One-Pot, Three-Component Synthesis of Novel 4-Phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]pyrimidine Libraries via Michael Addition, Cyclization, and C–C Coupling Reactions: A New MCR Strategy

Abstract

Privileged medicinal scaffolds based on the structures of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines have been synthesized via a single-step, three-component reaction­ of 3-(dimethylamino)-1-phenylprop-2-en-1-one (enaminone), 3-bromobenzimidamide hydrochloride, and various alkynes/alkenes/arylboronic acids. The mechanism of this multi-component reaction (MCR) involves a Michael addition, cyclization, isomerization, and dehydration, followed by Sonogashira, Heck or Suzuki coupling. This new MCR strategy afforded a new compound library based on pyrimidine framework.

Key words

multi-component reactions (MCRs) - Michael addition - Pd catalyst - C–C coupling reactions

The synthesis of ‘privileged medicinal scaffolds’ is highly important as these compounds often act as ligands for a number of functionally and structurally diverse biological receptors and further serve as a platform for developing pharmaceutical agents for diverse applications.[ ¹ ] For instance, pyrimidine and its derivatives are considered as ‘privileged scaffold’ due to their potential biological activities such as antihypertensive,[ ² ] antipyretic,[ ³ ] antibacterial,[4] [5] [6] antifungal,[ ^7,8 ] anticancer,[ ^9,10 ] anti-inflammatory,[11] [12] and cardio-protective activities.[ ¹³ ] The structural features of pyrimidines are also found in some pesticides,[ ¹⁴ ] herbicides, and plant growth regulators.[ ¹⁵ ] Consequently, methodologies for the synthesis of novel pyrimidines or pyrimidine-fused compounds are of particular interest in the medicinal and agrochemical research areas.[16] [17]

These vast applications have inspired the development of a number of methods for the preparation of pyrimidine derivatives.[ ¹⁸ ] In addition to reports about the variation of established protocols, new methods[ ¹⁸ ] were also described on the union of amine and carbonyl-containing fragments and N-vinyl, N-aryl amides and nitriles to gather the imperative pyrimidine substructures. Additionally, the advancement of transition metal-catalyzed methodologies for cross-coupling of activated azaheterocycles offer complementary access to substituted azaheterocycles.[ ¹⁹ ] However, literature studies reveal that, none has been reported on the synthesis of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidine derivatives from enaminone, 3-bromobenzimidamide hydrochloride, and various alkynes/alkenes/arylboronic acids via a single step, one-pot multi-component reaction. Multi-component reactions (MCRs) are powerful strategies for the quick synthesis of diverse and complex organic molecules of potential interest particularly in the area of material science and drug discovery.[ ²⁰ ] MCRs have attracted much attention owing to their excellent synthetic efficiency, intrinsic atom economy, high selectivity, procedural simplicity, and environmental friendliness.[20a] [21] As a result, the search and discovery of new MCR have attained significant value.[ ²² ]

Herein we report a new MCR strategy for the synthesis of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidine derivatives from the reaction of enaminone 1, 3-bromobenzimidamide hydrochloride (2), and various alkynes 3, alkenes 5 or arylboronic acids 7 in the presence of K₂CO₃ and Pd catalyst in DMF (Scheme [1]).

Scheme 1 One-pot three-component synthesis of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines

In the present study, our initial objective was to identify well-suited reaction conditions for MCR besides seeking an appropriate Pd catalyst, solvent, and base for the construction of pyrimidine scaffold followed by Sonogashira/ Heck/Suzuki coupling in a single step operation. We choose to assess the pyrimidine formation/Sonogashira coupling initially for this purpose. Accordingly, few palladium catalysts, solvents, and bases were examined to determine the effect on the course of MCR of enaminone 1, 3-bromobenzimidamide hydrochloride (2), and prop-2-yn-1-ol (3a) in the presence of CuI (Table [1]) as a model reaction. Initially, the reaction carried out by using 10% Pd/C catalyst with K₂CO₃ in DMF at 100 °C for 24 hours afforded the product 4a in 10% yield (Table [1], entry 1). Later, optimization of the reaction conditions was scrutinized to increase the yield of the product. Towards this direction, a variety of Pd catalysts, solvents, and bases were also examined. The catalysts and solvents, which provided poor to moderate yields, are listed in Table [1] (Table [1], entries 2–10). In contrast, the palladium catalyst, PdCl₂(PPh₃)₂, is the only catalyst, which afforded the highest yield (80%) of the desired product 4a in the presence of K₂CO₃ in DMF within 2.5 hours (Table [1], entry 11). When K₂CO₃ was replaced with an organic base such as Et₃N, a lower yield (60%) of the product 4a was noticed within 10 hours in the presence of the same catalyst and solvent (Table [1], entry 12). The same catalyst with K₂CO₃ in other solvents like DMSO and 1,4-dioxane gave moderate yields of the product 4a (Table [1], entries 13, 14). The reaction did not proceed in the absence of Pd catalyst (Table [1], entry 15).

