[Progress in Heterocyclic Chemistry] Progress in Heterocyclic Chemistry Volume 23 Volume 23 ||...

CHAPTER22

Progress in Heterocyclic CISSN 0959-6380, DOI

Synthesis of Heterocycles byPalladium-CatalyzedIntramolecular HeteroarylationDmytro Tymoshenko*, Gyorgy Jeges**, Brian T. Gregg**AMRI, 30 Corporate Circle, Albany, NY 12203, [email protected]; [email protected]**AMRI Hungary, Zahony u. 7, 1031 Budapest, [email protected]

2.1. INTRODUCTION AND SCOPE OF THE REVIEW

Palladium-catalyzed reactions are versatile and efficient methods for the synthesis of a

large number of heterocycles. Annulations of cyclic and bicyclic alkenes

h94AGE2379, 95ACR2, 96CRV365, 99JOM65i, unsaturated cyclopropanes and

cyclobutanes, allenes, 1,3- and 1,4-dienes h99JOM111i, as well as internal alkynesh99JOM42, 99JOM111i with appropriately substituted aryl or vinylic halides and

sulfonates have been extensively reviewed. Most frequently (Scheme 1), palladium-

catalyzed processes involve (route i) Heck, Stille, Suzuki, or Sonogashira reactions

leading to the open-chain precursors followed by (route ii) intramolecular C-hetero-

atom bond formation. The latter is achieved through transformation of electrophilic

functional group E or heteroatom to alkene/alkyne addition. Alternatively (route iii),

the C-heteroatom bond could be formed through a palladium-catalyzed Hart-

wig–Buchwald reaction h07MI564, 02TCC131, 98ACR805, 91JA6499, 97JA8232,

99PAC1417i, giving rise to a variety of heterocyclic systems as well as enabling tandem

C��C/C-Het palladium-catalyzed annulation sequences (route iv). Several examples of

such transformations were included in general palladium-catalyzed amination

h98AGE2046, 98ACR805, 99JOM125i and palladium-catalyzed cyclization

h04CSY47, 06CRV4644i discussions.

hemistry, Volume 23 # 2011 Elsevier Ltd.: 10.1016/B978-0-08-096805-6.00002-4 All rights reserved. 27

E

C C

E

A X

E

X A

A = double/triple bond, SnR3, B(OR)2

X = Hal, TfO

CC

[Pd] [Pd]

C C

X

[Pd]

i

iii

ii

i

A/X X/A

[Pd]

iv

X

N

NN

N N

N

Scheme 1

28 D. Tymoshenko et al.

The current review covers advances in palladium-catalyzed intramolecular het-

eroarylations (route iii) reported over the past 15 years. Mechanistic details of the

transformation are well documented h06CRV4644i; thus this survey involves the

synthetic aspects of the N-aryl bond forming cyclizations. The review is organized

by the size of the rings formed with further partition into subsections based on num-

ber of heteroatoms on the ring or fused ring systems. A separate section deals with

tandem sequences and cascades.

2.2. ANNULATION OF FIVE-MEMBERED AZA-RINGS

2.2.1 Indolines and IndolesThe pioneering work of Buchwald and coworkers h96T7525i for the synthesis of

indolines, oxindoles, and their six- and seven-membered homologs from secondary

amine or carbamate precursors served as a touchstone of the intramolecular palla-

dium-catalyzed processes. Usually, these reactions require a suitable ortho-halo-sub-

stituted precursor and the proper choice of palladium catalyst, ligand, and base.

The original reaction conditions (Scheme 2) result in good yields of cyclized pro-

ducts and include (i) for secondary amines, Pd(PPh)4 in toluene (or DMF) with

superior results when K2CO3 or its mixture with t-BuONa was used as a base; (ii)

for secondary amides, Pd2(dba)3 as a source of palladium, with P(2-furyl)3 as a ligand

with cesium carbonate as a base in toluene; (iii) the “reverse” amides 5 required

Pd2(dba)3 as a source of palladium, with more hindered P(o-Tol)3 ligand with potas-

sium carbonate as a base h96T7525i. It was noted that the coordination chemistry

involving the oxidative addition complexes of aryl iodides and aryl bromides is

substantially different in intermolecular cases; however, for intramolecular cases, no

differences were detectable.

X

NHBn

N

Pd(PPh)4

toluene, X = Br or IK2CO3—62–70%

K2CO3/t-BuONa—77–92%

nn

Bn1 2

Br

NHCOR

N

Pd2(dba)3, P(2-furyl)3

Cs2CO3, toluene100 �C, refluxR = Me, t-Bu

87–99%

nn

3 4

RO

Br

NHBn

On

N O

Pd2(dba)3, P(o-Tol)3 n

Bn

5 6

K2CO3, toluene100 °C, reflux

59–82%

Scheme 2

29Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation

Later developments (Scheme 3) h99OL35, 06SL115i indicated that ligands

capable of chelation, such as bis-phosphines or ligands with heteroatoms capable of

coordination, are superior in many instances for the palladium-catalyzed cyclization

of secondary amides and carbamates.

Br

NHBn

On

Br

NHR

N O

N

Pd(OAc)2, 9

base, toluene100 °C, reflux

Pd(OAc)2, 10

base, toluene100 °C, reflux

R = Ac, Boc, Cbz

n

n

n

BnN

O

NBn

OMe O

PPh2

O

Me Me

R7 8

5 6

9 10 11

14

PPh2

12a

OMe

R1

PPh2 PPh2 PPh2

PPh2

R1

Scheme 3 (Continued)

i-Pri-Pr

12b 13 13a12c

OMePPh2PPh2 PPh2

PPh2

PCy2

i-Pr

Scheme 3


Thus, in the case of o-bromo benzylamide 5 (n¼1), the reaction proceeded

smoothly in 82% yield when (�)-MOP 9 was used as a ligand and K2CO3. Synthesis

of indolines 8 (n¼1) requires Cs2CO3 as a base and DPEphos 10 as a ligand

h99OL35i. A comparative study of ligands for the formation of oxindole 6 (n¼1,

dioxane, Cs2CO3) revealed superior results for phosphine 12a in contrast to ligands

12b and 12c h06SL115i. A similar transformation using X-Phos (13a) and optimized

conditions [(Pd(OAc)2, K2CO3, t-BuOH)] allowed synthesis of pharmaceutically

valuable intermediate 14 in 90% yield h04TL8535, 07BML3421i.(S)-N-Acetylindoline-2-carboxylate 19, a key intermediate in the synthesis of the

ACE inhibitor 20, has been approached in a similar fashion by Buchwald and

coworkers h97JA8451, 03JA5139i. Methyl ester 19 was obtained by a palladium-cat-

alyzed intramolecular coupling of the optically active phenylalanine derivative 17a,

which was prepared by a Heck coupling reaction of o-bromoiodobenzene 15 with

methyl 2-acetamidoacrylate followed by a rhodium-catalyzed asymmetric hydroge-

nation of the resulting enamide 16 (Scheme 4) h97JA8451i. Alternatively, tert-butylester 17b was obtained by the asymmetric alkylation of 18 with commercially

available o-bromobenzyl bromide in the presence of a chiral spiro quaternary ammo-

nium phase-transfer catalyst. Subsequent hydrolysis with citric acid and N-acetylation

afforded 17b in 86% yield with 99% ee (S) h03JA5139i. In contrast to an intermo-

lecular process, which results in partial or full racemization upon treatment with

Pd2(dba)3/P(o-Tol)3, intramolecular palladium-catalyzed C��N coupling afforded

almost enantiopure 19 (94%, 99% ee).

1516

17a, R = Me17b, R = t-Bu

18

I

Br

CO2MeCO2Me

NHAc

Pd(OAc)2TEA, 100 �C

BrNHAc

[(COD)2Rh]OTf(S,S)-Et-DuPHOSH2, MeOH, rt

Br

CO2R

NHAcPh2C = N

O

O

Br

Br

chiral cat., toluene50% aq. KOH

0 �C, 24 h

1.

2. 1 M citric acid/THF3. AcCl/TEA, CH2Cl2

NCO2R

Ac

Pd2(dba)3, P(o-Tol)3Cs2CO3, toluene, reflux

NCO2H

OMe Me

CO2Et

19

20

Scheme 4


Another example of enantiomerically pure substituted 2-carboxy indolines 22

(n¼0) was reported by Jackson and coworkers h02J(P1)733i. The two-step proce-

dure included a palladium-catalyzed coupling of amino functionalized organozinc

reagents with 2-bromoiodobenzene, followed by a palladium-catalyzed intramolecu-

lar amination reaction. The yields in the initial coupling were modest (36–52%),

while the cyclization gave good to excellent yields of the chiral products with

>99% ee (Scheme 5).

I

Br

IZn NHBoc

CO2R CO2R

CO2RBr

NHBocn n n

n = 0, 1R = Me, Bn

Pd2(dba)3, (o-Tol)3PDMF, rt,36–52%

NH

Pd2(dba)3, P(o-Tol)3Cs2CO3, toluene, 100 �C

63–87%

20 21 22

Scheme 5

A new and flexible procedure for the synthesis of indolines has been reported

h03EJO2888i. The target compounds can be synthesized with high diversity from

three building blocks, that is, ortho-bromo- or ortho-chloro-iodobenzenes 23,

terminal alkynes, and primary amines. The synthetic strategies include Sonogashira

couplings and Cp2TiMe2-catalyzed hydroaminations of alkynes 24 (Scheme 6).

The key palladium-catalyzed intramolecular amination of o-halo-substituted phe-

nethylamines 25 and 2-benzyl pyrrolidines 27 results in good to excellent yields of

indolines 26. Depending on the nature of the halide (Br or Cl), different catalyst sys-

tems are used. The bromo derivatives are treated with t-BuONa and [Pd(PPh3)4],

while the chloro derivatives required the presence of t-BuOK, [Pd2(dba)3], and a

carbene ligand generated in situ from imidazolium salt 28.

Analogous synthesis of chiral N-Boc indolines 26 [R1¼4-Cl(Br), R2¼ (S)-Me,

i-Pr, Bn, CH2OTBS, R3¼Boc] has been reported using Pd(OAc)2, DPE-Phos,

and Cs2CO3 in toluene at 100 �C resulting in 51–97% yields of the products

h09TL1920i.

I

R1

R1

R2

R2

R3

R1

R1R1

R3R2+ R3= (CH2)n-2

H

i

R2

ii, iii

R3 NH2

HN

XX

X

iv or v

NR2

R2= (CH2)nNH2;

ii, iii

HN

X

n-2

23 24 25

2627

N N

Cl28

iv or v

Reagents and conditions: (i) PdCl2(PPh3)2. CuI, PPh3, HN(i-Pr)2, reflux, 78-99%; (ii) Cp2TiMe2,100 �C, 24 h; (iii) NaBH3CN, ZnCl2, MeOH, 25 �C, 12 h, 48-97%; (iv) X = Cl, Pd2(dba)3, t-BuOK, carbene ligand; (v) X = Br, Pd(PPh3)4, t-BuONa, 64-99%.

