new pathways for organic synthesis || formation of heterocyclic compounds

Chapter 4

Formation of Heterocyclic Compounds

4.1. Introduction

Whereas the formation of carbon-carbon bonds using transition metal intermediates has been relatively well studied, the synthesis of heterocyclic compounds using transition metals has attracted much less attention. Indeed in recent years only two reviews on the subject have appeared. 1 As the demand for new heterocyclic compounds increases, particularly for pharmaceutical and crop protection chemicals, then the use of transition metal species might well offer advantages over the more conventional routes in terms of milder reaction conditions, better selectivity, novel synthetic routes, or the use of more readily available starting materials. Already attractive new routes to known compounds have been discovered using transition metal catalysts. One area which could be commercially important, for example, is the cobalt-catalyzed synthesis of pyridines from acetylenes and nitriles. 2

At first sight the lack of information on the transition-metal-catalyzed synthesis of heterocyclic compounds appears understandable since many metal catalysts are inhibited when hetero atoms such as nitrogen, oxygen, and sulfur are present in the substrate. This chapter, however, will show that a variety of transition metals have been used both as catalysts and as stoichiometric reagents for the synthesis of nitrogen-, oxygen-, and sulfurcontaining heterocyclic compounds. Since the area is relatively new and few reviews are available, some of the work that will be described is of a

141 H. M. Colquhoun et al., New Pathways for Organic Synthesis© Plenum Press, New York 1984

142 Chap. 4 • Formation of Heterocyclic Compounds

more speculative nature than in other parts of the book, but it is hoped that it will demonstrate the enQrmous potential for the use of transition metal species in the synthesis of heterocyclic compounds.

To date there appears to be no particular pattern as to the type of metal or metal complex used for the synthesis of heterocyclic compounds, and the examples quoted will illustrate the wide range of transition metals that have been employed. The types of reaction that are involved are ones that appear in other parts of the book, e.g., cyclooligomerization, carbonylation and intramolecular alkylation, but to be of most use to the organic chemist the chapter is arranged in terms of the final organic product.

4.2. Nitrogen Heterocycles

4.2.1. Three-Membered Rings

N -Substituted aziridines (1) can be synthesized by the palladiumpromoted amination of olefins using primary amines, followed by oxidation with bromine.3 Aminopalladation of styrene with methylamine at -50°C gives the u-bonded complex 2, which on subsequent bromination produces

MeNH H

Ph"'1 ~H H PdCI

/\ 2

the aziridine (1; Rl = Ph, R2 = H, R3 = Me). Under similar conditions other ole fins also react; dec-l-ene, for example, gives the corresponding N -methylaziridine in an isolated yield of 43%.

4.2.2. Four-Membered Rings

The synthesis of {3 -lactams, which are of interest in connection with the synthesis of analogs of such antibiotics as penicillins and cephalosporins, has been achieved using a variety of transition-metal-mediated reactions. In the presence of catalytic amounts of Pd(OAch/PPh3 , carbon monoxide

Sec. 4.2 • Nitrogen Heterocycles 143

inserts into various 2-bromo-3-aminopropene (3) derivatives to give the corresponding a -methyl-p -lactams (4) in good yield.4

Pd(OAc)2/PPh3 • co

4

Preparation of N-benzyl-a-methylene-(3-lactam (4; RI = CH2Ph, R2 = H)4 2-Bromo-3(N-benzyl)-aminopropene (3; RI = CH2Ph, R2 = H)

(5.16 mM) and n-Bu3N (6.45 mM) in HMPA (CAUTION, TOXIC) are stirred at 100°C under CO (1 atm) with Pd(OAch (0.1 mM) and PPh3 (0.4 mM) for 5 h to afford N-benzyl-a-methylene-(3-lactam in 67% yield.

Addition of the keten silyl acetal 5 to the Schiff base 6 in the presence of TiCl4 gives, after hydrolysis, the p-amino-ester 7. Treatment of the ester with base gives the p-Iactam 8 in excellent yield. 5

R1CH=NR2 6

R3 + OMe

" / c=c / ". R4 OSIMe3

5

R1CHNHR2

I R3 -C-CO Me

I 2

R4 7

base --+

Preparation of 3,3-Dimethyl-1,4-diphenyl-2-azetidinone (8; R \ R2 = Ph, Rl, R4 = Me)s

To a 1 M solution of TiCl4 in CH2Cb (20 ml; 20 mM) is added dropwise a dichloromethane solution (20 ml) of benzylideneaniline (3.62 g; 20 mM) at room temperature with stirring. To the dark red solution is added dimethylketene methyl trimethylsilyl acetal (3.48 g, 20 mM) in CH2Cl2 (10 ml) and the mixture stirred for 1 h. After pouring into ice water the organic layer is washed with water, dried over MgS04 , and concentrated under reduced pressure. The residual crystals, after washing with pentane, give 4.79 g (85%) of the ester (7; RI, R2 = Ph; Rl, R4 = Me). This ester is dissolved in THF (30 ml) and the solution added to a solution of lithium diisopropylamide (17 mM) in n-hexane/THF (1: 1) (25 ml) at O°C with stirring. After 10 min the reaction mixture is poured into ice water and extracted with CH2Cl2 to give, after the usual work-up, 3,3-dimethyl-1,4-diphenyl-2-azetidinone (4.04g; 95%).


Nucleophilic addition of benzylamine to the complex 9 leads to the intermediate 10, which' is oxidized at -78°C with chlorine to give the p-Iactam (11) in 34% overall yield. 6 The reaction is stereospecific; for example, trans-but-2-ene (9; Rl, R3 = Me, R2 = H) gives only cis-3,3-dimethylazetidinone (11; Rl, R3 = Me, R2 = H).

R3 H R2 ~ Rl " / C=C

PhCH2NH2 , " " / Ci2 R3_C-C --/ I "Rl R +Fp

/ " -78' +NH 2 Fp

9 /

PhCH 2 10

Fp = ['I' -C,H,Fe(C0121

4.2.3. Five-Membered Rings

The substituted allylic acetate 12 cyclizes in the presence of catalytic amounts of Pd(PPh3)4 to produce the bicyclic compound 13 in over 50% yield.7 Moreover, only the cis product is formed. Cyclization of the related compounds 14 gives the isoquinuclidine skeleton (15) in -60% yield.

