[page 21↓]

2  Pyrazolo[1,5-a]pyrimidine derivatives

2.1 Introduction

Pyrazolo[1,5-a]pyrimidines are purine analogues and have useful properties as antimetabolites in purine biochemical reactions. Compounds of this class have attracted wide pharmaceutical interest because of antitrypanosomal activity [72], antischistosomal activity [73]. They are used as HMG-CoA reductase inhibitors [74], COX-2-selective inhibitors [75], AMP phosphodiesterase inhibitors [76], KDR kinase inhibitors [77], selective peripheral benzodiazepine receptor ligands [78], and antianxiety agents [79]. These interesting biological properties initiate activities to develop new efficient general procedures for the synthesis of pyrazolo[1,5-a]pyrimidine derivatives.

Pyrazolo[1,5-a]pyrimidine is composed of a pyrimidine ring and a pyrazole ring. The pyrimidine part is π-electron deficient, so the nucleophilic displacement takes place more readily. The 7-position is more active than the 5-position. The pyrazole part is π-electron excessive, and can readily undergo electrophilic substitution.

Although cross-coupling reactions have been extensively used in organic synthesis of heterocyclic compounds, to the best of our knowledge, only a few publications are devoted to cross-couplings of pyrazolo[1,5-a]pyrimidines. Shiota and Yamamori [80] reported the regioselective coupling of organzinc reagents 80 with 5,7-dichloropyrazolo[1,5-a]pyrimidine 79. When the reaction was catalyzed by lithium chloride, the 7-substituted product 81 was obtained, while catalysis by Pd(PPh3)4 afforded the 5-substituted product 82. By further Pd(PPh3)4 catalyzed reaction of 81 or 82 with phenylboronic acid, phenyl groups could be introduced into 5-position or 7-position respectively. (Scheme 2.1)


[page 22↓]

Scheme 2.1 Regioselective cross-coupling reactions of organzinc reagent with 5,7-dichloropyrazolo[1,5-a]pyrimidine

Kumar [81] reported the synthesis of 3-aryl-7-diethylamino-pyrazolo[1,5-a]pyrimidines 85 by Suzuki coupling of 3-bromopyrazolo[1,5-a]pyrimidines. Fraley reported the Suzuki cross-coupling reactions of 3-bromo-6-arylpyrazolo[1,5-a]pyrimidines [82] and 6-bromo-3-aryl- pyrazolo[1,5-a]pyrimidines [76] and obtained products 86 and 87, respectively.(Scheme 2.2)

Scheme 2.2 Suzuki corss-coupling of bromopyrazolo[1,5-a]pyrimidines


[page 23↓]

We envisaged the synthesis of calcineurin-inhibiting compounds with the general structure 8 with thepyrazolo[1,5-a]pyrimidine system as the core heterocycle. They would be synthesized by Pd-catalyzed cross-coupling reactions of halo-pyrazolo[1,5-a]pyrimidines. Routes to the starting materials are described in the following chapters. Since the reactivity of halo-leaving groups in Pd-catalyzed cross-coupling reactionsdrop in the sequence of I > Br >> Cl, we preferred to start with iodo- or bromo-pyrazolo[1,5-a]pyrimidines, but the chloro-compounds were also included.

2.2 Synthesis of substituted pyrazolo[1,5-a]pyrimidines

2.2.1 Synthesis of pyrazolo[1,5-a]pyrimidines by ring closure

The pyrazolo[1,5-a]pyrimidine skeleton is usually prepared by condensation of 3-amino-pyrazoles or 4-amino-pyrazoles with 1,3-diketones, using hydrochloric acid [83], acetic acid [84], ethanol [85, 86], or ethanol/hydrochloric acid as solvent. We synthesized a series of substituted pyrazolo[1,5-a]pyrimidine derivatives 88a-88h and 89a-89c in this way. (Scheme 2.3 and Table 2.1)

Scheme 2.3 Synthesis of substituted pyrazolo[1,5-a]pyrimidines


[page 24↓]

Table 2.1 Pyrazolo[1,5-a]pyrimidines 88 and 89

Product

R1

R2

R3

Yield (%)

Mp (°C)

