chapter 2shodhganga.inflibnet.ac.in/bitstream/10603/91985/9/09...4) homogeneous catalytic transfer...

CHAPTER 2

Reduction of Nitro Compounds

CHAPTER 2

Reduction of Nitro Compounds

Rapid and selective reduction of nitro compounds is of importance for the

preparation of amino derivatives in the organic synthesis both practically and

industrially, particularly when a molecule has other reducible moieties.28'i39-i42

The synthesis and biological evaluation of amines and their derivatives

constitute one of the active and most important areas of research.*^'^^

Numerous new reagents have been developed for the reduction of nitro

compounds. *5-i5o Most of the methods, viz., metal/acid reduction,i5i catalytic

hydrogenation,i52 electrolytic reduction,i53 homogeneous catalytic transfer

hydrogenation,i54 heterogeneous catalytic transfer hydrogenation^ss etc., are in

practice. However, these methods have one or more limitations:

1) Metal/acid system lacks selectivity and it needs strong acid medium.

2) Catalytic hydrogenation employs highly diffusible, low molecular

weight, flammable hydrogen gas and vacuum pump to create high

pressure within reaction flask.

3) Electrolytic reduction requires acidic or alkaline catholite; yields are

low and lack practical utility in academic institutions.

4) Homogeneous catalytic transfer hydrogenation requires expensive

complexes as catalysts; work up and isolation of the products are not

easy.

5) Heterogeneous catalytic transfer hydrogenation employs expensive

bulk or supported metals like palladium, platinum, ruthenium,

Raney nickel etc. The supported catalysts require stringent

precautions, because of their flammable nature in the presence of air.

55

Reduction of Nitro Compounds Chapter 2

Recently, metal mediated reactions have been foimd to have wide scope in

organic synthesis, because of their simple work-up and selectivity. Several

methods have been developed based on the use of a variety of metals such as

magnesium,i56 indium,i57,i58 tin,i59 zinc. ^" Magnesium is a powerful reducing

agent; it is used in the preparation of Grignard reagents^^i and for reduction of

various alkyl and aryl halides in protic solvents^^^ ^ also readily reduces

conjugated double bonds of esterS/i^nitriles^^ and amides,i*5,i66 as well as a, p-

acetylenic esters and triple bonds conjugated to two aromatic rings. ^^ Under

the same conditions, unactivated double and triple bonds are reduced in the

presence of Pd-C,^^ while desulfonation was also effected with magnesium in

methanol.!*' In aprotic solvents magnesium effects pinacol reductive coupling

of aldehydes and ketones.*^" In our earlier investigations, we had reported the

utility of magnesium^!* for deblocking of some commonly used protecting

groups in peptide synthesis and the utility of zinc for the synthesis of p-y

unsaturated ketones by a reaction of an acid chloride with allyl bromide^^ and

homoallylic alcohols^^^ has been demonstrated. Further, the zinc mediated

preparation of triphenyl phosphonium ylides,!^^ Friedel-Crafts acylation,!^*

carbamates formation!^ and zinc^ for the reductive cleavage of azo

compounds to corresponding amine/s has been demonstrated.

In this context, we have established two methods of reducing nitro compounds

to corresponding amines, which involve the use of cheaper metals. Magnesium

powder has been used with ammoniuni formate and Zinc dust is used with

Polymer supported formate (PSF). These systems are cost effective and chemo-

selective.

2.1: Magnesiuir/Ammonium Formate Promoted Rapid, Low-Cost and

Selective Reduction of Nitro Compounds.

The application of ammonium formate in the field of catalytic transfer

hydrogenation for the reduction of variety of organic compounds and the

synthesis of peptide has been reviewed. ^^^^^ The application of catalytic

56


transfer hydrogenation for reduction and reductive cleavage of organic

compounds and in peptide synthesis is mainly centered on the use of expensive

catalysts like Pd-Q Ru-Ca, Pt-Q Pt02, Pd-CaCOs, Ru-C and Raney Ni.io5,i55,i76

Some systems like HC02NH4/Pd-C,29'i78 HC02NH4/Pt-C,« HCO2NH4/

Raney-Ni,^ BioHi2/Pd-C,^o triethylammonium formate/Pd-C32 and

cyclohexene/Pd-O^' have been developed for the reduction of nitro

compounds to the corresponding amines. These systems require longer

reaction time at reflux and expensive catalysts like Pd-C, Pt-C and Raney-Ni.

