Solvent-free organic syntheses on mineral supports ... - Springer Link

Clean Products and Processes 1 (1999) 132–147 Q Springer-Verlag 1999

Solvent-free organic syntheses on mineral supports using microwave irradiation R. S. Varma

132 Abstract An expeditious and solvent-free approach for selective organic synthesis is described which involves simple exposure of neat reactants to microwave (MW) irradiation. The coupling of MW irradiation with the use of catalysts or mineral supported reagents, under solventfree conditions, provides clean chemical processes with special attributes such as enhanced reaction rates, higher yields, greater selectivity and the ease of manipulation. Our recent results on this eco-friendly approach utilizing recyclable inorganic oxides or supported reagents such as Fe(NO3)3-clay (clayfen), Cu(NO3)2-clay (claycop), NH4NO3-clay (clayan), NH2OH-clay, PhI(OAc)2-alumina, NaIO4-silica, CrO3-alumina, MnO2-silica, and NaBH4-clay etc. are exemplified in MW-assisted deprotection, condensation, cyclization, oxidation and reduction reactions including the efficient one-pot assembly of heterocyclic molecules from in situ generated intermediates.

1 Introduction Microwave (MW) irradiation, an unconventional energy source, has been used for a variety of applications including organic synthesis (Abramovich 1991; Caddick 1995; Bose et al. 1997; Langa et al. 1997; Varma 1997, 1999a, 1999b). This surge in popularity has occurred within a decade of the first reported acceleration of a chemical reaction under the influence of microwaves (Gedye et al. 1986, Giguere et al. 1986). In spite of the lack of a detailed theoretical understanding of the MWexpedited chemical reactions and the apparent confusion over non-thermal ‘microwave’ effect (Langa et al. 1997), the technique does provide access to clean processes that should find applications in the research laboratory and industrial chemical plants. Such reactions involve selective absorption of MW energy by polar molecules, nonpolar molecules being inert to MW dielectric loss.

However, in the solution-phase reactions, the development of high pressures and the use of pressurized reaction vessels (Teflon) are some of the limitations. Recently, we [Varma 1997, 1999a, 1999b; Varma et al. 1993a, 1993b, 1993c, 1993d; Varma et al. 1997a, 1997b, 1997c, 1997d, 1997e, 1998a, 1998b, 1998c, 1998d, 1998e; Varma and Dahiya 1997a, 1997b, 1998a, 1998b, 1998c, 1998d; Varma and Meshram 1997a, 1997b; Varma and Saini 1997a, 1997b, 1997c; 1998] and others (MarreroTerrero and Loupy 1996; Villemin and Alloum 1990; Lerestif et al. 1997) have added a practical dimension to the microwave heating protocols by accomplishing reactions under solvent-free conditions. In these reactions organic compounds adsorbed on the surface of inorganic oxides, such as alumina, silica and clay, or ‘doped’ supports absorb microwaves whereas the solid support does not absorb or restrict their transmission. These solventless MW-assisted reactions provide an opportunity to work with open vessels thus avoiding the risk of high pressure development and increasing the potential of such reactions to upscale. The solvent conservation made possible by these reactions can have a large impact on reducing waste discharge since solvents are often used in quantities 50–100 times those of the reacting materials. Herein, we describe results from our laboratory on an environmentally benign MW approach for the synthesis of a wide variety of industrially important compounds and intermediates namely, enones, imines, enamines, nitroalkenes, oxidized sulfur species and heterocycles which, when otherwise obtained by conventional procedures contribute to the burden of chemical pollution. Thus, the problems associated with the waste disposal of solvents (used several fold in chemical reactions) and excess chemicals are avoided or minimized.

2 Materials All the reactions described hereunder are performed at atmospheric pressure in open glass containers (test tubes, beakers and round-bottomed flasks) using neat reactants R. S. Varma under solvent-free conditions in an unmodified houseDepartment of Chemistry and Texas Research Institute for hold MW oven (2450 MHz, 800 or 900 Watts) on a gram Environmental Studies Sam Houston State University, Huntsville, Texas 77341-2117, USA scale. The results from MW-expedited reactions are e-mail: chm rsv6shsu.edu compared with those obtained under classical heating conditions by conducting the same reaction in an oil I am grateful for financial support to the Texas Advanced bath at the same temperature. The catalysts and reagents Research Program (ARP) in chemistry (Grant # 003606-023), the such as alumina, silica gel, montmorillonite K 10 clay, Retina Research Foundation, Houston and the Texas Research NaIO4-silica, NaBH4, CuSO4, (NH4)2S2O8 and H2O2 etc. Institute for Environmental Studies (TRIES). I am indebted to are used as received from Aldrich Chemical Co. Clayseveral associates and students, whose names appear in the supported iron(III) nitrate (clayfen) and copper(II) references, for their invaluable contribution. Received: 20 October 1998 / Accepted: 27 December 1998

R. S. Varma: Solvent-free organic syntheses on mineral supports using microwave irradiation

nitrate (claycop) are prepared according to the literature procedure (Balogh and Laszlo 1993). The products characterization is accomplished by comparison of the physical and chemical properties of the ensuing entities with the known samples or alternatively, in the case of new molecules, by spectroscopic analysis.

4.2

Deacylation of benzaldehyde diacetates

The deprotection of aldehyde diacetates has been reported often using toxic reagents namely boron triiodide-N,N-diethylaniline complex (Narayan et al. 1990) and ceric ammonium nitrate (CAN) on silica gel (Cotelle and Catteau 1992). The former gives poor yields (60–65%), whereas the latter fails in several instances and usually requires the presence of protic solvents that 3 Methods, results and discussion The practical feasibility of the approach has been demon- generates undesirable quinones. In contrast, we have strated by performing useful deprotection (cleavage) developed the simplest deprotection approach known to reactions of protected organic functional groups on inor- date using chromatography grade neutral alumina and ganic oxide surfaces as well as condensation, cyclization, microwaves where the regeneration of benzaldehydes is oxidation and reduction reactions using MW irradiation. completed in less than 1 min (Varma et al. 1993a) The general procedure essentially involves a simple (Scheme 2). mixing of neat reactants with the catalyst or their adsorpCHO CH(OCOCH3)2 tion on to mineral or ‘doped’ supports. The work-up procedure entails a simple extraction of the products R1 R1 Neutral Alumina from supports or passing the material through a small MW, 30 - 40 s bed of appropriate column, typical processes for the R3 R3 (88 - 98%) purification of organic compounds. In some cases, the R2 R2 products can be simply distilled from the reaction vessel. R1 = R2 = R3 = H; R1 = R3 = H; R2= CH3 R1 = R3 = H; R2 = OCOCH3; R1 = R3 = OMe; R2 = H R1 = R3 = H; R2 = NO2; R1 = R3 = H; R2 = CN

4 Deprotection (cleavage) reactions Deprotection reactions form an impotant part of synthetic strategy for the preparation of monomer building blocks, fine chemicals and precursors for pharmaceuticals. These reactions are often carried out using acidic, basic or hazardous, corrosive reagents and toxic metal salts. We have successfully demonstrated the solvent-free MW-assisted deprotection of protected alcohols and phenols (Varma et al. 1993d), aldehydes and ketones (Varma et al. 1997a; Varma and Saini 1997a; Varma and Meshram 1997a, 1997b) including facile debenzylation (Varma et al. 1993b) and desilylation reactions (Varma et al. 1993c).

