon centres has been realised in presence of Phenyl
Trimethyl ammonium tribromide (PTAB) mediated oxidative dearomatisation