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.

3 N O 1

(LXXXVIII)

2

4 5

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.

NH2

SH

NH

S

O

R1R

N

S

O

R1

R2

O

OEt

R

N

S

O

R2

R1R

BrRR1CCO2Et, NaOH, H2O

MW, 4 - 5 min, 70 - 90 %

BrRR1CCO2Et, NaOH, H2O80 0C, 1 h, 68 - 93 %

KOH, BrR2CHCO2Et, Acetone, 60 °C,

30 - 45 min

K2CO3, BrR2CHCO2Et,

Acetone, 60 °C, 6 - 12 hrs

LAH

THF, 0 °C - r.t 1 hr

(1) (2)

(3)(16)

(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).

NO2

OH

NH

O

O N

O

O

R2

R

R1

R

R1

R

R1

OEt

O

1) BrCH2CO2Et, K2CO3, DMF80 °C, 4.0 h

2) 10 % Pd-C, AcOH

60 PSI, H2. 6 h(36) (38) (41)

BrCHR2CO2Et, K2CO3, DMF80 °C, 4.0 h

N

OR

R1

(42)O

R2

LAHTHF

1h, r.t

(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.

NH

HN

O

NH2

NH2 N

N

O

R1

R2 OEt

O

1) R1Br, Na2CO3 aq. EtOH, 12 hrs

2) BrCH(R2)CO2Et,K2CO3, DMF

BrRCHCO2Et, NaOH

Water, 80 °C, 1.0 hr

BrRCHCO2Et, NaOH

Water, MW, 5 min

R RLAH, THF

0 °C - r.t, 1.0 hr N

N

R1

R

O

R2(55) (56) (58) (59)

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.

CHO

NO2 NH

O

R

N O

1) Ac2O, Et3NRCH2CO2H

2) 10 % Pd-CH2, 60 PSI

RBrR1CHCO2Et LAH, THF

0 0C - r.t, 1.0 hr

N

R

O

R1

K2CO3

R1 O

O

(75) (78) (79) (80)

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

SOME OTHER APPLICATIONS OF REDUCTIVE CYCLIZATION: OXAZINOTRI [6.6.6] RING SYSTEMS.

N

XLAH

R2

ON

X

ONH

X

CO2Et

K2CO3, DMF, 80 0C

RR2

O

R

R1

R

R1

R

R1THF

BrCH2CH2CO2Et

X = C, NBn, O, S

OXAZEPINES (TETRA CYCLIC [6.6.7.6] RING SYSTEMS)

NH

X

O

K2CO3, DMF, 80 0C

N

X

O

O

O

OEt

O

Br

N

X

LAH O

R

RR

THF

X = C, NBn, O, S

OXAZOLO TRICYCLIC [6.7.5] RING SYSTEMS

LAH

THFN

O

OEt

ONH O

BrCH2CO2Et NaH, r.t

NO

BENZO [b] FURO THIAZINES

SH

NH2

O

BrO

NH

S

O

OH

NaHCO3, Ethanil, 30 min

NaOH, water, MW, 3.0 min

Diethyl maleate

NH

S

O

CO2Et

Neat 190 - 210 0C

Neat, MW, 3.0 minBnBr, K2CO3 DMF

N

S

O

CO2Et

N

S

O

OH

N

S

O

LAH, THF

0 0C - r.t, 1.0 h

BnBr, K2CO3 DMF

BnBn Bn

LAH, THF

0 0C - r.t, 1.0 h