4.1

Deacylation reactions

The protection of hydroxyl group is a common reaction in the organic synthesis. Consequently, numerous methods are available in the literature (Green and Wuts 1991a) for regeneration of alcohols. Using a MW approach, even an orthogonal deprotection of alcohols can be achieved easily on neutral alumina surface (Scheme 1). Interestingly, chemoselectivity between alcoholic and phenolic groups in the same molecule can be achieved simply by varying the time of microwave irradiation; the phenolic acetates are deacetylated faster than alcoholic analogues (Varma et al. 1993d). (CH2)3

OR

Alumina MW, 30 s

RO

(CH2)3

OR

(CH2)3

OH

Alumina MW, 2.5 min

HO Where R = COCH3

HO

Scheme 1. Facile deacylation reaction on alumina surface promoted by microwaves

The optimization of relevant parameters such as the power level of microwave employed and pulse techniques (multistage, discontinuous irradiation to avoid the generation of higher temperatures) can be used to obtain the desired results in particular cases.

CH CH

CH(OCOCH3)2

CH

CH CHO

Neutral Alumina MW, 40 s, 92% yield

Scheme 2. Regeneration of aldehydes from 1,1-diacetate derivatives on alumina

A variety of arylaldehyde diacetates are easily deprotected on neutral alumina surface upon MW irradiation (Scheme 2). When R2 is OCOCH3, the diacetate is selectively removed in 30 s of MW irradiation, whereas both the diacetate and the ester groups are cleaved in 2 min of irradiation. The deprotection method is also applicable to the molecules encompassing olefinic moieties such as cinnamaldehyde diacetate and is efficiently deprotected in merely 30 s. The yields, in all the cases examined, are better than those obtained by conventional methods.

4.3

Debenzylation of carboxylic esters

The benzylic group provides a useful protection for the phenolic and carboxylic functionalities. Several methods namely catalytic hydrogenolysis, K2CO3, AlCl3, Na-NH4, Aq. CuSO4-EDTA, t-BuMe2SiHPd(OAc)2 and electrolytic reduction have been used for the debenzylation reaction (Green and Wuts 1991b). The promising solvent-free debenzylation of esters realized in our laboratory (Varma et al. 1993b) (Scheme 3) paves the way for the possible cleavage of the 9-fluorenylmethoxycarbonyl (Fmoc) group in protected amines by changing the surface characteristics of the support. The optimum conditions for cleavage of N-protected moieties require the use of basic alumina and irradiation time of 12–13 min at F130–140 7C. This approach, that may find application in peptide bond formation, would eliminate the use of irritating and corrosive chemicals such as trifluoroacetic acid and piperidine.

133

Clean Products and Processes 1 (1999)

CH CH CO2CH2Ph

CO2CH2Ph

7 min/Acidic, 92% (20 min)a


CH2CH2CO2CH2Ph

CO2CH2Ph

4.5

OMe

The chemistry of carbonyl compounds has a central role in organic synthesis. The carbonyl groups are normally protected by various strategies during the course of reactions that involve strong nucleophiles, acidic, basic, or organometallic reagents and oxidants. The cyclic thioacetals and ketals are among the most useful protecting groups although some stable derivatives such as imines, hydrazones and semicarbazones are also used that involve stringent conditions for deprotection.


NH2CHRCO2CH2Ph When R = H 4 min/Neutral, (95%) (10 min)a

134

OH

4.5.1

When R = CH2OH 3 min/Neutral, (92%) (10 min)a

10 min/Acidic, (92%)

Scheme 3. Cleavage of benzyl esters by microwave thermolysis on alumina. Time in parentheses refers to deprotection in oil bath at the same temperature

4.4

Desilylation and deacylation of protected alcohols

The tert-butyldimethylsilyl (TBDMS) group is one of the most widely used selective protecting group for the hydroxyl group in the organic synthesis. A variety of methods are available in the literature to cleave this protection for the regeneration of alcohols (Corey and Venkateswarlu 1972; Corey and Yi 1992). A few of the prominent methods use, tetramethylammonium fluoride/ THF, KF/crown ethers, HF/CH3CN, NaN3/DMF, NaH/ HMPA, catalytic transfer hydrogenation, ammonium fluoride/MeOH, tetrafluorosilane gas, KF/alumina. These protocols are cumbersome, time consuming and some of them involve toxic and corrosive reagents. We have discovered an environmentally benign method in which tert-butyldimethylsilyl (TBDMS) ether derivatives of a variety of alcohols are rapidly deprotected on alumina surface under MW irradiation conditions in 68–93% yields (Varma et al. 1993c) (Scheme 4). The approach eliminates the use of corrosive naked fluoride ions normally used in this cleavage reactions. R1

CH2OTBDMS

R R = OTBDMS; R1 = CHO, COCH3, (CH2)3OTBDMS 10-11 min, (78-93%)

(10 min, 93%)

TBDMSO O

CH3

R

OH R = Thymine, Adenine (11-18 min, 68-75%)

CH3

TBDMS

Regeneration of other carbonyl compounds

O (11 min, 93%)

Scheme 4. Microwave-assisted cleavage of the t-butyldimethylsilyl groups

Dethioacetalization

Among the regeneration of carbonyl compounds, the cleavage of acid and base stable thioacetals and thioketals are unique. The deprotection of thioacetals invariably requires the use of toxic heavy metals such as Hg c2, Ag c2, Ti c4, Cd c2, Tl c3, or reagents such as benzeneseleninic anhydride (Barton et al. 1977). We have achieved this task in high yield via a solid state dethioacetalization process using clayfen (Varma and Saini 1997a) (Scheme 5). R1

S

R3

S

R3

R1

Clayfen

C R2

C

Microwaves

O

R2

Scheme 5. Dethioacetalization with iron(III) nitrate-clay and microwaves Table 1. Dethioacetalization of aldehydes and ketones using clayfen Entry

R1

R2

R3––R3

Time a (sec)

Yield (%)

1 2 3 4 5 6 7

Et Ph Ph Ph 4-MeOC6H4 4-NO2C6H4 4-NO2C6H4

Et H Me Ph H H H

-(CH2)2– -(CH2)2– -(CH2)2– Et-Et -(CH2)2– -(CH2)2– -(CH2)3–

– – – – – 40 –

87 95 97 92 97 97 98

8

-(CH2)2–

–

94

9

-(CH2)3–

20

90

a Dash refers to reactions that are completed by admixing substrates with clayfen at room temperature

4.5.2

Deoximation reactions

The hydrolytic stability of oximes and their important role as protecting groups has provided motivation for the development of newer deoximation reagents such as pyridinium chlorochromate-H2O2, triethylammonium chlorochromate, Raney nickel, trimethylsilyl chlorochromate, dinitrogen tetraoxide, Dowex-50, dimethyl dioxirane (Olah et al. 1993), H2O2 over titanium silicalite-1, zirconium sulfophenyl phosphonate, N-haloamides and bismuth chloride (Boruah et al. 1997). We have accomplished deoximation of aldoximes and ketoximes to the corresponding carbonyl compounds by eco-friendly reagents ‘doped’ on silica surface.


4.5.3

Deoximation using ammonium persulfate on silica

The deprotection of aldoximes and ketoximes (Scheme 6) has been successfully demonstrated on silica surface using relatively benign ammonium persulfate, a reagent that is used in bleaching and pollution treatment. The neat oximes are mixed with the reagents and the contents are irradiated at full power in a microwave oven to regenerate pure aldehydes or ketones in high yields (Varma and Meshram 1997a). Our results are summarized in Table 2. R1

(NH4)2S2O8–Silica C

N

R1

OH

C Microwaves

R2

O

R2

Scheme 6. Solid state deoximation with persulfate-silica and microwaves Table 2. MW-assisted deoximation using ammonium persulfate-silica Entry

R1

1 2 3 4 5 6 7 8 9 10

R2

Ph Me Ph H Me 4-ClC6H4 Me 4-MeOC6H4 Me 4-MeC6H4 H 4-NO2C6H4 3,4-(MeO)2C6H3 H 1-Naphthyl H 2-Thienyl H Tetraline-1-oxime

Time (min)

Yield (%)

1.5 1.7 1.8 1.5 1.6 0.8 2.5 1.8 1.5 1.8

65 83 72 59 73 66 69 76 75 64

and then drying the reagent in an oven after removal of excess water. The reagent is first wetted with small amount of water and then mixed with neat ketoximes in a small beaker. The reaction mixture is placed in an alumina bath (heat sink) and irradiated in a MW oven for the stipulated time period (Table 3). On completion of the reaction, essentially pure products are obtained by simple extraction from the inorganic support.

