Synthesis of anti-2,3-dihydro-1,2,3-trisubstituted-1H-naphth [1,2-e][1,3]oxazine derivatives via multicomponent approach

Article abstract of DOI:10.1039/c3ra47211f

A series of anti-2,3-dihydro-1,2,3-trisubstituted-1H-naphth [1,2-e][1,3]oxazine derivatives 6 were exclusively obtained in high yields for the first time through multicomponent reactions (MCRs) of 2-naphthol, aromatic aldehydes and electron rich primary amines in ethanol at room temperature using CCl₃COOH as catalyst. The same reaction could be conducted effectively in solvent-free medium at 100 °C. The stereochemistry of the two hydrogens connected to C-2 and C-4 (1,3) positions of the oxazine ring are identified as anti-orientation by single crystal XRD, COSY and NOESY analysis.

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ARTICLE TYPE
Synthesis of anti- 2, 3-dihydro-1, 2, 3-trisubstituted-1H-naphth
[1, 2-e][1, 3] oxazine derivatives via multicomponent approach
*Ruli Borah,a Arup Kumar Dutta,a Parishmita Sarma,aChampak Dutta,a and Bipul Sarmaa
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A series of anti-2,3ꢀdihydroꢀ1,2,3ꢀtrisubstitutedꢀ1H-naphth [1,2ꢀe][1,3] oxazine derivatives 6 were exclusively obtained in high yields for
the first time through multicomponent reactions (MCRs) of 2ꢀnaphthol, aromatic aldehydes and electron rich primary amines in ethanol
at room temperature using CCl3COOH as catalyst. The same reaction could be conducted effectively in solventꢀfree medium at 100 C.
10 The stereochemistry of two hydrogen connected to Cꢀ2 and Cꢀ4 (1, 3) positions of the oxazine ring are identified as anti-orientation by
single crystal XRD, COSY and NOESY analysis.
best of our knowledge, there is no report for the multicomponent
INTRODUCTION
Multicomponent synthesis of fused 1,3ꢀoxazine
15 derivatives have emerged as a challenging structure development
in organic chemistry in the context of modern drug discovery.1
Various oxazine derivatives have been shown to exhibit wide
50 synthesis of 1,2,3ꢀtrisubstitutedꢀnaphthꢀ[1,3] oxazine 6 using acid
catalyst in solution as well as solvent–free medium. In literature
only few compounds of 1,2,3 trisubstitutedꢀnaphthꢀ[1,2ꢀ
e][1,3]oxazines were known without studying the orientation of
Hꢀ2 and Hꢀ4 protons in the oxazine ring. Cimarelli et al identified
spectrum of pharmacological activities such as antitumor, 55 the two derivatives of 1, 2, 3ꢀtrisubstitutedꢀnaphth[1,3]oxazines
positive alloasteric modulation, antimicrobial, antiꢀHIV and antiꢀ
20 malarial agent.2 Substituted naphthoxazine derivatives are used
for the therapy of Parkinson disease.3 Several one pot synthesis of
fused1,3ꢀoxazines have previously been reported which included
(19ꢀ28% yields) as side products during the stereoselective
synthesis of aminoalkylnaphthol at 60 C after 12ꢀ24 hours
reaction.9a Li et al reported the synthesis of 2ꢀbutylꢀ1,3ꢀdihydroꢀ
1Hꢀnaphthꢀ[1,2ꢀe] [1,3]oxazine by the MCRs of 2ꢀnaphthol,
pyrrolo/pyrido[2,1ꢀa]benzoxazinꢀones and pyrrolo/pyrido[2,1ꢀa] 60 butylamine and benzaldehyde in ethanol for 6 days stirring at
quinazolinones,4a
25 derivatives,4c
pyrido[2,3ꢀe][1,3]oxazine,4b
substituted imidazo[2,1ꢀb][1,3]oxazines
benzoxazine
room temperature.9b These studies revealed that there is a lot of
scope for generation of combinatorial library of novel 1,2,3ꢀ
trisubstituted naphthꢀ[1,3]oxazines using multiꢀcomponent
approach.
derivatives,5aꢀb substituted naphthꢀ[1,2ꢀe][1,3]oxazines etc.6ꢀꢀ8 The
synthesis of mono substituted naphthꢀ[1,3]oxazine was first
disclosed by Bruke et al and then by Shingare et al in PEGꢀ400
by stirring a mixture of 2ꢀnaphthol, formaldehyde and substituted
30 aniline(Figꢀ1, 1 ).6aꢀb It has been observed that the preparation of
1,3ꢀdisubstituted naphthꢀ[1,2ꢀe] [1, 3] oxazine is only limited to
the use of 1ꢀor 2ꢀnaphthol with various aryl and heteroaryl
aldehydes in dry methanolic ammonia solution at room
temperature with longer reaction time (24ꢀ48h) and lower yields
35 (Figꢀ1, 2, 4).7a Later on, the use of ammonium acetate reduced the
reaction time in solvent–free medium using thermal and
microwave energies.7b Substituent effects in the ring–chain
H
H
H
H
Ph
N
H
H
Ph
Ph
N
N
Ph
N
Ph
Ph
Ph
O
O
OH
O
2
4
3
1
65
Figure 1. Monoꢀsubstituted oxazine1 and tautomerism of 1, 3ꢀ
disubstitutedꢀnaphthꢀ[1,3] oxazines 2-4
Herein, we described an efficient trichloroacetic acid
70 catalyzed three component selective synthesis of antiꢀ1ꢀ2,3ꢀ
trisubstitutedꢀnaphthꢀ[1,3]oxazine diastereomer 6 in solution and
under solventꢀfree medium (Scheme 1).