88a

Ph

Me

Ph

89

185-186 (EtOH)

88b

4-Cl-Ph

Me

Ph

66

156-158 (EtOH)

88c

Me

Ph

Ph

74

113-114 ( EtOH/hexane)

88d

Ph

Me

4-Cl-Ph

77

155-117 (EtOH)

88e

Me

Me

Ph

78

81-82 (EtOH)

88f

Me

Me

Me

68

69-70 (hexane/Et2O)

88g

Ph

Ph

Ph

77

154-155 (EtOH)

88h

H

Ph

Ph

89

85-86 (EtOH)

89a

Me

Me

 

75

91-2 (EtOH/hexane)

89b

Me

Ph

 

86

124-5 (EtOHl)

89c

Ph

Ph

 

86

163-4 (EtOH)

In an analogous manner, mono- or dihydroxy-pyrazolo[1,5-a]pyrimidines *** were synthesized by using β-ketoesters or malonates instead of 1,3-diketones, e.g., 3-amino-4-phenylpyrazole was reacted with ethyl benzoylacetate, using acetic acid as solvent, affording the 2,5-diphenyl-7-hydroxypyrazolo[1,5-a]pyrimidine 90 [73]. 3-Amino-4-phenylpyrazole was reacted with diethyl malonate, using EtONa as base to obtain 3-phenyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine 91 [87]. 3-Amino-5-methylpyrazole reacted with ethyl acetoacetate and diethyl malonate giving 2,5-dimethyl-7-hydroxy-pyrazolo[1,5-a]pyrimidine 92 [88] and2-methyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine 93 [87],respectively. (Scheme 2.4)

***In fact, there are two tautomers in these hydroxypyrazolo[1,5-a]pyrimidines: pyrazolo[1,5-a]pyrimidone and hydroxypyrazolo[1,5-a]pyrimidine, moreover, pyrazolo[1,5-a]pyrimidone is the main structure, we wrote and named these compounds here hydroxypyrazolo[1,5-a]pyrimidines for convenience and simplifying.


[page 25↓]

Scheme 2.4 Synthesis of hydroxypyrazolo[1,5-a]pyrimidines

2.2.2 Halogen substituted pyrazolo[1,5-a]pyrimidines

There are three principal ways to prepare halopyrazolo[1,5-a]pyrimidines:

  1. cyclisation of halogen-containing open chain precursors.
  2. nucleophilic substitution of hydroxyl groups of pyrazolo[1,5-a]pyrimidines by halogen.
  3. electrophilic substitution of H-atoms of pyrazolo[1,5-a]pyrimidines by halogen.

Using bromine or NBS as bromating agent, 1,3-diketones are readily brominated at the active CH2 position [89, 90]. By further treatment with 3-aminopyrazoles, new 6-bromo-pyrazolo[1,5-a]pyrimidines 95 and 97 could be obtained by ring closure route (a). (Scheme 2.5)


[page 26↓]

Scheme 2.5 Synthesis of 6-bromo-pyrazolo[1,5-a]pyrimidines

Following the SN-route (b) for halopyrazolo[1,5-a]pyrimidines, 2,5-diphenyl-7-hydroxy-pyrazolo[1,5-a]pyrimidine 90 was refluxed with POCl3 or POBr3, using N, N-dimethylaniline as catalyst. The corresponding 7-Cl [74] and 7-Br substituted pyrazolo[1,5-a]pyrimidine products, 98 and 99, could be obtained in high yields. 2,5-Diphenyl-7-chloro-pyrazolo[1,5-a]pyrimidine 98 reacted with 57 % hydroiodic acid in a subsequent SN-reaction providing the corresponding 7-iodopyrazolo[1,5-a]pyrimidine 100. (Scheme 2.6)

Scheme 2.6 Synthesis of 7-halo-2,5-diphenylpyrazolo[1,5-a]pyrimidines


[page 27↓]

The structure of the new products 98, 99, 100 and 120 (also see page 39), were confirmed by NMR-data. It is worth mentioning that the compound 120 exhibits a strong up field shift of the H-6 signal as compared with its isomer 98. Furthermore a strong effect of the halo-substituents was observed on the 13C-signal of position C-6, within the series 98, 99, and 100.

