[page 64↓]

4  Pyrimidines and other monocyclic heterocycles

4.1 Synthesis of pyrimidine derivatives

Pyrimidine-containing molecules are of paramount importance in nucleic acid chemistry. Their derivatives including uracil, cytosine, adenine and guanine, are fundamental building blocks for deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Pyrimidine derivatives exist extensively in nature. They have biological and pharmaceutical activities. N-3-substituted pyrimidinones are potent AT1 selective angiotensin II receptor antagonists [144]. Pyrimidine amide derivatives are novel antiallergic agents [145]. S-alkylated derivatives are potent antiviral agents [146]. 6-Alkylaminoderivatives are inhibitors of bacillus subtilis DNA polymerase III [147]. Aziridino derivatives are new cytotoxic agents with tumour-inhibitory activity [148]. Arylamino derivatives of pyrimidines are potential anti-cytomegalovirus agents [149], 2- or 4-(4-methylpiperazino)pyrimidines are 5-HT2A receptor antagonists [150].

Due to the electronegativity of the two nitrogen atoms, pyrimidine is a π-electron-deficient heterocycle. Therefore, nucleophilic displacements of nucleofugal leaving groups take place readily. This trend also translates to palladium chemistry. 4-Chloropyrimidine oxidatively adds to Pd(0) more readily than 2-chloropyrimidine.

We tried to assemble calcineurin inhibiting products of the general structure 8 with pyrimidine as core heterocycle via Pd-catalyzed coupling reactions.

4.1.1 Overview of Pd-catalyzed coupling reactions of halopyrimidines Pd-catalyzed cross-coupling reactions of monohalopyrimidines

Halogenated pyrimidines can undergo a series of Pd-catalyzed cross-coupling reactions, for example, Suzuki reactions, Sonogashira reaction, Stille reactions, Negishi reactions, Heck reactions:

[page 65↓]

(1) Suzuki reactions

5-Bromo-2,4-di-tert-butoxypyrimidine 228 was coupled with 3-methyl-thiophene-2-boronic acid, and 5-substituted pyrimidine 229 was obtained [151]. Coupling of the 2-chloropyri-midine 230 with the arylboronic acid 231 afforded 2-arylpyrimidine 232 [152]. (Scheme 4.1)

Scheme 4.1

(2) Sonogashira reactions

2-Iodo-4,6-dimethylpyrimidine was coupled with a series of terminal alkynes, providing alkynylpyrimidines 233 in good to excellent yields [153]. The Sonogashira coupling of 5-bromopyrimidine with N,N-dimethylpropargylamine gave the aminoalkyne 234 [154]. (Scheme 4.2)

Scheme 4.2

[page 66↓]

(3) Stille reactions

5-Bromopyrimidinewas coupled with 1-(trimethylsilyloxy)vinyltin to give5-(1-trimethyl-silanyloxy-vinyl)-pyrimidine 235 in 67 % yield [155]. (Scheme 4.3)

Scheme 4.3

(4) Negishi reactions

2-Iodo-4,6-dimethylpyrimidine was coupled with 3-ethoxycarbonylpropylzinc iodide at room temperature, catalyzed by Pd(PPh3)4, to give 4-(4,6-dimethyl-pyrimidin-2-yl)-butyric acid ethyl ester 236 in 91 % yield [156]. (Scheme 4.4)

Scheme 4.4

(5) Heck reactions

2-Amino-5-bromo-pyrimidine was coupled with benzyl acrylate in 79 % yield [157], catalyzed by Pd(OAc)2/P(o-tolyl)3. 4,6-Dimethylpyrimidine-2-acrynitrile 238 was obtained in 61 % yield [158] by PdCl2-catalyzed reaction of 2-iodo-4,6-dimethylpyrimidine with acrylonitrile. (Scheme 4.5)

Scheme 4.5

[page 67↓]  Regioselective Pd-catalyzed couplings of polyhalopyrimidines

When more than one halo-substituent exist in a pyrimidine ring, the regioselectivity of cross-coupling has to be considered. If the halo-substituents are the same, the 4-position is in general more active than the 2-position in Pd-catalyzed cross-coupling reactions. But iodo-substituted positions are more active than chloro-substituted positions.