Scheme 6


N-Protected-R-aminoacyl-5,7-dinitroindolines 30 are inaccessible through the

direct acylation of 5,7-dinitroindoline 31 due to its low reactivity (Scheme 7). Never-

theless, they can be prepared in good yields from phenethyl amides 29 by intramolec-

ular amide N-arylation. Although initial attempts using CuI or Pd2(dba)3/Xantphos

failed, reactions succeeded under microwave irradiation using 2-dicyclohexylpho-

sphino-20-methylbiphenyl (Me-Phos) 32 as a ligand and Pd2(dba)3 as a palladium

source. Basic reaction conditions are not compatible with an Fmoc-protecting group,

but they tolerate N-Boc, N-Cbz, and serine O-t-Bu protection h09JOC4519i.

29

Pg

HN

OH

O

O2N

NO2

Br

NH

ONH

Pg

R1

N

OHN

PgR1

R1

O2N NO2

Pd2(dba)3, 32

HN

O2N NO2

X

30

31

K2CO3toluene/MeCN

MW, 100 �C

Me

PCy

32

Cy

Scheme 7


Intramolecular reaction of intermediate 33 in the presence of Pd2(dba)3,

P(o-Tol)3, and t-BuONa in toluene at 80 �C cleanly afforded the tricyclic indoline

34 which, when treated with 10 mol% Pd/C in the presence of ammonium formate,

gave indole 35 as a product of debenzylation and spontaneous oxidation. The latter

serves as an intermediate in the total syntheses of marine alkaloids damirone 36 and

makaluvamine 37 (Scheme 8) h96JA1028i.

NBn

NMe

HN

Bn

NMe

I

Pd2(dba)3, P(o-Tol)3t-BuONa, toluene,

80 �C, 72%

OMe

MeO

OMe

MeO

NH

NMe

OMe

MeO

Pd/C, HCO2NH4, 80%

33 34

35

N

NHO

O

Me

36

N

NHHO

O

Me

37

Scheme 8

Palladium-catalyzed cyclization methodology can be applied effectively to het-

eroaryl halides. The 9-hydroxy-1H-imidazo(1,2-a)indol-3-one moiety occurs in

the potent cholecystokinin antagonist asperlicin 40. The stereochemically controlled

method to the hydroxyimidazoindolones from a 3-alkyl indole includes the


palladium-catalyzed amidation reaction [Pd2(dba)3, P(o-Tol)3, K2CO3, toluene,

105 �C] and provided 48% of compound 39, containing the crucial imidazoindolone

moiety (Scheme 9) h98JA6417, 03JOC545i.

3. Pd2(dba)3, P(o-Tol)3K2CO3, toluene, reflux

N

CO2Ph

TrocHN1. Hg(OTFA)2, KI2. I2

O

NHCbz

48%

N

CO2Ph

TrocHN

NCbz

ON

NH

O

HO NH

NN

O

O

38 39 40

NNH

O

HO

N

N

41

NH

MeO

O

NNH

O

HO

N

N

42

NH

MeO

O

Scheme 9

A similar synthesis of the imidazoindolone motif has been reported by Snider and

coworkers as a part of the total synthesis of fumiquinazolines A (41) and B (42), cyto-

toxic compounds isolated from a strain of Aspergillus fumigatus in the gastrointestinal

tract of the fish Pseudolabrus japonicus h00OL4103i. Recently, a report on the synthe-

sis of chaetominine 45, a modified tripeptide alkaloid containing D-tryptophan, L-ala-

nine, and anthranilic acid moieties, came from the same group h07OL4913i. Thekey step in the synthesis was the palladium-catalyzed cyclization of iodo carbamate

43, which provided tricycle 44 in 64% yield (Scheme 10).

NI

O

NHCbz

Me

COO2Me

TrocHNPd2(dba)3, P(o-Tol)3K2CO3, toluene, reflux

N

COO2Me

TrocHN

64% NCbz

OMe

NN

O

O

Me

NNO

HO

H

9 steps

43 44 45

Scheme 10

Intramolecular arylations of properly substituted (hetero)aryl amines lead to

carbazoles or fused heteroaryl indoles. For example, a palladium-catalyzed cyclization

has been reported for the synthesis of staurosporine 48 (Scheme 11).


This well-known representative of 1H-indolo[2,3-a]pyrrolo[3,4-c]carbazole family of

natural alkaloids, isolated from Streptomyces staurosporeu, is the subject of numerous

synthetic studies aimed at the challenging distinction of the indole N12 and N13

with high regioselectivity. Regioselective synthesis of N13-protected precursor 47

was reported by Nomak and Snyder h01TL7929i starting from the open-chain ethyl

carbamate 46. The relatively low 29% yield can be explained by nonoptimized

conditions and 58% recovery of the starting carbamate 46.

NH

N

N O

Me

NH

HN

N O

Me

CO2Et CO2Et

Br Pd(OAc)2t-Bu3P, PhONa

29 %

N N

N

Me

O

NHMe

MeO

O

1213

4647 48

Scheme 11

Clausenamine-A 51 (Scheme 12) is a natural dimeric carbazole isolated from the

stem and root bark of Clausena excavata, which is used as a Chinese traditional

medicine for detoxication treatment caused by a poisonous snakebite. Its first synthe-

sis was completed h00T7163i through the intermediate diphenyl 49 which cyclized

to carbazole 50 under palladium-mediated conditions.

Pd(PPh3)4Na2CO3,toluene,reflux

97%

49

H2N OTs

MeMeO

MeO

Br

NH OTs

MeMeO

MeONH

HN

OH

MeHO

Me

OMe

OMe

MeO

MeO

50 51

Scheme 12

Identical conditions have been described for the preparation of a series of carba-

zole derivatives as neuropeptide Y1 receptor modulators (Scheme 13)

h07BML1043i. The central core for the library of amides was based on the ester

53 prepared from substituted methyl 6-amino-20-bromobiphenyl-3-carboxylate 52.

Pd(PPh3)4Na2CO3,toluene,reflux

74%

52

H2N O

COOMeBr

NH O

COOMe

53Cl

Cl

Scheme 13


Iodoquinoline 54 underwent an intramolecular palladium-catalyzed intramolecu-

lar amination readily to produce the tetracyclic quinolinoindole ring system 55 in a

65% yield (Scheme 14) h05OL763i.

N

I

N

NHH2N

PdCl2(dppf), dppft-BuOK, toluene/DMF

100 �C, 65%

54 55

Scheme 14

An aza-indole with the fused pyrimidine dione motif 58 has been reported as the

product of a two-step sequence. In the first step, chloro compound 56 underwent

Stille coupling to produce amine 57, which was further submitted to intramolecular

C��N bond formation to yield 71% of the tricyclic product 58 (Scheme 15)

h07BMC3235i.

56

57

NNH2

NNMeMe

O

O

NN

Me

Me

O

ON

Cl

Bu3SnCl

NH2

NNH

NN

Me

Me

O

O

Cl

Pd2dba3, PPh3

CuI, LiClDMF, 55%

Pd(OAc)2, XantphosCs2CO3, DMF

71%

58

Scheme 15


Suitably substituted imines derived from 2-arylacetaldehydes are convenient pre-

cursors of indoles synthesized by intramolecular amination. Thus, palladium-cata-

lyzed cyclization of N,N-dimethylhydrazones of o-chloroarylacetaldehydes 59

resulted in variable yields of N-dimethylaminoindoles 61 (Scheme 16)

h00AGE2501i. Sodium tert-butoxide can be used as a base along with cesium or

rubidium carbonates. Hindered phosphines, for example, tri-tert-butyl phosphine,

give good results, although 2-dimethylaminomethyl-1-di(tert-butyl-phosphanyl)fer-

rocene was the ligand of choice. The mechanistic details of the reaction remain

unknown, but a plausible mechanism involves imine-enamine tautomerization and

formation of aryl(enamido) palladium complex 60. In the case of dichloro derivatives

(R¼Cl), the reaction sequence was extended to a one-pot preparation of N-azole,

amino- or aryl-substituted products 62.

R

ClN

H

N

Me

Me

RN

NMe

Me

[Pd(dba)2]ligand, base

o-xylene, 120 �C

1. [Pd(dba)2] ligand, base o-xylene, 120 �C 18–74%

2. R = Cl, azole, amine or AB(OH)2

AN

NMe

Me

59 60

62

R

PdN

H

N

Me

Me

L

61

Scheme 16

Dihydroisoquinoline 63 and its analogues, prepared by the Bischler–Napieralski

reaction, were converted into indole-fused derivatives 64 by the action of Pd2(dba)3 with

N,N0-bis(20,60-diisopropylphenyl)dihydroimidazolium tetrafluoroborate (SIPr) as a

ligand (Scheme 17) h06S1375i. For undisclosed reasons, this new ring-closure protocol

does not work for the analogous closure of six-membered rings (n¼2). This palla-

dium-catalyzed reaction proceeds through the tautomeric enamine form of imines 63,

and the process was further extended to the preparation of racemic mangochinine 65.

N

MeOOBn

Br OMe

OBn

n = 1, Pd2(dba)3, SIPr

t-BuONa, toluene89%

NMeO

BnO

OMe

OBn

NMeO

BnO

OMe

OBn

Me I-

n

n = 2, no reaction6463

65

Scheme 17


An alternative route to the enamine species includes a Horner–Emmons reaction

of N-aryl a-phosphonylglycines 66, prepared according to the rhodium carbenoid

insertion method, with 2-iodobenzaldehydes (R2¼H, 5-NO2, 4-NO2, 5-OMe)

using DBU as a base at room temperature to give the corresponding vinyl amines

67 in good to excellent yields. The specific formation of (Z)-isomers from Hor-

ner–Emmons reaction is crucial to the success of the next step. Further treatment

of these compounds with PdCl2(dppf) and KOAc in DMF at 90 �C gave the substi-

tuted indoles 68 cleanly. Compounds with electron-withdrawing, neutral, or elec-

tron-donating groups reacted equally well, with traces of concomitant de-iodinated

products observed (Scheme 18) h00TL1623i.

NH

PO(OEt)2

EtO2CI

O

R1R1

R2

DBU, CH2Cl273–90%

NHEtO2C

IR2

R2

R1

PdCl2(dppf)

KOAc/DMF90 �C, 83–94%

NCO2Et

66 67 68

Scheme 18

Similar solid-phase synthesis has been reported by Kondo et al. (Scheme 19) h02J(P1)2137, 03JOC6011i. Intermediate resin 69 was prepared by a two-step process

involving a Heck reaction followed by sequential intramolecular palladium-catalyzed

C��N bond coupling and subsequent transesterification/cleavage to afford ester 70.

CbzNH

X

O

O

NH

CO2Me1. Pd2(dba)3, Cy2NMet-Bu3P, toluene, 80 �C

2. MeONa, MeOH/THF

69 70

Scheme 19


The palladium-catalyzed intramolecular cyclization methodology discussed above

for aryl halides can be successfully extended to vinyl halides. Compound 72, a pre-

cursor to b-lactam antibiotics, was synthesized using a palladium-catalyzed C��N

bond-forming reaction (Scheme 20). In this process, Pd(OAc)2 with DPEphos gave

superior results in contrast to other ligands. A significant increase in yields is observed

when Pd species are generated in the absence of base. Thus, addition of potassium

carbonate after 2 min, as compared to immediate addition, increased the yield from

59% to 74% in the case of bromide (X¼Br) and even more dramatically from

20% to 90% for iodide (X¼ I) h02TL111, 03JOC3064i.

