Synthesis of Five- and Six-Membered Heterocycles ... - Ingenta Connect

Current Organic Synthesis, 2004, 1, 47-63

47

Synthesis of Five- and Six-Membered Heterocycles Through PalladiumCatalyzed Reactions G. Kirsch*, S. Hesse and A. Comel Laboratoire d’Ingéniérie Moléculaire et Biochimie Pharmacologique, UFR Sciences Fondamentales et Appliquées, Université de Metz, 57000 Metz, France Abstract: Over the last years, palladium-catalyzed coupling reactions have been extensively studied and the names of Heck, Stille, Suzuki and Sonogashira are well known for their contribution to this chemistry. Extension of the coupling reactions allowing introduction of heteroatoms have followed and the Buchwald-Hartwig reaction is now a concept for this chemistry. Another achievement in this field is the possibility offered by the methodology to acceed to heterocyclic compounds either through a direct construction of the heterocyclic ring or by a two-step procedure (coupling followed by an heteroannulation). We are in the following paper going to review these ways of preparing heteroaromatic compounds either as single ring system or condensed to other aromatic rings.

I) P R E P A R A T I O N OF FIVE-MEMBERED AROMATIC HETEROCYCLES IN A ONE-STEP PROCEDURE I-1) Synthesis of Pyrroles The Sonogashira coupling of an alkyne chain containing a tosylhydrazone (1) with aryl iodides led to the formation of 2-benzylsubstituted pyrroles (2) in 40-70% yield; in the absence of aryl iodide, 2-methylsubstituted pyrroles were obtained [1]. NHTos NNHTos Arl, K2CO3 Pd(PPh3) 4 DMF, 60 oC

EtO2C

Ar

N EtO2C

1

2

Scheme 1.

Substituted pyrroles could also be synthesized from γ,δunsaturated ketone O-pentafluorobenzoyloximes (3) by an intramolecular Heck-type amination of the olefinic moiety catalyzed by Pd(PPh3)4 [2]. N

OCOC6 F5

1) Pd(PPh3)4 , Et2N, DMF

Ph

H N

2) Me 3SiCl

Ph 3

4

introduction of a triple bond. This triple bond was then used in a cyclization towards an heteroatom giving rise to the heterocyclic ring system. Mostly in this case five-membered rings were obtained in this one-step procedure. I-2-1) Preparation of Indoles and other Nitrogen Containing Heterocyles Indole synthesis has been certainly the most widely studied topic in this series certainly in relation with the usefulness of the nucleus in many biological active compounds. Palladium-catalyzed indole synthesis could be made through different cyclization routes. Some of them will give the indoles in one step from the appropiate starting material, others have to prepare first the needed starting compounds. This is generally made using a first coupling reaction. We will first describe methods using the one-step access to the indole nucleus (routes a, b, c and d, fig.1). The synthesis started from ortho-halo-anilines or their equivalents like triflates. The amines could be protected as amides or substituted with an alkyl group. In 1991 Larock et al. reported an excellent method for the preparation of indoles (6) that involved the palladium-catalyzed heteroannulation of internal alkynes with o-iodoanilines (5) [3a]. The cyclization was regioselective with unsymetrical alkynes. A detailed study about the reaction conditions was published later [3b].

Scheme 2.

R I

I-2) Preparation of Condensed Five-Membered Heterocyclic Systems This part has been the most widely described. Many ways are based on a Sonogashira coupling allowing the

R NH2

R

Pd(OAc) 2

R

PPh3, Bu4NCl

5

N H 6

Scheme 3. *Address correspondence to this author at the Laboratoire d’Ingéniérie Moléculaire et Biochimie Pharmacologique, UFR Sciences Fondamentales et Appliquées, Université de Metz, 57000 Metz, France; E-mail: [email protected] 1570-1794/04 $45.00+.00

Using the same methodology, Cook et al. [4a] have devised a synthesis of important tryptophan analogs (8) and Scammells et al. have described the preparation of psilocin © 2004 Bentham Science Publishers Ltd.

48 Current Organic Synthesis, 2004, Vol. 1, No. 1

Kirsch et al.

[4b]. The precursors to the tryptophan were obtained in good yields (50-80%) by heteroannulation of o-iodoanilines with a modified Schöllkopf’s chiral auxilliary (7). In some cases, depending on the substituent on the aromatic ring, the

presence of the regioisomer in 2-position was observed. Acidic hydrolysis of (8) gave the aminoacid. In a comparative study, Kabalka has shown that the proportion between indole (9) and the open alkyne precursor

X N

a

NHR

R

X

d

X e

b N R

N R

RHN f

c X

N R

N R

X = halogen

Fig. (1). Palladium-catalyzed indole synthesis. EtO N R EtO

I

N

N

R

TMS

TMS R

NH2

N

OEt

OEt

N H

7

8

Scheme 4. R I KF/Al2 O3 microwave

R

R N Y

NHY

NHY 10

9

Scheme 5. I X R

NH O 2S

Pd(PPh3) 2Cl2, Cul

R

X

Et3N, DMF

N

Ar

O 2S

X = H, F, MeO, CO2M e

Ar

11 12

CO2Me

R

X N

O2S Ar 13

Scheme 6.

