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A SYSTEMATIC INVESTIGATION FOR THE
PREPARATION OF A NOVEL POLYCYCLIC
[6.6.5], [6.6.6], [6.6.7.6] & [6.7.5] RING SYSTEMS
BY REDUCTIVE CYCLIZATION WITH LAH
1
Reduction & Reagents For Reduction
Reduction is defined in chemistry as loss of oxygen, gain of hydrogen
or gain of electrons.
A reducing agent is the substance which donates electrons in an
oxidation-reduction reaction. (A reducing agent is easily oxidized)
• In 1862 first reducing conditions Zn/acetic acid, Sodium
amalgam/acetic acid, Sodium in toluene/acetic acid or Iron/acetic acid.
• In 1903 Sodium/ethanol for reduction was discovered by Manich and
Bouveault & Blank.
• In 1925 aluminum ethoxide by Verly & Meerwein and in 1926
aluminum isopropoxide by Ponndorf.
• In 1939 Diborane, in 1942 NaBH4, in 1945 LAH were discovered
by H. I. Schlesinger.
2
Reductive Cyclization with L A H
S S
LAH
N O N
O
OH
O
X
LAH
S S
N
N O
O R
3
Optimization
S.No. LAH Ratio of products (%)
eq. S.M Cyclic Alcohol
1 0.5 60 40 0
2 1.0 4 96 0
3 1.1 0 100 0
4 2.0 0 97 0
5 4.0 0 91 9
6 6.0 0 72 28
4
Reduction with Different Reducing Reagents
S.N Reagent Conditions Results
Name Eq. Solvent Temp Time SM CY AL
5
Reduction with Different Reducing Reagents
8 NaBH4/NiCl2 1.1 / 1.1 MeOH r.t 4.0 √
9 NaBH3/H2SO4 2.4 / 1.2 THF 40 oC 12.0 √
10 BMS / NaBH4 1.1 / 0.5 THF r.t 6.0 √
11 BMS 1.1 THF r.t 6.0 √
12 BMS 1.1 THF 50 oC 6.0 √
13 BMS 2.4 THF 50 oC 6.0 √
14 L-Selectride 1.1 THF r.t 4.0 Not clean
15 9 BBN 1.1 THF r.t 6.0 √
16 BH3 1.1 THF r.t 6.0 √
17 BH3 2.2 THF r.t 24.0 **
18 DIBAL-H 1.1 THF r.t 24.0 √
6
Point of attack
S
N O
CO2Et
S S S S
X N S N S N
N S S
OEt OEt
O S
X
S
N O
7
Oxazolo Derivatives
Oxazole is a five membered heterocycle.
Its an integral part of many synthetic & natural products.
OH O H
N O
CN N O N N
N
Ph
O Ph Ph O O
Atisine Alkaloid Natural Product Anti viral Agent
HN HIV-1 inhibitor
O
O O
O F CO2H
N
N NBn
O 1, 3- Oxazole N O
R N N O
O
Antihypertensive agent
Antitumor agent Antibacterial agent
8
Oxazolo Derivatives
O O
S O
N N
N O
O O O
N O
Used in the Treatment Ph
Gastric Antisecretory agents of Congenital Disorders Synthetic importent
product
O O
N N
Ph O2N Ph N
O
O NH2
Synthetic importent O
(R)-(+) Salsolidine Synthetic importent
product
Starting material product
O
EtO2C O
S N N
N
Ph O
N O N O
CO2Et
Gastric Antisecretory agents Antihypertensive Drug
Synthetic biproduct
9
Preparation of Benzothiazinones
SH S R
NH2 N O
H
• Known Method: Chloroacetic acid, aq. NaOH, When R = H
• For R = alkyl/aryl, conditions are different, which involves,
more steps, harmful reagents/solvents
• New Method: BrCH(R)CO2Et, aq. NaOH
• R.T 3.0 h
• 70 – 80 oC, 1 h
• Parallel synthesis (8 Reactions at a time)
• Microwave irradiation 5.0 min.