4.5.5

Cleavage of semicarbazones and hydrazones

Aldehydes and ketones are also rapidly regenerated in good yields from the corresponding semicarbazone and hydrazone derivatives using ammonium persulfate impregnated on montmorillonite K 10 clay (Scheme 8) under microwave or ultrasound irradiation (Varma and Meshram 1997b). The effective time required for the sonochemical cleavage reaction in hours is reduced to less then 2 minutes using microwaves (Table 4). R1 C

N

NH

R

(NH4)2S2O8 - Clay MW or Ultrasound

R2

R1 C

O

R2

Scheme 8. Regeneration of carbonyl compounds from semicarbazones and phenylhydrazones Table 4. Cleavage of semicarbazones and phenylhydrazones with ammonium persulfate and clay using microwave or ultrasonic irradiation Entry

R1

R2

R

MW (Ultrasound) Time Yield [min (h)] (%)

4.5.4

Deoximation of ketoximes with NaIO4 on silica

In a deoximation reaction that is applicable to only ketoximes, the utility of sodium periodate (NaIO4) on wet silica (Scheme 7) has been demonstrated (Varma et al. 1997c). The reagent is prepared by adding silica gel (230–400 mesh) to a stirred solution of NaIO4 in water R1 C

N

OH

R2

Wet NaIO4–Silica

R1

Microwaves

R2

C

O

1 2 3 4 5 6 7 8 9 10

n-Bu Et n-Bu Et Ph Me Ph Me Me 4-ClC6H4 Me 4-HOC6H4 Me 4-NH2C6H4 4-MeOC6H4CH2CH2 Me –(CH2)5– Tetraline-1-semicarbazone

4.5.6

Dethiocarbonylation

Ph CONH2 Ph CONH2 CONH2 CONH2 CONH2 CONH2 CONH2

1.3 (1.00) 1.3 (2.50) 0.5 (1.50) 0.6 (0.75) 1.8 (3.00) 1.0 (1.00) 1.0 (1.50) 1.6 (3.00) 0.7 (1.50) 1.0 (2.00)

65 (71) 70 (79) 71 (82) 72 (77) 82 (90) 85 (94) 65 (62) 75 (71) 68 (69) 69 (58)

Scheme 7. Deoximation of ketoximes with wet silica supported periodate Table 3. MW-assisted deoximation using silica supported sodium periodate Entry

R1

R2

1 2 3 4 5 6 7 8 9

n-Bu Et Ph Ph Ph Me Me 4-ClC6H4 4-MeOC6H4 Me Me 4-MeC6H4 Me 4-NH2C6H4 Cyclohexyl oxime Tetraline-1-oxime

Time (min) 0.75 1.5 1.5 1.0 2.0 1.0 2.5 1.0

Several reagents such as benzoyl peroxide, sodium peroxide, bromate and iodide solutions, alkaline hydrogen peroxide, bases e.g. KOBu, singlet oxygen, Yield DMSO, trimethyloxonium fluoborate, dimethyl sele(%) noxide, tellurium based oxidants, photochemical transformations, halogen-catalyzed alkoxides under phase 68 transfer conditions, Hg(OAc)2, NaNO2/HCl, clay/ferric 89 80 nitrate (Chalais et al. 1985), CuCl/MeOH/NaOH, tetrabu75 tylammonium hydrogen sulfate/NaOH, and trifluoroacetic 93 anhydride (Masuda et al. 1991) have been used for 82 dethiocarbonylation. The usual limitations of these 83 methods have been the use of toxic oxidants in stoi78 chiometric amounts requiring longer reaction times in 86 cumbersome procedures.

135


O

S Clayfen (Clayan)

R1

R1

90 (60) s, 92-95 (82-87)% R R = H; R1 = Me R = H, Br, Me; R1 = Ph

R

O

R1

O

Clayfen (Clayan)

120 (90) s, 88-91 (82-86) %

R

R1

R O

S R = H; R1 = Ph, 4-MeC6H4, 4-MeOC6H4 R = OMe; R1 = 4-MeC6H4

136

Scheme 9. Dethiocarbonylation with clay ‘doped’ with nitrate salts

clay (Varma et al. 1997a) or a modified clay material, EPZGT, (Varma and Dahiya 1997a) (Scheme 10a, 10b) has been demonstrated by a facile preparation of imines and enamines via the reactions of primary and secondary amines with aldehydes and ketones, respectively, under solvent-free conditions. Microwaves, generated at 2450 MHz frequency, are ideally suited for removal of water in imine- or enamine-forming reactions. For the low boiling reactants, deployment of variable power intensities of microwaves coupled with pulsed techniques have proven useful.

5.1.1

Synthesis of imines

A simple microwave irradiation of a mixture of aldehydes and primary amines in the presence of clay or a ‘doped’ clay material (EPZGT) in open glass containers affords We have also extended our deprotection strategy using imines (Table 5). ‘doped’ clay materials to thioketones. A variety of thioke R2CH2 tones are readily converted into the corresponding K 10 Clay or EPZG R2CH C O + NHR R1 C NR R1 ketones under solvent-free conditions using clayfen or Microwaves, 2-6 min H H clayan. The neat reactants are mixed with the reagents followed by the irradiation in an unmodified household Scheme 10b. Clay-catalyzed formation of enamines using microwave oven (Varma and Kumar 1999) (Scheme 9). microwave irradiation Table 6. Synthesis of enamines using clay or EPZGT as catalysts

5 Condensation reactions 5.1

Synthesis of imines, enamines and nitroalkenes

The imines and enamines are important intermediates in the synthesis of several useful products. These are prepared by the condensation of carbonyl compounds and amines followed by the azeotropic removal of water from the intermediate that is the driving force for the above reactions. The reaction is normally catalyzed by ptoluenesulphonic acid (Cook 1988; Stork et al. 1963; Kuehne 1959), montmorillonite K 10 clay (Dewan et al. 1995), molecular sieves (Taguchi and Westheimer 1971) and titanium(IV) chloride (White and Weingarten 1967), using Dean Stark’s apparatus which requires a large excess of aromatic hydrocarbon solvents such as benzene or toluene for the removal of water. MW-induced acceleration of such dehydration reactions using a catalytic amounts of montmorillonite K 10

Entry

Ketone

Amine

Yield (%)

1 2 3 4 5

Cyclohexanone Cyclohexanone Cyclohexanone Cyclopentanone Cyclopentanone

Morpholine Piperidine Pyrrolidine Piperidine Morpholine

96 90 94 93 94

5.1.2

Synthesis of enamines

In an analogous manner, secondary amines and ketones readily produce enamines (Table 6) that can be elaborated in situ into useful products using microwaves.