Synthesis of Five- and Six-Membered Heterocycles

Current Organic Synthesis, 2004, Vol. 1, No. 1

(10) depended on the substituent on the nitrogen atom [5]. As Y was an electron-withdrawing group (amide, sulfonamide), the reaction occured in favor of the indole formation. In the case where Y = H, the open form existed in various ratio. Some of these indolizations have been run in a way to apply them to parallel synthesis on resin-supported reagents [6]. The attachment to the resin could be made either via a sulfonamide linkage on the nitrogen atom or via a substituent present on the aromatic ring. Maryanoff et al. [7] have described an access to trisubstituted indoles (13): o-iodoaniline attached via a sulfonamide linkage reacted with an alkyne to form (12). The halomercuration of (12) followed by Heck coupling with methylacrylate allowed the synthesis of (13), which could be released via basic hydrolysis. Wu et al. [8] have applied the same strategy to a bromoiodo aniline (14); coupling was selective with the iodine and allowed the access to 5-bromoindoles (15). Compound (15) could be acylated in the 3-position with different acylchlorides. The presence of the bromine was then used to introduce various aryl groups via a Suzuki coupling. A similar method developed by Maryanoff et al. [9] started from an o-iodo aniline linked through an amide linkage to the resin (Scheme 8). The iodo-aniline (16) was coupled and cyclized with a trimethylsilylalkyne or aryl acetylenes giving the trimethylsilyl or the aryl group in the 2 position (17) with or without a methyl group in position 3 for notably the aryl derivative. The presence of the trimethylsilyl group in position 2 in (17) allowed the iodination using NIS, the iodo compound being then coupled in a Suzuki reaction for giving the 2-arylindoles. Deprotection from the resin was made under strong acidic conditions (TFA). Berteina-Raboin et al. [10] have realized the synthesis of the indole skeleton of new melatoninergic analogs using solid-phase methodology in association with microwave irradiation. They showed that this combination speeded up the reactions. Bedeschi et al. have synthesized 2-subtituted indoles by reaction between resin-attached o-iodoaniline (ester linkage) and a terminal alkyne [11]. Br

Starting from o-iodo aminopyridines, 5-, 6- and 7azaindoles have been prepared by palladium-catalyzed heteroannulation using trimethylsilylalkynes in low to good yields (5-78%) depending on the substituents on the alkyne [12]. Scheme 9 shows the example for the preparation of 7azaindoles (18). R2 I R1 N

O2S

Pd(dppf)Cl2 , LiCl

R2

R1

Na2CO3 , DMF

N H

N

NH2

18

Scheme 9.

A study of the influence of the substituent on the nitrogen atom has been made in the case of 3-iodo 2-amino pyridines [13]. Depending on the substituent, they afforded the indoles or the open coupled alkyne form. With no substituent, a mixture of compounds was obtained, with an electron-withdrawing group, the open form existed and only indole formation took place with electron-donating groups. Yum et al. have also prepared substituted pyrrolo[3,2c]quinolines via the heteroannulation with internal alkynes of 3-iodo 4-amino quinolines [14]. A few cases of palladium-catalyzed annulation of 2haloanilines and ketones (19) have been reported [15]. The cyclization occured via an enolate arylation of Heck type. I

R R

Bn

PdCl 2(PPh3 )2 Cs2CO3

R

N

R N

O

Bn 20

19 R = alkyl or cycloalkyl

Scheme 10.

Indoles were also available from the cyclization of o-halo N-allylanilines by treatment with palladium acetate, tetrabutylammonium chloride and a base in DMF [16]. The same cyclization took place also with o-halo N-vinylanilines [17, 18].

I

Br Pd(PPh3)2 Cl2, CuI

R

NH

R

Et3N, DM F Ar

N O2S

Ar

14 15

Scheme 7. O

O I

N H

16

Me(H)

Me or

NH2

Scheme 8.

Me3Si

49

Pd(OAc) 2, PPh3 Bu4NCl,Na 2CO3, DMF

N H

SiM e3(Ar) N H

Ar 17


Kirsch et al. Ph

N

Ph 2 Ph

Pd(OAc)2 ,LiCl Na 2CO3, DMF

R

I R = Alkyl, aryl, CO2Et,...

21

N

R 22

Scheme 11.

Expecting the formation of quinolines, Larock et al. have reacted imines (21) with two equivalents of internal alkynes (Scheme 11). However under the conditions used in earlier annulation reaction, the quinolines did not form but isoindoloindoles (22) were isolated in good yields (50-80%) [19].

Recently a preparation of carbazoles through a double Buchwald-Hartwig coupling between anilines and o,o’dibromodiaryls has been described [22]. This carbazole nucleus formation has also been noticed as a unexpected product in the coupling of o-bromoiodobenzene with 5aminobenzo[b]thiophene derivatives [23].

Cyclization of N,N-dimethylhydrazones of arylacetaldehydes (23) using Pd(dba)2 and phosphane permitted the preparation of 1-aminoindoles (24) without substituents in 2 and 3 position [20]. In the case where in (23) X = Cl and in presence of an amine, an azole or an arylboronic acid, direct substitution of the chlorine could be made.

Indolines (27) as precursors to indoles were prepared by coupling of o-iodo anilines with 1,4 dienes [24-28] (Scheme 14). Reaction of o-iodo anilines with allenes allowed formation of 3-alkylidene indoline [29]. Another example of indoline formation on solid phase synthesis has used a Heck type cyclization on N-alkenyl anilines protected as an ethylcarbamate [30].