H

Pd(PPh,l. ~ Et)N • V-N/ Ph

OAc

()~~. 14

--15

H 'v 13

Isonitriles having an active a- hydrogen react with a,p -unsaturated esters or nitriles in the presence of catalytic amounts of cuprous oxide to produce I-pyrrolines (16).8

R2 Me 1 I / ~

R -C-NC+CH2=C ~ I "-H X

R',R2 = Ph,C02Me, H2C=CH-, orH

X = CN or CQ2Me

R2

.'t;') Me X

16


Preparation of 3-Methyl-3-methoxycarbonyl-5-phenyl-l-pyrroline (16; R I = Ph, R2 = H, X = C02Me)8

A mixture of benzyl isocyanide (10 mM), methyl methacrylate (20 mM), and CU20 (0.2 mM) is heated under reflux in benzene (3 ml) for 3 h. The product is isolated by fractional distillation in 94% yield as a 1 : 1 mixture of configurational isomers.

Allenic amines (17) in the presence of catalytic amounts of silver tetraftuoroborate cyclize readily at room temperature to give the pyrroline 18 in high yield (-90%).9 Since allenic primary and secondary amines are readily available from the corresponding alcohols, the synthetic procedure should be valuable in the preparation of the relatively rare 3-pyrrolines (18).

R1R2C=C=CHCH2NHR3 AgBF4 •

17

Preparation of I-Benzyl-3-pyrroline (18; RI, R2 = H; R3 = CH2Ph)9 Silver tetrafluoroborate (0.1 mM) is added to a solution of N -benzyl-2,3-

butadienamine (17; R\ R2 = H; R3 = CH2Ph) (1 mM) in chloroform (1 ml). The mixture is stirred for 5 h at room temperature and then shaken with saturated sodium chloride solution (0.1 ml) to precipitate the silver. The mixture is diluted with ether (10 ml), dried over K2C03-Na2S04, and filtered. The pyrroline is precipitated from the filtrate as the oxalate in 90% yield.

The reaction between phthalaldehyde and primary amines in the presence of tetracarbonylhydridoferrate [HFe(CO)4r yields either 2-arylisoindoles (19) or 2-arylisoindolines (20), depending on the nature of the amine.lO Aliphatic amines give selectively the isoindolines (20) in 30%-65% yield, whereas aromatic amines have a greater tendency to give

0'-':::: CHO + KHFe (CO)4 /~CHO

",NO! (CN-DR

19

(CNR

20


the isoindolines (9). By varying the condition, isoindoles can be obtained exclusively from p-toluidine, p-anisidine, and p-chloroaniline.

The palladium-catalyzed intramolecular cyclization of N -acryloyl-obromoanilines (21) gives the oxindole derivatives (22) in good yield. ll

H

Pd(II) (lrN)= .~,o

R Ph 21 22

Preparation of 3-Benzylidene-2-oxindole (22; R = H)l1 A solution of N -cinnamoyl-o-bromoaniline (10 mM), palladium acetate

(0.1 mM), tri-p-tolylphosphine (0.4 mM), and triethylamine (2 ml) is heated under nitrogen at 100°C in a Pyrex tube for 18 h. The cooled, partially solid reaction mixture is transferred to a flask using methylene chloride and the volatile material removed in vacuo. Ether (200 ml) and water (50 ml) are added to the residue and the two layers separated. The ether extract, after drying over MgS04 and removal of the solvent in vacuo, gives 3-benzylidene-2-oxindole (1.28 g; 58%).

A very similar cyclization to give oxindoles takes place in hot toluene in the presence of catalytic amounts of Ni(PPh3)4, which is prepared in situ from Ni(acach and AlEt3 in the presence of PPh3.12

Carbonylation by means of transition metals is a useful process but often requires drastic conditions. Isoindolinones (23), however, can be synthesized in good yield by reaction of o-bromoaminoalkyl-benzenes (24) with CO at 100°C and 1 atm pressure in the presence of catalytic amounts of Pd(OAch, PPh3, and n-Bu3N.13

~I NHR co , ~Br Pd(OAc)2-PPh, WR

24 o 23

Carbonylation of compounds having the generalized structure 25 provides a useful source of nitrogen heterocycles. 14 Schiff bases (25; X = CR, R = alkyl or aryl) react with carbon monoxide at 200-230°C and 100-200 atm pressure in the presence of catalytic amounts of Co2(CO)s. Benzylideneaniline, for example, gives an 85% yield of 2-phenyl isoindolinone (26; X = CR, R = Ph). With iron or rhodium catalysts lower yields are

Sec. 4.2 • Nitrogen Heterocycles

aX=NR

25 x = CHorCR

R = alkyl, aryl, OH, or NHPh

147

26

R' = alkyl or aryl

obtained. The reaction goes equally well for Schiff bases containing substituted N -aryl groups (see page 240).

Ketoximes (25; X = CR; R = OH) in the presence of CO2(CO)s and carbon monoxide also produce isoindolinones (26; X = CR, R' = H) rather than the N -hydroxy compounds, which presumably undergo hydrogenolysis. Thus benzophenone oxime gives 3-phenyl isoindolinone (26; X = CPh, R' = H) in 80% yield. 14 Isoindolinones are also obtained in good yield from phenylhydrazones (25; X = CR, R = NHPh) and appropriate semicarbazones-for example, compound 25 (X = CPh, R = NHCONH2).

Tertiary-butyl isonitriles in the presence of a nickel catalyst react with alkynes to give moderate yields (-40%) of pyrroles (27).15 Unsymmetrically substituted acetylenes give a mixture of the two possible pyrroles.

R1C:=CR2 _N_i(O_A_c)-=+2t

+ 'BuNC

R',R2 = H, Bu, or Ph 27

a -Dicarbonyl systems (28) react with vinylmagnesium bromide and acetic anhydride to give a -acetoxy-a -vinylalkanones (29), which, in the presence of benzylamine and Pd(PPh3)4, gives N-benzylpyrroles (30) with

--+ ACr' R2

RI ""0 29

PhCH2NH2

Pd(PPh3 ).