tautomerism
of
1,3ꢀdisubstituted
naphthoꢀ[1,3]ꢀoxazine
R
H
H
derivatives in solution were extensively studied by Fulop and his
40 group( Figꢀ1, 2ꢀ 4).7cꢀd Recently a copper catalyzed regioselective
intramolecular oxidative α–functionalization of tertiary
aminonaphthol were designed by Maycock et al for the synthesis
of some fused trisubstitutedꢀnaphtho[1,3]oxazine derivatives in pꢀ
xylene at 130 C within 2ꢀ7 hours.8a A low valent titanium
45 systems were also developed for the chemoselective conversion
of 1,3ꢀdiarylꢀ2,3ꢀdihydroꢀ1Hꢀnaphtho[1,2ꢀe][1,3]ꢀoxazines to
R1
N
R1
OH
R1CHO
O
RNH2
+
CCl3COOH (cat.)
or
EtOH/ r.t.
solventꢀfree/ heat
6
Anti
5
( )
R1 & R = Alkyl or aryl
75 Scheme 1.Multicomponent synthesis of anti-1, 2, 3ꢀtrisubstitutedꢀ
naphthꢀ[1,3]oxazine diastereomer
naphtho[1,2ꢀe][1,3]oxazineꢀ2(3H)ꢀcarbonyl
naphtho[1,2ꢀe][1,3] oxazineꢀ3ꢀone in THF under reflux.8b To the
chloride
and
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35 reduced the antiꢀproduct selectivity and generated various side
RESULTS AND DISCUSSION
The preliminary works involved with the optimization
products in ethanol at ambient temperature.
of condition for a typical reaction of 2ꢀnaphthol (1 mmol),
benzaldehyde (2 mmol) and aniline (1 mmol) in presence of three
acid catalysts such as acetic acid, trichloroacetic acid and
trifluroacetic acid at 25 C in CHCl3. We also studied the
catalytic activity of these acids for the same reaction under
solventꢀfree medium. Tableꢀ1 distinctly represented the selective
formation of antiꢀproduct 6a with the three catalysts in all
10 conditions out of the two possible diastereomers 6a and 7a. In
antiꢀproduct, the oxazine moiety suffers from less steric effect of
the three phenyl groups.
The effects of solvents were also studied for the same
reaction in protic and nonꢀpolar solvents under optimized
conditions using CCl3COOH as catalyst (table 2).
40
5
Table 2: Optimization of solvent at room temperature
Entry Solvents
Time(min) Conv.
6a
a, b
%
1
2
CHCl3/CH2Cl2
MeOH/EtOH/H2O
30/30
30/30/60
87/85
90/95/50
Table 1.Optimization of the reaction with acid catalysts
3
H2O + EtOH(1:1)
40
80
Ph
Ph
N
aIsolated yields; bUsing1:2:1 ratio of 2ꢀnaphthol, benzaldehyde and
aniline with 25mol % of trichloroacetic acid catalyst
H
H
Ph
H
H
Ph
Ph
N
PhCHO
PhNH2
+
Ph
OH
(2 mmol) (1 mmol)
O
O
45
+
The homogeneous phases of all reactants in chloroform,
dichloromethane and alcohol generated a suitable medium to
produce excellent yields of oxazine derivatives within half an
hour (table 2. entries 1ꢀ2). Alcohol may be the appropriate
50 solvent for this reaction to increase the stability of reaction
intermediates via Hꢀbonding (table 2, entry 2). The heterogeneous
phases of reactant in water had reduced the yield of product to
60% in 1 h reaction (entry 2). The use of 50% aqueous ethanol
improved the yield of product to 80% during 40 minutes (entry
55 3).
CCl3COOH (cat.)
5
(1 mmol)
Anti 6a
7a
( )
Syn
( )
or solventꢀfree/ heat
EtOH/ r.t.
15
Entry
Catalyst
Amt.(mol%)
Time
(min)
Conv.
6a
(%)a
75/82
1
2
3
4
CH3COOH
CCl3COOH
CF3COOH
CH3COOH
25
25
25
10
60b/40c
30b/20c
30b/20c
120b
87/92
93/30f
40
After optimization we had extended this study to get
structurally diverse novel antiꢀ1,2,3ꢀtrisubstituted naphthꢀ
[1,3]oxazine 6 as racemic mixture in achiral environment
(Scheme 1) by changing both aldehyde and amine compounds.
5
6
CCl3COOH
CF3COOH
10
10
40b
25b
75
80
30d/30e
12hb/4hc
85/75
40/50
60
7
8
CCl3COOH
No catalyst
25
ꢀ
Table 3. Substituent effects on the synthesis of antiꢀ1,2,3
trisubstitutedꢀnaphthꢀ[1,3]oxazine derivatives
R
aIsolated yields ; b Reaction in CHCl3 at room temperature ; c Reaction in
H
H
R1
N
o
o
R1
solventꢀfree medium at 100 C ; d Reaction in CHCl3 at 0 C ; e Reaction
R1
O
R1
R1CHO
+
RNH2
O
20 in solventꢀfree medium at 80 oC ; f Product decomposed.
R1
CH=NR
+
2ꢀNaphthol
+
+
CCl3COOH (cat.)
