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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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