Some NMR data of these compounds are shown in Table 2.2:

Table 2.2 NMR data of of compounds 98, 99, 100 and 120 (δ, ppm)

 

120

98

99

100

H-6

6.80

7.49

7.61

7.86

H-2

8.38

8.53

8.52

8.51

Ph-H

7.18-7.96

7.25-8.17

7.25-8.16

7.25-8.12

C-6

108.80

105.58

109.72

117.45

C-7

144.70

139.03

128.99

103.94

C-2

143.40

143.54

143.28

142.60

C-3

110.82

112.31

112.46

112.79

C-4

148.35

145.81

145.30

143.30

C-5

150.70

155.65

155.16

154.47

5,7-Dihydroxy-3-phenylpyrazolo[1,5-a]pyrimidine 91 and5,7-dihydroxy-2-methyl-pyrazolo[1,5-a]pyrimidine 93 could be transformed into the corresponding 5,7-dichloro-pyrazolo[1,5-a]pyrimidines 101 [91] and 102 [92],respectively, by refluxing in POCl3 in the presence of N,N-dimethylaniline. (Scheme 2.7)


[page 28↓]

Scheme 2.7 Synthesis of 5,7-dichloro- pyrazolo[1,5-a]pyrimidines

Following the route (c), i.e. to introduce halogen by electrophilic substitution of H-atoms, substitutedpyrazolo[1,5-a]pyrimidine 88a was treated with NBS, using CCl4 as solvent under reflux. The substituted3-bromopyrazolo[1,5-a]pyrimidine 103 was obtained in good yield. 88a-88h reacted with NIS [93] in THF under reflux providing substituted3-iodopyrazolo[1,5-a]pyrimidines 104a-104h. (Scheme 2.8, Table 2.3)

Scheme 2.8 Synthesis of 3-halopyrazolo[1,5-a]pyrimidines


[page 29↓]

Table 2.3 3-Iodopyrazolo[1,5-a]pyrimidines 104a-104h

Product

R1

R2

R3

Yield (%)

Mp (°C)

104a

Ph

Me

Ph

70

164-166 (EtOAc)

104b

4-Cl-Ph

Me

Ph

69

166-168 (EtOAc)

104c

Me

Ph

Ph

78

138-140 (EtOAc)

104d

Ph

Me

4-Cl-Ph

83

63-65 (EtOAc)

104e

Me

Me

Ph

63

90-91 (EtOAc)

104f

Me

Me

Me

45

132-133 (EtOAc)

104g

Ph

Ph

Ph

81

202-203 (EtOAc)

104h

H

Ph

Ph

90

160-161 (EtOAc)

We further chose a pyrazolo[1,5-a]pyrimidine compound, where the halo leaving group was found in a alkyl substituent, allowing uncatalyzed nucleophilic substitutions with substituted amines to introduce the functionalized side chain. 5-Methyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine 89b reacted with NBS in the presence of AIBN using CCl4 as solvent under reflux. 5-Brromomethyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine 105 was obtained. (Scheme 2.9)

Scheme 2.9 Synthesis of 5-bromomethyl-3,7-diphenylpyrazolo[1,5-a]pyrimidine


[page 30↓]

2.3  Heck cross-coupling of pyrazolo[1,5-a]pyrimidines

2.3.1 Heck cross-coupling of 3-halopyrazolo[1,5-a]pyrimidines

Heck cross-coupling reaction has shown great versatility in the construction of carbon-aryl bonds [94, 95]. Pd(PPh3)2Cl2 [bis(triphenylphosphino)palladium(II) chloride] and Pd(OAc)2 are usually used as catalysts. Therefore, we tried to apply this useful reaction to introduce alkene moieties with a terminal O- or N-containing functional group into pyrazolo[1,5-a]pyrimidines, allowing subsequent reduction to hydroxyl or aminoalkyl side chains.

3-Bromo-5-methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine103 was treated with methyl acrylate, using Pd(PPh3)2Cl2 as catalyst, triethylamine as base, acetonitrile as solvent under argon. No reaction took place, even at refluxing temperature. But using the same conditions, treatment of the corresponding iodo-compounds 104 with monosubstituted alkenes, such as methyl acrylates, acrylonitrile, or styrene, provided the anticipated coupling products 106-109 in high yields (Scheme 2.10 and Table 2.4). These products possess E-configuration, according to 1H-NMR spectra (CH=CH, J = 15-19 Hz).

