Six-membered ring systems: pyridines and benzo derivatives

261

Chapter 6.1

Six-membered ring systems: pyridines and benzo derivatives

Heidi L. Fraser and M. Brawner Floyd Chemical and Screening Sciences, Wyeth Research, Pearl River, NY, USA [email protected] and [email protected] Ana C. Barrios Sosa Pharmaceutical Process Development, Roche Carolina Inc., Florence, SC, USA ana.barrios [email protected]

6.1.1

INTRODUCTION

Pyridines and their benzo-derivatives have received considerable synthetic attention for a variety of reasons. They are key scaffolds in biologically active and naturally occurring substances; moreover, they have become important ligands for organometallic chemistry and material science. Two reviews published in 2004 illustrate the broad application of pyridines. The first focuses on 2,2'-bipyridines as functional nanomaterials <04EJO235> and the second describes the use of chiral pyridine JV-oxides as ligands for asymmetric catalysis <04TA1373>. Additional reviews on the chemistry of pyridines published in 2004 include Henry's review on de novo synthesis of pyridines <04T6043> and Lavilla's review on the chemistry of dihydropyridines and pyridinium salts <04CORC715>. This review includes a summary of the methods developed for the syntheses and reactions of pyridines, quinolines, isoquinolines, and piperidines that were disclosed in the literature in 2004. This chapter covers selected advances in the field and will serve an update to the review published last year in this volume.

6.1.2

PYRIDINES

6.1.2.1 Preparation of Pyridines Asokan et al. has developed a practical synthesis of 4-chloropyridines 1 from carbonyl compounds having two enolizable carbons adjacent to the carbonyl such as compound 2 <04T5069>. Ketone 2 was subjected to Vilsmeier-Haack reaction conditions leading to the

262

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

formation of conjugated iminium salts 3, which upon reacting with ammonium acetate cyclized to form the 4-chloropyridines 1 after basic workup.

ReiBig and co-workers discovered a new synthesis of trifluoromethyl-substituted pyridines 4 from the reaction of lithiated methoxyallenes and nitriles in the presence of trifluoroacetic acid <04CEJ4283>. The authors postulate that the reaction goes through initial protonation of iminoallene 5 followed by nucleophilic addition of the trifluoroacetate anion onto the iminoallene to give 6. Intermediate 6 then undergos intramolecular acyl transfer to give 7 and subsequent aldol condensation yields the pyridinol 4 as shown in Scheme 2. Kerwin et al. has shown that azaenyne allenes readily form the a,5-didehydro-3-picoline diradicals, which can then be trapped with 1,4-cyclohexadiene, chloroform-^, and methanol to produce various pyridine products <04OL2059>.

Baldwin et al. examined an interesting pyridine cyclization in a new synthesis of pyrazolo[4,3-c]pyridine core 8 <04T933>. This reaction proceeds through an initial iminohydrazone formation, followed by 9-endo-dig cyclization of the amidine moiety onto the terminal alkyne to give compound 9. Opening of the 9-membered ring of 9 by ammonia gives 10. Subsequent 5-endo-dig cyclization forming the pyrazole ring, followed by 6ite disrotory ring

Six-membered ring systems: pyridines and benzo derivatives

263

closure and elimination of ammonia gave the pyrazolo[4,3-c]pyridine 8. A similar alkynyl imine moiety has been reported by Shimizu and co-workers to react with (3-keto esters to produce 5acetyl-2-pyridones in good yield <04S1349>. n

The [4+2] disconnection continues to be an approach of choice for the synthesis of pyridine rings. Guingant et al. reacted amidine-azadienes with 2-bromo-[l,4]-naphthoquinones as an efficient one-pot approach towards the 5-aza-angucyclinone-ring skeleton <04TL4911>. Similarly, Delfourne and co-workers utilized a two step hetero-Diels-Alder reaction of quinoline5,8-diones with iV.Af-dimethylhydrazones to obtain a series of C and D-substituted phenanthrolin7-ones <04BMC3987>. Other synthetically useful aza-diene equivalents include oxazoles and 1,2,4-triazines. Ohba and co-workers exploited the intramolecular hetero-Diels-Alder reaction of an oxazole and tethered olefin in the synthesis of two Rauwolfia alkaloids <04TL6471; 04H2845>. 1,2,4-Triazines were used by Branowska in reaction with cyclic enamines to prepare two new classes of 2,2'-bipyridines <04T6021>. Raw et al. has elaborated this reaction using a tethered imine-enamine, which facilitates direct conversion of the 1,2,4-triazine 11 to the substituted pyridine 12 without the need for a second and discrete aromatization step <04CC508> as shown in Scheme 4. Compound 13 is postulated to exist in equilibrium with compound 14, which undergoes in situ elimination directly to pyridine 12.

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

264

Stanforth and co-workers made additional improvements on the hetero-Diels-Alder approach. They accomplished a 'one-pot' synthesis of pyridines from a,,(3-diketoesters and amidrazones <04T8893>. Deniaud et al. has investigated diazadienium iodide 15 as an aza-diene moiety in the synthesis of pyridines <04TL9557>. They have demonstrated that diazadienium iodide 15 reacts with ketenes, acetylenes and acrylic dienophiles to yield a variety of substituted pyridines as shown in Scheme 5. © e /

S

^

N

Y

C

°

2 R

,RO2C

ULOR ^

C

°2R

=-CO2R

'

S

^

N H 2

'

RHC=C=O

CH3CN,Et3N

L

CH3CN,Et3N

I8h,rt

^

18h,rt

R = Me, 62% R = Et, 66%

"" - ^ °

/S

N OH

XJL ^

R

R = CO2Me, 58% R = CO 2 B, 56% R = C6H5, 50%

1. (Boc) 2 0, Et3N, DMAP CH2CI2, 1h,rt90% 2. 60 °C, 18 h, = \ R R = COMe, 85% R = CHO, 65% R = CO2Me, 60% 3. TFA, CH2CI2,4 h, rt R = COMe, 70% R = CHO, 65% R = CO2Me, 53%

Scheme 5 Boruah et al. reported a facile and convenient synthesis of pyridines 16 from (5-formyl enamides 17 under microwave irradiation employing a Henry reaction <04SL1309>. The author postulates that nitromethane reacts with the formyl group, followed by dehydration and subsequent cyclization and aromatization to yield the nitro-pyridine 16. R2 R

CHO ANA0

MeNO2 8-10 min

17

R

Y^yN02

Ri^N^Me 16

Scheme 6 Kappe and co-workers also utilized microwave irradiation to facilitate a three component onepot synthesis of a library of 3,5,6-substituted 2-pyridones 18 <04T8633>. This method utilizes a CH-acidic substrate 19, dimethylformamide dimethylacetal (DMF-DMA) and diverse active methylene nitriles 20 as building blocks.

Six-membered ring systems: pyridines and benzo derivatives

I

R1^O

+

I

MW

^O^N^

I

*

I

I

100 °C, 5 min

R-S

19

R!

f

265

||

I

tfW

H

CN

18

20

Scheme 7 Various modifications have been made on the Bohlmann-Rahtz reaction for the preparation of pyridines. Bagley and co-workers have developed a three-component heteroannulation reaction that proceeds under mild non-acidic conditions <04TL6121>. In this reaction, a 1,3-dicarbonyl compound, an alkynone and excess ammonium acetate are combined and presumably generate a Bohlmann-Rahtz intermediate similar to 21, which then cyclizes to yield the 2,3,6-trisubstituted pyridine. Other work done in this group accomplishes a bromocyclization of the BohlmannRahtz intermediate 21 to generate the 2,3,5,6-tetrasubstituted pyridine 22 in good yield O4SL811> as shown in Scheme 8.

A3 O

RO2 C

I)

jf R

NBS, EtOH

(orCH2CI2) NH

2

R°2C.^Br R 2

ANAR3

83-98%

21

22 Scheme 8

1,4-Dihydropyridines continue to be of interest to medicinal chemists due to their biological activity. The synthesis of choice is the Hantzsch dihydropyridine synthesis <04JMC3180; 04JMC2688; 04JMC254; 04JMC3163>. Zolfigol et al. has developed a mild solvent free modification to this synthesis with improved yields <04SL827>. Tripathi and co-workers modified this method further through use of tetrabutylammonium hydrogen sulfate as a phase transfer catalyst and diethylene glycol as an eco-friendly solvent <04TL9011>. Dondoni et al. utilized a one-pot thermal Hantzsch reaction for the synthesis of highly functionalized |3pyridylalanines 23 as shown in Scheme 9 <04TL2311>. They simplified the purification process by incorporating polymer-supported scavengers to remove excess reagents. A mixed resin bed of strongly acidic resin and strongly basic resin was used to remove unreacted enamine and ketoester, respectively. The unreacted aldehyde and intermediate side products were scavenged with nucleophilic aminomethylated polystyrene.

