A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki-Miyaura cross-coupling reaction

A convenient route to symmetrically and unsymmetrically

substituted 3,5-diaryl-2,4,6-trimethylpyridines via

Suzuki–Miyaura cross-coupling reaction

Dariusz Błachut*1, Joanna Szawkało2 and Zbigniew Czarnocki2

Full Research Paper

Open Access

Address:

Beilstein J. Org. Chem. 2016, 12, 835–845.

1Forensic Laboratory, Internal Security Agency, 1 Sierpnia 30A,

02-134 Warsaw, Poland, Tel.: +48 693830760 and 2Faculty of

Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw,

Poland

doi:10.3762/bjoc.12.82

Received: 03 December 2015

Accepted: 08 April 2016

Published: 28 April 2016

Email:

Dariusz Błachut* - d.blachut@abw.gov.pl

Associate Editor: J. Aubé

* Corresponding author

License and terms: see end of document.

Keywords:

arylpyridines; cross coupling reaction; heteroaromatics; one-pot

reaction; palladium catalyst

Abstract

A series of differently substituted 3,5-diaryl-2,4,6-trimethylpyridines were prepared and characterized using the Suzuki–Miyaura

coupling reaction with accordingly selected bromo-derivatives and arylboronic acids. The reaction conditions were carefully opti-

mized allowing high yield of isolated products and also the construction of unsymmetrically substituted diarylpyridines, difficult to

access by other methods.

Introduction

Nitrogen heterocycles are an important class of compounds In our ongoing forensic chemistry programme directed toward

widely present in agrochemical products [1,2] and pharmaceuti- the identification and synthesis of novel byproducts of illegally

cals [3-9]. Pyridine can be considered as one of the simplest yet produced amphetamine analogues, we described the

popular members of this family. Differently substituted pyri- synthesis of several new nitrogen heterocycles. Among

dine rings are present in several drugs, e.g., clarinex, a dual them methylarylpyrimidines P1, benzylpyrimidines P2, and

antagonist of platelet activating factor or in pheniramine and aryl/methylpyridines P3, P4 attracted our special attention

related pyridine-containing antihistamines for allergy treatment (Figure 1) [23-27].

[10-13]. Other examples of pharmaceuticals containing a simple

pyridine ring are rabeprazole [14,15], pentoprazole [16,17] and These compounds were identified as impurities in ampheta-

lansoprazole [18], which represent the well-known class of mine or its analogues synthesized only by the Leuckart method

proton pump inhibitors. Furthermore, atropisomeric biaryls with starting from the corresponding 2-arylacetones. Therefore, the

a pyridine ring display promising properties in asymmetric ca- forensic community treats them as "route-specific impurities" or

talysis [19-22].

"route markers". The formation of these compounds results

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Beilstein J. Org. Chem. 2016, 12, 835–845.

Figure 1: Types of aryl pyridines and pyrimidines already prepared in our group [23-27].

Results and Discussion

Symmetrically substituted 3,5-diaryl-2,4,6-tri-

methylpyridines

The starting material in the synthetic sequence, 3,5-dibromo-

2,4,6-trimethylpyridine (1), can be easily prepared by simple

bromination of 2,4,6-trimethylpyridine in 60% oleum on a

multigram scale according to the procedure published by Drze-

niek and Tomasikl [37].

from the condensation of the drug precursors, like arylacetones

with formamide or ammonia, in the presence of formic acid.

This leads to di- and tetrahydrobenzyl/arylpyridines or pyrim-

idines with subsequent aromatization of the heterocyclic ring.

We also noticed that the final composition of these markers was

dependent on the reaction conditions during the drug synthesis

[24].

In order to unequivocally confirm the presence of newly identi-

fied markers in the reaction mixture, we decided to develop a In order to optimize the conditions for the preparation of diary-

convenient method for their preparation on a multimilligram lated pyridine 4, the coupling of dibromopyridine 1 with

scale. In traditional synthetic methods, the substituted pyridine phenylboronic acid was initially selected as a model reaction to

ring can be constructed, e.g., by Hantzsch reaction [28,29] or by study the effectiveness of various palladium sources, ligands,

condensation of amino-enone or aminonitrile derivatives with a inorganic bases and solvent systems. Our goal was to maximize

1,3-dicarbonyl system [30,31]. An important drawback of this the yield of product 4 while suppressing the formation of the

strategy, especially when the access to a wide library of intermediate 3 and its des-brominated derivative 2 (Table 1). In

diversely decorated derivatives is necessary, is that the prepara- a search for an efficient catalytic system, we took into consider-

tion requires an individually optimized synthetic procedure and ation that dibromopyridine 1 having reaction sites at positions 3

the use of different substrates. Therefore, a more general and 5 of the pyridine ring, being shielded by methyl groups,

strategy leading to a number of different 2,4- and 2,5-diaryl- might be less susceptible to the cross-coupling reaction. If

dimethylpyridines P3, P4 [25], 4-benzylpyrimidines P2 [26], the steric repulsion of the pyridine methyl group, at least in

and 4-methyl-5-arylpyrimidines P1 [26] was needed. For this part, corresponds to its van der Waals radii, the degree

purpose, we successfully used Suzuki and Negishi cross-cou- of steric repulsion of the selected ortho-substituents in aryl-

pling reactions between arylboronic acids/benzylzinc reagents boronic acids can be listed in the following order: I > Br > Me >

and halogenated pyridines and pyrimidines.

