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Synthesis 2015; 47(10): 1423-1435
DOI: 10.1055/s-0034-1380159
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© Georg Thieme Verlag Stuttgart · New York

Studies on the Cocatalyst in Ruthenium-Catalyzed C–H Arylation

Masahiko Seki*
Process R&D Department, Healthcare Business Division II, API Corporation, The Kaiteki Bldg., 1-13-4, Uchikanda, Chiyoda-ku, Tokyo 101-0047, Japan   Email: seki.masahiko@mm.api-corp.co.jp
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Publication History

Received: 28 December 2014

Accepted after revision: 16 January 2015

Publication Date:
27 February 2015 (online)

 
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Abstract

The performance of three types of Brønsted acid potassium salts, potassium carboxylates, potassium phosphates, and potassium sulfonates, has been tested as the cocatalyst in ruthenium-catalyzed C–H arylation. Among them, dipotassium glutarate, potassium bis(2-ethylhexyl) phosphate, and potassium 2,4,6-trimethylbenzenesulfonate provided higher activity. Potassium 2,4,6-trimethylbenzenesulfonate was the most active even for less reactive substrates, such as electron-deficient azoles and sterically demanding aryl bromides.


#

Key words

C–H activation - direct arylation - ruthenium - Brønsted acids - biaryls - heterocycles

Developing an efficient synthetic method to produce valuable molecules in a more economical and sustainable manner has been a topic of considerable interest for synthetic organic chemists.[1] The E factor,[2] an index to measure the extent of generating waste materials, in pharmaceutical industries is extremely high (25–100) compared to those in other communities such as the oil industry (<1). Hence, in this sector there has been a growing need to overcome this fundamental drawback.

Zoom Image
Scheme 1 Synthesis of angiotensin II receptor blockers 3 by C–H arylation of 5-phenyl-1H-tetrazole (1) with aryl bromide 2

The biaryl structure is an important structural motif that exhibits biological activity[3] and the efficient and general synthesis of biaryls has been a topic of intensive research. In the past, the C(sp2)–C(sp2) bond forming reaction required to obtain biaryls was conceptually difficult and to overcome it was an enormous challenge in synthetic chemistry. Cross-coupling reactions, such as Suzuki and Negishi coupling, address this challenge[4] and some examples of this reaction have been successfully applied in commercial production.[5] Nonetheless, the cross-coupling reaction needs an activating group, such as a boronic acid, which requires extra preparation steps. Toxic waste materials caused by the metallic leaving group in the reaction are also problematic and decrease the atom efficiency[6] considerably. To address these issues, conceptually efficient C–H arylation based on C–H activation[7] has been developed. It does not require an activating group and enables the direct coupling of arenes with aryl halides to give the desired biaryls in a highly atom economical manner. In a series of investigations with the aim to develop an efficient synthetic method for the production of active pharmaceutical ingredients, we reported a practical synthesis of angiotensin II receptor blockers 3 by ruthenium-catalyzed C–H arylation of 5-phenyl-1H-tetrazole (1) with aryl bromide 2a (Scheme [1]).[8]

A number of protocols for C–H arylation have been reported.[9] However, unfortunately, most of them were not suitable for industrial processes due to such drawbacks as the need of toxic additives, such as silver salts,[10] and the instability of the catalytic system especially on a larger scale.[11] In our process to develop angiotensin II receptor blockers, a lack of reproducibility is also observed in the coupling of 1 with 2a on a >100-gram scale; the reaction often stopped and very low conversion resulted.[8a] [b] [c] [d] [e] [f] Hence, a better catalytic system is required to enable the commercial application of this technology. This article describes our investigations of ruthenium-catalyzed C–H arylation focusing on the discovery of a new and robust catalytic system including a novel and efficient cocatalyst.

Zoom Image
Scheme 2 A possible mechanism of ruthenium-catalyzed C–H arylation

A possible mechanism for ruthenium-catalyzed C–H arylation is shown in Scheme [2].[11] It is thought to involve formation of a ruthenacycle C by removal of C–H hydrogen followed by cyclization. Subsequent oxidative addition of C with aryl halide followed by reductive elimination provides monoarylated product I. Potassium carboxylate might accelerate the entire process either by efficient removal of C–H hydrogen or by facilitating ligand exchange where ‘autocatalysis’ through protonation of carbonyl group of ligands by liberated carboxylic acid (AcOH in case of the reaction shown in Scheme [2]) takes place (A to B and C to D). Another important aspect of C–H arylation is the formation of diarylation product II. It is reported to take place by generation of ruthenacycle F from E followed by oxidative addition of aryl halide with F and subsequent reductive elimination (F to II). Decreasing the magnitude of this intuitive over-reaction has been a significant challenge in C–H arylation. In our process development of angiotensin II receptor blockers, the development of an efficient cocatalyst to avoid formation of the diarylation product is a crucial goal in the process because the diarylation product is carried over to the final active pharmaceutical ingredient and becomes a new impurity. Screening of the cocatalyst utilized the reaction of 5-phenyl-1H-tetrazole (1) with 4-bromobenzyl acetate (2a) to give 4, which is an intermediate for angiotensin II receptor blockers.

Potassium carboxylates as cocatalyst. In the ruthenium-catalyzed C–H arylation of 2-phenyloxazoline with an aryl bromide, Merck reported the use of potassium acetate[12] as a cocatalyst that considerably improved reproducibility in the synthesis of anacetrapib.[13]

In our initial study, the use of potassium carboxylates as a cocatalyst in the C–H arylation of 1 with 2a was examined (Table [1]). The reaction was first examined using the reported optimal conditions: stirring a mixture of 1 and 2a in the presence of [RuCl2(p-cymene)]2 (0.5 mol%), triphenylphosphine (1.0 equiv to Ru), and potassium carbonate in N-methylpyrrolidin-2-one at 138 °C for six hours; this gave a poor yield (39%) and the ratio of desired monoarylation product 4a to diarylation product 5a was moderate (4a/5a 89:11, entry 1). To improve the yield, the amount of tri­phenylphosphine was increased from one equivalent to two equivalents with respect to ruthenium. This provided a better yield and reproducibility issues on a >100 g scale were resolved. However, monoarylation selectivity was unaffected (4a/5a 89:11, 71% yield, entry 2). To improve the monoarylation selectivity, the use of other bulky potassium carboxylates, including well-documented cocatalysts such as potassium pivalate,[14] potassium adamantane-1-carboxylate,[15] potassium 2-ethylhexanoate, and potassium 2,4,6-trimethylbenzenecarboxylate,[15] was examined. However they did not improve the monoarylation selectivity (4a/5a 85:15 to 91:9, entries 3–8). The use of two equivalents of triphenylphosphine with respect to ruthenium gave better results than the use of one equivalent [conversion: entries 4 (78%) and 6 (73%) vs entries 5 (53%) and 7 (48%), respectively]. The diarylation product 5a can be removed by recrystallization. However, if the final product is an active pharmaceutical ingredient, the formation of much lower quantities of diarylation product is highly desired to substantiate the high quality of the product by minimal purification.