X

N Cl

NMe 2

Pd(dba) 2 phosphane xylene

X

I-2-2) Preparation of Benzo[b]Furans and Oxygen Containing Compounds

N NMe 2

23

24

Scheme 12.

Few other aromatic systems have been prepared using heteroannulation reactions. A preparation of indazole (26) was made by cyclization of N-aryl-N-(o-bromobenzyl) hydrazines (25) in presence of palladium acetate and dppf [21] (Scheme 13). Cyclization of [N-aryl-N-(o-bromobenzyl)hydrazinato-N]-triphenylphosphonium bromides led to the same compounds. NH Br

NH

N N

Pd(OAc)2, dppf

Changing to palladium dichloride, CuI and adding Et3N as a base allowed Kundu et al. to prepare benzofuran derivatives [32]. A detailed study of this heteroannulation was presented later [33]. Application to solid phase synthesis of 2-substituted benzofurans was made by attaching the iodophenol to a resin using an ester fonction on a 5- carboxylic acid [34]. The use of internal alkynes for the condensation to benzofurans has shown that it was more difficult than for the indole synthesis. It needed higher temperatures, had reduced

26

25

Comparatively to o-iodoanilines, o-iodophenols have been used to synthetize benzofurans in a one-step procedure (Scheme 15). A first example was published by Cacchi et al. using Pd(OAc) 2 (PPh 3 ) 2 and CuI yielding variously substituted benzofurans (29) from 2-iodophenols (28) and acetylenic derivatives (R2 = H) in 25-88 % yield [31]. Extension to the preparation of furo[3,2-b]pyridines was made.

Scheme 13.

I

R1

Pd (OAc) 2, Bu4NCl R1

NaHCO3, DMF

NHR

N R 27

Scheme 14. R2 I R1

R2

Pd(OAc) 2(PPh3) 2

OH 28 R1 = alkyl, aryl ....; R2 = H R1 = alkyl, aryl .....; R2 = Ph, CO2Et, SiMe 3

Scheme 15.

R1 O 29



regioselectivity and was limited to hindered alkynes, aryl, carboxy or silyl groups [35].

Another two-step synthetic way to furans was proposed by Balme et al. (Scheme 18). It is based on a three component reaction where a conjugate addition and a palladium coupling gave access to an intermediate tetrahydrofuran derivative (36), which on decarboxylative elimination afforded a trisubstituted furan (37) [39]. The reaction could also be run in a two-step one-pot procedure, where the intermediates were directly cyclized to the final compounds; the yields in the latter case being close to those obtained in the first one (40-60% compared to 45-65%).

A multi-component one-pot coupling procedure involving an initial deprotonation of a mixture of oiodophenol and a terminal alkyne, followed by a palladiumcatalyzed coupling and terminated by reacting with aryl iodide or alkenyltriflates gave rise to the formation of 2,3disubstituted benzofurans [36]. One example of synthesis of an indole derivative was presented in the same article. When the reaction was run in the last step in presence of carbon monoxide, the 3-acyl derivative was obtained.

II-2) Synthesis of Condensed Five-Membered Aromatic Heterocycles

The same study using microwave activation and KF/Al2O3 that has been made in the case of indole synthesis was run with o-iodophenols and terminal alkynes [5]. The yields in this case were from moderate to good.

II–2-1) Preparation of Indoles and other Nitrogen Containing Derivatives Routes e and f on figure 1 for the preparation of indoles involve generally a first reaction to introduce the necessary subtituents. Very often an alkynyl group has to be introduced in ortho to the amine via a coupling reaction and then cyclization can be made. A second general route was the cyclization of diarylamines, which were obtained by a Buchwald-Hartwig coupling.

II) SYNTHESIS OF FIVE-MEMBERED HETEROCYCLES IN A TWO-STEP PROCEDURE In the different routes described in the following part, one step in the reaction involved a palladium-catalyzed coupling reaction. The annulation part of the process can use another palladium catalysis or other type of cyclization.

Many papers were published using the cyclization of oalkynylanilines (38) (Scheme 19). The different methods described differ by the way the alkynyl substituent was introduced and, in which condition the annulation was run.

II-1) Synthesis of Furans Alkynyl substituted allylic alcohols are a major group of starting material for the synthesis of furans (Schemes 16/17). The alcohols were prepared by coupling reaction between terminal alkynes (30) or iodoalkenes (33) using Pd(0) and copper iodide with the corresponding aryl iodide or terminal alkynes. The allylic alcohols (31) and (34) obtained were cyclized with different kind of palladium catalysts [37, 38].

Taylor et al. [40] introduced a tolan substituent ((38), R1 = Ph (39), R1 = Ph , R2 = H) via a thallation reaction, cyclization being made with palladium chloride. Cyclization using Pd II and reacting the palladium intermediate with allyl chlorides allowed Utimoto et al. [41] the introduction Ph Me

Me R + Phl

Pd(0), Cu I

Pd(OAc)2

Me

or Pd(PPh3)4

R

HO

Ph

R

O

HO

30

31

32

Scheme 16. R1 F3C

I R

Pd(PPh3) 4

R1

F3C

F 3C

PdCl2(CH2CN) 2

CuI

R

R

HO

R1

O

HO 33

34

35

Scheme 17. EtO2C

CO2 Et

PdCl 2 PPh3

CO2Et

R1

CO2Et

R1X + R2

OLi

OEt

R2

O 36

Scheme 18.