266

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa f-BuO2C^

Ph

1

H^CO2f-Bu PhCHO + T II H2N^Me

| ° + J BnO2C '"NHBoc

1.4-AMS.MJuOH 70 °C, 24 h, A ' • (A-15) 2 Q -r S O 3 H ^ © e

a

f-Bu02CvJy502f-Bu 1 JL s -f^' Me J. H BnO2C NHBoc -

NMe3OH (Ambersep)

3. / - v _ {^J^HH2

(AM-resin)

"

Yield; 7 5 %

Purity: 92%

Scheme 9 6.1.2.2 Reactions of Pyridines Palladium couplings of pyridines, although not novel, continue to be used and elaborated. Suzuki couplings with 2-halopyridines <04JMC1575; 04JMC4277; 04BMCL4511>, 3halopyridines <04OL3; 04JMC4588> and 4-halopyridines <04BMCL4603> are used frequently by medicinal chemists in the preparation of innovative biologically active molecules. Likewise 3-pyridyl boronates <04OPRD955> have also been used in this manner. Delfourne and coworkers utilized a Stille aryl-aryl cross-coupling reaction as a key bond-forming step in the synthesis of subarine, a marine alkaloid, <04EJO1891> as shown in Scheme 10. O O o ^Y^O^ Pd(PPh3)4 f^y^O^ ^Y^0^ ^ Jl^N 1,4-Dioxane U J\^N TFA, CH2CI2 l ^J L , N K24h

o I J

NHB0C

TT 0

Br

Me3Sn

-L

n 1J

rt 24

'

h

oil)

YJ O

Yl

HN

l^.NHBoc

\J\

Subarine

Scheme 10

Stille cross-coupling reactions have also been used in the synthesis of bipyridines <04SC3227> and other biologically active compounds <04JMC2453>. Palladium catalyzed carbonylation reactions have been improved for chloropyridines <04OL2097; 04H411> and examined in cobalt-catalyzed cross-coupling reactions <04CL1240>. Maes developed a unique elaboration of Buchwald chemistry <04CC2466>. They accomplished the first tandem double palladium-catalyzed amination of 2-chloro-3-iodopyridine 24 with aminoazines 25 or aminodiazines, shown in Scheme 11, to prepare complex heterocycles such as compound 26. Munson also utilized Buchwald chemistry for the synthesis of 2-alkylamino-3-fluoropyridines <04SC759>.

a

1

Pd(OAc) 2

|^J*^

ci+ ^rANH2

BINAPorXANTPHOS %

CS2C 3

°

|/5V'N\V_

^r/V^A

toluene, reflux, 17 h

24

25

\=~/

26

Scheme 11

Six-membered ring systems: pyridines and benzo derivatives

267

interest in copper-catalyzed coupling reactions has resurged due to the economic attractiveness of copper. Two different groups described the use of copper as a catalyst for efficient arylation reactions. Cristau and Taillefer detailed a mild copper-catalyzed N- and Carylation with aryl bromides and iodides with various substrates <04CEJ5607>. One reaction examined was JV-arylation of 2-pyridones. Li et al. has explored the copper-catalyzed coupling reaction of 2-pyridones 27 with aromatic halides 28 based on Buchwald's protocol to prepare JVaryl-2-pyridones 29 <04TL4257> as shown in Scheme 12.

a Pj

°

-^jj.

(f 3 ~ R 2 if

20 mol% Cul 40 mol% Ligand

2 equiv. K3PO4 1,4-dioxane, 110 °C 16 24h

' 27

"

/^Ss

R 1 - £ "l H , ° R2jfS

R

28

l^jJ 29

Scheme 12 Metalation of pyridines is another powerful and well-studied way to elaborate pyridines. Specifically, the "halogen dance" has been used to prepare 2,3,4-trisubstituted pyridines <04T6113> and 2,4-disubstituted pyridines <04S2614>. Scheme 13 shows the conversion of 2fluoropyridine 30 to a 2,3,4-trisubstituted pyridine 31 via the "halogen dance", where iodine migrates to the 4-position and the subsequently added electrophile is incorporated at the 3position of the pyridine ring. I

f%

1.LDA>

rj^Y'

30

1. LDA ^

Af* 31

Scheme 13 Schlosser and co-workers have completed an exhaustive analysis of the metalation of halotrifluoromethylpyridines . This group has also examined the metalation of 2,6-difluoropyridine <04EJO1018> to incorporate fuctional groups at the 3position of the pyridine ring. Moreover, Mongin et al. examined the deprotonation of various chloro- and fluoropyridines with lithium magnesates <04TL7873; 04TL6697>. Song and coworkers used magnesium-halogen exchange in the preparation of 5-bromo-2-substituted pyridines 32 from 5-bromo-2-iodopyridine 33 because of the increased stability of the Grignard reagent as compared with the aryllithium and the decreased likelihood of magnesium migration as shown in Scheme 14 <04OL4905>.

268

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

B

/-prMgci, B y ^

y^ %*N

°°

C

B r

_ ^

T l k

^N^MgCI

33

NAE

32

Scheme 14 Fort and Gros have discovered an unusual induction of ortto-lithiation versus halogen-lithium exchange with reaction of/-BuLi and 3-bromopyridines 34 <04SL2319>. This reaction showed a strong dependence on addition order; when 7-BuLi was added to a solution of the 3bromopyridine 34, orr/zo-lithiation was exclusively observed to give 4-substituted-3bromopyridine 35. In the inverse addition order, the major product was that resulting from halogen-lithium exchange, which yielded 3-substituted pyridines 36. SiMe3

|j^Y

Br

^-N^

1. f-BuLi,THF

[j^YBr

-78 °C, 5min *" ^ N ^ 2. TMSCI,-78°C 35

34

134 THF

t-BuU

-

-78 °C, 5min 2. TMSCI, -78 °C

(J N 36

Scheme 15 In the last year, a lot of attention has been paid to the efficient directing effects of 2-pyridyl groups to facilitate a number of useful synthetic transformations. Mongin and co-workers have examined 2-pyridyl groups to direct metalation of 2-phenylpyridines 37 <04JOC6766>. Under the kinetic conditions studied no nucleophilic addition to the azine ring was observed. Lithiation occurred cleanly at the 2'-position of the benzene ring, as shown in Scheme 16, to yield compounds 38.

ril2'

"75°c

riT

r\

4'

E r\

R = F, CI.Br

37

38

Scheme 16 Chang et al. has developed an efficient copper-catalyzed aziridination route based on chelation of the pyridine nitrogen to copper <04OL4109>. Yamamoto et al. used the chelation

269

Six-membered ring systems: pyridines and benzo derivatives

of the 2-nitrosopyridine to promote the catalytic and highly enantio and diastereoselective nitroso Diels-Alder reaction <04JA4128>. Itami and Yoshida et al. have studied the directing effect of the 2-pyridyl groups in detail. They have shown, through an X-ray crystal structure determination, that homocoupling reactions of alkenyl(2-pyridyl)silanes <04OL3695>, illustrated in Scheme 17, and Pauson-Khand reactions proceed through formation of a copper complex in which the pyridine nitrogen is bonded to copper as in complex 39. II Ph^^ si A^J Me2

CuX, CsF P

Me CN,rt,3h

h

^ ^

P

h

Me2 39

Scheme 17 Pyridine-ethynylenes have received notice in the past year as a result of their biological activity as well as their physiochemical properties. These compounds have typically been formed using Sonogashira couplings between bromopyridines and terminal acetylenes <04BMCL3893; 04BMCL3993; 04OL2373; 04BMCL2401; 04AG(E)366; 04JA10389; 04JOC8723>. Extensions of this chemistry encompass a multi-component coupling reaction to give propargylic amines <04TL2607>. Wolf et al. has demonstrated that the Sonogashira coupling can be accomplished in water under an air atmosphere <04OBC2161>. Moreover, Sonogashira coupling of a diethynylpyridine, in combination with copper catalyzed sp-sp carbon-carbon bond formation, developed by Eglinton and Galbraith, was used to prepare a pyridinophane <04SL182>. An alternative approach to using pyridine-ethynylenes was developed, which used a double elimination of p-substituted sulfone 40. This arises through deprotonation a- to the sulfone to give in situ formation of compound 41, which undergoes elimination of both the phosphonate and sulfone to generate the pyridylacetylene 42 <04CL1298>. Likewise compound 42 can be prepared from the respective benzyl sulfone and pyridine-2-carboxaldhyde. rf^i

BuLi, THF

'LMAv^SO2Ph

PhCHO CIP(O)(OEt)2

40

LiHMDS 84%

^ 5 .

([ 1 N

^ ^

42

S

K

r

^

T J ^ ^

BuLi, THF

|P**| N

OP(O)(OEt)2

J 1 ^ \

LiHMDS

-HOP(O)(OEt)2

PhSO2 \^>

f S

N^Y*^^1 PhSO2

41 Scheme 18

\j?

270

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa

Zard illustrated a radical cyclization onto the pyridine ring to generate bicyclic 6,5-and 6,6pyridine heterocycles <04OL3671> as shown in Scheme 19. Work has also been done with pyridyl radicals. Burgos has studied the intramolecular heteroarylation of pyridyl radicals with arenesulfonamides to form biaryl compounds <04T11843> and Builla has accomplished an intermolecular addition of a heteroaryl radical onto an aromatic solvent <04T6217>. BOYS

CI^N^V"

DLp,DCE

'

C ! - W

J^o

R

) n

!