Cl > NO2 > CO2H > OMe > F > H [38,39]. The results of a

series of the preliminary reactions are summarized in Table 1

During our search for new "route markers" of amphetamine an- and in Supporting Information File 1.

alogues synthesized by the Leuckart method, we focused our

attention on two groups of heterocycles, that were preliminary The ligand-free system based on palladium acetate (10 mol %)

identified by GC–MS analysis as 3,4,5-triaryl-2,6-dimethylpyri- or palladium chloride (10 mol %) in the presence of K3PO4 and

dines P5 [32,33] and 3,5-diaryl-2,4,6-trimethylpyridines P6.

K2CO3 in a mixture of toluene/H2O (6:1) was initially tested.

Recently, several ligand-free catalytic systems have been

In this study we report on the synthesis of a series of 3,5-diaryl- applied successfully in Suzuki cross-coupling reaction between

2,4,6-trimethylpyridines P6 (4–29) with substitution pattern at various aryl and heteroaryl halides and triflates with alkenyl and

the phenyl ring as present in the most popular amphetamine- arylboronic acids [40-43]. The evaluation of such catalysts,

type drugs [23,27,34-36] (4-MeO, 4-MeS, 4-F, 4-Me, 3,4- especially in water-based solvents, is important from the point

OCH2O). We also decided to explore the possibility of the syn- of view of so-called “green chemistry” and also its economic

thesis of diarylpyridines P7 (46–66) with different aryl rings efficiency [44,45]. In our hands, all attempts to carry out the

(Ar1 ≠ Ar2) as model compounds in a further study on the reaction with both palladium acetate or palladium chloride

mechanism of their formation during amphetamine synthesis. gave the desired diarylated product 4 with unacceptable yield

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Beilstein J. Org. Chem. 2016, 12, 835–845.

Table 1: Optimization of the reaction conditions.

Entry Catalyst (mol %)

Basea

Solventb

Time [h]

Conversionc

Yield [%]d

2

3

4

1

Pd(OAc)2 (10)

K3PO4

Na2CO3

NaOH

toluene/H2O

24

0.25

0.5

1

8

6

1

2

Pd(OAc)2 (10)

toluene/H2O

11

7

2

3

PdCl2 (10)

toluene/H2O

10

6

3

1

4

Pd(OAc)2 (4), P(o-tol)3 (8)

Pd(PPh3)4 (5)

toluene/H2O/EtOH

1,4-dioxane

85

4

51

49

20

17

12

3

30

42

77

80

85

92

94

~1

77

80

9

5

94

3

6

~100

100

76

3

7

2

3

8

6

3

9

16

8

5

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

traces

6

Pd(PPh3)4 (5)

75

traces

5

–

Pd(PPh3)4 (5)

Cs2CO3

K3PO4

Cs2CO3

K3PO4

Cs2CO3

K3PO4

Na2CO3

K2CO3

K3PO4

CsF

100

58

23

15

32

9

Pd(PPh3)4 (5)

DMF

4

Pd(PPh3)2Cl2 (6)

toluene/H2O/EtOH

1,4-dioxane

100

78

–

91

81

90

26

36

86

98

99

98

99

95

88

98

89

97

~99

97

88

31

95

~99

Pd(PPh3)2Cl2 (6)

8

–

19

6

Pd(PPh3)2Cl2 (6)

16

0.25

0.5

1

4

Pd(OAc)2 (4), P(Cy)3 (12)

Pd(OAc)2 (4), P(Cy)3 (12)e

Pd(dppf)Cl2 × CH2Cl2 (4)

1

51

50

11

–

87

1

~99

100

64

2

8

1

–

3

1

–

3

2

–

3

1

–

4

5

–

toluene/H2O/EtOH

1,4-dioxane

8

7

4

Cs2CO3

CsF

16

8

2

–

6

5

Cs2CO3

K3PO4

KF

1,4-dioxane

4

3

–

1,4-dioxane

4

–

DMF

6

1

2

1,4-dioxane

16

8

10

14

5

2

Pd2(dba)3, (4) Symphos (8) K3PO4

1,4-dioxane

19

–

Pd2(dba)3 (4), P(Cy)3 (12)

Pd(OAc)2 (3), S-Phos (6)

Pd(OAc)2 (3), X-Phos (6)

K3PO4

1,4-dioxane

8

100

toluene

1

–

toluene

1

–

a4 Equiv of base was used. bTemperature of the reaction: toluene, 1,4-dioxane, DMF, toluene/H2O: 90 °C; solvent system toluene/H2O/EtOH: 85 °C.

cThe conversion of substrate was measured by GC–MS. It was calculated as a percent ratio of unreacted 1 and the sum of the peak areas of 2, 3 and

4. dThe yield was estimated by GC–MS by comparison of peak area of particular product with the sum of areas of the rest of the products and uncon-

verted substrate. eTemperature of reaction 30 °C.