51

OEt

R1

CO2Et

t-BuOK R2

O 37


Kirsch et al. R1

R2 "Pd" R1

NHR

N R

38

39

Scheme 19.

COR RX, CO, Pd(PPh3) 4

NHCOCF3

K2CO3, MeCN

NHCOCF 3

N N F 3C

40

41

Scheme 20.

of an allyl substituent in position 3 of the indoles ((39), R1 = CO2Me R2 = allyl). Reacting an N-trifluoromethyl aniline with Pd(PPh3)4 in presence of aryl halides or alkenyltriflates gave Arcadi et al. [42] access to 2,3 substituted indoles ((39), R2 = aryl or alkenyl). The same reaction was run in the presence of carbon monoxide and methanol to give the 3carbomethoxyindole derivative ((39), R2 = CO2Me) [43]. Cacchi et al. have described [44] the palladium-catalyzed cyclocarbonylation of bis(o-trifluoroacetamidophenyl) acetylene (40) with aryl or vinyl halides to obtain 12acylindolo[1,2-c]quinazolines (41). R1

R1 R2

R2

Pd(OAc) 2

R3 N

N H

R3 43

42

Scheme 21.

Dai et al. [45] prepared the alkynyl derivatives by coupling of o-N-acetamidophenol triflates with terminal alkynes, the open intermediates were cyclized using t-BuOK.

Replacement of the amine by a benzylidene and refluxing the compound in dioxanne in presence of palladium acetate and tri-n-butylphosphine permitted to obtain the 3-alkenyl-2arylindoles (43) (Scheme 21) [46]. The synthesis was also run starting from the amine in presence of an aldehyde under the same conditions. In this case condensation and cyclization took place giving directly the substituted indoles. Coupling enaminones (44) with o-dibromobenzene in the presence of Pd2(dba)3, cesium carbonate and a phosphine ligand gave in the first step an N-aryl-enaminone (45), which was cyclized by addition of another amount of catalyst and ligand (Scheme 22) [47]. Chen et al. have also reported the utilization of bromoenaminones to access to 1,2,3,4tetrahydro-4-oxo-β-carbolines [48], whereas Kondo et al. have applied this strategy to immobilized enaminoesters in solide phase synthesis [49]. Taking account that Buchwald–Hartwig coupling gave diarylamines (47) and that those can be cyclized under oxidative conditions, Queiroz et al. [23] have used the method to synthetize some thienocarbazoles (48), sulfur analogs of ellipticines (Scheme 23). The first coupling could either been made between aniline and the bromobenzothiophene or between the aminobenzothiophene

O Br Pd2(dba) 3 Br

Cs2CO3 Ligand

H 2N 44

Scheme 22.

Br

N H 45

(Cy) 2P

ligand =

O

O

NMe 2

Pd2(dba) 3 Ligand

N H 46



R1

R1

R1

S

Pd(OAc) 2 NH2 (Br)

Pd(OAc) 2

BINAP tBuONa

S

Br (NH2)

53

N H

S

N H 47

48

Scheme 23.

R N

Pd(ll) or Pt(ll)

CO2R'

R'OH

R

Pdo / Cul

R

OCO2R'

N

NCO

50b

CO2 R' 50a

49

Scheme 24.

and bromobenzene, the second route giving the better results. The same group has also used the reductive cyclization of ortho-nitrobiaryls to prepare thienoindoles [50]. In this case, the nitro derivative was obtained by a one-pot three-step reaction involving a lithium-bromine exchange, a boronation and a Suzuki coupling with substituted nitrobenzenes on 5bromo trimethylated benzo[b]thiophenes. The intermediate o-nitrodiaryl derivatives were then cyclized by reacting with tri-n-butylphosphine. Yamamoto et al. [51] have described the synthesis of N(alkoxycarbonyl)indoles (50) from 2-(alkynyl)phenylisoI cyanates (49) either by a bimetallic catalysis Pd°-Cu in presence of allyl carbonates or by reaction with alcohols (Scheme 24). II-2-2) Synthesis of Benzo[b]Furans and 2,3-Dihydrobenzo[b]Furans

aryl) were obtained [53]. No benzofuran was formed with R1 = H or SiMe3 in (51). In this case iodination took place on the aromatic ring. The presence of iodine on the benzofuran ring opened the possibility for further coupling reactions. Cyclization using palladium in presence of potassium carbonate was described by Cacchi et al. [54] giving access to 2-substituted benzofurans. Carbonylative cyclization on (51) was made by palladium-catalyzed reaction in presence of carbon monoxide and methanol affording the 3-carbomethoxy derivatives ((52), R2 = CO2 Me) [43]. An extension of this method allowed the preparation of benzo[b]furo[3,4-d]furanones (54) (Scheme 26) [55]. R2

O

R1 R

The same approach was used for the synthesis of benzofurans as for that of indoles. Formation of o-alkynyl phenols was the first step, the cyclization step being different depending on the authors. For example, a variously substituted derivative (51) (R1 = SiMe 3 ) was cyclized in high yields to the 2trimethylsilylbenzofuran (52) using 1,1,3,3-tetramethylguanidine [52]. (Scheme 25). The combined use of TMG and SiO2 in the coupling reaction produced directly the corresponding (52). When iodine was used as the cyclization agent, 3-iodobenzofurans ((52) R2 = I, R1 = alkyl, vinyl or

OH

OH

O

Pd ll, CO CsOAc, CH3CN

R O

53

Scheme 26.