CIANAN;>n

J^o

DLP = [CH3(CH2)10CO]2O2

J^Q

n = 1, R = COCH2CH3; 84%

n = 1, R = COCH2CH3; 50%

n = 2, R = COCH3; 92%

n = 2, R = COCH3; 74%

Scheme 19

Adib has shown that pyridines undergo reaction with dialkyl acetylenedicarboxylates in the presence of isocyanates to produce functionalized 2-oxo-l,9a-dihydro-2//-pyrido[l,2a]pyrimidines 43 in good yield <04TL1803>. The author postulates that the reaction proceeds through initial reaction of the pyridine 44 with the acetylenic ester 45, and the resulting anion then attacks the isocyanate 46 to yield a zwitterionic intermediate. The nitrogen of the zwitterionic intermediate adds to the pyridinium moiety thus generating the pyrido[l,2a]pyrimidines 43. R

ffS

U 44

R 1

R O2C-=^CO2R

1

R2-N=C=O

45

^ KKR2

CH2C 2

',

(fS

R1O2C^Y^° CO2R1

46

43

Scheme 20 Sarkar et al. has generated pyridine o-quinodimethane 47 through a formal imine tautomerization of 48 with subsequent intramolecular trapping to obtain the Anabasine ring system illustrated with compound 49 <04JMC6691>. Hoornaert and co-workers generated (IH)pyridinone o-quinodimethane, via thermolysis of [3,4-6]sulfolene pyridinone, which was trapped with various dienophiles to form bi- and tricyclic ring systems <04T429>.

i ^

N

cAAc.

>

N ( /-p r)2 B cico e

^

i

^

cAA.b02Me

y

^ [

C/N^C,

Xylene 48

47

Scheme 21

i

49

> fc02Me

Six-membered ring systems: pyridines and benzo derivatives

271

6.1.2.3 Pyridine A'-Oxides and Pyridinium Salts Pyridinium salts are involved in a wide variety of synthetically useful reactions. Many workers utilized the electrophilic nature of the pyridinium salts to incorporate substitution into the pyridine scaffold. Specifically, acylpyridinium salts have been reacted with Grignard reagents O4J0C2863; 04OL3553> and organozinc reagents O4J0C5219; 04JOC752> to form key carbon-carbon bonds. Charette utilized the addition of nucleophiles to 3-substituted pyridinium salts prepared from Af-methylbenzamide <04OL3517> as illustrated in Scheme 22. This methodology was applied to the enantioselective synthesis of (-)-L-733061, a highly potent Substance P antagonist.

Recently, polymer-supported pyridinium reagents have become of interest. Tye et al. described the preparation of a polymer-supported Mukaiyama reagent 50 from Merrifield's resin, which was then used for the preparation of carbodiimides through the dehydration of thioureas and for the guanylation of primary amines <04TL3401>. Swinnen et al. reported the preparation of a similar reagent, 50, from Wang resin, as shown in Scheme 23, and used it as a coupling reagent for the synthesis of esters or amides from carboxylic acids and corresponding alcohols or amines <04OL4579>. Moreover, Taddei has prepared a polymer-supported Mukaiyama reagent with a spacer between the resin and the pyridine ring, compound 51, <04JOC9316>. This reagent was prepared from Merrifield's resin in three steps as shown in Scheme 23 and was utilized for the generation of ketenes for Staudinger cycloaddition reactions with imines. Solidphase chemistry has also been used in the preparation of biologically active pyridinium compounds <04JMC6025>; here the molecule is built on the resin and is then cleaved off in a Zincke reaction to generate the pyridinium salt.

272

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

1,3-Dipolar cycloadditions of pyridinium ylides have been used to prepare indolizines. Woisel et al. reported reaction of bipyridinium ylides with an electron deficient propynamido-|3cyclodextrin forming the pyridinoindolizine-|3-cyclodextrin conjugates <04TL1557>. Moreover, Wu has reported the reaction of pyridinium halides with 2,2-difluorovinyl tosylate in the presence of base to yield monofluorinated indolizines <04T5487> as shown in Scheme 24. When unsymmetrical pyridinium halides were used, a mixture of isomers represented by 52 and 53 was obtained. R2

Pyridine jV-oxides are also useful synthetic intermediates in organic synthesis. In the past year, two new methods for the preparation of pyridine A^-oxides have been disclosed. Sain et al. used bromine-T with catalytic ruthenium trichloride in alkaline acetonitrile/water to accomplish this oxidation <04TL4281>. Zhong and co-workers performed this oxidation with trichloroisocyanuric acid in the presence of acetic acid and sodium acetate in acetonitrile/water <04SC247>. While metals have aided in the oxidation of pyridines to iV-oxides, they also have been used as effective catalysts for deoxygenation. Yoo reported the facile and efficient deoxygenation of A'-oxides with gallium in water <04SC3197>. Pyridine A'-oxides have also been used in the presence of a ruthenium catalyst for oxidation of alkanes <04CC798; 04OBC1013> and terminal alkenes to give the unexpected "Wacker type oxidation" <04AG(E)4950>.

273

Six-membered ring systems: pyridines and benzo derivatives

Picoline JV-oxide was used as an intramolecular catalytic group to secure stereochemical integrity of the phosphorus center in a stereospecific synthesis of dinucleoside phosphorothioate diesters <04CC290>.

6.1.3

QUINOLINES

Synthetic approaches to the construction of pyrrolo[3,2-c]quinoline systems were compiled in a review by Nyerges <04H1685>. Recent advances in the synthesis of the Martinelline alkaloids are also described. 6.1.3.1 Preparation of Quinolines The synthesis of quinoline derivatives using metal catalyzed processes continues to be of interest. A modified preparation of 2,3-dialkylquinolines was reported <04JHC423> from nitroarenes and tetraalkylammonium halides via an in situ ruthenium-catalyzed reduction followed by an intrinsic amine exchange reaction using tin(II) chloride. One of the examples reported is shown below in Scheme 25.

a

+

Bu 4 NBr

NO 2

RuCI 2 (PPh 3 ) 3

^^x-^/

_ SnCI 2 »2H 2 O

(I I \ \S^ N ^v/

Scheme 25 A one-pot quinoline synthesis from 2-aminobenzyl alcohol 54 and a,p-unsaturated ketones using ruthenium-grafted hydrotalcite as the heterogeneous catalyst was also described <04TL6029>. In this approach molecular oxygen was used for the oxidation of the ruthenium species and styryl quinolines, such as 55, were produced in good yields. Notably, other donors, such as 1-octanal and phenylacetonitrile were also reacted with 2-aminobenzyl alcohol 54 to give 3-amylquinoline 56 and 2-amino-3-phenylquinoline 57 in good yields.

a

^OH

NH 2

LRu/HT-N, O2

2.

[f^I^I

O

-^°\X^ T ^^\

M

I

1.Ru/HT-N,02

,

2. 1-octanal

kA N ^^p^ 0 ^ 84%

Kj^N^ 8 1 %

1.Ru/HT-N,02 rt^^r^^CN K^

5 6

/W^J^ ^ ^ N 90 %

Scheme 26

55

NH2 57

^ ^ o ^

274

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

In another report, 2-aryl-2,3-dihydroquinolinones were synthesized from 2-aminochalcones using indium(III) chloride supported on silica gel in a solvent-free system <04S63>. Palladium chemistry was investigated to develop a convergent one-pot cascade sequence for the synthesis of 3-aryl naphthyridones and quinolinones as shown in Scheme 27. This approach relies on a palladium-catalyzed cross-coupling reaction of 2-bromonicotinaldehyde or 2bromobenzaldehyde 58 with 2-phenylacetamide 59 in the presence of cesium carbonate and xantphos. Good yields of product 60 were obtained following the cyclodehydration of the resulting amide intermediate <04OL2433>.

Pd2(dba)3 Xantphos

59

58

60

X = C, N

T| K^f>

X = C (94%), N (91 %)

Scheme 27 Titanium catalyzed reactions were further investigated in the past year for the synthesis of quinolines. As part of the ongoing efforts to develop methods for the generation of compound libraries, titanium alkylidene reagents were treated with resin-bound esters followed by acid mediated cleavage to give arylammonium salts 61. 2-Substituted quinolines 62 were obtained upon oxidation of the ammonium salt 61 with manganese dioxide in high purity and moderate yields <04TL8879>.

rV^JL

R^N(TMS)Boc 2. wash 3.10% TFA

resin

R

^V^^R1 ^=^NH

3

Mn

°z,

D2^Y^1

^^N^R1

CF3CO2

61 Scheme 28

62

The synthesis of azatitanacyles was achieved intermolecularly from the reaction of imines 63 and Grignard reagents in the presence of Ti(O-/-Pr)4. Treatment of the titanium species with electrophiles yielded the corresponding substituted tetrahydroquinoline 64 in good yields <04TL9037>. N"^Ph ^jJJ \^N"~^ Bn 63

i.Ti(o-/-Pr)4 /-PrMgCI iiH2

° 94%

H ph y ^ ^ - ^ o ' ' 1

^ ^ N ^ 64

Scheme 29

^ ^

96:4

275

Six-membered ring systems: pyridines and benzo derivatives

A variety of non-metal catalyzed processes for the synthesis of quinolines were also described in the literature. Several 2,4-disubstituted quinolines were synthesized in satisfactory yields by reaction of o-isocyano-|3-methoxystyrene derivatives with nucleophiles, such as alkyl or aryllithiums, lithium benzenethiolate or lithium dialkylamides . The formation of 6-sulfamoylquinoline-4-carboxylic acids was reported using Pfitzinger conditions. In this case quinolines were produced in moderate yields over the corresponding 2-oxo-l,2dihydroquinoline-4-carboxylic acids <04TL5473>. A one-step methodology for the synthesis of 4-hydroxy-2-quinolones was described in which dimethyl or diethyl malonate was reacted with the 1-hydroxybenzotriazole ester of an jV-substituted anthranilic acid <04BCJ1505>. Radical chemistry previously investigated by Naito and coworkers led to a formal synthesis of Martinelline <04TL3481>. In other reports, Mannich reaction of a-ketohydrazones 65 gave (2aryl or alkylquinolin-3-yl)-phenyldiazines 66 in good yields. Conversion of the Mannich adduct 67 to the quinoline 66 derivative was achieved via an Aza-Friedlander reaction <04SC109>.