EtOH/ r.t. or
OH
23
OH
The synꢀproduct 7a will be unstable from the above mentioned
steric effects. The optimization results identified 25 mol % of
CCl3COOH as the suitable catalyst to complete the reaction
25 within short time in solution at 25 °C and 100 °C in absence of
solvent (table 1, entries 2). Decreasing reaction temperature had
reduced the yield of product under solventꢀfree condition with the
best catalyst as compared to solution at 0°C (entry 7). The higher
acidity of CF3COOH destabilized the oxazine ring at high
30 temperature, but it gave excellent result in chloroform under mild
condition (entry 3). The lower acidity of acetic acid increased the
reaction time to give good yield of product (entry 1). Without
catalyst, the reactions were uncompleted for longer reaction time
(entry 8). Again, use of stronger acids like H2SO4 and HCl
18
Anti 6
)
(
solventꢀfree/ heat
24
65
NH2
nꢀC3H7CHO
Y
NH2
X
CHO
12
X= H
Cl
8
9
Y= H
13
14
17
nꢀC4H9NH2
C(Me)2
NO2
16
NO2 10
CH3 11
15
entry
R1
R
Time
(min)
Product(s) Yield (%)a, d
18
6
23
24
1
2
3
8
8
8
13/14
30b/30 b
20c/20c
30 b/40 b
ꢀ
85(6a)
/82(6b)
92(6a)
/96(6b)
90(6c)
/85(6d)
ꢀ
13/14
16/15
ꢀ
ꢀ
ꢀ
ꢀ
2
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4
8
16/15
20c/25c
ꢀ
94(6c)
/92(6d)
ꢀ
ꢀ
40 obtained from nꢀbutanal prevents the formation of desired
product in solution (entry 11). Significantly the high temperature
R1
R1
5
6
8
17
16
2h b/1 h c
30 b /30c
40 b/30 b
20d/30d
85/40
ꢀ
/25
/30
ꢀ
+
O
24
9
82 /92(6f)
ꢀ/85(6h)
ꢀ/92(6h)
ꢀ /80(6j)
ꢀ/ 87(6j)
ꢀ
ꢀ
ꢀ
OH
OH
23
OH
H+
7
10
10
11
11
12
13/16
13/16
87 /ꢀ
18 /ꢀ
88 /ꢀ
20/ꢀ
20/25
ꢀ
2
+
RNH2
R1CHO
H+
R1
8
60/
ꢀ
15/
R
N
-H2O
9
13/16 12hb/45b
O
H+
R1
R1 CH
18
N R
6
R1 CH N
H
R
40c/30c
ꢀ
65/
19
10
11
13/16
13/16
-H2O H+
R1
O
H
O
2 h b/1hb
ꢀ
1
R
R1
H
N
R1
R1
R
-H+
H+
R1
R
N
H
H
O
H+
N
1h c/1hc
1hb/1hb
15/5
ꢀ
ꢀ
ꢀ
ꢀ
60/65
ꢀ
OH
OH
12
13
12
8e
13/16
H
OH
22
20
13/16
86/88
21
Scheme 2 : Plausible mechanism
a Isolated yields ; b Reaction in ethanol at room temperature ;
45
c
Reaction in solventꢀfree medium at 100 ºC ; d 23 and 24 are known
reaction directed to the synthesis of dibenzoxanthene product 24
in dry medium (entry12). Formations of imines were the only
products from the reactions of 1ꢀnaphthol with aromatic
aldehydes and electron rich amines in solution (entry 13). All
50 these new products were characterized by H NMR, 13C NMR,
compounds11;eUsing1ꢀnaphthol as starting compound.
5
In a typical procedure, the mixture of 2ꢀnaphthol (1
mmol), aldehyde (2 mmol) and primary amine (1 mmol) was
stirred at room temperature in ethanol (or treated under solventꢀ
free medium at 100°C) using 25 mol % of trichloroacetic acid as
10 catalyst for the specified time. After completion of the reaction as
monitored by thin layer chromatography the product was isolated
as pure solid from the reaction mixture by following a steps of
work up procedure.10All these results are included in table 3.
The one pot synthesis of antiꢀ1,2,3ꢀtrisubstituted
1
FTꢀIR and CHN analytical techniques.
The exact orientation of naphthꢀ[1,3]oxazine
diastereomer was determined from the COSY and NOESY
interaction of Hꢀ2 and Hꢀ4 protons of oxazine ring of the
55 compounds 6a and 6j . They showed two singlets within the
chemical shift values of 5.48ꢀ6.08 ppm and 5.79ꢀ6.24 ppm
without any cross peak in their COSY and NOESY spectra which
is possible only by anti-orientation of Hꢀ2 and Hꢀ4 protons in
pseudoꢀaxial equatorial conformation of oxazine ring (Fig 2). The
60 HETCOR spectra of these two compounds assigned the positions
of two singlet’s by their cross peak with Cꢀ2 and Cꢀ4 carbons of
the oxazine moiety. The three DEPT spectra 135º, 90º, and 45º of
6a are identical. For 6j, the DEPTꢀ135 spectrum reveals three
negative signals for –CH2ꢀ groups, four positive signals for two –
65 CHꢀ and three –CH3 groups in the aliphatic region and other
positive signals for –CHꢀ atoms of aromatic region while no
15 naphthꢀ[1,3]oxazine 6 is possible only in situ formation of the
reaction intermediates 18,19, 20, 21 and 22 during the course of
reactions(Scheme 2). Another competitive reaction also observed
in these multicomponent reactions which leads to the formation
of dibenzoxanthene derivative 24 and its precursor 23. The
20 success of this method depends on the reversible nature of imine
bond formation followed by driving the protonation of imine in
one direction under thermodynamic equilibrium to form 1ꢀ
alkylaminomethyl 2ꢀnaphthol intermediate 21.12 Then
nucleophilic attack of this intermediate to the second aldehyde
25 molecule yield the stable naphthoxazine derivatives 6. The
protonation of imine equilibrium can be driven in the favor of
desired product by adjusting acidity of catalyst, solvent and
temperature, steric and electronic factors of substrates. We
observed higher yields (80 ꢀ 94 %) of naphthoxazines from the
30 reaction of aromatic aldehydes and aliphatic primary amines in
both conditions (tableꢀ3, entries 3ꢀ4, 6ꢀ10) with the formation of
electron rich Nꢀalkyl substituted imine. The same type of imines
could be obtained from 4ꢀisopropyl aniline and benzaldehyde
(entries 1ꢀ2). Electron deficient imine had no tendency for
35 protonation to give the required product in solution (entry 5, 7).