(1) Stille reaction:

The positional reactivity of 5-bromo-2,4-dichloropyrimidine in Stille reactions is: 4-Cl > 5-Br > 2-Cl. Three different substituents could be introduced by stepwise Stille couplings to afford product 243 [159]. (Scheme 4.6)

Scheme 4.6

(2) Suzuki reaction:

Reaction of 2,4,6-trichloropyrimidine with one equivalent of phenylboronic acid in the presence of Pd(OAc)2/PPh3 gave rise to the formation of 2,4-dichloro-6-phenylpyrimidine 239 with complete regioselectivity in high yield. Accordingly, 2,4,6-trichloropyrimidine formed 2-chloro-4,6-diphenylpyrimidine 240, with two equivalents of phenylboronic acid, under the same conditions [160]. (Scheme 4.7)

[page 68↓]

Scheme 4.7

(3) Sonogashira reactions

2,4-dichloropyrimidine reacted with one equivalent of 1-hexyne at room temperature, catalyzed by Pd(PPh3)2Cl2 and CuI, to give the 2-chloro-4-alkynylpyrimidine 244.Subsequent coupling of 244 with 1-hexyne at 65 °C, afforded 2,4-dialkynylprimidine 245 [161]. The iodo atom of 5-bromo-2-iodopyrimidine was selectively substituted by terminal alkynes under typical Sonogashira conditions, affording 5-bromo-2-alkynylpyrimidines 246 [162]. (Scheme 4.8)

Scheme 4.8

(4) Heck reaction

In 5-bromo-4-iodo-2-isopropyl-6-methylpyrimidine 247, a selective substitution of the iodo atom was observed in Heck reaction, leading to the 4-styrylpyrimidine 248 [163]. (Scheme 4.9)

[page 69↓]

Scheme 4.9

4.1.2 Synthesis of aryl substituted halopyrimidines

The halopyrimidines used in our investigations of Pd-catalyzed cross-couplings were obtained via corresponding pyrimidinones. Following a well-established pyrimidine synthesis, 2,6-diphenylpyrimidin-4-one 249 was obtained from benamidine and ethyl benzoylacetate [164]. 249 was further refluxed with POCl3 and PCl5 to give 75 % of 4-chloro-2,6-diphenylpyrimidine 250 [165]. After chloro-iodo exchange with HI 4-iodo-2,6-diphenylpyrimidine 251 was obtained in 42 % yield [165]. (Scheme 4.10)

Scheme 4.10

Similarily, 4,6-dichloro-2-phenylpyrimidine 253 and 4,6-diiodo-2-phenylpyrimidine 254 were obtained in a straight forward way, starting frombenzamidine and diethyl malonate [166]. (Scheme 4.11)

Scheme 4.11

[page 70↓]

2-Chloro-4,6-diarylpyrimidines 240 were synthesized in high yields by Suzuki coupling of 2,4,6-trichloropyrimidine with 2 equivalents of arylboronic acid [160]. (Scheme 4.12)

Scheme 4.12

Using the same conditions, 2-chloropyrimidine 255 with different aryl substituents at position 4 and 6 was prepared by stepwise Suzuki reactions of 2,4,6-trichloropyrimidine. (Scheme 4.13)

Scheme 4.13

4.1.3 Introduction of side chains into pyrimidines Sonogashira cross-coupling of halopyrimidines

In order to introduce teminal heteroatom functionalized chains into pyrimidines, diaryl-halopyrimidines were coupled with propargyl amine. Thus, 4-iodo-2,6-diphenylpyrimidine 251was treated with N,N-dimethylpropargyl amine, catalyzed by Pd(PPh3)2Cl2 and CuI, providing [3-(2,6-diphenyl-pyrimidin-4-yl)-prop-2-ynyl]-dimethyl-amine 256 in 76 % yield. 256 was further hydrogenated in the presence of Pd/C to give [3-(2,6-diphenyl-pyrimidin-4-yl)-propyl]-dimethyl-amine 257 in 76 % yield. Analogously, the phthalimidopropynyl pyrimidine 258 was obtained in high yield. (Scheme 4.14)

