synthesis of 3h-quinazolin-4-ones and 4h-3,1-benzoxazin-4...
TRANSCRIPT
Chapter II
61
Synthesis of 3H-Quinazolin-4-ones and 4H-3,1-Benzoxazin-4-ones via
Benzylic Oxidation and Oxidative Dehydrogeantion using Potassium Iodide
and tert-Butyl Hydroperoxide
2.1 Introduction:
Constructions of nitrogen based heterocycles are highly important in synthetic organic
chemistry, mainly because they are widely exist in natural products and biologically active
molecules. Among them, quinazolinones are core structural subunits in a number of natural
alkaloids and pharmaceutically important compounds.(1)
Some of the natural products having
quinazolinones frame work are: Aperlicin C, Benzomalvin A, Circumdatin F, Sclerotigenin and
Luotonine A.(2)
Quinazolinones exhibit broad spectrum of biological and pharmaceutical activities
including anti-hypertensive,(3)
anti-diabetic,(4)
anti-inflamatory,(5)
anti-bacterial,(6)
anti-
convulsant,(7)
anti-tumor,(8)
central nervous system (CNS) depressants (9)
and diuretic activity.(10)
Along similar lines, benzoxazinones are important scaffold and present in many biologically
active compounds. In particular, 2-substituted-4H-3,1-benzoxazin-4-ones are used as
chymotrypsin inactivators,(11a)
inhibitors of human leukocyte elastase(11b,c)
and serine
protease.(11e)
2.2 State of the art:
Conventional methods for the preparation of 4H-3,1-benzoxazin-4-ones and 3H-
quinazolin-4-ones employs the coupling of 2-aminobenzoic acid (anthranilic acid) or its
derivatives with acylchloride or carboxylic acid anhydride to give benzoxazinone and subsequent
addition to an amine yields the 3H-quinazolin-4-ones (Scheme 1).(12)
Chapter II
62
Scheme 1
O’Mohony and co-worker have described synthesis of 3H-quinazolin-4-ones using
aldehyde functionalized resin via the solid and solution phase methodologies (Scheme 2).(13)
Pol O
H
Pol NH
R1R1-NH2
HO
O
O2N O NO2
Pol N
R1
O NH2
Pol N
R1
O HN
Pol N
R1
R3
O
R3
O
HO
R2 R2
R2
O HN
HN
R1
R3
O
R2
i
ii
iii
iv
vvi
R2R2
N
N
R3
R1
O
Pol= Resin
overall yield = 11-20%
Scheme 2: Reagents: (i) NaBH(OAc)3, DMF/AcOH; (ii) DIC, HOBt, DMF; (iii) SnCl2.2H2O,
DIEA, NMP; (iv) DIC, pyridine, dioxane ; (v) gaseous HF (vi) TMSCl, DMEA, MeCN.
Xue and co-workers have demonstrated the synthesis of 3H-quinazolin-4-ones under
cyclization condition using N-acylanthranilic acid and aniline as a starting materials and
phosphorus trichloride (PCl3) as condensing agent (Scheme 3).(14)
OH
O
NH
R3
R4
R1O
R2
NH2R5
R3
R5
R2
N
N
R1
O
+PCl3
R5
87-98% yield
Scheme 3
OH
O
NH2 N
O
R
O
N
N
R
O
R1
100 0C 130 0C
R O
O O
RR1NH2
R Cl
O
OR
Chapter II
63
Liu and co-workers have developed the microwave assisted one-pot, two-step reaction for
the synthesis of 3H-quinazolin-4-ones via sequencial addition of anthranilic acids, carboxylic
acids and amines (Scheme 4).(15)
OH
O
NH2 N
NR2
R1
OR1COCl/P(PhO)3
Pyridine
or
R1COOH/P(PhO)3
Pyridine,
microwave
N
O
R1
O
R2NH2R
R RNH
O
NH
R1O
R2
micro wave
46-88% yield
250 0C, 3-10 min
Scheme 4
Dandia et al. have reported the multi-component procedure for the synthesis of 3H-
quinazolin-4-ones under microwave irradiation using neat reaction condition (Scheme 5).(16)
OH
O
NH2 N
NR2
R1
O
R1COCl R2NH2+ +microwave 88-93% yield
Scheme 5
Salehi and co-workers have successfully synthesized 3H-quinazolin-4-ones via one-pot,
three component reaction of isotoic anhydride and orthoester with primary amine under solvent
free conditions using silica sulphuric acid as a catalyst (Scheme 6).(17)
OH
O
NH2 N
NR2
R1
O
R1COCl R2NH2+ +microwave
75-86 %
Scheme 6
Su and co-workers have demonstrated the synthesis of 3H-quinazolin-4-ones derivatives
using bis(trichloromethyl) carbonate (BTC) as condensing agent (Scheme 7).(18)
Chapter II
64
OH
O
NH
R1O
N
NR2
R1
O
+BTC
R2-NH2
50 0C, 15 h
53-83% yield
Scheme 7
Alper and co-worker have developed the palladium-catalyzed cyclocarbonylation of o-
iodoanilines with imidoyl chlorides and carbon monoxide to give the substituted 3H-quinazolin-
4-ones (Scheme 8).(19)
N
N
O
R2R
IR
NH2
N
Cl R2
R1
Pd(OAc)2/CO/PPh3
Et3N,THF
R1
R = Me, Cl,CN R1, R2 = Alkyl, Aryl
Scheme 8
Yu and co-workers have developed a Pd(II)-catalyzed protocol for the direct ortho-
carboxylation of anilides to form N-acylanthranilic acids and subsequent treatment with anilines
and phosphorous trichloride (PCl3) afforded the substituted 3H-quinazolin-4-ones (Scheme 9).(20)
HN
OR
R2H
HH
H
Pd(OAc)2
p-TsOH ·H2O,
CO atm, NaOAc/dioxane,
60 oC, 24 h
1 equiv of benzoquinone,
(i)
(ii) R2-Anilines, PCl3, MeCN
50 oC,4 h
N
N
O
R
R1 = CF3, OMe, R2 = Cl, R =OMe
R2
R1
72-94% yield
Scheme 9
Similarly, most of the reported methods for the synthesis of benzoxazinones have used
anthranilic acid and its derivatives as a starting material. Prasad et al.(21a)
reported the synthesis
of 4H-3,1-benzoxazin-4-one derivatives from anthranilic acid and anhydrides. In this reaction
anhydride was employed as solvent, co-solvents like chloroform, (21b)
dioxane, (21c)
toluene (21d)
are used by other people (Scheme 10).
Chapter II
65
NH2
COOHX
(RCO)2O
Temp
O
N
O
R
X=H, Halo, OMe, COOH, NO2
R= Me, Et, n-Pr, Ph, CF3
X
Scheme 10
Bain et al. synthesized benzoxazinone derivatives in good yields, by reacting anthranilic
acid with two equivalents of acid chloride derivatives in pyridine as a solvent (Scheme 11).(22)
NH2
COOH
2RCOCl
pyridine
O
N
O
R
R= Aliphatic, Aromatic
75-90%
Scheme 11
Ramana et al. prepared 2-phenyl-3,1-benzoxazin-4-one derivatives in good yields, by
using two equivalents of ortho or para substituted benzoic acid in presence of tosyl chloride
(Scheme 12).(23)
NH2
COOH
+
COOH
X
N
O
O
X
TsCl
pyridine
X= H, Cl, Me, OMe, NO2
32-62%
Scheme 12
Climence et al. prepared benzoxazinone derivatives in good yields, by the reaction of
equimolar quantities of 3-trifluoromethylanthranilic acid and Boc-protected amino acid with an
equivalent of isobutyl chloroformate in presence of N-methylmorpholine (Scheme 13).(24)
Chapter II
66
NH2
COOH N
O
OCF3
R COOH
NHBoc+
ClCOO-iBu
NMM R
NHBoc
39-57%
R=H, Me, Et, i-Pr CF3
Scheme 13
Besson et al. demonstrated the synthesis of 2-cyano-3,1-benzoxazin-4-one, by treating
anthranilic acid with 4,5-dichloro-1,2,3-dithiazolium chloride in DCM with pyridine (Scheme
14).(25)
NH2
COOH
+ S+
SN
Cl_
pyridine
N
O
O
CN
46%DCM
Scheme 14
Errede et al. carried out the reaction with N-Acylanthranilic acids with acetic anhydride
under reflux condition resulted in benzoxazin-4-one derivatives. The cyclization can
accommodate a wide variety of acyl groups where R may be hydrogen, alkyl, substituted phenyl,
chloroalkyl and trifluoromethyl groups (Scheme 15).(26)
NHCOR
COOH N
O
O
RX
Ac2O
refluxX
65-78%
X=Electon Donatingor
Electron Withdrawing
Scheme 15
Balasubramaniyan et al. synthesized 2-substituted-benzoxazin-4-one derivatives
quantitatively, from N-acylated anthranilic acid with acetic anhydride under reflux condition.