10
Benzothiazinones
S A= 94 % S
A= 60 % S A= 62 %
B= 96 % B= 65 % B= 65 %
N O N O
H C= 96 % N
H
O C= 77 % H C= 71 %
S Et A= 68 % A = Conventional S Ph A= 63 %
B= 67 % B= 69 %
N O B = Parallel N O
H C= 73 % H C= 74 %
C = MW
S Pr A= 53 % S i
Pr A= 51 % S Hex A= 39 %
B= 59 % B= 62 % B= 42 %
N O N O N O
H C= 61 % H C= 65 % H C= 57 %
11
“Oxazolo Thiazines”
S R
S R BrCH(R)CO2Et LAH S R
N O
K2CO3, DMF N
N O R 1 O THF, r.t O
H 1.0 hr
r.t – 80 oC O R1
R R1 Yield R R1 Yield
H H 80 % Hex H 52 %
Me H 56 % Ph H 63 %
DiMe H 61 % H Et 71 %
Et H 56 % H Pr 61 %
Pr H 54 % H Ph 46 %
i
Pr H 49 % H Ar 41 %
12
Ar = 4-Methoxy Phenyl
Mechanism
13
Proposed Mechanism for Cyclization
S
S S
N O
N O OM
OEt N O
OH
O
S S S
N N OM N O
OH OH
14
“Oxazolo Oxazines”
NO2
R OH R O CO2Et R O R2
R1 NO2
(a) 1 R2 (b) R1 N O
R H
R O R2 R O R2
(c) (d)
R1 N O R1 N O
OEt
R3 R3
O
N O N O N O Me N O
76 % 72 % 75 % 69 %
O O O O
MeS N O MeO2S N O N O N O
45% 42 %
71 % 68 %
Me Et
O O O O
N O N O N O N
42 % 48 % O
39 % 59 %
Pr Ph
16
Structure Confirmation by XRD
O O2N O
HNO3
N O Ac2O
N O
17
Oxazolo Quinoxalines”
BrCH(R)CO2Et, NaOH
NH2 N O
BrCH(R)CO2Et, DMF H
H H H H
N N N N
N O N O N O N O
H H H H
A = 74 % A = 69 % A = 49 % A = 65 %
B = 79 % B = 75 % B = 73 % B = 73 %
H H H
N N N
N O N O N O
H H H
A = 68 % A = 59 % A = 63 %
B = 76 % B = 68 % B = 75 %
18
Bn Bn
H N R LAH, THF N R
N R 1) BnBr,Na CO , aq. EtOH
2 3
1 O 0C - r.t, 1.0 hr
2) BrCH(R )CO2Et, K2CO3, DMF N O N O
N O
H OEt
R1 R1
O
Bn Bn Bn Bn
N N Ph N N
N O N N N O
O O 66 %
75 % 69 % 54 %
Bn Bn Bn
N Bn
N N Ph
N
N O N O N O
49 % 58 % 49 % N O
63 %
Hex Ph Ph
19
Oxazolo Quinolines”
CHO R R
(i) Ac2O, Et3N, RCH2CO2H BrR1CHCO2Et R
LAH, THF
R1 CO2Et R1
Ph Ph
N O N O N O
69 % 65 % 52 %
Ar Ar
Ar
Ar
N O N O
N O
N O 52 % 45 %
49 %
58 % Hex
20
Oxazino[6.6.6]ring systems
O
S R OEt S R S R
Br
LAH
N THF, 0 - r.t
N O K2CO3, DMF, 80 0C O N O
H 1.0 min
CO2Et
OEt R O R O
R O Br LAH, THF
0 - r.t, 1 h
K CO , DMF, 80 C ° R1 N O R1 N O
1
R N O 2 3
H CO2Et
21
Oxazepio[6.6.7.6]ring systems
X X X
N O K2CO3 LAH
H N O O
Br N
DMF, 80 °C THF, 0 - r.t
1.0 min
O
OEt
O
O
O S
N O O O
N N
78 %
93 % 87 %
22
Confirmed by XRD
23
Oxazolo[6.7.5]ring systems
LAH
N 49 % N
N O
H O O
O
H3CH2CO
Cl Cl Cl
Cl Cl Cl
N N N
H O O OH
O
H3CH2CO
24
Furo[6.6.5]ring systems
NaHCO3,
Ethanol, 30 min
Neat 190 - 210 °C
O S OH
S SH Br
CO2Et
Diethyl maleate O N O
N O NH2 H
BnBr, H BnBr,
K2CO3 K2CO3
NaOH, water,
DMF Neat, MW, 3.0 min DMF
MW, 3.0 min
N O 0 °C - r.t, 1 h N O 0 °C - r.t, 1 h N O
Bn Bn
Bn
25
Application of the Methodology:
H
N H
X N
O
N O
H N
H
CP 99, 994
O X
N O O
O N
O O OH O
Muscle relaxant
O
H
N
N R
N Ph H
H
Salsildone analog
26
Advantages
• We have developed a method for the
synthesis of novel polycyclic Heterocycles.
28
Thanks To All