R2

RIO N I

CH 2 Ph 30

substituents in the 2- and/or 3-position.16 By selective protection of one of the carbonyl groups the reaction can be extended to unsymmetrical a -diketones. Yields for this pyrrole synthesis are variable but are generally around 50%.

A related synthesis of the N -substituted pyrroles (31) takes place on reacting 1,4-dihydroxy-cis-but-2-ene (32) with a primary amine in the presence of palladium black.17 The reaction goes in 81 % yield and is


thought to proceed by a sequence of steps involving dehydrogenation, Schiff base formation, hydrogenation, and palladium-induced ring closure.

A variety of substituted pyrroles (33) have been synthesized by the nickel-catalyzed reaction of 2H-azirines (34) with activated ketones.1s The

RI

Nq + R2CH2CO· R3

Ph

NHacaC)2.

34

product is easily isolated in almost quantitative yield by precipitation with water. With sufficiently activated CH2 groups the reaction proceeds to completion even at room temperature, and the scope of the reaction appears to be limited only by the number of 2H -azirines.

Reaction of 2-aryl-azirines (35) with either CO2(CO)s 19a or [RhCI(C02)]2 19b gives the styryl indoles (36) in up to 90% yield. These products could be useful intermediates in alkaloid synthesis. From a synthetic point of view the reaction using CO2 (CO)g appears to be simpler and to give better yield.

N

~I V Co2(CO).

R V ---=-----=.. ?' ,; I co--ro R~ I N ~ R

35 H 36

Preparation of 2-Styrylindoles (36) from 2-Aryl-azirines (35)19a A mixture of 2-phenyl-azirine and CO2(CO)s in benzene is stirred at

room temperature under nitrogen for 24 h. The solution is filtered, the filtrate concentrated to small volume and then purified by chromatography on Florisil or silica gel to give the 2-styryl indole (36) in 52%-95% yield.

2,2-Diphenyl-2H-azirines (37) are converted into indoles (38) in quantitative yield in the presence of catalytic amounts of PdCh(PhCNh,20 The reaction proceeds via the complex 39, which can be isolated as a yellow precipitate.

Sec.4.2 • Nitrogen Heterocycles

Ph

Ph>V-R N

37

PdCI2(PhCN)2 •

149

-38

39

A useful synthesis of indoles (40) from o-allylanilines (41) proceeds in the presence of either stoichiometric or catalytic amounts of palladium complexes.21 This is a particularly neat synthesis of indoles since the starting materials for the cyclization, the o-allylaniline (41), can be synthesized in good yield by reaction of the appropriate 1T-allylnickel halide with the o-bromo-aniline (42).21a

QBr I .Q NHR' +

X 42

-x = H. Me. C02EI. or OMe Rt = H. Me. or COMe R2 = HorMe

Preparation of 2-Methyl Indole (40; X, R" R2= H)210 In a 250 ml flask are placed PdCh(MeCNh (0.195 g; 0.75 mM), benzo

quinone (0.812 g; 7.52 mM), and LiCI (3.16 g; 75.2 mM). THF (70 ml) is then added and the mixture stirred for 5 min. 2-(2-Propenyl)aniline (41; X, R' = H; R2 = H) (1.0 g; 7.52 mM) in THF (25 ml) is then added to the flask via a syringe and the mixture heated under reflux for 5 h. After removal of the solvent in vacuo the residue is stirred with ether and decolorizing charcoal for 20 min and filtered. The filtrate is washed with 1 M NaOH (5 x 50 ml). Removal of the solvent in vacuo followed by chromatography of the residue on silica (3: 1 petrol/ether) gives 2-methylindole in 85% yield.

By conducting the cyclization of N -substituted o-a1lylanilines (41) in the presence of carbon monoxide and methanol, the dihydroindolacetic acid ester 43 is obtained in good yield (-70%). 21b

41 CO/MeOH

Pd

~R2

~NI\...-C02Me RI

43


A somewhat related synthesis of indoles has been studied by Japanese workers, whereby 2-chloro-N -methyl-N -allylaniline (44; R = Me) cyclizes to 1,3-dimethylindole (45; R = Me) in 46% yield in the presence of an equimolar amount of Ni(PPh3k 22 More recently an improvement in this type of cyclization has been reported using Pd(OAch in acetonitrile as

44

Ni(PPh3 )4

or Pd(OAch

Me

~ ~I

R 45

catalyst.23 Apparently the catalyst is deactivated during the reaction and periodic provision of fresh catalyst gives a much improved yield. Using this technique, 3-methyl indole (45; R = H) was obtained from 2-iodo-N -allyl aniline in 87% isolated yield.

4.2.4. Six-Membered Rings

A simple synthesis of N -substituted piperidines (46) from glutaraldehyde and primary amines uses tetracarbonylhydrido-ferrate,

KHFe(COJ4~ 0 co

N R 46

[HFe(CO)4r.24 The KHFe(CO)4, which is generated in situ from Fe(CO)s and KOH, is mixed with the amine and glutaraldehyde in an atmosphere of carbon monoxide at room temperature. Yields are -80% for a variety of aromatic and alkyl amines.

Rearrangement of the aziridine 47 with a catalytic amount of PdCh(PhCNh gives the N -carboxy-nortropidine 48 in quantitative yield.25

This is a particularly useful reaction since the product (48) is the backbone of the tropane alkaloids.

48

Bis-1T-allyl complexes are active intermediates in the reaction of butadiene with alkenes, alkynes, and carbonyl compounds (see, for


example, Chapter 3). All these reactions involve insertion of a mUltiple bond into a carbon-metal bond. The carbon-nitrogen double bonds of Schiff bases and isocyanates are also reactive toward some carbon-metal bonds. Butadiene, for example, in the presence of catalytic amounts of palladium nitrate and triphenylphosphine (Pd: PPh3 = 1: 3), reacts with Schiff bases in DMF at 80°C to give the substituted piperidines (49) in 70% yield. 26

2f + R1N=CHR 2 ~ If. ~ N R2

I RI 49

Similarly, cocyclization of phenyl isocyanate and isoprene in benzene at 100°C in the presence of catalytic amounts of [bis(triphenylphosphine) (maleic anhydride) palladium] produces the piperidones 50 and 51 as a 1: 1 mixture in 82% yield.27 Butadiene and phenyl isocyanate react similarly.

