SYNOPSIS OF THE Ph.

D THESIS

“A SYSTEMATIC INVESTIGATION FOR THE PREPARATION OF

TRICYCLIC [6:6:5] OXAZOLO DERIVATIVES BY
REDUCTIVE CYCLIZATION WITH LAH”

by
VENUGOPAL RAO VEERAMANENI, M.Sc.

Research Supervisor:
Dr. Venkateswarlu Akella
(Dr. Reddy’s Research Foundation, Hyderabad)

Research Co-Supervisor:
Dr. Pramod Kumar Dubey
(J.N.T. Univ., Hyderabad)

Submitted to

JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY

HYDERABAD, (A.P) INDIA
JANUARY - 2004
 Oxazole (LXXXVIII) is a five membered heterocycle, which contains one oxygen and one
nitrogen as heteroatoms in 1 and 3 positions.
2
3N O1
4 5
(LXXXVIII)
The oxazolo moiety is frequently found to be an integral part of many biologically active
molecules and natural products. Oxazole moiety may also be found in fusion with other heterocycles
such as pyridines, piperidines, indoles, quinolines, benzoxazines, pyrimidines, naphthyridines,
quinazolines etc. The oxazole ring is an integral part of bioactive compounds such as HIV-1
inhibitors, antitumor agents, antihypertensive agents, antibacterial agents, gastric antisecretory agents,
compounds used in the treatment of congenital disorders and other interesting synthetic compounds.
The present work involves studies on reductive cyclization using lithium aluminumhydride
with various carboxamido esters yielding oxazolo compounds.
The thesis consists of five Chapters; first one being introductory chapter deals with Literature Survey
describing synthesis of oxazolo derivatives by known methods and the remaining four are
Experimental Chapters.

CHAPTER – I: INTRODUCTION AND LITERATURE SURVEY

This chapter deals with the introductory aspects, Literature Survey and use of Lithium
aluminum hydride as a reducing agent an fused oxazoles several of which are biologically important
molecules.

CHAPTER – II: STUDIES ON SYNTHESIS OF OXAZOLO THIAZINES

This chapter describes facile synthesis of substituted tricyclic-6.6.5-oxazolo thiazines (16).
This was achieved as follows:-
Commercially available 2-aminothiophenol (1) was treated with chloroacetic acid in the
presence of sodium hydroxide to obtain 1,4-benzothiazine-3(4H)-one (2). The latter on treatment with
ethyl 2-bromoacetate in the presence of potassium hydroxide in acetone at 60 °C for 30 min. gave a
product which was found to be 3. Treatment of 3 with 1.1 eq. of LAH in THF followed by simple
processing gave the oxazolothiazines 16.
 KOH,
BrRR1CCO2Et,
BrR2CHCO2Et,
NaOH, H2O
Acetone, 60 °C,
80 0C, 1 h,
30 - 45 min
68 - 93 % R R
R R1
S R1 S R1 S
SH LAH

THF, 0 °C - r.t
N 1 hr N O
NH2 N O O
H
OEt
(1) BrRR1CCO2Et, K2CO3, R2
(2) R2
NaOH, H2O BrR2CHCO2Et,
O (16)
MW, 4 - 5 min, Acetone, 60 °C, (3)
70 - 90 % 6 - 12 hrs

(R = H, Me, Et, Pr, iPr, Hexyl, Aryl; R1 = H, Me; R2 = H, Me, Et, Pr, iPr, Hexyl, Phenyl)

Structures of oxazolothiazines 16 prepared were confirmed by analytical & spectral data. Reaction
conditions were optimized by differing equivalents of LAH and various other reducing reagents.

CHAPTER – III: STUDIES ON SYNTHESIS OF OXAZOLO OXAZINES

This chapter describes facile synthesis of substituted tricyclic 6,6,5 oxazolo oxazines (42).
This was carried as follows:-
o-Nitrophenol (36) was treated with ethyl 2-bromoacetate in the presence of potassium
carbonate as a base to obtain ethyl 2-(2-nitrophenoxy)acetate (37), which on reduction with hydrogen
in the presence of 10 % Pd- C gave 38. The latter on treatment with ethyl 2-bromoacetate in the
presence of potassium carbonate in DMF at 80 °C gave 3,4 dihydro-3-oxo-2H-1,4-benzoxazine –4-
acetic acid ethyl esters (41). Treatment of 41 with 1.1 eq. of LAH in THF followed by usual workup
gave the requisite substituted tricyclic[6.6.5]oxazolooxazines (42).