Rc

PhHN'N.7

65

67

^

N

~ B n

66 R = Me (73%), Ph (82%)

Scheme 30

Variations of the Friedel Crafts and Diels-Alder reactions continue to be of interest for the synthesis of quinolines. Intramolecular cyclization of propargyl trimethylsilyl ethers was achieved via a BF3OEt2 assisted ring-closing Friedel-Crafts reaction to produce 4(vinylidene)tetrahydroquinolines, which were isomerized and aromatized to give quinoline derivatives. A similar approach using TMSOTf as the Lewis acid provided isoquinoline analogs <04OL2361>. One-pot Diels-Alder reactions mediated by FeCl3-NaI <04TL3507> or sulfamic acid <04S69; 04S949> were reported for the synthesis of tetrahydroquinolines. In addition, a one-pot three-step liquid phase aza-Diels-Alder protocol using PEG 4000 as a soluble polymer support was developed for the synthesis of tetrahydroquinolines <04SL1175>. An intramolecular aza Diels-Alder (Povarov) reaction was employed for a total synthesis of the alkaloid Luotonin A 68 (Scheme 31) and the formal synthesis of Camptothecin <04OL4913>.

H

°v f

CL rO 1 N

X^NT I

i

2

R V*° R1

Dy(OTf) 3 (10mol%)

\

II

^l

X^N R 2 -V^° R1

n

—J

J

51%

T n N

V\

XN w^0 R2 k^ R1 = R2 = H ; X = CH

68

Scheme 31

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

276

Methods for the synthesis of quinoline bearing fluorine or difluoromethyl substituents were the focus of various reports. Ichikawa and co-workers described the synthesis of 3fluoroquinolines 69 by intramolecular cyclization of o-substituted p,|3-difluorostyrenes 70, which were generated as key intermediates from the reaction of a-trifluoromethylstyrenes with a nucleophile <04CL590; 04SL1219>, as illustrated in Scheme 32. As an extension of this work, Ichikawa and co-workers also showed that CF2H-substituted quinoline frameworks, 71 (Scheme 32), could be generated via a cyanide ion catalyzed intramolecular cyclization of omethyleneamino-substituted a-trifluorostyrenes 72 <04CL1206>. Notably, Piatnitski and coworkers reported that the reaction of (2-trifluoromethyl)aniline 73 with esters of arylacetic acids produced 4-fluorinated quinolinones 74 <04OL4061>.

catKcN

F 70

r i 1 i ~F L

&

J

catKCN

f*

DBU ^

RXUX^

72

2

71 R2-CH2COOR r Base 1

II —R 73

69

H

^A^/^

., ., ^^^Si,

T

*"

2

"I ^V^i

]

L

R1 J

| N** s K V' ; s ^

*"

]

II

R1

H 74

Scheme 32 6.1.3.2 Reactions of Quinolines The hydrogenation of quinolines has been widely studied for the synthesis of a number of heterocycles. A solvent dependent regioselective hydrogenation in the presence of RJ1/AI2O3 was investigated for the synthesis of tetrahydroquinolines and decahydroquinoline analogs. A combination of long reaction times and use of hexafluoroisopropanol as the solvent often led to complete formation of decahydroquinolines in good yields <04SL2827>. In another report, tetrahydroquinolines were also produced via a [Cp*IrCl2J2 catalyzed transfer hydrogenation reaction using 2-propanol as a hydrogen source <04TL3215>. Various methods for the functionalization of quinolines were also investigated. Hydroxylated heteroarenes were reacted with acetylene in the presence of SnCU and an amine <04H1839>. An Ir-catalyzed addition of ethynyltrimethylsilane to quinoline 74 was used to generate 2trimethylsilylethynyl-l,2-dihydroquinoline 75 as shown in Scheme 33. In this procedure quinoline 74 was activated by phenyl chloroformate, although the addition of AgOTf was also needed to facilitate the functionalization of quinolines bearing electron-withdrawing substituents <04CL1316>. This approach can also be applied to the synthesis of 1-trimethylsilylethyny 1-1,2dihydroisoquinoline 75, which are formed in good yields.

277

Six-membered ring systems: pyridines and benzo derivatives „.

|^^;5Y'Br

TMo

|

b

CICO2Ph

[lrCI(COD)]2

74

Rr

(^y^Y CO2Ph

TMS

80% 75

Scheme 33 The functionalization of two model substrates, namely 4-bromo-6-fluoro- and 4-bromo-7fluoro-2-(trifluoromethyl)quinoline, was investigated using iodine and trimethylsilyl groups as auxiliary substituents for the targeted introduction of a carboxy unit. Steric shielding by the trimethylsilyl groups and deprotonation-triggered iodine migration are believed to contribute to the regiocontrol of these reactions <04EJO1008>. The reaction of l-methyl-3,6,8-trinitroquinoline with enamines was performed for the synthesis of 4-acylmethylquionlones <04CPB1334>. A novel ring expansion of quinolines for the synthesis of benzoazepines was reported by Yadav and coworkers. Quinolines 76 (Scheme 34) were reacted with various diazocarbonyl compounds 77 in the presence of copper(II) triflate to generate the seven-membered azepine ring system 78 in good yields. Isoquinolines were also shown to undergo ring expansion under the same conditions <04CC2124>. R-i

EtO^O 76

0A U

77

C R2

°

OEt 78

Scheme 34 Solid phase chemistry has been an area of much investigation. Recently, solid phase supports were used for the synthesis of polycyclic tetrahydroquinoline based heterocycles using a ring closing metathesis and hetero Michael addition as the key steps <04JCO54>. Solid phase supported quinolines were also used for the development of an iV-acyl dihydroquinoline//V-acyl quinolinium-switch based safety-catch linker that is prepared from a resin-bound iminium intermediate via an aza-Diels-Alder reaction <04TL2251>. A multicomponent reaction was studied using Kobyashi's modification of the Grieco reaction for the synthesis of 4-phenylthio1,2,3,4-tetrahydroquinolines. Using solution phase and solid phase applications these intermediates were oxidized and pyrolyzed to provide a library of 2-substituted quinolines <04JCC768>. 6.1.4

ISOQUINOLINES

A review by Chrzanowska and Rozwadowska <04CRV3341> summarizes two key strategies for the synthesis of isoquinoline alkaloids: stereochemically modified traditional methods and recent advances using the Cl-Ca connectivity approach. Literature from late 1993 to late 2003 is covered in this review.

278

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

6.1.4.1 Preparation of Isoquinolines Various isoquinoline derivatives were constructed using organometallic reagents. In one report, reaction of o-alkynylarylimines with allyltributylstannanes and allyl chloride, employing allyl palladium chloride dimer and Cu(OAc)2 as co-catalysts, resulted in the formation of 1,4diallyl-l,2-dihydroisoquinolines <04TL7339>. A regioselective palladium-mediated C-H insertion was applied to the synthesis of the Amaryllidaceae alkaloids. Scheme 35 shows the synthesis of anhydrolycorine 79, which is a member of this class. The synthetic strategy relied on the intramolecular coordination of the amine group of the dihydroindole 80 to the metal and produced the desired framework in moderate yields <04T1611>. A similar bi-aryl-Pd reaction was optimized by the same group for the synthesis of benzonaphthazepines, which often result as a by-product of benzo[c]phenanthridone formation <04S1446>.

S ^i~ 5 mol %

„

-

KC

.