[page 71↓]

Scheme 4.14

More forcing conditions were necessary for Sonogashira reactions of 2-chloro-4,6-diaryl-substituted pyrimidines 240 or 255. After heating at 100 °C for 24 h, the [3-(4,6-diaryl-pyrimidin-4-yl)-prop-2-ynyl]-dimethylamines 259a-259c were obtained. KOAc turned out to be advantageous over triethylamine. (Scheme 4.15)

Scheme 4.15

The C-C triple bonds of 259a-259c could be further hydrogenated in the presence of 10 % Pd/C (0.2 equiv.). In the case of the chlorophenyl substituted pyrimidines 259b-259c, the chloro substituent was lost during the reduction of the triplet bond [167], i.e. the desired [page 72↓]target molecules with chloro substituted phenyl groups could not obtained by this route. (Scheme 4.16)

Scheme 4.16 Nucleophilic substitution of halopyrimidines

In potential calcineurin inhibiting compounds fitting into the general structure 8 the side chain can also be connected to the core heterocycle via a heteroatom. Such compounds can either be obtained by nucleophilic substitution or by Pd-catalyzed coupling.

N,N-dimethyl-1,3-propanediamine, 2-dimethylaminoethanol, and 2-dimethylamino-ethanethiol, were applied in uncatalyzed nucleophilic substitution with 2-chloro-4,6-diarylpyrimidine 240.

While high yield of N'-(4,6-diphenyl-pyrimidin-2-yl)-N,N-dimethyl-propane-1,3-diamine 261 was achieved. N'-(4,6-diphenyl-pyrimidin-2-yl)-N,N-dimethyl-propane-1,3-diamine 262 and [2-(4,6-diaryl-pyrimidin-2-yl-sulfanyl)-ethyl]-dimethyl-amine 263 were formed in low yield (about 30 %). Probably, competing oxidation of the 2-dimethylaminoethanethiol to the corresponding disulfide or substitution of chloride by tert-butoxide, respectively, could be responsible for the low yields. (Scheme 4.17)

[page 73↓]

Scheme 4.17

Reaction of 2,4,6-trichloropyrimidine [168] with two equivalents of propanolamine afforded two isomers 264a and 264b in a ratio of 40:49. Subsequent attempts to submit 264a to a twofold Suzuki reaction to give 265 were unsuccessful. (Scheme 4.18) Therefore, the reversed sequence, i. e. first Suzuki coupling and then introduction of the side chain seems to be advantageous.

Scheme 4.18

[page 74↓]

4.2  Synthesis of pyridine derivatives

Many pyridine-containing molecules are important because of their biological and pharmacological properties. They have found applications as precursors of pharmacological compounds [169], in the synthesis of liquid crystals [170] or polymers [171], as well as ligands [172] for a lot of transition metal complexes.

Pyridine is a π-electron-deficient heterocycle. Due to the electronegativity of the nitrogen atom, the corresponding α and γ position of pyridine bear partial positive charge, making them prone to nucleophilic attacks. A similar trend occurs in the context of Pd-catalyzed coupling reactions.

4.2.1 Overview of Pd-catalyzed coupling reactions of halopyridines

Halogenated pyridines underwent a series of Pd-catalyzed cross-coupling reactions, for example, Suzuki reactions, Sonogashira reaction, Stille reactions, Negishi reactions, Heck reactions, Buchwald-Hartwig amination, etc. Iodide, bromide and chloride could be used as suitable leaving groups. If two halogen atoms are found in the pyridine ring, it is possible to substitutite one and keep the other. (e.g. formation of 268)

(1) Suzuki reactions[173, 174]

Scheme 4.19

(2) Kumada reactions[175]

Scheme 4.20

[page 75↓]

(3) Stille reactions[176]

Scheme 4.21

(4) Negishi reactions[173]

Scheme 4.22

(5) Sonogashira reactions[177]

Scheme 4.23

(6) Buchwald-Hartwig aminations[178]

Scheme 4.24

[page 76↓]

(7) Heck reactions[179]

Scheme 4 25

Mono couplings are regioselective if two or more different halogen atoms are attached in the pyridine ring (I > Br > Cl) or equal halogen atoms are found at different positions (2-position > 4-position > 3-position).