(1–2%) with low conversion of the precursor (8–11%). In drastic conditions (xylene, 130 °C, 48 h; not mentioned

each case, monoarylpyridine 2 was observed as the main in Table 1) led only to fast debromination of the starting

product with trace amounts of its bromo derivative 3. More material 1.

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Beilstein J. Org. Chem. 2016, 12, 835–845.

The screening was then continued with Pd(OAc)2 and tri-(o- screening was continued with PdCl2(dppf)×CH2Cl2 (4 mol %)

tolyl)phosphine (P(o-tol)3) used as a catalyst in the mixture tol- in 1,4-dioxane and DMF in the presence of various bases. The

uene/water/ethanol as solvent system and with sodium results show that the catalyst is highly effective with combina-

carbonate as a base. In order to control the progress of the tion of dioxane and K3PO4 as a base (Table 1, entry 31). Ac-

process, the mixture was regularly sampled and the compo- cording to Hayashi et al. [51,52], superior activity of dppf is due

nents ratio of was analysed by GC–MS (Table 1, entries 4–9). to favourable bite angle induced by the ligand in the catalytic

Full conversion of the starting material 1 was accomplished complex.

within 1 hour. However, the transformation of intermediary

bromophenylpyridine 3 into 4 required further 15 hours. It was As can be seen from Table 1, entries 34 and 35, the nature of

observed that during the last hour of the reaction, a significant the ligand affects the activity of the catalyst. The initially poor

acceleration of the dehaloganation process of 3 into mono- result obtained for Pd2(dba)2/Symphos (Table 1, entry 17) was

phenylpyridine 2 was observed. This phenomenon can be greatly improved when P(Cy)3 was applied.

assigned to the stepwise slow decomposition of the catalytic

complex into palladium metal. The effectiveness of commer- The best outcome in terms of the reaction time, yield of the

cially available Pd(PPh3)4 was verified in systems containing diarylated product 4 and the content of byproducts were ob-

various bases and solvents (Table 1, entries 10–14). Full tained using Pd(OAc)2 as palladium source and Buchwald

conversion of the substrate and highest yields of 4 were ob- ligands S-Phos and X-Phos [53-55] in toluene in the presence of

tained when mild bases (Na2CO3, K3PO4, Cs2CO3) and tolu- K3PO4. As it was shown by GC–MS, full conversion of the sub-

ene/EtOH/H2O and dioxane were applied (Table 1, entries 10, strate and almost quantitative formation of diarylated pyridine 4

12 and 13). However, the bromophenylpyridine 3 was still was achieved within 1 hour.

present in the reaction mixture. Dioxane and a solvent system

based on toluene were more effective than DMF (Table 1, entry With the optimized conditions in hands, a library of 3,5-diaryl-

14), for which the yield of the main product was only 9%. Sur- 2,4,6-trimethylpyridines 4–29 was prepared using variously

prisingly, the use of NaOH as a base led primarily to monoary- substituted arylboronic acids 32–41 as cross-coupling partners

lated product 2. The comparison of these results with those ob- (Scheme 1).

tained for catalyst Pd(P(o-tol)3)4 clearly confirms that the later

compound is more active in the cross-coupling reaction [46].

The results of the cross coupling depend on electronic and steric

properties of the ligands coordinated to the metal atom. In the

case of phosphine-based ligands, the structure of the aryl and

alkyl moiety is of crucial importance. As it was shown by Shen

[47], Fu [48,49] and Monteith [50], the use of bulk and strongly

electron-donating ligands (i.e., P(Cy)3 or P(t-Bu)3) accelerated

the rate of the oxidative addition of aryl halides to the Pd-com-

plex centre promoting the ligands dissociation leading to a more

active monophosphine Pd complex. In our case, tricyclo-

hexylphosphine associated with Pd(OAc)2 in toluene/H2O/

EtOH confirmed its utility as a powerful catalytic system,

giving fast and clean conversion of substrate 1 within

2–3 hours. When the reaction was performed with 2.8 equiv of

phenylboronic acid in the presence of Pd(OAc)2/P(Cy)3, the

final diarylpyridine 4 was obtained in each case in very good

yield (95–99%, Table 1, entries 21–26) and the outcome of the

reaction was independent on the base and the solvent used. The

only exception was entry 27, where CsF as a mild base was

applied. Fluorides are slightly less effective as bases in the case

of other catalytic systems (Table 1, entries 29 and 33). It is

worth to note that the increased activity of the catalyst based on

tricyclohexylphosphine led us to perform the reaction at room

Scheme 1: Synthesis of diarylpyridines 4–29.

temperature also in high yield (Table 1, entry 28). The

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Beilstein J. Org. Chem. 2016, 12, 835–845.