Furthermore, in solventꢀfree medium the acid catalysed activation
of carbonyl group observed the preferred path to get
dibenzoxanthene products instead of electron deficient imine
(entries 5, 8, 10). The rapid reversible equilibrium of aldimine
peaks for quaternary carbons.
pseudoꢀequatorial
Ph
3
N
H
4
2
Ph
1
O
Ph
H
pseudoꢀaxial
6
5
Figure 2. Pseudoꢀaxial –equatorial conformation of oxazine ring
70
Cambridge Structural Database (CSD)13 shows no structural
report for this series of compounds, except 6c and 6d.9bꢀc Crystals
of 6c have regrown and the structure was evaluated with better
data parameter ratio in comparison with reported structure. The
75 C HꢁꢁꢁO and πꢁꢁꢁπ interactions are predominant in generating 3D
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structure of 6c (Fig. 3a). Literature reveals only the emphasis on
conformational studies of oxazine family specially naphthoxazine
by NMR and semi empirical minimization theory.7d, 9a Difficulties
solution as well as in solventꢀfree medium using trichloroacetic
acid catalyst. The present approach has the ability to synthesize a
variety of structurally diverse anti-trisubstitutedꢀnapthꢀ[1,3]
in growing suitable crystals for this class of compounds ensue 30 oxazines derivatives within short time. In addition, it has opened
5
single report in CSD. We were able to crystallize out colourless
block crystal of compound 6b from 1:1 ethanolꢀchloroform
solvent mixture. Single crystal Xꢀray data were collected.
up the possibility of asymmetric synthesis of 1, 2, 3ꢀ
trisubstitutedꢀnaphthꢀ[1, 3] oxazine products in near future.
EXPERIMENTAL SECTION
35
General methods: All the chemicals and solvents were obtained
from Merck, Alfaꢀaser, Aldrich and used as received without any
further purification
Melting points were determined in a digital melting point
.
TLC was monitored on silica gel glass plate.
40 apparatus. The NMR spectroscopic data of oxazine derivatives
were recorded in CDCl3 with a JEOL 400 MHz spectrometer
using TMS as internal standard. Coupling constants are (J)
expressed in Hertz (Hz), and spin multiplicities are given as s
(singlet), d (doublet), t (triplet), m (multiplet), dd (double
45 doublet). IR spectra of all compounds were recorded on a Nicolet
Impactꢀ410 spectrometer. Elemental analyses were done with
Perkin Elmer 20 analyzer. All new products were identified by
FTꢀIR, 1H NMR, 13C NMR spectroscopic data and CHN
analyses. We had taken COSY, NOESY, HETCOR and DEPT
50 spectra of two compounds (6a and 6j) to identify exact
orientation of naphthoxazine diastereomers. All these spectra are
included as soft copy in the supplementary file.
(a)
General procedure for the syntheses of 2, 3-dihydro-1, 2, 3-
trisubstituted -1H-naphth[1, 2-e][1, 3] oxazine derivatives
55
A mixture of 2ꢀnaphthol (1 mmol), primary amine (1 mmol),
and aldehydes (2 mmol) was stirred at room temperature in
ethanol(2 mL) or heated in an oil bath for the specified time in
absence of any solvent at 100°C using 0.25 mmol of
trichloroacetic acid as catalyst. After completion of the reaction
10
(b)
60 as monitored by TLC, the reaction mixture was diluted with 5 mL
of dichloromethane and washed with an aqueous solution of
sodium hydroxide for removal of unreacted 2ꢀnaphthol and acid
catalyst.The product mixture was extracted with dichloromethane
(3 x 3 mL) and distilled under reduced pressure to get the crude
65 mixture in rotary evaporator. The pure product was precipitated
from the saturated solution of crude mixture in ethanol at room
temperature.
Spectral analysis of the prepared compounds
1. 2,3ꢀDihydroꢀ1,2,3ꢀtriphenylꢀ1Hꢀnaphth[1,2ꢀ
70
75
80
e][1,3]oxazine(table 3, 6a): White amorphous solid, M.p.:
15
(c)
0
206ꢀ207 C ; FTꢀIR (KBr) cmꢀ1 : 3030, 2918, 1596, 1494,
1449, 1396, 1335, 1222, 944, 703; 1H NMR (CDCl3,
400MHz) : δ 6.08(d,J=4.1Hz,1H), 6.25(d,J=5.1Hz,1H),
6.85ꢀ6.88(m,1H),7.01ꢀ7.06(m,2H), 7.18ꢀ7.37(m,12H), 7.48
(d,J=6.9Hz,2H),7.55(d,J=6.9Hz,2H),7.78ꢀ7.83 (m,2H) ; 13C
NMR (CDCl3,100MHz) : δ 65.3, 84.3, 113, 119.1, 123.1,
123.4, 123.6, 125.4, 126.6, 127.6, 127.9, 128.4, 128.5,
129.2, 129.3, 129.5, 137.3, 142.8, 147.1, 153; CHN analysis
(%) : C30H23NOCal. C 87.17, H 5.57, N 3.39; Found C
87.23,H 5.54, N 3.43.
Figure 3. (a) Crystal structure of compound 6c , (b) Molecular
packing shows C HꢁꢁꢁO and πꢁꢁꢁπ interactions in compound 6b,
(c) Overlay of two symmetry independent molecules of structure
6b shows a narrow angle deviation in the isopropyl group.