Scheme 2.10 Heck cross-coupling of 3-halopyrazolo[1,5-a]pyrimidines with mono-substituted alkenes


[page 31↓]

Table 2.4 Pyrazolo[1,5-a]pyrimidines 106-111

Product

R1

R2

R3

R4

Yield (%)

Mp (°C)

106a

Ph

Me

Ph

CO2Me

91

155-156

106b

4-Cl-Ph

Me

Ph

CO2Me

93

149-151

106c

Me

Ph

Ph

CO2Me

94

164-165

106d

Ph

Me

4-Cl-Ph

CO2Me

89

162-164

106e

Me

Me

Ph

CO2Me

90

194-196

106f

Me

Me

Me

CO2Me

62

173-175

106g

Ph

Ph

Ph

CO2Me

90

215-216

106h

H

Ph

Ph

CO2Me

86

134-135

107a

Ph

Me

Ph

CN

52

206-208

107b

4-Cl-Ph

Me

Ph

CN

43

180-182

107c

Me

Ph

Ph

CN

79

164-165

108

H

Ph

Ph

Ph

36

174-176

109

H

Ph

Ph

CO2CH2-

CH2NMe2

57

glassy material

Using the same conditions, treatment of 104e or 104h with di-substituted alkenes such as methyl methylacrylates, or methyl crotonate, gave only low yields of coupling products 110 and 111, respectively.Remarkably, the Z-isomers were formed in these cases, according to NOE spectra, where NOEs were observed between =C-H and =C-CH3 or =C-CH2. (Scheme 2.11)

Scheme 2.11 Heck reactions of 3-iodopyrazolo[1,5-a]pyrimidines with di-substituted alkenes


[page 32↓]

Attempts to use dimethyl maleate or dimethyl fumarate as alkenes in Heck reaction of 3-iodopyrazolo[1,5-a]pyrimidines 104 failed, as did the reaction with acrolein diethyl acetal (3,3-diethyl-1-propene).

2.3.2 Heck cross-coupling of 7-iodopyrazolo[1,5-a]pyrimidine

Attempts to use 7-iodo-3,5-diphenylpyrazolo[1,5-a]pyrimidine to undergo Heck cross-coupling reactions with methyl acrylate, using several kinds of reaction conditions were unsuccessful. Only unchanged starting materials were isolated. (Scheme 2.12)

Scheme 2.12 Heck cross-coupling reaction of 100

It seems that position 7 of the pyrazolo[1,5-a]pyrimidine is not active enough to undergo Heck coupling. However, in Suzuki coupling, it turns out to be possible to act as reactant (see Scheme 2.17,page 39).

2.4 Sonogashira cross-coupling of halopyrazolo[1,5-a]pyrimidines

2.4.1 Sonogashira cross-coupling of 3-iodopyrazolo[1,5-a]pyrimidines

(a) Pd/C as catalyst


[page 33↓]

3-Iodo-5-methyl-2,7-diphenylpyrazolo[1,5-a]pyrimidine 104a was first chosen as staring material in cross-coupling with propargyl alcohol in several kinds of catalytic systems. The homogeneous catalytic systems of Pd(PPh3)2Cl2, Pd(PPh3)4, and Pd(OAc)2 werenot active enough and failed or provided only low yields of coupling product. But using Pd/C as heterogeneous catalyst, CuI as co-catalyst, PPh3 as ligand, K2CO3 as base in DME/water, it turned out to be more effective. The optimization of reaction conditions are shown in Table 2.5.