The best yields: 96%, 92% and 90% were obtained for phenyl- lines [63], pyrazoles [64] pyrroles [65], pyrimidines [66,67],

boronic acid and its 4-methyl and 4-ethyl-substituted deriva- benzofuranes [68], imidazo[1,2-a]pyridines [69], diaryl/

tives, respectively. Arylboronic acids with electron-with- heteroaryl methanes [70], and indoles [71], bearing differently

drawing and electron-donating groups attached at meta or para substituted arene rings. An elegant approach to variously

position of the phenyl ring afforded diarylpyridines in moder- arylated pentaarylpyridines was recently proposed by Reimann

ate to good yields (approx. 60–90%).

et al. [60]. The final outcome of such a procedure is governed

by many factors, including differences in site reactivity of poly-

The arylboronic acids functionalized with strongly electron- haloarenes (concerning both regio- and chemoselectivity), reac-

withdrawing (3-CF3, 4-CF3, products 14 and 15) and with more tion conditions (the nature of the palladium/ligand, temperature,

than one electron-donating groups (2,5-di-MeO, 3,4,5-tri-MeO, base, solvents) and the steric interactions between both cross-

gave products 16 and 17) with low yield and required further coupling partners. Minard et al. [59] pointed out that if an aryl-

addition of reagents also with increased reaction time to com- boronic acid involved in sequential couplings bears substituents

plete the diarylation. The attachment of small substituents at with electron-withdrawing and electron-donating groups, the

ortho positions in arylboronic acids did not retard the reaction choice of the order of its introduction may be crucial for the

(products 5, 8, 10, 18, 22, 24, 25, 29). However, the GC–MS final outcome. Our starting material constitutes a special case

analysis revealed an increased formation of the corresponding where both coupling sites are isoelectronic and equivalent in

biaryls, monoaryl- and bromoarypyridines, which difficult chro- terms of steric hindrance. Such dihaloarenes, owing to the

matographic separation also accounted for the low yield of the lack of electronic and steric differences between reaction

isolated final products. Attempted cross coupling of pyridine 1 sites, treated with 1 mol equivalent of boronic derivatives

with 4 mol excess of 2-chlorophenylboronic acids afforded a usually create a statistical distribution of products (1:2:1 for

complex mixture of products with 3,5-bis(2-chlorophenyl)- substrate:monaryl:diaryl). As can be found in many reports

2,4,6-trimethylpyridine in low yield (approx. 5%, not isolated), [72,73], the yield of the monoarylation reaction in similar cases

mainly because of the additional side-reactions that took place does not exceed 50–60%. An exception is the reaction in which

between 3-(2-chlorophenyl)-5-bromo-2,4,6-trimethylpyridine/ the first introduced aryl ring with halogen substituent increases

diarylpyridine and 2-chlorophenylboronic acids at the Cphenyl- the reactivity of the pyridine toward further diarylation acti-

Cl position, as was confirmed by GC–MS. The arylboronic acid vating the second reaction site, thus supporting the diarylation

with a valuable but unstable 2-formyl group gave again a low reaction.

yield of product 24 (35%). Initially, our attempts to obtain pyri-

dine 29 completely failed due to a very low solubility of Three different approaches leading to unsymmetrically 3,5-

2-aminophenylboronic acid hydrochloride in toluene. The prob- diarylated trimethylpyridines 46–66 have been considered

lem was overcome by addition of a small amount of water (Scheme 2, routes 1, 2, and 3, respectively). In the first one, we

(approx 10 mol %) as a co-solvent with toluene. On the other considered synthesizing the monoarylated intermediate 42–45

hand, the attempted coupling of compound 41 with 2-nitro- first, which after isolation and analytical characterization, would

phenylboronic acid and (2-chloro-6-methoxyphenyl)boronic act as the substrate for the subsequent arylation (Scheme 2,

acid failed. Despite more drastic conditions (xylene, DMF, route 1). This simple approach is tedious and time consuming;

145 °C, 48 h, 8 mol % Pd(OAc)2/16 mol % S-Phos) any amount however the proper choice of conditions allows obtaining satis-

of 3,5-bis(2-nitrophenyl)-2,4,6-trimethylpyridine and 3,5-bis(2- factory yields of the unsymmetrically substituted diaryls in most

chloro-6-methoxyphenyl)-2,4,6-trimethylpyridine could be cases.

detected.

The first step of such multistep processes requires fine tuning of

Unsymmetrically substituted 3,5-diaryl-2,4,6-

trimethylpyridines

the reaction conditions to maximize the yields of the monoary-

lated intermediate. Two alternative approaches were based on a

In continuation of the study on the transformation of dibro- one-pot reaction concept, which is advantageous from the point

mopyridine 1 into diaryl derivatives, we focused our attention of view of costs (solvents, adsorbents etc.) and work-up proce-

on de-symmetrization of the double cross coupling with the idea dure. Route 2 is based on the stepwise diarylation of 1 without

to obtain trimetylpyridine P7 (46–66) decorated with different isolation of the monoarylated product. We also expected that si-

aryl rings. We envisaged that our goal could be achieved multaneous addition of two different arylboronic acids to the

through sequential two-step reaction of 1 with the correspond- reaction vessel would produce, apart from diarylpyridines P6

ing arylboronic acids. Such approach was widely applied by (4–29), also the desired unsymmetrical product P7 (46–66)

many research teams in the construction of polyarylated (route 3). A similar idea of an one-pot double cross-coupling

benzenes [56], pyridines [57-60], thiophenes [61,62], quinoxa- strategy was applied by Beaumard et al. [72] in construction of

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Beilstein J. Org. Chem. 2016, 12, 835–845.