2Y +PhNCO ~ H.. + H.. d~ it;~ ~ NON 0

\:: Ph \:: Ph

50 51

The C02(CO)8-catalyzed carbonylation of the unsaturated amide 52 produces the cyclic imide 53 in 41 % yield, although the reaction conditions are somewhat vigorous (300 atm CO, 250°C).28 With acyclic a,p-unsaturated carboxamides (54) a mixture of five- and six-membered cyclic imides are produced, the proportions of products obtained from 54 being very dependent on the degree of alkylation of the acrylamide double bond.

MeCR=CHCONH2

54

coz(CO).

co

Coz(CO).

co w: R

rtMe o N 0

H R~H 68% R~Me 0%

o 53

R

+))0 H

19%

67%


The cyclization of 0 -chloroallylaniline derivatives in the presence of nickel catalysts has already been discussed in relation to the synthesis of indole derivatives (Section 4.2.3). Cyclization of the related compound 55 in the presence of the Grignard reagent MeMgBr and a catalytic amount of NiCh(PPh3h gives 1-methyl-4-methylene-1,2,3,4-tetrahydroquinoline (56) in 91 % yield.22b

NiCI2(PPh,)2.

MeMgBr ~ UN) Me

56

In the presence of a catalytic amount of Pd(OAch-PPh3 and under an atmosphere of carbon monoxide, N -alkyl-o-bromophenethylamines (57) cyclize to give N -substituted 1,2,3,4-tetrahydroisoquinolin-1-ones (58) in good yield. 13

~ Pd(OAc)2/PPh, VBr NHR --C-o-=-------=.·

57

OOR o

58

Preparation of N-Benzyl-1,2,3,4-tetrahydroisoquinolin-1-one (58; R = CH2Ph)

A mixture of N -benzyl-o-bromophenethylamine (57; R = CH2Ph) (1 mM), n-Bu3N (1.1 mM), Pd(OAch (0.02 mM), and PPh3 (0.04 mM) is added to a reaction vessel that is connected to a balloon filled with CO, and heated at 100°C for 26 h. After cooling, ether is added to the solution and the ether layer washed with 10% hydrochloric acid and dried over MgS04 •

After removal of the solvent in vacuo the reaction product is purified by chromatography on silica gel (benzene/ether 1: 1) to give the product (58; R = CH2Ph) in 65% yield.

The cobaltacyclopentadiene complex 59, which is easily obtained by reaction of 'TJ 5 -cyclopentadienyl-bis-triphenylphosphinecobalt with two moles of alkyne, reacts with isocyanates to give 2-pyridones (60) in 70% yield.29 With unsymmetrical complexes, for example, 59 (R 1, R 3 = COzMe,


R2, R4 = Ph), the reaction proceeds regiospecifically to afford one product (60; R 1, R3 = C02Me, R2, R4 = Ph). Although this reaction might not look very attractive to the synthetic organic chemist there is the possibility of the reaction being made catalytic in that one could envisage co-trimerization of acetylenes and isocyanates to give the desired product in the presence of catalytic amounts of complex 59.

It has already been shown that intramolecular cyclization of olefinic compounds via oxypalladation is a useful route for the synthesis of heterocyclic compounds. Another example of this type of reaction is the cyclization of 2,4-pentadienamides (61) with palladium salts to give the corresponding 2-pyridone (62).30

RCH=CH-CH=CH·CO·NHz Li2PdCI4~ 0 61 RIlN''-~O

H 62

In a related reaction, o-vinylbenzamides (63) cyclize to isoquinolines (64) in the presence of lithium chloropalladite.31

o

~NH2 ~R

63

OH

LiPdCI4 , COl ""N

~ .o::R

64

Preparation of I-Hydroxy-3-phenylisoquinoline (64; R = Ph)3!

I-hydroxy

A solution of 2-styrylbenzamide (10 mM), Et3N (20 mM), and Li2PdCl4

(10 mM) in dry acetonitrile (40 ml) is stirred at 60°C for 6 h. After filtering off the palladium black, the filtrate is evaporated to dryness in vacuo and the residue chromatographed on silica gel with benzene to give the product (64; R = Ph) in 62% yield.

Reaction of 2-iodoanilines (65) with dimethyl maleate in the presence of Pd(OAch gives the expected 2-amino ester intermediate 66, which then cyclizes to the quinoline 67 in reasonable yield (30%-70%)? The lowest

65

R ~ H. Br, or OH

""Ok". R~M' VNH2~02Me

1 66

RP'y~t' VNAO

67


yield is from the 4-hydroxy compound, which is not unexpected in view of the low yields obtained in a variety of similar reactions when strongly electron-donating substituents are present in the aryl iodide.

The related palladium-catalyzed cyclization of a -substituted N -acryloyl-o-bromoanilines (68) does not give the expected 3-substituted but rather the 4-substituted quinoline (69) in 40% yield. 11 This rearrangement is rationalized on the basis of an initial ring closure of the organopalladium intermediate to a five-membered ring product (70) containing a 3-palladiomethyl group. In this complex there is no {3 hydrogen to be eliminated

Pd(OAc)2/P(R')3

• IOO"C

-0=::0 R CH2 Pd(PR;)Br

70

69

71

with the palladium as there is when the a carbon is unsubstituted. Because the usual decomposition reaction is not possible, elimination of the aminocarbonyl group with palladium appears to occur and this is followed by a reverse readdition of the aminocarbonylpalladium group to give the adduct 71, which can now eliminate a hydridopalladium group irreversibly to give the observed 4-substituted-2-quinoline (69).

One of the most potentially useful syntheses of heterocyclic compounds is the organocobalt-catalyzed synthesis of substituted pyridines (72) by cyclotrimerization of alk-l-ynes and nitriles.2•33 A variety of organocobalt catalysts can be used, among the more suitable for practical applications being 1,5-cyclooctadiene (cyclooctenyl) cobaJt2 and cobaltocene.33 The reaction will also proceed if the catalyst is generated in situ, the simplest system being CoCh·6H20/NaBH4 •2 Using these techniques a variety of


[Co] •

72 73

2-substituted pyridines (72; R2 = H) have been synthesized from acetylene and carbonitriles in excellent yield.