Table 1 Screening of Potassium Carboxylates as a Cocatalyst for C–H Arylation of 1-Benzyl-2-phenyl-1H-tetrazole (1) with 4-Bromobenzyl Acetate (2a)a

Entry

Cocatalyst

Ratiob 4a/5a

Conv.b (%)

Yieldc (%) of 4a

 1d

KOAc

89:11

51

39

 2

KOAc

89:11

80

71

 3

86:14

71

64

 4

88:12

78

77

 5d

91:9

53

52

 6

86:14

73

71

 7d

85:15

48

29

 8

88:12

67

62

 9

(CO2K)2

92:8

70

63

10

CH2(CO2K)2

90:10

63

59

11

(CH2)2(CO2K)2

96:4

41

38

12

(CH2)3(CO2K)2 (GLDK)

90:10

86

77

13

(CH2)4(CO2K)2

92:8

72

65

a Reaction conditions: 1 (2.0 g, 8.46 mmol), 2a (2.13 g, 9.31 mmol, 1.1 equiv), [RuCl2(p-cymene)]2 (26 mg, 0.0423 mmol, 0.5 mol%), Ph3P (44 mg, 0.168 mmol, 2.0 equiv to Ru), cocatalyst (0.168 mmol, 2.0 equiv to Ru), K2CO3 (1.17 g, 8.46 mmol, 1.0 equiv), NMP (10 mL), 138 °C, 6 h.

b Determined by HPLC.

c Assay yield.

d Ph3P (22 mg, 0.084 mmol), 1.0 equiv to Ru) was employed.

According to the mechanism of the ruthenium-catalyzed C–H arylation shown in Scheme [2], the ‘autocatalytic process’ has been demonstrated where rate-acceleration of the process is achieved by free carboxylic acid (AcOH) resulting from the removal of the C–H hydrogen by potassium carboxylate (Scheme [2]). The carboxylic acid is thought to activate C–H arylation by protonation of the carbonyl group of the ligands to facilitate ligand removal/exchange from the ruthenium center intermolecularly (A to B and C to D in Scheme [2]). Based on this hypothesis, we anticipated a better activation in C–H arylation intramolecularly rather than intermolecularly by employing dipotassium dicarboxylates in place of potassium monocarboxylates as depicted in Figure [1].

Zoom Image
Figure 1 Intramolecular activation of ligand removal/exchange
Zoom Image
Figure 2 Effect of chain length of dipotassium dicarboxylate [(CH2)n(CO2K)2] on the C–H arylation of 1 with 2a

To screen the cocatalyst, dipotassium dicarboxylates of varying chain length [(CH2)n(CO2K)2, n = 0–4] were tested. When dipotassium oxalate (n = 0) was employed, higher monoarylation selectivity than for potassium carboxylates was obtained while the conversion was moderate (4a/5a 92:8, 63% yield, entry 9 vs entries 2–4, 6, and 8, 4a/5a 86:14–91:9, 67–80% yield). The conversion decreased when dipotassium malonate (n = 1) and dipotassium succinate (n = 2) were used (59% and 38% yield, respectively, entries 10 and 11). In contrast, good yield and slightly better mono­arylation selectivity were achieved when dipotassium glutarate (GLDK, n = 3) was employed (4a/5a 90:10, 77% yield, entry 12). The use of dipotassium adipate (n = 4) with a longer chain length provided a lower yield than that of dipotassium glutarate (4a/5a 92:8, 65% yield, entry 13). Figure [2] illustrates effect of the chain length of the dipotassium dicarboxylate on C–H arylation. It shows that dipotassium glutarate (n = 3) gave the best result and either increasing or decreasing the chain length resulted in an inferior outcome (Figure [2]). Dipotassium glutarate has another practical advantage, it is less hygroscopic than other potassium carboxylates, which makes it more convenient in a practical sense. The efficiency of dipotassium glutarate might be ascribed to more appropriate intramolecular activation of the carboxylate by favorable 5-5 fused orientation shown in Figure [3]. In contrast, a notable decrease in yield (entry 11, Figure [3]) using dipotassium succinate (n = 2) can be accounted for by the formation of an unfavorable seven-membered structure.

Potassium phosphates as cocatalyst. In the search for a better cocatalyst for C–H arylation, we next examined the use of potassium phosphates. Ruthenium phosphate generated during the reaction might remove C–H hydrogen by its Lewis basic P=O oxygen (Scheme [3]).[16] Two substituents (R) on the phosphate would increase the basicity of the P=O oxygen by an inductive effect as well as prevent further diaryl­ation by steric repulsion.

Zoom Image
Figure 3 Possible mechanism for intramolecular activation in the ruthenium–glutarate complex
Zoom Image
Scheme 3 Ruthenium phosphate as a potential catalyst for C–H arylation

Table 2 Screen of Potassium Phosphates as a Cocatalyst for C–H Arylation of 1-Benzyl-2-phenyl-1H-tetrazole (1) with 4-Bromobenzyl Acetate (2)a

Entry

Cocatalyst

Ratiob 4a/5a

Conv.b (%)

Yieldc (%) of 4a

1

KOP(O)(OEt)2

94:6

62

56

2

KOP(O)(OBu)2

97:3

34

25

3

(KO)2P(O)(OBu)

96:4

40

29

4

97:3

25

16

5

KOP(O)(OPh)2

93:7

66

60

6

KOP(O)[OCH2CH(Et)(CH2)3Me]2 (BEHPK)

95:5

87

82

7d

KOP(O)[OCH2CH(Et)(CH2)3Me]2 (BEHPK)

97:3

 7

 9

8

MgOP(O)[OCH2CH(Et)(CH2)3Me]2

91:9

72

61

a Reaction conditions: 1 (2.0 g, 8.46 mmol), 2a (2.13 g, 9.31 mmol, 1.1 equiv), [RuCl2(p-cymene)]2 (26 mg, 0.0423 mmol, 0.5 mol%), Ph3P (44 mg, 0.168 mmol, 2.0 equiv to Ru), cocatalyst (0.168 mmol, 2.0 equiv to Ru), K2CO3 (1.17 g, 8.46 mmol, 1.0 equiv), NMP (10 mL), 138 °C, 6 h.

b Determined by HPLC.

c Assay yield.

d Ph3P (22 mg, 0.084 mmol, 1.0 equiv to Ru) was employed.

The reaction with potassium phosphates (Table [2]) was first examined using potassium diethyl phosphate; monoarylation selectivity improved, but the yield is poorer (4a/5a 94:6, 56% yield, entry 1). More sterically hindered potassium dibutyl phosphate provided a lower yield while dipotassium butyl phosphate gave a similar result (25% and 29% yield, respectively, entries 2 and 3). The use of cyclic potassium 1,1′-binaphthyl-2,2′-diyl phosphate did not improve the yield (16%, entry 4), while using potassium diphenyl phosphate, gave a higher, though still unsatisfactory, yield (60% yield, entry 5). It should be noted that without exception monoarylation selectivity is high when potassium phosphates were employed. To improve the yield, a more electronegative aliphatic branched potassium bis(2-ethylhexyl) phosphate (BEHPK) was then tested. Gratifyingly, using potassium bis(2-ethylhexyl) phosphate as a cocatalyst gave a much better yield while high monoarylation selectivity was retained (4a/5a 95:5, 82% yield, entry 6). The addition of two equivalents of triphenylphosphine with respect to ruthenium is needed to attain a high conversion (87% conversion, entry 6 vs 7% conversion, entry 7). Changing the metal salt of the phosphate from potassium to magnesium resulted in slightly lower monoarylation selectivity and conversion (4a/5a 95:5, 87% conversion, entry 6 versus 4a/5a 91:9, 72% conversion, entry 8). Good performance of phosphonate as a directing group for C–H arylation has been reported acting intramolecularly.[17] However, the use of phosphate as a cocatalyst intermolecularly has not been reported. Potassium bis(2-ethylhexyl) phosphate is inexpensive and widely available, and, hence, readily applicable to commercial-scale production.

