CHAPTER III

PART I

CHEMISTRY OF N-O BOND

CLEAVAGE

3.1.1 Chemistry of N-O bond cleavage

A variety of naturally occurring compounds especially alkaloids are great medicinal

value1. Many of these compounds have evoked considerable synthetic interest and have been

synthesized using the intermediates where N-O bonds are frequently used. Compounds having

N-O bonds are categorized into a broad range of functionality in organic chemistry. They

include oximes, O-alkyl and O-benzyllhydroxylamines, hydroxamic acids, isoxazoles, oxazines

etc. Some of the reactions which generally result in the formation of such N-O bonds are

classified as follows.

Reaction of carbonyl compounds with hydroxyl amine hydrochloride to generate the oxime.

R

O

R1

NH2OH. HCl

R

NOH

R1

(equation 12)

Alkenes readily undergo rearrangement with acyl nitroso compounds which result in the

formation of N-O bond2.

.

+N

O

O

N

O

OH

(equation 13)

N-O in isoxazolines are formed by the [3 +2] cycloaddition of nitrones3 with alkenes as shown

in equation 14.

N

Me

O

+O

N

CH3

Ph

(equation 14)

Hassner and Rai showed that nitrile oxide can be generated using Chloramine–T from

oximes which then undergo [3 +2] cycloaddition to generate isoxazolidines4.

NOHH3C Chloramine-T, Ethanol

reflux, 82%

O

NH3C

CH3

CH3

(equation 15)

Nitroalkene undergo cycloaddition with dienes to from six membered rings having N-O

bonds.

R1

N

O O

+

N

OO

R1

(equation 16)

1,2-oxazines are formed by the [4 +2] cycloaddition6 of the alkenes with α-nitrosoalkene

generated from α-halooximes as described below in equation 17.

NOH

Br

CO2Et

C6H13

N

OC6H13

CO2Et

(equation 17)

Cleavage of N-O bond is an important reaction through which several important

functional moieties are synthesized. Several reagents have been used for the cleavage.

Cleavage of N-O bonds in N-acyl derivatives of O-alkylhydroxylamine are promoted by

samarium iodide7 (equation 18, 19)

Ph N

O

CH3

O

Ph

Ph NH

O

CH3

SmI2

87%

(equation 18)

Hydroxamic acids are also reduced using SmI27 to an amide as is shown below.

Ph N

O

CH3

OH

SmI2

45% Ph NH

O

CH3

(equation 19)

Isoxazole are used as 1,3-dicarbonyl equivalents since, on cleavage, they furnish 1,3-

dicarbonyl compounds in good yields. A wide spectrum of reagents serve this purpose as

described below.

One of the earlier methods reported in literature uses sodium in amylalcohol for the

reductive cleavage of N-O bonds as shown in the example8 below.

NO

Na, amyl alcoholNH2 O

(equation 20)

Sodium in t-butanol in the presence of ammonia furnishes different products with

different equivalents of t-butanol9. More equivalents of butanol results in further reduction to an

amino ketone 83.

NO

Na, NH3, 1 equivalent t-buOH NH2 O

NH2 ONa, NH3, 3 equivalent t-buOH

Scheme 26 83

Hydrogen and raney nickel is also used in the cleavage of N-O bonds10

as in equation 21.

NO

H2, Raney nickel NH2 O

(equation 21)

Molybdenum hexacarbonyl when used gives 1,3-dicarbonyl compounds. Unexpected

pyrazole formation 84 was observed in some cases11

.

O

N

N

HO

H3C

NH

N

O

H3C

+

O

O

H2N

H3C

Mo(CO)6, H2O,

(equation 22)

84

Other common reagents which finds use in the cleavage of N-O bonds of isoxazoles are

H2/Pd/C in ethanol, Hydrogen/ Lindlar’s catalyst in presence of methanol, zinc /acetic acid and

sodium borohydride/nickel chloride12

(Scheme 27).