NH

HTBDMSO

O

HMe

X CO2Et

10 mol% Pd(OAc)215 mol% DPEphos

K2CO3, toluene, reflux, 36 h N

HTBDMSO

O

H Me

CO2Et71 72

X = Br, 59%X = Br, 74%(add base after 2 min)X = I, 20%X = I, 90%(add base after 2 min)

Scheme 20

Another example is an intramolecular process for bromo-olefins 73, which were

subjected to catalytic amidation conditions [Pd(OAc)2 and DPEphos] to give the

exo-methylene spiro[4,4]- and spiro[5,4]amides 74a and 74b with 66% and 40%

yields, respectively (Scheme 21) h07SL1037i.

Pd(OAc)2DPEphos

K2CO3, tolueneRCONHPh

Br

O

nR

O

n

N

O

Ph 74a, n = 1, R = 2-furoyl, 66%74b, n = 2, R = Ph, 40%

73

Scheme 21

Suitably substituted vinyl triflates can serve as precursors of ring systems via pal-

ladium-catalyzed cyclizations. Thus, construction of the highly strained tetracycles

77, which are represented as a structural motif in (þ)-nodulisporic acids A and B,

was achieved through a new modular indole synthesis, with the Buchwald�Hartwig

cyclization as the last step (Scheme 22) h06OL2167, 07JOC4611i. Removal of the

Boc group from intermediates 75 or 76 can be followed by intramolecular Buch-

wald–Hartwig cyclization between an enol triflate and a secondary amine. Interest-

ingly, initial efforts to achieve the requisite C��N bond formation employing

Pd2(dba)3/Xantphos and strong bases (e.g., LiHMDS, t-BuONa) in toluene failed,

presumably due to incompatibility of strongly basic conditions with the enol triflate

moiety. This conversion was achieved employing a milder base, Cs2CO3, in THF.

75

N n

n

NBoc

TfO

n

NBoc

TfOor

2. Pd2(dba)3, XantphosCs2CO3, THF

reflux, 55–72%

1. TMSI, CH2Cl2, -78 �C

76 77

Scheme 22


Several substitution patterns appropriate for further intramolecular C��N bond

formation can be achieved through Ugi multicomponent reactions. A novel two-

step solution phase procedure for the preparation of substituted 3-amino oxindoles

80 has been reported (Scheme 23) h06TL3423i. It includes a Ugi four-component

reaction of R1-substituted 2-bromobenzaldehydes, R2-isocyanides, R3-amines, and

R4-acids, followed by intramolecular palladium-catalyzed cyclization. The use of

catalytic system consisting of Pd2dba3, P(o-Tol)3, and Cs2CO3 (for aliphatic isocya-

nide-derived intermediates) or K2CO3 (for benzylic derivatives) in refluxing toluene

resulted in low yields of highly diverse 3-amino oxindoles 80.

78

N

N

N

N

N

R2

O

NR3

R4

O

R1

R1 R1

O R4

R2

O

R3

OR3

R4

OR2

R1 O

R1

NH2

BrR1

Br

OH

O

CN R2

H2N R3

HOOC R4

CF3CH2OH

rt, 36–72% HNR2

O

NR3

R4

O

R1

XX

Cs2CO3 or K2CO3,toluene

reflux, 4–22%

2. Pd2(dba)3, P(o-Tol)3

79 80

818483

82

Scheme 23

Application of iodobenzaldehydes (X¼ I) in combination with microwave irradi-

ation and proper choice of ligand significantly improves the yields of intramolecular

N-arylation conditions h06OL4351i. The optimized conditions [Pd(dba)2, Me-Phos,

K2CO3, MW, 100 �C, PhMe/MeCN 3:1] were applied to the combination of two

aldehydes, six amines, five carboxylic acids, and six isonitriles. A range of functional

groups such as ester, amine, ether, and heterocyclic nuclei (e.g., pyridine and indole)

are tolerated. Even in the case of sterically hindered amides such as tert-butylamide,

Ugi intermediates were readily cyclized to give the corresponding oxindoles

(R1¼H, R2¼ t-Bu, R3¼n-Bu, R4¼Me) in 60% yield.

A similar strategy applied to 2-bromoanilines 81 and 2-bromobenzoic acids 83

usually resulted in moderate 25–50% yields of diverse 3,4-dihydroquinoxalin-2-ones

82 and 3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-diones 84, correspondingly

h06TL3423i.


2.2.2 IndazolesThe first report on intramolecular palladium-catalyzed indazole synthesis included

preparation of 1-aryl-1H-indazoles 87 (Scheme 24) h01TL2937i. The reaction

involves the corresponding N-aryl-N0-(o-bromobenzyl)hydrazines 86 as starting

materials and a catalytic system of Pd(OAc)2/dppf with t-BuONa (150 mol%) as a

base in toluene at 90 �C. Under these conditions, cyclization was followed by spon-

taneous aromatization. Phosphonium bromides 85, which serve as precursors of N,

N0-disubstituted hydrazines 86, when submitted to similar reaction conditions (Pd

(OAc)2/dppf, 250 mol% of t-BuONa, dioxane at 90 �C) also led to formation of

the corresponding 1-aryl-1H-indazoles. The extra equivalent of the base is presum-

ably needed to deprotect the triphenylphosphonium species.

Br

N

HNPh3

+P

R1

R2

NNR1

R2

Pd(OAc)2dppf, t-BuONa

toluene, 80–93%

Br

HN

HN

R1

RNaOH

Br-

85 86

87


toluene, 41–60%

Br

N

HN

R1

R2

88

Pd(dba)2

ligand, base,40–96%

Scheme 24

Similarly, palladium-catalyzed cyclization of arylhydrazones of 2-bromoalde-

hydes 88 (and 2-bromoacetophenones) gave 1-aryl-1H-indazoles h05JOC596i.Cyclization of the arylhydrazones of 2-bromobenzaldehydes can be performed with

good to high yields using Pd(dba)2 and chelating phosphines, of which the most

effective are rac-BINAP, DPEphos, and dppf, in the presence of Cs2CO3 or

K3PO4. Commonly used for intermolecular aminations, electron-rich and bulky

ligands such as t-Bu3P and o-PhC6H4P-t-Bu2 are ineffective for cyclization and lead

to intractable reaction mixtures. The method developed is applicable for preparation

of diverse indazoles bearing electron-donating or electron-withdrawing substituents,

including unprotected carboxyl and various indazole hetero analogues. Notably, the

purity of the starting hydrazone is a critical parameter, as various impurities inhibit

the cyclization.

Analogous transformations have been reported for N,N-substituted hydrazines 89

to produce good yields of 2-aryl indazoles 90 (Scheme 25) h00OL519i.


toluene, 51–62%Br

NNH2

R1

R2

89

NN

R2

90

R1

Scheme 25


An efficient method for the preparation of 3-substituted indazoles 92 was devel-

oped using the palladium-catalyzed intramolecular amination of 2-bromo(chloro)

phenyl hydrazone derivatives 91 (Scheme 26) h04CL1026i. Good functional group

compatibility was observed under mild reaction conditions, and various 3-substituted

indazoles were obtained in moderate to excellent yields.

X

N

NHTosN

N

Tos

Pd2(dba)3, P(o-Tol)3LiHMDS, toluene, reflux

R1R1

91 92

Scheme 26

A new method for the synthesis of tricyclic indolo[1,2-b]indazoles 95 in high

yields starts from N-acetamino-2-(2-bromo)arylindolines 93, which are available in

three steps starting from 2-(2-bromo)indoles (Scheme 27) h02TL3577i. Intramolec-

ular C��N bond formation catalyzed by palladium acetate gave excellent yields of

intermediates 94. Their further hydrolysis and basic aluminum oxide catalyzed air

oxidation allowed the preparation of fused indazoles 95 in high yields.

93

Pd(OAc)2DPEphos

Cs2CO3, toluene,reflux, 18 h,

81–99%

1. NaOH, aq. MeOH2. Al2O3, CH2Cl2

NN

R2R1

NN

R2R1

Ac

NNH

R2

Ac

Br

R1

94

9584–96%

Scheme 27


Synthesis of indazolone derivative 98 has been reported starting from o-iodoben-

zoic acid 96 through intermediate hydrazide 97 accessible by Schotten-Baumann

acylation (Scheme 28) h08JMC2137i.

96

COOH

I I

N

O

Bu1. SOCl2, CH2Cl2

2. n-Bu-NHNH2·C2O4H2, CH2Cl2, NaOH, H2O

NaOH, C2H5OH

Pd(dppf)2Cl2

NH2

N

O

BuNH

9897

Scheme 28

2.2.3 Fused Imidazoles, Thiazoles, and OxazolesA palladium-catalyzed N-arylation that provides a novel synthesis of benzimidazoles

from (o-bromophenyl)amidine precursors has been reported h02TL1893i. The

catalytic system needed extensive optimization as no reaction was observed using

“Buchwald’s conditions” [Pd2(dba)3/P(o-Tol)3 with Cs2CO3, K2CO3 or t-BuONa

in m-xylene after 18-h reflux]. The same result was obtained when starting amidine,

and Pd(OAc)2 and Na2CO3 were heated under reflux in DMF for 18 h. On the

other hand, reaction with Pd2(dba)3/BINAP in toluene for 18 h under reflux was

successful. Another successful reaction condition was the use of Pd(PPh3)4(5–10 mol%) and a mixture of t-BuONa (1.6 equiv.) and K2CO3 (1.6 equiv.) in tol-

uene for 18 h under reflux, which was selected as the optimal protocol. The

improved conditions were further developed and optimized (Scheme 29)

h03JOC6814i. A range of benzimidazoles was prepared rapidly and in excellent yields

using of Pd2(dba)3 and PPh3 in 1:8 molar ratio, NaOH as a base in H2O/DME at

160 �C under microwave irradiation in combination with a “catch and release” purifi-

cation strategy on Amberlyst 15. The route is flexible and allows for the preparation of

highly substituted benzimidazoles including regioselective N-substitution.

NHN

R3

Br

R2

R1

N

NR3

R2

R1

1. Pd2(dba)3, PPh3 NaOH, 50% H2O/DME MWI, 160 �C

2. Amberlyst, CH2Cl23. TEA 50%/CH2Cl2

66–98%99 100

N

NNH

Ph100a

N

NNH

Bn100b

Ph

Bn

Scheme 29

In a related synthesis of 2-aminobenzimidazoles (R3¼ substituted amine)

h02TL1893, 03OL133i, the palladium-mediated process was disadvantageous com-

pared to copper(I)-catalyzed cyclization due to purification issues. Notably, when


derivatives of primary amines are used (R2¼Ph; R3¼NHBn), the copper-catalyzed

process led exclusively to exo-benzyl product 100a, while Pd catalysis results in the

mixture of exo- and endo-products 100a and 100b h03OL133i. A related synthetic

strategy has been reported h10BML526i for the synthesis of 1-(3-aryloxyaryl)benz-

imidazole sulfones as liver X receptor agonists.