Table 3 Screening of Potassium Sulfonates as Cocatalyst for C–H Arylation of 1-Benzyl-2-phenyl-1H-tetrazole (1) with 4-Bromobenzyl Acetate (2a)a

Entry

Cocatalyst

Ratiob 4a/5a

Conv.b (%)

Yieldc (%) of 4a

1

MeSO3K

94:6

75

60

2

PhSO3K

97:3

35

28

3

4-MeC6H4SO3K

94:6

60

50

4d

4-MeC6H4SO3K

94:6

41

34

5

4-Me(CH2)11C6H4SO3K

94:6

59

46

6

2,4,6-Me3C6H2SO3K (TMBSK)

92:8

86

77

7d

2,4,6-Me3C6H2SO3K (TMBSK)

98:2

18

14

a Reaction conditions: 1 (2.0 g, 8.46 mmol), 2a (2.13 g, 9.31 mmol, 1.1 equiv to 1), [RuCl2(p-cymene)]2 (26 mg, 0.0423 mmol, 0.5 mol%), Ph3P (44 mg, 0.168 mmol, 2.0 equiv to Ru), cocatalyst (0.168 mmol, 2.0 equiv to Ru), K2CO3 (1.17 g, 8.46 mmol, 1.0 equiv to 1), NMP (10 mL), 138 °C, 6 h.

b Determined by HPLC.

c Assay yield.

d Ph3P (22 mg, 0.084 mmol, 1.0 equiv to Ru) was employed.

Potassium sulfonates as cocatalyst. The reactivity of the cocatalyst depends, in part, on ligand exchange by means of protonation of a carbonyl group present in the ligand; the activation is increased using a stronger Brønsted acid. Hence, the use of potassium sulfonates as cocatalysts was also examined. The conjugate acid of potassium sulfonate has a lower pK a value than that of the corresponding phosphoric and carboxylic acid [RSO3H > RP(O)(OH)3 > RCO2H].[18] The reaction was examined under similar conditions to those used for potassium carboxylates and potassium phosphates employing [RuCl2(p-cymene)]2 (0.5 mol%), triphenylphosphine (2 equiv to Ru), cocatalyst (2 equiv to Ru), and potassium carbonate in N-methylpyrrolidin-2-one at 138 °C for six hours (Table [3]). When the simplest example, potassium methanesulfonate, was employed as the cocatalyst, high monoarylation selectivity similar to that for potassium bis(2-ethylhexyl) phosphate was obtained, though the yield decreased (4a/5a 94:6, 60% yield, Table [3], entry 1 vs 95:5, 82% yield, Table [2], entry 6). The use of aromatic potassium benzenesulfonate, potassium 4-toluenesulfonate, or potassium 4-dodecylbenzenesulfonate did not improve the yield, while the monoarylation selectivity was retained (28–50% yield, entries 2–5).

Further screening of the additive found that potassium 2,4,6-trimethylbenzenesulfonate (TMBSK) provided a higher yield which is similar to that of potassium bis(2-ethylhexyl) phosphate (4a/5a 92:8, 77% yield, Table [3], entry 6). The amount of triphenylphosphine in the reaction is also significant. The conversion was considerably decreased when the amount of triphenylphosphine was reduced from two to one equivalents with respect to ruthenium (34% and 14%, Table [3], entries 4 and 7 versus 50% and 77%, Table [3], entries 3 and 6).

Generality experiments on C–H arylation in the presence of a potential cocatalyst. Dipotassium glutarate, potassium bis(2-ethylhexyl) phosphate, and potassium 2,4,6-trimethylbenzenesulfonate have relatively higher potency as a cocatalyst in the C–H arylation of 1-benzyl-2-phenyl-1H-tetrazole (1) with 4-bromobenzyl acetate (2a) (Tables 1–3). General experiments using various substrates and cocatalysts were then examined to check the scope of the cocatalysts (Table [4], for selected substrates: see, Figure [4]). The use of reactive azoles and aryl bromides such as electron-rich 2-phenylpyridine and less sterically demanding electron-deficient methyl 4-bromobenzoate gave complete conversion using dipotassium glutarate, potassium bis(2-ethylhexyl) phosphate, and potassium 2,4,6-trimethylbenzenesulfonate (entries 1, 2, 5, 6, 8, 11, 12, 15, 16, 19, 20). However, using electron-deficient 2-phenyloxazoline and less reactive 4-bromobenzyl benzoate gave a different outcome depending on the cocatalyst. In the reactions employing substrates shown in Table [4], general order of the reactivity: dipotassium glutarate < potassium bis(2-ethylhexyl) phosphate < potassium 2,4,6-trimethylbenzenesulfonate was observed. Potassium 2,4,6-trimethylbenzenesulfonate had the best performance and complete conversion was obtained even for the less reactive 2-phenyloxazoline (Table [4], entries 27 and 28). Figure [4] shows the high activity of potassium 2,4,6-trimethylbenzenesulfonate over dipotassium glutarate and potassium bis(2-ethylhexyl) phosphate. As an application of potassium 2,4,6-trimethylbenzenesulfonate, the reaction of 1-benzyl-5-phenyl-1H-tetrazole (1) with 4-bromobenzyl benzoate (2b) provided an intermediate 6 for candesartan cilexetil (3c)[8h] [l] in 80% assay yield (Table [4], entry 32, Scheme [4]).

Zoom Image
Figure 4 Performance of cocatalysts [dipotassium glutarate (GLDK), potassium bis(2-ethylhexyl) phosphate (BEHPK), and potassium 2,4,6-trimethylbenzenesulfonate (TMBSK)] in C–H arylation (2-PhPy = 2-phenylpyridine; 1-PhPz = 1-phenylpyrazole; 2-PhOx = 2-phenyloxazoline); see data shown in Table [4].
Zoom Image
Scheme 4 Synthesis of key intermediate for candesartan cilexetil

In conclusion, an efficient cocatalyst for the ruthenium-catalyzed C–H arylation of azoles with aryl bromides has been explored and potassium 2,4,6-trimethylbenzenesulfonate was found to provide the highest performance based on reactivity and versatility. The ease of operation of this catalytic process, low price of the reagents, high yield of the reaction, and reproducibility in scale would permit ready access to arylated azoles of pharmaceutical importance. The findings of the present study open a door to use potassium 2,4,6-trimethylbenzenesulfonate as a potential cocatalyst for other types of C–H activation.

Melting points are uncorrected. 1H and 13C NMR spectra were recorded with TMS as internal standard. HRMS was conducted by ESI-TOF. Silica gel column chromatography was performed using Kieselgel 60 (E. Merck). TLC was carried out on E. Merck 0.25-mm precoated glass-backed plates (60 F254). Development was accomplished using 5% phosphomolybdic acid in EtOH with heating or visualized by UV light where feasible. The characterization data of compounds 4a, 5a, 9, and 10 except those shown below were previously reported.[8b] [c] [d] , [8j] [k] [l]

Table 4 C–H Arylation of Arenes 6 with Aryl Bromides 7 in the Presence of Dipotassium Glutarate (GLDK), Potassium Bis(2-ethylhexyl) Phosphate (BEHPK), and Potassium 2,4,6-Trimethylbenzenesulfonate (TMBSK)a

Entry

Arene 7

R

Cocatalyst

Ratio 9/10

Conv.b (%)

Yieldc (%)