5.1.3

Synthesis of nitroalkenes

Another reaction that involves the elimination of water is the Henry reaction (Jones 1967), the condensation of  carbonyl compounds with nitroalkanes to afford nitroalCH CHO H2N K 10 Clay or EPZG N R R kenes. The Henry reaction proceeds rapidly via this + Microwave, 1–3 min microwave approach and requires only catalytic amounts of ammonium acetate in reactions involving neat reacScheme 10a. Clay-catalyzed formation of imines using microtants thus avoiding the use of a large excess of polluting wave irradiation nitrohydrocarbons normally employed as reactants as well as solvent (Varma et al. 1997b) (Scheme 11, Table 7). Table 5. Synthesis of imines using clay or EPZGT as catalysts The reduction, oxidation and cycloaddition reactions Entry R Time Yield of a,b-unsaturated nitroalkenes provide easy access to an array of functionalities such as nitroalkanes, N-substi(min) (%) tuted hydroxylamines, amines, ketones, oximes, and a1 H 1.0 97 substituted oximes and ketones. Consequently, this 2 3 4 5 6

2-OH 4-OH 4-Me 4-NMe2 4-OMe

1.0 3.0 2.5 3.0 2.5

92 91 90 96 95

R

CHO + R1CH2NO2

NH4OAc Microwaves

NO2 R R1

Scheme 11. Facile synthesis of nitroalkenes using microwaves


Table 7. Microwave-assisted synthesis of a,b-conjugated nitroalkenes Entry

R

R1

Time (min)

Yield (%)

m.p. (Lit) ( 7C)

1 2 3 4 5 6 7 8 9 10 11

H H 4-OH 4-OH 4-MeO 3,4-(MeO)2 3,4-(MeO)2 3-MeO-4-OH 3-MeO-4-OH 1-Naphthyl 2-Naphthyl

H Me Me H Me H Me H Me H H

8.0 7.0 3.5 4.0 4.0 2.5 3.0 3.0 3.0 8.0 7.5

80 83 89 88 90 90 92 89 91 80 83

58 (58-9) 64 (64-5) 124 (124-5) 165 (168-9) 44 (44-5) 139 (141-2) 66 (67-8) 166 (167-8) 100 (100-1) 76 (72-74) 121 (121-2)

strategy can provide ready access to several useful precursors and building blocks for fine chemical and pharmaceutical industries (Varma and Kabalka 1986; Kabalka and Varma 1987, Kabalka et al. 1990).

5.2

Expedient synthesis of heterocylic compounds

5.2.1

R1

Synthesis of isoflavenes

Isoflav-3-enes, which possess chromene nucleus, are well known estrogens and several derivatives of these oxygen heterocycles have attracted the attention of medicinal chemists over the years (Lawson 1954; Durani et al. 1979; Grese and Pennington 1995). Despite the existence of several methods for the synthesis of chromenes, there is still demand for development of environmentally friendly synthetic methods for these derivatives. Earlier, we discovered a facile and general method for the synthesis of isoflav-3-enes substituted at 2 position with basic moieties (Dean et al. 1982; Dean and Varma 1982, 1981) (Scheme 12). PhCH2

C O + HN

H OH R

1975). These compounds exhibit an array of biological activity and have proven useful in the treatment of various diseases. Flavones have been synthesized by various methods such as Allan-Robinson synthesis from chalcones and via an intramolecular Wittig strategy (Varma et al. 1998g). The most popular route, however, involves the Baker-Venkataraman rearrangement wherein o-hydroxyacetophenone is benzoylated followed by the base (pyridine/KOH) treatment of the benzoyl ester to effect an acyl group migration to produce a 1,3-diketone (Varma et al. 1998g). The cyclization of the ensuing diketone is usually accomplished under strongly acidic conditions using sulfuric acid and acetic acid to generate the flavone. We envisaged that the development of a facile and clean approach will be beneficial especially for the cyclization step that utilizes benign and readily available starting materials. A solvent-free synthesis of flavones is developed which requires microwave irradiation of o-hydroxydibenzoylmethanes intermediates adsorbed on montmorillonite K 10 clay for 1–1.5 min. The readily and exclusive formation of cyclized flavones occurs in good yields (Varma et al. 1998g) (Scheme 13, Table 8).

+ CHO

PhCH H

C N

MW 2 min

OH

R1

MW, 1-1.5 min

R O

O

K 10 Clay R

O

O R = H; R1 = H, Me, OMe, NO2 R = OMe; R1 = H, Me, OMe

Scheme 13. Clay catalyzed synthesis of flavones from o-hydroxydibenzoylmethanes Table 8. Synthesis of flavones from o-hydroxydibenzoylmethanes on clay Entry

R

R1

Yield (%)

m.p. ( 7C)

1 2 3 4 5 6 7

H H H H OCH3 OCH3 OCH3

H p-CH3 p-OCH3 p-NO2 H p-CH3 p-OCH3

75 77 76 78 73 80 72

96 108–109 155–157 244–245 161 161–162 193–194

PhCH

NH4OAc R MW, 2-6 min

C N H O

N

R = H, Cl, OMe, NO2 N = morpholinyl, piperidinyl, pyrrolidinyl

Scheme 12. One-pot synthesis of 2-aminosubstituted isoflav-3enes

5.2.3

Synthesis of hydroquinolones

Tetrahydro-4-quinolones serve as valuable precursors to The MW approach has now been extended to a several medicinally important compounds. A growing convergent one-pot synthesis of 2-aminosubstituted interest in the synthesis and oxidative cyclization of 2bisoflav-3-enes that involves the generation of the enamine aminochalcones has been stimulated, in part, by the derivatives in situ followed by the reactions with salicypossible transformation of such compounds into 2-aryllaldehydes in the same reaction vessel (Varma and 1,2,3,4-tetrahydro-4-quinolones (Donnelly and Farrel Dahiya 1998a) (Scheme 12). 1990). In a solvent-free cyclization reaction similar to diketones, readily available 2b-aminochalcones can easily be 5.2.2 Synthesis of flavones Flavonoids are a major class of naturally occurring cyclized to 2-aryl-1,2,3,4-tetrahydro-4-quinolones using phenolic compounds that are widely distributed in plant montmorillonite K 10 clay and microwave irradiation kingdom, the most abundant being the flavones (Janzso (Varma and Saini 1997b) (Scheme 14, Table 9).

137


R1 NH2

R2

K-10, Clay MW

C

R1

H N

R2

C

Entry

R

R1

Time (min)

Yield (%)

m.p. ( 7C)

1 2 3 4 5 6 7 8

4-ClC6H4 4-ClC6H4 4-ClC6H4 4-ClC6H4 4-MeOC6H4 4-MeOC6H4 4-MeOC6H4 4-MeOC6H4

H Cl Me OMe H Cl Me OMe

3.0 4.0 5.0 3.0 4.0 3.0 3.0 3.5

90 94 92 90 91 96 92 88

105 144 169–70 139–40 98–99 154 149–50 169–170

O

O

Scheme 14. Synthesis of 2-aryl-1,2,3,4-tetrahydro-4-quinolones on clay Table 9. Preparation of 2-aryl-1,2,3,4-tetrahydro-4-quinolones on montmorillonite K 10 clay under microwave irradiation

138 Entry

R1

R2

m.p. ( 7C)

Lit. m.p. ( 7C)

Yield (%)

1 2 3 4 5 6 7

H Cl Br Me OMe OMe NO2

H H H H H OMe H

148–50 167–68 171 148 146–47 136–37 192–93

149–50 170–71 171 149 waxy solid – 194

80 80 72 77 78 72 70

5.2.4

Table 10. Synthesis of substituted thiazoles from a-tosyloxyketones on clay

5.2.5

Synthesis of substituted thiazoles

Synthesis of thiazoles and their derivatives is generally accomplished by a-haloketones (Fefer and King 1961) or a-tosyloxyketones (Prakash et al. 1992) and thiamides or ethylenethiourea under acidic conditions. However, these methods often involve longer reaction times and suffer from the requirement of the use of lachrymatory a-haloketones and hazardous reagents that generate a waste stream of spent solvents. In view of the pharmacological importance of the thiazoles and the limitations of the use of strong mineral acids under drastic conditions in many previous methods, we have succeeded in optimizing a rapid solvent-free approach to thiazoles by simple mixing of thiamides or ethylenethiourea with a-tosyloxyketones in a clay-catalyzed reaction that is accelerated by MW irradiation. In a typical experiment, thiamides, a-tosyloxyketones and montmorillonite K 10 clay are admixed in a glass tube and the reaction mixture is irradiated in an microwave oven for 3–6 min with intermittent irradiation; substituted thiazoles are obtained in good (89–96%) yields. A clay-catalyzed solid state synthesis of thiazoles from ethylenethioureas and a-tosyloxyketones is similarly achieved in excellent yields that is enhanced by microwave activation (Varma et al. 1998d) (Scheme 15, Table 10). O S R C NH2 + R1