O

N

NH2

NH2

NH

OH

HCl

H2/ Lindar's catalyst, 94%

Zn/AcOH/ 70oC, 98%

H2/Pd(C)/EtOH, 1.0N HCl, 92%

NaBH4/ NiCl2, 78%

Scheme 27

3.1.2 N-O bond cleavage of 5,6-dihydro-4H-1,2-oxazines:

Six membered cyclic oxime ethers or 5,6-dihydro-4H-1,2-oxazines are prominent

intermediates in the synthesis of several natural products. One of the main reasons for this is the

ease at which it can be converted to main stream heterocycles and other functional groups. The

strategy generally employed is the reductive cleavage of oximino bond of the 5,6-dihydro-4H-

1,2-oxazines.

The formation of pyrrolidines 86, 87 and 1,4-amino alcohols 85 were explained in detail

by Sema Ioffe et al12

. Here presence of substituents at C-6 of the oxazine ring determines the

formation of different products. The alkoxy group at C-6 (equation 24) gives rise to

pyrrolidines. The initial step in the formation of both pyrrolidines, furans and 1,4-alcohols are

the cleavage of N-O bond of the oxazine.

O

N

Ph

CO2CH3

H3C

H3C20 bar H2, Raney Nickel

MeOH, 70-80oC

Ph

CO2CH3

NH2

H3C CH3

OH

(equation 23)

85

O

N

CO2CH3

20 bar H2, Raney Nickel

MeOH, 70-80oC

Me

MeO

OCH3

NH

Me

NH

OCH3

+

Me

(equation 24)

28% 52%

OCH3

86 87

The synthesis of Z-Jasmone (88) was accomplished using an oxazine intermediate. Here

also the cleavage of N-O bond of the oxazine results in dicarbonyl comounds which are then

converted to the required natural product13

(Scheme 28).

O

N

Ph

Me3SiO

CO2Me H2, Raney nickel

CO2Me

O

O

O

CO2H

O

Et

Scheme 28

88

γ-hydroxy ketones are isolated or formed in situ from 5,6-dihydro-4H-1,2-oxazines using

hydrogen and boric acid14

which are the converted to cyclic ethers.

3.1.3 Chemistry of γ-hydroxy ketones

γ-Hydroxy ketones are used in the synthesis of different naturally occurring compounds.

Literature reveals various synthetic routes and the use diverse functional moieties to synthesize

γ-hydroxy ketones. One of the methods recently reported uses phenyliodine diacetate (PIDA)

mediated oxidative cleavage of cyclobutanols 89 to γ-hydroxy ketones.

HO

RR1

PIDA

HFIP/H2OR

O

R1

OH

(equation 25)

89 90

Work on the synthesis of γ-hydroxy ketones was reported in 1980 and 1990s. Some

reports indicate the use of 1,2-epoxides as starting materials in the synthesis of γ-hydroxy

ketones. Lithium enolates derived from ketones opened 1,2-epoxides 91 in presence of ytterbium

triflate to give γ-hydroxy ketones16

.

O

H H

R2H

H

H R1

OLi

Y(OTf)3

R2

OH

R1

O

(equation 26)

91 92

Lithium chlorate was also used instead of ytterbium triflate in the above synthesis17

.

Synthesis of γ-hydroxy ketones was also done from 3-diphenylphosphinoyl propanols by

acyl transfer18

.

As reported earlier in this Chapter, the reductive cleavage of oximino bond of 5,6-

dihydro-4H-1,2-oxazines are an important route to the synthesis of different organic compounds.

Several reagents like H2/Raney nickel19

,H2/Pd/C13

, LiAlH420,21

, DIBAL-H22

and Mo(CO)623

are

used for this purpose. This methodology is also used in the synthesis of γ-hydroxy ketones. The

reagents generally used for this purpose are hydrogen/acid14

and zinc/acid24

.

3.1.4 Chemistry of reduction using zinc

One of the earliest reports in literature indicates the use of zinc and ammonium chloride

for the reduction of nitro compound 93 to hydroxyl amine94

25.