Table 2.5 Effect of reaction conditions of Sonogashira cross-coupling

Entry

Catalyst

Base

Solvent

Temperature

Yield (%)

      

1

Pd(PPh3)2Cl2, CuI

Et3N

MeCN

RT

9

2

Pd(PPh3)2Cl2, CuI

(i-Pr)2NEt

CH2Cl2

RT

14

3

Pd(OAc)2, PPh3,

Bu4NHSO4

Et3N

MeCN-H2O

RT

27

4

Pd(PPh3)2Cl2, CuI

Et3N

Et3N-DMF

50°C

50

5

Pd(PPh3)2Cl2, CuI

Et3N

Et3N

80°C

0

6

Pd(PPh3)2Cl2, CuI

Et3N

DMF-Et3N

100°C

0

7

Pd(PPh3)4, CuI,

Et3N

Et3N-DMF

50°C

43

8

Pd(PPh3)2Cl2, CuI

Et2NH

Et2NH

50°C

40

9

10% Pd-C, CuI, PPh3

K2CO3

DME-H2O

80°C

72

Pd/C is one of the most common heterogeneous palladium catalysts, and many recent reports have demonstrated it is a convenient, inexpensive, reusable, and highly active catalyst [96]. [page 34↓]Pd/C catalyst is widely used in Suzuki-Miyaura coupling [97], Heck coupling [98], and Sonogashira coupling [99]. Using Pd/C catalyst in aqueous media, substituted 3-iodo-pyrazolo[1,5-a]pyrimidines 104a-104d, 104h were successfully coupled with N,N-dimethylpropargyl amine, propargyl alcohol, and 3-butyn-1-ol (see Table 2.6).

Table 2.6 Pd/C catalyzed Sonogashira reactions of 3-iodo-pyrazolo[1,5-a]pyrimidines

Product

R1

R2

R3

R

Yield (%)

113a

Me

Ph

Ph

CH2NMe2

76

113b

H

Ph

Ph

CH2NMe2

91

113c

Ph

Me

Ph

CH2NMe2

70

113d

p-Cl-Ph

Me

Ph

CH2NMe2

69

113e

Ph

Me

p-Cl-Ph

CH2NMe2

54

113f

H

Ph

Ph

CH2OH

78

113g

Ph

Me

Ph

CH2OH

72

113h

Ph

Me

Ph

CH2CH2OH

71

113i

H

Ph

Ph

CH2CH2OH

75

113j

Me

Ph

Ph

CH2CH2OH

70

104a reacted with3-butynyl p-toluenesulphonate to give only 18 % yield of the desired product 113k. However, 36 % yield of the 3-but-3-en-1-ynyl substitutedpyrazolo[1,5-a]-pyrimidine 114 was isolated as major product. Under the same reaction conditions, the reaction of the 3-iodo pyrazolo[1,5-a]pyrimidine 104h with 3-amino-phenylacetylene, did not result in the desired product, but a homo-coupling (Glaser coupling) product 115 in high yield (Scheme 2.13). Obviously, two hydrogen atoms were removed, although there is no definite [page 35↓]dehydrogenating agent in the reaction systems. This unusual result was independently found by Faivlamb [100]. Mechanistic explanation is not on hand yet. When the experiment was repeated under the same conditions without 104h, the diyne 115 was isolated only 74 %. The result indicated that 104h accelerated the home-coupling of 3-amino-phenylacetylene.

Scheme 2.13

113a and 113b were hydrogenated with H2, catalyzed by 10 % Pd/C in ethanol at room temperature and atmosphere pressure. The desired target products 116a, and 116b were isolated in modest yields (Scheme 2.14).

Scheme 2.14 Catalytic hydrogenations of 113a and 113b


[page 36↓]

Attempts to use Pd/C catalyst to undergo cross-coupling of 3-iodo-pyrazolo[1,5-a]pyrimidine 104h with N-methylpropargylamine, propargylamine or N-propargyl-phthalimide, were unsuccessful. Therefore, other catalytic systems were tested for these cases.

