chapter 5 27 sep 2011 - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/9218/11/11_chapter 5...

Chapter 5

Functional Group Transformation through

Catalytic Reactions

Introduction

Formation of C-C and C-N bonds is among the most important fundamental

processes in organic and biochemistry. Many significant products (drugs, materials,

optical devices, etc.) commercialized or under development are constructed of C-C and

C-N bonds. Therefore, the development of any new and general technology for the

formation of these bonds can be of great scientific interest. Furthermore, given the

exponential number of publications in this field, the present thesis has been focused on

aromatic C-C and C-N bond formation reactions.

The catalyzed C-C bond forming reactions are very powerful and well-known

chemical tools. Such reactions are important in many functional group transformations

(alkylation, arylation, acylation etc.). The last year (2010) Nobel Prize in Chemistry has

shared by three researchers, Professor Richard F. Heck, Professor Ei-ichi Negishi, and

Professor Akira Suzuki, for: “palladium-catalyzed cross couplings in organic synthesis”.

These discoveries have had a great impact on academic research, the development of new

drugs and materials, and are used in many industrial chemical processes for the synthesis

of pharmaceuticals and other biologically active compounds. Through the assembly of

carbon atoms into chains, complex molecules, e.g. molecules of life, can be created. The

use of Pd-catalyzed cross-coupling reactions has significantly increased among the

methods to make C-C bonds.[1]

Many modern organic synthesis for C-C coupling

reactions have been described in the literature, such as the Miyaura-Suzuki (boron-

mediated),[2]

Corriu-Kumada-Tamao (magnesium-mediated),[3]

Kosugi-Migita-Stille (tin-

mediated),[4]

Neghishi (zinc-mediated),[5]

Sonogashira (copper-mediated),[6]

Heck-

Mizokori (Pd-mediated),[7]

and Hiyama (Pd-mediated)[8]

coupling reactions. Other C-C

bond forming reactions using Mn-mediated catalysts were also described, particularly in

the case of the acylation reaction.[9]

The importance of the synthesis of C-C bonds is

Studies on the novel oxidative methods using green bromine as an alternative approach for functional group

transformation reactions in organic synthesis

99

Ph. D. Thesis of Mr. Rajendra D Patil Bhavnagar University, Regtn. No.1300, dated 10/04/2008 Ref. No. Acad/Ph.D./917/1725/2009, dated 23/07/2009

reflected by the fact that for the development of C-C bond forming reactions in past also

awarded with Nobel Prizes in this area: The Grignard reaction (1912), the Diels-Alder

reaction (1950), the Wittig reaction (1979), and olefin metathesis to Y. Chauvin, R. H.

Grubbs, and R. R. Schrock (2005). Inspite of huge importance of these reactions; some

problems associated with these reactions are use of stoichiometric use of Grignard

reagents (Miyaura-Suzuki, Corriu-Kumada-Tamao and Negishi reactions), moisture

sensitive, use of toxic and expensive metals and problem of waste treatment or recovery.

In the catalysis over the last few years there is an advancement of a practical, mild

and efficient protocol for catalytic C-N bond forming reactions. The independent

investigations by, Buchwald[10]

et al. and Hartwig[11]

et al. were the first reported the

catalytic aminations of aryl bromides with free amines. The synthesis of novel pyridine

alkaloids, isolated as biologically active compounds from marine sponges (Theonella

swinhoei),[12]

was readily accomplished utilizing the Mitsunobu C-C and C-N bond

forming reactions.[13]

The outcome of C-N bond forming reactions are N-Arylamines, N-

arylpyrroles, N-arylindoles, N-arylimidazoles, and N-arylpyrazoles compounds which are

important for biological, pharmaceutical, and material chemistry.[14]

Another classical

example to explain the significance of C-N bond forming reactions is the imine synthesis.

Copper-catalyzed Ullmann-type traditional reactions are known.[15]

Long reaction period,

high temperatures and many functional groups are not amenable to this procedure,

therefore these factors limits the usage of such reagents. To overcome these drawbacks,

several Pd-catalyzed C-N formation reactions have been discovered, which require

sterically hindered phosphine ligands, to proceed the reactions under relatively mild

conditions.[16]

However, for industrial applications these methods are not suitable due to

the air and moisture sensitivity, as well as the high costs of Pd catalysts.

Even though significant progress has been made in the reactions forming C-C and C-

N bond, it is still challenging to develop more economical, sustainable and environment-

friendly technologies. Copper-mediated C-C and C-N bond forming reactions have been

known for more than 100 years;[17]

however, these reactions have been overshadowed by

the scope and versatility of analogous Pd-catalyzed coupling methods. The dramatic

success of Pd catalysis due to the availability of sophisticated insights into the

fundamental organometallic chemistry of palladium, including knowledge of the



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reactivity of organopalladium complexes in different oxidation states. Fundamental

studies of copper chemistry could play a similar role in copper catalysis. Copper in

combination with atmospheric oxygen was found to be an effective catalytic oxidizing

system for the direct synthesis of imines (C-N bond formation) from amines and it was

explored in the present thesis work.