The precursor of N-acylated anthranilic acid derivative was prepared by the acylation of
anthranilic acid with succinic anhydride and followed by esterification (Scheme 16).(27)
Chapter II
67
NH
COOH N
O
O
Ac2O
O
COOR
up to 98% yieldreflux
COOR
Scheme 16
Mohapatra et al. reported the synthesis of benzoxazinone derivatives from acylation of
anthranilate with N-protected amino acids followed by esterification, hydrolysis and subsequent
treatment with Boc-anhydride provided corresponding products in good yield (Scheme 17).(28)
NH
COOH N
O
O
Ac2O
O
NHBoc
R
R
NHBoc
90-94% yield
Scheme 17
Ecsery et al. prepared 2-dichloromethyl-3,1-benzoxazin-4-one derivatives in 85% yield,
by treatment of acylated anthranilicacid derivatives with DCC in THF at room temperature
(Scheme 18). (29)
NH
COOH N
O
OO
Cl
Clup to 85% yield
Cl
DCC
THF
Cl
Scheme 18
Few methods have been reported on the synthesis of 4H-3,1-benzoxazin-4-one
derivatives from the isatoic anhydride as the starting material. For example Rao et al.
synthesized benzoxazinone derivatives with isatoic anhydride and acetic anhydride under reflux
condition.(30a)
Other conditions like acetic anhydride/pyridine(30b)
or trifluoro acetic
anhydride/pyridine(30c)
at room temperature were also employed for the synthesis of
benzoxazinone derivatives (Scheme 19).
Chapter II
68
N
O
O
R
up to 94% yield
NH
O
O
O
(RCO)2O
R=Me, CF3
Scheme 19
Crabtree et al. prepared benzoxazinone derivatives, by pyrolysis of isatoic anhydride and
diethyl phthalate or ethyl anisate in moderate (37-60%) yields (Scheme 20).(31)
N
O
O
NH
O
O
O
R1 R2
R1=H, COOEt R2=H, OMe
37-60% yield
R1 R2
EtOOC
Scheme 20
Hooper and co-workers synthesized 2-phenyl-benzoxazinone derivative in reasonably
good yields from 2-substituted indoles with m-CPBA as oxidant (Scheme 21).(32a)
N
O
O
m-CPBA up to 61% yield
NH
Phether or CHCl3
Scheme 21
Braudeau et al. reported the synthesis of benzoxazinone derivative from 2-substituted
indoles with monoperphthalic acid as an oxidant, but yields are very low (Scheme 22).(32b)
N
O
O
R
5-58% yieldNH
R Monoperphthalic acid
ether, 20 oC
Scheme 22
Garg et al. prepared benzoxazinone derivative by photo-oxygenation of 2-phenyl indole
in methanol using Rose Bengal as a sensitizer (Scheme 23).(32c)
Chapter II
69
N
O
O
[O], Rose Bengal28% yield
NH
Phmethanol
Scheme 23
Eckroth et al. prepared benzoxazinone derivatives, by photolysis of 2-phenylisatogen in
cyclohexane resulting in good yield (Scheme 24).(33)
N
O
O
N
hv
O
O
R
R
53-93% yield
R=H, Br
Scheme 24
Richman et al. synthesized benzoxazinone derivatives, by the oxidation of 2-
phenylindolenin-3-one with meta-chloroperbenzoic acid (m-CPBA) in chloroform (Scheme
25).(34)
N
O
Rm-CPBA
N
O
O
R
60-71% yield
R=H, NMe2
Scheme 25
G. S. Reddy et al. reported the synthesis of benzoxazinone derivatives, by condensation
of 2-azidobenzoic acid with substituted benzaldehyde at 120 oC (Scheme 26).
(35)
COOH
R
N
O
O
R
60-72% yield
CHO
N3
+120 oC
R=H, Cl, Me, OMe, NO2
-NO2
Scheme 26
Pinkus et al. synthesized benzoxazinone derivatives in 93% yield by treating 3-benzoyl-
2,1-benzisoxazole with acetic anhydride in pyridine (Scheme 27).(36)
Chapter II
70
NO
COPh
Ac2O
pyridine N
O
O
93% yield
Scheme 27
Cacchi et al. prepared the steroidal benzoxazinone derivative from o-iodo aniline and
triflatesteroide derivative in presence of carbon monoxide and palladium catalyst (Scheme
28).(37)
NH2
I
+
TfO
O
CO, K2CO3
Pd(PPh3)4
O
N
O
O
78% yield
Scheme 28
Alper and co-worker synthesized benzoxazinone derivatives from o-iodo aniline
derivatives by incorporating carbon monoxide and acid chlorides in the presence of palladium
acetate and diisopropyl ethylamine at 100 oC (Scheme 29).
(38)
NH2
I
+Pd(OAc)2, CO
R1N
O
O
63-99% yield
Cl
O
R1 THF, (i -Pr)2NEt
100oC, 24 h
RR
Scheme 29
However, the problem associated with these methods are multi-step procedures,
employing harmful reagents and harsh reaction conditions. Therefore, discovery of new protocol
to synthesis these scaffolds using simple starting materials, reagents under mild reaction
conditions are more welcome.
Chapter II
71
2.3 Present work:
In this section one-pot synthesis of 3H-Quinazolin-4-ones via benzylic oxidation and
oxidative dehydrogeantion using potassium iodide (KI ) as catalyst and 70% of tert-butyl hydro
peroxide in water (TBHP) as an external oxidant under mild conditions is described. Further this
strategy has extended for the synthesis of benzoxazinones derivatives (Scheme 30).
benzylic oxidation
Dehydrogenation
N
N
O
R
R'
NH
X
RH
H H
[O]
[O]
NH2
X
H R
O EtOH
KI/TBHP
X= NR'
X= OH
N
O
O
Ri. NaOClii. KI/TBHP
Scheme 30
2.4 Results and discussion:
2.4.1 One-pot Synthesis of 3H-Quinazolin-4-ones via Benzylic Oxidation and Oxidative
Dehydrogenation.
The higher activity of benzylic C-H bond adjacent to heteroatom like oxygen and
nitrogen as well as our previous work(39)
on the synthesis of 2-quinazolines via cross-
dehyderogenative coupling prompted us to explore the KI/TBHP system for the synthesis of 3H-
Quinazolin-4-ones and 4H-3,1-benzoxazin-4-ones (Scheme 31). For this we have synthesized
substituted N-(2-aminobenzyl)amines as the starting material, presuming that benzylic oxidation
will take over the aromatization of the condensed cyclic product.
Chapter II
72
benzylic oxidation
Dehydrogenation
N
N
O
R
R'
ArH
O
NH
NH
H -H2O -H2O N
N
Ar
2-QuinazolinesNH
NH
Ar
Previous work
Present work
NH
NR'
RH
H H
[O]
[O]
[O]
NH2
NH
R'H H
H R
O -H2O
[O] = oxidant,
Scheme 31. Synthesis of 3H-quinazolin-4-ones via benzylic oxidation and dehydogenation.
Schematic representation for the synthesis of 3H-quinazolin-4-ones was given in scheme
32. The initial coupling partner, i.e., N-(2-aminobenzyl)aniline (5a) was synthesized from 2-nitro
benzaldehyde (3) via reductive amination to yield 4a followed by further reduction.(40)
Initial
studies were performed by treating 5a with benzaldeyhde in ethanol to yield the cyclic product
(6a), which on further treatment with KI/TBHP resulted in the desired product 8a along with 4-t-
butyl peroxy 2,3-diphenyl quinazoline (7a) as the major product. The product 7a was isolated
and characterized by 1H NMR. The formation of 7a was rather obvious, considering the literature
precedence for this intermediate in oxidative iminium ion formation from tert- amine with TBHP
as the oxidant.(41,42)
However, when 7a was further treated with piperidine, the desired product
8a was obtained in quantitaive yields via Kornblum type decomposition which was finally
confirmed by 1H NMR,
13C NMR and ESI-MS analysis (Figure 1a-1c).
(43)
Chapter II
73
NO2
O
H
NO2
NH
Ph
NH2
NPh
N Ph
NPh
NH
Ph
OO
NPh
N Ph
O
NH
Ph
34a
5a
6a7a
8a
Ph-NH2 (1 equiv.)NaBH4, EtOH, rt H2, PtO2, EtOH, rt PhCHO, EtOH
rt, 5h
KI, TBHP in H2O, rt, 6h
Piperidine, 50 oC for 15 min
rt, overnight
Scheme 32. Synthesis of 2,3-diphenyl-3H-quinazolin-4-one using KI/TBHP catalytic system.
Further reactions were performed one-pot without isolating the peroxy ether
intermediates (7). Various N-(2-aminobenzyl) substituted amines were coupled with structurally
diverse aromatic and aliphatic aldehydes to obtain 2,3-Substituted-3H-quinazolin-4-ones (Table
1). When N-(2-aminobenzyl)aniline was taken as the amine variant along with various
substituted benzaldehydes and aliphatic aldehydes, there was no appreciable change in term of
yields (Table 1, 8a-8e). On the other hand, reactions with N-(2- aminobenzyl) o-substituted
aniline resulted in lower yields, which may be due to the steric influence (Table 1, 8f, 8g). With
N-(2- aminobenzyl) aliphatic amines, the yields were good irrespective of the aldehyde variant
(Table 1, 8i-8j).