2 °3

80

f

I

—x

1

°W d Q

~
50%

V ^ I ^ N I / L

lf^%

V ^ O ^

79 Scheme 35 One-pot metal-catalyzed reaction sequences were also studied for the synthesis of isoquinolines. Tetrahydroisoquinolines were formed in moderate yields using a Pd(OAc)/tri-2furylphosphine catalyzed one pot 3-bond formation consisting of metal mediated oalkylation/alkenylation and an intramolecular aza-Michael reaction <04TL6903> shown in Scheme 36. I

(\

k^

NHCbz +

(^

Br

+

J

Pd(OAc)2/TFP Cs

—

CO 2 Me

^ ^ ^ 1

2 C °3 .

k

K->^

[^—(

^r~-~7 IXjf .CO2Me

65%

I PdBrLol ii NHCbz Vjs**^

L

NHCbz

_

Scheme 36 A one-pot 4-component Ugi reaction and Pd-catalyzed intramolecular Heck reaction was developed for the synthesis of two types of isoquinoline scaffolds illustrated in Scheme 37. In this approach an amine, an aldehyde, a carboxylic acid, and an isocyanide react to provide a diversity of a-acylamino amides 81 and 82 which undergo a Pd-catalyzed intramolecular Heck and double bond isomerization reaction to generate the isoquinoline products 83 and 84

279

Six-membered ring systems: pyridines and benzo derivatives <04OL3155>. <04TL417>.

A similar reaction sequence was reported by Gracias and co-workers

CHO ^ ^ 1

R -NC

CO2H ^ ^

(V 80-98%

R3

{J

HH2

/~

(T^f^ V^

K

I HI R1 ll 81

!H0 f2H K

^Y^V^ P d

R

^

H

W

%1

75-98%

I 83

o O^i r T ^ T ^ v ^ ? R 2

f<^i MeOH 1 I n \X k/ ^ 83-90% R3f ] J T Pd(OAc)2 ^

Ri-NC ^ ^ N H

OR2

0

HN

^

pc

^Ri

|| 82 Scheme 37

2

y3

1

I

o T

H N

- R I

1 3

3

A ^ O

80-92% R {rJJ 84

Catalyzed cyclization reactions for the synthesis of isoquinolines were the focus of various reports. 4-Aryl-l,2,3,4-tetrahydroquionlines were synthesized in good yield via a quinone methide mediated cyclization in the presence of zinc chloride <04TL7487>. The intramolecular radical cyclization of oc,|3-unsaturated amides 85 was reported for the synthesis of isoquinoline analogs 86. In this study cc-unsubstiuted acrylamides afforded 6-exo products exclusively. On the other hand, substrates bearing an a-chlorine (X = Cl) substituent provided the 1-endo benzazepine derivatives <04TL2335>.

o ^ • Y ^ Y ^ N ^ T ^

lL^

2

D

R X

Bu3SnH

AIBN *" X

85

=

R1

N/5*Y^N'R2

I^ok^s.

H

48-55%

I 86

Scheme 38 The synthesis of Amaryllidaceae alkaloids siculine, oxocrinine and peicrinine was reported using a key phenyliodine(III) bis(trifluoroacetate)-mediated intramolecular p-p 'diphenol coupling reaction of norbelladine derivatives followed by an intramolecular Michael addition <04T4901>. An alternative approach to isoquinoline derivatives was reported by Chang and coworkers. In this report the benzene nucleus is installed via an intramolecular electrophilic cyclization of 3,4-disubstituted lactams 87 to provide 3,4-dihydrobenzo[g]isoquinoline-l(2/f)one 88 and 3,4-dihydroisoquinoline-l(2/f)-one 89 derivatives in good yields <04TL10637>.

280

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

R

VvVBn

UU

*-9 / s v^r^N- Bn

\\ Ts R-\T

Ti

HC1

0^NJ

HCI

" ^UU 89 DDQ I '

Bn 87

0

Ra-k^A^ 1

O

o

DDQ

R2-kA^k^

88

Scheme 39 A three-step synthesis of lOb-substituted-hexahydropyrroloisoquinolines from Z-tartaric acid was achieved using an acid-catalyzed C-C bond forming reaction via an JV-acyliminium ion. This approach offers the desired products with moderate to good stereoselectivity. The selectivity of the reaction was dependent on the size of the substituent introduced during the generation of the acyliminium functionality <04TL6011>. A three-step domino reaction mediated by AlMe3, illustrated in Scheme 40, was reported for the synthesis of the skeleton of Erythrina and B-homoerythrina alkaloids 90. The reaction is believed to proceed via an Nacyliminium ion and a metalated amide <04AG(E)5391>.

l^J

R O ^ ^

79 . 89 o /o

90

ff

|_

'"

W^' n

Scheme 40 In a study on the activation of macrocyclic enediynes by transannular cyclization it was found that the deprotection of the sulfonamide group of ketone 91 triggered the formation of aminol 92 which readily provided the isoquinoline derivative 93 via a Bergman cyclization reaction <04AG(E)132>.

281

Six-membered ring systems: pyridines and benzo derivatives

N

[f^f

"^

PhSH, K2CO3

y ^ ^ ^

O

I

92

HN

O

^^jfC^/

93

H

° —'

HO

Scheme 41 The acid catalyzed cyclization of 2-acylphenylacetonitriles 94 was investigated using strong acidic conditions. It was found that the use of Amberlyst ion exchange resins, such as A-15 and A-XN1010 in place of sulfuric or methanesulfonic acid provided 1-substituted 2//-isoquinolin-3ones 95 (Scheme 42) in improved yields <04JHC979>. r^j^CN

\^S^°

Amberlyst

95%

94

^y^yP

k^y NH 95

Scheme 42 Methods for the synthesis of isoquinolines using solid-phase supports were also described in the literature. The solid supported synthesis of tetrahydroisoquinolines using a Pictet-Spengler reaction was performed using (4-hydroxyphenyl)sulfide resin (Marshall linker) <04JCO487; 04JCO564>. Tetrahydroisoquinolines were also formed on solid support using a BischlerNapieralski cyclization reaction <04TL8323>.

6.1.3.2 Reactions of Isoquinolines The alkylation of isoquinolines with diethyl malonate mediated by LiCl was reported. This reaction was found to proceed in the absence of Pd catalysts to give dihydroisoquionline derivatives in good yield <04T19049>. An alternative method for the allylation of isoquinolines was developed using indium and allyl bromides to provide allyldihydroisoquinolines in the presence of phenyl chloroformate. This approach circumvents the formation of benzoisoquinuclidine byproducts observed in the allylation reaction of activated isoquinolines with allylsilanes <04OBC2170>. Oxidative and reductive conditions were investigated for the radical cyclizations to isoquionline systems as shown in Scheme 43. For example, isoquinoline 96 was reacted with iron sulfate and hydrogen peroxide (Fenton-type conditions) or n-

282

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

BirjSnH/AIBN to give the desired tricyclic framework 97 and 98 in moderate and good yields, respectively <04L2855>. ^W^Y—
^^Y -yf o

X

""Bu3SnH f j ^ r ^ S AIBN

88% 98

N

^ ^ y

V" R

i V

FeS

°4 7H2O [ j ^ V ^ l

H2O2, DMSO'

^y

N v

o

o

n = 1 , R = H , X = Br

28%

(^

Mr

97

96

Scheme 43 l-( Alky lidene)-l,2,3,4-tetrahydro-./V-(trichloroacetyl)isoquinolines 99 were shown to undergo oxidative cyclization with migration of the trihalogenomethyl group in the presence of lead tetraacetate to provide the corresponding oxazoloisoquinolinone derivatives 100 in good yields <04HCA690>. Rv

"[f^T~^

cc| coci

3

^"v^1^^

R"^R

LTA

R1

V^I/XI

R^R

ClaC^o R R 100

99

Scheme 44 The degradation of 2,2-dimethylisoquinolinium iodides 101 was carried out for the synthesis of phenanthrene alkaloids. Hoffmann elimination of the quaternary ammonium salt gave a stilbene intermediate 102 (Scheme 45), which was used as substrate for a photochemical electrocyclization to afford phenanthrene derivatives 103 in moderate to good yields <04TL4171>.

ir^T R—

rr^r R—

'e

102

I

101

hv, U, O2

^°

\

ill 103

Scheme 45

Y% R—

283

Six-membered ring systems: pyridines and benzo derivatives

A catalytic enantioselective alkynylation of tetrahydroisoquinoline 104 was carried out using CuOTf (Scheme 46). The relatively high enantioselectivity observed for tetrahydroisoquinoline 105 is attributed to a combination of steric effects and possible coordination of the oxygen of the methoxy substituent to copper <04OL4997>. 10 mol % Cu OTf

[f^V^

||

15mol%L

|

f-BuOOH

\_J

f^Y^

^v^v^N-v1X'^1

T

V^/

jf

J

61%, 74%ee 105

Scheme 46

6.1.5

PIPERIDINES

A comprehensive review article on the synthesis of piperidines by Buffat was published in 2004. The review covers many different methodologies applicable to simple piperidines and complex natural products. Pertinent literature through early 2003 is included <04T1701>. A review on the history, chemistry, and biology of the alkaloids from Lobelia inflate by Felpin and Lebreton includes useful information on the synthesis of piperidine alkaloids, with an emphasis on asymmetric methods <04T10127>. 6.1.5.1 Preparations of Piperidines Much effort has been devoted to the application of olefin metathesis to the synthesis of piperidines. Some of this work was outlined as part of a review by Deiters and Martin on ringclosing metathesis (RCM) in the synthesis of oxa- and azacycles <04CRV2199>. Shown below in Schemes 47 and 48 are reactions involving diverse precursors using one of the ruthenium catalysts "Ru" developed by Grubbs and others and always producing a piperidine product. The choice of a particular "Ru" is important in these examples. Diester 106 was prepared as an intermediate for constrained analogs of aminomalonic acid <04TL9607>. A similar RCM reaction was used in the preparation of 107, which was then elaborated to a phenylalanine mimetic constrained in a proline-like conformation <04OBC2365>.