Scheme 2: Synthetic routes leading to unsymmetrically substituted arylpyridines.

unsymmetrically arylated pyrroles, thiophenes and 2,6- and 3,5- The formation of a similar pyridine derivative was observed as

diarylpyridines.

the main product (49% and 61%) when the mixture of 4-fluoro-

phenyl (34) and 4-methoxyphenylboronic acid (39) were

In order to test the utility of the above mentioned approach, a reacted with 1 in the presence of both catalytic systems A or B.

series of trial cross couplings were performed on a microscale It should be noted that in both cases the yield of the desired

according to route 3 with a variety of electron-poor and elec- 3-(4-fluorophenyl)-5-(4-methoxyphenyl)-2,4,6-trimethylpyri-

tron-rich boronic acids (Table 2).

dine (63, Table 2, entry 19 and 20) remained on a reasonable

level (43 and 36%). Again, when the reaction was carried out

The steric hindrance introduced by ortho-substituted boronic with strong electron-poor 4-(trifluoromethyl)phenylboronic acid

acids was also investigated. In order to check how the elec- (35) combined with PhB(OH)2 (32), the differences in the yield

tronic and steric factors affect the distribution of homo- and of symmetrical diarylated products were even more pro-

heteroarylated products, various combinations of arylboronic nounced, in favour of the 4-fluoromethyl-substituted derivative

acids (32–41) were applied as partners for the cross coupling 15 (4% for 4 vs 62 % for 15; Table 2, entry 8). Higher yields of

with 1. Initially, the reactivity of phenylboronic acid (32, with a products containing electron-withdrawing groups probably

unsubstituted phenyl ring) was chosen as a reference standard in resulted from an increased reactivity of the monobromo inter-

the comparative study. All reactions were performed under two mediate toward the second cross-coupling reaction. This obser-

sets of conditions (A = 1.0 equiv of 1, 1.2 equiv Ar1B(OH)2, vation was mentioned by Minard et al. [59] in the course of a

1.2 equiv Ar2B(OH)2, 5 mol % Pd(OAc)2, 10 mol % S-Phos, one-pot two-step Suzuki cross coupling of 3,5-, 2,6-dibromopy-

4.0 equiv K3PO4, toluene; B = 1.0 equiv of 1, 1.2 equiv ridines and dibromobenzenes with various arylboronic partners

Ar1B(OH)2, 1.2 equiv Ar2B(OH)2, 5 mol % PdCl2(dppf) × of different electronic properties.

CH2Cl2, 4.0 equiv K3PO4, dioxane). The reaction mixtures

were heated until all the starting material was consumed (moni- We then investigated a one-pot, double cross-coupling strategy

toring by GC–MS). GC–MS examination of the final crude with mixtures of more sterically demanding boronic acids con-

products revealed in most cases the presence of three major taining ortho-substituents. The cross coupling of 1 with the

products: symmetrical triaryls P6 (4–29) along with the desired mixture of 2-methoxyphenyl (33) and 4-methoxyphenylboronic

pyridines P7 (46–66) with two different aryl rings. The results acid (39) gave a higher yield of the sterically uncrowded prod-

were collected in Table 2. Trial reactions with mixtures of uct 12 (43%, Table 2, entry 18) as expected. The ratio of prod-

phenylboronic acids 32 with para-substituted arylboronic acids ucts obtained from the mixtures of phenylboronic acid (32) with

(34, 35, 38, 39, Table 2, entries 1–8) in the presence of its 2-methyl (37), 2-methoxy (33) and 2-trifluoromethyl (41)

Pd(OAc)2/S-Phos in toluene led to mixtures of diarylpyridines derivatives clearly indicate that steric factors play an important

4, 7, 12, 13, 15 and unsymmetrically arylated pyridines 49 and role, in each case favouring the synthesis of diphenylpyridine 4

57–59 generally in a statistical ratio of 1:2:1 for the Ar1/ (Table 2, entries 11–15). The formation of the expected

Ar1:Ar2/Ar1:Ar2/Ar2 products, respectively (Table 2, entries 1, unsymmetrical pyridines was still observed in moderate yield

3, 5 and 7). The yield of unsymmetrical diarylpyridines ranged (37–51%). Two reactions failed when mixtures of phenyl/2-(tri-

from 47 to 52%. Similar results of differentially substituted fluoromethyl)phenyl- and 2-methylphenyl/2-(trifluoromethyl)-

heteroaryls were reported by Beaumard et al. [72]. The combi- phenylboronic acids were applied in the presence of

nation of electron-poor 4-fluorophenylboronic acid (34) with PdCl2(dppf) × CH2Cl2 (Table 2, entries 16 and 26), respective-

phenylboronic acid (32) in the presence of PdCl2(dppf) × ly. In the case of both sterically demanding reagents, the

CH2Cl2 gave a reaction mixture containing an increased con- catalytic system based on S-Phos worked more efficiently

centration of pyridine 7 (Table 2, entry 4), in comparison to 4. giving diarylated products partially contaminated with

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Beilstein J. Org. Chem. 2016, 12, 835–845.