9

10

 1

CO2Me

GLDK

 3:97

100

 3

97

 2

CH2OAc

GLDK

 4:96

100

 4

93

 3

CH2OBz

GLDK

 9:91

 45

 4

41

 4

Me

BEHPK

 5:95

100

 2

97

 5

CO2Me

BEHPK

 4:96

100

 1

99

 6

CH2OAc

BEHPK

 0:100

100

93

 9

 7

CH2OBz

BEHPK

31:69

100

28

61

 8

CO2Me

TMBSK

 5:95

100

 8

84

 9

CH2OBz

TMBSK

20:80

100

 7

93

10

Me

GLDK

21:79

 48

10

38

11

CO2Me

GLDK

18:82

100

19

70

12

CH2OAc

GLDK

2:98 

100

 2

98

13

CH2OBz

GLDK

13:87

 52

 4

30

14

Me

BEHPK

21:79

 48

10

38

15

CO2Me

BEHPK

 8:92

100

 8

85

16

CH2OAc

BEHPK

 1:99

100

 1

94

17

CH2OBz

BEHPK

12:88

 91

12

88

18

Me

TMBSK

60:40

100

46

44

19

CO2Me

TMBSK

 5:95

100

 5

93

20

CH2OAc

TMBSK

 8:92

100

 8

88

21

CH2OBz

TMBSK

 1:99

100

 0.3

99

22

Me

GLDK

28:72

 57

16

41

23

CO2Me

GLDK

14:86

 93

 9

84

24

CH2OAc

GLDK

26:74

 60

14

39

25

Me

BEHPK

21:30

 51

17

26

26

CH2OAc

BEHPK

31:69

 45

14

31

27

CH2OAc

TMBSK

 3:97

100

 3

95

28

CH2OBz

TMBSK

 1:99

100

 0.3

99

29d

CH2OBz

GLDK

92:8

79

73

6

30d

Me

BEHPK

95:5

81

77

3

31d

CH2OBz

BEHPK

92:8

77

68

4

32d

CH2OBz

TMBSK

89:11

83

80

9.9

a Reaction conditions: 7 (6.44 mmol), 8 (14.2 mmol, 2.2 equiv), [RuCl2(p-cymene)]2 (20 mg, 0.0322 mmol, 0.5 mol%), Ph3P (34 mg, 0.129 mmol, 2.0 equiv to Ru), cocatalyst (27 mg, 0.129 mmol, 2.0 equiv to Ru), K2CO3 (0.89 g, 6.44 mmol, 1.0 equiv), NMP (5 mL), 138 °C, 6 h. Characterization data of 9 and 10 is available in the literature.[8b] [c] [d] [j]

b Determined by HPLC.

c Assay yield.

d Bromide 8 (1.1 equiv).


#

5-(2-{4-[(Benzoyloxy)methyl]phenyl}phenyl)-1-benzyl-1H-tetrazole and 1-Benzyl-5-(2,6-bis{4-[(benzoyloxy)methyl]phenyl}phenyl)-1H-tetrazole (Table [4,] Entry 32); Typical Procedure for C–H Arylation

Into 50-mL 2-necked flask were sequentially added 1-benzyl-5-phenyl-1H-tetrazole (1, 2.0 g, 8.46 mmol), 4-bromobenzyl benzoate (2b, 2.71 g, 9.31 mmol), Ph3P (44 mg, 0.168 mmol), K2CO3 (1.17 g, 8.46 mmol), TMBSK (46 mg, 0.168 mmol), and NMP (10 mL) at 25 °C under a N2 atmosphere. The mixture was heated to 138 °C and [RuCl2(p-cymene)]2 (26 mg, 0.0423 mmol) was added in one portion under stirring. The heating was continued at 138 °C for 6 h. The mixture was cooled to 25 °C prior to the addition of t-BuOMe (20 mL) and then stirred for 10 min. The mixture was filtered through a sintered funnel and the residue was washed with t-BuOMe (20 mL). The organic solutions were combined and a sample was submitted for HPLC assay analysis. It was then washed with water (2 × 10 mL). The separated aqueous layer was extracted with t-BuOMe (2 × 10 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (1 × 20 mL), dried (Na2SO4), and filtered. The filtrate was submitted to HPLC analysis (9: 3.0 g, 80%; 10: 550 mg, 9.9%) and evaporated under reduced pressure. HPLC [Cadenza CD-C-18 (4.6 × 150) mm, 3 μ; A: 0.03 M KH2PO4 buffer–MeCN, 95:5; B: 0.03 M KH2PO4 buffer–MeCN, 40:60, isocratic, A–B, 10:90; 1.0 mL/min; 225 nm, injection volume: 10 μL, column oven temp.: 40 °C, sample conc.: 1000 ppm in MeCN)]. An analytical sample of 5-(2-{4-[(benzoyloxy)methyl]phenyl}phenyl)-1-benzyl-1H-tetrazole and 1-benzyl-5-(2,6-bis{4-[(benzoyloxy)methyl]phenyl}phenyl)-1H-tetrazole was obtained by purifying the residue by column chromatography (silica gel, hexane–EtOAc, 4:1). For the reactions in Table 4, entries 1–28, bromide 8 was employed.


#

5-(2-{4-[(Benzoyloxy)methyl]phenyl}phenyl)-1-benzyl-1H-tetrazole

White solid; mp 105.6 °C.

IR (KBr): 3055, 3033, 2934, 2884, 1719, 1598, 1461, 1449, 1403, 1263, 1117, 1102, 775, 697 cm–1.

1H NMR (CDCl3): δ = 8.10 (d, J = 7.2 Hz, 2 H), 7.66–7.56 (m, 3 H), 7.48–7.35 (m, 6 H), 7.26–7.12 (m, 5 H), 6.76 (d, J = 7.2 Hz, 2 H), 5.35 (s, 2 H), 4.83 (s, 2 H).

13C NMR (CDCl3): δ = 166.3, 154.5, 141.2, 138.6, 136.0, 133.1, 132.9, 131.6, 131.2, 130.3, 129.7, 128.8, 128.7, 128.5, 128.4, 127.9, 127.7, 122.6, 65.9, 50.8.

MS: m/z = 469.1 [M + Na]+.

HRMS: m/z calcd for C28H22N4O2Na [M + Na]+: 469.1640; found: 467.1640.


#

1-Benzyl-5-(2,6-bis{4-[(benzoyloxy)methyl]phenyl}phenyl)-1H-tetrazole

White solid; mp 118.2 °C.

IR (KBr): 3061, 3034, 1717, 1451, 1378, 1315, 1271, 1109, 1102, 1070, 1023, 800, 713, 689 cm–1.

1H NMR (CDCl3): δ = 8.07 (d, J = 7.6 Hz, 4 H), 7.71 (t, J = 8 Hz, 5 H), 7.57 (t, J = 7.2 Hz, 2 H), 7.50 (d, J = 7.6 Hz, 2 H), 7.45 (t, J = 7.6 Hz, 4 H), 7.26–7.18 (m, 1 H), 7.12 (t, J = 7.6 Hz, 2 H), 7.00 (d, J = 8.0 Hz, 4 H), 6.68 (d, J = 7.6 Hz, 2 H), 5.30 (s, 4 H), 4.74 (s, 2 H).

13C NMR (CDCl3) δ =166.2, 152.8, 143.0, 138.7, 135.6, 133.2, 133.0, 132.5, 131.7, 131.3, 129.9, 129.6, 129.1, 128.7, 128.6, 128.3, 128.0, 127.8, 123.9, 121.2, 65.93, 50.7.

MS: m/z = 657.2 [M + H]+.

HRMS: m/z calcd for C42H32N4O4Na [M + Na]+: 679.2321; found: 679.2321.


#

5-{2-[4-(Acetoxymethyl)phenyl]phenyl}-1-benzyl-1H-tetrazole (4a) (Table [3,] Entry 6)

Assay yield: 2.50 g (77%); mp 73.4 °C.

IR (neat): 1741, 1603 cm–1.

