Metal-free new synthesis of 1,3-naphthoxazines via intramolecular cross dehydrogenative-coupling reaction of 1-(α-aminoalkyl)-2-naphthols using hypervalent iodine(III) reagent

Article abstract of DOI:10.1016/j.tetlet.2015.12.117

A series of 1-(α-aminoalkyl)-2-naphthols were synthesized via three-component Betti reaction of β-naphthol, aldehyde, and cyclic secondary amine under reflux conditions. The subsequent reactions of 1-(α-aminoalkyl)-2-naphthols with (diacetoxyiodo)benzene

Full text of DOI:10.1016/j.tetlet.2015.12.117

Accepted Manuscript
Metal-free new synthesis of 1,3-naphthoxazines via intramolecular cross dehy-
drogenative-coupling reaction of 1-(α-aminoalkyl)-2-naphthols using hyperva-
lent iodine(III) reagent
Nitin A. Waghmode, Amit H. Kalbandhe, Prerana B. Thorat, Nandkishor N.
Karade
PII:
S0040-4039(15)30531-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.117
TETL 47164
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 October 2015
28 December 2015
30 December 2015
Please cite this article as: Waghmode, N.A., Kalbandhe, A.H., Thorat, P.B., Karade, N.N., Metal-free new synthesis
of 1,3-naphthoxazines via intramolecular cross dehydrogenative-coupling reaction of 1-(α-aminoalkyl)-2-naphthols
using hypervalent iodine(III) reagent, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.12.117
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Graphical Abstract
Metal-free new synthesis of 1,3-naphthoxazines via
Leave this area blank for abstract info.
intramolecular cross dehydrogenative-coupling
reaction of 1-(-aminoalkyl)-2-naphthols using
hypervalent iodine(III) reagent
Nitin Waghmode, Amit H. Kalbandhe, Prerana B. Thorat and Nandkishor N. Karade*

1
Tetrahedron Letters
Metal-free new synthesis of 1,3-naphthoxazines via intramolecular cross
dehydrogenative-coupling reaction of 1-(-aminoalkyl)-2-naphthols using
hypervalent iodine(III) reagent
Nitin A. Waghmode, Amit H. Kalbandhe, Prerana B. Thorat and Nandkishor N. Karade*
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra 440 033, India
E-mail: nnkarade@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of 1-(aminoalkyl)-2-naphthols were synthesized via three-component Betti
reaction of β-naphthol, aldehyde and cyclic secondary amine under reflux conditions. The
subsequent reactions of 1-(-aminoalkyl)-2-naphthols with (diacetoxyiodo)benzene
resulted in the formation of 1,3-napthoxazines. This reaction demonstrates the formation of
C-O bond formation via cross dehydrogenative-coupling (CDC) under transition metal-free
conditions.
Available online
Keywords:
Betti reaction,
hypervalent iodine reagents,
cross dehydrogenative-coupling (CDC),
1,3-naphthoxazines,
2009 Elsevier Ltd. All rights reserved.
imminium ion
formaldehyde and secondary amine,14 (ii) aza-acetalizations of
aromatic aldehydes with 2-(N-substituted aminomethyl)phenols
in presence of an acid as catalyst,15 (iii) electrooxidative
cyclization of hydroxyamino compounds,16 (iv) visible light
photooxidative cyclization of amino alcohols,17 and (v) cross-
dehydrogenative coupling (CDC) using transition metal
oxidant.18-20
Cross-dehydrogenative coupling (CDC) involves the elimination
of a hydrogen atom from each molecule leading to the formation
of C-C and C-heteroatom bond. This synthetic strategy is
emerging as a popular tool in modern organic chemistry due to
the accomplishment of certain principles of Green Chemistry.1
Some of the features associated with CDC are (a) high atom
economical efficiency, (b) the reduction of number of steps of the
organic synthesis, (c) avoids the preactivation of substrates in the
form of functional groups such as such as -Hal, -OTf, -BR2, -
SnR3, -SiR3, -ZnHal, -MgHal, and (d) minimization of byproduct.
CDC can be induced using Ru,2 Fe,3 Rh,4 V,5 and Cu6 based
transition metal oxidants. The toxicity of certain transition metals
along with the cost, high loading of the catalyst and harsh
reaction conditions demands the search for new oxidizing agents
for executing CDC reactions. Among them, hypervalent iodine
reagents are promising as an alternative to the transition metal
oxidants.7 The environmentally benign nature, mild reaction
conditions and commercial availability makes them preferred
oxidizing agents over transition metal oxidants in modern organic
synthesis.8
Figure 1 Biologically active molecules with 1,3-oxazines as sub-
structural heterocyclic unit
Dihydro-1,3-oxazine heterocycles act as a privileged structural
motif of various pharmacological active molecules displaying
antibacterial,9 fungicidal,10 antitumor,11 and antituberculosis,12
(Figure 1). Some 1,3-naphthoxazine have found applications in
synthesis of chiral 1-(-aminoalkyl) naphthols.13 Owing to the
biological and synthetic importance of benzofused 1,3-oxazines,
various methods have been developed for its synthesis involving:
(i) Mannich three-component condensation of 2-naphthol,
Three component condensation of 2-naphthol, aldehydes, and
cyclic amines under refluxing conditions form 1-(-aminoalkyl)-
2-naphthols via a century old Betti reaction.21 Owing to the
simplicity in the synthesis of 1-(-aminoalkyl)-2-naphthols by
Betti reaction, its applications in the synthesis of 1,3-
naphthoxazines via oxidative cross-dehydrogenative coupling has
received
considerable
attention.
A
copper-mediated