Table 2: Results of the preliminary study on the double one-pot arylation of 1 with a mixture of arylboronic acids Ar1B(OH)2 and Ar2B(OH)2 32–41.

Entry Catalytic Ar1

systema

Ar2

Yieldb [%]

Ar1/Ar1 pyridine (P6) Ar1/Ar2 pyridinec (P7) Ar2/Ar2 pyridinec (P6)

1

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

A

B

C6H5 (32)

4-EtC6H4 (38)

23 (4)

31 (4)

20 (4)

17 (4)

34 (4)

30 (4)

22 (4)

4 (4)

52 (49)

52 (57)

53 (57)

47 (58)

49 (58)

51 (59)

34 (59)

49 (60)

50 (60)

51 (46)

37 (46)

51 (61)

49 (61)

43 (48)

–d (48)

53 (62)

48 (62)

43 (63)

36 (63)

47 (64)

33 (64)

25e,f (65)

17h,f (65)

19i,f (66)

–g (66)

25 (13)

17 (13)

28 (7)

2

4-EtC6H4 (38)

3

4-FC6H4 (34)

4

4-FC6H4 (34)

30 (7)

5

4-MeOC6H4 (39)

4-CF3C6H4 (35)

3,4-OCH2OC6H3 (40)

2-MeC6H4 (37)

2-MeOC6H4 (33)

2-CF3C6H4 (41)

22 (12)

21 (12)

27 (15)

62 (15)

19 (21)

23 (21)

13 (8)

6

7

8

9

32 (4)

26 (4)

36 (4)

59 (4)

28 (4)

48 (4)

47 (4)

–d (4)

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

4 (8)

21 (10)

8 (10)

10 (31)

–d (31)

27 (12)

43 (12)

8 (12)

2-MeOC6H4 (33) 4-MeOC6H4 (39)

20 (10)

9 (10)

49 (7)

61 (7)

31 (15)

64 (15)

30e,f (30)

27h,f (30)

37i,f (8)

–g (8)

4-FC6H4 (34)

4-MeOC6H4 (39)

3 (12)

4-CF3C6H4 (35) 3,4-OCH2OC6H3 (40)

22 (21)

3 (21)

2-ClC6H4 (36)

2-MeC6H4 (37)

2-CF3C6H4 (41)

5e,g (31)

7f,g (31)

9h,i (31)

–i (31)

aConditions: A – Pd(OAc)2, S-Phos, K3PO4, toluene, 90 °C; B – PdCl2(dppf)xCH2Cl2, dioxane, K3PO4, 90 °C. bYields estimated on the base of

GC–MS analysis [35]. cSome of these products were tentatively identified by GC–MS – see mass spectra in Supporting Information File 1. dPoor

conversion of substrate ~20% – mixture of monoarylated and monobromoarylated products, only traces of 1a and 3,5-bis(2-trifluorophenyl)-2,4,6-

trimethylpyridine were identified. eReaction mixture contained approx. 40% of monoarylated and monobromoarylated products – as indicated by

GC–MS analysis. fThe yield of products was calculated by comparison of the peak area of the products with the sum of the peak areas recorded for

the precursor (if it was still present). The structures of some monoarylpyridines, bromoarylpyridines and those unsymmetrical diarylpyridines, which

had not been synthesized on the preparative scale, were elucidated primarily by the analysis of their mass spectra. Each pyridine derivative exhibited

a characteristic mass spectrum with the base peak corresponding to the molecular ion. This feature together with characteristic MS isotopic patterns

of the bromine atom led us to recognize the corresponding pyridine derivative. For MS spectra of all tentatively identified pyridines see Supporting

Information File 1. gOnly a mixture of 3-(2-methylphenyl)-2,4,6-trimethylpyridine and 8 in a ratio of 1:3 was observed. hReaction mixture contained

approx. 50% of monoarylated and monobromoarylated products – as indicated by GC–MS analysis. iReaction mixture contained approx. 35% of

monoarylated and monobromoarylated products – as indicated by GC–MS analysis.

monoaryl- and monobromoarylpyridines (as was confirmed With optimized reaction conditions in hands, we repeated the

by GC–MS). These confusing results of the final product one-pot double cross-coupling reaction on the 20-fold scale.

distribution cannot be simply rationalized since it is the Synthetic procedures with mixtures of phenyl/4-ethylphenyl-

result of a complicated balance of electronic and steric boronic acid (32/38) and phenyl/4-methoxyphenylboronic acid

requirements between both intermediates and arylboronic (32/39) gave also mixtures of diarylpyridines with unsymmetri-

reagents.

cally arylated pyridines 49 and 3-(4-methoxyphenyl)-5-phenyl-

841

Beilstein J. Org. Chem. 2016, 12, 835–845.