1H NMR (CDCl3): δ = 7.63 (td, J = 7.6, 1.4 Hz, 1 H), 7.57 (dd, J = 7.6, 1.4 Hz, 1 H), 7.44 (td, J = 7.6, 1.4 Hz, 1 H ), 7.34 (dd, J = 7.6, 1.4 Hz, 1 H), 7.27 (d, J = 8.6 Hz, 2 H), 7.22 (t, J = 8.6 Hz, 1 H), 7.16 (t, J = 8.6 Hz, 2 H), 7.13 (d, J = 7.2 Hz, 2 H), 6.76 (d, J = 7.2 Hz, 2 H), 5.09 (s, 2 H), 4.82 (s, 2 H), 2.11 (s, 3 H).

13C NMR (CDCl3): δ = 170.7, 154.5, 141.2, 138.6, 135.9, 133.0, 131.6, 131.3, 130.3, 129.2, 129.1, 128.6, 128.0, 122.6, 65.5, 51.3, 21.0.

MS: m/z = 385 [M + H]+.

HRMS: m/z calcd for C23H20N4O2 [M + Na]+: 407.1484; found: 407.1482.


#

1-Benzyl-5-{2,6-bis[4-(acetoxymethyl)phenyl]phenyl}-1H-tetrazole (5a) (Table [3,] Entry 6)

Assay yield: 281 mg (6%); light brown solid; mp 155.3 °C.

IR (KBr): 1740, 1730, 1252, 1226 cm–1.

1H NMR (CDCl3): δ = 7.70 (t, J = 7.6 Hz, 1 H), 7.49 (d, J = 7.6 Hz, 2 H), 7.26–7.22 (m, 1 H), 7.17–7.12 (m, 6 H), 6.96 (d, J = 8.0 Hz, 4 H), 6.68 (d, J = 7.2 Hz, 2 H), 5.03 (s, 4 H), 4.73 (s, 2 H), 2.10 (s, 6 H).

13C NMR (CDCl3): δ = 170.8, 152.9, 143.1, 138.8, 135.6, 132.6, 131.4, 129.7, 129.1, 128.8, 128.7, 128.2, 128.1, 121.3, 65.7, 50.8, 21.0.

MS: m/z = 555.2 [M + Na]+.

HRMS: m/z calcd for C32H28N4O4Na [M + Na]+: 555.2008; found: 555.2009.


#

2-{2-[4-(Methoxycarbonyl)phenyl]phenyl}pyridine (Table [4,] Entry 1)

Assay yield: 73 mg (3%); yellowish solid; mp 130.9 °C.

IR (KBr): 2951, 2924, 1723, 1707, 1275, 1110, 760, 704 cm–1.

1H NMR (DMSO-d 6): δ = 8.52 (d, J = 4.0 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.63–7.60 (m, 2 H), 7.55 (t, J = 3.6 Hz, 2 H), 7.48 (d, J = 3.2 Hz, 1 H), 7.24 (t, J = 8.4 Hz, 3 H), 7.04 (d, J = 8.0 Hz, 1 H), 3.84 (s, 3 H).

13C NMR (DMSO-d 6): δ = 166.0, 158.2, 149.2, 145.2, 139.4, 139.1, 135.9, 130.5, 130.2, 129.6, 128.9, 128.6, 128.1, 127.8, 124.7, 121.9, 52.1.

MS: m/z = 290.0 [M + H]+.


#

2-{2,6-Bis[4-(methoxycarbonyl)phenyl]phenyl}pyridine (Table [4,] Entry 1)

Assay yield: 3.45 g (97%); white solid; mp 196.5 °C.

IR (KBr): 2948, 1715, 1285, 1102, 768, 706 cm–1.

1H NMR (DMSO-d 6): δ = 8.35 (d, J = 4.0 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 4 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 2 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 4 H), 7.07 (t, J = 7.6 Hz, 1 H), 6.94 (d, J = 7.6 Hz, 1 H), 3.81 (s, 6 H).

13C NMR (DMSO-d 6): δ = 166.0, 157.4, 148.5, 145.9, 140.4, 138.4, 135.4, 129.7, 128.6, 128.5, 127.6, 126.6, 121.7, 52.1.

MS: m/z = 424.0 [M + H]+.


#

2-{2-[4-(Acetoxymethyl)phenyl]phenyl}pyridine (Table [4,] Entry 2)

Assay yield: 103 mg (4%); greenish thick oil.

IR (KBr): 1738, 1585, 1462, 1231 cm–1.

1H NMR (CDCl3): δ = 8.63 (dt, J = 4.8, 0.8 Hz, 1 H), 7.70–7.66 (m, 1 H), 7.49–7.45 (m, 2 H), 7.44–7.38 (m, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 6.8 Hz, 2 H), 7.14–7.09 (m, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 5.08 (s, 2 H), 2.10 (s, 3 H).

13C NMR (CDCl3): δ = 170.7, 1590, 149.3, 141.1, 139.9, 139.3, 135.2, 134.2, 130.3, 129.7, 128.4, 127.7, 127.6, 125.2, 121.3, 65.8, 20.8.

MS: m/z = 304.0 [M + H]+.

HRMS: m/z calcd for C20H17NO2Na [M + Na]+: 326.1157; found: 326.1152.


#

2-{2,6-Bis[4-(acetoxymethyl)phenyl]phenyl}pyridine (Table [4,] Entry 2)

Assay yield: 3.55 g (93%); greenish solid; mp 192 °C.

IR (KBr): 1729, 1241 cm–1.

1H NMR (CDCl3): δ = 8.33–8.32 (m, 1 H), 7.55–7.50 (m, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.32 (dt, J = 7.2, 0.8 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 4 H), 7.09 (d, J = 8.0 Hz, 4 H), 6.96–6.92 (m, 1 H), 6.88 (d, J = 7.6 Hz, 1 H), 5.03 (s, 4 H), 2.08 (s, 6 H).

13C NMR (CDCl3): δ = 170.8, 158.7, 148.6, 141.5, 141.4, 138.4, 135.0, 133.9, 129.8, 129.6, 128.3, 127.5, 126.7, 121.1, 66.0, 21.0.

MS: m/z = 452.0 [M + H]+.

HRMS: m/z calcd for C29H26NO4 [M + H]+: 452.1862; found: 452.1865.


#

2-(2-{4-[(Benzoyloxy)methyl]phenyl}phenyl)pyridine (Table [4,] Entry 3)

Assay yield: 124 mg (4%); yellowish thick oil.

IR (KBr): 3419, 3059, 3030, 3008, 2954, 1918, 1718, 1584, 1461, 1269, 1107, 757 cm–1.

1H NMR (DMSO-d 6): δ = 8.55 (d, J = 4.0 Hz, 1 H), 7.99 (d, J = 7.6 Hz, 2 H), 7.67 (t, J = 7.2 Hz, 1 H), 7.60–7.43 (m, 7 H), 7.35 (d, J = 7.6 Hz, 2 H), 7.23 (t, J = 5.6 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.0 (d, J = 8.0 Hz, 1 H), 5.33 (s, 2 H).

13C NMR (DMSO-d 6): δ = 165.5, 158.6, 149.2, 140.7, 139.6, 139.3, 135.7, 134.5, 133.4, 130.4, 130.3, 129.5, 129.4, 129.2, 128.8, 128.5, 127.6, 127.5, 124.7, 121.7, 65.8.

MS: m/z = 366.0 [M + H]+.

HRMS: m/z calcd for C25H20O2N [M + H]+: 366.1494; found: 366.1491.


#

2-(2,6-Bis{4-[(benzoyloxy)methyl]phenyl)}phenyl)pyridine (Table [4,] Entry 3)

Assay yield: 1.99 g (41%); white solid; mp 159.4 °C.