(1) Kumada reactions [180]

Scheme 4.26

(2) Sonogashira reactions[181, 182]

Scheme 4.27

(3) Suzuki reactions[183, 184]

Scheme 4.28

[page 77↓]

(4) Heck reactions[185, 186]

Scheme 4.29

(5) The carbonylation reactions[187]

Scheme 4.30

(6) Buchwald-Hartwig amination[188]

Scheme 4.31

4.2.2 Introduction of dimethylaminopropyl chain into pyridine

We synthesized the dimethylaminopropyl pyridine 287 as a novel representative of calcineurin inhibitors of the general structure 8, starting from 2-amino-3,5-dibromopyridine and demonstrating the versatility of Pd-catalyzed cross-coupling reactions to introduce all three important peripheral groups into the central pyridine ring.

[page 78↓]

2-Amino-3,5-dibromopyridine was first treated with phenylboronic acid to give 2-amino-3,5-diphenylpyridine 283 under Suzuki conditions [71]. Then 283 was transformed into the 2-iodo-3,5-diphenylpyridine 284, while some pyridinone 285 was formed as by product. (Scheme 4.32)

2-Iodo-3,5-diphenylpyridine 284 was submitted to Sonogashira coupling with N,N-dimethylpropargylamine in the presence of Pd(PPh3)2Cl2, CuI and TEA, affording high yield of the alkynylated pyridine product 286. Final catalytic hydrogenation of 286 (using 10 % Pd/C as catalyst, at room temperature under atmosphere pressure) gave 3,5-diphenyl-2-(3-dimethylaminopropyl) pyridine 287 asdesired target product in 71 % yield. (Scheme 4.32)Interestingly, the deaminated 2-propylpyridine 288 was isolated as by-product in 16 % yield. Similarly reductive deamination was reported in literature [189].

Scheme 4.32 Synthesis of 3,5-diphenyl-2-(3-dimethylaminopropyl) pyridine

[page 79↓]

4.3  Synthesis of pyrazine derivatives

Minuscule quantities of naturally occurring pyrazines have been found in some foodstuffs and are largely responsible for their flavor and aroma. Pyrazine derivatives have potent pharmaceutical activities [190].

Pyrazine is an electron-deficient, 6π-electron heteroaromatic compound. The inductive effects of the nitrogen atoms induce a partially positive charge on the carbon atoms. As a consequence, oxidative addition of chloropyrazine takes place more readily than with chlorobenzene, and chloropyrazines undergo a wide range of palladium-catalyzed carbon-carbon bond formation reactions:

(1) Stille reactions[191]

Scheme 4.33

(2) Suzuki reactions[192, 193]

Scheme 4.34

(3) Sonogashira reactions[194, 195].

Scheme 4.35

[page 80↓]

(4) Heck reactions[196, 197]

Scheme 4.36

According to the general structure 8, we aimed to pyrazines substituted by two aryl groups and one dimethylaminopropyl group.

5-Chloro-2,3-diphenylpyrazine 297, as suitable starting material for the Pd-catalyzed introduction of the aminoalkyl group, was known and can easily be synthesized in high yield [198] starting from benzil and glycine amide in two steps.(Scheme 4.37)

Scheme 4.37

Only modest yield of 298 was achieved in the Sonogashira coupling of 5-chloro-2,3-diphenylpyrazine 297 with N,N-dimethylpropargylamine in TEA and DMF. In the case of the analogous Sonogashira coupling of 2-chloropyrimidine 240a (see chapter 4.1.3), the application of potassium acetate was advantageous over TEA. In the case of 298, it also led to an increase in the yield from 38 % to 51%. Pd-catalyzed hydrogenation of 298 provided the desired [3-(5,6-diphenyl-pyrazin-2-yl)-propyl]-dimethyl-amine 299 in 58 % yield. (Scheme 4.38)

[page 81↓]

Scheme 4.38

4.4 Synthesis of oxazole derivatives

In the last decade, several oxazole-containing natural products have been isolated and found to be biologically active. Much synthetic effort has been expended in their total synthesis.