Preparation of 2-Phenylpyridine 33

Cobaltocene (0.38 g; 2 mM) is placed in a 200-ml autoclave in an atmosphere of nitrogen. Toluene (20 m'I) and benzonitrile (14.5 ml; -140 mM) are introduced via a syringe. After flushing the vessel four times with acetylene, the acetylene is introduced up to a pressure of 9 atm while the autoclave was mechanically shaken at room temperature. The autoclave is heated to 150°C and after 2 h, when the pressure has dropped to 3 atm, more acetylene is added (13 atm at 150°C). After 7 h the reaction mixture is fractionally distilled to give 2-phenylpyridine (15.8 g; 73% yield).

Reactions of substi~uted alkynes with carbonitriles always produce the two isomeric pyridines 72 and 73. The symmetrically substituted product 72 is formed as the major product, while the asymmetric type 73 is formed in about 30% relative yield.

Starting from the readily available pyridine carbonitriles 74, reaction with terminal alkynes leads to bipyridines 7S and 76. Use of acetylene as

()-CN + 2RC=CH ~ N

74

R

00·· N

75 76

the alkyne component gives the parent compound (for example, 2,2'bipyridine from 2-cyanopyridine in 95% yield). Substituted alkynes give two positional isomers, with type 7S usually predominating.

Extensive modifications of the cyano component in the pyridine synthesis can be tolerated. Cyanamide, for example, in the presence of certain cobalt catalysts will react to give 2-aminopyridines (77). Alkyl thiocyanates


will also react with alkynes to give alkyl-thiopyridines (78), but in this case catalyst turnover numbers are low.

A further variation on the cobalt-catalyzed synthesis of pyridines is the one-step synthesis of annulated pyridines (79) by the cooligomerization of diynes (80) with a variety of substituted nitriles.34 The reaction goes in good yield and with remarkable selectivity using the commercially available catalyst (CsHs)Co(COh.

C=CH I

(CH2). + RCN I

C=CH

80

CpCo(COI2 ro.1 R -'---~. (CH2).

~ N n = 3,4, or 5 79

Preparation of Ethyl-3- (5,6, 7,8)-tetrahydroisoquinoline acetate (79; n = 4), R = CH2C02Et)34

A solution of 1,7-octadiyne (80; n = 4) (5.00 mM), ethyl cyanoacetate (5.00mM), and (CsHs)CO(CO)2 (0.50 mM) in xylene (15 ml) is added over 117 h (by syringe pump) to o-xylene (15 ml) warmed to reflux under N2•

After removal of the solvent in vacuo, the reaction mixture is chromatographed on silica with ether. Microdistillation of the crude product gives the product as a clear oil in 47% yield.

Although y,8 -unsaturated ketoximes (81) are known to cyclize at 300°C, the reaction can be induced under much milder conditions in the presence of PdCh(PhCNh/NaOPh.35 The reaction products are substituted pyridines (82), which are obtained in moderate yield.

The cyclopalladated complex 83, formed in 60% yield from the appropriate acetanilide and Pd(OAch, reacts with various a,p -unsaturated carbonyl compounds to give the intermediate 84, which can then undergo acid-catalyzed cyclization to give compound 85.36 The last two steps each go in yields of 40%-:80%.

Sec. 4.3 • Oxygen Heterocycles 157

CH,=CHCO'Z, 0""':: NHCOMe Et,N R § CH= CHCO'Z

84 85

83 Z ~ H, Me, or OMe

Primary aromatic amines react with aldehydes in the presence of a rhodium catalyst to give quinolines (86) in variable yields (30%-80%)?

[Rh]

Ph NO,

86

Preparation of 2-Ethyl-3-methylquinoline (86; R = Me, X = H)37 A mixture of aniline (40 mM), propanal (88 mM), nitrobenzene (60 mI),

ethanol (20 ml), and [Rh(norbornadiene)Clh (0.03 mM) is stirred under an argon atmosphere at 180°C for 4 h in an autoclave. Vacuum distillation of the reaction mixture gives 2-ethyl-3-methylquinoline in 50% yield.

4.2.5. Seven-Membered Rings

Using the same procedure as for the synthesis of the related five- and six-membered benzolactams (24 and 58), the benzoazepinone derivatives (87) have been synthesized in good yield (-50%)?

4.3. Oxygen Heterocycles

Pd(OAcl,/PPh,

• co rY\ ~~R

o 87

In general there are fewer examples of the synthesis of oxygen heterocycles than nitrogen heterocycles using transition metal reagents or catalysts. The main area of work has been the synthesis of five- and six-membered lactones by various carbonylation reactions and, as this type of reaction will be discussed in Chapter 6, and the literature reviewed up to 1973.t this topic will not be discussed in great detail.


4.3.1. Five-Membered Rings

In contrast to other alkenes that are oxidized to carbonyl compounds by palladium salts, allyl alcohol undergoes an oxidative cyclodimerization to 4-methylene-tetrahydrofurfuryl alcohol (88) and 4-methyl-2,5-dihydrofurfuryl alcohol (89), although the yield is poor. The other main product of the reaction is propene, which apparently results from hydrogenolysis of the allyl alcohol. 38

The related Pd(II)-Cu(II)-catalyzed intramolecular cyclization of "Y,~unsaturated alcohols (90) gives the tetrahydrofurans 91 in moderate yield.39a The product is usually a mixture of the two diastereoisomers, but

Pd(DAc)2 ~

Cu(DAc)2

with 91 (R 1 = Ph, R2 = H) only one isomer, trans-2-vinyl-5-phenyltetrahydrofuran, is produced in 40% yield. Under similar reaction conditions 2-vinyl-2,3-dihydro-benzofuran (92) is prepared from 2-(2'butenyl)phenol. 39b

Pd(DAc)2~ ~ Cu(DAc)2 ~j

92

Tetrahydrofuran derivatives are often formed during the hydroformylation of unsaturated alcohols. An early example was the formation of tetrahydrofurfuryl alcohol (93) from either I-butene-3,4-diol or 2-butene-1,4-diol in the presence of catalytic amounts of CO2(CO)8 and under CO/H2

pressure.40

HOCH2CH=CHCH20H or

HOCH2CH=CH2 I OH 93


Another more recent example is the hydroformylation of coniferyl alcohol 94 to give compound 9S in 25% yield together with several other

. d 41 mmor pro ucts.