Some of these molecules are having biological importance and were used in
quinazolinone based drugs. For example mecloqualone (8g), and etaqualone (8h) has sedative,
hypnotic and anxiolytic properties and was used for the treatment of insomnia. Similarly NPS
53574 (8l) is found to be potent calcium receptor antagonist.
Chapter II
74
Table 1. Synthesis of 2,3-Substituted-3H-quinazolin-4-ones using KI/TBHP.(a)
NH2
O
H R2
NH
N
R2
R1
N
N
R2
R1
O
EtOH
5h, r t.
1. KI , TBHP 6hr, rt
2.Piperidine , 50oC,
15 min to rt, Overnight
NH
R1
+
8 (a-m)5 6
Entry R1
R2
Product
Ph
N
N
O
N
N
O
N
N
O
CF3
N
N
O
Ph
Ph
Ph CF3
Ph
Yield [%]a
Ethyl
8a
73
84
68
76
N
N
O
MethylPh68
b
N
N
OCl
N
N
O
Cl
Cl
Ph
Cl
Methyl
57
35b
8b
8c
8e
8f
8g
N
N
O
Methyl8h
63b
8d
1
2
3
4
5
6
7
8
Chapter II
75
Entry R1
R2
Product
N
N
O
Ph
O
NO2
Ph
Yield [%]a
8i
Butyl
Butyl
Butyl
Ph
Ph
N
N
O
N
N
O
N
N
O
N
N
O
NO2
O
70
61
68
O
O
88
60
8j
8k
8l
8m
9
10
11
12
13
(a) Yields refer to the isolated yield of pure products.
(b) Acetaldehyde was dropped slowly into the solution of N-(2-aminobenzyl)substituted amines
in ethanol at 0 oC.
Chapter II
76
Table 2: Optimization of the Reaction Conditions for construction of 2-Subsitituted-
benzo[d][1,3]oxazin-4-ones.(a)
N
O
N
O
O
NH
O
O
H
+
(12a) (13a)(11a)
Catalyst
OxidantSolvent, 24h
Entry Catalyst OxidantConversion [%]
[b]
2--
1 --
3
4
5
6
7
8
Solvent
12a 13a
CH3CN _ _
CH3CN
CH3CN 10 15
30 70
TBHP
TBHP
9
TBHPTHF 20 15
10
TBHP1,4-Dioxane 15 15
11
TBHPDCM 10 13
12
TBHP DMSO 06 10
13
TBHPDMF 11 10
14 CH3CNc
90 10TBHP
KI
KI
KI
KI
KI
KI
KI
KI
CH3CNc
85 15TBHPI215
CH3CNc,d
60 10TBHPKI17
CH3CN
CH3CN
CH3CN
05
_ _
10_
_
_ _
UHP
NaOCl
mCPBA
TBHP in Decane 10 05
KI
KI
KI
KI
KI
CH3CN
CH3CN
H2O2
CH3CNc
-- ----16 I2
(a) Reaction Conditions: (11a) (1 mmol), Catalyst (0.2 equiv), Oxidant (3.8 equiv), Solvent ( 3
mL).
(b) Conversion based on GC with respect to (11a).
(c) Reaction was carried out at 80 oC for 6h.
(d) 3 equiv. of TBHP was used.
Chapter II
77
2.4.2 Synthesis of benzo[d][1,3]oxazin-4-ones via Benzylic Oxidation and Oxidative
dehydrogenation.
The above strategy was further applied for the synthesis of 2-Phenyl-
benzo[d][1,3]oxazin-4-one using 2-aminobenzyl alcohol as the coupling partner. Under the
similar reaction conditions, treatment of 2-aminobenzyl alcohol with benzaldehyde yielded
cyclized product, which on further oxidation with KI/TBHP resulted in 2-Phenyl-
benzo[d][1,3]oxazin-4-one (12a) in trace amount along with undesired product. So instead of
performing the reaction in one pot, we have synthesized 2-phenyl-4H-benzo[d][1,3]oxazine
(11a) by our earlier reported method,(39)
which on further treatment with KI/TBHP at room
temperature resulted in the desired product (12a) along with the cleaved product (13a) (Scheme
33).
OH
NH2 NH
O
Ph N
O
Ph
N
O
Ph
O
NH
O
Ph
O
H+
(12a) (13a)
(11a)(10a)(9)
Ph-CHO,EtOH, rt, 5h NaOCl, rt, Overnight
KI, TBHP,
CH3CN, Ref lux, 6h
Scheme 33. Synthesis of 2-Phenyl-benzo[d][1,3]oxazin-4-ones using KI/TBHP.
Optimization studies for the construction of 2-Phenyl-benzo[d][1,3]oxazin-4-ones(12a)
from 2-phenyl-4H-benzo[d][1,3]oxazine (11a) with different solvents and oxidants were given in
table 2. Control experiments showed that the catalyst was crucial for this oxidative
transformation (table 2, entry 1-3). Screening of various solvents, such as THF, 1,4 Dioxane,
DCM, DMSO and DMF did not improve the yield of the desire product (table 2, entries 4-8).
Chapter II
78
When the reaction was examined with different oxidants such as H2O2, urea hydrogen peroxide
(UHP), mCPBA, TBHP in decane and NaOCl, the yields were negligible (table 2, entries 9-13).
Table 3. Synthesis of 2-subsitituted-benzo[d][1,3]oxazin-4-ones using KI/TBHP.(a)
NH2 H R
O O
N R
(i) EtOH, 5h
(ii) NaOCl,Overnight
KI/TBHP,
CH3CN
80oC, 6h
OH
11 (a - e)
+ O
N R
O
12 (a - e)
O
N
O
N
NO2
O
N
O
O
N
O
N
F
Br
O
N
O
N
NO2
O
N
O
O
N
O
N
F
Br
O
O
O
O
O
11a, 60%
11b, 61%
11c, 52%
11e, 51% 12e, 74%
12d, 78%
12c, 56%
12a, 85%
12b, 80%
11d, 51%
(a) Reaction Conditions: 11(a-e) (1 mmol), KI (0.2 mmol), TBHP (3.8 equiv), CH3CN (3 mL),
80 oC, 6 h. (b) Yields refer to the isolated yield of pure products.
There was no significant improvement in yield of the desire product when molecular
iodine was used as the catalyst (table 2, entry 15). When the reaction was carried out with iodine
(I2) as an oxidant, the reaction was not proceeded (table 2, entry 16). There was a dramatic
decrease in the yield when less amount of oxidant was employed (table 2, entry 17). From these
optimization studies it is clear that 0.2 equiv. of KI as catalyst, 3.8 equiv. TBHP as oxidant in 3
Chapter II
79
mL of CH3CN under reflux conditions proved to be the best ( Table 2, entry 14). With optimized
reaction condition in hand, we have performed the reactions with pre-synthesized 2-substituted
4H-Benzo[d][1,3]oxazines (table 3, 11 a-e) and the compounds were characterised by 1H NMR,
1H NMR,
13C NMR and GC-MS analysis (Figure 2a-2c). Irrespective of the electronic nature of
the substrates all the oxidized products (table 3, 12a-e) were obtained in moderate to good yields
and analysed by 1H NMR,
13C NMR and GC-MS analysis (Figure 3a-3c).
2.4.3 Mechanistic Considerations
Although the exact mechansim is not clear right now, a possible pathway involving three
key steps for the formation of 3H-quinazolin-4-ones is shown in scheme 34. The first step
involves the oxidation of KI with TBHP to molecular iodine and potassium hydroxide, which
subsequently oxidizes the cyclic compound (6) to hypothetical intermediates (In1 and In2) in the
second step. Finally the intermediates reacts with one equivalent of the TBHP to form the
product 7, which was isolated and well characterized. The following experiments have been
carried out to establish the above proposed mechanism. To prove that TBHP oxidise KI to
iodine, a blank reaction with 0.2 mmol of KI in presence of 3 equiv. of TBHP in water as well as
CH3CN was performed, where we could observe an immediate change in colour (dark brown
solution). The liberation of iodine was further confirmed by addition of starch solution which
instantaneously changed to bluish black. The liberation of iodine occurs very fast (within 1
minute) which is much faster than the time scale of our reaction. Apart from the formation of I2
and KOH in the first step, involvement of other species such as formation t-BuOI cannot be ruled
out. It has been reported that under alkaline conditions iodine involves in multiple equilibriums,
in which hypoiodous acid is one of the possible intermediate.(44)
Similar intermediate was also
proposed under acidic conditions with NaI and H2O2 in the alpha-iodination of ketones.(45)
Chapter II
80
Regarding the second step, we have performed two experiments, one with cyclic product
6 in the presence of three equivalents of I2 and KOH and the second one with I2 and KOH with
cyclic product 6 in the presence of TBHP. In the former case we could not observe any product.