IR (KBr): 3059, 3027, 2932, 1723, 1449, 1267, 1109, 709 cm–1.

1H NMR (DMSO-d 6): δ = 8.31 (d, J = 4.0 Hz, 1 H), 7.98 (d, J = 7.6 Hz, 4 H), 7.68–7.65 (m, 1 H), 7.61–7.51 (m, 6 H), 7.45–7.42 (m, 3 H), 7.27 (d, J = 7.6 Hz, 4 H), 7.10–7.02 (m, 5 H), 6.96 (d, J = 7.6 Hz, 1 H), 5.23 (s, 4 H).

13C NMR (DMSO-d 6): δ = 165.5, 158.1, 148.3, 140.9, 138.4, 135.2, 134.1, 133.4, 129.5, 129.4, 129.3, 129.2, 128.8, 128.3, 127.2, 126.5, 121.4, 65.8.

MS: m/z = 576.0 [M + H]+.

HRMS: m/z calcd for C39H30O4N [M + H]+: 576.2175; found: 576.2170.


#

2-[2-(4-Methylphenyl)phenyl]pyridine (Table [4,] Entry 4)

Assay yield: 41 mg (2%); yellow thick oil.

IR (KBr): 3054, 3021, 2922, 2858, 1584, 1556, 1486, 1460, 1424, 1150, 795, 740 cm–1.

1H NMR (DMSO-d 6): δ = 8.63 (d, J = 4.0 Hz, 1 H), 7.69–7.67 (m, 1 H), 7.46–7.37 (m, 4 H), 7.11–7.04 (m, 5 H), 6.89 (d, J = 7.6 Hz, 1 H), 2.31 (s, 3 H).

13C NMR (DMSO-d 6): δ = 159.3, 149.3, 140.5, 139.3, 138.3, 136.3, 135.1, 130.4, 129.5, 128.7, 128.4, 127.3, 125.3, 121.2, 21.1.

MS: m/z = 246.0 [M + H]+.


#

2-[2,6-Bis(4-methylphenyl)phenyl]pyridine (Table [4,] Entry 4)

Assay yield: 2.75 g (97%); greenish color solid; mp 154.2 °C.

IR (KBr): 3023, 2993, 2918, 1583, 1560, 1512, 1451, 1419, 817, 799, 744 cm–1.

1H NMR (DMSO-d 6): δ = 8.33 (d, J = 4.4 Hz, 1 H), 7.50–7.46 (m, 1 H), 7.41 (d, J = 7.2 Hz, 2 H), 7.33–7.25 (m, 1 H), 7.04–6.87 (m, 10 H), 2.26 (s, 6 H).

13C NMR (DMSO-d 6): δ = 159.2, 148.4, 141.7, 138.6, 138.4, 135.7, 134.8, 133.4, 129.3, 128.3, 128.0, 126.7, 120.7, 21.0.

MS: m/z = 336.0 [M + H]+.


#

1-[2-(4-Methylphenyl)phenyl]pyrazole (Table [4,] Entry 10)

Assay yield: 198 mg (10%); yellow liquid.

IR (KBr): 3025, 2921, 1517, 1393, 1044, 937, 820, 703 cm–1.

1H NMR (DMSO-d 6): δ = 7.70 (s, 1 H), 7.60–7.48 (m, 4 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.09 (d, J = 7.6 Hz, 2 H), 6.93 (d, J = 8.0 Hz, 2 H), 6.29 (s, 1 H), 2.27 (s, 3 H).

13C NMR (DMSO-d 6): δ = 139.9, 138.2, 136.6, 136.5, 135.3, 131.6, 130.8, 128.9, 128.5, 128.1, 128.0, 126.7, 106.5, 20.6.

MS: m/z = 235.0 [M + H]+.


#

1-[2,6-Bis(4-methylphenyl)phenyl]pyrazole (Table [4,] Entry 10)

Assay yield: 1.04 g (38%); yellow-colored solid; mp 110.4 °C.

IR (KBr): 1517, 1456, 1048 cm–1.

1H NMR (CDCl3): δ = 7.53 (t, J = 6.8 Hz, 1 H), 7.47–7.40 (m, 3 H), 7.09 (d, J = 4.0 Hz, 1 H), 7.05–6.98 (m, 8 H) 6.08 (t, J = 2.0 Hz, 1 H), 2.31 (s, 6 H).

13C NMR (CDCl3): δ = 140.3, 139.2, 136.8, 136.3, 135.8, 132.4, 129.8, 129.0, 128.7, 128.0, 105.9, 21.1.

MS: m/z = 325.1 [M + H]+.

HRMS: m/z calcd for C23H20N2Na [M + Na]+: 347.1524; found: 347.1521.


#

1-{2-[4-(Methoxycarbonyl)phenyl]phenyl}pyrazole (Table [4,] Entry 11)

Assay yield: 447 mg (19%); white solid; mp 113.0 °C.

IR (KBr): 1723, 1281, 1116, 760, 706 cm–1.

1H NMR (DMSO-d 6): δ = 7.85 (d, J = 8.4 Hz, 2 H), 7.58 (t, J = 4.4 Hz, 6 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.32 (s, 1 H), 3.84 (s, 3 H).

13C NMR (DMSO-d 6): δ = 165.9, 134.2, 140.2, 138.3, 135.6, 130.8, 129.2, 129.05, 128.73, 128.5, 128.4, 126.7, 106.7, 52.11.

MS: m/z = 279.0 [M + H]+.


#

1-{2,6-Bis[(4-methoxycarbonyl)phenyl]phenyl}pyrazole (Table [4,] Entry 11)

Assay yield: 2.44 g (70%); gray solid; mp 199.6 °C.

IR (KBr): 1717, 1275, 1102, 768, 706 cm–1.

1H NMR (DMSO-d 6): δ = 7.81 (d, J = 8.0 Hz, 4 H), 7.75 (t, J = 8.0 Hz, 1 H), 7.65 (d, J = 7.6 Hz, 2 H), 7.49 (s, 1 H), 7.37 (s, 1 H), 7.21 (d, J = 8.0 Hz, 4 H), 6.13 (s, 1 H), 3.83 (s, 6 H).

13C NMR (DMSO-d 6): δ = 165.9, 142.9, 139.5, 138.9, 136.1, 133.4, 130.5, 129.7, 128.8, 128.4, 128.3, 106.4, 52.1.

MS: m/z = 413.0 [M + H]+.


#

1-{2-[4-(Acetoxymethyl)phenyl]phenyl}pyrazole (Table [4,] Entry 12)

Assay yield: 49 mg (2%); dark brown semisolid.

IR (KBr): 1918, 1734, 1249 cm–1.

1H NMR (CDCl3): δ = 7.63 (d, J = 1.6 Hz, 1 H), 7.60 (dt, J = 8.4, 4.1, 1.2 Hz, 1 H), 7.48–7.45 (m, 3 H), 7.27 (d, J = 7.2 Hz, 2 H), 7.10 (dd, J = 5.6, 2.4 Hz, 3 H), 6.21 (t, J = 2.4 Hz, 1 H), 5.09 (s, 2 H), 2.11 (s, 3 H).

13C NMR (CDCl3): δ = 170.7, 140.2, 138.4, 138.3, 136.1, 135.0, 131.2, 130.9, 128.6, 128.4, 128.2, 128.1, 127.7, 126.6, 106.4, 65.7, 20.9.

MS: m/z = 314.8 [M + H]+.

HRMS: m/z calcd for C18H16O2N2Na [M + Na]+: 315.1109; found: 315.1114.