These catalysts are flammable nature in the presence of air and presents

considerable hazards during handling. In addition to above mentioned

limitations, most of these methods are unfortunately subject to substantial

limitations as concerns the reducible functionalities and lack therefore desired

generality for the true synthetic utility. Moreover, poor selectivity was reported

in the reduction of aromatic nitro compounds, which have halogen, nitrile,

carboxyl, hydroxyl etc., as substituents. Reduction at reflux temperature^^sAso

for hours together can cause rearrangements and cyclization in poly-functional

nitro compounds. Therefore, we examined several methods to improve

reduction process, and especially to obtain selectivity over reducible or other

labile substituents.

In this context, we found that Mg/HC02NH4 system could be conveniently

employed for the rapid and simple reduction of both aliphatic and aromatic

{Scheme 2.1) nitro compounds to corresponding amino derivatives. This new

system reduced with ease a wide variety of nitro compounds to corresponding

amines. Many primary and secondary functional groups like -CH3, -OH,

-OCH3, CONH2, -COOH, -CI, -Br, -CN, -COOR, etc., are tolerated.

Mg/HCOoNH. R — N O , ^ R — N H 2

2 CH3OH, r.t ^

R= alkyl or aryl

Scheme 2.1

57


The reduction of both alkyl {Table 2.1) and aryl {Table 2.2) nitiro compounds in

the presence of Mg/HCOaNHj was completed within two to ten min. The

course of reaction was monitored by thin layer chromatography and IR spectra.

Table 2.1: Mg/HC02NH4 Promoted Reduction of Alkyl Niti-o Compounds.

SI -T-x_ J Time -T Nitrocompound , . . No. ^ (mm) A m i n e

Yield. "PCq (O/Q\ Found

(Lit.)i8i

1 CH3-NO2

2 CH3-CH2-NO2

3 CH3-CH2-CH2-NO2

CH3-CH2-CH2-CH2-NO2

3

3

CH3-NH2

CH3-CH2-NH2

CH3-CH2-CH2-NH2

CH3-CH2-CH2-CH2-NH2

81^

83*

81^

74b

230-232 (232-234) 106-108

(107-108) 158-161

(160-162) 77-79 (78)182

^ Isolated yields are based on single experiment and the yields were not optimized. b Boiling point. <: Isolated as hydrochloride salt.

Table 2.2: M g / H C C h N H i P romoted Selective Reduct ion of Aromat ic Ni t ro Compounds.

SI No

Nitroarene Time (min) Amine

Yield. "P'^Q /o/„\ Found

(Lit.)i8i

W // NO, Q^m

2 MeH^^N02

3 " 0 ~ { ^ N O a

2

2

NO,

{_J-^o,

90b

91

93

93

182-185 (184-186)

44-45(45)

189-190 (188-190)

110-112 (111-123)182

94c 58-60 (60)182

Table Cont inued . .

58


.. .Table Continued

6

7

8

9

10

11

12

13

14

15

16

17

18

19

21

H a N H ^ ^ N O s

H 2 N ^ / = \

0 r<=^^°^

CI—<^^^N02

CI

^ - N O ,

Br^(^J>-N02

Br

NO2

< Q - N 0 2

COOH

HOOC—(v ^ N O a

MeO—^ ))—NO2

N C - ^ ^ ^ N 0 2

NC ^^^-^

0 r^^°^ H a C ^ N " ^

^ H

3

3

3

3

5

5

5

4

8

5

7

6

4

6

5

H a N H ^ ^ ^ N H a

H2N / = \

0 f ^ ' ^ '

C I — < ^ ^ N H 2

CI

Q K N H 2

Q ^ N H 2

Br-^^^NH2

Br

< Q - N H 2

NH2

< ( ^ N H 2

^COOH

< ^ N H 2

HOOC—(( V-NHj

MeO—^ /—NH2

N C H ^ ^ ^ N H 2

, , ^ - ^ ^ " ^

H

95

92

93d

93

90b

89^

90

94c

93

88

89

93

90

91

92

142-144 (141)

115-116 (114)

148-151 (150)182

70-72(71)

208(206-208)

230(228-229)

66-67 (65-67)

115-118 (116)

103-104 (102-104)

146 (144-146)

186-187 (183-185)

58-66 (56-59)

84-85 (83-85)

46-48 (45-48)

163-165 (163)

Îsolated yields are based on single experiment and the yields were not optimized. ''BoUing point. Îsolated as benzoyl derivative. Îsolated as acetyl derivative.