Co2ICO). .H0O-O~ _ 0 CO/H2 -MeO

9S

114

The aminoalkynes 96 undergo carbonylation in the presence of CO2(CO)s to form the furan derivatives 97 in up to 44% yield.42

o II H

R~NCtJ C02 ICO),. R 2 \,

CO \ NR' H 0 2

R~NCH·C=CH ~2

96 97

Dihydrofurans (98) are also obtained by the reaction of fJ -diketones or (3 -ketoesters with alkenes in the presence of Mn(OAch.43 The reaction is thought to go via a free radical mechanism in contrast to the ionic mechanism observed in the case of lead tetraacetate. The dihydrofurans produced in the Mn(OAch-promoted reaction of acetylacetone with terminal alkenes consist of only one isomer, the 5-substituted 2-methyl-3-acetyl-4,5-dihydrofuran (98), in sharp contrast to those produced in the presence of thallic acetate or lead tetraacetate, where the 4-substituted isomer predominates.

MeyyR' +

o 0

Rl = MeorOEt

Mn(OAch

98

Preparation of 3-Acetyl-2,5-dimethyl-5-phenyl-4,5-dihydrofuran (98; R 1,

R3 = Me, R2 = Ph)43 Mn(OAch-2H20 (0.25 mol), prepared from potassium permanganate

and manganese acetate, is dissolved in glacial acetic acid (lliter) at 45°C under hydrogen. To this solution is added a mixture of a-methylstyrene (15.3 g; 0.13 mol) and acetylacetone (75 g; 0.75 mol).

After lOmin the brown manganic color has disappeared, indicating that the reaction is complete and the dihydrofuran is isolated in quantitative yield by extraction with ether followed by distillation.


a-Bromo-ketones react with nickel carbonyl on heating in DMF to produce 2,4-disubstituted furans 99.44 By doing the reaction at room temperature the p-epoxy-ketone (100) is isolated in good yield (60%-80%), and on heating above l30°C dehydrates to give the furan (99).

R Ni(CO)4 I .1 R

~ RCO'CH 'C-CH --+ 0" 2 "I 2 I \ o R

100 0 99

Good yields of tetrahydro-2-furanones (101) can be obtained by hydroformylation of a,p -unsaturated esters.4S Typical reaction conditions involve heating the substrate at 250°C under 300 atm pressure of CO /H2 in benzene in the presence of catalytic amounts of CO2(CO)s.

Rl CO2(CO). ~ /\'"