The reported reactions for C-C bond formation are generally catalyzed by transition

metal and their complexes. However, most of such reactions suffer from deactivation of

catalyst in hostile reaction conditions and requirement of specific reaction conditions.

On the other hand, parallel researches in non-transition metal catalyzed C-C bond

reactions provides an alternate to the existing methods and reduce the burden on

transition metal catalysis. This purpose can be solved by employing easily available, low

cost, reusable mild Bronsted acids. Therefore hydrated potassium hydrogen sulphate

(KHSO4) a heterogeneous catalyst was employed for the construction of C-C bonds for

hydroarylation of styrenes in the part of present thesis work.

5.1 Hydroarylation of styrenes (C-C bond formation)

The C-C bond forming reactions represents the heart of organic chemistry. Usually,

C-C bonds are formed by coupling two carbons each of which are already functionalized

or activated in some way, for example the displacement of a C-Br with NaCN to form

C–CN bond. It would be more efficient, and potentially less expensive and less polluting

if one of the partners would be an ordinary C-H bond. Exploration of simple olefins

represents one of the most fundamental transformations for the synthesis of number of

fine chemicals and pharmacologically relevant target molecules.[18]

In this context, the

addition of a reagents HX (X= halogen, OH etc), X2 ( X = halogen), etc. add across a

C=C double bond to form a functionalized alkane is well known chemical reaction, that

has attracted considerable scientific commitment in the past.[19]

Reactions of alkenes

with electron-rich aromatic compounds so called hydroarylation are especially

interesting topic of current research,[20]

as they combine the benefits of olefin

hydrofunctionalizations with a C-H activation of an aromatic compounds. Furthermore,

hydroarylation of alkenes with arenes are considered as an atom economical alternative

to classical Friedel–Crafts-type alkylations of arenes.[21]



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The majority of known fine chemicals, pharmaceuticals, agrochemicals, dyes, etc.

contain aromatic and/or heteroaromatic backbone.[22]

To diverge and improve the

properties of these compounds the functionalization of aromatic core structures are of

fundamental importance to organic chemistry. The functionalization of arenes and

heteroarenes is of great importance in the synthesis of pharmaceuticals, agro-, and fine

chemicals. In the past and still today most aromatic products are prepared on the

industrial/plant scale by well-known classic transformations such as Friedel–Crafts

alkylations, Friedel–Crafts acylations, nitrations, and halogenations.[23]

Although these

methods work reliably with a variety of substrates, they often have major drawbacks

such as need of drastic reaction conditions (high temperature, strong acidic conditions),

low regioselectivity, and stoichiometric amounts of (salt) by-products generation. In

addition, it is common that the construction of specific C-C bonds on the aromatic core

requires several steps including introduction of activating groups and protection and

deprotection steps. Therefore, the development of new direct C-C coupling reactions of

arenes has become an important topic in catalysis. Recently, promising transition-metal

and acid-catalyzed C-H activation of arenes and heteroarenes have been reported.[24]

A

number of catalytic systems, including ruthenium,[25]

palladium,[26]

platinum,[27]

nickel,[28]

and indium[29]

have been employed for the functionalization of heterocycles

through C-C bond formation reactions. Prominent systems, Bi(OTf)3, [30]

, BiCl3 [31]

, and

FeCl3 [32]

catalyzed hydroarylation of styrenes were also reported for the synthesis of a

variety of 1,1-diaryl alkanes in good yields. Boronic esters/acids with palladium

complex,[33]

, iodine,[34]

and an ion exchange resin[35]

are the most recent developments in

the hydroarylation of alkenes. However, these methods requires the use of stoichiometric

or excess amounts of strong acids/bases and air-sensitive/moisture-sensitive

organometallic reagents or solid supports. In most studies, the halide salts are obtained

as by-products which limit processes.

Now days the development of sustainable or green protocols using abundant and

cheap catalysts emerging as a model for the development of new C-C bond formation

strategies. Precious metals, which still play a fundamental role as the central metal in

catalysis, but are expensive and are becoming increasingly rare as they are non-



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renewable natural resources. On the other hand, the exploration of main group metal

catalyzed organic reactions has received very little attention in the past.

In view of ongoing quest for green and sustainable processes for functionalization

of alkenes[36]

and alkynes[37]

for diverse applications, transition metal-free catalyst

system for hydroarylation of styrenes with aromatic compounds in the presence of

KHSO4 (10 mol%) as an efficient catalyst under mild conditions was developed

(Scheme 5.1).