(b) Other conditions for Sonogashira reactions of 3-iodo-pyrazolo[1, 5-a]pyrimidine

3-Iodo-pyrazolo[1,5-a]pyrimidine 104a reacted with (4-ethynyl-phenyl)-N,N-dimethylamine, using Pd(PPh3)2Cl2 as catalyst (no CuI) in a solution of piperdine at 80 °C for 24 h, 44 % of coupling product 117 was isolated. On the other hand, using Pd(PPh3)2Cl2 and CuI as catalyst in a solution of Et3N and DMF at 50°C, it turned out to be suitable for the coupling of 3-iodo-pyrazolo[1, 5-a]pyrimidine 104c with N-propargyl-phthalamide, 36 % of the coupling product 118 was isolated. (Scheme 2.15)

Scheme 2.15

2.4.2 Sonogashira cross-coupling of 7-halopyrazolo[1, 5]pyrimidine

Attempts to use 7-halopyrazolo[1,5-a]pyrimidines in Sonogashira cross-coupling reactions with N,N-dimethylpropargyl amine or propargyl alcohol were unsuccessful, although several kinds of Pd catalysts and reaction conditions were applied. Unfortunately, no definite products could be isolated (Table 2.7).


[page 37↓]

Table 2.7 Reaction conditions of Sonogashira cross-coupling

Entry

Reactant, X

R

Reaction conditions

Result

1

 

99, Br

 

OH

Pd(PPh3)2Cl2, CuI, Et3N, RT, 24 h

NDP*

2

99, Br

NMe2

Pd(PPh3)2Cl2, CuI, Et3N, DMF,

80°C, 24 h

NDP

3

100, I

NMe2

Pd(PPh3)4, CuI, Et3N, 50°C ,24 h

NDP

4

100, I

NMe2

10% Pd/C, CuI, PPh3, K2CO3, DME-H2O, 80°C, 24 h

NDP

5

100, I

NMe2

10% Pd/C, CuI, PPh3, K2CO3, DME-H2O, 80°C, 24 h

NDP

6

100, I

NMe2

Pd(PPh3)2Cl2, CuI, Et3N, 80°C,

24 h

NDP

7

100, I

NMe2

Pd(PPh3)2Cl2, CuI, (i-Pr) 2NEt, CH2Cl2, RT, 24 h

NDP

8

98, Cl

NMe2

Pd(PPh3)2Cl2, CuI, Et3N, DMF, 100°C, 24 h

starting material

* NDP: no definite products

2.5 Suzuki cross-coupling of halopyrazolo[1,5-a]pyrimidines

When 5,7-Dichloro-3-phenylpyrazolo[1,5-a]pyrimidine 101 was treated with three equivalents of phenylboronic acid and 1.2 equivalent of potassium carbonate using toluene as solvent and Pd(PPh3)4 as catalyst, 3,5,7-triphenylpyrazolo-[1,5-a]pyrimidine 89c was isolated in 86 % yield. (Scheme 2.16)


[page 38↓]

Under the same conditions as above, 5,7-dichloro-3-phenylpyrazolo[1,5-a]pyrimidine 101 was coupled with one equivalent of phenylboronic acid and afforded two isomers 98 and 120 in a ratio of 23:54. The regio-selectivity could be increased by using 2 M aqueous Na2CO3 and DME at lower temperature (80 °C) providing 120in 72% yield. (Scheme 2.16)

Scheme 2.16 Suzuki cross-coupling of 101 with phenylboronic acid

3-Iodo-5,7-diphenylpyrazolo[1,5-a]pyrimidine 104h and 3-iodo-3,5-diphenylpyrazolo[1,5-a] pyrimidine 100 could be coupled with phenylboronic acid, catalyzed by Pd(PPh3)4, in the presence of K2CO3 in toluene to provide 3,5,7-triphenylpyrazolo[1,5-a]pyrimidine 89c in 62% and 99%, respectively, after 16 h at 100°C. (Scheme 2.17)


[page 39↓]

Scheme 2.17

It is worth mentioning that the reactant 100 turned out to be an unsuccessful reactant to other Pd-catalyzed cross-coupling reactions, such as Heck coupling reaction and Sonogashira coupling (see chapter 2.3.2 and chapter 2.4.2).

Further attempts to introduce aminopropyl or hydroxypropyl chains into the halopyrazolo-[1,5-a]pyrimidines 104a or 99 by the help of corresponding 9-BBN derivated borane 121 were performed. Unfortunately, Pd(PPh3)4 catalysis failed under normal reaction conditions. (Scheme 2.18)

Scheme 2.18


[page 40↓]

2.6  Attempts to Buchwald-Hartwig amination and Negishi coupling of halopyrazolo[1,5-a]pyrimidines

While 7-chloro or 7-bromopyrazolo[1,5-a]pyrimidine can easily undergo nucleophilic substitution with substituted amines, 3-bromo- or 3-iodopyrazolo[1,5-a]pyrimidine resists uncatalyzed nucleophilic substitution.