NO2 Zn

Aq. NH4Cl

NHOH

(equation 27)

93 94

Zinc is also used in combination with other reagent to effect several functional group

transformations. Zinc and sodium hydroxide in aqueous methanol is used to reduce

nitro compounds to azo compounds 9526.

NO2

Zn, NaOH

aq. MeOH,

N

N(equation 28)

95,

Zinc and ammonium formate or ammonium chloride27

and zinc-hydrazinium

monoformate has been used in the conversion of nitro compounds to the corresponding amino

derivatives. One of the oldest reports cites the use of zinc in Clemmensen reduction28

. Recent

literature reports a modified procedure29

in which zinc/hydrochloric acid in ether is used at lower

temperature (equation 29).

O

C8H17

H

O

C8H17

H

Zn, HCl

Et2O

-20oC to 0oC

(equation 29)

Zinc and ammonium chloride has been used for reduction of some of the some more

functional groups. Aiqiao Mi etal30

has carried out the reduction of alkyl 96 and acyl azides 97 to

amines 98 and amides 99 using Zn/NH4Cl in EtOH/water (3:1).

N3

NH2

EtOH/water

Zn/NH4Cl, 87%

(equation 30)

96 98

N3NH2

EtOH/water

Zn/NH4Cl, 94%

O O

(equation 31)

97 99

1,4-reduction of chalcones 100 was also carried out by zinc and ammonium chloride in

ethanol/water31

to ketones 101 in good yields.

O

Zn/NH4Cl, 95%

EtOH/water

O

(equation 32)

100 101

Reductive elimination of α-alkoxy-β-halides 102 to olefins 103 was accomplished using

zinc and ammonium chloride32

.

O

O I

O

O

Ph

Ph

Zn/ NH4Cl

MeOH, 60oC, 3h, 80%

O

O

O

Ph

102 103

(equation 33)

Sheldrake and Wallace accomplished the reduction of propargyl sulfones 104 to Z-allylic

aulfones 10533

HOSO2Ph Zn and NH4Cl

SO2Ph

OH

H2O, THF, 25oC, 99%+

OH

SO2Ph

104 105

(equation 34)

PART II

DISCUSSION ON THE NOVEL

METHODOLOGIES OF REDUCTIVE

CLEAVAGE OF OXIMINO BONDS

3.2.1 Plan of synthesis

Our synthetic strategy for a novel route to tetralone rings envisages the synthesis of γ-

hydroxy ketones from 5,6-dihydro-4H-1,2-oxazines. The oxazines prepared in Chapter 3 of this

book were converted to respective γ-hydroxy ketones. The reported reagents of hydrogen and

acid or zinc and acid can be useful but harsh conditions are generally employed for these

reagents. Hence there was a need to find out a mild and effective methodology for the cleavage

of N-O bonds of the oxazines.

R1

R2

O

N

R3

R1

R2

OH

O

R3

(equation 35)

Zn/NH4Cl

Zn/Aq. etheror

76 77

R1 = H, R2 = H, R3 = H

R1 = H, R2 = F, R3 = H

R1 = OMe,R2 = OMe, R3 = H

R1 = H R2 = Br, R3 = H

R1 = H, R2 = CH3,R3 = H

R1 = Cl, R2 = Cl, R3 = H

R1 = Cl, R2 = OH, R3 = Cl

a

b

c

d

e

f

g

Here in, we report two facile, simple and novel methodologies for the reductive cleavage of 5,6-

dihydro-4H-1,2-oxazines to γ-hydroxy ketones. The reduction carried out were using

1. zinc/ammonium chloride as the reagent in methanol

2. zinc/chelating aqueous ethers

3.2.2 Discussion on the experiments for reduction of 3-aryl-6-phenyl,5,6-dihydro- 4H-

1,2-oxazines

3.2.2.1 Reduction using zinc and ammonium chloride

The reductive cleavage was achieved using three moles of zinc and about ten moles of

ammonium chloride in methanol/water. The reaction stalled with lesser amounts of zinc and

ammonium chloride. The reaction easily happened with 6-phenyl derivatives.