Oxazole is a π-electron-excessive heterocycle. The electronegative nitrogen atom attracts electrons so that C(2) is partially positive and therefore susceptible to nucleophilic attack. In the other side, electrophilic substitution of oxazoles takes place at the electron-rich position C(5) preferentially. More relevant to palladium chemistry, 2-halooxazoles are prone to oxidative addition to Pd(0). Even 2-chlorooxazoles are viable substrates for Pd-catalyzed reactions. Some examples of known Pd-catalyzed coupling reactions are shown in Scheme 4.39-Scheme 4.43:

[page 82↓]

(1) Suzuki reactions [199]

Scheme 4.39

(2) Stille reactions [199]

Scheme 4.40

(3) Negishi reactions [199]

Scheme 4.41

[page 83↓]

(4) Sonogashira reactions [200]

Scheme 4.42

(5) Heck reactions [200]

Scheme 4.43

4-Bromo-2,5-diphenyloxazole 310 was readily available [201] by bromination of 2,5-diphenyloxazole. (Scheme 4.45)

Scheme 4.44

We used4-bromo-2,5-diphenyloxazole 310, as reactant to introduce an aminopropyl chain by Sonogashira coupling with N,N-dimethylpropargylamine. Optimized conditions [Pd(Ph3)2Cl2, CuI, AcOK, DMF, 100 °C] provided the coupling product 311 in 66 % yield. 311was further hydrogenated,using H2 and Pd/C, to give [3-(2,5-diphenyl-oxazol-4-yl)-[page 84↓]propyl]-dimethyl-amine 312 in 58 % yield. 312 was a further new example of potential calcineurin inhibiting compound of the general structure 8. (Scheme 4.45)

Scheme 4.45

The aminophenylethynyloxazole 313 represents a further variation of the general structure 8. The side chain amino group is attached to an aromatic ring rather than to a sp3 carbon atom. This product was obtained by Sonogashira coupling of 310 with 3-aminophenylethyne. (Scheme 4.46)

Scheme 4.46

Buchwald-Hartwig amination of 4-bromo-2,5-diphenyloxazole 310 with N-methyl-piperazine furnished low yield of an oxazole 314, which is related to the general structure 8. The side chain amino group is part of a saturated ring. (Scheme 4.47)

Scheme 4.47

[page 85↓]

4.5  Synthesis of pyrazole derivatives

Aryl pyrazoles possess widespread occurrence as substructures in a large variety of compounds with important biological and pharmacological properties. Among them, 1,5-diphenylpyrazoles are novel non-nucleoside HIV reverse transcriptase inhibitors [202] and cyclooxygenase-2 inhibitors [203]. 1,3,5-Trisubstituted pyrazoles are inhibitors of cholesterol [204]. Moreover, some substituted pyrazole compounds are potent inhibitors of p38 MAP kinase [205] and estrogen receptors [206].

Pyrazole is a π-electron-excessive heterocycle. The electronegativity of the nitrogen atom attracts electrons so that C(3) and C(5) are partially electropositive and therefore susceptible to nucleophilic attack. On the other side, electrophilic substitution of oxazoles takes place at the electron-rich position C(4) preferentially. Several Pd-catalyzed coupling reactions of halopyrazoles have been reported:

(1) Suzuki reactions [206-208]

Scheme 4.48

[page 86↓]

(2) Sonogashira reactions [209, 210]

Scheme 4.49

Starting from phenylhydrazine and benzoylacetone [202] and iodination [204] of the intermediate 320,4-iodo-3-methyl-1,5-diphenylpyrazole 321 was obtained.(Scheme 4.50) With its two phenyl groups at the pyrazole ring, compound 321 just needs an additional aminoalkyl group to fit into the potential calcineurin inhibiting structure 8.