Scheme 5.1: Hydroarylation of styrenes

Initially, to establish the optimum reaction conditions, the reaction of β-naphthol 1

with styrene 2 using catalytic amount of KHSO4 and in different solvent media were

investigated, the reaction progress and yield were monitored by GC (Table 5.1). The

reaction of equimolar amount of 1 with 2 in dichloroethane (5 mL) at reflux temperature

with 10 mol% of KHSO4 resulted the complete conversion to a desired product 3 during a

period of 8 h (Table 5.1, entry 1). The GC-MS analyses of the reaction mixture disclosed

98% conversion of 1 to yield the arylated product 3 with more than 99% selectivity

(Table 5.1, entries 1). The use of excess amount of KHSO4 under the same reaction

conditions resulted with less conversion and leads to the formation of undesired products

(Table 5.1, entries 2-4). When reaction was carried out under neat conditions, indeed it

gave >99% selective product 3, but led to less conversion (Table 5.1, entry 5). The 10

mol% of KHSO4 showed highest catalytic activity and selectivity for hydroarylation

styrene with β-naphthol (Table 5.1, entry 1). While switching over to other solvent

systems led to a lesser conversion and low yields under these conditions (Table 5.1,

entries 6-10). Various other catalysts were also screened out for the hydroarylation

reaction, but showed lower catalytic activity and with low yield of the desired product

(Table 5.1, entries 11-17) than that of KHSO4. The effect of temperature on the formation

3 under the conditions of Table 5.1 was also studied. This study showed that, at room



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Table 5.1: Screening of various catalysts and solvents for hydroarylation of styrene with

β-naphthola

aReaction Conditions: 3.5 mmol of 1, 3.5 mmol of 2, catalyst, 5 mL solvent,

reflux, 8 h. bGC conversions based on 1.

cGC yields of arylated products

based on conversion. dSelectivity deternined by GC of 3 to others.

PTS= p-Toluene sulfonic acid.

temperature and at 40°C there is no conversion by GC analysis even the reaction was

continued up to 15 h (Table 5.2, entries 1 & 2). However at 60°C, 9% conversion and

100% selectivity of the desired product 3, was observed (Table 5.2, entry 3). At reflux

temperature of dichloroethane the better conversion and selectivity was observed (Table

5.2, entry 4). Therefore the rest of the experiments were carried out under these

optimized conditions.

The scope of the KHSO4 catalyzed hydroarylation reactions of various styrenes with

β-naphthol were examined under the optimized reaction conditions and results are



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Table 5.2: Effect of temperature on hydroarylation of styrene with β-naphthol

aGC conversions based on 1.

bGC yields of arylated products.

cSelectivity

deternined by GC of 3 to others.

indicated in Table 5.3. The hydroarylation reaction of β-naphthol with various styrenes

having electron-donating substituents, proceeded efficiently to give the corresponding

arylated products in good to high yields with high selectivity (>99:1) (Table 5.3, entries

1-3).

Table 5.3: Hydroarylation of β-naphthol with different styrenesa

aReaction conditions: 3.5 mmol of 1, 3.5 mmol of 2(a-g), 5 mL DCE.

bIsolated

yields. cDetermined by

1H-NMR of desired product to other isomer.

DCE = 1, 2 dichloroethane



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Styrenes having electron –withdrawing substituents were also offered high yields, and

high selectivity (Table 5.3, entries 4 & 5) except with 4-acetoxy styrene (Table 5.3, entry

6) it gave 73% yield with 93% selective product 3f, which may be due to strong electron

withdrawing property of acetoxy group. All the products of Table 5.3, showed with high

selectivity (except entry 6) of the desired product 3(a-f) as determined by 1H-NMR of

purified products.

To study the reusability of KHSO4, after completion of the reaction, the KHSO4 was

retrieved from the reaction mixture, by simple filtration, dried and recycled under the

similar experimental conditions employed in Table 5.3, GC analysis showed no

formation of hydroarylated product. Further to corroborate the reusability of the catalyst

another reaction was carried out by the addition of a trace amount of water (through

syringe) to the recovered catalyst under the same conditions; by GC analysis, 85%

conversion with 97% selectivity of the desired product was observed (Fig 2). This

suggests that, the hydrated form of the catalyst is active for this transformation. Although

a small amount of water was beneficial for the recyclization of the catalyst (KHSO4),

when the reaction was tested without KHSO4, but the addition of a drop of water no

product was detected by GC-MS analysis. This study support to rule out the contribution

of H2O alone to promote the hydroarylation reactions. In another set of recyclization of

KHSO4, when D2O was added instead of H2O, no deuterated product was detected;

however the desired hydroarylated product was obtained. Therefore it is reasoned that

water is not involved in the catalytic cycle and that a trace amount of water could help to

disperse the KHSO4 to facilitate the hydroarylation reaction[38]

.

As can be evidenced from the SEM (scanning electron microscope) images (Fig 5.1)

of fresh and recovered KHSO4, the fresh KHSO4 is surrounded by number of H2O

molecules than in case of recovered KHSO4. The surrounded water molecules help for

the dispersion of the catalyst, and thus activate the hydroarylation reaction. As evident

from the recyclability chart of KHSO4 (Fig 5.2), that, the catalyst would be easily

recovered and reused up to three consecutive cycles with good conversions. Therefore a

schematic mechanism for the KHSO4 catalyzed hydroarylation of styrenes with 2-

naphthol was proposed in scheme 5.2.