Different reagents were tried for the conversion. Trials using hydrogen gas and boric acid lead to

cleavage of N-O bonds but also resulted in the removal of some functional groups like aromatic

chloro group. Also the use of zinc and acetic acid for the cleavage resulted in the reduction of

aromatic chloro groups in the system. Our look out for a milder reagent for the preparation of γ-

hydroxy ketones from 1, 2-oxazines led to the choice of the zinc and ammonium chloride which

can accomplish the hydrogenolysis in a single pot.

The reactions were initiated at lower temperatures (50oC, 60

oC) but took longer time for

completion. This also resulted in more tar formation. The temperature of 70oC was the optimum

temperature for the conversion. All the γ-hydroxy ketones were purified by column chromatogra-

phy using hexane/ ethyl acetate as eluent and characterized by 1H and

13C-NMR. The yields of γ-

hydroxy ketones (after column purification) were in the range of 63-76%. The hydroxyl group in

the γ-hydroxy ketones were characterized by 1H-NMR (by deuterium exchange using D2O) and

using IR-spectra.

The reductive cleavage using zinc and ammonium chloride reported here surpassed the

other methods of reduction of 1, 2-oxazines in that it can be carried out without hydrogen gas,

metals like Pd and Raney nickel and avoids expensive regents like LiAlH4, DIBAL-H. The other

major advantage is that this reagent being milder, reduction can tolerate different functional

groups like chloro and methoxy. The keto group in the product remained unaffected after the

reaction.

R1

R2

O

N

R3

R1 = H, R2 = H, R3 = H

R1 = H, R2 = F, R3 = H

R1 = OMe,R2 = OMe, R3 = HR1 = H, R2 = CH3,R3 = H

R1 = Cl, R2 = Cl, R3 = H

a

b

c

d

g

R1

R2

NH

OH

R2

R1

NH2

OH

Zn/NH4Cl

MeOH

H

major

77

minor

76

R1

R2

OH

O

R3

R3

R3

106

107

Scheme 29

The initial step of the reaction is the cleavage of the oximino bond of the oxazine 76 to the

1,4-iminoalcohol 106. The hydrolysis of the imino-alcohol results in γ-hydroxy ketones 77.

When the reaction was performed with electron donating groups on the phenyl ring at the 3-

position of the oxazine, some traces of 1,4-aminoalcohols 107 were also formed. These are

formed from the subsequent reduction of 1,4-iminoalcohols. Formation of minor amounts of 4-

amino-4-(3,4-dimethoxy-phenyl)-1-phenyl-butan-1-ol 77d was observed. 1,4-aminoalcohol 107

formed were removed by column chromatography. 1,4-aminoalcohols were not formed for other

substrates probably due to the ease of hydrolysis of the intermediate 1,4-iminoalcohol with these

substrates compared to the competitive hydrogenation reaction.

3.2.2.2 Reduction using zinc and aqueous chelating ethers.

Our probe into the reduction methodologies for the cleavage of N-O bonds helped us

develop a facile, efficient, mild method for the conversion of 5,6-dihydro-4H-1,2-oxazine to γ-

hydroxy ketones. This method is a novel approach to oximino bond cleavage using zinc which

was accomplished in the absence of acids/bases and at neutral pH. The reaction was done using

zinc in aqueous chelating ethers which resulted in good yields of γ-hydroxy ketones. The ether

acts as ligand and co-solvent for the reaction. It is considered that the ability of zinc ions to form

stable complexes with chelating ethers could activate zinc towards reduction.

One of the major advantages of this reagent is that being milder , reduction can tolerate

different functional groups like aromatic bromo, chloro, fluoro and methoxy. The keto group

formed in the reaction is also unaffected.

The cleavage of N-O bond of 3-aryl-5, 6-dihydro-4H-1,2-oxazines was accomplished

using 5-10 equivalents of zinc in presence of chelating ether and water at 70-75 oC. Lesser

amount of zinc resulted in incomplete conversion. The reaction was completed in 10-12 h.