Synthesis of 2, 3-dihydrobenzofurans, which can be considered as precursors to benzofurans, have also been described by two different routes involving palladium chemistry. The methods are based on cyclization forming cyclic ethers. One cyclization was based on a Heck type reaction from ethers (55) (Scheme 27) and has been used to R2

I R1

Pd coupling

cyclization

R

OH

R

R1 O

OH 51

Scheme 25.

R1

54

R1

R

R2

52


Kirsch et al.

X R O

N

Pd(PPh3)4, Et3N CO2Et

N

CO2Et

R O

55

56

Scheme 27.

build a morphine skeleton [56] or constrained arylpiperidines [57]. The second method was the internal ether formation between an alcohol and a bromide (Scheme 28) [58]. OH Pd(OAc)2 X

R

R

Cs2CO3

O

III) PREPARATION OF SIX-MEMBERED HETEROCYCLES IN A TWO OR MULTI-STEP PROCEDURE If for the five-membered heterocycles, the one-step procedure has often been used, in the case of six-membered ring two or multi-step reactions were generally prefered. We present here this procedure first and then the possible onestep access.

X = Br, Cl R= H, CH3

III-1) Synthesis of Pyranones

Scheme 28.

In a earlier paper, Dyker has noted the formation of a mixture of benzofurans and their dihydro derivatives when reacting o-iodoanisoles with vinylic bromides in the presence of palladium acetate [59]. II-2-3) Synthesis of Benzo[b]Thiophenes Palladium-catalyzed methods to benzo[b]thiophenes preparation were relatively poorly investigated certainly due to the incompatibility of palladium with sulfur containing compounds. The synthesis described involved electrophilic substitution on o- alkynylthiophenolethers (58) obtained by a Sonogashira coupling of terminal alkynes with oiodothiophenolethers (57) (Scheme 29). R1

Over the past few decades, many 2-(2H )-pyranone derivatives have been isolated from natural sources and many of these compounds have been shown to display a wide range of biological activities. As a consequence, numerous reports on the preparation of these heterocyles have been published [62]. Bellina and co-workers [63] have found that treatment of Z-(2)-en-4-ynoic acids (60) with aryl halides in presence of a catalytic quantity of Pd(PPh3 ) 4 provided mixtures of 6-substituted-5-aryl-2(2H)-pyranones (61) and stereodefined 5-[(1,1-unsymmetrically disubstituted) methylidene]-2(5H)-furanones (62). These last compounds were unfortunately the major products (Scheme 30). Ar R1

CO2H

I

CH3CN, 70-80oC.

R1

O

O

61 0-7%

SR

SR 57 R = Bn, Me

X

60 R1 = alkyl, aryl

Pd/Cu

R1

Ar

Pd(PPh3)4, K2CO3

58 R 1 = Alkyl,aryl,.... E

O Ar

E+

R1

R1

S 59 E + =I 2, Br 2, NBS, ArSCl, PhSeCl

Scheme 29.

Flynn et al. [60] have prepared the benzylthioether (58) by a palladium-catalyzed coupling of o-iodobromobenzene with benzylthiol. Cyclization of (58) with iodine gave the iodo-compound, which was used in a next coupling reaction to introduce aryl substituents. Larock and Yue extended the cyclization conditions to different electrophiles giving access to different substitutions in the 3 position [61]. It has to be noted that when the cyclization was made using bromine on a trimethylsilylderivative ((58) R1 = SiMe3) 2,3-dibromobenzo[b]thiophene was obtained.

O

62 26-38%

Scheme 30.

More recently [64], they have developed a convenient two-step synthesis of 5,6-disubstituted 2-(2H)-pyranones. In particular, they found that treatment of 5-substituted Z-(2)en-4-ynoic acids (63) (obtained by Sonogashira crosscoupling reaction of methyl (Z)-3-bromo-2-propenoate with several alkynes) with iodine and NaHCO3 in acetonitrile afforded mixtures of compounds (64) and (65). Compounds (65) were the major products and were easily separated chromatographically from iodides (64) (Scheme 31). They could be involved in Stille coupling to yield 5,6disubstituted 2-(2H)-pyranones (66). Bellina et al. [62] have extended their study to the formation of trisubstituted 2(2H)-pyranones (67) (Scheme 32).



55

I O

I2 3eq., NaHCO3 R1

CO2H

I

O

R1

CH3CN, 1.5 h at R.T.

O

O

R1 64

63

65 R2SnBu3 PdCl2(PPh3)2 THF R2

R 1 = alkyl, aryl, alkynyl R 2 = aryl, alkenyl, alkynyl, methyl R1

O

O

66

Scheme 31. R1

1) PdCl2(PhCN)2 As Ph3, NMP 2) KF

SnBu3

3) LiOH THF 4) 10% H2 SO4

Br Br

Br R1

I 2 3eq, NaHCO3 CH3 CN, 1, 5 h at R.T.

CO2H

I

R1

CO2Me

Br

O

O

67

Scheme 32.