Similarly, 2-amino- and 2-alkyl-benzothiazoles have been efficiently prepared by

palladium-catalyzed cyclization of o-bromophenylthioureas and o-bromophenylthio-

mides. Pd2(dba)3/o-biphenylP(t-Bu)2 provided the best synthetic results (Scheme 30)

h03TL6073i.

HN R1

SBr

S

NR1

Pd2(dba)3, ligandt-BuONa or Cs2CO3

68–100%

101 102

Scheme 30

N-Substituted o-chloroanilines or 2-chloro-3-aminopyridines 103 can be effi-

ciently converted into benzo(pyrido)imidazolones 105 through intermediate primary

ureas 104, which undergo palladium-catalyzed cyclization in a final step. The Pd

(OAc)2/dppb catalyst system was effective for the 2-chloropyridine series (X¼N).

For the less reactive o-chloroanilines (X¼CH), the use of more active Xantphos

ligand produced good yields of the products (Scheme 31) h06OL3311i.

X Cl

NH21. RCHO, NaBH4

2. CSI

3. H2O X Cl

N O

NH2

X = N, Pd(OAc)2, dppbX = CH, Pd(OAc)2, Xantphos

NaHCO3, THF or i-PrOH60–99%

X NH

NO

1

3

RR

N Cl

HN

HN

O

PhPd(OAc)2, Xantphost-BuONa, THF

N N

HN

O

1

343%

PhNCO X = N

NN

NO

OMe

Nn-Pr

n-Pr

Me

GW808990

103104

105

106 107

Scheme 31

In the same way, 3-substituted derivative 107 can be obtained starting from the

corresponding secondary urea 106 h06SL2083i. This synthetic approach has been

recently reported for the synthesis of a potent CRF antagonistGW808990 h06SL2716i.


3-Anilino-pyrazinones are readily available from dichloro pyrazinones which

demonstrate significant electrophilicity under acidic catalysis using camphorsulfonic

acid (CSA). They can be easily converted to the tricyclic substituted pyrazino[1,2-

a]benzimidazol-1(2H)ones by applying a microwave-assisted Buchwald–Hartwig-

type cyclization (Scheme 32). The best results were obtained using Pd(PPh3)4 as a

catalyst and potassium carbonate as base although reaction time was still considerable

(12 h), while using microwave conditions at 150 �C for 25 min with 10% Pd(PPh3)4and anhydrous potassium carbonate in DMF resulted in good yields of the products

(Scheme 32) h08T8128i.

108

N

N

Cl

OR1

R2

Cl

NH2

Br R3

R4

NHBr R3

R4

N

N OR1

R2

ClCSA, i-PrOH N

R3

R4

N

N O

R1

R2

ClK2CO3, Pd(PPh3)4

109 110 111

reflux, 48 h51–82%

DMF, 150 �C (MW)150 W, 25 min

61–78%

Scheme 32

An analogous transformation was reported for 2-(2-bromoanilino)quinolines 112

which resulted in the synthesis of benzimidazo[1,2-a]quinolines 113. The intramo-

lecular Buchwald–Harwtig-type heteroarene N-arylation was applied using opti-

mized reaction conditions. In general, excellent yields (70–93%) of substituted

benzimidazo[1,2-a]quinolines 113 were obtained from substrates bearing methyl,

isopropyl, or methoxy groups in various positions of either the quinoline ring or

the anilino moiety (Scheme 33) h06JOC1280i.

NH

NBr

N

NR3

R3

R4

R2

R1

R4

R1R2

Pd(PPh3)4

DMF/K2CO3130–140 �C

112 113

Scheme 33

2.3. ANNULATION OF SIX-MEMBERED AZA-RINGS

2.3.1 Quinolines and Their Di- and Tetrahydro DerivativesLike indolines and oxindoles (Section 2.2.1, Scheme 2), the six-membered homologs

when prepared from secondary amide or secondary carbamate precursors (1 and 3,

correspondingly, n¼2) require a proper choice of palladium catalyst, ligand, and base


h99OL35, 06SL115i. As in the case of oxindole 2 (n¼1), reaction using the (�)-

MOP 5 ligand and potassium carbonate resulted in a 94% yield of quinolone

2 (n¼2). Synthesis of tetrahydroquinolines 4 (n¼2) required Cs2CO3 and BINAP

ligand 13 h99OL35i. Comparative study of ligands in the formation of quinolone

6 (n¼2, dioxane, Cs2CO3) revealed superior results for phosphines 12a and 12c

with lower yields for ligand 12b h06SL115i.Interestingly, chiral N-sulfinyl amine 7 (n¼2, R¼SO-t-Bu, R1¼n-Bu,

Scheme 3, Section 2.2.1) undergoes spontaneous sulfinyl deprotection under palla-

dium-catalyzed cyclization conditions [Pd2(OAc)3, BINAP, Cs2CO3] resulting in

the corresponding unsubstituted tetrahydroquinolines 8 (R¼H) h10JOC941i. Syn-thesis of optically active atropisomeric anilide derivatives through a catalytic asym-

metric N-arylation reaction h05JA3676, 06JA12923, 08TL471i can be further

extended to the intramolecular variation (Scheme 34). The reaction of anilide

114a (X¼Y¼CH2, R¼H) in the presence of Cs2CO3 in toluene using Pd

(OAc)2/(S)-BINAP catalytic system gave the corresponding lactam 115a in 70%

ee and 95% yield. Although further attempts to improve enantioselectivity for this

product were unsuccessful, the reaction with 2,5-bis-tert-butylanilide 114b

(X¼Y¼CH2, R¼ t-Bu) led to high enantioselectivity affording atropisomeric

lactam 115b of 96% ee and in 95% yield.

114a, 115a; R = H, X = Y = CH2; 95%, 70% ee;114b, 115b; R = t-Bu, X = Y = CH2; 95%, 96% ee;114c, 115c; R = t-Bu, X = NBn, Y = CH2; 82%, 94% ee;114d, 115b; R = t-Bu, X = CH2, Y = NBn; 95%, 96% ee

Pd(OAc)2, (S)-BINAPCs2CO3, toluene 80 �C

YX NH

O

t-Bu

R

IN

XY

O

t-Bu

R114a-d

O

O

O

O

PPh2

PPh2

116, (R)-SEGPHOS

115a-d

Scheme 34

A recent study reported the use of Pd(OAc)2 and (R)-SEGPHOS 116 as condi-

tions which produce the products in a highly enantioselective manner (89–98% ee)

h10T288i.Malonamides 117 bearing 2-bromoarylmethyl groups upon treatment with Pd

(OAc)2 and various ligands undergo intramolecular double N-arylation giving excel-

lent yields of spiro derivatives 118 (Scheme 35). While treatment with DPEphos

gave only a racemic mixture, the use of (S)-BINAP resulted in up to 70% ee of

spirobi(3,4-dihydro-2-quinolone) derivatives 118 h09OL1483i.

117

NNR

ROO

NH

NH

R

R

O O

Br

Br

Pd(OAc)2, (S)-BINAPK3PO4

118

97%

Scheme 35


Amino-ester 119 can be prepared by enantioselective Mannich reaction and

sequential SmI2 reduction and was further transformed into 1,2,3,4-tetrahydroquino-

line 120 in 73% yield (Scheme 36) h08JA6676i.

119

Br

NH2

MeOMe

O

NH

OMe

O

Me

1) 5 mol% Pd2(dba)320 mol% XPhos

toluene, 90 �C2) SmI2

73%120

Cs2CO3

Scheme 36

Intramolecular Buchwald–Hartwig aryl amination is a crucial step in the synthesis

of (þ)-virantmycin 123, an unusual chlorinated tetrahydroquinoline present in a

strain of Streptomyces nitrosporeus (Scheme 37) h04AGE6493i. Aryl aminations with

aliphatic amines containing a-quaternary centers are quite rare, and initial attempts

using a variety of conditions and ligands gave unsatisfactory results. However, the

treatment of formamide 121 with Pd2(dba)3 in the presence of the Keay ligand

(BINAPFu) resulted in quantitative cyclization to the precursor 122. The selection

of BINAPFu 123 as the Pd ligand of choice was based on model studies of the aryl

aminations of other quaternary amines (1-adamantylamine and methyl a,a-dimethyl-

glycinate) with methyl 4-bromo-3-methylbenzoate. Other ligands, such as BINAP,

DPPF, PCy3, o-biphenyl-PCy2, o-biphenylPtBu2, DPEphos, MAP, and IMES

hydrochloride, failed or produced very low yields of the corresponding arylamines.

121 122

Pd2(dba)3/BINAPFuCs2CO3

Br

MeO2C

OAc

NHCHO

OMeMe Me

Me

N

HOOC OAc

MeMe

MeOMe

CHO

100%

NH

HOOC Cl

MeMe

MeOMe

O

O

PPh2Ph2P

BINAPFu =

123124

Scheme 37


Preparation of the toad poison dehydrobufotenine 127 was one of the first appli-

cations of intramolecular palladium-catalyzed arylation in total synthesis (Scheme 38)

h96JA1028i. The tryptamine derivative 125 (R1¼Me, R2¼CO2Et, R3¼Bn) when

treated with Pd(PPh3)4, K2CO3, and NEt3 gives the tricyclic intermediate 126 in

good yield. Unusually, high temperatures are required for this cyclization as only

mild potassium carbonate can be used because stronger bases cleave the N-indole

carbamate protecting group. Sequential treatment of 126 with BBr3 led to cleavage

of both the carbamate and the O-methyl groups and then in situ quaternization by

addition of excess MeI and KHCO3 produced 127 as its iodide salt. A recent alter-

native route h10T4452i included 5-O-silyl and N-tosyl protecting groups, although

a lower, 43% yield of intermediate 126 was produced.

125

N

NHR3

I

NR2R2

NR3

Pd(PPh3)4

K2CO3, TEAtoluene, 200 �C

(i) R1= Me, R2= CO2Et,R3= Bn, 81%

(ii) R1= TBDMS, R2= Ts,R3= Me, 43%

R1O R1O

NH

NMeHO

MeI-

126127

Scheme 38

Extension of palladium-catalyzed C��N bond formation to supercritical carbon

dioxide media resulted in the synthesis of N-tosyl and N-methylsulfonyl tetrahydro-

quinolines 129 (Scheme 39) h05OBC3767i. The potential issue with carbamic acid

formation is avoided through the use of N-silyl sulfonylamides as the coupling


precursors to increase the yield of the mesyl derivative (R¼Me) from 22% to 55%.

The effect of N-silylation on tosyl derivative (R¼p-Tol) is less significant.

N

TMS

Br

128

SO2R

Pd(OAc)2, P(t-Bu)2(o-biphen),Cs2CO3, scCO2, 1800 psi,

100 �C, 20–61% N

SO2R

129

Scheme 39

In a similar fashion, intermediate 131, obtained from Baylis–Hillman acetate 130

and p-toluenesulfonamide, underwent cyclization in the presence of palladium ace-

tate and BINAP in toluene at 100 �C for 12 h to give dihydroquinoline 132 in

81% yield (Scheme 40) h07SC2677i.