20
CONCLUSION
In conclusion, we have reported two efficient
multicomponent conditions for the selective synthesis of anti-
2,3ꢀdihydroꢀ1,2,3ꢀtrisubstitutedꢀ1H-naphth[1,2ꢀe][1,3]ꢀoxazine
The COSY, NOESY, HETCOR and DEPT spectra are
included in the supplementary file.
25 for the first time in higher yields utilizing a mixture of 2ꢀ
naphthol, aryl aldehyde and electron rich primary amines in
4
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2. 2,3ꢀDihydroꢀ2ꢀ(4ꢀisopropylphenyl)ꢀ1,3ꢀdiphenylꢀ1Hꢀ
naphth[1,2ꢀe][1,3]oxazine(table 3, 6b) White solid;
400 MHz) : δ 0.78(t,J=7.4Hz,3H), 1.14(m,1H), 1.31(m,1H),
1.58ꢀ1.62(m,2H), 2.44ꢀ2.48(m,2H), 5.58(s,1H), 5.69(s,1H),
7.31(d,J=8.7Hz,2H), 7.39ꢀ7.40(m,2H), 7.55(m,2H), 7.72
(d,J=8.7Hz,2H), 7.88(d,J=8.7Hz,2H), 8.21(d,J=8.3Hz,2H),
8.24(d,J=8.7Hz,2H) ; 13C NMR (CDCl3, 100 MHz): δ 14,
20.3, 31.2, 45.6, 58.6, 85.5, 111, 118.9, 123.5, 123.8, 124.1,
127.3, 127.6, 129.1, 130.5, 144.8, 147.4, 147.9, 150.1,
152.5 ; CHN analysis (%) : C28H25NO Cal. C 69.57, H 5.17,
N 8.70 ; Found C 69.60, H 5.20, N 8.72.
:
M.p.:171ꢀ173 C ; FTꢀIR (KBr) cmꢀ1 : 3026, 2953, 2379,
2150, 1606, 1507, 1451, 1397, 1336, 1222, 954, 813, 704;
1H NMR(CDCl3,400 MHz) : δ1.08(s,6H), 2.68(m,1H),
6.04(d,J=5.1Hz,1H), 6.21(d,J=5.1Hz,1H), 6.87(m,2H), 7.08
(m,2H), 7.20ꢀ7.38(m,10H), 7.45ꢀ7.48(m,2H), 7.54(m,2H),
7.78ꢀ7.82(m,2H) ; 13C NMR(CDCl3, 100 MHz): δ 23.8,
23.9, 30.9, 33.2, 65.2, 84.5, 113.6, 119.2, 123.2, 123.4,
125.2, 126.4, 126.6, 126.7, 127.5, 127.9, 128.4, 128.5,
129.3, 129.4, 137.5, 143, 144, 144.8, 153.1; CHN analysis
(%) : C33H29NO Cal.C 87.03, H 6.37, N 3.08 ; Found C
87.12, H 6.41, N 3.11.
0
60
5
10
15
20
25
30
35
65
7. 2ꢀButylꢀ2,3ꢀdihydroꢀ1,3ꢀdipꢀtolylꢀ1Hꢀnaphth[1,2ꢀ
e][1,3]oxazine( table 3,6j ) :Shiny brown solid ; M.p.:165ꢀ
0
166 C ; FTꢀIR (KBr)cmꢀ1 : 3297, 2919, 1618, 1510, 1458,
1394, 1234, 938, 809 ;1H NMR(CDCl3,400MHz) : δ 0.77
(t,J=7.4Hz, 3H), 1.12ꢀ1.18(m,1H), 1.30ꢀ1.37(m,1H), 1.53ꢀ
1.61(m,2H), 2.33(s,3H), 2.35(s,3H), 2.37ꢀ2.38(m,1H), 2.63ꢀ
2.66(m,1H), 5.49(s,1H), 5.8(s,1H), 7.09(d, J=7.8Hz,2H),
7.14(d,J=8.3Hz, 2H), 7.23ꢀ7.34(m,5H), 7.41ꢀ7.45(m,3H),
7.75ꢀ7.78(m,2H) ; 13C NMR (CDCl3,100 MHz) : δ 14, 20.3,
21.2, 21.3, 44.9, 58.8, 86.1, 112, 119.1, 123.2, 123.3, 126.5,
128.6, 128.7, 128.9, 128.9, 129.5, 135.4, 136.7, 137.3,
153.1 ; CHN analysis (%) : C30H31NO Cal. C 85.51, H 7.36,
N 3.33 ; Found C 85.58 H 7.42, N 3.31.
3. Butylꢀ2,3ꢀdihydroꢀ1,3ꢀdiphenylꢀ1Hꢀnaphth[1,2ꢀe][1,3]
oxazine (table 3,6c): White crystalline solid ; M.p.: 133–
70
0
135 C; FTꢀIR (KBr) cmꢀ1: 3062, 2946, 2848, 1601, 1507,
1452, 1392, 1333, 1233, 1125, 945, 813, 700; 1H NMR
(CDCl3, 400 MHz):
δ
0.77(t, J=7.3Hz,3H), 1.12ꢀ
1.19(m,1H), 1.29ꢀ1.36(m,1H), 1.53ꢀ1.64(m,2H), 2.35ꢀ
2.40(m,1H), 2.58ꢀ2.64(m,1H), 5.54(s,1H), 5.82(s,1H), 7.22ꢀ
7.37(m,11H), 7.44(d,J=7.4Hz, 1H), 7.55(d,J=6.8Hz,2H),
7.78ꢀ7.82(m,2H) ;13C NMR(CDCl3, 100MHz) : δ 13.9,
20.2, 31.1, 44.8, 58.9, 85.9, 112.5, 119, 123.1, 123.3, 126.5,
127.1, 127.7, 127.9, 128.2, 128.6, 129.1, 129, 129.5, 138.2,
143.2, 152.9 ; CHN analysis (%) : C28H27NO Cal. C 85.5, H
6.87, N 3.56 ; Found C 85.54, H 6.91, N 3.58.