2,4,6-trimethylpyridine (58) as main products, respectively. and K3PO4 as a base provided, after 2–4 hours at 65 °C the

Unfortunately, we were not able to obtain the desired com- monoarylated products 3, 43–45 in moderate yields (38–43%,

pounds in analytically pure form and in reasonable amount (iso- Scheme 3).

lated yields less than 5%) due to practical problems associated

with chromatographic purification. Their structures were there- The GC–MS analysis of the crude reaction mixture indicated

fore proposed on the basis of GC–MS analysis. Since a step- the presence of the starting material, monoarylbromopyridines

wise transformation of 1 according to route 2 led to a similar and diarylpyridines (4, 8, 9 and 27) in approx. 1:2:1 ratio.

inseparable mixture of symmetrical and unsymmetrical diaryl- Bromoarylpyridines 3 and 43–45 were then applied for the

pyridines, we applied route 1 as the way to obtain the desired second cross-coupling process under more drastic conditions.

diarylpyridines P7 (46–66).

Increasing the temperature to 90 °C and introducing the catalyt-

ic system based on Pd(OAc)2/S-Phos in toluene, it was possible

Several examples of monoarylation of symmetrical dihaloarenes to obtain the desired unsymmetrical derivatives 46–56, in a

have been published so far. A low molar ratio of dihaloarene/ yield range of 82–91%, in less than 1 h, with exception of 48

arylboronic acid often promoted a single coupling [56,74-78]. (68%) and 52 (62%). In these cases the use of sterically

When the substrate/arylboronic acid ratio was gradually in- hindered and less reactive 2-trifluorophenylboronic acid needed

creased, also the increased presence of the dicoupled product a longer reaction time of 3 hours and an increased arylboronic

was observed. However, the final separated yield decreased and acid/substrate ratio.

most of the starting material could be recovered. Another im-

portant problem in sequential cross-coupling reactions is the In order to obtain the reference standard for our optimization

proper choice of arylboronic acid for the first reaction. It was study, 3-bromo-5-phenyl-2,4,6-trimethylpyridine (3) was

confirmed that electron-deficient arylboronic acids activate the dehalogenated into 2 in a usual manner by means of ethanol

monoarylated intermediate for the oxidative addition to the under hydrogen atmosphere in the presence of Pd/C.

palladium species thus increasing the yield of diarylated by-

Unsymmetrically substituted 3,5-diaryl-4-

products [59].

chloro-2,6-dimethylpyridines

We then attempted the preparation of unsymmetrical diarylpyri- Finally, we needed to access a small library of unsymmetrical

dines 46–56, directly from 1 by two sequential cross couplings 3,5-diarylpyridines bearing a chlorine atom at C-4 position at

with the isolation and full characterization of the intermediates the pyridine ring P9 (68–71, Scheme 4). In a further study we

3 and 43–45. Thus, the treatment of 1 with 1.1 equiv of phenyl-, tested, after transhalogenation into 4-bromo derivatives, if

2-methylphenyl-, 4-methylphenyl and 2-naphthylboronic acid in pyridines 68–71 were suitable substrates for synthesis of vari-

dioxane in the presence of PdCl2(dppf) × CH2Cl2 (5 mol %), ously substituted 3,4,5-triarylpyridines. Additionally, the

Scheme 3: Preparation of unsymmetrical 3,5-diaryl-2,4,6-trimethylpyridines 46–56.

842

Beilstein J. Org. Chem. 2016, 12, 835–845.

dehalogenation of 68–71 may provide 3,5-diarylo-2,6-dimethyl- position C-2, C-6 and 2-methylthio groups attached to the phen-

pyridines. These compounds can be regarded as "route specific yl rings. A similar separation was observed for all methyl

markers" for amphetamine analogues synthesized by the groups which are present in ortho-substituted pyridines 8, 18,

Leuckart method. We choose 3-bromo-4-chloro-2,6-dimethyl-5- and 26. This phenomenon may be simply attributed to the

phenylpyridine (67) as a substrate, whose preparation we de- restricted rotation around single C3,5pyridine–Cphenyl bonds

scribed previously [25]. We expected that under mild condi- caused by the steric interaction of the ortho substituents at the

tions the position C-3 occupied by the bromine atom would be phenyl rings (or naphthalene ring for 26) with three methyl

preferentially arylated despite the fact that generally in the groups of the pyridine ring. Consequently, the inhibited rota-

cross-coupling reaction of halopyridines, the reactivity of cou- tion of the phenyl rings led to the formation of stable diastereo-

pling sites changes in the following order: C-2 > C-4 > C-3. We meric atropisomers which could be detected in NMR spectros-

expected that the presence of the less reactive chlorine atom at copy. The interconversion barrier is probably remarkably high

C-4 together with the proximity of a bulky phenyl ring should in 3,5-bis(2-trifluromethylphenyl)-2,4,6-trimethylpyridine [79],

redirect the cross coupling onto position C-3 of the pyridine since both atropisomers of this compound could be observed

ring.

during GC–MS analysis as a pair of well-separated Gaussian

peaks at the temperature of elution approaching 290 °C. A simi-

lar phenomenon was observed for pyridine 8 and recently in the

case of tri-3,4,5-(2-methoxyphenyl)-2,6-dimethylpyridine, and

also for some ortho-substituted derivatives of 3,5-diaryl-

4-methoxy-2,6-dimethylpyridine [32]. In the case of com-

pounds 46–49, 51–54, and 68–71, the steric hindrance caused

by only one ortho-substituted aryl ring should generate the cor-

responding enentiomeric conformations, stable at least in the

NMR time scale. Indeed, the presence of enantiomeric forms of

47 and 69 was confirmed by 1H NMR recorded in the presence

of (+)-butylphenylphosphinothioic acid [80] as a chiral

solvating agent. Recently, we have employed a similar ap-

proach in the determination of the enantiomeric purity of (+)-

crispine [81] and (R)-(+)-harmicine after their stereoselective

Scheme 4: Preparation of unsymmetrical 3,5-diaryl-4-chloro-2,6-

dimethylpyridines 68–71.