Synthesis of 2-aroylbenzofurans

Among naturally occurring compounds, benzo[b]furans encompass a large group and display a wide variety of valuable pharmacological activity. 2-Aroylbenzofurans, initially isolated from the flower heads of Helichrysum arenarium DC possess a wide range of pharmacological activities (Bisagni et al. 1955). A manipulatively simple synthesis of 2-aroylbenzofurans is achieved by the condensation of a-tosyloxyketones with a variety of salicylaldehydes on potassium fluoride ‘doped’ alumina under solvent-free conditions using microwave irradiation (Varma et al. 1998d) (Scheme 16, Table 11). O R

CHO

OTs

R

R1

KF-Al2O3

+ OH R1

Microwaves

O O

Scheme 16. Synthesis of 2-aroylbenzo[b]furans on potassium fluoride-alumina Table 11. Synthesis of 2-aroylbenzofurans from a-tosyloxyketones Entry

R

R1

Time (min)

Yield (%)

m.p. ( 7C)

1 2 3 4 5 6 7 8

H H H H Cl Cl Cl Cl

H Cl Me OMe H Cl Me OMe

3.0 3.0 2.5 3.5 2.5 2.5 2.5 3.5

94 94 91 89 95 92 96 89

90–91 153–54 95–96 97–98 136–37 184–85 167–68 136–37

H OTs

K 10 Clay R1 Microwaves

6 Oxidation reactions

S N

R

Scheme 15. Synthesis of substituted thiazoles from a-tosyloxyketones

Oxidation reactions are abundantly used in synthesis where the addition of electronegative elements (O, N, or halogens) or loss of electrons or hydrogen occurs. These reactions, conducted in excess of solvents, entail the use of strong oxidants such as acids, peracids, peroxides, halogens, transition metals or their salts which contribute to pollution burden. Consequently, organic chemists have


been exploring selective methods (Marko et al. 1996) with Table 12. Oxidation of alcohols by clayfen under microwave irradiation newer reagents but there is still a need for efficient and cleaner oxidants. Our approach eliminates or reduces the Entry R1 R2 Time Yields use of strong oxidants as exemplified below in several (sec) (%) oxidation reactions.

6.1

Oxidation of alcohols

The oxidation of alcohols to carbonyl compounds is an important transformation in organic synthesis and several methods have been devised to accomplish this conversion (Trost 1991). The conventional oxidizing reagents employed for organic functionalities are peracids, peroxides, manganese dioxide (MnO2), potassium permanganate (KMnO4), chromium trioxide (CrO3), potassium chromate (K2CrO4) and potassium dichromate (K2Cr2O7), although selective methods (Einhorn et al. 1996; Muzart et al. 1994) are sought that are not detrimental to the environment.

1 2 3 4 5 6 7 8

Ph H Ph Et Ph PhCO H 4-MeC6H4 H 4-MeOC6H4 4-MeOC6H4CO 4-MeOC6H4 Tetrahydrofurfuryl H –(CH2)5–

15 30 60 15 – 60 30 30

92 87 93 94 96 94 90 89

Typical experimental procedure for oxidation of alcohols. The oxidation of benzoin is representative of the general procedure employed. Clayfen (0.125 g) was thoroughly mixed with neat benzoin (0.106 g, 0.5 mmol) in the solid state using a vortex mixer and the material was placed in an alumina bath inside the household microwave oven equipped with a turntable and irradiated at full power (900 Watts). Upon completion of the 6.1.1 Selective and solventless oxidation with clayfen reaction, monitored on TLC (hexane:AcOEt, 10 : 1, v/v), the We have developed a facile method for the oxidation of product was extracted into methylene chloride. The bulk alcohols to carbonyl compounds using montmorillonite K temperature of the alumina bath, which serves as a heat sink 10 clay-supported iron(III) nitrate, clayfen, under solvent- and convenient site to hold the reaction vessel inside the microwave oven, reached F65 7C after 30 seconds of irradiation free conditions in a process that is accelerated by MW as measured by inserting a thermometer into the alumina bath.

irradiation (Varma and Dahiya 1997b). The reaction presumably proceeds via the intermediacy of nitrosonium ions and no formation of carboxylic acids occurs in the oxidation of primary alcohols. The experimental procedure involves a simple mixing of neat alcohols with clayfen and irradiating the reaction mixtures in a MW oven for 15–60 seconds in the absence of solvent. This extremely rapid, manipulatively simple, inexpensive and selective protocol avoids the use of excess solvents and toxic oxidants. Using clayfen [iron(III) nitrate-clay] in solid state and in amounts that are half that of used earlier (Balogh and Laszlo 1993), carbonyl compounds are obtained in high yields (Varma and Dahiya 1997b) (Scheme 17, Table 12).

Using manganese dioxide-silica, we have achieved an expeditious and high yield route to carbonyl compounds. Benzyl alcohols are selectively oxidized to carbonyl compounds using 35% MnO2 ‘doped’ silica under MW irradiation conditions (Varma et al. 1997d) (Scheme 18, Table 13).

R1

Scheme 18. Oxidation of alcohols with active manganese dioxide-silica

Clayfen CH

R2

OH

Microwaves

R1 C

O

R1 CH

OH

R2

MnO2-Silica Microwave

R1 C

O

R2

R2

Scheme 17. Selective oxidation of alcohols with clayfen and microwaves

6.1.2

6.1.3 Oxidations with activated manganese dioxide (MnO2)

Oxidation reactions with metal oxides

Metal-based reagents have been extensively used in organic synthesis. The utility of such reagents in the oxidative transformation is compromised due to their inherent toxicity, cumbersome preparation and potential danger (ignition or explosion) in handling of its complexes, difficulties in terms of product isolation and waste disposal. Introduction of metallic reagents on solid supports has circumvented some of these problems and provided an attractive alternative in organic synthesis in view of the selectivity and associated ease of manipulation. Further, the immobilization of metals on the surface avoids their leaching into the environment.

Table 13. Solvent-free oxidation of alcohols using MnO2–silica Entry

R1

1 2 3 4 5 6 7 8 9

Ph H Ph Et Ph Ph Ph PhCO PhCHpCH H H 4-MeC6H4 H 4-MeOC6H4 4-MeOC6H4CO 4-MeOC6H4 Hydroquinone

6.1.4

R2

Time (sec)

Yields (%)

20 60 45 50 50 45 30 45 36

88 84 85 86 67 81 83 85 76

Oxidations with claycop-hydrogen peroxide

Metal ions play a significant role in many of these reactions as well as in biological dioxygen metabolism. Copper(II) acetate and hydrogen peroxide (H2O2) have

139


been used to produce a stable oxidizing agent, hydroperoxy copper(II) compound, which is also obtainable from copper(II) nitrate and hydrogen peroxide (Eq. 1) (Capdevielle and Maumy 1990). The ensuing nitric acid requires neutralization by potassium bicarbonate to maintain a pHF5.