Whereas, in the later case we have observed the small amount of 7 along with some undesired
products. This clearly indicates the unstable nature of intermediates (In1 and In2) which requires
the presence of TBHP for the formation of product 7. Similar to iminium ion (In2) intermediates
is known to occur through benzylic tert-amine oxidation in presence of I2 and base,(41)
which
upon nucleophilic capture yields 7.(42)
Treatment of 7 with piperidine yields the desired product 8
through Kornblum type decomposition.(43)
2KI + H2O
I2 + 2KOH
NH
N
R2
R1
N
N
R2
N
N
R2
R1
O
N
N
R2
R1
N
N
R2
OO
t-Bu
R1
R1
(7) (8)
-t-BuOH
t-BuOOH
t-BuOOH
t-BuOH -H2O
-H2O
(6)
OHNH
(In1)
(In2)
4KI + 2 H2O
2I2 + 4 KOHN
O
R
N
O
R
OH
NH
O
R
O
N
O
R
O
2-tBuOOH
2-tBuOH
- H2O
(11)
(12)(In3) (In4)
Scheme 34. Plausible mechanism for the formation of 3H-quinazolin-4-ones and 2-Subsitituted-
benzo[d][1,3]oxazin-4-ones.
To investigate the possibility for the generation of any radical type of intermediates, the
reaction was performed adapting the earlier reported procedure.(46)
To a solution of N-(2-
aminobenzyl)aniline (5a) (3 mmol) in 12mL of ethanol, benzaldehyde (3 mmol) was added and
Chapter II
81
stirred at room temperature for 5 hours. To the same solution KI (0.6 mmol) was added and the
reaction vessel was sealed with a septum, allowing inclusion of air. An empty balloon was added
to capture any oxygen generated during the course of the reaction. To the reaction mixture 70
wt% TBHP in H2O (2.1 mL, 5 equivalent) was added in one portion via syringe and stirred at
room temperature for 6 hours. There was no inflation of the balloon suggesting that there is no
oxygen evolution, implying that there is no formation of radical intermediates i.e., tertbutyl
peroxy radical, which is known to dimerize to di-tertbutyltetraoxide which in turn release
oxygen.(46)
In similar lines, the conversion of 11 to 12 occurs via oxidation followed by ring
cleavage to yield In3, which is on equilibrium with In4. The intermediate In3 was isolated and
characterized by 1H NMR and ESI-MS spectral analysis.
2.5 Conclusion
In summary, we have demonstrated the simple, efficient and straight forward approach
for the construction of structurally diverse biologically important nitrogen heterocycle, namely,
3H-quinazolin-4-ones using simple strating materials and catalytic system (KI/TBHP) under
mild reaction conditions. Apart from, this method has applied to prepare mecloqtualone and
etaqualone which are important quinazolinone based drugs used for the treatment of insomnia.
Furthermore, we applied this stategy for the synthesis of 4H-3,1benzoxazin-4-one derivatives in
two-step fashion using sodium hypochloride (NaOCl) and KI/TBHP cataltic system.
2.6 Experimental Section
General Information :
All chemicals were purchased from Sigma-Aldrich and S.D Fine Chemicals, Pvt. Ltd.
India and used as received. ACME silica gel (100–200 mesh) was used for column
chromatography and thin-layer chromatography was performed on Merck-pre-coated silica gel
Chapter II
82
60-F254 plates and visualized by UV-light and developed by Iodine. All the other chemicals and
solvents were obtained from commercial sources and purified using standard methods.
Melting point of all compounds were recorded on Barnstead electrothermal melting point
apparatus. The IR spectra of all compounds were recorded on a Perkin-Elmer, Spectrum GX
FTIR spectrometer. The IR values are reported in reciprocal centimeters (cm-1
). All 1H,
13C {
1H}
NMR spectra were recorded on a Varian-Gemini 200 MHz, Avance-300, Inova-500 MHz
Spectrometer. Chemical shifts (δ) are reported in ppm, using TMS (δ =0) as an internal standard
in CDCl3. GC were recorded on Shimadzu-2014 using BP-01 (30M X 0.25 mm X 1.0 m)
column. GC-MS spectra were recorded on Thermo Trace DSQ GC-MS spectrometer using BP-
01 (30M X 0.25 mm X 1.0 m) column. Mass spectral data were compiled using MS (ESI),
HRMS mass spectrometers.
General procedure for preparation of N-(2-aminobenzyl)aniline:(40)
A solution of 1.86 g (20 mmol) of 2-nitrobenzaldyhyde and 3.02 g (20 mmol) aniline in
38 mL of benzene was refluxed for 5 hours to remove water with Dean Stark apparatus. Then the
reaction mixture was concentrated by rotary evaporation and the residue was dissolved in 57 mL
of ethanol. The solution was treated with 1.5 g (39 mmol) of NaBH4 in small portion and the
mixture was stirred at room temperature for overnight. The mixture was concentrated and the
residue was extracted with water and CHCl3. The resulting extract was washed with brine and
dried over Na2SO4. The residue in 40 mL ethanol was catalytically hydrogenated with 0.057 g of
PtO2 and after the completion of reaction; the catalyst was removed by filtration. The filtrate was
evaporated under reduced pressure to give pale brown solid in quantitative yield. The product
was purified by column chromatography using hexane/ethyl acetate mixture as eluent. Other N-
(2-aminobenzyl)substituted anilines were prepared by the same method. In case of N-(2-
Chapter II
83
aminobenzyl)alkylamines, the products were purified by column chromatography using DCM:
methanol mixture as eluent.
General Procedure for the One-pot Synthesis of Substituted Quinazoline-4(3H)-ones via
Benzylic oxidation and Oxidative Dehydrogenation using KI/TBHP
To a solution of N-(2-aminobenzyl) substituted amines (1 mmol) in 4mL of ethanol,
aldehyde (1 mmol) was added and stirred at room temperature for 5 hours. To the same solution,
KI (0.2 mmol) and 0.66 mL of 70 wt% TBHP in H2O (5 equivalent) was added drop wise for 5
minutes and stirred at room temperature for 6 hours. The solvent was removed under reduced
pressure. The residue was treated with 0.25 mL of piperidine. The mixture was heated to 50 oC
for 15 minutes, allowed to cool to room temperature and stirred for overnight. The residue was
mixed with water and extracted with ethyl acetate. The extract was washed with brine, dried over
Na2SO4 and solvent was removed by rotary evaporation. The product was isolated by column
chromatography using hexane/ethyl acetate mixture as eluent and was analyzed by 1H NMR,
13C
NMR, IR, ESI-MS and ESI-HRMS (Figure 1a-1c).
General procedure for synthesis of 2-Substituted-4H-benzo[d][1,3]oxazines via Cross-
Dehydrogenative Coupling:
A solution of 2-amino-benzylalcohol (3 mmol) and aldehyde (3 mmol) in 9mL of
methanol was stirred at room temperature for 5 hours, followed by addition of 3ml of NaOCl
(4% available chlorine) (3equiv.) drop wise and the reaction mixture was stirred at room
temperature for Overnight. The solvent was evaporated under reduced pressure; the residue was
mixed with water and extracted with ethyl acetate. The extract was washed with brine, dried over
Na2SO4 and solvent was removed by rotary evaporation. The product was isolated by column
chromatography using hexane/ethyl acetate mixture as eluent (Figure 2a-2c).
Chapter II
84
General procedure for synthesis of 2-substituted-benzo[d][1,3]oxazin-4-one via Benzylic
Oxidation using KI/TBHP .
To a solution of 2-Substituted-4H-benzo[d][1,3]oxazine (1 mmol) in 3 mL of CH3CN, KI
(0.2 mmol) and 0.5 mL of 70 wt% TBHP in H2O (3.8 equivalent) was added drop wise for 5
minutes. Then the reaction mixture was refluxed for 6 hours and allowed to cool to room
temperature. The solvent was evaporated under reduced pressure. The residue was mixed with
water and extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4
and solvent was removed by rotary evaporation. The product was isolated by column
chromatography using hexane/ethyl acetate mixture as eluent and was analyzed by 1H NMR,
13C
NMR, IR, ESI-MS and ESI-HRMS (Figure 3a-3c).
Spectral data of compounds:
2,3-Diphenyl-3H-quinazolin-4-one: (Table 1, entry 1, 8a)
Pale yellow solid. (Hexane/Ethyl acetate = 3:2, Rf = 0.5). Isolated yield = 73%. m.p: 154 -155
oC. IR (neat) cm
-1: 1683 [(C=O)].
1H NMR (CDCl3, 300 MHz, ppm): δ 8.35 (d, J = 8.3 Hz, 1 H),
7.81-7.75 (m, 2 H), 7.53-7.48 (m, 1H), 7.36-7.10 (m, 10H). 13
C NMR (75 MHz, CDCl3, ppm): δ
162.2, 155.1, 147.4, 137.6, 135.4 134.7, 129.3, 129.2, 129.0, 128.4, 128.0, 127.9, 127.2, 127.1,
120.8. MS (ESI): m/z (amu) = 299 (M+H)+.
N
N
O
Chapter II
85
3-Phenyl-2-p-tolyl-3H-quinazolin-4-one: (Table 1, entry 2, 8b)
White solid. (Hexane/Ethyl acetate = 3:2, Rf = 0.6). Isolated yield = 84%. m.p: 174-175 oC. IR
(neat) cm-1
: 1684 [(C=O)]. 1
H NMR (CDCl3, 300 MHz, ppm): δ 8.32 (d, J= 8.3 Hz, 1H), 7.79-
7.73 (m, 2H), 7.51-7.45 (m, 1H), 7.34-7.25 (m, 3H), 7.20-7.11 (m, 4H), 6.98 -6.96 (d, J=7.5 Hz,
2H), 2.28 (s, 3H). 13
C NMR (75 MHz, CDCl3, ppm): δ 162.4, 155.3, 147.5, 139.4, 137.8, 134.6,
132.5, 129, 128.9, 128.6, 128.3, 127.6, 127.1, 127, 120.8, 21.23. MS (ESI) m/z (amu) = 313
(M+H)+.