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SEM image of Fresh KHSO4 SEM image of recovered KHSO4

Figure 5.1: Scanning Electron Microscope (SEM) images of KHSO4 catalyst

98

85 83 82

0

20

40

60

80

100

Co

nvers

ion

(%

)

Fresh 1 2 3

No of Cycles

Figure 5.2: KHSO4 recyclability chart

Scheme 5.2: Proposed mechanism for KHSO4 catalyzed hydroarylation of styrenes with 2-naphthol

In order to explore the scope and limitations of the present catalytic procedure,

representative examples of functionalized aromatic and heteroaromatic compounds were

treated with styrene and substituted styrenes and results are summarized in Table 5.4. As

shown in Table 5.4, various substituted styrenes reacted smoothly with α-naphthol to

give corresponding hydroarylated products in 48-72% isolated yields with 90 to 98%



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Table 5.4. Hydroarylation of arenes and heteroarenes with styrenesa

aReaction Conditions: 3.5 mmol of arene/heteroarene, 3.5 mmol of styrene, 10 mol%

KHSO4, 5 mL DCE, 80° C, 8 h. bIsolated yield.

cDetermined by

1H-NMR of purified

main product:other isomer.

selectivity (Table 5.4, entries 1-3). The reaction of phenol with t-Bu styrene (Table 5.4,

entry 4) and styrene (Table 5.4, entry 5) gave moderate yields (43 and42%) of

hydroarylated product with high selectivity (>99:1) in the former case. The same trend

has been observed in the case of p-cresol with methyl styrene and t-Bu styrene (Table

5.4, entries 6 & 7), but with good yields. The relatively low yield of thiophene with

styerene is due to the low boiling nature of the substrate (Table 5.4, entry 8). However

the reaction of 2-methy thiophene with t-Bu styerene gave corresponding hydroarylated

product in good yield with high selectivity (Table 5.4, entry 9).

In this section, an efficient method for the hydroarylation of styrenes with various

aromatics and heteroaromatics using KHSO4 (10 mol%) as a highly efficient and

selective heterogeneous catalyst is described. Styrenes with electron donating substituents

showed high selectivity for the hydroarylation reactions than that of electron withdrawing

substituents. The KHSO4 could be recovered and reused up to a minimum three



108


consecutive cycles with good conversion under the conditions studied. Present catalytic

system has a remarkable advantageous such as: good activity and selectivity in a number

of cases, no need to maintain dry or inert atmospheric conditions, chemicals are readily

available, low cost, recoverable and reusable catalyst, and importantly does not generate

any toxic waste. The C—H activation has been achieved in the present work under

transition metal-free conditions. This simple procedure offers a very attractive alternative

for the synthesis of motifs that are found in various bioactive molecules.

5.2 Imine synthesis (C-N bond formation)

Imines are important intermediates in the synthesis of various biologically active

nitrogen-heterocyclic compounds and industrial important synthetic processes.[39]

Imines

can act as electrophilic reagents in a number of reactions, including reductions, additions,

condensations, and cycloaddition reactions.[40]

Imines are also used as intermediates for

the synthesis of herbicides, pharmaceuticals, and other fine chemicals.[41]

The synthesis of

imines has attracted much attention in the field of coordination chemistry. The presence

of the lone pair on the nitrogen atom of the imine group enables the coordination to a

numerous metal cations, especially when the imine function has located at the ortho

position of the heteroaromatic cycles such as pyridines. Such molecules have been known

for interesting applications as ligands in various homogeneous catalytic reactions such as

hydrosilation, Mukaiyama aldolization, cyclopropanation,[42]

homologation of aromatic

aldehydes,[43]

and ethylene polymerization.[44]

Furthermore, hydrogenation of the C=N

bond of imines affords an alternative to the synthesis of secondary amines.

Generally, imines are synthesized by the condensation of primary amines with

carbonyl compounds.[45]

Significant progress has been made in recent years for the

synthesis of imines, including direct synthesis of imines from amines and alcohols in the

presence of catalyst,[46]

self-condensation of primary amines with oxidant[47]

and

oxidation of secondary amines.[48]

Recently, the direct synthesis of imines from

nitroarenes and carbonyl compounds have been reported using Au/TiO2[49]

or Ni/SiO2[50]

as catalyst in the presence of H2, or using PdCl2(PPh3)2–SnCl2 as catalyst in the presence

of CO,[51]

or using Fe–HCl as both catalyst and reductant.[52]

But these processes are not

much practical due to the use of H2, CO. Moreover, most of these reactions were



109


performed under solvent conditions. However, no attempts were made for the synthesis

of imines by the direct oxidation of primary amines to corresponding imines under neat

conditions, probably due to the rapid dehydrogenation of imines to nitriles.[53]

Notably,

most of the applications are based on complexes of precious metals such as palladium,

ruthenium, gold, tin and vanadium etc. The limited availability of these metals and their

high price makes it highly desirable to search for more economical and environmentally

friendly alternatives.

5.2.1 Synthesis of imines from amines using Green Brominating

Reagent (BR-S)

The oxidative functionalization of alkenes, alkynes, vic-dibromo to α-

bromoketones, methylarenes to benzoic acid and benzyl halides to aldehydes is

described in the last chapters (Chapter 3 and 4). The BrOH is the main species involved

in this transformation.