III-2) Synthesis of Benzopyrones and Aurones The benzopyrone ring system is present in a number of natural products including flavonoids that interact with various enzymes and receptor systems of pharmalogical significiance (tyrosine, protein kinase C inhibitors…). Acyl chlorides from protected salicylic acids were used in Sonogashira coupling with terminal alkynes [65]. Benzopyrones (69) were constructed by 6-endo cyclization of the alkynones (68) under controlled conditions that preclude formation of aurones (70). O

alkynylbenzoic acids (71) were especially synthesized by Sonogashira coupling of alkynes with halogenobenzoic acids, triflates [66] or nonaflates [67]. Sashida et al. [67] have shown that o-ethynylbenzoic acids (71) could lead to isocoumarins by cyclization in presence of a catalytic palladium species. The 6-endo cyclization was often the predominant pathway but the 5-exo reaction could proceed when a bulky group was present at the end of the triple bond (Scheme 34). O-ethynylbenzamides ((71) X=N-nBu) led to 3-substituted isoquinolin-1-ones unless R was a bulky group (no cyclization was observed in this case).

O OTBS

1) (COCl) 2 2)

OTBS

PdCl2(MeCN) 2

G

OTBS

G

X

XH O

CuI, PdCl2(PPh3) 2

O

68

72

71

O

R O

Et2NH EtOH

R

R

G

X O

G O

69 major

O

70 minor

73 (72)

(73)

Scheme 33. X = OH

III-3) Synthesis of Isocoumarins and Phtalides As for cyclization of compounds (68) where the free phenolic hydroxyl could effected 6-endo or 5-exo cyclization to yield either benzopyrones or aurones respectively, oalkynylbenzoic acids (71) could afford 3-alkylidenephtalides (73) or isocoumarins (72) depending on conditions used. O-

X = N-nBu

Scheme 34.

R = Bu

73%

/

R = tBu

48%

38%

R = Bu

77%

R = tBu

/


Kirsch et al.

Pr Pr

Pr

OMe

O

O

OH OMe

O

74

O

OMe 76

75

AgNO3 20 mol% palladacycle Ag 10 mol%

acetone, 24h, 20oC toluene, 6h, 110oC DMF, 48h, 60oC

O

(75) 94 80 29

(76) 6 8 7

Scheme 35.

Bellina and co-workers [68] have also studied different catalysts to cyclize o-alkynylbenzoic acids (74); they have shown that AgNO3 favored the 6-endo process (as palladium catalysts did) whereas Ag promoted the formation of phthalides (76) (Scheme 35). Balme et al. [69] have described recently the formation of γ-arylidenelactones (78) via a tandem carbopalladationheterocyclization sequence (Scheme 36). Later, they wished to prepare 3-(1’-indanylidene)phtalide (80) from linear acid (79) by a biscyclization reaction. [70]. However this concept was difficult to apply to compound (79), as four products could be formed in this reaction (Scheme 37). Study of influence of the nature of catalysts and bases showed that compound (80) has been obtained in 64% yield when reaction was performed in DMSO in presence of Cs2CO 3, Pd(OAc)2, PPh3 and NaBH4.

Kirsch et al. [71] have studied a multi-step process to synthesize heterocyclic analogs of isocoumestane (Scheme 38). Suzuki coupling between 3-bromo-2-formylbenzo[b] furane, -thiophene and –selenophene (81) and 2-methoxyphenylboronic acid afforded the biaryls (82). Oxidation of aldehydes and cyclization yielded to isocoumestane derivatives (83). The same procedure was applied to 2thiomethoxyphenylboronic acid in order to synthesize isothiocoumestane [72]. OMe

Br

B(OH) 2 CHO

Pd(PPh3)4 Na2 CO3, DME

X 81 X = O, S, Se

O CO2H I

O

Base Pd(0) 5%

OMe

O

CHO X

X

82

Scheme 36.

Other pathways including a palladium-catalyzed step to form isocoumarin moiety have been described : indeed, the palladium cross-coupling methodology has also been used in the formation of a conveniently substituted "biaryl system" (that would allow further cyclization) as well as in the ringclosure step.

83

Scheme 38.

Reactivity of β-chloroacroleins (84) in Suzuki coupling (under Jeffery’s conditions) has also been investigated [73] and a convenient access to new coumarin derivatives (86) has then been reported [74] (Scheme 39).

O

79

Scheme 37.

O O

O

CO2H I

O

78

77

O

O O

O

Bas e Pd(0) 5% 80

I

I



Cl

MeO CHO

O

o-anis ylboronic acid Bu4 NBr, K2CO3

CHO O

Pd(OAc) 2, H2O, 45oC

n

X

57

n

X

X = CH2 O n = 1, 2 84

X

85

n

86

Scheme 39.

OTf

OMe

Pd(PPh3) 4 CO2Et

N

BBr 3

CO2Et

Et3N, DMF

N Me

Me

O

88

87

O

N ) 3 4 F PPh Pd( , DM N 3 Et

Br

Me 89

O CO2Et

N H

O

N Me

90

91

Scheme 40.

Merour et al. [75] have described two different pathways to synthesize compound (89). The first sequence involved a Suzuki coupling of triflate (87) with o-anisylboronic acid and cyclization of (88) by boron tribromide whereas the second way used the palladium cross-coupling methodology in the ring-closure step to form the lactone (Scheme 40).

III-4) Synthesis of Pyridine and Isoquinoline Derivatives 5-Methylbenzo[b]heteroaryl[2,3-c]isoquinolines (95) have been prepared [76] by a Bischler-Napieralski cyclization of 2acetamido-3-phenylheteroarenes (94), which were synthesized

Br Pd catalyzed CHO

CHO X

X 92 X = S, Se

N

NHCOCH3 X

X 94 OTf COCH3 X 93 X = S, Se

Scheme 41.