2
Tetrahedron Letters
any isolable yield of 2a. The other trivalent iodine reagents such
intramolecular -functionalization of tertiary amines through
C_H bond oxidative activation (benzylic and non-benzylic) is
employed to synthesize diverse dihydro-1,3-oxazines through
C_O bond formation. The method is very simple and uses
inexpensive Cu(OAc)2·H2O as the catalyst.18a The similar kind of
transformation for the synthesis of 1,3-naphthoxazine has been
recently reported using stoichiometric Ag2O19 as well as CuI20 as
the catalysts and L-proline as the ligand. In spite of these
advances, there is a need to develop transition metal-free
oxidative conditions for the synthesis of 1,3-naphthoxazines from
as PhICl2 and PhI(OCOCF3)2 were unsuccessful for the formation
of 2a (entries 6-8). Encouraged by the result of DIB reaction with
1a, we attempted the CDC coupling for C-O bond formation
using the in situ generated hypervalent iodine(III) reagents from
the reactions of catalytic iodoarene with terminal oxidants such
as MCPBA or oxone (entries 9-10). However in both the cases,
we couldn’t get corresponding 2a.
With the optimized conditions, we continued to study the
substrate scope by using
a variety of substituted 1-(-
the
1-(-aminoalkyl)-2-naphthols.
1-(-Aminoalkyl)-2-
aminoalkyl)-2-naphthols 1, as summarized in Table 2.23 The
resultant 1,3-naphthoxazines 2 which contain a broad range of
substituents could be obtained in moderate to excellent yields.
The pyrolidine derivatives of Betti bases provided better yield of
1,3-naphthoxazines compared to those of piperidine and
morphiline. The effect of substituents on the phenyl ring (Ar)
was also examined and found that there was no such large
reactivity difference between substrates bearing electron-
donating and electron-withdrawing groups. The reaction was
found to be completely diastereoselective as only one
naphthols, a Betti base is a typical phenolic substrate with the
speculation of oxidation with hypervalent iodine reagents.
Therefore, its reaction study with hypervalent iodine reagents is
worth to investigate. Herein, we report a facile synthesis of 1,3-
naththoxazines from 1-(-aminoalkyl)-2-naphthols using
(diacetoxyiodo)benzene as the oxidant under exceptionally mild
conditions.
1
diastereomer was formed according to the H NMR spectra of all
the products 2 (Supplementary material).
The tentative mechanism for CDC induced by DIB is shown in
Scheme 2. The trivalent iodine reagents are well documented for
the oxidative aromatization of phenol to form quinone-type
product.23 The o-quinone methide 6 or 7 as intermediate has been
previously proposed in the reaction of 1-(-aminoalkyl)-2-
naphthols with Cu(OAc)2,18a Ag2O19 and CuI20 to form 1,3-
naphthoxazines. However, the reaction of DIB with phenolic
substrate 1 can inhibit the oxidative dearomatization due to the
formation of putative six membered iodine(III) heterocycle 4.24
The propensity of 4 for reductive elimination of iodobenzene will
Scheme
synthesis
1
(Diacetoxyiodo)benzene mediated 1,3-naphthoxazines
We examined the conversion of 1a into 2a as a model for
optimization of the reaction conditions. Different solvents and
hypervalent iodine reagents as oxidizing agents were screened
(Table 1). The trivalent iodine reagent, (diacetoxyiodo)benzene
(DIB) was found to induce the CDC for the formation of 2a
(entry 1). Increasing the quantity of DIB up to 2.2 equivalents
(entries 2-3) improved yield of the product 2a.22 The other
solvents such as CH3CN and THF (entries 4-5) failed to produce
generate the requisite imminium ion
5 which will be
intramolecularly trapped by phenoxide anion to form trans-1,3-
naphthoxazine 2.
Table 1 Optimization of reaction conditions
Entry Oxidizing agent (equiv)
Solvent
Reaction Yield of 2a (%)a
time (h)
1
2
PhI(OAc)2 (1.1 equiv)
PhI(OAc)2 (1.5 equiv)
PhI(OAc)2 (2.2 equiv)
PhI(OAc)2 (2.0 equiv)
PhI(OAc)2 (2.0 equiv)
PhICl2 (1.5 equiv)
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
24
24
8
39
62
77
00
00
00
00
00
00
00
3
4
24
24
24
24
24
5
6
CH2Cl2
CH2Cl2
CH2Cl2
7
PhICl2 (2.0 equiv), pyridine (1.5 equiv)
PhI(OCOCF3)2 (2.0 equiv)
8
9
PhI (0.5 equiv), MCPBA (3 equiv), reflux AcOH, CH2Cl2 24
PhI (0.5 equiv), oxone (1.5 equiv), reflux AcOH, CH2Cl2 24
10
aIsolated yields