3-Phenyl-2-(4-trifluoromethyl-phenyl)-3H-quinazolin-4-one: (Table 1, entry 3, 8c)
Pale yellow solid. (Hexane/ethyl acetate = 3:2, Rf = 0.5). Isolated yield = 68%. m.p: 150-151 oC.
IR (neat) cm-1
:1685 [(C=O)]. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.35 (d, J = 7.28 Hz, 1H),
7.82-7.76 (m, 2H), 7.56-7.53 (t, J = 7.28 Hz, 1H), 7.49 –7.45 (m, 4H), 7.36-7.32 (m, 3H), 7.15 -
7.13 (d, J = 7.28 Hz, 2H). 13
C NMR (75 MHz, CDCl3, ppm): δ 161.8, 153.6, 147.1, 138.7, 137.1,
134.8, 129.3, 129.1, 128.9, 128.7, 127.7, 127.6, 127.1, 120.9. ESI MS m/z (amu) = 367 (M+H)+,
333, 158. HRMS-ESI m/z calculated for C21H14F3N2O (M+H)+= 367.1058 amu, found =
367.1042 amu.
N
N
O
N
N
O
CF3
Chapter II
86
2-Methyl-3-phenyl-3H-quinazolin-4-one: (Table 1, entry 4, 8d)
Pale yellow solid; (Hexane/Ethyl acetate = 3:2, Rf = 0.3). Isolated yield = 68%. m.p: 143-144 oC.
IR (neat) cm-1
: 1682 [(C=O)]. 1
H NMR (CDCl3, 300 MHz, ppm): δ 8.24 (d, J = 7.55Hz, 1H),
7.75 -7.41 (m, 6 H), 7.26-7.23 (m, 2H), 2.29 (s, 3H). 13
C NMR (75 MHz, CDCl3, ppm): δ162.2,
154.1, 147.4, 137.6, 134.5, 129.9, 129.2, 128.8, 127.9, 126.9, 126.6, 126.5, 120.6, 24.3. MS (ESI)
m/z (amu) = 237 (M+H)+, 209, 86 .
2-Ethyl-3-phenyl-3H-quinazolin-4-one: (Table 1, entry 5, 8e)
Pale brown solid; (Hexane/Ethyl acetate = 3:2, Rf = 0.4). Isolated yield = 76%. m.p: 124-125
oC. IR (neat) cm
-1: 1682 [(C=O)].
1H NMR (CDCl3, 300 MHz, ppm): δ 8.24 (d, J = 8.3 Hz, 1H),
7.75 -7.68 (m, 2H), 7.56-7.39(m, 4H), 7.25-7.22 (m, 2H), 2.42 (q, J=6.79 Hz, 2H), 1.21 (t, J =
7.55 Hz, 3H). 13
C NMR (75 MHz, CDCl3, ppm): δ 162.3, 157.6, 147.4, 137.2, 134.3, 129.7,
129.1, 128.2, 126.9, 126.8, 126.4, 120.6, 29.2, 11.1. MS (ESI): m/z (amu) = 251 (M+H)+.
HRMS-ESI (M+H)+ m/z calculated for C16H15N2O = 251.1184 amu, found = 251.1174 amu.
N
N
O
N
N
O
Chapter II
87
3-(2-Chloro-phenyl)-2-phenyl-3H-quinazolin-4-one: (Table 1, entry 6, 8f)
Pale yellow solid; (Hexane/Ethyl acetate = 3:2, Rf = 0.6). Isolated yield = 57%. m.p: 139-140 oC.
IR (neat) cm-1
: 1684 [(C=O)]. 1H NMR (CDCl3, 300 MHz, ppm): δ 8.34 (d, J = 8.3 Hz, 1H),
7.83-7.76 (m, 2H), 7.56-7.48 (m, 1H), 7.40-7.36 (m, 3H), 7.28-7.16 (m, 6H). 13
C NMR (75 MHz,
CDCl3, ppm): δ 161.4, 154.9, 147.4, 135.6, 134.8, 132.8, 131.0, 130.1, 129.5, 128.9, 128.3,
127.9, 127.7, 127.4, 127.3, 127.2, 120.7. MS (ESI): m/z (amu) = 335, 333 (M+H)+, 315, 122,
100.
3-(2-Chloro-phenyl)-2-methyl-3H-quinazolin-4-one: (Table 1, entry 7, 8g)
Pale yellow gummy solid. (Hexane/Ethyl acetate = 3:2, Rf = 0.4). Isolated yield = 35%. IR (neat)
cm-1
: 1687 [(C=O)]. 1H NMR (CDCl3, 300 MHz, ppm): δ 8.25 (d, J = 8.3 Hz, 1H), 7.7-7.72 (m,
1H), 7.65-7.59 (m, 2H), 7.47-7.44 (m, 3H), 7.34-7.31 (m, 3H), 2.20 (s, 3H). 13
C NMR (75 MHz,
CDCl3, ppm): δ`161.4, 153.7, 147.5, 135.4, 134.7, 134.6, 132.6, 130.8, 129.8, 128.4, 127.1,
126.9, 126.6, 23.5. MS (ESI): m/z (amu) = 273, 271 (M+H)+, 243, 86.
N
N
OCl
N
N
OCl
Chapter II
88
3-(2-Ethyl-phenyl)-2-methyl-3H-quinazolin-4-one: (Table 1, entry 8, 8h)
Pale yellow gummy solid (Hexane/Ethyl acetate = 3:2, Rf = 0.3). Isolated yield = 63%. IR (neat)
cm-1
:1683 [(C=O)].1H NMR (CDCl3, 300 MHz, ppm): δ 8.26 (d, J = 7.93 Hz, 1H), 7.76-7-7.63
(m, 2H), 7.47-7.43 (m, 3H), 7.39-7.32 (m, 1H), 7.13-7.11 (d, J = 7.74 Hz ,1H), 2.247-2.38 (q, J =
7.74 Hz , 2H), 2.164 (s, 3H), 1.19 (t, J = 7.55 Hz, 3H). 13
C NMR (75 MHz, CDCl3, ppm): δ
161.8, 154.4, 147.5, 140.6, 136.1, 134.4, 134.2, 129.6, 129.4, 127.9, 127.4, 127.0, 126.6, 126.4,
120.6, 23.9, 23.5, 13.5. MS (ESI): m/z (amu)= 265 (M+H)+, 237, 217, 86.
3-Butyl-2-phenyl-3H-quinazolin-4-one: (Table 1, entry 9, 8i)
White solid; (Hexane/Ethyl acetate = 3:2, Rf = 0.6). Isolated yield = 88%. m.p: 114-115 oC.
IR
(neat) cm-1
: 1671[(C=O)]. 1H NMR (CDCl3, 300 MHz, ppm): δ 8.32 (d, J= 7.95 Hz, 1H), 7.73 (t,
J = 6.96 Hz, 1H), 7.69 ( d, J =7.95 Hz ,1H), 7.52-7.47 (m, 6H), 3.98 (t, J = 7.95 Hz , 2H), 1.63-
1.57 (m, 2H), 1.24-1.16 (m, 2H), 0.79 (t, J = 7.95 Hz, 3H). 13
C NMR (75 MHz, CDCl3, ppm): δ
162.1, 156.2, 147.1, 135.5, 134.2, 129.7, 128.7, 127.7, 127.3, 126.90, 120.7, 45.6, 30.6, 19.8,
13.3. MS (ESI): m/z (amu)= 279 (M+H)+, 265.
N
N
O
N
N
O
Chapter II
89
3-Butyl-2-(4-methoxy-phenyl)-3H-quinazolin-4-one: (Table 1, entry 10, 8j)
Pale brown solid. (Hexane/Ethyl acetate = 3:2, Rf = 0.5). Isolated yield = 60%. m.p: 67- 68 oC.
IR (neat) cm-1
: 1673[(C=O)]. 1H NMR (CDCl3, 300 MHz, ppm): δ 8.28 (d, J = 7.55 Hz, 1H),
7.73-7.64 (m, 2H), 7.46-7.43 (m, 3H), 6.99 (d, J = 9.06 Hz, 2H), 3.99 (t, J = 7.55 Hz, 2H), 3.88 (s,
3H), 1.66-1.56 (m, 2H), 1.30-1.17 (m, 2H), 0.813 (t, J = 7.55, 3H). 13
C NMR (75 MHz, CDCl3,
ppm): δ 162.2, 160.5, 156.0, 147.1, 134.0, 129.3, 127.9, 127.2, 126.63, 120.7, 113.0, 55.2, 45.6,
30.6, 19.8, 13.3. MS (ESI): m/z (amu)= 309 (M+H)+. HRMS ESI (M+H)
+ m/z calcd for
C19H21N2O2 = 309.1603 amu, found = 309.1608 amu.