Br

OAc

COOEt TosNH2

EtOHBr

COOEt

NHTos

Pd(OAc)2BINAP

K2CO3, toluene81% N

Tos

COOEt

130 131 132

Scheme 40

Like 2-arylacetaldehyde derivatives (Scheme 16, Section 2.2.1), substituted

imines derived from 3-aryl propionaldehydes are prone to intramolecular palla-

dium-catalyzed N-arylations. Thus, cyclization of N,N-dimethylhydrazones of

2,6-dichlorophenyl propionaldehyde 133 resulted in 5-chloro-1-dimethylamino-

4H-quinoline 134 in 32% yield (Scheme 41) h00AGE2501i.

Cl

N

H

NMe

Me

N

NMe Me

[Pd(dba)2]ligand, base

o-xylene, 120 �C

133 134

ClCl

Scheme 41

Tricyclic aldehyde 136, a key intermediate in the synthesis of conformationally

restricted pyrrole-based inhibitors of HMG-CoA reductase, was obtained from

anilide 135 using a standard C��N bond coupling procedure (Scheme 42)

h07BML4531i.

135

NNH

OPh

Br

MeMe

F

OPd(OAc)2, Xantphos

Cs2CO3, toluene

NN

OPh

Me

Me

F

O

37%

136

Scheme 42


2.3.2 QuinazolinesThe use of 2-(dicyclohexylphosphino)-biphenyl as the ligand of choice with K3PO4

as base and Pd2dba3 as the palladium source leads to the smooth cyclization of aryl

benzyl ureas 137 to dihydroquinazolinones 138 (Scheme 43) h04BML357i. Thereaction works for either activated aryl chlorides (X¼Cl, R1¼NO2) or aryl bro-

mides (X¼Br, R1¼H). Good to excellent yields were obtained regardless of the

substitution pattern on the N-aryl substituent.

137

R1

X

NH

NH

O

Ar

N

NH

O

R1Pd2(dba)3/ligandK3PO4

R1= H, NO253–93%

Ar

138

Scheme 43

Another example is the one-pot reaction between secondary o-bromobenzyla-

mines and isocyanates leading to dihydroquinazolinones (Scheme 44) h03S1383i.Thus, addition of isocyanates 140 to the mixture of amine 139, Pd(Ph3P)4, and

K2CO3 in anhydrous toluene or DMF and heating for 8–30 h resulted in satisfac-

tory-to-good yields of cyclic products 141.

139

Pd(PPh3)4K3PO4

toluene,50–85%

140

Br

NH-BnR1 N C O

N

N O

R1

Bn

141R1 = n-Bu, p-MeOC6H4CH2, Ph, p-ClC6H4, p-CNC6H4

Scheme 44

Like anilides 114a and 114b, reaction of 2,5-bis-tert-butyl urea 114c (X¼NBn,

Y¼CH2, Scheme 34, Section 2.3.1) proceeded with excellent enantioselectivity

(94% ee) to give the cyclic urea 115c in 82% yield h05JA3676, 06JA12923, 08TL471i.


2.3.3 Quinoxalines, Benzo-oxa(thia)zines, Phenazines, andRelated RingsLimited examples exist in the literature for quinoxaline ring synthesis through palla-

dium-catalyzed intermolecular reactions. Like 3-amino-indol-2-ones 80 (Sec-

tion 2.2.1, Scheme 23) h06TL3423i, quinoxalin-2-ones 82 can be obtained in two

steps. The first step includes a Ugi four-component reaction of R1-substituted 2-

bromoaniline 81, R2-isocyanides, R3-aldehydes, and R4-acids, followed by intramo-

lecular palladium-catalyzed cyclization. An analogous transformation has been

reported for linear o-iodo amides 142, prepared in one step by the Ugi four-compo-

nent reaction, which can be converted into 3,4-dihydroquinoxalin-3-ones 143 or into

2-(2-oxoindolin-1-yl)acetamides 144 dependent on the catalytic conditions. Micro-

wave irradiationwas essential for reaction efficiency, while the choice of ligand diverges

the reaction pathway. Heating a solution of 142 in dioxane/MeCN in the presence of

Pd(dba)2 and Cs2CO3 using X-Phos as a ligand afforded the 3,4-dihydroquinoxalin-

3-one 143 via an intramolecular N-arylation of the secondary amide. However, using

BINAP as ligand under the same conditions, intramolecular R-CH arylation of tertiary

amide occurred to give oxindole 144 (Scheme 45) h09JOC3109i.

I

N

OC3H7

i-Pr

O

NH

t-Bu

Pd(dba)2Cs2CO3,

ligand

dioxane/MeCNMWI, 150 �C

N

N

N

t-Bu

OC3H7

O

i-Pr

C2H5

O

i-Pr

NH-t-Bu

O

142 143 144

Ligand 143 144XPhos 91% 0%BINAP 0% 80%

Scheme 45

As described above for anilides derived from 3-phenylpropanoic acid (Scheme 34,

Section 2.3.1), reaction of glycine derivative 114d (X¼CH2, Y¼NBn) proceeded

with excellent enantioselectivity (95% ee) to give piperazinone 115d in 71% yield

h05JA3676, 06JA12923, 08TL471i.An efficient synthetic route to aryl- and benzylamino-substituted 4H-1,3-ben-

zothiazines has been developed (Scheme 46) h08SL2433i. 1-(2-Bromobenzyl)-

(X¼Br) and 1-(2-iodobenzyl)-3-phenyl-thiourea (X¼ I) 145 are readily available by

the condensation of the corresponding o-halobenzylamine and phenylisothiocyanate.

Applying the palladium-catalyzed protocol to 1-(2-bromobenzyl)-3-phenyl-thiourea

using Pd(PPh3)4 in the presence of triethylamine in refluxing dioxane resulted in only

16% of the product 146 (R1¼R2¼H, R3¼Ph) while the iodo derivative afforded a

55% yield. Addition of an extra 10 mol% of triphenylphosphine further increased the

yield to 67%. Interestingly, when benzyl urea was used as a starting material

(R3¼Bn), a stronger base (DBU) was required to yield the product quantitatively.

145

N

RX

NH

S10 mol% Pd(PPh3)410 mol% Ph3P

Et3N or DBUdioxane, reflux

S

N

NH

R3

R1R1 R2 R2

R3

146

Scheme 46


As compared to quinoxalines and benzothiazines, the palladium-catalyzed syn-

thesis of benzoxazines is more common. Thus, the crucial step in the synthesis of

8H-[1,4]oxazino[2,3-f]quinolin-8-ones 149 with androgen receptor modulating

activity was the annulation of the morpholino ring according to Scheme 47 (yields

are not reported) h07BML5442i.

147

N

O

Br

NH2R

O

CF3

Pd2dba3, BINAPt-BuONa, toluene

reflux

N

ONH

R

O

CF3

CF3

NH

ONH

R

O

148 149

Scheme 47

Similarly, synthesis of another series of selective androgen receptor modulators,

[1,4]oxazino[3,2-g]quinolin-7-ones 151, has been reported. The key step in the

8-step synthetic sequence was palladium-catalyzed amination of intermediate 150

(Scheme 48) h08BML2967i.

NH

O

HN

O

CF3

R

NH

O

Br

O

CF3

NH2

HR

Pd2dba3, t-BuOK

BINAP, toluene90 �C

R = CH2CF3, Bn,CH2CH2SMe

150 151

Scheme 48

1,2-Cyclic sulfamidates 152 undergo efficient and regiospecific nucleophilic

cleavage with 2-bromophenols 153 (X¼O), followed by Pd-mediated amination

giving access to substituted and enantiomerically pure 1,4-benzoxazines 155

(X¼O). The related anilines (X¼NH) and thiophenols (X¼S) can be used to pro-

duce the corresponding quinoxalines 155 (X¼N) and 1,4-benzothiazines (X¼S).

This chemistry provides a short and efficient entry to (3S)-3-methyl-1,4-benzoxa-

zine 156, a late stage intermediate in the synthesis of antibiotic levofloxacin 157

(Scheme 49) h07OL3283i.

152

N OS

O O

R1

Br

XH

NH X

R1

R2 R2

Br

NaH, DMF

Pd(OAc)2, Xantphos,t-BuONa, toluene

N

X

R1

R2

R1 = Me, Ph, BnR2 = Me, Bn, Boc

65–88%

HNO

R1

F

F

NO

R1

N

F

N

OHOOC

Me

153

154 155

156 157

Scheme 49


The new 2,3,7,8-tetrachlorodibenzo-p-dioxin analogue, phenothiazine 161

(TCPT), has been developed and explored to take advantage of the low-dose effects

of dioxins that have potential application as therapeutics. It can be synthesized in

three steps with the key ring-closing step performed utilizing a Buchwald–Hartwig

amination in the presence of 2-(dicyclohexylphosphino)-biphenyl (DCPB) ligand

to provide TCPT in 37% yield (Scheme 50) h07MI890i.

Cl

Cl

Cl

SH

O2N

F

Cl

Cl

Cl

Cl

Cl

S

Cl

Cl

Cl

Cl S

Cl

Cl

HN

1. K2CO3, CaCO3 CH2Cl2, 97%

2. Fe/AcOH acetone/H2O, 86%

Pd(OAc)2/DCPB

t-BuONa, DMF200 �C, MW, 2 min

37%

158 159

NH2

160

161

Scheme 50

Following a report on phenazine synthesis h05OL1549i, a novel methodology

for the synthesis of dihydrodipyridopyrazines 164 was developed h09OL5502i.Intermediates 162 (R¼Me, Bu), obtained by Smiles rearrangement of nitro-substi-

tuted N,N0-dipyridinylamine precursors, cyclize to 5-alkyl-5,10-dihydrodipyrido

[3,2-b:30,20-e]pyrazines 163, which can be further alkylated at position 10 providing

moderate yields of 5,10-disubstituted products 164 (Scheme 51). Applying the same

reaction conditions to isomeric dipyridinylamine precursor 165 gave [3,2-b:30,20-e]pyrazine 167 as the product of oxidative aromatization of unstable dihydro-deriva-

tive 166 h09EJO3753i.

NBr

NH

N

N

N N

HNPd(OAc)2, Xantphos

K2CO3, dioxane

162 163

NH

R R

N

N NH

NH2

Cl N

N N

NPd(OAc)2, Xantphos

K2CO3, dioxane

MeI, NaH, DMF

32–33%over 2 steps

N

N N

N

164

R

Me

165 167

N

NH

N

HN

166

79%

Scheme 51


2.3.4 [1,2]-Fusion of Azoles to Six-Membered RingsA special case of bi- or polycyclic ring construction is the fusion of a six-membered

ring to pyrrole (or pyrrolidine), indole, or imidazole when N1 and C2 atoms of the

latter serve as fusion sites. Thus, pyrrolo[1,2-a]quinoxalines, indolo[1,2-a]quinoxa-

lines, and their aza-analogues of the general formula 169 can be efficiently prepared

by palladium-catalyzed intramolecular C��N bond formation (Scheme 52)

h05S2881i.

NH

R2

R1 N

O

Me Y

Z

X

R3

N

R2

R1N

O

Y Z

Me

R3

Pd(OAc)2, BINAP

Cs2CO3, toluene100 �C

Y = CH, NZ = CH, NR3= H, Cl, Me

66–95%

168 169

Scheme 52

Similar intramolecular arylation of the indole ring requires a hindered t-Bu3P

ligand and produced alkaloid arnoamine B 171, a known topoisomerase inhibitor

(Scheme 53) h07H(71)1801i.