59


The disappearance of asymmetric and symmetric stretching bands near 1520

cm-i and 1345 cirr^ due to the N-TTTTTO of NO2 and the appearance of two

strong bands near 3500-3300 cm-i of -NH2 stretching (due to primary amine) in

the IR spectra clearly indicated the conversion(Fi^res 2.1-2.3) . The work-up

and isolation of the products were easy. Thus, all the compounds reduced by

this system were obtained in good yields (90-95%). All the products were

characterized by comparison of their TLQ IR spectra and melting points with

authentic samples. A control experiment was carried out using nitro

compounds with ammonium formate in absence of magnesium powder and

this does not yield the desired product. No other intermediates, such as

nitroso or hydroxylamine could be detected in the reaction mixture. The

magnesium/HCO2NH4 system is more effective than either triethylammoiuum

foramte/5% Pd-C" or cyclohexene /10% Pd-C2 or hydrazine hydrate/Fe(III)25

and equally compatible with the systems like HCO2NH4/10%Pd-C28 and

HC02NH4/5% Pt-C.48 A plausible mechanism for the reduction of nitro

compounds to amines is proposed (Scheme 2.2).

Studies were also carried out to determine the optimum conditions for

reduction. These include the excess of donor required, the catalyst, solvent and

concentration. An excess of 2-3 equiv. of ammonium formate was found to be

ideal. The rate of transfer reduction decreased substantially when orUy

1 equiv. of ammonium formate was used. On the other hand, a large excess of

ammonium formate (20 equiv.) produced only a marginal increase in the rate

of reaction. A large excess of catalyst improved the rate of transfer

hydrogenation. We have also observed that, 1 equiv. of catalyst were ideal.

Larger amounts of catalyst resulted in only minor improvement. Methanol was

the most effective solvent. The reduction proceeded at the rate described above

when the concentrations of substrate are in the range of 0.75 - 0.5 mmol/mL.

At lower concentration, the rate of reaction decreases substantially.

60


tU

61


I I I I I ' l r j ' l M I ' I "I "I r"i I T\ 1 1 I" !• M I

O H O

8 ^ 8 t 0 o 6

62


.s

•a <

u OH

Pi

O 1- O

,S * 8 o g

o o d s

o 8

o 5?

o Q 6 N

a 6

o d

63


Plausible Mechanism of Reduction of Nitro Compounds by M^HC02NH4

HCO2NH4 ^S=

o - X- .

H O + NH^

Mg

O u

-*- H—Mg O

R-N

n^fX^o-H\

-H,0 R-N=0

O ' " 1 +

R-N-H I o_

H t o

I O - M g ^ O ^

" R ^ - H -Mg,-CO„-NH3 ^_

O

X H — M g ^ ^ O

H

- P»A- "T". ) ^ ^ 0—Me

R—N-H

-Mg.-COj,-NH3 '^^-N R ^ . ^ H

H\ ^H

-Mg, -CO,, -NH, H

R—NH, R-N-Mg H

H-N—H' I H

R = alkyl or aryl residue

-Hfi H

O X R - ^ M ^ ^ ^ O

O H

Scheme 2.2

Thus the reduction of nitro compounds can be accomplished with magnesium

powder instead of expensive platinum or palladium etc., without effecting the

reduction of any reducible or hydrogenolysable substituents. The yields are

virtually quantitative and analytically pure. The obvious advantages of

proposed method over previous methods are: (i) selective reduction of nitro

compounds, in the presence of other reducible or hydrogenolysable groups.

64


(ii) ready availability and ease of operation, (iii) rapid reduction, (iv) high

yields of substituted amines, (v) avoidance of strong acid media, (vi) no

requirement of pressure apparatus and (vii) cost effective. This procedure will

therefore be of general use, especially in the cases where rapid, mild and

selective reduction is required.