3-Butyl-2-(4-nitro-phenyl)-3H-quinazolin-4-one: (Table 1, entry 11, 8k)
Yellow solid; (Hexane/Ethyl acetate = 3:2, Rf = 0.4). Isolated yield = 70%. m.p: 126-128 oC. IR
(neat) cm-1
: 1682 [(C=O)]. 1
H NMR (CDCl3, 300 MHz,ppm): δ 8.41 (d, J = 8.3 Hz, 2H), 8.31-
8.28 (m, 1H), 7.78-7.71 (m, 3H), 7.66 (d, J = 8.3 Hz, 1H), 7.54-7.49 (m, 1H), 3.93 (t, J = 7.55
Hz, 2H), 1.63-1.53 (m, 2H), 1.26-1.14 (m, 2H), 0.813 (t, J = 7.55 Hz, 3H). 13
C NMR (75 MHz,
CDCl3): δ 161.6, 153.8, 148.4, 146.7, 141.3, 134.5, 129.1, 127.5, 127.4, 126.8, 123.9, 120.9,
45.6, 30.7, 19.8, 13.3. MS (ESI): m/z (amu)= 324 (M+H)+, 309, 305, 279, 149, 74. HRMS ESI
(M+H)+ m/z calcd for C18H18N3O3 =324.1348 amu, found = 324.1363 amu.
N
N
O
NO2
N
N
O
O
Chapter II
90
2-Furan-2-yl-3-phenethyl-3H-quinazolin-4-one: (Table 1, entry 12, 8l)
Pale yellow solid, (Hexane/Ethyl acetate =3:2, Rf = 0.5). Isolated yield = 61%. m.p: 101-102 oC.
IR (neat) cm-1
:1676 [(C=O)]. 1
H NMR (CDCl3, 300 MHz, ppm): δ 8.3 (d, J = 7.80 Hz, 1H),
7.73-7.64 (m, 3H), 7.46 (t, J = 7.80 Hz, 1H), 7.26-7.16 (m, 6H), 7.092 (d, J = 2.92 Hz, 1H), 6.59
(m, 1H), 4.426 (t, J = 7.80 Hz, 2H), 3.09 (t, J = 8.8 Hz, 2H). 13
C NMR (75 MHz, CDCl3, ppm): δ
162.1, 147.8, 147.2, 144.0, 138.0, 134.2, 128.7, 128.5, 127.4, 127.1, 126.7, 126.5, 125.8, 121.4,
120.6, 115.2, 111.9, 77.4, 76.9, 76.5, 47.0, 35.1. MS (ESI): m/z (amu) = 317 (M+H)+, 223, 213,
105. HRMS-ESI (M+H)+: m/z calculated for C20H17N2O2 = 317.1290 amu, found = 317.1280
amu.
3-Phenethyl-2-phenyl-3H-quinazolin-4-one: (Table 1, entry 13, 8m)
White solid, (Hexane/Ethyl acetate = 3:2, Rf = 0.6). Isolated yield = 68%. m.p: 174-175 oC. IR
(neat) cm-1
:1673 [(C=O)]. 1H NMR (CDCl3, 300 MHz, ppm): δ 8.34 (d, J = 7.55 Hz, 1H), 7.77-
7.66 (m, 2H), 7.49-7.47 (m, 4H), 7.37-7.35 (d, J = 7.6 Hz, 2H), 7.14 - 7.13 (m, 3H), 6.85-6.83
(m, 2H), 4.15 (t, J = 8.3 Hz, 2H), 2.88 (t, J = 8.3 Hz, 2H). 13
C NMR (75 MHz, CDCl3, ppm): δ
161.8, 155.9, 147.2, 137.6, 135.6, 135.5, 134.2, 129.6, 128.7, 128.6, 128.5, 127.8, 127.5, 126.9,
126.8, 126.6, 121.0, 96.1, 47.5, 34.7. MS (ESI): m/z (amu) = 327 (M+H)+, 292, 248, 101.
N
N
O
N
N
O
O
Chapter II
91
Jm
4-tert-Butylperoxy-2,3-diphenyl-3,4-dihydro-quinazoline: (Scheme 32, 7a)
Pale yellow gummy solid, (Hexane/Ethyl acetate = 3;2 :, Rf = 0.8). 1
H NMR (CDCl3, 300 MHz,
ppm): δ 7.71-7.68 (m, 2H), 7.54-7.41 (m, 3H), 7.26-7.21 (m, 6H), 7.17-7.12 (m, 2H), 7.02-6.97
(m, 1H), 6.26 (s, 1H), 1.19 (s, 9H). 13
C NMR (75 MHz, CDCl3, ppm): δ 153.8, 144.7, 136.2,
131.0, 129.9, 129.4, 128.8, 128.6, 127.9, 127.4, 125.4, 125.3, 125.0, 124.9, 122.2, 122.2, 120.3,
90.6, 80.5, 26.2.
2-Phenyl-4H-benzo[d][1,3]oxazine: (Table 3, 11a)
White solid. (Hexane/Ethyl acetate = 4:1, Rf = 0.6). Isolated yield = 60%. m.p: 92-93 oC. IR cm
-
1: 2945, 2834, 1697, 1452, 1316, 1160, 1110, 1024, 752.
1H NMR (CDCl3, 300 MHz, ppm): δ
8.16 (d, J = 8.3 Hz, 2H), 7.41–7.52 (m, 3H), 7.26 – 7.34 (m, 2H), 7.15–7.26 (m, 1H), 7.01 (d, J =
7.36 Hz, 1H), 5.5 (s, -CH2, 2H). 13
C NMR (75 MHz, CDCl3, ppm): δ 160.4, 153.5, 139.6, 132.3,
131.4, 129.0, 128.2, 126.0, 126.4, 124.6, 123.7, 122.3, 66.4. MS (ESI): m/z (amu) = 210
(M+H)+, 132, 106.
N
N
OO
O
N
Chapter II
92
2-(4-Methoxy-phenyl)-4H-benzo[d][1,3]oxazine: (Table 3, 11b)
White solid. (Hexane/Ethyl acetate = 4:1, Rf = 0.5). Isolated yield= 52%. m.p: 140-141oC. IR
cm-1
: 2959, 2920, 2853, 1613, 1509, 1257, 1028, 774. 1H NMR (CDCl3, 300 MHz, ppm): 8.12-
8.00 (m, 2H), 7.28-6.86 (m, 6H), 5.33(s, 2H), 3.85 (s, 3H). 13
C NMR (75 MHz, CDCl3, ppm): δ
162.3, 157.7, 140.1, 131.9, 130.3, 129.8, 128.9, 126.2, 125.9, 125.5, 124.3, 122.2, 113.6, 66.3,
55.3. MS (ESI): m/z (amu)= 240 (M+H)+, 132, 121.
2-(4-Nitro-phenyl)-4H-benzo[d][1,3]oxazine: (Table 3, 11c)
Yellow solid, (Hexane/Ethyl acetate = 4:1, Rf = 0.5). Isolated yield = 61%. m.p: 158-159 oC. IR
cm-1
: 2924, 2864, 1619, 1589, 1516, 1314, 1073, 769, 694. 1H NMR (CDCl3, 500 MHz, ppm): δ
8.31-8.24 (m, 4H), 7.30 (t, J = 7.80 Hz, 1H), 7.25 (d, J = 7.80 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H),
6.9 (d, J = 7.8 Hz, 1H), 5.43 (s, 2H). 13
C NMR (75 MHz, CDCl3, ppm): δ 155.2, 149.3, 138.7,
138.1, 129.1, 128.6, 127.4, 125.1, 123.7, 123.2, 121.8, 66.6. MS (ESI): m/z (amu)= 255 (M+H)+,
132.
O
N
O
N
O
NO2
Chapter II
93
2-(4-Bromo-phenyl)-4H-benzo[d][1,3]oxazine: (Table 3, 11d)
White solid. (Hexane/Ethyl acetate = 4:1, Rf = 0.6). Isolated yield = 51%. m.p: 137-138 oC.
IR
cm-1
: 2921, 2854, 2311, 1597, 1480, 1389, 1245, 1007, 763. 1H NMR (CDCl3, 300 MHz, ppm):
δ 8.04 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.16-7.35 (m, 3H), 7.01 (d, J = 7.4 Hz, 1H),
5.42 (s, 2H). 13
C NMR (75 MHz, CDCl3, ppm): δ 156.7, 139.3, 131.4, 131.2, 129.4, 129.0, 126.6,
126.1, 124.6, 123.7, 122.0, 66.5. MS (ESI): m/z (amu) = 288 (M+H)+, 290, 149, 132, 106.
2-(4-Fluoro-phenyl)-4H-benzo[d][1,3]oxazine : (Table 3, 11e)
White solid. (Hexane/Ethyl acetate = 4:1, Rf = 0.5). Isolated yield = 51%. m.p: 105-106oC. IR
cm-1
: 2956, 2867, 1617, 1598, 1508, 1383, 1228, 1076, 760. 1
H NMR (CDCl3, 300 MHz, ppm):
δ 8.16-8.09 (m, 2H), 7.30-6.95 (m, 6H), 5.36 (s, 2H). 13
C NMR (75 MHz, CDCl3, ppm): δ 166.5,
163.1, 139.5, 130.2, 130.1, 128.9, 126.4, 124.5, 123.6, 122.0, 115.4, 115.1, 66.4. GC MS: 227
MS (ESI): m/z (amu) = 228 (M+H)+, 132, 106. HRMS (ESI) (M+H)
+ m/z calculated for
C14H11FNO = 228.0825, found = 228.0829.