Surprisingly, attempted reactions of 67 with both 2-(trifluoro- synthesis [82].

methyl)phenyl (41) and (2-methylphenyl)boronic acid (37) in

dioxane in the presence of PdCl2(dppf) × CH2Cl2, K3PO4, at The results of a more detailed study on the stereochemistry of

65 °C, provided only a mixture of debrominated and dechloro/ atropisomeric enantiomers will be published elsewhere.

debrominated phenylpyridines with only little quantities of the

desired products 70, and 68 (<5%), respectively (estimated by Conclusion

GC–MS). Fortunately, when 67 was applied in the cross-cou- Herein, we described an easy and convenient synthesis of

pling reaction with 1.3 equiv of arylboronic acids in the pres- symmetrically and unsymmetrically substituted 3,5-diaryl-

ence of Pd(OAc)2/S-Phos, the desired pyridines 68–70 were 2,4,6-trimethylpyridines via Suzuki–Miyaura cross-coupling

isolated in good yields (65–74%). Dehalogenated and diary- reaction. Several diarylpyridines with mixed aryl rings were

lated products were also present in the reaction mixture but only produced by sequential two-step Suzuki cross-coupling reac-

in trace amounts. Interestingly, the result of the reaction with tion with separation of intermediary 3-aryl-5-bromo-2,4,6-tri-

naphthalen-1-ylboronic acid was different. The main product methylpyridines. We also proved that a similar set of unsym-

was 3,4-bis(naphthalen-1-yl)-2,6-dimethyl-5-phenylpyridine, metrical products could be accessible via a one-pot double cross

which was also isolated along with the desired 4-chloro-3- coupling by treatment of dihalopyridine with a mixture of aryl-

(naphthalen-1-yl)-2,6-dimethyl-5-phenylpyridine (71, yield boronic acids. However, chromatographic separation of the

25%) in 49% yield.

products is tedious and requires more efficient techniques

(preparative HPLC). The library of synthesized compounds will

be used as a reference standard during our study on impurity

NMR and GC–MS analysis

All isolated products were characterized by 1H NMR, markers in illegally produced amphetamine analogues. In

13C NMR, IR spectroscopy and MS and HR-MS spectrometry. several cases of ortho-aryl-substituted pyridines, stable atrop-

The examination of the 1H NMR spectra of pyridine 22 isomers were observed and this phenomenon will be elaborated

revealed the presence the separated signals of methyl groups at in a separate study.

843

Beilstein J. Org. Chem. 2016, 12, 835–845.

14.Shea, T. A.; Burburan, P. J.; Matubia, V. N.; Ramcharan, S. S.;

Rosario, J., Jr.; Parkin, D. W.; Stockman, B. J.

Supporting Information

Bioorg. Med. Chem. Lett. 2014, 24, 1080–1084.

doi:10.1016/j.bmcl.2014.01.014

Supporting Information File 1

Experimental procedures, spectroscopic and analytical data,

and copies of NMR spectra for representative compounds.

[http://www.beilstein-journals.org/bjoc/content/

supplementary/1860-5397-12-82-S1.pdf]

15.Sugimoto, M.; Shirai, N.; Nishino, M.; Kodaira, C.; Wotami, T.;

Sahara, S.; Ishikawa, H.; Kagami, T.; Sugimoto, K.; Faruta, T.

Eur. J. Clin. Pharmacol. 2014, 70, 1073–1078.

doi:10.1007/s00228-014-1713-y

16.Vora, J. J.; Trivedi, P. K.; Kshatriya, R. S. Adv. Appl. Sci. Res. 2011, 2,

89–93.

17.Hammami, S.; Affes, H.; Ksouda, K.; Feki, M.; Sahnoun, Z.;

Zeghal, K. M. Therapie 2013, 68, 361–368.

Acknowledgements

doi:10.2515/therapie/2013061

Financial support from the National Science Centre in the form

of grant NCN-2012/05/B/ST5/00713 is kindly acknowledged.

We also thank Mrs. Krystyna Wojtasiewicz for her valuable

technical assistance.

18.Ko, J. W.; Sukkova, N.; Thacker, D.; Chen, P.; Flochart, D. A.

Drug Metab. Dispos. 1997, 25, 853–862.

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Frampton, C. S. J. Chem. Soc., Perkin Trans. 1 2000, 3460–3468.

doi:10.1039/b004704j

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A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki-Miyaura cross-coupling reaction

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