N

NH Br

OMe

Pd(OAc)2, t-Bu3PK2CO3, xylene, 110 �C

81%

N

N

MeO

170 171

Scheme 53


Synthesis of the bis(imidazole)-annulated terphenyls 173, planar disc-shaped

building blocks for organic semiconductors, can be started from bis-imidazole deriv-

ative 172 and involved the intramolecular C��N bond formation using palladium

acetate, triethylphosphine, and sodium tert-butoxide, affording 72–87% yields of

the desired products (Scheme 54) h06JMA4058i.

172 173

Pd(OAc)2, PEt3

t-BuONa, toluenereflux, 48 h,

R = p-C6H4-OAlk, 72–87%

N

NH

N

HN

Cl

Cl

R

R

R

R

N

N

N

N

R

R

R

R

Scheme 54

Heterocyclic enamines 174 undergo regioselective C-benzylation and C-ben-

zoylation with o-bromobenzyl bromide and o-halobenzoyl chloride to yield the

corresponding C-substituted enamines 175 and 177 as suitable precursors for annula-

tions. Subsequent intramolecular arylation led to the fused 1,4-dihydroquinolines

176 or quinolin-4-ones 178 (Scheme 55) h03ARK146i. The latter do not require

the presence of palladium catalyst. The ring size of the cyclic enamine affects the

reactivity, and decreased yields of products 176 were found with increasing numbers

of atoms n in the ring.

174

NH

H

EtO2C

n

NHEtO2C

nO

Br

NHEtO2C

n

Br

N

O

CO2Et

N

CO2Et

nn

NaH, THF,n = 1–3

40–52%

Br

Cl

O

pyridineCH2Cl285–87%

Br

Cl

NaH33–57%

Pd(dba)2DPPP, t-BuONan = 1, 51%n = 2, 36%

175 177

176 178

Scheme 55


A practical and highly efficient route for the synthesis of pharmaceutically interesting

quinoxalinone cores 180 has been reported (Scheme 56) h10OL3574i. The key step

involved an intramolecular palladium-catalyzed N-arylation under microwave irradia-

tion. Catalytic system optimization showed that imidazole carbene ligand 181 gives

the highest (up to 95%) conversion of starting materials and, in many cases, nearly quan-

titative yields of the products. The developed methodology tolerates a variety of bromo-

anilides 179 affording a diverse collection of bicyclic and polycyclic quinoxalinones.

179

NH

N

O

N N

NH

HN

O

Br

Pd2(dba)3ligand, t-BuOKdioxane, MW

R = H, quant yield

180 181

R R

BF–4

Scheme 56

2.4. ANNULATION OF MEDIUM SIZE AZA-RINGS

The first palladium-catalyzed syntheses of benzazepines were reported by Buchwald

and coworkers h96T7525i and later followed by optimization studies h06SL115i.Optimized reaction conditions for indolines and oxindoles (Scheme 3, Section 2.2.1)

were smoothly transferred to benzazepine derivatives prepared from secondary amide

or secondary carbamate precursors (5 and 7, correspondingly, n¼3). Thus, reaction

using (�)-MOP 9 ligand and cesium carbonate resulted in 79–88% yields of benza-

zepines 6 and 8 (R¼Boc, Cbz), which are comparable to those of five-membered

homologs. Under the same conditions, Xantphos was the ligand of choice for N-ace-

tyl benzazepine 8 (R¼Ac). A recent report h09T525i revealed that sterically bulky

monophosphines X-Phos 13a and P(t-Bu)3 are particularly effective for the forma-

tion of 7-benzolactams using palladium-catalyzed aryl amidation reactions.


A synthetic route to 1-benzyl-tetrahydro-1-benzazepines 184 with alkyl and aryl

substituents at C2 of the azepine ring has been reported (Scheme 57) h03TL3675i.Palladium catalysis can be utilized in two of the three steps (i.e., Heck condensation

and C��N bond formation) constructing the seven-membered rings effectively from

2-bromoiodobenzene 182. The reactive intermediate 185 undergoes competitive

b-hydride elimination, and imine 187 was the main product in the attempted C��N

bond formation in the case of a bulky substrate (R¼ t-Bu). Use of bulky phosphine

ligands under milder reaction conditions to suppress the b-hydride elimination

pathway was not effective and resulted only in the recovery of starting material.

I

Br

OH

R

Pd(OAc)2, DMFR = H; Bu4NCl, NaHCO3

R = Me, Ph, t-Bu, LiCl, DIEA56–89%

2. BnNH2, Ti(i-OPr)4NaBH4, 60–80%

Br

R

HN

NBn

R

Pd(dba)2/PPh3t-BuONa/K2CO3R = H, Me, Ph

182183 184

1.

Bn60–83%

Pd(dba)2/PPh3t-BuONa/K2CO3

R = t-Bu

NPd

PhL

elimination

X

H

NPd

PhHN

H

Ph reductive β-H-elimination

185186187

Scheme 57

Like 3-amino-indol-2-ones 80 and quinoxalin-2-ones 82 (Scheme 23, Sec-

tion 2.2.1) h06TL3423i, benzodiazepine-2,5-diones 84 can be obtained in two steps.

The first step includes a four-component Ugi reaction of R1-substituted 2-bromo-

benzoic acid, R2-isocyanides, R3-amines, and R4-aldehydes, followed by intramo-

lecular palladium-catalyzed cyclization.

A convenient procedure for the preparation of tetrahydro-1,4-benzodiazepin-3-

(3H)-ones 188 from chiral a-substituted N-n-butyl-N-(o-iodobenzyl)glycinamides

187 has been developed. Seven-membered ring formation occurs through an intra-

molecular N-arylation catalyzed by palladium and bis(phosphine) ligands. The use

of chelating bis-phosphines allows minimization or entire suppression of C2 racemi-

zation, which occurs when a mono-phosphine ligand is used (Scheme 58)

h01SL803i. Recently, analogous synthetic methodology has been reported for the

synthesis of benzodiazepine type agents for suppression of vitamin D receptor

(VDR)-mediated transcription h10BML1712i.

187

I

N

O

Bu NH2

R1

Pd2(dba)3

BINAP or DPPEt-BuOK or Cs2CO3

N

HN

O

R1

Bu

188

189

N Cl

N

O

R HN N

N

N

O

R

190

Pd(OAc)2

BINAPt-BuOK or Cs2CO3

Scheme 58


A similar transformation was reported for the synthesis of pyrido[2,3-e] pyrrolo

[1,2-a][1,4]diazepin-10-ones 190 h10TL4053i. Notably, N-unsubstituted proline

amide 189 (R¼H) failed to cyclize due to the predominant Z-rotamer conforma-

tion unfavorable for cyclization.

An improved synthesis of oxazepine and thiazepine ring systems 192 (Scheme 59)

h03JOC644i includes a palladium-catalyzed intramolecular amination. General con-

ditions include Pd2(dba)3, t-Bu3P, and t-BuONa alone (X¼O) or with K2CO3

(X¼S) in toluene at 95 �C. Interestingly, attempted cyclization of o-aminobenzyl

ether 191 did not give the expected cyclization product. Substitutions on the phenyl

ring gave the expected electronic trends: electron-deficient and neutral substitutions

on the bromo-substituted ring facilitated transformations, while yields from

electron-rich substrates were slightly lower.

191

O

NH2Br N

H

XX

NH2Br

Pd0

no reaction X = S, 65%X = O, 82%

Pd2(dba)3, t-Bu3Pt-BuONa/K2CO3toluene, 95 �C

193192

Scheme 59

Palladium-catalyzed intramolecular aryl amination on sugar derivatives has been

accomplished by using bulky biaryl phosphine ligands. An application of this methodol-

ogy on a variety of D-glucose-derived substrates 194 led to the synthesis of highly

functionalized cis-fused tricyclic oxazocines 195 (Scheme 60) h06JOC3291i. Preparativeapproach to the analogous tricyclic diazocines has been reported recently h10EJO1754i.

O

R2

R3

X

O

O O

HN

R1

R2

R3O

NO

O

O

R1

Pd(OAc)2, BINAP

K2CO3-t-BuOK, toluene90 �C, 48 h, 68–77%

194 195

Scheme 60


Pyridobenzodiazepinones 198 (and dibenzo[b,e][1,4]diazepinones, not shown in

the scheme) have been approached by intramolecular Buchwald–Hartwig reactions

between an (hetero)aryl halide and the aromatic amino group intermediate 197

(Scheme 61) h05T61i.

196

NO2

Cl

O

NCl

H2N

1. pyridine

NO2

O

N

Cl

N

1. Fe/AcOH

2. Pd(OAc)2BINAPt-BuOKtoluene

HN

O

N

NMe

Me

2. MeI, NaH DMF

197 198

Scheme 61

The final step in a synthesis of the 9-membered triaza o-cyclophane ring system

was a palladium-catalyzed Buchwald–Hartwig N-arylation affording N,N0-dimethyl-

tribenzo-1,4,7-triazacyclononatriene 201 in 50% yield (Scheme 62) h10JOC7887i.

NH

NN

Me

Me

NH2

ClN

Me

O2N

IN

ClN

MeMe

NH2

Pd(dba)2BINAPt-BuOKtoluene

199 201

1.

2. Me2SO4, 86%3. CuCl, KBH4, 100%

50%

200

Scheme 62

The amino group of 3-amino-4-cyano-5-aryl pyrazoles 202 is reactive enough to

participate in intramolecular palladium-catalyzed reactions leading to benzo[d]pyra-

zolo[1,5-a][1,3]diazepine 203a (n¼1) and benzo[d]pyrazolo[1,5-a][1,3]diazocine

203b (n¼2) ring systems, respectively, lymphocyte-specific kinase (Lck) inhibitors

(Scheme 63) h10BML112i.

Pd2(dba)3BINAPCs2CO3dioxane

202

50%

NN

Br

R2

R1

H2N

NC Ar

nN

N

NC Ar

HN

R2

R1

n

203a, n = 1203b, n = 2

Scheme 63


2.5. MACROCYCLES

Palladium-catalyzed macrocyclizations are rare but they provide novel approaches to

large ring systems. Thus the synthesis of benzoaza crown ethers 205 with 12- to

18-membered rings has been reported by Fort et al. (Scheme 64) h07MI322i.The key to successful cyclization is the use of N,N0-bis(20,60-diisopropylphenyl)dihy-droimidazolium tetrafluoroborate (SIPr) ligand. The chelation study using different

metal tert-butoxides revealed that the 12-membered product 205 (n¼1) can be

formed efficiently in the presence of t-BuOLi and t-BuONa (77% and 75% yields,

respectively) with a lower, 43% yield using t-BuOK. In the case of the 15-membered

crown ether (n¼2), comparable 55% and 45% yields were found using t-BuONa or

t-BuOK. The use of t-BuOLi furnished only 25% of the product. An 18-membered

ring (n¼3) was produced in 35% yield under optimized conditions using t-BuONa.