N
O
Br
O
N
F
Chapter II
94
2-Phenyl-benzo[d][1,3]oxazin-4-one: (Table 3, 12a)
White solid. (Hexane/Ethyl acetate = 4:1, Rf = 0.5). Isolated yield = 85%. m.p: 116-117 oC. IR
(neat) cm-1
: 1753 [(C=O)]. 1
H NMR (CDCl3, 500 MHz, ppm): δ 8.32 (d, J=7.28 Hz, 2H), 8.21
(d, J=7.28 Hz, 1H), 7.81-7.78 (m, 1H), 7.6 (d, J=8.32 Hz, 1H), 7.56-7.48 (m, 4H). 13
C NMR (75
MHz, CDCl3, ppm): δ 159.8, 155.3, 146.9, 136.5, 132.5, 136.1, 128.9, 128.7, 128.5, 128.2,
127.4, 127.1, 116.9. GC-MS: 223. MS (ESI): m/z (amu) = 224 (M+H)+.
2-(4-Methoxy-phenyl)-benzo[d][1,3]oxazin-4-one: (Table 3, 12b)
White solid. (Hexane/Ethyl acetate = 4:1, Rf = 0.4). Isolated yield = 61%. m.p: 145-146 o
C. IR
(neat) cm-1
: 1755 [(C=O)]. 1H NMR (CDCl3, 500 MHz, ppm): δ 8.25 (d, J = 9.3Hz, 2H), 8.20
(d, J = 7.28 Hz, 1H), 7.77 (t, J = 8.3 Hz, 1H), 7.61(d, J = 8.3 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H),
6.95 (d, J = 8.3 Hz, 2H), 3.90. 13
C NMR (75 MHz, CDCl3, ppm): δ 163.2, 159.7, 147.3, 136.4,
130.2, 131.0, 129.3, 128.5, 127.6, 126.9, 122.5, 116.7, 114.1, 55.5. MS (ESI): m/z (amu) = 254
(M+H)+, 135, 73.
O
N
O
O
N
O
O
Chapter II
95
2-(4-Nitro-phenyl)-benzo[d][1,3]oxazin-4-one: (Table 3, 12c)
Yellow solid, (Hexane/Ethyl acetate = 4:1, Rf = 0.4). Isolated yield = 56%. m.p: 196-198 oC. IR
(neat) cm-1
:1769 [(C=O)]. 1
H NMR (CDCl3, 300 MHz, ppm): δ 8.51, (d, J = 8.8 Hz, 2H), 8.36 (d,
J = 8.8 Hz, 2H), 8.26 (d, J =7.7 Hz, 1H), 7.87 (t, J = 8.12 Hz, 1H), 7.71 (d, J =7.7 Hz, 1H), 7.59
(t, J = 7.93 Hz, 1H). δ 13
C NMR (75 MHz, CDCl3): δ 158.6, 154.9, 150.0, 146.2, 136.8, 129.2,
129.1, 128.7, 123.8, 127.5,117.0. MS (ESI): m/z (amu) = 269 (M+H)+, 205,181.
2-(4-Bromo-phenyl)-benzo[d][1,3]oxazin-4-one: (Table 3, 12d)
White solid, (Hexane/Ethyl acetate = 4:1, Rf = 0.5). Isolated yield = 78%. m.p: 175-176 oC. IR
(neat) cm-1
: 1763 [(C=O)]. 1H NMR (CDCl3, 300 MHz, ppm): δ 8.23 - 8.17 (m, 3H), 7.83-7.18
(m, 1H), 7.65-7.62 (m, 3H), 7.54-7.48 (m, 1H) .13
C NMR (75 MHz, CDCl3, ppm): δ 159.1,
159.2, 146.6, 136.6, 132.0, 129.6, 129.0, 128.6, 128.4, 127.6, 127.1, 116.8. MS (ESI): m/z (amu)
= 304 (M+2+H)+, 302 (M+H)
+, 282, 279. HRMS (ESI) (M+H)
+ m/z calcd for C14H9NO2Br
=301.9816 amu, found = 301.9817 amu.
O
N
NO2
O
O
N
O
Br
Chapter II
96
2-(4-Fluoro-phenyl)-benzo[d][1,3]oxazin-4-one: (Table 3, 12e)
White solid, (Hexane/Ethyl acetate = 4:1, Rf = 0.4). Isolated yield = 74%. mp. m.p: 143-146 oC.
IR (neat) cm-1
:1763 [(C=O)]. 1H NMR (CDCl3, 300 MHz): δ 8.36 -8.31 (m, 2H), 8.23 -8.20 (m,
1H), 7.82-7.77 (m, 1H), 7.65-7.62 (m, 1H), 7.52-7.47 (m, 1H), 7.21-7.15 (m, 2H). 13
C NMR (75
MHz, CDCl3, ppm): δ 167.2, 151.9, 146.8, 136.6, 130.7, 130.6, 128.6, 128.6, 128.2, 127.1,
116.8, 116.1, 115.8. MS (ESI): m/z (amu) =242 (M+H)+, 152, 120.
HRMS (ESI) (M+H)
+ m/z
calcd for C14H9NO2F =242.0617 amu, found =242.0608 amu.
N-(2-Formyl-phenyl)-benzamide: (Scheme 33, 13a)
Pale yellow solid.(Hexane/Ethyl acetate = 4:1, Rf = 0.4). m.p: 67-68oC. IR cm
-1: 3415, 3066,
2926, 1687, 1584, 1473, 1341, 1282, 1116. 1H NMR (CDCl3, 500 MHz, ppm): δ 12.08 (br S,
1H), 10.01 (s, 1H), 9.01 (d, J=8.32 Hz, 1H), 8.07 (d, J=8.32 Hz, 2H), 7.71-7.66 (m, 2H), 7.58-
7.50 (m, 3H), 7.25- 7.23 (m, 1H) . 13
C NMR (75 MHz, CDCl3, ppm): δ 195.7, 165.9, 141.0,
136.2, 136.0, 134.1, 132.0, 128.7, 127.3, 122.9, 121.8, 119.8. ESI-MS: m/z (amu) = 248 [M +
Na]+
.
O
N
O
F
H
O
NH
O
Chapter II
97
2.7 References:
1. (a) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893; (b) S. Johne,
In Supplements to the 2nd Edition of Rodd’s Chemistry of Carbon Compounds; M. F.
Ansell, Ed.; Elsevier: Amsterdam, 1995; Vol. IV I/J, p 223; (c) S. B. Mhaske, N. P.
Argade Tetrahedron 2006, 62, 9787.
2. (a) M.-C.Tseng, H.-Y. Yang, Y.-H. Chu, Org. Biomol. Chem. 2010, 8, 419; (b) M.-C.
Tseng, C.-Y, Lai, Y.-W. Chu, Y.-H. Chu, Chem. Commun. 2009, 445; (c) M.-C. Tseng,
Y.-H. Chu, Tetrahedron 2008, 64, 9515; d) M.-C. Tseng, Y.-W. Chu, H.-P. Tsai, C.-M.
Lin, J. Hwang, Y.-H. Chu, Org. Lett. 2011, 13, 920.
3. (a) H. J. Hess, T. H. Cronin, A. Scriabine, J. Med. Chem. 1968, 11, 130; (b) M.
Ishikawa, Y. Eguchi, Heterocycles 1981, 16, 31.
4. M. S. Malamas, J. Millen, J. Med. Chem. 1991, 34, 1492.
5. 5. G. Leszkovsky, L. Tardos, Chem. Abstr. 1965, 62, 16821; (b) S. Saxena, M. Verma,
A. K. Saxena, K. Shanker, Indian J. Pharm. Sci. 1991, 53, 48.
6. P. P. Kung, M. D. Casper, K. L. Cook, L. Wilson-Lingard, L. M. Risen, T. A. Vickers,
R. Ranken, L. B. Blyn, R. Wyatt, P. D. Cook, J. Ecker, J. Med. Chem. 1999, 42, 4705.
7. A. Mannscherck, H. Koller, G. Stuhler, M. A. Davis, J. Traber, Eur. J. Med. Chem.
1984, 19, 381.
8. (a) J. Felter, T. Czuppo, G. Hornyak, A. Feller, Tetrahedron 1991, 47, 9393; (b) L. A.
Sorbera, J. Bolos, N. Serradell, M. Bayes, Drugs of the future, 2006, 31, 778.
9. (a) M. L. Gujral, P. N. Saxena, R. S. Tiwari, Indian. J. Med. Res.1955, 43, 637; (b) B. L.
Chenard, A. R. Reinhold, W. M. Welch, European Patent Application EP 0884310A1,
1998.
Chapter II
98
10. E. Cohen, B. Klarberg, J. R. Vaughan, J. Am. Chem. Soc. 1960, 82, 2731.
11. (a) L. Hedstrom, A. R. Moorman, J. Dobbs, R. H. Abeles, Biochemistry, 1984, 23, 1753.