Since 3-iodopyrazolo[1,5-a]pyrimidines could successfully be submitted to Suzuki, Heck and Sonagashira cross-coupling reactions, Pd-catalyzed amination (also called Buchwald-Hartwig amination) was advisable. Unfortunately, all attempts for Buchwald-Hartwig amination of 3-halopyrazolo[1,5-a]pyrimidines with several kinds of substituted amines under various reaction conditions were unsuccessful.(Table 2.8)

Table 2.8 Reaction conditions of Buchwald-Hartwig amination

Entry

Reactants

Amines

Reaction conditions

Results

1

103

H2N(CH2)3NMe2

PdCl2(dppf), dppf, t-BuOK, dioxane 100°C, 4 days

NDP

2

104a

H2N(CH2)3NMe2

Pd2(dba)3, BINAP, t-BuONa, toluene, 100°C, 24 h

NDP

3

104a

H2N(CH2)3NMe2

K2CO3, glycol, 140°C, 24 h

NDP

4

104a

H2N(CH2)3NMe2

Microwave, 180°C, 170W,

20 min

NDP

5

104a

H2N(CH2)3NMe2

Pd2(dba)3, BINAP, t-BuONa, toluene, 80°C, 24 h

NDP

6

104h

H2N(CH2)3NMe2

Pd2(dba)3, BINAP, t-BuONa, toluene, 80°C, 4 days

NDP

7

104h

H2N(CH2)3NMe2

Pd(OAc)2, BINAP, t-BuONa, toluene, 100°C, 24 h

NDP

8

104h

Morpholine

Pd(OAc)2, BINAP, t-BuONa, toluene, 100°C, 24 h

deiodoproduct

9

104h

NH(n-Bu)2

Pd(OAc)2, (t-Bu)3P, t-BuONa, toluene, 100°C, 24 h

deiodoproduct 80%


[page 41↓]

4-Ethoxycarbonyl-butylzincbromide was envisaged to introduce an alkyl chain into halopyrazolo[1,5-a]pyrimidine 104a or 100, which could be reduced to a hydroxybutyl group later on. Again, all attempts failed, although several catalysts and different conditions were used. (Scheme 2.19)

Scheme 2.19

2.7 Pd-free synthesis of pyrazolo[1,5-a]pyrimidine derivatives

2.7.1 Nucleophilic substitution of halopyrazolo[1,5-a]pyrimidine

Chloroatoms adjacent to a 6-ring-N-heteroaromatics are prone to uncatalyzed nucleophilic substitutions by amines. Thus, we tried to introduce amino groups into 5-chloro-3,7-diphenylpyrazolo[1,5-a]pyrimidine 120. The desired products 127 and128 were obtained in good yields. (Scheme 2.20)


[page 42↓]

Scheme 2.20

The latter product 128 fits well into the pattern of envisaged calcineurin inhibitors 8,where the side chain is connected to the core heterocycle via a nitrogen atom.

By benzylic-type nucleophilic subsititution at 5-bromomethyl-3,7-diphenylpyrazolo[1,5-a]-pyrimidine 105 a further variation of the side chain was achieved, where a nitrogen atom wasin the centre of the alkyl chain.(formation of 129, Scheme 2.21)

Scheme 2.21

2.7.2 Synthesis of pyrazolo[1,5-a]pyrimidine derivatives by ring-chain-transformation

As mentioned before (see chapter 1.1.3, page 4), the ring-chain-transformation is an effective tool to synthesize ω-functionalized heterocycles. We tried to apply this type of reaction to synthesize 5-hydroxypropylpyrazolo[1,5-a]pyrimidine 131. The known 1,3-dicarbonyl precursor 130 [102] was obtained by condensation of acetophone with γ-butyrolactone, and could be ring-chain-transformation with 3-amino-4-phenylpyrazole to the desired product 131 in high yield. (Scheme 2.22)

Scheme 2.22


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