2.2: Polymer-Supported Formate (PSF) and Zinc: A Novel System for the

Transfer Hydrogenation of Aromatic Nitro Compounds.

In recent years, polymer-supported reagents, catalysts, and scavengers are

ubiquitous throughout the fields of combinatorial chemistry, organic synthesis

and catalysis.18^ '5 xhe use of polymer-supported reagents couples the

advantages of solution phase chemistry (ease of monitoring the progress of the

reaction by using chromatographic and spectroscopic techniques) with those of

solid phase methods (use of excess reagents and easy isolation and purification

of products). The utility and power of such reagents has been exquisitely

demonstrated by the groups of Ley and others in synthesizing several complex

natural products by multi-step sequences requiring many different kinds of

heterogenized reagents, which can be removed by simple filtration.^*^ '

However, in view of the rapid development in the field of polymer-supported

chemistry over the last few years, there is a pressing need for the proper

exploitation of functionalized polymer-supported reagents in organic

synthesis.

In this section, we report that the PSF can be conveniently employed as

hydrogen donor for the clean and efficient reduction of aromatic nitro

compounds to the corresponding anilines in excellent yields using readily

available inexpensive commercial zinc dust as catalyst under ambient

temperature {Scheme 2.3).

65


^—^ HCOONHj/Zn „ ,,

R — M^OH.r.t. ^

R = halogen, -CH=CH2, -CN, -CHO, -COR, -COOR, -CONH2, -OCH3 and -OH.

Scheme 2.3

The scope of this new system is illustrated in Table 2.3, where we examined

series of aromatic nitro compounds with a variety of substituents. All the

products were characterized by comparison of their TLC, melting points, IR

spectra (Figures 2.4-2.6), and ^H-NMR spectra with authentic samples. The

reactions are, on the whole, reasonably fast and high yielding (92-98%). It is

worth to note, our system selectively reduced aromatic nitro compounds to the

corresponding amines in the presence of other sensitive functional groups such

as halogen (Table 2.3, entries 1-3), alkene (Table 2.3, entry 4), nitrile (Table 2.3,

entry 5), and carbonyl (Table 2.3, entries 6 & 7), groups which are susceptible to

reduction under transfer hydrogenation conditions. In addition, many other

functional groups such as ester, amide, methoxy, acid, and hydroxyl groups are

also compatible with the present system. A plausible mechanism for the

reduction of rutro compounds to amines is proposed (Scheme 2.4).

The separation of products from the reaction mixture is simple and involves, in

most of the cases, direct removal of the catalyst and resin by filtration and

evaporation of the solvent under vacuum. The crude product, so isolated, was

of excellent purity for most purposes. Hence, this procedure is highly

advantageous to obtain water-soluble aromatic amines in high yields

(Table 2.3, entries 1, 3, 7, 12-15). It is noteworthy here that the polymer-

supported formate was regenerated and could be reused for further

hydrogenolysis process. In total, ten successive recycle runs were possible

before there was an appreciable decrease in the reaction yield (Table 2.4).

66


Table 2.3: CTH of Aromatic Nitro Compounds Using PSF/Zinc.

Entry Substrate Time

_JhL_ Product Yield^ mp

(%) (°C)181

1 CI \ \ //

-NO,

2 I—<\ />—NO, \ \ / /

Br

COOH

NO,

' M=r'°^ NC \ \ /

-NO,

6 O H C — / V - N O ,

7 HXOC

8 H,NOC

W /

w /

NO,

NO,

OMe

10

11 ^ '

1.0 CI

1.0 H,COC

1.0 H,NOC

OMe

2.0

1.5

CH,

^ NH,

96 71

98 62

93 217-219182

95 212-214b'C

98 46-48

97 70-72

96 104-106182

95 114-116

94 86-87d

92 205-207

97 110-112^

12 HOOC-iv />—NO, 2.5 HOOC \ /

NH, 96 186-187

Table continued

67


Table continued

13 3.0 N NO, N ^ N H ,

95 57-58182

14 ^^3C0CHN^ ^ N O , ^ 5 H,COCHN-<v A-NH, 98 163-164

15

16

HOOC

CHo

2.0

2.5

HOOC 96 150-152182

90 143-144

CH,

17 (HgQjN—{^ / - N O 2 2.5 (HgQjN-d^ / ) -NH2 85 113-115

18 3.0 NH,

93 110-112 (112)182

^Yields of isolated products; ''Boiling point; <='Yhe spectra were compared to those of a commercial sample; " Isolated as acetyl derivative;

Table 2.4: Recycling of Polymer-Supported Formate for the Reduction of p-Chloro Nitrobenzene.