Pd catalyzed

COCH3 X

95


Kirsch et al.

CHO

CHO

Ph

N

t-BuNH2

t-Bu N

electrophile

PdCl 2(PPh3) 2 CuI, Et3N

HaI

Ph Ph

Ph HaI = Br, l

X

97

96 I2 lCl PhSeCl AgNO3

6 eq. 4 eq. 2eq. 5mol%

98 30 min 30 min 24 h 24 h

X=1 X=1 X = PhSe X =H

68% 67% 76% 82%

Scheme 42. R R I N

N

CuI 10 mol%

t-Bu

CHO N

N

N Me

Me

Me 100

99

101

R = alkyl, aryl

Scheme 43.

by palladium-catalyzed cross-coupling reactions starting either from triflates (92) or bromides (93) (Scheme 41).

IV PREPARATION OF SIX-MEMBERED HETEROCYCLES IN A ONE-STEP PROCEDURE

Another access to pyridine and isoquinoline derivatives (via cyclization of iminoalkynes) has been extensively studied by Larock and co-workers. Iminoalkynes (97) were obtained via a two-step procedure involving a Sonogashira coupling of aryl [77] and vinyl [78] bromides or iodides and the transformation of aldehydes (96) into tert-butylimines. Compounds (97) were then cyclized by electrophiles [77] (I2, ICl, PhSeCl, AgNO3…) or by palladium or copper catalysis [78, 79, 80] (scheme 42). Larock et al. have further extended this methodology to other compounds and especially to halogenoindole derivatives (99) [79, 80] (Scheme 43). Hesse et al. [81] have described the same kind of synthesis of pyridine-fused ring systems from β-chloroacroleins.

IV-1) Synthesis of Pyranones Larock and co-workers [82] have found that the annulation of internal alkynes by cyclic and acyclic vinylic iodides, bromides and triflates (compounds (102) and (104)) provided a convenient synthesis of variety of 3,5,6trisubstituted and 3,4,5,6-tetrasubstituted α-pyrones. This process was generally regioselective, although mixtures of regioisomers have occasionally been observed when relatively unhindered vinylic substrates (104) were used (Scheme 44). Reactivity of compound such as (104) with terminal alkynes has also been studied. Indeed, Kirsch et al. [83] O

CO2Me Ph

CO2Et

X

Pd(OAc) 2 Na 2CO3 LiCl, DMF

O Ph CO2Et

X, = I, Br, OTf

103

102

O

O Ph

CO2Me Me l 104

Scheme 44.

CMe 3

Pd(OAc) 2 Na2CO3 LiCl, DMF

Ph

Ph

O

O

Me

CMe 3 CMe 3

Me 105 40%

106

23%



59

O CO2H O Ph Br

Pd(PPh3)4 , Cul Et3N, CH3CN

Cl

Cl 108

107

Scheme 45.

CO2 Me Cl

PdCl 2(PPh3) 2 Et3N, toluene 120oC, sealed tube

O

109

O 110

Scheme 46. O

R R

CO2Et

Br

CO2Et

I R

R

O

NiCl2 (PPh3) 2 / Zn

NiBr 2 / Zn

R

CO2Et

R

111

R

R

112

113

Scheme 47.

have shown that cinnamic acids (107) underwent a crosscoupling lactonization sequence to yield rubrolides (108) (Scheme 45). Whereas Larock only studied bromo and iodo vinylic compounds, Tanaka et al. [84] have found that β-chloro-α,βunsaturated esters (109) could also form pyrones (110) but reaction conditions were stronger (20h in toluene at 120°C in a sealed tube). Unsymmetrical alkynes ended up with the formation of regioisomers and terminal alkynes did not cyclize at all (Scheme 46).

IV-2) Synthesis of Isocoumarins and Phtalides In 1998, Kundu and co-workers [87] described the palladium/copper-catalyzed heteroannulation of o iodobenzoic acids with terminal alkynes that led to the synthesis of Z-3-alkylidenephtalides (117) as the major products (Scheme 49). In many cases, phtalides were found to be the exclusive products. The heteroannulation process was found to be completly stereospecific, since only Zisomers were obtained. R

It should also be noted that Takahashi [85] reported an halogen-dependent catalytic reaction of alkynes with halopropenoates, where (Z)-3-bromopropenoate afforded cyclopentadienes (112) and (Z)-3-iodopropenoate gave pyrones (113) (Scheme 47). Duchêne et al. [86] described another strategy to synthesize α-pyrone from allenyl stannanes (114) and β-iodo vinylic acids. This regio- and stereoselective annulation probably proceeded through a Stille reaction/cyclization sequence (Scheme 48).

I

CO2H

R

O

PdCl2(PPh3) 2 CuI, DMF

O

116

117

Scheme 49.

It is also to be noted that Liao and Cheng [88] observed that the reaction of o-iodobenzoic acids with terminal R

CO2H

R

I

R2

R1

114

Scheme 48.

Pd(OAc)2, PPh3 Na 2CO3, Bu4 NBr

R2 R1

Bu3Sn

R = alkyl, aryl

O 115

O


Kirsch et al.

alkynes in the presence of palladium catalysts and an equivalent amount of zinc chloride led to the isocoumarins as the major products.