It has been explored that, BrOH is shown to be a very good oxidizing agent as well

as oxybrominating reagent and employed for the oxidation as well as oxybromination of

many organic substrates. Therefore, in the present study it is expected that the same

species would be well serve for the oxidation of amines to give imine. To the line of

expectation the species were acted for the purpose of oxidation of amines and provided

the some interesting results. Initially the reaction of benzyl amine with BR-S (Eq. 1) was

performed in water as well as in different organic solvents at room temperature. It was

observed that, the good conversion of benzyl amine in 1,3-dioxane and acetonitrile

solvents but provided less yield of imine (Table 5.5, entry 2 and 3 ). While the reactions

in water and toluene gave 7% and 5% desired imine product (Table 5.5, entry 1 and 4).

There was no imine observed when the reaction was performed in DCM as solvent

(Table 5.5, entry 5). The differences observed might be due to biphasic nature of two

solvents DCM and toluene in water. Because dioxane and acetonitrile are water miscible

system and allowing substrate and reagents interact together effectively. From the above

study (Table 5.5) acetonitrile was found suitable solvent compare to other solvents



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Table 5.5: Oxidation of 1 to 2 using various halogenating reagentsa

aReaction conditions unless otherwise stated, benzyl amine (0.1gm), halogenating reagent,

reflux, open atmosphere. bYield based on GC-area %;

cReaction carried out at RT.

d2.0 equivalent

of acid was used.

therefore further reactions were studied in water/acetonitrile solvent system. Further

improvement was found in the yield of imine product (42%), when the reaction was

carried out at higher temperature in acetonitrile/water system using Br-S (1.0 eq.) as a

Entr

y

Halogenating

Reagent

(equiv.)

Temp

.

(°C)

Solvent Time

(h)

Conv.

(%) 2 Yield

b

(%)

Select.

(%)

1d Br-S (1) RT Water 20 38 7 18

2d Br-S (1) RT Dioxane 3 100 26 26

3d Br-S (1) RT ACN 3 100 30 30

4d Br-S (1) RT Toluene 3 15 5 33

5d Br-S (1) RT DCM 3 13 -- --

6d Br-S (1) 100 ACN 18 99 42 42

7 Br-S (0.5) 100 ACN 18 92 58 63

8 Br-S (2.0) 100 ACN 18 100 1 1

9 NBS (1) 100 Dioxane 20 100 37 37

10 HBr/H2O2

(1)

100 Water 20 38 17 45

11 HCl/H2O2 (1) 100 Water 20 33 33 100

12 Iodine (0.1) 80 Neat 18 55 55 100

13 Iodine (1) 80 THF 20 68 68 100

14 Iodine (0.1) 80 THF 35 71 71 100

15 Iodine (0.1) 80 Dry

THF

30 35 35 100



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reagent (Table 5.5, entry 6). To study the effect of amount of reagent on the efficiency of

the reactions, two different experiments were carried out using 0.5 eq and 2.0 eq. of the

BR-S at high temperature. The result with 0.5 eq. of reagent having positive output

giving good yield of imine (58%) (Table 5.5, entry 7) while 2.0 eq. of reagent reaction is

completely non-selective towards imine having only 1% of yield (Table 5.5, entry 8). For

the comparative study with BR-S, other halogenating reagents such as NBS, HBr/H2O2,

HCl/H2O2 and iodine were employed. The results obtained with NBS, HBr/H2O2,

HCl/H2O2 reagents under similar experimental conditions are comparable with the result

obtained with BR-S (Table 5.5, entries 9-11). However, the results with iodine were

encouraging (Table 5.5, entries 12-15). Particularly, 0.1 eq. of iodine in THF giving good

yield of desired imine with high selectivity (Table5.5, entry 14). It is interesting to note

that, at the same reaction in dry THF showed low yield (Table 5.5, entry 15). It supports

the fact that water might be act as an additive role to catalyst for the synthesis of imines.

Iodine is Lewis acid and being effective for oxidation of benzylamines. However, it is

volatile and destructive at higher temperature. Therefore studies were continued to

replace moleculer iodine with easily available, effective and stable metal catalysts.

Particularly transition metal catalysts are the best candidates as they have rich history in

catalysis. Selective oxidation of organic compounds with oxygen as a sole oxidant is

valuable from both environmental and economic point of view.[54]

For this reason,

considerable efforts have been devoted in recent years to develop transition metal-

catalyzed aerobic oxidation reactions. Among the transition metals, Cu is the one of the

attractive catalyst. It was hypothesized that copper salts may be better alternatives owing

to its easy availability, low cost and environmental acceptance. Copper species in aerobic

conditions act as very good oxidizing system and it is well explored in the literature.[55]

Atmospheric oxygen as oxidant is clean source and available in free of cost from nature.

Therefore, copper/oxygen system was efficiently utilized for the direct oxidation of

amines to imines in the present thesis work also.