Cycle

1

2

3

4

5

6

7

8

9

10

Time (hr)

1.0

1.0

1.0

1.0

1.5

1.5

1.5

2.0

2.0

2.5

Yield

(%)

96

95

95

94

94

94

93

94

93

93

68


<u.

O u O

5a.

Pi

rl 0)

[t4

71


B

I Z

i

01

PH

70


c

a o o 2 u

1

a S en

b

71


Plausible Mechanism of Reduction of Nitro Compounds by Zi^PSF

NH3 HCOO H 0 + NH,

O u

Zn+ H^'^6

0 R^K,"°

- H- Zr/^6 R- ti{ X-J' 0-^—-^ Q-

H

O . R-N=o "—:H;O"

H-Z)

o

r R-N—H

a

NH. 2 t .0

H' £M. o--Za-CO, ^ _ ^ ^ ^

y i i i 111MIM11111 Z J r O

NHo-

-Zn,-C02 TM o

NH,

®^>^, NH2 -

Zn, -CO2 R-

H il -H,0

NH,

H"

R-NH2

Scheme 2.4

^N

O—H

P ^

O

ZiAb

? X-O—H H

72


A control experiment was carried out using nitro compounds with polymer

supported formate, but without zinc powder, does not yield any reduced

product and the starting material is recovered in 100%. This confirms the role

of zinc as catalyst. Further, another control experiment was carried out by

refluxing r\itro compounds with zinc powder in methanol and in the absence of

polymer supported formate yielded no desired product. Even after long

duration we could not obtain any reduced product. This clearly confirms that

methanol serves only as solvent and not as hydrogen source.

In conclusion, we have developed a novel CTH system for the clean and

efficient reduction of aromatic nitro compounds to the corresponding amines

using polymer-supported formate and zinc. The major advantages of this

method include the ability to obtain aromatic anunes in pure form with no

work-up, and the enhanced chemo-selectivity. Thus, the use of resin bound

hydrogen donor combines the advantages of polymer-supported chemistry

with the flexibility of CTH technique. The catalyst is non-pyrophoric in nature

and another interesting behavior of Zn dust lies in the fact that it can be

recycled after simple washing with EtaO and dilute HCl, rendering thus

process more economic. The present method offers an economical safe and

environmentally benign alternative to available procedures.

2.3: Experimental.

2.3.1: General. The ^H NMR spectra were recorded on an AMX-400 MHz

spectrometer using CDCI3 as the solvent and TMS as internal standard and IR

spectra on a Shimadzu FTIR- 8300 spectrometer. The melting points were

determined by using Thomas-Hoover melting point apparatus and are

uncorrected. Thin layer chromatography was carried out on silica gel plates

obtained from Whatman Inc., using the solvent systems; 100:0 chloroform,

80:20 chloroform:methanol, 85:15 chloroform:methanol, 90:10

chloroform:methanol, 95:5 chloroform:methanol. The compounds on TLC

plates were detected by UV light, by ninhydrin or by exposing to iodine

73


vapors. The substrates were either commercial products and were used as

purchased or were prepared according to literature procedures. Merrifield

resin was purchased from Advanced Chem tech (1% DVB cross-linked, 100-200

mesh, 2 nunol/g). Ammonium formate was purchased from Aldrich chemical

company (USA). Zinc dust (Particle size < 45 |im) was purchased from E-Merck

(India) Ltd. Magnesium powder purchased from SISCO Research Laboratories

Pvt. Ltd., Bombay (India), was treated with O.OIN hydrochloric acid for about 2

min. It was filtered through a sintered glass funnel and washed with water, dry

methanol and dry ether. This magnesium was then vacuum dried and stored.