204 205

O

Cl

OO

NH2n

ONH

OO

n

Pd(OAc)2, SIPr, t-BuOM1,4-dioxane, 100 �C

n = 1−3, M = Li, Na, K25–77%

Scheme 64

Macrocyclic compounds 208 were designed as BACE-1 inhibitors, promising

therapeutics for the treatment of Alzheimer’s disease h07BML5831i. They were

synthesized from 2-chloropyridine derivatives 206. Reductive amination was fol-

lowed by palladium-catalyzed macrocyclization and deprotection resulting in good

yields of the target compounds 208 (Scheme 65).

206

N

NMe Ms

O O

NHBoc

Me

NH2Cl

N

Cl

NMe Ms

O O

NHBoc

Me

NH

RRCHO, NaBH(OAc)3

60–80%

N

NMe Ms

O O

NH2

Me

R N

1. Pd[P(t-Bu3)3]2K3PO4, DMA

65–82%

2. TFA, CH2Cl299%

207

208

Scheme 65


The synthesis of conformationally constrained cyclic peptides 210 with biaryla-

mine linkers using palladium-catalyzed intramolecular Buchwald–Hartwig C��N

coupling has been described h06JOC8954i. A wide variety of di-, tri-, and tetrapep-

tides with 16- to 22-membered rings were prepared in good yields with no

racemization (Scheme 66).

209

H2N

R

O

NH

OR1O

HN

OHN

R2

R3

( )nHN

R

O

NH

OR1O

HN

OHN

R2

R3

( )n

Br

Pd(OAc)2rac-BINAP

t-BuOK, CH3CN,100 �C, 15 h

210, 32–50%

R = H, CH3, R1= CH2Ph

R2= CH3, CH(CH3)2R3= CH3, CH(CH3)2,

CH2CH(CH3)2

n = 1–2

Scheme 66

Several macrocyclizations have been reported for symmetrical di-bromoaryls and

diamines. Although formally an intermolecular process, it apparently involves a late

stage intramolecular cyclization. Thus, palladium-catalyzed amination of 3,5-dibromo-

and 3,5-dichloropyridines 211with a variety of linear polyamines 212 led to the forma-

tion of pyridine-containing macrocycles 213 in low to moderate yields (Scheme 67)

h05HCA1983i. Open-chain mono- and bis(5-halopyridin-3-yl)-substituted polya-

mines 214 and 216 and 3,5-bis(polyamino)-substituted pyridines 215 were used as

intermediates for the preparation of macrocycles with larger cavities.

211

N

X X

H2NX

NH2

Pd(dba)2, BINAPt-BuONa, dioxane

N

HN NH

N

HN

X

NH2

Br

X

N

HN NH

X X

H2NNH2

N

Br

NH

X

HNN

Br

213, 5–42% 214, 10–36%

215, 6–14% 216, 3–33%

212

X = NH; CH2NHCH2; NH(CH2)2NH; NH(CH2)3NH; CH2NH(CH2)2NHCH2; CH2NH(CH2)3NHCH2; NH[(CH2)2NH]2; NH[(CH2)2NH]3; O(CH2)2O

Scheme 67


A fragment-coupling approach for the synthesis of azacalix[m]arene[n]pyridines

has been developed by Wang et al. h04AGE838i. It includes (Scheme 68) the con-

densation of m-phenylenediamine with 2,6-dibromopyridine in the presence of an

excess of t-BuOK to give N,N0-bis(6-bromopyrid-2-yl)-m-phenylenediamine 217

in excellent yield. Further treatment with methyl iodide followed by palladium-cat-

alyzed double aryl amination with N,N0-dimethyl-m-phenylenediamine in refluxing

toluene gave macrocyclic azacalix[2]arene[2]pyridine 219a (n¼1) and azacalix[4]

arene[4]pyridine 219b (n¼3) in 26% and 22% yields, respectively. The larger ring

compound 219b was obtained as a single product in 26% yield when the reaction

was performed at a lower temperature.

Pd(dba)2/dpppt-BuONa

H2N NH2 NBr Br NBr NH

NH

N Br

t-BuOK, THF

rt, 97%

MeI, t-BuOK,THF, 90%

NBr N N N Br

Me Me

NH

NH

Me Me

N N

N N

Me

Me Me

Me

n

219a, n = 1, 26%219b, n = 3, 22%

217

218

Scheme 68


In the pursuit of ligands with multidentate coordination sites and significant flex-

ibility for preparation of oligonuclear metal complexes, Yamaoto et al. h05SL263ireported the synthesis of N-(p-Tol)azacalix[n](2,6)pyridines 221 (Scheme 69).

Synthetic routes included palladium-catalyzed (or Cu-catalyzed) aryl amination reac-

tions, and macrocycles with various numbers (1–5) of an N-(p-Tol)aminopyridine

recurring unit were isolated.

220

N

N

NN

N

N

R

R

R

nN N

H

RBr

R=p-tolylPd2dba3, Xantphos

t-BuONa, toluene80 �C, 5 d

n = 1, 38%n = 2, 31%n = 3, 6%n = 4, 7%n = 5, 2%

221

Scheme 69

2.6. TANDEM SEQUENCES, CASCADES, AND MISCELLANEOUSCYCLIZATIONS

Palladium-catalyzed C��N bond formation can be a part of various synthetic

sequences including tandem reactions and cascades resulting in molecular entities

of varying complexity. Thus, dipyrido[1,2-a:30,20-d]imidazole 224 (Scheme 70)

and its benzo- and aza-analogues (not shown) can be prepared by a novel tandem

process using intermolecular Buchwald–Hartwig amination followed by intramolec-

ular ring formation with excellent 82–98% isolated yields h04CC2466i.

222

N

I

Cl N NH2N N

NPd(OAc)2BINAP or Xantphos

Cs2CO3, toluene, reflux

224223

Scheme 70

A new palladium-catalyzed one-pot methodology for the synthesis of N-arylated

heterocycles has been developed (Scheme 71) h04S2527i. The process involves a sequen-tial intra- and intermolecular amination, and it includes the use of an in situ generated Pd

catalyst supported with N,N0-bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene

(SIPr) ligand and t-BuONa. It allows, in one pot, the synthesis of a wide range ofN-ary-

lated nitrogen five-, six-, and seven-membered heterocycles 227.

Cl

X NH2n

NH

X

n

Pd(OAc)2,SIPr.HClt-BuONadioxane

ArCl

N

X

n

ArX = CH2, On = 1–3, 41–99%

225 226 227

Scheme 71


A variety of 2,3,4,9-tetrahydro-1H-carbazoles has been accessed through a

three-step synthetic sequence (Scheme 72) h05AGE403i. The first step involved

palladium-catalyzed a-arylation of cyclohexanone followed by formation of triflate

229. The latter produced tetrahydrocarbazoles 230 through an inter-/intramolecular

double amination cascade with the best yields reported for Xantphos and DPEphos as

ligands. The method was extended to a variety of cyclic and acyclic 1,2-disubstituted

indoles.

Pd2(dba)3ligand, Cs2CO3

46–86%

OTfBrO

Pd2(dba)3, XantphosCs2CO3, toluene

78%

I

Br

OBr

PhNTf2, NaHTHF, 0 �C

87%

RNH2

NR

228 229 230

Scheme 72

In a similar fashion, 2-(2-haloalkenyl)aryl halides 231 can undergo two sequential

palladium-catalyzed amination reactions, the first intermolecular, the second intra-

molecular, providing efficient routes to a range of N-functionalized indoles 232

(Scheme 73) h06ASC851, 07CC4764i. The sequence tolerates a wide variety of

substituents, although a careful choice of ligands and halogen leaving groups is

required. Thus, the use of 20-dimethylamino-2-dicyclohexylphosphine (233a) as a

ligand is superior for dichlorides 231 (X¼Y¼Cl), while dimethoxy ligand S-Phos

(233b) was more efficient in the case of dibromo substrates (X¼Y¼Br)

h06ASC851i. Use of sterically hindered amines (tert-butyl amine, 1-adamantyl

amine, 2,6-di-isopropyl aniline) required P(t-Bu)3 ligand as its HBF4 salt

h07CC4764i. An interesting variation is a synthetic sequence starting from 2-(2-bro-

movinyl)-1,3-dichlorobenzene with the addition of one equivalent of secondary

amine (morpholine) which resulted in the one-pot preparation of functionalized

indole 234 in 55% yield h06ASC851i.

Y

R2

X

NH2 R3

R1 Pd2(dba)3ligand

t-BuONa46–86%

NR3

232

R1 R2

231

NMe2

PCy2

OMeMeO

PCy2

233a 233b

N

234

N

O

OMe

BrCl

Cl

Scheme 73

The complex polycyclic structure of (�)-murrayazoline 238 has been con-

structed by a combination of the intramolecular Friedel–Crafts-type Michael

addition and palladium-catalyzed C��O coupling reactions of the key intermediate


237 (Scheme 74, h08OL1999i). This N-substituted carbazole was synthesized by a

one-pot double N-arylation of sterically hindered amine 236 with a dibromobiphe-

nyl derivative 235. The use of Pd2(dba)3 as a palladium source, XPhos 13a ligand,

and t-BuONa gave acceptable results when the sterically hindered amine 236 was

used, providing a 59% yield. The use of other ligands resulted in lower yields of

the carbazole 237.

OMOM

Br Br

MeO

O

Me

Me

NH2

N

MeMe

O

O

OMOM

Me

Pd2(dba)3, ligand,t-BuONa, toluene

16–59%

NO

Me

MeMe

Me

235

236

237 238

Scheme 74

The palladium-catalyzed inter-/intramolecular sequence discussed above

h05AGE403, 06ASC851, 07CC4764i can be further extended to an intermolecular

aminocarbonylation/intramolecular amidation cascade for an efficient transformation

of various 2-(2-haloalkenyl)aryl halides 239 into the corresponding 2-quinolones 241

in 33–80% yields (Scheme 75). Delaying the introduction of the CO allows another

sequence, which starts with amination on a vinyl moiety and is followed by carbon-

ylation, to produce isoquinolone 242 in 68% yield h09OL583i.

X

R2

X

COR1

N

R2

O

R3

R1

Pd2(dba)3, ligandCs2CO3, toluene, 100 �C239 241

1. o-Toluidine, Pd2(dba)3Xantphos, t-BuONa

2. CON

242R1= R2= HX = Br

Me

O

R3NH2, 240

Scheme 75

A cascade process with two C��N arylation steps was used for amines 243 and was

achieved using P(t-Bu)3 ligand in Pd-mediated cross-coupling reaction conditions (Pd

(dba)2, t-BuONa, refluxing toluene). Although the resulting polycyclic amino-ether

244 (X¼O)was produced in 34% yield, application of similar conditions to a thioether

starting material (X¼S) gave the product in less than 3% yield, but this was improved

by switching to copper catalysis (Scheme 76) h04CL1174, 05AGE4056i.

243

Pd(dba)2, P(t-Bu)3t-BuONa, toluene

X = O, 34%X = S, 3%

NH2

X X

Br Br

N

X X

244

Scheme 76


Another synthetic sequence involving a final C��N intramolecular coupling was

established as a new route to antiepileptic drug oxcarbazepine 249 (Scheme 77)

h05OL4787i. The sequential key steps were palladium-catalyzed intermolecular

C-arylation of ketone enolates and intramolecular N-arylation reactions. Interest-

ingly, Xantphos, a ligand commonly employed in N-arylation reactions but rarely

used in C-arylation of enolates, is the best ligand for the preparation of C-arylated

product 247. This protocol can be readily extended h07T690i to benzazepinones

with annulated thiophene rings 250 complementing the traditional methods of ben-

zothienoazepinone synthesis h08AHC1i. The proposed reaction pathway did not

afford pyridine annulated target 251 for undisclosed reasons under a variety of reac-

tion conditions.