140

Table 15. Oxidation of alcohols with wet CrO3–alumina Entry

R1

1 2 3 2 Cu (NO3)2cH2O2c2 H2O ] 2 CuO2Hc4 HNO3 (1) 4 5 Copper(II) nitrate impregnated on K 10 clay 6 (claycop)-hydrogen peroxide system is an effective 7 reagent for the oxidation of a variety of substrates and 8 provides excellent yields of products (Varma and Dahiya 9

R2

Ph Ph Ph Ph 4-MeC6H4 4-MeOC6H4 4-NO2C6H4

H Ph Me PhCO H H H –(CH2)5– Tetraline-1-ol

1998b) (Scheme 19, Table 14). The method does not require the maintenance of pH of the reaction mixture. Using 0.8 mmol equivalents of the copper(II) nitrate,

6.1.6

Time (sec)

Yield (%)

– 35 – 30 – – 40 40 –

76 87 84 72 83 80 76 90 87

Oxidation with iodobenzene diacetate on alumina

Iodoxybenzene, o-iodoxybenzoic acid (IBX), bis(trifluorR1 R1 oacetoxy)-iodobenzene (BTI) and Dess-Martin periodiClaycop–H2O2 CH R3 C O nane (Munari et al. 1996; Dess and Martin 1983) are the Microwaves R2 R2 common organohypervalent iodine reagents which have been used for the oxidation of alcohols and phenols in Scheme 19. Oxidations with claycop and hydrogen peroxide solution phase chemistry. Also, IBX has been reported to be explosive under heavy impact and heating over 200 7C. Table 14. Oxidation of organic substrates by claycop and However, the use of iodobenzene diacetate (IBD) in this hydrogen peroxide area, in spite of its low cost, has not been fully exploited. We have optimized a rapid and facile oxidation of Entry R1 R2 R3 Time Yields alcohols to carbonyl compounds using alumina(min) (%) supported IBD as an oxidant under solvent-free conditions using MW irradiation in quantitative yields (Varma 1 Ph H COOH 1.00 83 et al. 1998b). The importance of alumina can be visual2 Ph Ph COOH 1.30 82 3 Ph H CN 0.75 80 ized by the comparison of the yields obtained from the 0.50 76 4 Ph H NH2 reactions with alumina-IBD and neat IBD (Scheme 21, 5 Ph H Br 0.50 75 Table 16). Interstingly, 1,2-benzenedimethanol undergoes H H 1.30 69 6 4-NO2C6H4 cyclization under these conditions to afford 1(3H)7 Triphenylphosphine 0.25 85 isobenzofuranone. 8 Hydroquinone 0.50 71 R1

phenyl acetonitrile is converted into phenylacetic acid.

6.1.5 Oxidations with chromium trioxide impregnated on wet alumina Chromium trioxide (CrO3) impregnated on pre-moistened alumina is yet another oxidizing agent which oxidizes benzyl alcohols by simple mixing at room temperature (Scheme 20). The reactions are relatively clean with no tar formation, typical of many CrO3 oxidations. Interestingly, no overoxidation to carboxylic acids is observed (Varma and Saini 1998). The mole ratio of the subtrate and the reagent used is 1 : 2 except in case of benzoin where a mole ratio 1 : 3 is used. Our results are summarized in the Table 15. R1 CH R2

Wet CrO3-Al2O3 OH

Microwaves

R1 C

O

R2

Scheme 20. Chromium trioxide oxidations on premoistened alumina

R1

IBD/Alumina CH

OH

R2

C

Microwaves

O

R2

Scheme 21. Oxidation of alcohols by iodobenzene diacetatealumina system

Table 16. Oxidation of alcohols with IBD on alumina under MW irradiation Entry

1 2 3 4 5 6 7 8 9 a

R1

R2

PhI (OAc)2

Al2O3PhI(OAc)2

Time (min)

Yields (%)

Time (min)

Yield (%)

89 83 90 88 91 81 a

1.0 2.0 2.0 1.0 2.0 1.5 3.0 1.0 0.5

94 89 90 92 95 86 96 69 43

Ph H 2.0 Ph Et 2.0 Ph PhCO 2.0 H 2.0 4-MeC6H4 4-MeOC6H4 H 1.5 1,2-benzenedimethanol 1.5 Anisoin Hydroquinone Catechol mixture of products formed

a a


6.1.7 Oxidations with copper sulfate or oxoneT on wet alumina The oxidative transformation of benzoins to benzils has been accomplished by a variety of reagents such as nitric acid, thallium(III) nitrate (TTN) (McKillop et al. 1973), nickel acetate (Hammond and Wu 1973), ytterbium(III) OH

O

 R2 CuSO4–Al2O3 or Oxone –Al2O3

R1

R2 R1

Microwave O

O

Scheme 22. Solid state oxidation of a-hydroxyketones with copper sulfate or OxoneT-‘doped’ alumina Table 17. Solvent-free oxidation of alcohols using OxoneT and microwaves Entry R1

R2

CuSO4–Al2O3 OxoneT-Al2O3 Time Yield Time Yield (min) (%) (min) (%)

1 2 3 4 5 6 7 8 9

Me Ph Ph Ph 4-MeC6H4 4-MeOC6H4 4-MeOC6H4 4-ClC6H4 2-Furanyl

Ph Ph 4-MeC6H4 4-MeOC6H4 4-MeC6H4 4-MeC6H4 4-MeOC6H4 4-ClC6H4 2-Furanyl

2.0 2.0 3.0 2.5 2.0 1.5 2.5 3.5 2.5

92 96 81 85 92 90 86 82 82

3.0 2.0 2.5 2.0 3.0 2.0 3.0 2.0 2.0

71 88 72 81 73 80 77 79 78

hydrogen peroxide, dinitrogen tetraoxide, chromic acid, ozone, peracids, periodates, chromium trioxide-acetic acid and ruthenium trichloride, HOF-CH3CN (Whitaker and Sisler 1960; Leonard and Johnson 1962; McKillop and Tarbin 1983; Su 1994; Rozen and Bareket 1994). Besides extended reaction period, most of these processes suffer from the drawbacks such as the use of corrosive and hazardous acids, peracids, and toxic metallic compounds that generate waste streams. Consequently, there is a need for the development of environmentally friendly solvent-free methods.

6.2.1

Oxidation with sodium periodate

This oxidative transformation is accomplished with desired selectivity either to sulfoxides or sulfones using 10% sodium periodate ‘doped’ on silica and by varying the power of MW irradiation and reaction time (pulsed techniques) (Varma et al. 1997e). Consequently, a much reduced amount of the active oxidizing agent is employed that is safer to handle (Scheme 23, Table 18). Interestingly, various refractory thiophenes that are often not reductively removed by conventional refining processes can be oxidized under these conditions e. g. benzothiophenes are oxidized in solid state to the corresponding sulfoxides and sulfones using ultrasonic and microwave irradiation, respectively, in the presence of NaIO4-silica. A noteworthy feature of the protocol is its applicability to long chain fatty sulfides which are insoluble in most solvents and are consequently difficult to oxidize using conventional solution phase chemistry. O

R-SO2-R1

20% NaIO4-Silica (3.0 eq.) Microwaves

R-S-R1

20% NaIO4-Silica (1.7 eq.) Microwaves

nitrate (Girard and Kagan 1975) and ammonium chlorochromate-alumina (Zhang et al. 1997). Most of these processes entails the use of corrosive acids and toxic metallic compounds that generate undesirable waste materials. Consequently, the oxidation of benzoins can benefit from the development of a manipulatively easy and an environmentally benign solvent-free protocol. Both symmetrical and unsymmetrical benzoins are rapidly oxidized to benzils in high yields by solid reagent systems, copper(II) sulfate-alumina (Varma et al. 1998c) or OxoneT-wet alumina (Varma et al. 1998a) under the influence of microwaves (Scheme 22). Interestingly, under these solid state reaction conditions, primary alcohols e.g. benzyl alcohol and secondary alcohols e.g. 1-phenyl-1-propanol undergo only limited oxidative conversion which is of little practical utility. Apparently, the process is applicable only to a-hydroxyketones as exemplified by various substrates including a mixed benzylic/aliphatic a-hydroxyketone, 2-hydroxypropiophenone that affords the corresponding vicinal diketone (Table 17).