5.2.2 Synthesis of imine from amines using copper salts in aerobic

conditions



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Table 5.6: Optimization of conditions for copper-catalyzed oxidation of 1a

aReaction conditions unless otherwise stated, benzyl amine 1 (9.3 mmol),

catalyst, T=100°C, open atmosphere; time = 18 h. bYield based on GC-area %;

cReaction carried out at RT (entry 1) and at 60°C (entry 2);

dReactions carried

out in toluene (entry 6) and THF (entry 7) as solvents.

The study was initiated for the oxidation of amines to imine using various copper salts

under different experimental conditions (Table 5.6). It was found that copper catalysts

Entry Catalyst (mol%) Conv.

(%)

Yield (%)

b

Select.

(%)

1 CuCl (0.5)c - - -

2 CuCl (0.5)c 68 68 100

3 CuCl (0.5) 100 >99 100

4 CuCl (0.2) 53 52 98

5 CuCl (1.0) 100 >99 100

6 CuCl (0.5)d 40 34 85

7 CuCl (0.5)d 91 85 93

8 No catalyst - - -

9 CuCl2 (0.5) 77 77 100

10 Cu(ClO4)25H2O(0.5) 100 27 27

11 CuI (0.5) 100 89 89

12 CuBr (0.5) 78 73 94

13 CuBr2(0.5) 88 83 94

14 CuF2(0.5) 22 22 100

15 Cu(OAc)2.H2O(0.5) 97 78 80

16 Cu(NO3)23H2O(0.5) 81 72 89

17 CuO(0.5) 31 31 100

18 CuSO4.5H2O(0.5) 48 47 98



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functions well for the aerobic oxidative imination of benzyl amine to coressponding

imine under mild and solvent free conditions. Initially, the reaction of benzyl amine with

0.5 mol % CuCl was carried out and reaction mixture was stirred in open atmosphere at

room temperature for 20 hr. After the reaction (after 20 h), the part of the benzyl amine

converted into white solid while rest of substrate remains as such (Table 5.6, entry 1).

There was no imine product observed. The identification of the resulted solid was

attempted but attempt were failed and study has been continued. Then the reaction was

performed at the 60°C, 68 % (GC) formation of imine was observed (Table 5.6, entry 2).

Inspired by this result, further reaction was performed at higher temperature (100°C). At

this temperature, the complete conversion of benzyl amine to benzylimine (GC-MS) was

observed with imine as the only sole product (Table 5.6, entry 3). Employing 0.5 mol %

of copper(I) chloride as a catalyst under neat condition is the key step for high efficiency

of this transformation (Table 5.6, entries 2 and 3). No reduction of time was observed

when the catalyst loading was increased to 1 mol% (Table 5.6, entry 5). Further, no

improvements were observed when the reaction carried out in toluene and THF (Table

5.6, entries 6 and 7). Reaction does not proceed without catalyst (Table 5.6, entry 8).

Attempts were made to use other copper-halides and copper catalysts but they are not

efficient to achieve required conversion and selectivity (Table 5.6, entries 9-18). After

extensive screening of various copper catalysts, it was identified that 0.5 mol % CuCl at

100ºC under air were the optimized reaction conditions for the present investigation

(Table 5.6, entry 4). Under these optimized conditions, various imines were produced

from their corresponding benzyl amines (Table 5.7). The results in Table 5.7 demonstrate

that, this reaction has a high degree of functional-group tolerance. Both electron-rich

(para, meta, and ortho substituted) and electron-deficient substrates were well-tolerated

and produced moderate to excellent yields. It is noteworthy that halo-substituted benzyl

amines survived well, leading to halo-substituted imine compounds (Table 5.7 , entries

5–10), which could be used for further transformations along with imine functionality.

Further, it should be noted that with the use of more than stoichiometric amount of gold

catalyst (2.5 eq. w.r.t. substrate) only 7% yield of 2h was reported.[48j]

However, under

present conditions using copper (I) chloride as catalyst (0.005 eq. w.r.t. substrate) the

same product 2h could be obtained in 90% yield (Table 5.7, entry 8). Furthermore, it is



114


admitted that, isolated products of Table 5.7, indicate the presence of some aldehyde

could be due to hydrolysis of imine during work up.[53e]

This is also evidence from (Table

5.6, entry 3), when the crude mixture was analyzed by GC-MS, it showed only imine and

no evidence for the formation of aldehyde. In order to check versatile nature of the

present catalytic copper system, the methodology was applied to other substrates under

similar experimental

Table 5.7: Copper-catalyzed aerobic oxidation of benzyl amines to imines.a

aConditions: 1 (10 mmol), CuCl (0.05 mmol), T=100°C, open atmosphere.

bIsolated products.

cSelectivity determined by

1H NMR.

dRest of starting benzyl amine recovered.

conditions (Table 5.8). It was found that, this transformation is very general for a wide

range of amines such as dibenzyl amine (Table 5.8, entry 1), cyclic secondary amine



115


(Table 5.8, entries 2 & 3), heteroaromatic amine (Table 5.8, entry 4) and aliphatic amine

(Table 5.8, entry 5) substrates and produced corresponding imines in good yields. In case

of pyridin-2-ylmethanamine, 60% of picolinamide (GC-MS) also obtained in addition to

desired imine (Table 5.8, entry 4) which is apparent according to the literature.[41c]