#

1-{2,6-Bis[4-(acetoxymethyl)phenyl]phenyl}pyrazole (Table 4, Entry 12)

Assay yield: 3.65 g (98%); gray solid; mp 162.8 °C.

IR (KBr): 1729, 1243 cm–1.

1H NMR (CDCl3): δ = 7.57 (t, J = 6.8 Hz, 1 H), 7.48 (d, J = 7.2 Hz, 2 H), 7.39 (d, J = 1.6 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 4 H), 7.11–7.07 (m, 5 H), 6.08 (t, J = 2.0 Hz, 1 H), 5.07 (s, 4 H), 2.10 (s, 6 H).

13C NMR (CDCl3): δ = 170.7, 140.2, 139.8, 139.4, 138.4, 136.2, 134.8, 132.3, 130.1, 129.1, 128.5, 128.2, 128.3, 127.7, 106.1, 65.7, 20.8.

MS: m/z = 441.2 [M + H]+.

HRMS: m/z calcd for C27H24O4N2Na [M + Na]+: 463.1634; found: 463.1636.


#

1-(2-{(4-[(Benzoyloxy)methyl]phenyl}phenyl)pyrazole (Table [4,] Entry 13)

Assay yield: 120 mg (4%); white solid; mp 103.4 °C.

IR (KBr): 3114, 1713, 1275, 1106, 706 cm–1.

1H NMR (DMSO-d 6): δ = 8.01 (d, J = 7.2 Hz, 2 H), 7.68 (t, J = 7.2 Hz, 1 H), 7.60–7.55 (m, 8 H), 7.39 (d, J = 7.6 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 6.31 (s, 1 H), 5.34 (s, 2 H).

13C NMR (DMSO-d 6): δ = 165.6, 140.1, 138.2, 138.0, 136.2, 135.2, 133.4, 131.7, 131.0, 129.5, 129.2, 128.8, 128.7, 128.5, 128.3, 127.8, 126.8, 106.6, 65.8.

MS: m/z = 355.0 [M + H]+.

HRMS: m/z calcd for C23H18O2N2Na [M + Na]+: 377.1266; found: 377.1271.


#

1-(2,6-Bis{4-[(benzoyloxy)methyl]phenyl}phenyl)pyrazole (Table [4,] Entry 13)

Assay yield: 1.43 g (30%); white solid; mp 122.4 °C.

IR (KBr): 2933, 1721, 1267, 1177, 706 cm–1.

1H NMR (DMSO-d 6): δ = 8.01 (d, J = 7.6 Hz, 4 H), 7.68 (t, J = 6.8 Hz, 3 H), 7.56–7.51 (m, 7 H), 7.38–7.33 (m, 5 H), 7.12 (d, J = 8.0 Hz, 4 H), 6.12 (s, 1 H), 5.32 (s, 4 H).

13C NMR (DMSO-d 6): δ = 165.6, 139.6, 139.3, 138.1, 136.1, 135.0, 133.4, 130.2, 129.5, 129.2, 128.8, 128.2, 127.5, 106.2, 65.8.

MS: m/z = 565.0 [M + H]+.

HRMS: m/z calcd for C37H28O4N2Na [M + Na]+: 587.1947; found: 587.1948.


#

2-[2-(4-Methylphenyl)phenyl]oxazoline (Table [4,] Entry 22)

Assay yield: 321 mg (16%); yellow viscous liquid.

IR (KBr): 3057, 2967, 2877, 1649, 1478, 1236, 1078, 1038, 940, 759 cm–1.

1H NMR (DMSO-d 6): δ = 7.66 (d, J = 7.2 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.44–7.39 (m, 2 H), 7.21 (s, 4 H), 4.09 (t, J = 9.6 Hz, 2 H), 3.78 (t, J = 9.6 Hz, 2 H), 2.36 (s, 3 H).

13C NMR (DMSO-d 6): δ = 164.5, 140.9, 137.6, 136.4, 130.6, 130.1, 129.9, 128.7, 127.9, 127.4, 126.9, 67.3, 54.6, 20.7.

MS: m/z = 238.0 [M + H]+.

HRMS: m/z calcd for C16H16ON [M + H]+: 238.1232; found: 238.1232.


#

2-[2,6-Bis(4-methylphenyl)phenyl]oxazoline (Table [4,] Entry 22)

Assay yield: 1.13 g (41%); white solid; mp 151.1 °C.

IR (KBr): 3052, 2899, 2873, 1668, 1243, 1099, 1038, 820, 795, 760, 704 cm–1.

1H NMR (DMSO-d 6): δ = 7.59 (t, J = 7.6 Hz, 1 H), 7.38 (d, J = 7.6 Hz, 2 H), 7.29 (d, J = 7.6 Hz, 4 H), 7.22 (d, J = 8.0 Hz, 4 H), 3.91 (t, J = 9.2 Hz, 2 H), 3.50 (t, J = 9.2 Hz, 2 H), 2.33 (s, 6 H).

13C NMR (DMSO-d 6): δ = 162.7, 141.5, 137.4, 136.5, 129.9, 128.7, 128.6, 128.1, 127.0, 66.8, 54.6, 20.7.

MS: m/z = 328.0 [M + H]+.


#

2-{2-[4-(Methoxycarbonyl)phenyl]phenyl}oxazoline (Table [4,] Entry 23)

Assay yield: 214 mg (9%); white solid; mp 56.5 °C.

IR (KBr): 2961, 1709, 1644, 1285, 1117, 770, 706 cm–1.

1H NMR (DMSO-d 6): δ = 7.99 (d, J = 8.0, 2 H), 7.75 (d, J = 7.2 Hz, 1 H), 7.61 (t, J = 7.2 Hz, 1 H), 7.53–7.46 (m, 4 H), 4.09 (t, J = 9.6 Hz, 2 H), 3.88 (s, 3 H), 3.80 (t, J = 9.6 Hz, 2 H).

13C NMR (DMSO-d 6): δ = 166.1, 163.9, 145.5, 140.0, 130.8, 130.2, 130.0, 128.9, 128.6, 128.3, 127.9, 127.3, 67.7, 54.6. 52.1.

MS: m/z = 282.0 [M + H]+.

HRMS: m/z calcd for C17H16O3N [M + H]+: 282.1130; found: 282.1135.


#

2-{2,6-Bis[4-(methoxycarbonyl)phenyl]phenyl}oxazoline (Table [4,] Entry 23)

Assay yield: 2.95 g (84%); white solid; mp 226.3 °C.

IR (KBr): 2950, 1726, 1711, 1287, 768, 707 cm–1.

1H NMR (DMSO-d 6): δ = 8.01 (d, J = 8.0 Hz, 4 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.54 (d, J = 7.6 Hz, 6 H), 3.90 (t, J = 9.6 Hz, 2 H), 3.88 (s, 6 H), 3.51 (t, J = 9.2 Hz, 2 H).

13C NMR (CDCl3): δ =166.9, 163.4, 145.4, 141.5, 129.9, 129.4, 129.2, 129.1, 128.6, 127.4, 67.5, 674, 55.1, 52.2, 52.1.

MS: m/z = 416.0 [M + H]+.

HRMS: m/z calcd for C25H22O5N [M + H]+: 416.1498; found: 416.1494.


#

2-{2-[4-(Acetoxymethyl)phenyl]phenyl}oxazoline (Table [4,] Entry 24)

Assay yield: 349 mg (14%); dark brown viscous liquid.

IR (KBr): 1735, 1648, 1226 cm–1.