245

NHTs

Me

O

Br

Br NHTs

O

Br

NH

O

N

O

NH2O

Pd(OAc)2, XantphosCs2CO3, toluene

100 �C

86% 2. Pd(OAc)2, BINAPK3PO4, toluene, 100 �C

91%

1. H2SO4

N

O

NH2O

N

N

O

NH2O

SR

246

247

248 249250 251

steps

Scheme 77

The similarity of the reaction conditions for palladium-catalyzed C��N and C��C

bond couplings encouraged extensive studies of precursors demonstrating such

dual reactivity. Thus, a novel two-step procedure was devised for the preparation of

1-methyl-4-(hetero)aryl oxindoles 254 in moderate to high yields (Scheme 78)

h06TL4361i. The key steps comprise an intramolecular palladium-

catalyzed amidation reaction followed by an in situ intermolecular Suzuki cross-cou-

pling reaction in a one-pot reaction. In the absence of boronic acid, bis-oxindole 253

was the sole product as the result of C��N intramolecular arylation followed by dimer-

ization via oxindole a-arylation and palladium-catalyzed debromination.

Br

Br

NH

O

Me

Ar

NO

Me

ArB(OH)2

Pd(OAc)2, XantphosK2CO3, t-BuOH, 85 �C

18–90%252 254

NO

Me

NOMe

253

Scheme 78


A one-pot procedure involving a tandem cyclization–coupling process for the

preparation of 2-functionalized indoles starting from readily accessible 1,1-

dibromo-1-alkenyl aniline derivatives 255 (X¼NAc) has been developed by Bisseret

and coworkers (Scheme 79) h04TL907i. This method involves Suzuki or Stille

coupling with the higher reactivity of the trans C��Br bond relative to the cis C��Br

bond toward oxidative Pd insertion followed by intramolecular palladium-catalyzed

C��N bond formation. This process is complementary to the most efficient palla-

dium- or copper-catalyzed processes for the preparation of similar heteroaryls involv-

ing alkynes instead of dibromoalkenes. A similar reaction starting from the

corresponding phenol derivatives led to benzo[b]furans 257 (X¼O).

XHBr

Br X = O, Pd(OAc)2, dppfX = NAc, Pd2(dba)3, dppf

TEA, toluene 100 °C

Ar-SnMe3 or ArB(OH)2

XHBr

Ar

XAr

70–91%

255 256 257

Scheme 79

Another report revealed that amino group protection is not required for a Suzuki

cyclization cascade when SPhos is used as a ligand in the presence of potassium phos-

phate giving rise to N-unsubstituted indoles in 73–86% yields h05OL3549i. In addi-

tion, the corresponding gem-dichlorides can be used instead of bromides 255 when a

higher (5%) loading of the catalyst is used. Later work h08JOC538i disclosed that the

C��N bond formation could be the first coupling step followed by a Suzuki process,

although no reaction was observed in the absence of boronic acid.

This methodology was further applied as a general method for the preparation of

diverse indoles. Thus, an efficient synthesis of KDR kinase inhibitor 258 (Figure 1),

using similar palladium-catalyzed tandem C��N/Suzuki coupling as the key step,

was reported h07JOC1341i providing 86% yield of the intermediate for the key

palladium-catalyzed cascade step.

NH

NHO

258, 86%

N

N

N

N N N N N

N N

Bn

Ph

260d, 90%

Ph

Boc

260c, 87%

Ph

Boc

260b, 87%

Cbz

Ph

260a, 75%

O-

S

SPhPh

Boc Boc

259a, 73% 259b, 76%

NN

Ms

+

Figure 1


A palladium-catalyzed reaction of gem-dichloro olefins and a boronic acid via a

tandem intramolecular C��N and intermolecular Suzuki coupling process gave

two isomers of thienopyrroles 259a and 259b and all four isomers of azaindoles

260a–d in good to excellent yields h07JOC5152i.Lautens and coworkers reported a catalyzed indole synthesis involving not only a

C��N/Suzuki h08JOC538i but also a C��N/Heck combination h06OL4203i.Thus, the tandem reaction including a Buchwald–Hartwig/Heck sequence

(Scheme 79) h06OL4203i did not require expensive phosphine ligands and involved

tetramethylammonium chloride, producing moderate to good yields of alkenes 262.

An intramolecular version used substrates 263 where the alkene moiety is tethered to

the nitrogen of the ortho-gem-dibromovinylaniline and provided tricyclic systems

264. Various palladium sources and ligands were screened, and Pd2dba3 with n-

Bu4NCl in the presence of NEt3/K3PO4 in toluene at 120 �C gave the desired tri-

cyclic adduct in good yield (76%) as a mixture of two easily separable isomers

264a and 264b, formed in 3:1 ratio (Scheme 80).

NHBr

Br

Pd(OAc)2, Me4NClTEA/K3PO4, toluene

reflux39–69%

N

CO2t-Bu

CO2t-Bu

N

CO2t-Bu

NHBr

Br

R1

R2

NR1

R2CO2t-Bu

CO2t-Bu

Pd2(dba)3, n-Bu4NClTEA/K3PO4, toluene

reflux76%

CO2t-Bu

261 262

263 264a 264b

Scheme 80

Another variation of the Heck/Buchwald–Hartwig cascade was reported for the

preparation of 4-aryl-2-quinolones 267 (Scheme 81). They were prepared from

readily available o-bromocinnamamide 265 and aryl iodides using phosphine-free

palladium(II) acetate as the catalyst and a molten tetra(n-butyl)-ammonium acetate/

tetra(n-butyl)ammonium bromide mixture as the reaction medium. The reaction

proceeds through a pseudo-domino process involving two mechanistically indepen-

dent, sequential catalytic cycles: a Heck reaction followed by an intramolecular

Buchwald–Hartwig C��N bond formation h07ASC297i.

Br

NH2

O Br Ar

OH2N

n-Bu4NOAc (2.5 equiv.),n-Bu4NBr (4 equiv.), 120 �C

48 h, 33–73%

Pd(OAc)2ArI

Pd(OAc)2 NH

Ar

O

265 267266

Scheme 81


Recent developments of the Heck/C��N arylation sequence include synthesis of

diverse 3-methylindoles 271 (Scheme 82) h10OL668i. Although each of the steps, thatis, a Heck reaction, carbamate/aryl chloride coupling, and isomerization, is run sepa-

rately, the elaborated route is highly efficient and general, enabling the regiocontrolled

synthesis of substituted indoles starting from readily available chloro-triflates.

268

Cl

OTf

R

NHBoc

Pd(OAc)2, dppf,AcONa, MeCN Cl

R

NHBoc Pd(OAc)2, XPhos,K2CO3, DMF

R

N

Boc

CSA, CH2Cl2 R

N

Me

Boc54–80%

over 3 steps

269

270 271

Scheme 82

A four-step approach to alkyl- and aryl-substituted dihydro benzoxazines can be

accomplished by a palladium-catalyzed domino C��C/C��N bond coupling using a

norbornene template (Scheme 83). The route begins with oxidative insertion of

palladium(0) into the aryl iodide 272 followed by carbopalladation with norbornene

leading to 273. This is followed by intramolecular C��H functionalization, oxidative

addition of 1-bromoalkane (or arene), and reductive elimination to form palladium

species 274. Next, retro-carbopalladation of norbornene, which occurs as a result

of the steric constraints imposed by the two ortho substituents, leads to the formation

of 275, which undergoes an aromatic amination resulting in benzomorpholine 276.

Extension of this method gave phenoxazine 277 and dihydrodibenzoxazepine 278

h10JOC3495i.

Pd(OAc)2,P(2-furyl)3,

norbornene,Cs2CO3, MeCN

272

O

HN

PMPO

HN

PMPPdL2I

I RBrO

HN

PMPPdL2Br

R

O

HN

PMP

R

BrL2Pd

O

N

R

PMP

273 274

275 276

O

HN

Ar Ar

O

HN

277 278

Scheme 83


A catalytic domino process that generates significant molecular complexity was

established by Zhu et al. (Scheme 84) h03AGE4774, 04JA14475i. This novel processwas applied to the construction of azaphenanthrenes fused with an 8-, 9-, 10-, 11-,

and 13-membered lactam motif 280.

279

NH

NH

OOI I

n

Pd(dppf)Cl2

KOAc, DMSO80–120 �C18–57%

N

OHN

O

n 280

NN

O

Me

RO

NN

O

O

281 282

Scheme 84

It is suggested that a domino process starts with an intramolecular Buch-

wald–Hartwig amination, followed by C��H activation, and aryl-aryl bond forma-

tion to produce polyheterocycles 280 from linear diamides 279 h04JA14475i. Incontrast to other intramolecular amide N-arylations, this process is much less sensi-

tive to the ligands used. Both bidendate phosphines, such as dppf and BINAP, and

the monodentate ligand PPh3 were suitable, while t-Bu3P seemed to be less efficient.

Potassium acetate was more effective than cesium carbonate as base, while DMSO

was a better solvent than DMF and toluene. The optimal conditions involved

PdCl2(dppf) as the catalyst, KOAc as the base in DMSO at 120 �C. The scope of

the process was further extended to the polycyclic systems 281 and 282, derived

from acyclic amino acids (51–98%) and L-proline (97% yield), correspondingly.

A regiocontrolled palladium-catalyzed domino sequence involving an intramo-

lecular N-arylation followed by intermolecular Heck reaction provided rapid access

to functionalized benzodiazepine-2,5-diones 284 (Scheme 85). The reaction of 283

in the presence of dihydrofuran afforded the expected benzodiazepinedione in 54%

yield (Scheme 85). Notably, a two-step procedure involving a copper-catalyzed ben-

zodiazepinedione synthesis, followed by a Heck reaction, resulted only in a 25%

yield of the product h08OL857i.

I

HN

O

N

O I

283

N

N

O

O

OPd(OAc)2, KOAc,dihydrofuran, 120 �C

54%

284

Scheme 85


2.7. CONCLUSIONS

The current review includes numerous very useful cyclizations or annulations that

involve palladium-catalyzed C��N bond formation. This chemistry generally involves

initial oxidative addition of an organic halide or triflate to the palladium(0) complex,

which readily undergoes intramolecular nucleophilic attack by a neighboring nitrogen

nucleophile to form the ring or to produce reactive organopalladium intermediates

useful in the subsequent transformations. Another type of development covered by this

survey is the formation of organopalladium intermediates as a result of C��C bond

couplings, usually Suzuki or Heck processes, which are prone to intramolecular

C��N bond formation. The reactions proceed under relatively mild conditions and

tolerate a wide variety of functional groups enabling the construction of a wide range

of heterocycles. One can expect numerous future examples of heterocyclic systems

synthesized based on this methodology. We hope this review to be a background

for such advances in heterocyclic, medicinal, and natural products chemistry.

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