75
The COSY, NOESY, HETCOR and DEPT spectra are
Included in the supplementary file.
80
8. Phenylꢀbisꢀ(2ꢀhydroxyꢀ1ꢀnaphthyl)methane (table 3, entryꢀ
5,23 )11 : White solid ; M.p. : 203ꢀ205 0C; FTꢀIR (KBr) cmꢀ1:
3422, 2926, 2378, 1953, 1618, 1505, 1436, 1358, 1257,
4. Benzylꢀ2,3ꢀdihydroꢀ1,3ꢀdiphenylꢀ1Hꢀnaphth[1,2ꢀe][1,3]
oxazine(table 3,6d) : White crystalline solid ; M.p.:191–
1930C ; FTꢀIR (KBr) cmꢀ1: 3023, 2881, 2837, 1595, 1496,
1210, 1146, 1031, 957, 813, 749, 699
(CDCl3,400MHz) 7.91(d,J=8.2Hz,2H),
7.8(d,J=8.2Hz,2H), 7.7(d,J=9.1Hz,2H), 7.20ꢀ7.39(m,9H),
7.01(d,J=8.7 Hz,2H), 6.3(s,1H) NMR
13C
;
1H NMR
85
:
δ
1449, 1391, 1331, 1229, 935, 813, 744, 693
NMR(CDCl3,400 MHz) 3.34(d,J=13.7,1H),
;
1H
:
δ
;
3.88(d,J=14.2Hz,1H), 5.39 (s,1H), 5.99(s,1H), 7.22ꢀ
7.24(m,7H), 7.30ꢀ7.33(m,8H), 7.40(t, J=7.8Hz,2H), 7.68(d,
(CDCl3,100MHz) : δ 152.9, 140.6, 133.6, 130.1, 129.9,
129.7, 129, 128.4, 127.5, 123.6, 122.6, 119.9, 118.6, 42.7 ;
CHN analysis (%) : C27H20O2 Cal. C 86.17 , H 5.31 ; Found
C 86.21, H 5.35.
J=7.3Hz,2H),
7.81ꢀ7.85(m,2H)
;
13C
NMR
90
(CDCl3,100MHz) : δ 49.6, 57.8, 85.5, 112.1, 118.8, 123,
123.4, 126.4, 126.6, 127.2, 127.9, 128, 128.2, 128.3, 128.6,
129.2, 129.4, 133.5, 138.1, 139.5, 143.1, 152.6 ; CHN
analysis (%) : C31H25NO Cal. C 87.12, H 5.85, N 3.28 ;
Found C 87.17, H 5.88, N 3.30.
9. 14ꢀphenylꢀ14H-dibenzo [a.j] xanthene (table 3, entryꢀ5,
0
24)11 : Pale yellow ; M.p.: 182ꢀ183 C; FTꢀIR (KBr) cmꢀ1
:
3066, 3022, 2884, 1620, 1589, 1513, 1486, 1456, 1401,
1
95
1250, 1080, 1023, 965, 824, 746, 699 ; H NMR (CDCl3,
40 5. 2ꢀButylꢀ1,3ꢀbis(4ꢀchlorophenyl)ꢀ2,3ꢀdihydroꢀ1Hꢀ
naphth[1,2ꢀe][1,3]oxazine( table 3, 6f ) :Yellow solid ;
M.p.:163ꢀ165 0C; FTꢀIR (KBr) cmꢀ1: 3227, 2954, 2859,
2377, 1617, 1483, 1399, 1331, 1235, 1088, 948, 815, 745
;1H NMR (CDCl3, 400MHz ) : δ 0.78(t, J=7.2Hz,3H),
400 MHz):δ 8.38(d, J=8.7Hz,2H), 7.78(d, J=8.2Hz,2H),
7.77(d, J=9.1Hz,2H), 7.45ꢀ.56(m,5H), 7.38(t, J=7.8Hz,2H),
7.12(d, J=7.3Hz,2H), 6.96(t, J=7.3Hz,2H), 6.46(s,1H) ; 13C
NMR (CDCl3, 100 MHz) :δ 148.8, 145, 128.9, 128.7, 128.5,
123.3, 126.8, 124.3, 122.7, 118, 38.1 ; CHN analysis (%) :
C27H18O , Cal. C 90.5,.H 5.02 ; Found C 90.57, H 5.08.
100
45
50
55
1.12(m,1H), 1.32(m,1H), 1.54ꢀ1.58(m,2H), 2.35(m,1H),
2.53(m,1H), 5.46(s,1H), 5.69(s,1H), 7.25ꢀ7.27(m,5H), 7.32ꢀ
7.38(m,5H), 7.46(d,J=8.7Hz,2H), 7.79ꢀ7.83(m,2H) ;13C
NMR (CDCl3,100 MHz) : δ 13.9, 20.2, 31.1, 44.9, 58.3,
85.4, 111.9, 118.9, 122.8, 123.5, 126.8, 127.9, 128.2, 128.4, 105
128.7, 129.4, 130.8, 136.5, 141.7, 152.6 ; CHN analysis (%)
: C28H25NO Cal. C 72.73, H 5.41, N 3.03 ; Found C 72.75,
H 5.46, N 3.07.