1H NMR (CDCl3): δ = 7.77 (dd, J = 7.8, 1.2 Hz, 1 H), 7.50 (dt, J = 7.6, 6.4 Hz, 1 H), 7.41–7.36 (m, 6 H), 5.15 (s, 2 H), 4.14 (t, J = 9.2 Hz, 2 H), 3.92 (t, J = 9.2 Hz, 2 H), 2.13 (s, 3 H).

13C NMR (CDCl3): δ = 170.8, 165.8, 141.2, 141.1, 134.7, 130.5, 130.3, 130.1, 128.4, 127.8, 127.4, 127.2, 67.7, 65.9, 54.9, 20.9.

MS: m/z = 296.0 [M + H]+.

HRMS: m/z calcd for C18H18NO3 [M + H]+: 296.1286; found: 296.1285.


#

2-{2,6-Bis[4-(acetoxymethyl)phenyl]phenyl}oxazoline (Table [4,] Entry 24)

Assay yield: 1.46 g (39%); pale yellow solid; mp 152.5 °C.

IR (KBr): 1725, 1665, 1246 cm–1.

1H NMR (CDCl3): δ = 7.53 (t, J = 7.2 Hz, 1 H), 7.45 (d, J = 6.4 Hz, 4 H), 7.38 (dd, J = 8.0, 3.2 Hz, 6 H), 5.15 (s, 4 H), 3.91 (t, J = 9.6 Hz, 2 H), 3.61 (t, J = 9.6 Hz, 2 H), 2.13 (s, 6 H).

13C NMR (CDCl3): δ = 170.8, 163.7, 141.8, 140.7, 134.9, 129.6, 128.9, 128.7, 127.8, 127.4, 67.3, 65.9, 55.01, 20.97.

MS: m/z = 444.1 [M + H]+.

HRMS: m/z calcd for C27H26O5N [M + H]+: 444.1811; found: 444.1810.


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2-(2-{4-[(Benzoyloxy)methyl]phenyl}phenyl)oxazoline (Table [4,] Entry 28)

Assay yield: 9.1 mg (0.3%); off-white solid; mp 78.3 °C.

IR (KBr): 3065, 2952, 1716, 1648, 1279, 1103, 938, 710 cm–1.

1H NMR (DMSO-d 6): δ = 8.03 (d, J = 7.6 Hz, 2 H), 7.69 (t, J = 7.6 Hz, 2 H), 7.60–7.43 (m, 7 H), 7.37 (d, J = 7.6 Hz, 2 H), 5.41 (s, 2 H), 4.10 (t, J = 9.6 Hz, 2 H), 3.80 (t, J = 9.6 Hz, 2 H).

13C NMR (DMSO-d 6): δ = 165.6, 164.3, 140.6, 140.4, 135.0, 133.5, 130.7, 130.3, 130.0, 129.6, 129.5, 129.3, 128.9, 128.7, 128.6, 128.5, 128.3, 127.7. 127.4, 67.4, 65.9, 54.6.

MS: m/z = 358.0 [M + H]+.

HRMS: m/z calcd for C23H20O3N [M + H]+: 358.1443; found: 358.1440.


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2-(2,6-Bis{4-[(benzoyloxy)methyl]phenyl}phenyl)oxazoline (Table [4,] Entry 28)

Assay yield: 4.75 g (99%); white solid; mp 136.3 °C.

IR (KBr): 3034, 2932, 1723, 1663, 1449, 1267, 1109, 709 cm–1.

1H NMR (DMSO-d 6): δ = 8.05 (d, J = 7.6 Hz, 4 H), 7.72–7.64 (m, 3 H), 7.59–7.54 (m, 8 H), 7.49–7.45 (t, J = 8.0 Hz, 6 H), 5.43 (s, 4 H), 3.95 (t, J = 9.6 Hz, 2 H), 3.53 (t, J = 9.6 Hz, 2 H).

13C NMR (DMSO-d 6): δ = 165.6, 162.5, 141.2, 140.0, 135.3, 133.4, 130.1, 129.6, 129.3, 129.0, 128.8, 128.4, 127.7, 127.0, 67.0, 65.9, 54.7.

MS: m/z = 568.0 [M + H]+.

HRMS: m/z calcd for C37H30O5N [M + H]+: 568.2124; found: 568.2126.


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1-Benzyl-5-[2-(4-methylphenyl)phenyl]-1H-tetrazole (Table [4,] Entry 30)

Assay yield: 2.12 g (77%); off-white solid; mp 140 °C.

IR (KBr): 1455, 1093 cm–1.

1H NMR (CDCl3): δ = 7.61 (dt, J = 8.0, 1.6 Hz, 1 H), 7.56 (dd, J = 7.8, 0.8 Hz, 1 H), 7.39 (dt, J = 7.8, 1.2 Hz, 1 H), 7.33 (dd, J = 7.8, 1.2 Hz, 1 H), 7.22–7.08 (m, 5 H), 7.03 (d, J = 8.4 Hz, 2 H), 6.75 (d, J = 7.2 Hz, 2 H), 4.76 (s, 2 H), 2.34 (s, 3 H).

13C NMR (CDCl3): δ = 154.5, 141.4, 137.7, 135.6, 132.9, 131.3, 130.9, 129.9, 129.4, 128.4, 128.2, 127.6, 127.3, 122.3, 50.5, 20.8.

MS: m/z = 327.0 [M + H]+.

HRMS: m/z calcd for C21H18N4Na [M + Na]+: 349.1429; found: 349.1425.


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1-Benzyl-5-[2,6-bis(4-methylphenyl)phenyl]-1H-tetrazole (Table [4,] Entry 30)

Assay yield: 106 mg (3%); off-white solid; mp 183.5 °C.

IR (KBr): 3061, 3033, 2917, 2858, 1736, 1513, 1457, 1439, 1404, 1104, 798.

1H NMR (CDCl3): δ = 7.65 (t, J = 7.6 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.28–7.20 (m, 1 H), 7.13 (t, J = 8.0 Hz, 2 H), 6.96 (d, J = 8.0 Hz, 4 H), 6.84 (d, J = 8.0 Hz, 4 H), 6.70 (d, J = 7.2 Hz, 2 H), 4.71 (s, 2 H), 2.24 (s, 6 H).

13C NMR (CDCl3): δ =153.1, 143.5, 137.4, 136.1, 132.7, 131.1, 129.2, 128.9, 128.7, 128.6, 128.5, 128.2, 121.2, 50.6, 21.0.

MS: m/z = 417.0 [M + H]+.

HRMS: m/z calcd for C28H24N4 [M + H]+: 417.2079; found: 417.2080.


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Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1380159.
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Zoom Image
Scheme 1 Synthesis of angiotensin II receptor blockers 3 by C–H arylation of 5-phenyl-1H-tetrazole (1) with aryl bromide 2
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Scheme 2 A possible mechanism of ruthenium-catalyzed C–H arylation
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Figure 1 Intramolecular activation of ligand removal/exchange
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Figure 2 Effect of chain length of dipotassium dicarboxylate [(CH2)n(CO2K)2] on the C–H arylation of 1 with 2a
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Figure 3 Possible mechanism for intramolecular activation in the ruthenium–glutarate complex
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Scheme 3 Ruthenium phosphate as a potential catalyst for C–H arylation
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Figure 4 Performance of cocatalysts [dipotassium glutarate (GLDK), potassium bis(2-ethylhexyl) phosphate (BEHPK), and potassium 2,4,6-trimethylbenzenesulfonate (TMBSK)] in C–H arylation (2-PhPy = 2-phenylpyridine; 1-PhPz = 1-phenylpyrazole; 2-PhOx = 2-phenyloxazoline); see data shown in Table [4].
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Scheme 4 Synthesis of key intermediate for candesartan cilexetil