284

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa "Ru"

PCM, 25 °C

^ k^NAc EtOOC

f^\ L^NAc

*"

COOEt

EtOOC

COOEt 106

k

N A CO 2 Me Ph^O

benZene ref UX

'

'

V^CO2Me Ph^O 107

Scheme 47 A chiral 1,6-diene 108 provided the azaspirocycle 109, an intermediate for the total synthesis of pinnaic acid <04SL2295>. A careful choice of catalyst, solvent, and temperature permitted the highly diastereoselective tandem RCM conversion of a tetraene 110 to the azaspirocycle 111 <04T8869>. The key conversion in a synthesis of (-)-allosedamine 112 entailed the extrusion of ethyl acrylate in an RCM reaction as shown <04TL1919> in Scheme 48. A similar RCM reaction involving the extrusion of styrene was used in a total synthesis of some potent polyhydroxylated piperidine glycosidase inhibitors <04JOC1497>. Spirolactams were prepared by RCM of appropriate 6-alkenyl-6-(3-butenyl)-2-piperidones <04T5613>. iV-acryloyl derivatives of substituted (3-butenyl)amines readily undergo RCM reactions to give 6-substituted 5,6-dihydropyridin-2-ones <04JOC6305; 04OL493; 04JCO684>.

TBSCL^LJc^^*" ^^ N '•, Ph^ \

C^\ iH

"Ru"

r~"i T

toluene, 80 °C

N Ph^

^
rs_

DCM,40°C,

^^I'-^N-fl F 3 COC'

"

110

OTS?AC ^ f^^Ph

Jr\ //

109

^ t V ^ .RU"

J B02C^

X ^^

108

5

f\ "

TBSO —

'Ku" toluene, reflux •

" ^ 111

f^l OAc N-WSh

k

Ts H

^ k

- * «•

OH N^T"Ph Me

H

112

Scheme 48 Additional applications of olefin metathesis shown below in Scheme 49 and 50 are indicative of the extent to which the olefmic moieties in the primary products may be transformed to complex piperidine-containing molecules, such as polyhydroxylated indolizidine alkaloids and

Six-membered ring systems: pyridines and benzo derivatives

285

iminosugars. A synthesis of (-)-swainsonine 113 used a ring rearrangement metathesis (RRM) reaction of substrate 114 as the key step to provide the tetrahydropyridine 115 <04JOC7284>. A RCM reaction of 116 provided 117, which was converted to 118 by catalytic OsO4 in high overall yield <04TL761>. HO A c

-

N

^ ^

"Ru"

BnO J L a i B S W

H

^C

/~~\

°™, 4CTC C M ^ H2C=CH2

114 EtO

TBSO

^

^ " ^ S

B n O ^ ^

H O ^ - ^

115

2 c - N ^^v5^X ^ ^

"Ru" DCM,40°C

113

TBSO., ^ 5 . [ |

0TBS

•

CO2Et

116

OH HO,,^L,OH [ | CO2Et

117

118

Scheme 49 The /V-allyllactam 119 was converted by RCM to 120, which on catalytic osmylation provided the polyhydroxylated indolizidine 121 <04OBC3128>. An analog 122 of the iminosugar siastatin B was prepared from the tetrahydropyridine 123. The relative configuration of the substitiuents in the latter were defined by the RCM reaction precursor 124 derived from a 2-azetidinone <04SL2776>. H OTBS

N

^\ 119

TBSO^^oH

,,D „

H?TBS

—* y

120

Dc;40OCTBSO^^

v^, 124

Boc 123

H?

——

H

^ N ^° H 121 OH

TBSO^J Boc 122

Scheme 50 Sequential RRM and cross metathesis (CM) reactions were used in a carefully-designed step in a synthesis of (-)-lasubine 125. The cyclopentenone 126 undergoes RRM to provide the intermediate 127, which reacts with 128 in a CM to provide the intermediate 129 <04T9629>.

286

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa

o

r

f >

I

"Ru"

^

PCM. 40-C

\/~^/N-Boc

I

II

.

^ N ^ - ^ /

B

°C

<^"^Y \

127 L

126

^ - O M e

J

\

CiH J L JJ

M e O ^ ^

128

^ Boc

125

^^^ B /, 129

^

OMe

Scheme 51 A CM reaction of the allylic alcohol derivative 130 and the enone 131 provided the acyclic precursor 132 for the synthesis of (+)-carpamic acid 133 . ™

S 0

V^^ T

+

^NHCbz

"Ru" 9 toluene, 80 » c T M S O ^ / ^ > k ( C H 2 ) 7 C O 2 M e

^ 1 ^^^(CH2)7CO2Me

130

^NHCbz

131

/

132

^N^(CH2)7CO2H H

133 Scheme 52 Finally, RRM was used to convert a diastereomeric mixture 134 to 135 <04S3047> and 136 into 137 <04T6437> in high yields.

a

U DCM 50°C

^

^ ^ ^

P

134

T

ll

r

f f-\

H 2 C=CH 2

N Ns

!

PAc

"RU"

^^CS Pr

C]

QAC

• IS

135

136

137

Scheme 53 Ring formation by reaction of a N-nucleophile on an electrophilic carbon atom continues to be a reliable route to piperidines. The examples shown in Scheme 54, 55 and 56 demonstrate recent applications of closure of nitrogen on an s;?3-carbon atom. Treatment of an aminoalcohol 138 with Ph3P/CBr4/TEA afforded the polyhydroxyindolizidine alkaloid precursor 139

Six-membered ring systems: pyridines and benzo derivatives

287

<04JOC3139>. The reaction of a sulfonamidomesylate 140 with K2CO3/DMF gave the azasugar-type intermediate 141 <04JMC1930>. BnQ

°

MsO

pBn

H

H

BnO

pBn

138

139

HN^'"CO 2 Me SO2Ar

^NT'"C0 2 Me SO2Ar

140

141 Scheme 54

Cyclization of the N-Boc derivative of an aminoalcohol mesylate was used in a synthesis of enantiopure 3-hydroxy-4-phenylpiperidine derivatives from Z-phenylglycine <04TL987>. Alternatively, such 7V-Boc-aminoalcohol derivatives may be subjected to Mitsunobu reaction conditions, as in the preparation of 142, an intermediate in a route to 1-deoxy-Dgalactohomonojirimycin <04JOC2229>. O

cA .

\

AA

I

DEAD

o

\

/

w 142

Scheme 55 A double, regiospecific intramolecular cyclization was employed in the selective generation of 143, an intermediate in a new synthesis of nicotine <04HCA2712>.

I LH C \_J -mC02Me l7\-NHBn

6

NaH/THF. /^/~~N, "" [^ ^TH CO2Me B^n ° 143

Scheme 56

288

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa

"Linchpin dialkylation" of primary amines continues to be a useful concept in the synthesis of piperidines. Such a ring closure was used in the synthesis of paroxetine intermediate 144 <04TL8065> (Scheme 57). {^/r~~Y^<^

BnNH 21

/^Y^^

[-Lores

^O-^OTBS

1

144 Scheme 57

A method which uses a primary amine - diol pair in iV-heterocyclization has been developed. It features the catalytic activity of an iridium complex bearing pentamethylcyclopentadienyl (Cp*) ligands, and produces only water as a byproduct. The method was used in the two-step asymmetric synthesis of (5)-2-phenylpiperidine 145 from (7?)-phenylethylamine 146 <04OL3525>. NH 2 1

cat [Cp*lrCI 2 ] 2

^^Ph

KOAc

146 +

...

^ ^

[ J _ ^

toluene 100 X

*"

pn'

N

[ J Ph' N

^ 145

HO^^'^^OH Scheme 58

Ring formations by reactions of a 7V-nucleophile on carbonyl groups or their equivalents are shown in Scheme 59, 60 and 61. The most familiar application, reductive amination, was used in the synthesis of azasugar derivative 147 from a diol precursor as shown in Scheme 59 <04TL5751>. NHCbz

^ T 0O>^^SDH

/—>.

1.NalO4 2. NaBH3CN r

/^-Q °''-f^S 147

^—S

Cbz

Scheme 59 A key step in the synthesis of optically pure 5-hydroxypipecolic acid derivatives was effected by PTSA-DMF in refluxing toluene to give 148 <04OL4941>. A similar acid-catalyzed ring closure of a hemiacetal gave 149 <04JOC1872>.

289

Six-membered ring systems: pyridines and benzo derivatives

J

H0

-^\

ff^l

f

PTSA-DMF II. JL

HN^^CO2Me

toluene

—-

Cbz

f

i

n

Cbz R

1

R^^N^-COjH

148

_

OH

iV^JL,Ph

PPTS/THFi

T

R2^J

Ri

R

k

.