10. 4ꢀNitrophenylꢀbisꢀ(2ꢀhydroxyꢀ1ꢀnaphthyl)methane (table 3,
entryꢀ8 ,23 ) : Yellow solid ; M.p. : 145ꢀ147 0C; FTꢀIR
(KBr) cmꢀ1 : 3394, 2927, 2858, 2379, 2285, 1603, 1511,
1342, 1257, 1209, 1147, 954, 811, 743 ;1H NMR (CDCl3,
400 MHz): δ 8.06(d,J=6.9Hz,2H), 7.92(d,J=8.2Hz,2H),
7.81(d,J=7.3Hz,2H), 7.68(d,J=8.2Hz,2H), 7.24ꢀ7.42(m,7H),
6.98(m,2H) ; 13C NMR (CDCl3, 100 MHz) : δ 152.2, 150.4,
146.5, 135, 130.3, 129.3, 128.6, 127.7, 123.9, 123.7, 122.2,
119.3, 118.1, 42.2 ; CHN analysis (%) : C27H19O4N Cal. C
76.95 , H 4.51 , N 3.33 ; Found C 77.10, H 4.55 , N 3.36.
6. 2ꢀButylꢀ2,3ꢀdihydroꢀ1,3ꢀbis(4ꢀnitrophenyl)ꢀ1Hꢀnaphth[1,2ꢀ
e][1,3]oxazine (table 3,6h) : Yellow solid ; M.p.: 168ꢀ171 110
0C; FTꢀIR (KBr) cmꢀ1 : 3465, 2931, 2854, 1646, 1594, 1531,
1
1411, 1344, 1184, 1104, 982, 847, 696 ; H NMR (CDCl3,
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11. 14ꢀ(4ꢀNitrophenyl)ꢀ14H-dibenzo[a.j]xanthene(table 3,entryꢀ
8, 24)11 : Light yellow; M.p. : 303ꢀ305 0C ; FTꢀIR (KBr) cmꢀ
: 3418, 2924, 2853, 2372, 2188, 1719, 1591, 1509, 1397,
1335,1240, 1099, 952, 810, 741 ; 1H NMR (CDCl3, 400
MHz) : δ 8.28(d,J=8.2Hz,2H), 7.99(d,J=8.2Hz,2H), 7.81ꢀ
7.85(m,4H), 7.65(d,J=8.3Hz,2H), 7.58(t,J=7.8Hz,2H),
Karim, A.; Gilmore, C. J.; Haltivanger, R.C.; Bryan, R. F. J. Am.
Chem. Soc. 1972, 94, 1354ꢀ1356. (c) Mosher, H. S.; Frankel, M.
B.; Gregory, M. J. Am. Chem. Soc.1953, 75, 5326ꢀ5328.
3. Joyce, J. N.; Presgarves, S.; Renish, L. Exp. Neurol. 2003, 184,
60 393ꢀ407.
4. (a) Feng, E.; Zhou, Y.; Zhang, D.; Zhang, L.; Sun, H.; Jiang,
H.; Liu, H. J. Org. Chem. 2010, 75, 3274ꢀ3282. (b) Kurz, T.
Tetra. 2005, 61, 3091ꢀ3096. (c) Shen, G.; Chen, D.; Zhang,Y.;
Sun, M.; Chen, K.; Jin, C.; Li, K.; Bao, W. \Tetra. 2012, 68,
65 166ꢀ172.
5
10
15
20
25
30
7.50(d,J=9.2Hz,2H), 7.40ꢀ7.44(m,2H), 6.95(s,1H) ; 13
C
NMR (CDCl3,100 MHz) :δ 152, 148.9, 146.4, 131.1, 129.7,
129.1, 129, 127.3, 124.7, 123.9, 122.1, 118.1, 116, 37.9
;CHN analysis (%) : C27H17O3N,Cal. C 80.39,H 4.21 ,N
3.47 ; Found C 80.43, H 4.24 , N 3.51.
5. (a) Adib, M.; Sheibani, E.; Mostofi, M.; Ghanbary, K.;
Bijanzadeh, H. R.; Tetra. 2006, 62, 3435ꢀ3438. (b) Tukulula, M.;
Sharma, RꢀK.; Meurillon, M.; Mahajan, A.; Naran, K.; Warner,
D.; Huang, J.; Mekonnen, B.; Chibale, K. Am. Chem. Soc. Med.
12. 14ꢀ(4ꢀMethylphenyl)ꢀ14H-dibenzo [a.j]xanthene (table 3,
entryꢀ10,24)11: Yellow solid; M.p. : 227ꢀ2280C; FTꢀIR
(KBr) cmꢀ1 : 3068, 2917, 1626, 1597, 1515, 1466, 1437,
1404, 1258, 1125, 1087, 967, 840, 815, 785, 745 ; 1H NMR 70 Chem. Lett. 2013, 4, 128ꢀ131.
(CDCl3, 400 MHz) : δ7.69ꢀ7.78(m, 3H), 7.36(d, J= 7.8 Hz,
3H), 7.27(t, J= 6.9Hz, 1H), 7.13ꢀ7.16(m, 6H), 6.91(t, J= 7.3
6. (a) Shinde, P.V.; Kategaonkar, A.H. ; Shingate, B.B.; Shingare
, M.S. Chin .Chem. Lett.2011, 22, 915ꢀ918. (b) Burke, W. J.;
Hz, 1H), 6.77(d, J=7.8 Hz, 2H), 6.14(s, 1H), 2.3(s, 3H) ; 13
C
Nasutavicus, W. A.; Weatherbee
C.; J. Org. Chem.1962,
NMR (CDCl3, 100 MHz) : δ 156, 146.5, 138.4, 130, 129.9,
129.4, 129.1, 128.9, 127.9, 126.8, 122.8, 121.4, 199.9, 75 7. (a) Turgut, Z.; Pelit, E.; Koycu, A.;Molecule,2007,12,345ꢀ352.
116.5, 11.8, 62.7, 21.1 ; CHN analysis (%) : C28H20O, Cal.