However, the conversion of cyclic amines[48]

(Table 5.8, entries 2 & 3) and n-hexyl

amines (Table 5.8, entry 5) could be obtained in good yields under the present

Table 5.8: Copper-catalyzed aerobic oxidation of other amines to iminesa

aConditions: 1 (10 mmol), CuCl (0.05 mmol), T=100°C, open

atmosphere. bYields based on

1H NMR of crude product unless

otherwise stated. cIsolated yield.

reaction conditions which were reported to be unaffected even with metal organic

framework solid catalytst.[47c]

By using the newly established protocol, the oxidation of aniline to coressponding

azo compounds was also attempted however it was not successful. However, the mixture

of benzyl amine and anilines when subjected to the similar reaction conditions

symmetrical as well as unsymmetrical imines was obtained. Thus, syntheses of

unsymmetrical imines 5 were carried out by reacting benzyl amine 1a with different

anilines 4a-e, 3-methyl-2-aminopyridine 4f and aliphatic amines 4g under neat conditions

(Table 5.9). Anilines bearing electron releasing and electron withdrawing substituents

provided good yields of imines (Table 5.9, entries 1-4). The reaction of benzyl amine

with strong electron withdrawing 3-nitro aniline, produced only symmetrical imine 2a



116


Table 5.9: Synthesis of unsymmetrical imines

Entry Time/h Imine yield (%)b

1 18

2

4

NH2

5 : 2

NH2 15

3

NH2MeO 16

4

5

7

NH2

NH2O2N

NH2Cl 20

20

18

Conv.a

100

100

100

100

100

100

4a

4b

4c

4d

4e

4g

78

86

82

93

97[c]

78

23:77

86:14

17:83

33:67

--:100

56:44

N NH220 1004f 94[c] --:1006

aConversions based on benzyl amine 1a (GC area%).

bIsolated

yield unless stated. cGC yields w.r.t. 1a (4e & 4f are remain

unreacted).

(Table 5.9, entry 5). Similar inclination was observed with hetero aromatic amine

substrate (Table 5.9, entry 6). This is due to the competitive nueleophilicity of amines.

Thus, 3-nitro aniline and 3-methyl-2-amino pyridine were recovered as such. Particularly,

in unsymmetrical imine syntheses (Table 5.9), nueleophilicity of amines plays a major

role and lead to a mixture of imines 5 and 2. However, n-hexyl amine as substrate

produced the desired unsymmetrical imine in good yield (Table 5.9, entry 7).

5.2.3 Imine synthesis from amines using copper powder in aerobic

conditions

In the previous section (Section 5.2.2), the copper (I) chloride was employed as

catalyst for the synthesis of imines from amines. However, copper (I) chloride is reactive

salt and degraded in open atmosphere therefore its storage and handling requires extra

precautions. In addition to this, the desire imines products were contaminated with small

quantity of aldehyde as by-products. This may be due to hydrolysis of imines during

purification process. To overcome this drawback, the methodology was further studied by

using relatively stable copper metal powder as catalyst under similar experimental



117


conditions. The similar results were obtained when copper (I) chloride was replaced with

commercially available copper powder [copper (0) metal]. To identify the source of

impurity (aldehyde) formation along with desired imine in earlier work (Section 5.2.2),

different separation processes were studied to isolate the product. The separation and

purification of crude imine in a reaction mixture was tried with column chromatography

on silica gel, neutral alumina and basic alumina as stationary phase while hexane and

hexane/ethyl acetate as mobile phase. None of the above separation methods satisfactory

and accompany with small amount of aldehyde impurity (by 1H NMR). Therefore in the

present work, the method of imine purification by column chromatography was skipped

and alternative method was identified.

The reaction of benzyl amine to imine was performed with copper powder as

catalyst at 90°C. After complete conversion of starting benzylamine, the reaction mixture

contains only imine as sole product (TLC) along with some undissolved solid impurity. It

was thought that, instead of column chromatographic separation of imine, simple

filtration may provide pure imine. Therefore after complete reaction, the reaction mixture

Table 5.10: Reactions carried out in different atmospheric conditions using copper

catalysta

aReaction conditions: benzylamine 1 (9.3 mmol), catalyst, T=90°C,

open air atmosphere; time=20 h ( unless otherwise stated). bGC yield.

was filtered through simple filter paper (cellulose paper sheet) and washed with minimum

quantity of diethyl ether. Removal of the solvent from the filtrate obtained pure imine as

Sr.

No.

Reaction Conditions Conv.b Imine

yieldb

1 open atmosphere 100 99>

2 oxygen atmosphere 100 33

3 argon atmosphere 26 26

4 nitrogen atmosphere 22 22



118


analyzed by 1H NMR.

1H NMR shows only imine as product and there was no aldehyde

impurity observed (Table 5.10, entry 1). Further to understand the role of oxygen,

reactions were performed under nitrogen and argon atmosphere, which showed 33% and

26% of imine (Table 5.10, entries 3 and 4). This study indicates that atmospheric oxygen

plays a crucial role for the effective conversion of amines to imines.