3
Scheme 2 Mechanism for dehydrogenative C-O bond formation using (diacetoxyiodo)benzene
Table 2 Synthesis of 1,3-naphthoxazines from 1-(-aminoalkyl)-2-naphthols using (diacetoxyiodo)benzenea
Reaction conditions: 1-(-aminoalkyl)-2-naphthols (1 equiv), DIB (2.2 equiv), and CH2Cl2 (5 mL) at room temperature
stirring

4
Tetrahedron
(10) (a) Bouaziz, Z.; Riondel, J.; Mey, A.; Berlion, M.; Villard, J.;
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In conclusion, we have developed an efficient intramolecular
CDC
reaction
of 1-(-aminoalkyl)-2-naphthols
using
(diacetoxyiodo)benzene as the oxidant to form 1,3-naphthoxazine
in moderate to good yield. This synthesis of 1,3-naphthoxazine
involves transition metal-free cross-dehydrogenative C-O bond
formation at sp3 C-H bond adjacent to tertiary nitrogen. The
product formation took place under exceptionally mild reaction
conditions compared to literature methods employing transition
metal oxidants.
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Supporting Information for this article is available online
at
http://www.thieme-
connect.com/products/ejournals/journal/10.1055/s-
00000084.
Acknowledgment
The authors are thankful to the Department of Science and
Technology, New Delhi, India (No. SR/S1/OC-72/2009) for the
financial support. The authors are also grateful to SAIF, Punjab
University, Chandigarh, India, for recording the NMR spectra.
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(22) General procedure for the synthesis of 1, 3- naphthoxazines
(2a-2l): To the solution of substrate 1-(-aminoalkyl)-2-
naphthols
1 (1 mmol) in dichloromethane (5 mL),
(8)
(9)
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5
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