IV-3) Synthesis of Flavones Miao and Yang [91] described a regiospecific carbonylative annulation of o-iodophenol acetates (125) and acetylenes (126) mediated by the palladium-thiourea complex in the presence of base at 40°C under a balloon pressure of CO. Several flavones (127) were obtained in good yields (Scheme 53). The presence of the acetoxy group is essential as the same reaction from o-iodophenols led to lower yields (49-79%) of flavones and a significant amount of aurones (10-20%) has been isolated.

Larock et al. have extended their methodology used for the synthesis of pyrones [82] to the synthesis of isocoumarins [89]. Annulation of halogenobenzoate esters (118) by internal alkynes gave indeed good yields (Scheme 50). The above chemistry was also extended to a double heteroannulation process of geminal-dihalosubstituted esters (120) (scheme 51). O

IV-4) Synthesis of Pyridines and Isoquinolines

CO2Me R1

R2

O

Pd(OAc)2 , Na 2CO3 LiCl, DMF

I

Before Larock’s studies, there were only few reports on synthesis of isoquinolines by employing palladium methodology and most of them suffered the major disadvantage that they were stoichiometric with respect to palladium. Larock and co-workers investigated a catalytic version of these syntheses. They reported [92] that the palladium-catalyzed iminoannulation of internal alkynes afforded a wide variety of nitrogen heterocycles including pyridine and isoquinoline. They showed that tertbutylimines may undergo iminoannulation while methyl-, isopropyl-, allyl- and benzylimines did not allow the formation of the desired products. Aryl and vinylic imines ((128) and (130)) could yield to isoquinoline (129) and

R2 R1

118

119

Scheme 50.

Coumarins were also synthesized via carbonylative annulation of internal alkynes with o-iodophenols (122) (Scheme 52). In this study, Larock [90] has found that, unlike most of the previous work on the palladium-catalyzed carbonylation of alkynes, the insertion of the internal alkyne occurred in preference to the insertion of CO.

CO2R Ph

CO2R Ph

+ 4 I

Ph

Pd(OAc)2, Et 3N LiCl, DMF

Ph

Ph

I

Ph

120 121

Scheme 51. R2

R1 I +

R1

R2

CO

OH

R

Bu4NCl Py, DMF

O

R 123 122

R1

R2

Pd(OAc)2

O

O

R 124

major

R = CO2Et, OM e - R1 = alkyl, aryl - R 2 = Ph, SiMe 3

Scheme 52. O PdCl2(PPh3)2 thiourea, dppp

I R

CO, Et2NH, DBU OAc

R1

126 125 R = OMe, COMe, CO2Me CH=CH(CO2Me) R1 = OMe, OBz

Scheme 53.

R O R1 127 68-92%

minor

O


N


t-Bu R1

N

Pd(OAc) 2, PPh3

R2

61

o

Na2CO3, DMF, 100 C

I

R2 R1

128

129

R 1 = Ph, CO2Et, Me, CH(Me)OH R 2 = Ph, M e, CH2OH

N

t-Bu Ph

N

Pd(OAc) 2, PPh3

Ph

o

Na2CO3, DMF, 100 C

Br

Ph Ph

130a

Me

131 a

N

Me

t-Bu Ph

Ph

CH2OH

I

N

Pd(OAc) 2, PPh3 Na2CO3, DMF, 100oC

Ph

Ph CH2OH 131b

130 b

Scheme 54.

pyridine derivatives (131) with high regioselectivity in most cases (Scheme 54). These preliminary results were greatly extended a few years later (50 examples) [93] and they reported the full details of this catalytic annulation chemistry. The same year, Zhang and Larock [94] also described the preparation of βand γ-carbolines. A variety of aryl-, alkyl-, ester- and hydroxymethyl-substituted acetylenes underwent iminoannulation by N-substituted 3-haloindole-2-carboxaldehyde and 2-haloindole-3-carboxaldehyde. Mixtures of regioisomers were observed in most cases when unsymmetrical alkynes were employed. The reactivity of imines of β-chloroacroleins was also investigated by Hesse and Kirsch [81]. Chloro compounds (that are known to be generally less reactive than their bromo- and iodo-counterparts) allowed the formation of pyridine-fused ring systems (133) in an one-pot process (Scheme 55). Cl

N

X = CH2, O, S 132

Ph N

Me

Me

Bu

N

NC

Br

Pd(OAc) 2, PPh3 Na2 CO3, DMF, 100oC

Bu

136 X

Ph

135 10%

134

N N

N

t-Bu

Br

Ph

t-Bu Ph

X

1,1-dimethylallene by using stoichiometric palladium. In their further study [86], they showed that o-halidesubstituted imines could react with mono-substituted allenes under palladium catalysis to yield pyridines and isoquinolines. Tert-butylsubstituted imines (134) led exclusively to attack at the less substituted end but the tertbutyl group is sometimes difficult to remove so that moderate yields were finally obtained. 3-aminopropionitrile imines ( 1 3 6 ) reacted with higher yields but lower regioselectivity was observed (Scheme 56).

59% (60:40)

133

Scheme 55.

Pyridines and isoquinolines could also be synthesized via palladium-catalyzed iminoannulation of allenes. In a first paper, Frühauf et al. [95] described the formation of Nheterocycles from cyclopalladated α-tetralone ketimines and

N Bu

Scheme 56.


In summary, palladium chemistry has allowed in the last years a great advance in the chemistry of heterocyclic compounds. The great possibilities offered by these types of compounds in many applications from biology to material sciences is noteworthy. REFERENCES

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