6.2

Oxidation of sulfides

Sulfides are usually oxidized to sulfoxides under drastic conditions using strong oxidants like nitric acid,

R-S-R1

Scheme 23. Oxidation of sulfides to sulfoxides and sulfones with periodate-silica

Table 18. Oxidation of sulfides to sulfoxides and sulfones using wet NaIO4–silica Entry

1 2 3 4 5 6 7 8

R

R1

n-Bu n-Bu n-C12H25 Me Ph Me Ph Ph Ph PhCH2 PhCH2 PhCH2 –CH2–CH2–CH2–CH2– Dibenzothiophene

Sulfoxides

Sulfones

Time (min)

Yield (%)

Time (min)

Yield (%)

0.7 1.25 2.0 2.0 2.5 2.5 0.5 –

76 80 80 85 83 80 82 –

1.0 2.5 2.5 2.4 2.5 3.0 1.0 3.0

72 80 82 93 87 80 72 74

6.2.2 Oxidations of sulfides with iodobenzene diacetate on alumina Solid reagent system, IBD-alumina, is a useful oxidizing agent under solvent-free conditions as described earlier for alcohols (section 3.1.6) and can be effectively used for expeditious and selective oxidation of alkyl, aryl and cyclic sulfides to the corresponding sulfoxides in excellent yields under MW activation (Varma et al. 1998f) (Scheme 24, Table 19).

141


O PhI(OAc)2-Alumina

R1—S—R2

R1—S—R2

Microwaves

Scheme 24. Selective oxidation of sulfides to sulfoxides with IBD-alumina system Table 19. Oxidation of sulfides using IBD-alumina under microwave irradiation Entry

R1

R2

1 2 3 4 5 6 7 8 9

i-Pr n-Bu Ph Ph PhCH2 PhCH2 n-C12H25

142 i-Pr n-Bu Me Ph Ph PhCH2 Me –(CH2)4– –(CH2)3CO(CH2)3–

6.2.3

Time (sec)

Yield (%)

40 40 45 90 90 90 90 – 90

80 82 82 88 86 90 88 82 85

Oxidations of sulfides with clayfen

Alkyl, aryl and cyclic sulfides are also rapidly oxidized to the corresponding sulfoxides in high yields upon microwave irradiation with iron(III) nitrate impregnated on clay (clayfen) under solvent-free conditions; the conversion also occurs in refluxing methylene chloride (CH2Cl2) but requires much longer time period for completion of the reaction (Varma and Dahiya 1998c) (Scheme 25, Table 20).

also been achieved by mixing carbonyl compounds with NaBH4 and storing the mixture in a dry box for five days (Toda et al. 1989). The major disadvantage in the heterogeneous reaction with NaBH4 is that solvent reduces the reaction rate while in the solid state reactions time required is too long (5 days) for it to be of any practical utility.

7.1 Reduction of carbonyl compounds with sodium borohydride We have developed a facile method for the reduction of aldehydes and ketones by alumina supported NaBH4 (Varma and Saini 1997c) that proceeds in the solid state using microwaves. The process in its entirety involves a simple mixing of carbonyl compound with (10%) NaBH4alumina and irradiating the mixture in an unmodified household MW oven for the time specified (Scheme 26). The useful chemoselective feature of the reaction is apparent from the reduction of trans-cinnamaldehyde (cinnamaldehyde/NaBH4-alumina, 1 : 1 mol equiv.); olefinic moiety remains intact and only the aldehyde functionality is reduced in a facile reaction that takes place at room temperature (Table 21). No side product formation is observed in any of the reactions investigated and no reaction occurs in the absence of alumina. Further, the recovered alumina can be recycled by mixing with fresh borohydride and reused for subsequent reductions without any loss in activity. The water molecules present on alumina surface facilitate the reaction. The air used for cooling the magnetron ventilates the microwave cavity thus preventing hydrogen from reaching explosive concentrations.

O O

Clayfen R1

S

R2

R1

CH2Cl2 or MW

S

R2

Scheme 25. Oxidation of sulfides with clayfen and microwave irradiation Table 20. Oxidation of sulfides with clayfen and microwave or classical conditions Entry

1 2 3 4 5 6 7 8 9

R1

R2

i-Pr i-Pr n-Bu n-Bu n-C12H25 Me Ph Me Ph Ph Ph PhCH2 PhCH2 PhCH2 –(CH2)4– –(CH2)3CO(CH2)3–

CH2Cl2

MW

Time (h)

Yield (%)

Time (min)

Yield (%)

16 12 18 18 20 23 24 11 12

84 83 88 90 72 84 10 78 79

0.5 – 0.5 0.25 1.0 1.0 1.0 – 1.0

89 86 90 91 75 85 15 81 83

7 Reduction reactions Relatively inexpensive sodium borohydride (NaBH4) has been extensively used as a reducing agent in view of its compatibility with protic solvents and safe nature (Banfi and Riva 1995). The solid state reduction of ketones has

R1

C

R2

NaBH4-Al2O3 Microwaves

OH R1

CH

R2

Scheme 26. Borohydride reduction of carbonyl compounds on alumina Table 21. Solid state reduction of carbonyl compounds using NaBH4-Al2O3 Entry

R1

R2

Substrate/ NaBH4 (equiv.)

Time (sec)

Yield (%)

1 2 3 4 5 6 7 8 9

H H H Cl Me Me NO2 OMe

Me Ph –CH(OH)Ph H H Me H –CH(OH)C6H4-OMe-p 1-Tetralone

1:1 1:5 1:8 1:1 1:1 1:1 1:2 1:5 1:7

30 120 180 – – 90 40 120 120

87 92 79 93 90 90 87 62 85

Typical experimental procedure for reduction of carbonyl compounds The reduction of acetophenone is representative of the general procedure employed: Freshly prepared NaBH4-alumina 1 (1.13 g, 3.0 mmol of NaBH4) was thoroughly mixed with neat acetophenone (0.36 g,


3.0 mmol) in a test tube and placed in an alumina bath inside the household microwave oven (operating at 2450 MHz) equipped with a turntable at full power (900 Watts) and irradiated for 30 s. The bulk temperature of the alumina bath (heat sink) inside the microwave oven reached F70 7C after 30 s of irradiation. Upon completion of the reaction, monitored on TLC (hexane:EtOAc, 8 : 2, v/v), the product was extracted into methylene chloride (2x 15 mL). Removal of solvent under reduced pressure essentially provided pure sec-phenethyl alcohol in 87% yield. Caution: The air used for cooling the magnetron ventilates the microwave cavity thus preventing any ensuing species from reaching explosive concentrations. Although we did not encounter any accident during these studies, we recommend extreme caution for reactions on larger scale 1. 1 (10%) NaBH4-Alumina, was prepared by thoroughly mixing NaBH4 (5.0 g) with neutral alumina (45.0 g) in solid state using a pestle and mortar; admixing three components, carbonyl substrate, NaBH4 and alumina together was equally efficient. The use of premoistened alumina further accelerated the reaction.