OH

y~^A^^Ph

2-(T T

O^OH NHBoc

O^Y 149 Scheme 60

Boc

The aza-Achmatowicz oxidation of (2-furylcarbinyl)amines continues to be a valuable method for the preparation of highly-substituted piperidines. The methoxy group in 150, prepared as shown in Scheme 61, underwent displacement reactions to provide useful carbon substituents, for example as a route to racemic azimic acid 151 <04OL4029>. Treatment of 152 with mCPBA/DCM gave 153, presumably with maintenance of chiral integrity <04JOC2892>.

F \ ^ ^ M e 2.(MeO)3CH-catBF3| 0

<*^f 1

]LT

MeO ' N

_ ^ Me

r>' HO2C(H2C)5"

150

)=/

mCPBA/DCM L

NHTs

N

Me

151

1

II ,i.H UH

152

153

Scheme 61 In Scheme 62 are shown recently developed cyclization reactions of JV-nucleophiles on olefmic electrophiles to give piperidines. In an iodolactamization method, chiral 154 gave 155 in 90% yield and 97% de. <04JOC7906>. A tandem Heck-allylic substitution reaction served to convert 156 to 157 with modest diastereoselectivity. A proposed intermediate is the allylic palladium species 158 <04T9687>. An amidomercuration reaction of similar olefinic substrates to give 2,6-dialkylpiperidines has been reported <04OL3067>.

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

290

" > f M ,LHi '-CP H

O

^

2.l 2 ,

0A

- S ^

THF

/ ^'\-°

154 r

r^Y

MUT NHTs

igand

156

155 -l

Ts

H

C r e ^

ACN

Me

T~

Ts i ,_.

Pd(OAc)2 +

/

;

Me |_

s^^s

158

L rt

PdBr

J

157

Scheme 62 Lactamization of suitable 5-aminoacyl derivatives, to give 2-piperidones, continues to be employed in diverse situations (Scheme 63). Acylation of Meldrum's acid with TV-protected |3aminoacids, followed by thermolysis of the resultant Af-protected 5-amino-|3-ketoacid, gave dioxopiperidines 159 <04JOC130>. The key step in a chiral synthesis of (+)-febrifugine was the reductive deamination-recyclization of proline derivative 160 to give 161 <04TL6221>. Formal addition of ammonia to 162 gave the epimeric mixture 163 in fair yield <04JOC1872>. Lithium (S)-iV-benzyl-/V-a-methylbenzamide was used as a chirality source in a synthesis of 6-substituted 2-piperidones, which featured a lactamization reaction <04OBC1387>. O Boc, NH O

;M«

Jl

E c DcM 2 ^ rr 1.Meldrum's Acid

[

°*N * Boc

159 TBSO

A|

TBSO

H

H

160 o

161

Ph V ~ \

Q

NH4QH-NH4CI/Me0H

^/^°^Ph

H

162

163 Scheme 63 Aza-cycloaddition reactions, especially of the [4+2]- type, continue to be of interest for the synthesis of piperidines in various oxidation states. Danishevsky's diene 164 and N-

291

Six-membered ring systems: pyridines and benzo derivatives

functionalized imines gave 4-piperidone derivatives (Scheme 64). The ethyl glyoxylate-derived imine 165 reacted with 164 in the presence of a (S^-BINOL-zinc complex to give 166 after hydrolysis, with moderate to high enantioselectivity <04SL711>. iV-Phosphorylarylimines 167 were used in a study with 164 and various Lewis acid catalysts. Whereas Cu(OTf)2 gave the best chemical yield of racemic 168, the (5)-BIN0L-zinc complex was the only system able to effect an asymmetric (77% ee) result <04SL708>. The aza-cycloaddition of 164 with JV-arylimincs in supercritical CO2 has been studied <04T6163>. CO2Et

.. Me

OTMS

N

M e O ^ ^

^^^OMe

Y l

164

XJ °

^JT\

BINOL-metal complex

165

EtO2C^^O 166 E t

N -PO 3 Et 2 Ar

J

2°3

P

-

N

1.164/DCM ,

^

Ar^^O

2. TFA/DCM

167

168

Scheme 64 In a route to meso-2,6-diaryl-4-piperidones, a diene partner 169 was reacted with Ar-matched yV-allylimine 170 in the presence of Cu(OTf)2 in THF to give, after hydrolysis, 171 with generally high yield and de >99% <04TL4357> (Scheme 65). A [4+2] cycloaddition of |3,yunsaturated a-bromoketenes 172 and imines 173 was studied in detail. Some of the 2-piperidone adducts underwent reaction with allylamine to give aziridines with 99% de. For example, 174 afforded 175 in 85% yield <04T5031>.

„

Ph

Ar^-^y

+

1

J

+

170

PCM

^N--

P h

O 172

[

171

^

\

J

Ar'^^O

Ph

(

X 1

Cu(OTf)2/THF

f

169

r^

j

173

174

Ph

^l

^N>-Ph

allylamine v

O

Ph

175

Scheme 65 The structures of l-aza-2-siloxydienes 176, prepared by silylation of a,|3-unsaturated amides, were rigorously proven. A study of the Lewis acid-catalyzed reactions of 176 with simple dienophiles showed that the [4+2] cycloaddition products 177 did form, along with several

292

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa

byproducts <04S2222>. Hydrazone derivatives 178 have been used in aza-[4+2] cycloadditions with very reactive dienophiles to provide allyl boronate intermediates, which can be trapped with aldehydes to afford highly functionalized piperidines. Some of these were transformed to (-)methyl palustramate 179 and similar compounds <04AG(E)2001; 04JOC8429>. f> CO2Me ^vXO2Me

TBSoAj

+

f

TBSOTf/DCE

J^^]

Ph

Ph

176

177

'

OH

178

179 Scheme 66

Inverse electron-demand cycloadditions of N-sulfonyl vinylimines and allenamides, exemplified by the formation of 180 from 181 and 182, have been examined. The synthetic limitations, mechanistic issues, and stereochemistry of the process have been addressed <04T7629>. Fulvenes have been used as dienophiles with N-sulfonyl vinylimines to synthesize the [l]pyrindine system <04OL3453> and in a formal [6+3] cycloaddition with an appropriate 2//-azirine to give the [2]pyrindine system <04TL1663>. V" N V_

SO2Ph

J*

+

X

^ ^ / ^

f ».

181

PhSo/^N

ACN,50°C

,,N

N

>-

XX -

182 Scheme 67

180

Radical chemistry has found some application in the synthesis of piperidines. An enhanced diastereoselectivity in the reductive cyclization of bromide 183 to the ?ra«,y-disubstituted piperidine 184 was found with fra(trimethyl)silane in place of tributyltin hydride <04OBC2270> (Scheme 68). t-BuO2C. Br

\

t-BuO2C. \

,1 J i-Pr- ^ N ^

TTMSS-AIBN

^K.

toluene, 90 °C

I J i-Pr" ^ N ^

Ts 183

Is 184 Scheme 68

Six-membered ring systems: pyridines and benzo derivatives

293

Tributyltin hydride-promoted cyclization of enamide 185 via a 6-endo-trig process to give 186 showed 6:1 diastereoselectivity. Ph

I Ph

Ph

1 " ° R 185

R = Me TBTH-AIBN toluene, A

jf "1 Ph^N^O Me 186

Scheme 69

A second 5-exo-trig cyclization of an intermediate occurred with the enamide 187 to give 188 <04T8181>. The tributyltin hydride-promoted ring expansion of 189 to 190 demonstrates the key step in a novel protocol for the conversion of electron deficient pyrroles to functionalized piperidines <04CC1422>. Ph i%.

J l Jsv Ph^N^O R

Ph R = 3-butenyl ^

^oc

^

Ph

toluene, A

w^N^O ^—'

187

jJo/WPr

^

TBTH-AIBN

''JL X . 188

X=H 2

'°

TBTH-AIBN toluene, A

189

X^N^CO 2 i-Pr Boc

190

Scheme 70 Ring expansion reactions of 2-substituted pyrrolidines to piperidines have been useful in certain cases, particularly in the iminosugar area. A careful analysis of the formation and fate of the condensed aziridinium ion intermediate 191 was made for the Mitsunobu reaction of 192 to maximize formation of 193 relative to simple alkylation O4SL1711> (Scheme 71). The known conversion of chiral prolinol 194 to 195 was used in the synthesis of thymine PNA monomer 196 <04BMCL2147>.

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa

294 OBn B n

r

N

°^v

HO^^N;

, >

R0H

\ ^

DIAD ,

BnO. / W

192

RONA^OBn

N

^

^ - • • * \

B n

Bn

191

'"r>^

1.TFAA ,

Bn

2. DIPEA 3. H2O

94

U

193

TBSO..,^ V OH

LN^0H 1

OBn

Lft> \J

Bn

T B S O

-,

Q B

T^^,,NHBoc

LNJ

=ST T J

'

^ ^COaH

" 195

196 T = thymine

Scheme 71 Miscellaneous ring closure reactions involving carbon-carbon bond formation are shown in Scheme 72 and 73. An oxidation-cyclization-oxidation process was effected by PCC to convert alcohols 197 to 4-piperidones 198 <04JOC3226>. Intramolecular alkylation was used to covert chiral enaminone 199 to 200, a key intermediate in the total synthesis of lepadin alkaloids <04AG(E)4222>. OH

<


J^^

O

PCC/DCM t

i

r-R

j^Y^-R i

Ts 197

Ts 198

A V T B S TEA-N3, , r V Y 0 1 6 3 kANX..