Various substituted benzyl amines were then subjected to this oxidative imination

and the coresponding imines obtained are presented in table (Table 5.11). It should be

noted that the separation of imines by filtration is applicable for only benzyl amine and

their derivatives (Table 5.11, entries 1-9). In the case of other amine substrates, final

reaction mixture contains starting substrate as well as side products (TLC) and therefore

the desired imine products were separated by column chromatography (Table 5.11,

entries 10-13). The results summarized in Table 5.11, shows that various benzylimines

are synthesized in their pure form in good to high yields (Table 5.11, entries 1-9).

However, in the case of 2 and 3-fluoro substituted benzylamines, the desired imine yields

were lower as compared to other substrate. Generally, the purification of aliphatic imines

by column chromatography is a difficult task due to their unstable nature in open

atmosphere or in aqueous conditions. In the present work also attempts were made to

synthesize and purify the aliphatic imines but results are not much encouraging. In the

case of 2-phenyl ethylamine as substrate 16% isolated yield was achieved (Table 5.11,

entry 14). In the case of pentyl amine and heptyl amine efforts were unsuccessful to

isolate the corresponding imine by column chromatography however; GC-MS analyses of

crude mixture showed 33% and 26% imine products respectively (Table 5.11, entry 15

and 16).

After the completion of reaction, copper powder (catalyst) was recovered through

filtration from the reaction flask and washed with diethyl ether, dried and studied its

morphological changes using SEM before and after the reaction (Fig 5.3). SEM image of

fresh copper shows plane and shining surface [Fig 5.3(a)]. However, SEM image of

recovered copper powder after the reaction carried out in oxygen atmosphere [Fig 5.3(b)]

clearly shows the formation of pits on the surface of copper due to the oxidative

corrosion i.e oxidation of copper by aerial oxygen and one can easily understand why it

act as efficient oxidizing system for imine synthesis. Moreover, the role of oxygen as



119


Table 5.11: Copper-catalyzed aerobic oxidation of benzyl amines to imines.a

Entry Time/hAmine Imine

1 20

Yield %b

NH2 N

NH22

N76

NH2

Cl

NH2

F

NH2

O

NH2

Cl

NH2

F

NH2

F

NH2

Cl

3

4

5

6

7

8

9

88

20

18N

NCl Cl

Cl Cl

N

Cl Cl90

84

86

90N

F F

N

F F

NF F

N

O O

62

60

21

22

22

22

24

18 88

11

14

NH

N

N82

NH2 34C

12

1833

NH2

15

N 5536C16 18

N

NH210N

N

N24 20

PhNH2 Ph

NPh 1620

13

NH 6519N

N

N

N 58

12

19NH

aConditions: 1 (10 mmol), Cu (0.05 mmol), T=90°C, open atmosphere.

bIsolated products.

cGC yield

oxidant was counter checked by performing reaction in argon atmosphere (in absense of

oxygen). After the completion of reaction, SEM image of recovered copper catalyst was

studied. It was observed that though the original surface of the catalyst (external surface

of fresh copper) somewhat different than that of original, there were no pits formation

observed (no corrosion of copper) on the surface unlike the reaction under oxygen



120


Fig 5.3. SEM images of copper powder (a) fresh copper (before the reaction)

(b) after the reaction (reaction carried out in oxygen atmosphere.

(c) after the reaction (reaction carried out in argon atmosphere).

atmosphere [Fig 5.3(c)]. This explains the crucial role of oxygen as oxidant in the present

reactions for imine synthesis. Particularly copper powder is more effective catalyst than

its counter bulk metal because the former has faster oxidative property than the later and

that is why copper-powder used as a catalyst in the present work.

The probable reaction mechanism for this transformation has outlined in scheme 5.3.

In the proposed mechanism first step is the formation of complex A with oxidative

addition of amine to the copper.[56]

In the second step will be reductive elimination of

copper from complex A, provided methanimine B and regenerated the copper (0).

Reaction of methanimine B with another amine leads the final imine product with

Scheme 5.3: Possible mechanism for the copper-catalysed aerobic oxidation of primary amines to imines.

liberation of ammonia (path 1). On the other hand the presence of water partly hydrolyses

the methanimine B to aldehyde (path 2). The final step in path 2 is the condensation of the

aldehyde with the amine leading to the formation of the imine.

a c b



121


In conclusion, copper-catalyzed novel methods were developed to synthesize various

imine compounds. Even though both copper-powder and copper(I) chloride are utilized as

catalyst for the synthesis of imines; copper-powder is more preferred than copper(I)

chloride due to its relatively easy availability, low cost and better stability. Moreover, pure

benzylimines were achieved by simple filtration. Therefore, the present protocols are

highly useful for benzyl imines synthesis. Both symmetrical and cyclic imines can be

conveniently prepared by this route. Oxidation of organic compounds with molecular

oxygen as a sole oxidant is valuable. The nominal catalyst loading is another vital

advantage from economical point of view as well as from the view point of green

chemistry.

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