All the solvents used were of analytical grade or were of purified according to

standard procedures. For preparative TLC, the plates were prepared from

Kieselgel 60 GF254, Merck, Darmstadt and for column chromatography 60-120

mesh silica gel was used obtained from SISCO Research Laboratories. For

further purification/separation of products, the residue was purified either by

preparative TLC or subjected to column chromatography by using 60-120 mesh

silica gel and a suitable eluting system (50:50 chloroform:benzene, 60:40

chloroform:benzene, 80:20 chloroform:benzene, 90:10 chloroform:benzene,

50:50 chloroform:hexene, 60:40 chloroform:hexene, 80:20 chloroform:hexene,

90:10 chloroform:hexane, 100:0 chloroform, 80:20 chloroform:methanol, 85:15

chloroform:methanol, 90:10 chloroform:methanol, 95:5 chloroform:methanol).

2.3.2: Preparation of Phthalimidomethylpolystyrene Resin.

Chloromethylpolystyrene (Advanced Chemtech, 1% DVB cross-linked, 100-200

mesh, 2 mmol/g) was suspended in 150 ml of dry distilled dimethylformamide

(DMF) and 2.77 g of potassium phthalimide was added. The mixture was

stirred at 50 °C for 18 hours, after which the resin was washed three times each

with DMF, methanol, water and methanol and dried in vacuum overnight to

obtain Phthalimidomethylpolystyrene in good yield.

74

Reduction of Nitro Compounds ^ Chapter 2

2.3.3: Preparation of Aminomethylpolystyrene Resin.

Phthalimidomethylpolystyrene 20 g was treated overnight with 1.5 ml of

hydrazine hydrate in refluxing ethanol. The resin was filtered froni the hot

ethanol and washed three times with ethanol, 5% aqueous KOH, water, and

ethanol and dried in vacuum overnight to obtain aminomethylpolystyrene

resin in good yield.

2.3.4: Preparation of Polymer-Supported Formate.

The aminomethylpolystyrene was washed with an excess of 50% solution of

formic acid in dichloromethane. The resulting polymer was washed thoroughly

and successively with dichloromethane and ether, and dried under vacuum.

The obtained resin was used as such for the reduction.

2.3.5: General Procedure for the Reduction of Nitro Compounds Using

Mg/HCOONH4.

A suspension of an appropriate nitro compound (5 mmol) and magnesium

powder (10 mmol) in methanol or in any other suitable solvent (5 mL) was

stirred under nitrogen atmosphere with ammoruum formate (0.5 g), at room

temperature. After the completion of the reaction (morutored by TLC), the

catalyst was filtered off. The residue was extracted with chloroform or

dichloromethane or ether (15 mL). The extract was washed twice with

saturated sodium chloride solution (15 mL) and then with water (10 mL). The

organic layer was dried (Na2S04) and then evaporated to obtain the desired

anuno derivative.

In order to obtain good yield of volatile aliphatic amine, the reaction was

carried out using a condenser cooled with ice water and by immersing the

reaction flask in a cold-water bath. After filtration, the reaction mixture was

neutralized with HCl. The solvent was evaporated under reduced pressure.

The residue was lyophilized or subjected to column chromatography by using

75


60-120 mesh silica gel and a suitable eluting system. Aliphatic amines were

obtained as their hydrochloride salts in up to 80% yield.

2.3.6: General Procedure for the Reduction of Nitro Compounds Using

PSF/Zinc.

To a solution of nitro compound (1 mmol) in methanol (15 mL) taken in a

horizontal solid phase vessel, polymer-supported formate (1 g) and zinc dust

(1 mmol) were added. The suspension was shaken well (The reaction mixture

was subjected to shaking using a manual shaker as the shaking of the polymer-

supported formate instead of stirring increases its life for recycling purpose)

for the specified time at room temperature {Table 2.3). After consumption of

the starting material, as monitored by TLC, the reaction mixture was filtered

and washed thoroughly with methanol. The combined washings and filtrate

were evaporated under reduced pressure. The crude product was found to be

analytically pure in most cases. Where necessary, the crude product was taken

into organic layer and washed with saturated sodium chloride.

For recycling purposes, the residue containing polymer-supported formate and

the catalyst was washed thoroughly and successively with DMF,

dichloromethane, 50% solution of formic acid in dichloromethane,

dichloromethane and ether. Thus activated resin along with the catalyst was

dried under vacuum and used as such for further reduction reactions.

76

chapter 2shodhganga.inflibnet.ac.in/bitstream/10603/91985/9/09...4) homogeneous catalytic transfer...

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