(b) R. L. Stein, A. M. Strimpler, B. R. Viscarello, R. A. Wildonger, R. C. Mauger, D. A.
Trainor, Biochemistry 1987, 26, 4126; (c) A. Krantz, R. W. Spencer, T. F. Tam, T. J.
Liak, L. J. Copp, E. M. Thomas, S. P. Rafferty, J. Med. Chem. 1990, 33, 464; (e) S. J.
Hays, B. W. Caprathe, J. L. Gilmore, N. Amin, M. R. Emmerling, W. Michael, R.
Nadimpali, R. Nath, K. J. Raser, D. Stafford, D. Watson, K. Wang, J. C. Jaen, J. Med.
Chem. 1998, 41, 1060.
12. (a) E. C. Taylor, R. I. Knopf, A. L. Borror, J. Am. Chem. Soc. 1960, 82, 3152; (b) T. G.
Jackson, S. R. Morris, R. H. Turner, J. Chem. Soc. (C). 1968, 13, 1592; (c) L. A. Errede,
J. Org. Chem. 1976, 41, 1763; (d) H. Kotsuki, H. Sakai, H. Morimoto, H. Suenaga,
Synlett. 1999, 1993; (e) B. L. Chenard, W. M. Welch, J. F. Blake, T. W. Butler, A.
Reinhold, F. E. Ewing, F. S. Menniti, M. J. Pagnozzi, J. Med. Chem. 2001, 44, 1710; (f)
S. Xue, J. McKenna, W. C. Shieh, O. Repic, J. Org. Chem. 2004, 69, 6474.
13. D. J. R. O’Mahony, V. Krchnˇa´k, Tetrahedron Lett., 2002, 43, 939.
14. S. Xue, J. McKenna, W. C. Shieh, O. Repic, J. Org. Chem. 2004, 69, 6474.
15. J. F. Liu, J. Lee, A. M. Dalton, G. Bi, L. Yu, C. M. Baldino, E. McElory, M. Brown,
Tetrahedron Lett. 2005, 46, 1241.
16. A. Dandia, R. Singh, P. Sarawgi, Organic preparations and procedures int., 2005, 37,
397.
17. P. Salehi, M. Dabiri, M. A. Zolfigol, M. Baghbanzadeh, Tetrahedron Lett. 2005, 46,
7051.
Chapter II
99
18. W. K. Su, D. Z. Wu, Y. Y. Xie, J. J. Li, Organic preparations and procedures int. 2006,
38, 39.
19. Z. Zheng, H. Alper, Org. Lett., 2008, 10, 829.
20. R. Giri, J. K. Lam, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 686.
21. (a) R. Prasad, A. P. Bhaduri, Indian. J. Chem. Sec. B. 1979, 18, 443; (b) R. S. Atkinson,
M. P. Coogan, C. L. Cornell. J. Chem. Soc. Perrkin Trans. 1996, 1, 157; (c) J. Bergman,
S. Bergman, J. Org. Chem. 1985, 50, 1246. (d) A. Varnavas, L. Lassiani, E. Luxich, M.
Zacchigna, E. Boccu. Farmaco, 1996, 51, 333.
22. D. I. Bain, R. K. Smalley. J. Chem. Soc. (C), 1968, 1593.
23. D. V. Ramana, E. Kantharaj, Org. Prep. Proced. Int. 1993, 25, 588.
24. (a) F. Climence, O. L. Martret, F. Delevallee. U.S. Patent. No : 4636512, 1985. (b) F.
Climence, O. L. Martret, F. Delevallee, J. Benzoni, S. Jouquey, M. Mouren, R. Deraedt.
J. Med. Chem. 1988, 31, 1453.
25. (a) T. Besson, K. Emayan, C. W. Rees, J. Chem. Soc. Chem. Comm. 1995, 1419. (b) T.
Besson, C. W. Rees. Bioorg. Med. Chem. Lett. 1996, 6, 2343.
26. L. A. Errede, H. T. Oien, D. R. Yarian, J. Org. Chem. 1977, 42, 12.
27. V. Balasubramaniyan, N. P. Argade, Indian. J. Chem. Sect. B. 1988, 27, 906.
28. D. K. Mohapatra, A. Datta, Bioorg. Med. Chem. Lett. 1997, 7, 2527.
29. Z. Ecsery, J. Hermann, A. Albisi, E. Somfai, British Patent No: 1389128, 1972. Chem.
Abstr, 1973, 78, 147976.
30. (a) Y. R. Rao, M. Bapuji, S. M. Mohapatra, Indian Patent No: 150839, 1979. Chem.
Abstr, 1983, 99, 158452. (b) M. Tsobuta, M. Hamashima. Heterocycles 1984, 21, 706.
(c) L.Yang, C. Chen, K. Lee, Bioorg. Med. Chem. Lett. 1995, 5, 465.
Chapter II
100
31. H. E. Crabtree, R. K. Smalley, H. Suschitzky, J. Chem. Soc. (C), 1968, 2730.
32. (a) T. H. C. Bristow, H. E. Foster, M. Hooper, J. Chem. Soc. Chem. Comm. 1974, 677.
(b) E. Braudeau, S. David, J. C. Fischer, Tetrahedron 1974, 30, 1445; (c) H. S. Garg, D.
S. Bhakuni, Indian. J. Chem. Sec. B. 1986, 25, 973.
33. (a) D. R. Eckroth, R. H. Squire, Chem. Comm. 1969, 312; (b) D. R. Eckroth, R. H.
Squire, J. Org. Chem. 1971, 36, 224.
34. (a) R. J. Richman, A. Hassner, J. Org. Chem. 1968, 33, 2548; (b) J. Adam, T. Winkler,
Helv. Chim. Acta. 1984, 67, 2186.
35. G. S. Reddy, K. K. Reddy, Indian. J. Chem. Sec. B. 1978, 16, 1109.
36. J. L. Pinkus, H. A. Jessup, T. Cohen, J. Chem. Soc.(C), 1970, 242.
37. S. Cacchi, G. Fabrizi, F. Marinelli, Synlett. 1996, 997.
38. C. Larksarp, H. Alper, Org. Lett. 1999, 1, 1619.
39. C. U. Maheswari, G. S. Kumar, M. Venkateshwar, R. A. Kumar, M. L. Kantam, K. R.
Reddy, Adv. Synth. Catal. 2010, 352, 341.
40. F. Ishikawa, Y. Watanabe, J. Saegusa, Chemical & Pharmaceutical Bulletin; 1980, 28,
1357.
41. N. J. Leonard, G. W. Leubner, J. Am. Chem. Soc. 1949, 71, 3408.
42. (a) A. J. Cattino, J. M. Nichols, B. J. Nettles, M. P. Doyle, J. Am. Chem. Soc. 2006, 128,
5648; (b) Z. Li, C. J. Li, J. Am. Chem. Soc. 2005, 127, 3672.
43. N. Kornblum, H. E. DeLaMare, J. Am. Chem. Soc. 1951, 73, 880.
44. S. Yamada, D. Morizono, K.Yamamoto,Tetrahedron Lett. 1992, 33, 4329.
45. J. Barluenga, M. M-Arias, F. G-Bobes, A. Ballesteros, J. M. Gonza´lez, Chem.
Commun. 2004, 2616.
Chapter II
101
46. (a) A. J. Catino, R. E. Forslund, M. P. Doyle, J. Am. Chem. Soc. 2004, 126, 13622; (b)
P. D. Bartlett, P. Gunther, J. Am. Chem. Soc. 1966, 88, 3288; (c) P. D. Bartlett, G.
Guaraldi, J. Am. Chem. Soc. 1967, 89, 4799.
Chapter II
102
Figure 1a:1H NMR of compound 8a.
Figure 1b:13
C NMR of compound 8a.
N
N
O
N
N
O
Chapter II
103
Figure 1c: ESI of compound 8a.
N
N
O
Chapter II
104
Figure 2a: 1H NMR of compound 11e.
Figure 2b: 13
C NMR of compound 11e.
N
O
F
N
O
F
Chapter II
105
Figure 2c: GC-MS compound 11e.
RAK-80-2-12H #767 RT: 17.58 AV: 1 NL: 2.58E6
T: + c Full ms [ 40.00-600.00]
50 100 150 200 250 300 350 400 450 500 550 600
m/z
0
10
20
30
40
50
60
70
80
90
100
Re
lative
Ab
un
da
nce
123.0
95.0
78.1 227.1
51.0198.1
124.1170.1 228.1
229.2 281.0 517.7342.1 466.4437.7 574.1363.6
N
O
F
Chapter II
106
Figure 3a:
1H NMR of compound 12a.
Figure 3b: 13
C NMR of compound 12a.
N
O
O
N
O
O
Chapter II
107
Figure 3c: GC-MS of compound 12a.
RAK-49-12H #842 RT: 19.01 AV: 1 NL: 4.54E6
T: + c Full ms [ 40.00-600.00]
50 100 150 200 250 300 350 400 450 500 550 600
m/z
0
10
20
30
40
50
60
70
80
90
100
Re
lative
Ab
un
da
nce
223.0
105.0
179.0
77.0
146.0
224.0
51.0 180.0
106.0 222.0225.0 281.0 355.1 383.2314.1 415.2 460.1 528.2 596.3
N
O
O