Reactions done at lower temperatures took extended time for completion. A temperature of 70-

75oC was found to be the optimum temperature for the reaction. At the end of the reaction, the

mixture of zinc hydroxide and unreacted zinc were filtered. The crude products obtained were

purified by column chromatography on silica gel. The reaction did not proceed when other water

miscible solvents like methanol, acetonitrile, DMF, DMSO etc were used as a substitute for

ether. The substrates which are reduced using 1,3-dioxolane as the solvent are shown in Scheme

30.

R1

R2

O

N

R3

R1

R2

NH

OH

77

76

R1

R2

OH

O

R3

R3

106

Scheme 30

Zn

, H2O, 70-75oC

O

O

R1 = H, R2 = H, R3 = H

R1 = H, R2 = F, R3 = H

R1 = OMe,R2 = OMe, R3 = H

R1 = H R2 = Br, R3 = H

R1 = H, R2 = CH3,R3 = H

R1 = Cl, R2 = Cl, R3 = H

R1 = Cl, R2 = OH, R3 = Cl

a

b

c

d

e

f

g

Investigation of the reaction mechanism was done by using 6-phenyl-3-(p-tolyl)-5,6-

dihydro-4H-[1,2]oxazine 76b as model compound. To find out the role of water in the reaction, a

trial was done in the absence of water. The reaction failed to give the product without water. This

led to the fact that water could be the hydrogen source. To establish this result, a control

experiment using D2O was done. This led to the formation of γ-deuterioxy ketone 108 which was

confirmed by 1H-NMR that matches with D2O exchanged

1H-NMR for compound 76b. This

result confirmed that water acts as proton donor in the reaction.

O

N

PhO

OD

PhZn

, D2O, 70-75oC

O

O

76 b 108

(equation 36)

Experiments were done with other ethers like diethoxymethane, 1,2-dimethoxyethane,

dimethoxymethane and diglyme. This also fetched γ-hydroxy ketones in good yields. The

reductions were done using 76b as the substrate. The results are summarized in the Table I

below. These results confirmed that the ethers reported here works as a ligand which activates

the zinc towards reduction. A control experiment done in THF/water mixture did not give the

product.

Table I: Reduction of 6-phenyl-3-p-tolyl-5,6-dihydro-4H-[1,2]oxazine 76 b to 4-Hydroxy-4-

phenyl-1-p-tolyl-butan-1-one 77 b using zinc and various aqueous ethers

Ether Yield

(%)

O

No product

O

O

75

O

O

77

O O 81

O

OO

76

O O 78

O

O 80

Based on the results obtained from the probing experiments, a mechanism has been

proposed (Scheme 31, 32). The affinity of zinc ions to form stable complexes with chelating

ethers (illustrated using 1,2-diethoxymethane) leads to the activation of zinc towards the release

of electrons (Scheme 32). These electrons then attack the aromatic ring conjugate to the C=N

bond of the 1,2-oxazine leading to a 1,4-iminoalcohol. The imino alcohol undergoes hydrolysis

to γ-hydroxy ketone. A molecule of zinc hydroxide was formed. Thus ether acts as a ligand and

co-solvent for the reaction.

O

OO

O

Zn2+

O OZn

+ 2e-

+2 H2O Zn (OH)2 +

2

+

2 H+O

OO

O

Zn2+

O O2

Scheme 31

Since 1,3-dioxolane and 1,4-dioxane forms azeotrope with water , they are easily distilled

and reused. For the experiments using other ethers, the filtrate, after the removal of solids, was

added to excess water and extracted with ethyl acetate. The ethyl acetate layer was then

evaporated to get crude γ-hydroxy ketone. These were then purified by column chromatography

on silica gel. 1,4-aminoalcohols 107, which are generally reported as by- products in such

reactions were not observed.

O

N

PhO

HN

Ph

H+e-

O

HN

Ph

NH

Ph

O

Ph

H+

OHOH

e-

H2O

Scheme 32

The yields obtained after purification were in the range of 67-78%. All the compounds

prepared were purified by column chromatography on silica gel and characterized by 1H and

13C-

NMR. The hydroxyl group of γ-hydroxy ketone was confirmed using D2O exchange.

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