CO/H2 ~,):::::-O

101

A simple one-step synthesis of 'Y-Iactones (102) consists of the reaction of Mn(OAch with alkenes and carboxylic acids.46 Other high-valent metal salts, for example, Ce(OAc)4 and N~ V03 , also work, but the manganese salts appear to be the most readily available. High yields of lactone are obtained from both internal and terminal alkenes and, in all cases studied, the lactone obtained from terminal alkenes contains the oxygen of the carboxylic acid bonded to the more substituted 2-position of the alkene. Lactones were also obtained from both conjugated and nonconjugated dienes.

~~~ R2

102

Preparation of y-n-Octylbutyrolactone (102; Rl = CJl17; R2R3R4R5R6 = H)46

Mn(OAch·4H20 (212 g; 0.84 mol) is dissolved in acetic acid (1200 ml) by warming to 90°C. To this solution is added KMn04 (32 g; 0.2 mol) with stirring. When the exothermic reaction has subsided and the temperature has dropped to 90°C, acetic anhydride (300 ml) and sodium acetate are added. Dec-l-ene (85 g; 0.6 mol) is added and the reaction mixture heated under reflux for 1 h. Extraction and distillation give pure y-n-octylbutyrolactone (66.4 g; 67% yield).


The formation of a-methylene-y-Iactones (103) by carbonylation of the acetylenic alcohol 104 is a very attractive route to these useful compounds.47 The original method47a used Ni(CO)4, acetic acid, and water, but a more recent procedure47b uses a palladium chloride/thiourea catalyst.

104

PdCI2

co

In a typical reaction the acetylenic alcohol 104 in acetone is stirred overnight at 50°C under CO (50 psi) with a catalytic amount of PdCh/thiourea. With the cyclic acetylenic alcohol104(Rt, R2 = -(CH2)4-) the corresponding a-methylene-y-Iactone 103 (Rt, R2 = -(CH2)4-) is obtained in 94% yield.

In the presence of a base the homoallylic alcohols (lOS) are converted into a -methylenebutyrolactones (106) using nickel tetracarbonyl. 48 The

KOAc R'ij'

o 106

choice of base appears to be very important since in the presence of potassium acetate yields are around 60%, whereas using sodium methoxide they drop to 4 %.

The anion [Co(C(I)4r, generated by vigorously stirring CO2(CO)8 in a mixture of benzene and aqueous sodium hydroxide containing the phase transfer catalyst cetyltrimethylammonium bromide, reacts with alkynes and methyl iodide in the presence of carbon monoxide to give the but-2-enolides 107.49 Although the reaction looks potentially very useful only a limited number of acetylenes were studied and product yields were variable.

RC=:CH + Mel + CO [",<eo,,]; "Q Me OH

107

Sodium tetracarbonyl cobalt ate, NaCo(CO)4, reacts with alkyl or acyl halides in the presence of CO to form the acyl cobalt tetracarbonyl 108,


which then reacts with alkynes in the presence of dicyclohexylamine to give the 2,4-pentadieno-4-lactone 109.50 The reaction is catalytic in cobalt and yields are around 60% for a variety of substituted alkynes and alkyl halides.

R ICH2Br + NaCo(CO)4 co~ R ICH2CO.CO(CO)4

108

A potentially attractive route to benzo-2-furanones (110) is the CO2 (CO)s-catalyzed reaction of o-methyl phenols with carbon monoxide. 51

The reaction is believed to go via the o-quinonemethide 111, but the reported reaction conditions (300°C; 1000 atm) are somewhat vigorous and consequently the product is isolated in low yield (14%).

OMe ~ ::::::,.. iOH - ~O -

III

(0=0 110

The reaction of acetylene with carbon monoxide at 100°C and 1000 atm in the presence of catalytic amounts of CO2 (CO)s produces the trans-bifurandione 112 in 70% yield.52 Substituted alkynes also react to give the substituted bifurandiones in similar yield. At lower temperatures in benzene the major products are the cis and trans isomers of 2,4,6,8-decatetraene-l,4,7,10-diolide (113), with only minor amounts of the bifurandione.53

O~CH-CH~O o 0 113

4.3.2. Six-Membered Rings

Earlier in this chapter the synthesis of piperidines (49) and piperidones (50) from butadiene and Schiff bases or isocyanates in the presence of a palladium catalyst was described. In a related reaction benzaldehyde reacts with butadiene in the presence of a catalyst generated from 1T-allylpalladium chloride, triphenylphosphine, and sodium phenoxide to give the pyran


114.54 The analogous reaction of formaldehyde with butadiene produces the pyrans 115 and 116 as il 2 : 1 mixture. 55

,( + PhCUD.!<. ~ Ph~O~1

114

+D~ o

116

Monoalkenes, after complexation with palladium chloride, react with formalin to form 1,3-dioxanes.56 3-Methyl-l-butene, for example, gives in 70% yield a mixture of compounds 117 and 118, with 117 predominating.

PdClz •

117 118

Hydroformylation of a,(j -unsaturated esters in the presence of CO2(CO)s produces a mixture of tetrahydro-2-furanones and tetrahydropyranones, with the latter product predominating when the double bond is able to undergo prior migration from the a,(j to the (j,y position, as is illustrated by the formation of 119 and 120.45 This reaction can also be applied to the preparation of fused ring compounds (for example, the synthesis of 121 in 96% yield).45

CO,\CO).

CO/Hz

119 120

·W Me Me

121


Carbonylation of the acetylenic alcohol 122 in the presence of aqueous acidic nickel carbonyl produces the tetrahydropyranone 123 in 20% yield.47a

HC=C(CH2hOH

122

Ni(CO)4 a I

o 0 123

Reaction of the epoxy-alkene 124, prepared by epoxidation of the appropriate diene, ~ith carbon monoxide in the presence of it: rhodium catalyst produced the p,,},-unsaturated lactone 125, whereas carbonylation in the presence of iron or cobalt catalysts gives the a,p -unsaturated lactone 126.57 Yields are quoted as being in the range 10%-75% but experimental details are lacking.

R2

"0 .~ RI +CO

Rh R6 -- R41 R4 ~/

~c. 0 RS RS R6

124 125

126

Isocoumarins (127) have been synthesized from 2-alkenyl benzoic acids (128) using. a palladium-assisted cydization reaction. 58 The reaction, which goes in f:J.igh yield, is thought to proceed by initial coordination of the alkene to the palladium, attack of carboxylate on this complex to produce

the cyclized 0 -alkyl palladium complex 129, whieh then undergoes elimination of PdH, and rearrangement to give the product 127. By incorporating CuCh and oxygen into the system to reoxidize the Pd(O) the reaction can

Sec.4.4 • Sulfur Heterocycles 165

be made catalytic in palladium but the reaction is then slow. The starting materials (128) for this reaction are synthesized by the reaction of the appropriate 2-bromobenzoic acid with a 1T-allyl nickel halide complex.

-PdH (YO • ~ ---+ 127

~I 129

Preparation of 3-Methylisocoumarin (127; Rl = H; R2 = Me) To a stirred solution of 2-(2-propenyl)benzoic acid (0.2 g; 1.23 mM) and

PdCh(MeCNh (0.32 g; 1.24 mM) in THF (15 ml) is added Na2C03 (0.19 g; 1. 78 mM) and the resulting mixture stirred for 3 h at 25°C. After routine isolation and purification by preparative t.l.c. (benzene/ ether 2 : 1) the product is obtained in 86% yield.

A range of di- and tri-oxabicyclo [X,2,1] systems have been prepared by a PdCh-CuCh-catalyzed oxidative intramolecular cyclization of terminal alkenes containing suitably located vicinal diols. 59 Thus the alkene diol130 (R 1 = H; R2 = Et), obtained via a butadiene telomerization, gives the beetle pheromone endo-brevicomin (131; Rl = H; R2 = Et) in 30% yield. Other related dioxabicyclo [3,2,1] and [4,2,1] systems are similarly synthesized, and using allyl ethers (132), the reaction can be extended to the trioxabicyclo [3,2,1] series (133).