1) BrCH2CO2Et, BrCHR2CO2Et,
K2CO3, DMF K2CO3, DMF R O LAH R O
R OH R O
80 °C, 4.0 h THF
80 °C, 4.0 h
1h, r.t
2) 10 % Pd-C, R1 N O R1 N O
R1
NO2 R1 N O (42)
(36) AcOH (38) H (41)
OEt
60 PSI, H2. 6 h R2 R2
O

(R = H, F, Me, SMe, SO2Me; R1 = H, F, Me; R2 = H, Aryl; R3 = H, Me, Et, Pr, Hex and Substituted
Aryls)

In this chapter is explained the effect of substitution on the aromatic ring during reductive
cyclization and the structure was confirmed by single crystal XRD.
 CHAPTER – IV: STUDIES ON SYNTHESIS OF OXAZOLO QUINOXALINES

Studies on synthesis of tricyclic oxazolo[3.2-a]quinoxalines (59) are described in this chapter.

o-phenylenediamine (55) was treated with ethyl 2-bromo acetate in DMF in the presence of
microwave irradiation for 5.0 min to obtain substituted 3,4-Dihydro-1H-quinoxalin-2-ones (56). The
latter on treatment with alkyl/aryl bromides in the presence of sodium carbonate in aq.ethanol gave 4-
benzyl-1,2,3,4-tetrahydro-2-quinoxalinone (57), which was alkylated with ethyl 2-bromoacetate in the
presence of K2CO3 as base in DMF at 80 0C for 12.0 hrs to yield ethyl 2-(4-benzyl-2-oxo-1,2,3,4-
tetrahydro-1-quinoxalinyl)acetate (58). Treatment of 58 with 1.1 eq. of LAH in THF followed by
simple processing gave the oxazoloquinoxalines 59.
BrRCHCO2Et,
NaOH
Water, 80 °C,
R1 R1
1.0 hr H 1) R1Br, Na2CO3
NH2 N R N R N R
aq. EtOH, 12 hrs LAH, THF
2 0 °C - r.t,
NH2 N O 2) BrCH(R )CO2Et, N O 1.0 hr
N O
(55) H K2CO3, DMF (58) (59)
BrRCHCO2Et, (56) OEt
R2 R2
NaOH
Water, O
MW, 5 min
R = H, DiMe, Ph; R1 = Et, Bn; R2 = H, Me, Et, Pr, Hex and Substituted Aryls)

CHAPTER – V: STUDIES ON SYNTHESIS OF OXAZOLO QUINOLINES

This chapter deals with the studies on synthesis of tricyclic oxazolo[3.2-a]quinolines (80).
This was carried out as described below;-
2-Nitrobenzaldehyde (75) was reacted with arylacetic acid in the presence of triethylamine
and acetic anhydride to obtain 3-(2-Nitrophenyl)acrylic acids 77, which by reductive cyclization with
Pd-C in the presence of hydrogen gas afforded 3,4-dihydro-1H-quinolin-2-ones (78). The latter on
treatment with ethyl 2-bromo acetate in the presence of potassium carbonate gave 79, which with
lithium aluminumhydride yielded the expected oxazolo[3.2-a]quinolines 80.
1) Ac2O, Et3N
CHO R R R
RCH2CO2H BrR1CHCO2Et LAH, THF
K2CO3 0 0C - r.t,
NO2 2) 10 % Pd-C N O N O N O
(75) H2, 60 PSI H (79) 1.0 hr
(78) O (80)
R1
R1
O

(R = H and Substituted Aryls; R1 = H, Me, Et, Hexyl and Aryl)

SOME OTHER APPLICATIONS OF REDUCTIVE CYCLIZATION:
OXAZINOTRI [6.6.6] RING SYSTEMS.
R X R2 R X R2
R X R LAH
BrCH2CH2CO2Et
K2CO3, DMF, THF
R1 R1 N O
N O R1 N O
H 80 0C
CO2Et
X = C, NBn, O, S

OXAZEPINES (TETRA CYCLIC [6.6.7.6] RING SYSTEMS)

X R X R
Br
K2CO3,
OEt
DMF, 80 0C
N LAH N O
O
O THF

X R
X = C, NBn, O, S
O

N O
H O

OXAZOLO TRICYCLIC [6.7.5] RING SYSTEMS

BrCH2CO2Et LAH
NaH, r.t
THF
N
N
N O
O
H O
OEt

BENZO [b] FURO THIAZINES

NaHCO3,
Ethanil, 30 min
Neat 190 - 210 0C
S O S OH
CO2Et SH
Br
Diethyl maleate
O
N O N O
H NH2
H
Neat, MW, 3.0 min
BnBr, NaOH, water,
MW, 3.0 min BnBr,
K2CO3
DMF K2CO3
DMF

S S OH
S
CO2Et LAH, THF LAH, THF

0 0C - r.t, 1.0 h O 0 0C - r.t, 1.0 h

N N O
N O
Bn Bn
Bn