DMF.110-C KJL X...

H

H

199

200

Scheme 72 Dieckmann cyclization of diester 201 gave the 3-piperidone derivatives 202, aseco ergoline derivative <04JMC5620>. A stepwise [3+3] annulation was effected by sodium hydride to give glutarimide 203, which was found to be a valuable intermediate for piperidine syntheses <04T10223>.

295

Six-membered ring systems: pyridines and benzo derivatives o AxO 2 Et

.CO2B

f| /-CO 2 Et Jj 1 ^J^,N.Me LiHMDS/THF ^ - ^ Y Me 201

0

1

202

1

^H

NaH/THF

EtcAo

J

"

T

O^N^O

R

R

203 Scheme 73 Simple access to piperidines is available in many cases through the reduction of pyridine derivatives (Scheme 74). Recent preparations of 2- and 4- arylmethylpiperidines 204 entailed the addition of aryl Grignard reagents to the requisite aldehydes to give the arylcarbinols 205, followed by a designed sequential hydrogenolysis and ring saturation <04EJO3623>. In a preparation of 4-arylpiperidines 206, aryl Grignard reagent addition to the requisite acylpyridinium salts afforded the dihydropyridines 207, which were hydrogenated selectively in the presence of Wilkinson's catalyst .

f\cHO k

N^

ArMgX,

if^L/0"

H

k

HCI-EtOH

N^Ar

^ 2 5 °C

205

CI^^^CN

T

if^l L

II JL 207

60 °C,

^N^^Ar

RhCI(TPP)4

(^ |j

-I

Ar

204

Jl A 206

Scheme 74 6.1.5.2 Reactions of Piperidines An important area of research in piperidine chemistry involves the synthesis and modification of chiral compounds of general structure 208 derived from (R)- and (S)- phenylglycinol (Scheme 75). The chiral cyanopiperidine 209 was oxidized by permanganate to the lactam 210. Further non-racemizing transformations included chemoselective hydrogenation to 211 and formation of lactone 212 on acid treatment <04EJO4823>.

296

H.L. Fraser, M.B. Floyd and A.C. Barrios Sosa DE

208

OXN1CN \^

_J
y

acetone-H2 Ph

'" RaNi/THFJ

2 09

O

j

H e / ™ 210

MVK

\HCI/EtOH

ji

\

cfV 213

>h 211 .-

r>

Ph ^o

—'.

_^MgBr |

215

HC/

O

>h i

_?U oX N X.NH2

/

>h 214

216

212

217

Scheme 75 The piperidine 213, prepared from 209 by reductive decyanation with Raney nickel, has been shown to be a versatile intermediate. This most simple example of 208 can react via its ringchain enamine tautomer to provide 3-substituted piperidines. For example, reaction of 213 with MVK provided 214 in 63% yield with 92% de <04JOC3836>. With vinylmagnesium bromide, 213 gave a separable mixture of diastereomers from which 215 was prepared by non-reductive removal of the chiral auxiliary followed by acylation. The key aza-Claisen rearrangement of 215 gave 10-membered ring lactam 216. A subsequent sequence of reactions gave (+)-(R)haliclorensin 217 <04OLl 139>. Other complex, chiral oxazolidines of this type have proved to be useful in natural product synthesis (Scheme 76). The epimeric esters 218 were separately converted to their respective Obenzylcarbinols 219. These were subjected to a desaturation-oxidation sequence to give 220. Lactam reduction followed by N- and O-hydrogenolysis gave the azasugars 221 <04TL4903>.

Six-membered ring systems: pyridines and benzo derivatives ^ X O 2 M e I LMe

yy

^ ^ , - O B n f TMe

2.NaH,BnBr

\J

Ph

Ph 218

OH HO^A^OBn

1-PhSeBr

3. OsO4-Ba(CIO3)2

o^N^o

o, Q 219

^-^ P h ' ^

220

1.BH 3 -Me 2 S/ 2. H 2 ^ ^

OH

HO

297

YV"OH

^"^

H 221

Scheme 76 In related work esters 222 and 223 were each converted to the respective alkaloids (-)lupinine 224 and (-)-5-epitashiromine 225 by sequences which featured intramolecular reductive amination reactions <04T5433>. Reduction of advanced intermediate 226 with LAH, followed by hydrogenolysis and deketalization gave 1-deoxy-D-gulonojirimycin 227 <04TL5355>.

1

X

°

~ ^ N ^ ° \ 2. PTSA

P°

I

1

h J 3 ^et°ne-H?O ^ N ^ S

Ph

4. LAH 222

224

^,.CO2Me

1BH3/THF

rX»k^\J O

N

N Ph

o

^,--^OH

2PTSA °

LJ,

acetone-H2O

/—'

3~Tb 223

*"

4. LAH

r-r\° H ^"^.A n O j —\ 226

N

°

N

••

^—' 225

HO f OH 1.LAH/THF , 2.H2-Pd(OH)2 HCI-MeOH

f

T

HO^,,XNJ H 227

Scheme 77 Modification of the piperidine ring using readily-available 2-piperidone-derived intermediates has been actively studied (Schemes 78 and 79). The lactam 228 has been shown to undergo Cu(OTf)2-catalyzed conjugate addition of organozinc reagents in the presence of asymmetric

298

H.L. Fraser, M.B. Floyd and A. C. Barrios Sosa

phosphorus ligands. The resulting zinc enolates can be trapped with electrophiles, for example with acetaldehyde to give, after oxidation, 229 with 94% ee <04CC1244>. O

u

X-NJ

1. Et2Zn-Cu(OTf)2

7 CO2Ph

Et

J[

toluene, -78 °C 2 . acetaldehyde

J

Cr>J co 2 Ph

228

229 Scheme 78

A synthesis of vinyl boronate 230 has been described. Coupling with a variety of aryl- and heteroaryl bromides to give 231 was effected with either of two palladium catalyst systems <04TL5271>. Simple A^-protected 2-piperidones such as 232, when converted to their zinc enolates with the appropriate base present, have been found to react with aryl bromides to give coupling products 233 in generally useful yield <04T9757>.

V/0-B^N^ ^ 6 Cbz

ArBr <°)

,

Pd

230

] | O^N^ Bn

Ar'Nr 6bz 231

1. LiHMDS, ZnCI2 IHE . 2 ArBr pd - (°)

232

" Y ^ O^"N^ Bn 233

Scheme 79 6.1.6

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300 04JMC1575 04JMC1930 04JMC2453 04JMC2688 04JMC3I63

04JMC3180 04JMC4277 04JMC4588 04JMC5620 04JMC6025 04JMC6691 04JOC130 04JOC752 04JOC1497 04JOC1872 04JOC2229 04JOC2863 04JOC2892 04JOC3139 04JOC3226 04JOC3836 04JOC5219 04JOC6305 04JOC6766 04JOC7284 04JOC7906 04JOC8429 04JOC8723 04JOC9316 04OBC1013 04OBC1387 04OBC2161 04OBC2170 04OBC2270 04OBC2365 04OBC3128

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Six-membered ring systems: pyridines and benzo derivatives 04OL3 04OL493 04OL1139 04OL2059 04OL2097 04OL2361 04OL2373 04OL2433 04OL3067 04OL3155 04OL3453 04OL3517 04OL3525 04OL3553 04OL3671 04OL3695 04OL4029 04OL4061 04OL4109 04OL4579 04OL4905 04OL4913 04OL4941 04OL4997 04OPRD955 04S63 04S69 04S949 04S1349 04S1446 04S1619 04S2222 04S2614 04S3047 04SC109 04SC247 04SC759 04SC3197 04SC3227 04SL182 04SL708 04SL711 04SL811 04SL827 04SL1175 04SL1219 04SL1309 04SL1711 04SL2295 04SL2319 04SL2776 04SL2827 04TA1373

301

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302 04T429 04T933 04T1557 04T1611 04T1701 04T2311 04T4901 04T5031 04T5069 04T5433 04T5487 04T5613 04T6021 04T6043 04T6113 04T6163 04T6217 04T6437 04T7629 04T8181 04T8633 04T8869 04T8893 04T9629 04T9687 04T9757 04T10127 04T10223 04T10637 04T11367 04T11639 04T11843 04T11869 04TL417 04TL761 04TL987 04TL1167 04TL1663 04TL1803 04TL1919 04TL2251 04TL2335 04TL2607 04TL2855 04TL3215 04TL3401

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Six-membered ring systems: pyridines and benzo derivatives 04TL3481 04TL3507 04TL4171 04TL4257 04TL4281 04TL4357 04TL4903 04TL4911 04TL5271 04TL5355 04TL5473 04TL5751 04TL6011 04TL6029 04TL6121 04TL6221 04TL6471 04TL6697 04TL6903 04TL7339 04TL7487 04TL7873 04TL8065 04TL8323 04TL8879 04TL9011 04TL9037 04TL9049 04TL9557 04TL9607

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