C 90.32 , H 5.37 ; Found C 90.37, H 5.40.
29,407ꢀ410.
(b) Sapkal, S. B.; Shelke, K. F.; Kategaonkar, A. H.; Shingare, M.
S. Green Chem. Lett.and Rev. 2009, 2, 57ꢀ60. (c) Szatmari, I.;
Martinek, T. A.; Lazar, L.; Fulop F. Eur, J. Org. Chem. 2004, 10,
2231ꢀ2238. (d) Szatmari, I.; Martinek, T. A.; Lazar, L.; Fulop,
13.14ꢀ(nꢀButylphenyl)ꢀ14H-dibenzo [a.j]xanthene (table 3,
entryꢀ12,24)11: Off white ; M.p.:172ꢀ1750C; FTꢀIR (KBr)
cmꢀ1 : 3045, 2920, 1621, 1588, 1558, 1514, 1455, 1384, 80 F. Tetra.2003, 59, 2877ꢀ2884.
1
1237, 1209, 1138, 1100, 1043, 965, 825, 745 ; H NMR
8.(a) Deb, M.L.; Dey, S.S.; Bento, I.; Barros, M.T.; Maycock,
(CDCl3,
400
MHz)
:δ
8.26(d,J=8.7Hz,2H),
C.D. Angew. Chem. Int. Ed.2013, 52, 9791ꢀ9795.(b) Shi, D.;
Rong, S.; Dou, G.; Wang, M. J.Com. Chem.2010,12,25ꢀ30.
9. (a) Cimarelli, C.; Mazzanti, A.; Palmieri, G.; Volpini, E. J.
7.87(d,J=7.8Hz,2H),7.78(d,J=8.7Hz,2H),.61(t,J=8.2Hz,2H)
,
7.44(t,J=7.8Hz,2H), 7.33(d,J=8.7Hz,2H), 5.56(s,1H),
1.98ꢀ2.02(m,2H),
0.97ꢀ1.03(m,1H),
0.83ꢀ0.88(m,1H), 85 Org. Chem. 2001, 66, 4759ꢀ4765. (b) Li, Y. H.; Zhao, M. M.;
0.59(t,J=7.4Hz,3H) ; 13C NMR (CDCl3,100MHz) : δ148.9,
129.99, 127.8, 127.1, 125.5, 123, 121.4, 116.5, 115.7, 37.2,
29.9, 17.1, 13.0 ; CHN analysis (%): C24H20O, Cal. C 88.88,
H 6.17; Found C 88.92, H 6.21.
Zhang, Y ActaCryst. 2008, E64, 01972.(c) Zhang, Y.; Li, Y.H.
ActaCryst. 2009, E65, 01796.
10. Procedures are included in experimental section.
11. (a) Kumar, A.; Sharma, S.; Maurya, R.A.; Sarkar, J. J. Comb.
35 Acknowledgement. The authors are thankful to Sophisticated 90 Chem. 2010,12, 20ꢀ24.(b) Ohishi, T.; Kojima, T.; Matsuoka, T.;
Analytical Instrumentation Centre, Tezpur University, for
analysis of various samples for this work and also to CSIR, New
Shiro, M.; Kotsuki, H. Tetra. Lett.2001,42, 2493ꢀ2496.
12.Belowich, M.E.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41,
2003ꢀ2024.
13.CCDC 968939ꢀ968940 (for 6b, 6c) contains the
95 supplementary crystallographic data for this paper. This data can
be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.ac.uk./data/_request/cifor from the
supporting information.
Delhi, India for granting
02(0067)/12/EMRꢀII to R. B.
a
research project no.
40 Notes and references
a Department of Chemical Sciences, Tezpur University, Napaam,Tezpur,
Assam, India, 784028 . Fax: +91 3712 267005/6; Tel:09435380377; E-
mail: ruli@tezu.ernet.in
Electronic Supplementary Information (ESI) available: This
45 documents contains the1 H NMR and 13C NMR spectra of
products 6 ; COSY, NOESY, HETCOR and DEPT spectra of 6a
100
and 6j ; and the crystal structure of 6b and 6c.
See DOI: 10.1039/b000000x/
1. (a) Ganem, B. Acc. Chem. Res. 2009, 42, 463ꢀ472.(b)
50 Domling, A.;Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168ꢀ3210.
(c) Domling, A. Chem. Rev. 2006, 106, 17ꢀ89.
105
2. (a) Mueller, R.; Li, Y. X.; Hampson, A.; Zhong, S.; Harris, C.;
Marrs, C.; Rachwal, R.;
Ulas, J.; Nielsson, L.; Rogers, G.
Bioorg. Med. Chem. Lett. 2011, 21, 3923ꢀ3926. (b) Kupchan, S.
55 M.; Komoda, Y.; Court, W. A.; Thomas, G. J.; Smith , R. M.;
6
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DOI: 10.1039/C3RA47211F
Synthesis of anti- 2, 3-dihydro-1, 2, 3-trisubstituted-1H-naphth
[1, 2-e][1, 3] oxazine derivatives via multicomponent approach
*Ruli Borah,a Arup Kumar Dutta,a Parishmita Sarma,a Champak Dutta,a and Bipul Sarmaa
X
R
H
H
X
X
N
OH
CCl3COOH (cat.)
O
RNH2
+
+
EtOH / r.t.
or
solvent-free/ heat
CHO
Where
6
Anti
( )
X=H , C l, NO2 , CH3
&
80-96% yield
R= Akyl or aryl
This is the first acid catalysed multicomponent synthesis of anti-2,3-dihydro-1,2,3-trisubstituted-1H-naphth [1,2-e][1,3]
oxazines in solution at mild condition and solvent-free medium at 100 C with excellent yields.