130 x = CH 2

132 x = 0

4.4. Sulfur Heterocycles

PdCI 2

CuCl,

In general this is an area that has not been well studied. To date most of the syntheses of sulfur heterocycles using transition metal species have resulted from the reaction of metallocyclopentadienes with either sulfur or carbon disulfide and they are not particularly useful reactions.60 As an illustration, however, the cobalt complex 134 reacts with sulfur to produce


the thiophene 135 in 75% yield, and with CS2 to produce the dithiopyranone 136 in 50% yield.

Ph PhC PPh 3

Co"""'" Ph~ ~

Ph ~

134

Ph

PhCS Ph~

Ph

135

Ph

Ph0Ph

Phll_A S s

136

An alternative approach to the synthesis of sulfur heterocycles is illustrated by the reaction of thiobenzophenones (137) with Fe2(CO)9 to produce the ortho -metalated complex 138 which can then be oxidatively degraded to the thiolactone 139 in good yield. 61 With unsymmetrical thiobenzophenones one ortho -metalated complex 138 is usually formed predominantly.

137

--+

R' = HorCFl

R' = HorOMe

RQ2~ ~ Ii s YC'.- ~Fe(COh

H I Fe(COh

I d-R' 138

R2

9 Do u

R' 139

4.5. Cyclic Compounds Containing Two Hetero Atoms

Azobenzenes have proved to be useful starting materials for synthesis of a variety of heterocyclic compounds using transition metal complexes. An early example is the reaction of azobenzene with carbon monoxide in the presence of CO2(CO)8.62 Reaction at 190°C leads to incorporation of one molecule of CO to produce indazolone (140) in 55% yield, whereas at 230°C two molecules of CO are incorporated to give 3-phenyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (141) in 80% yield. Using nickel carbonyl as the catalyst the main product is 142.63

Sec. 4.5 • Cyclic Compounds Containing Two Hetero Atoms

H

co/'" --o~ ,./190°C a N- N I -

:::::,.. ""'co 230'C"-,.

o

0=:0) o

142

cr;NP' 140

o

H

~'f°141 ~NPh

o

167

Reaction of azobenzene with PdCh produces the ortho-metalated complex 143, which will react with CO in water or ethanol at 100°C and 15 atm to form the indazolone 140 in 90% yield.64 The palladium complex 143 will further react with an isocyanide to give the stable complex 144, which thermally decomposes at lOO°C to give the 3-imino-2-phenylindazoline 145 in good yield.65

140

RNC -+

Ph

2:i(R 144

IOO'C ---+

145

In addition to azobenzene, palladium can form ortho-palladated complexes with Schiff bases, benzaldazine, acetophenone dimethylhydrazone, and 1-methyl-1-phenylhydrazones. These complexes will then undergo insertion reactions with carbon monoxide under mild conditions to produce a range of heterocyclic compounds.66 The hydrazone-palladium acetate


complex 146, for example, reacts with CO at lOO°C in xylene to produce the acetate 147 in SJ% yield.

146

co ----+

147

A variety of heterocycles have been synthesized by the reaction of amines with carbon tetrachloride in the presence of a metal carbony1.67 Benzylamine, for example, reacts with CCl4 at 150°C in the presence of CO2(CO)s to produce the triphenylimidazole 148 and the imidazoline 149.67a At reaction temperatures below 120°C no debenzylated products

PtN Ph r )Ph +

N R

148

H Ph+N

H;(_JPh Ph N

R 149

R ~ HorCH2Ph

are obtained, whereas shortening the reaction time produces more of the imidazoline (149). In the presence of MO(CO)6 or bis(7T-cyclopentadienylmolybdenum tricarbonyl) the imidazoline (149) and dibenzylamine are produced.

Whereas aniline reacts with CCl4 and carbon monoxide in the presence of a metal carbonyl to form amidine (150), substituted anilines react to

o-~ 7NPh H1N C

"-- NHPh 150

produce heterocyclic compounds.67b m-Chloroaniline, for example, reacts with CCI4/CO in the presence of MO(CO)6 or Cr(CO)6 to produce the quinazolinone 151 in 80% yield. m-Bromo- and 3,4-dichloroaniline also

NH2 N O M(CO)., CINl~~ ~ I CI -C-Cl-4 /---CO"---+ ~N~CI

o \J 151

Sec. 4.5 • Cyclic Compounds Containing Two Hetero Atoms 169

give quinazolinones, but m - and p -toluidine give the quinazolinedione 152. The reaction mechanisIlls of these CCI4/CO reactions are not clear, but appear to go via free radical pathways.

The reaction of ethylene with carbon monoxide and concentrated aqueous ammonia in the presence of a rhodium catalyst at 150°C and 250 atm does not produce the expected propionamide as the major product, but a 52% yield of 2,4,5-triethylimidazole 153.68 Other terminal olefins

Rh NH EtrlN~ 3CH2=CH2 + 3CO + NH3 -- Et·CO·CHEt·NH·COEt ---4 EttL /Et

154 N 153

react in a similar way. The reaction is thought to go via conversion of ethylene to 3,4-hexanedione, which then undergoes condensation with propionamide to produce 154, which can subsequently cyclize with ammonia to give the imidazole 153. In support of this r:nechanism the reaction in dilute aqueous ammonia gives the intermediate 154 in 40% yield.

Isonitriles in the presence of PdCh react with a -amino acid esters to produce imidazolones (1SS) in about 70% yield.69

BuNC + RCH(NH2)·C02Et

H 0

PdCl2 , R+i NVNBu

155

A versatile synthesis of compounds of general type 156 involves the reaction of isonitriles with amino alcohols, with diamines, or with aminothiols in the presence of catalytic amounts of silver cyanide.70

Yields are around 70% and the reaction can also be applied to 0 -amino phenol, o-phenylenediamine, and o-aminothiophenol to give benzoxazole (54%), benzimidazole (64%), and benzothiazole (93%), respectively.70b Palladium chloride is also an excellent catalyst for this reaction and can be used on substrates bearing ester groups, a reaction where the silver

I f ·1 70a cata yst al s.


X=O,S,orNH

AgCN ---+

Preparation of 5,6-Dihydro-4H-1,3-oxazine (156; X = o)70a A mixture of 3-amino propanol (1.5 g; 20 mM), t-butyl isocyanide (1.7 g;

20 mM), and silver cyanide (0.13 g; 1 mM) is heated at 90°C for 12 h with stirring in a nitrogen atmosphere. Direct distillation of the reaction mixture gives the product in 66% yield.

Isonitriles containing an acidic a-hydrogen atom undergo a cycloaddition with the carbon-oxygen double bond of carbonyl compounds in the presence of a catalytic amount of cuprous oxide to form the 2-oxazoline (157) in good yield. 8 The key intermediate in the reaction is thought to be the organocopper-isonitrile complex 158 formed from the isonitrile and CU20.

Preparation of 5-Methyl-4,5-diphenyl-2-oxazoline (157; Rl = H, R2, R3 = Ph,R 4 =Me)

A mixture of benzyl isonitrile (10 mM), acetophenone (20 mM), and CU20 (0.2 mM) is heated under reflux in benzene for 3 h. The product is obtained by fractional distillation in 75% yield.

An interesting (4 + 2) cycloaddition across the diheterodiene system in the copper complex 159 occurs with dimethyl acetylenedicarboxylate to give the substituted l,4-benzoxazine 160.71 Yields are excellent (-90%) for a variety of substituted complexes and it is noteworthy that no reaction occurs with the uncomplexed nitroso phenols.

-(X0~ R CU-)2 +

:::::,... +/ N I

-0

---. R-o(I pC02Me :::::,... )JC02 Me

N I

OH

159 160

Sec. 4.5 • Cyclic Compounds Containing Two HeteTO Atoms 171

161

Cooligomerization of butadiene with ketazines or aldazines in the presence of a nickel phosphine or phosphite catalyst gives the 3,3,12,12-substituted 1,2-diaza-1,5,9-cyclododecatriene 161 in 50%-80% yield.72

new pathways for organic synthesis || formation of heterocyclic compounds

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