Scheme 4.50

According to our experienced strategy for the introduction of a dimethylaminopropyl chain by Sonogashira coupling with N,N-dimethylpropargyl amine, followed by catalytic hydrogenation, the envisaged target 323 was afforded in high yield. Remarkably, catalysis [page 87↓]with Pd(PPh3)2Cl2 and CuI completely failed, while Pd/C, PPh3 and CuI provided quantitative Sonogashira coupling.(Scheme 4.51)

Scheme 4.51

4.6 Synthesis imidazole derivatives

The imidazole ring is present in a number of biologically important molecules as exemplified by the amino acid histidine. It can serve as a general base (pKa = 7.1) or a ligand for various metals in biological systems. Furthermore, the chemistry of imidazole is prevalent in protein and DNA biomolecules in the form of histidine or adinine/guanine, respectively.

Aryl substituted imidazoles exist extensively in nature. They have important biological and pharmaceutical activities. For example, substituted 4,5-diaryl-2-thio-imidazoles are potent inhibitors of cholesterol acyltransferase [211], 1,2-diarylimidazoles are new series of COX-2 selective inhibitors [212]; aryl-heteroaryl-imidazoles are potent inhibitors of the MAP kinase p38 [213] and highly active, selective histamine H1-receptor agonists [214].

Imidazole is aπ-electron-excessive heterocycle. Electrophilic substitution normally occurs at C(4) or C(5), whereas nucleophilic substitution takes place at C(2).

[page 88↓]

In Pd-catalyzed coupling reactions, a halo leaving group can be found in any C-position of imidazoles. Several known examples are shown below:

(1) Suzuki reaction [215]

Scheme 4.52

(2) Stille reactions[215]

Scheme 4.53

(3) Negishi reactions [216]

Scheme 4.54

(3) Sonogashira reactions [217]

Scheme 4.55

[page 89↓]

(4) Heck reaction [218]

Scheme 4.56

As expected in Pd-catalyzed cross-coupling of polyhaloimidazoles, the 2-position is more active than the 4-position and the 5-position.

(1) Suzuki reaction [219]

Scheme 4.57

(2) Stille reaction [215]

Scheme 4.58

(3) Sonagashira reaction[220]

Scheme 4.59

[page 90↓]

4,5-Diphenylimidazole was chosen as starting material and a series of imidazole derivatives were prepared to achieve potential calcineurin inhibiting compounds, which fitted into the general structure 8.

The 1-(3-aminopropyl)-imidazole 335, where the side chain is not attached to a carbon atom but to a nitrogen atom, was synthesized in a Pd-free reaction. Alkylation of4,5-diphenylimidazole with N-3-bromopropylphthalimide, and final deprotection of the phthalimido product 334 gave 3-(4,5-diphenyl-imidazol-1-yl)-propylamine 335 in 85 % yield. (Scheme 4.60)

Scheme 4.60

We further tried to introduce an aminoalkyl chain into position 2 of the imidazole ring. 4,5-diphenylimidazole was first N-protected by benzylation [221], thus adding a third aryl group to the core heterocycle. (Scheme 4.61)

Scheme 4.61

[page 91↓]

Halogenation of1-benzyl-4,5-diphenyl-imidazole 336 with NBS was successful, but failed with NIS in THF. (Scheme 4.62)

Scheme 4.62

Sonogashira coupling of 1-benzyl-2-bromo-4,5-diphenylimidazole 338 with N,N-dimethyl-propargylamine in the presence of Pd(PPh3)2Cl2/CuI gave low yield in DMF. However, when TEA was used as solvent, the coupling product 339 could be obtained in 43 %. 339 was further hydrogenated with hydrogen, catalyzed by 10 % Pd/C, providing [3-(1-benzyl-4,5-diphenyl-imidazol-2-yl)-propyl]-dimethyl-amine 340 in 63 % yield. (Scheme 4.63)

Scheme 4.63

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