R1 R2

C

O + H2N R3

Clay MW, 2 min

R1 R2

C

N

R3

7.2

Reductive alkylation of amines

Reductive alkylation of amines has been well documented with sodium cyanoborohydride (Borch et al. 1971), sodium triacetoxyborohydride (Abdel-Magid et al. 1996) and NaBH4 coupled with sulfuric acid (Giancarlo et al. 1993) which either produce waste stream or involve the use of corossive acids. Recently, zinc borohydride (Ranu et al. 1997) prepared from sodium borohydride has been used for the reduction of imines. In continuation of our ongoing program to develop eco-friendly methods, we have conducted a solvent-free reductive amination of carbonyl compounds by wet montmorillonite K 10 clay supported sodium borohydride activated by microwave irradiation (Varma and Dahiya 1998d) (Scheme 27, Table 22). The practical applications of the reducing ability of NaBH4 supported on K 10 clay surface for the reduction of in situ generated Schiff’s bases via the solid state reductive amination of carbonyl compounds have been realized (Varma and Dahiya 1998d). Clay not only behaves as a Lewis acid but provides water from its interlayers that is responsible for the acceleration of the reducing ability of NaBH4.

NaBH4–Clay

R1

H2O, MW

R2

CH

N

R3 H

Scheme 27. Reductive amination of carbonyl compounds with borohydride on clay

Table 22. Reductive alkylation of amines using NaBH4 supported on K 10 clay R1

R2

R3

Time a (min)

Yield (%)

1 2

Ph Ph

H H

Ph n-C7H15

– –

97 94

3

Ph

H

1.50

90

4 5 6 7 8 9 10 11 12 13 14

2-HOC6H4 2-HOC6H4 4-ClC6H4 4-ClC6H4 4-MeOC6H4 4-MeOC6H4 4-NO2C6H4 3,4-(MeO)2C6H3 i-Bu (C2H5)2CHCH2 (C2H5)2CHCH2

H H H H H H H H H H H

– 1.00 0.50 0.75 0.25 0.75 1.25 0.50 1.00 0.75 1.50

96 88 90 84 93 81 78 91 78 87 86

15

2-Pyrrolyl

H

1.50

81

16 17 18 19 20

Ph Ph –(CH2)5– –C2H5CH(Me)C2H5– –(CH2)5–

Me Me

Ph PhCH2 Aniline PhCH2 n-C3H7

1.50 2.00 1.00 2.00 0.75

92 66 89 85 79

PhCH2

1.50

91

Ph Morpholine Piperidine

1.00 2.00 2.00

83 81 78

Entry

21 22 23 24

Et n-C5H11 n-C5H11

Et Me Me

Ph 4-NO2C6H4 Aniline 4-HOC6H4 Ph 4-HOC6H4 Aniline 4-ClC6H4 Ph Ph n-C10H21

a Time for the reduction of in situ generated Schiff’s bases in microwave oven. The dash refers to the reductions at room temperature that are completed on simple mixing of the Schiff’s base with NaBH4-wet clay

143


8 Miscellaneous reactions 8.1 A single step conversion of arylaldehydes to aromatic nitriles

144

NO2

Clayfen (Clayan) oil bath or MW

X

The conversion of aldehydes to the corresponding nitriles is well documented in the literature. This transformation is accomplished by the conversion of aldehydes to aldoximes followed by dehydration using a wide variety of reagents namely chloramine/base, O,N-bis-(trifluoroacetyl)-hydroxylamine or trifluoroacetohydroximic acid, triethylamine/dialkyl hydrogen phosphinates, triethylamine/phosphonitrilic chloride, TiCl4/pyridine, p-chlorophenyl chlorothionoformate/pyridine, (H2SO4/SiO2), 1,1bdi-carbonylbiimidazole and TiCl4/pyridine (Mowry 1948; Sampath Kumar et al. 1997; Friedrich and Wallensfels 1970). In most of these conventional methods, the dehydration of aldoxime generally proceeds at a much slower rate requiring long reaction times. Arylaldehydes bearing both electron releasing and electron withdrawing substituents, are rapidly converted into nitriles in good yields (89–95%) with clay supported hydroxylamine hydrochloride coupled with MW irradiation in the absence of solvent (Varma and Naicker 1998) (Scheme 28, Table 23).

CHO

+ X

A

X

B

C

Scheme 29. Solid state nitration of styrenes using clay impregnated with nitrate salts

Table 24. Product distribution in the nitration of styrenes under solvent-free conditions using clayfen and clayan Entry

1 2 3 4

Clayfen

Clayan

A

B

C

B

C

Styrene p-Chlorostyrene p-Methylstyrene p-methoxystyrene

68 (56) 52 (41) 52 (41) 14 (14)

21 (35) 10 (22) 11 (24) 09 (150)

59 (47) 49 (37) 44 (35) 13 (12)

20 (35) 11 (23) 15 (26) 12 (15)

Reaction conditions: for clayfen, 15 min in oil bath and 3 min in MW at 100–110 7C and for clayan, 15 min in oil bath and 3 min in MW at 60–67 7C. The relative amounts of product formation are determined by GC-MS analysis and the results in the parentheses refer to the corresponding yields obtained using MW irradiation

O R1 R2

C

H

K10 Clay–NH2OH.HCl Microwaves

R1

C

R2

Scheme 28. A one-pot direct conversion of arylaldehydes to nitriles

N

It appears that gradual heating in the above reaction provides a better result (Table 24) when compared to microwave heating.

9 Conclusion

The above summary of recent research activity from our laboratory highlights the eco-friendly features of these solvent-free reactions that are activated by exposure to Entry R1 R2 Time Yields microwave irradiation. The solventless approach using a variety of supported reagents on mineral oxides paves the (min) (%) way for conducting efficient and selective organic func1 H H 1.5 92 tional group interconversions in an expeditious manner. 2 H OH 1.5 91 The work described above is performed using an unmod3 H Br 1.5 91 ified household microwave oven (multimode applicator) 4 H Me 1.5 89 and demonstrates the immediate practical applications in 5 H OMe 1.0 95 research laboratory setting. Additional research by others 6 H NO2 1.5 92 does point out the advantages of using monomode 7 OMe OMe 1.0 93 systems with focused electromagnetic waves (Prolabo) 8 Cinnamonitrile 1.5 91 where relatively large scale reactions (1 liter capacity) can be conducted (Liagre et al. 1998) with improved features of MW devices such as temperature/power control and 8.2 Solvent-free side chain nitration of styrenes A facile solvent-free synthesis of b-nitrostyrenes is options for continuous operation. The industrial applicadescribed from styrene and its substituted derivatives tions of MW-expedited clean chemistry include the using inexpensive ‘doped’ clay reagents, clayfen and preparation of hydrogen cyanide, a chlorination plant, clayan (Varma et al. 1998e) (Scheme 29, Table 24). In a pasteurization of food products and the drying of phartypical experiment, the neat styrene and the clay ‘doped’ maceutical powders. The engineering and scale-up with nitrate salts is mixed in a glass container and the aspects for the chemical process development have also solid mixture is heated in an oil bath (F100–110 7C, been discussed (Mehdizadeh 1993). 15 min) or irradiated in a microwave oven (F100–110 7C, Although not delineated completely, the reaction rate 3 min). In the case of clayan, intermittent warming is enhancements achieved in these methods may be ascribrecommended with 30 seconds intervals to maintain able to non-thermal effects and are being investigated at temperature below 60–70 7C. Interestingly, the reaction the present time. These solvent-free protocols do have occurs only in solid state and leads to polymeric products the distinct advantage in terms of the reduction or elimiin the presence of solvents. nation of solvents thereby preventing pollution ‘at Table 23. One pot synthesis of nitriles from arylaldehydes and hydroxylamine


source’. The preparation of high value chemicals via chemo-, regio- or stereoselective synthesis may provide the impetus for the translation of these laboratory experiments to large-scale plant production. These endeavors would require a multi-disciplinary effort from a team of chemical and electrical engineers working in close association with chemists to harness the true potential of this clean technology.

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