Table 1 Optimization of the Reaction Conditions for the Formation of 3-[3-(4-phenylpyrimidin-2-yl)phenyl]prop-2-yn-1-ol^a

Entry	Catalyst	Solvent	Base	Time (h)	Yield (%)b
1	10% Pd/C	DMF	K2CO3	24	10
2	20% Pd(OH)2	DMF	K2CO3	24	40
3	20% Pd(OH)2	DMSO	K2CO3	24	30
4	20% Pd(OH)2	1,4-dioxane	K2CO3	24	25
5	Pd(dppf)Cl2	DMF	K2CO3	14	55
6	Pd(dppf)Cl2	DMSO	K2CO3	20	40
7	Pd(dppf)Cl2	1,4-dioxane	K2CO3	20	42
8	Pd(PPh3)4	DMF	K2CO3	07	55
9	Pd(PPh3)4	DMSO	K2CO3	10	50
10	Pd(PPh3)4	1,4-dioxane	K2CO3	10	45
11	PdCl2(PPh3)2	DMF	K2CO3	2.5	80
12	PdCl2(PPh3)2	DMF	Et3N	10	60
13	PdCl2(PPh3)2	DMSO	K2CO3	07	65
14	PdCl2(PPh3)2	1,4-dioxane	K2CO3	07	60
15	–	DMF	K2CO3	24	0

^a The reaction was carried out using 1 (0.41 g, 2.339 mmol), 2 (0.5 g, 2.123 mmol), Pd catalyst (0.0712 mmol), base (1.02 g, 7.380 mmol), CuI (0.04 g, 0.21 mmol), and prop-2-yn-1-ol (0.128 g, 2.282 mmol) in a solvent (2.5 mL) at 70–75 °C.

^b Isolated yield.

With the help of optimized reaction conditions, the further scope and generality of this process for pyrimidine formation and Sonogashira coupling were examined and the results obtained are presented in Table [2].

Table 2 Synthesis of 4-Phenyl-2-[3-(alkynyl)phenyl]pyrimidines 4 via Sonogashira Coupling MCR^a

Entry	Alkyne	Product	Time (h)	Yield (%)b	Rf c
1	3a	4a	2.5	80	0.3
2	3b	4b	3.0	78	0.2
3	3c	4c	4.0	70	0.22
4	3d	4d	3.4	80	0.4
5	3e	4e	3.0	83	0.8
6	3f	4f	3.2	85	0.85

^a All the reactions were carried out using 1 (2.339 mmol), 2 (2.123 mmol), CuI (0.21 mmol), terminal alkyne derivatives 3a–f (2.282 mmol), DMF (2.5 mL), PdCl₂(PPh₃)₂ (50 mg, 0.0712 mmol), K₂CO₃ (7.380 mmol) at 70–75 °C.

^b Isolated yield.

^c Retention factor; eluent: 10% EtOAc in PE.

Encouraged by these results, the possibilities of the construction of pyrimidine scaffold and Heck coupling in a single step were examined. Initially, a reaction was carried out using enaminone 1, 3-bromobenzimidamide hydrochloride (2), and methyl acrylate (5a) in the presence of PdCl₂(PPh₃)₂ and K₂CO₃ in DMF at 80–85 °C. The reaction proceeded smoothly to give the corresponding product 6a in 83% yield. Other alkenes were examined and the results obtained are presented in Table [3]. All reactions required 5–7 hours for completion and to provide the desired alkene derivatives 6a–f. Based on ¹H NMR data all the prepared alkenes were confirmed as E-isomers (J = 16.8–16.0 Hz).

Table 3 Synthesis of (E)-4-Phenyl-2-[3-(alkenyl)phenyl]pyrimidines 6 via Heck Coupling MCR^a

Entry	Alkene	Product	Time (h)	Yield (%)b	Rf c
1	5a	6a	5.0	83	0.2
2	5b	6b	5.4	78	0.25
3	5c	6c	6.0	80	0.4
4	5d	6d	6.3	78	0.1
5	5e	6e	6.0	81	0.1
6	5f	6f	7.0	73	0.1

^a All the reactions were carried out using 1 (2.339 mmol), 2 (2.123 mmol), PdCl₂(PPh₃)₂ (50 mg, 0.0712 mmol), alkene derivatives 5a–f (2.555 mmol), K₂CO₃ (7.380 mmol) in DMF (2.5 mL) at 80–85 °C.

^b Isolated yield.

^c Retention factor; eluent: 15% EtOAc in PE.

Table 4 Synthesis of 2-(Biphenyl-3-yl)-4-phenylpyrimidines 8 via Suzuki Coupling MCR^a

Entry	Arylboronic acid	Product	Time (h)	Yield (%)b	Rf c
1	7a	8a	2.0	90	0.3
2	7b	8b	2.6	85	0.4
3	7c	8c	2.3	80	0.4
4	7d	8d	3.5	74	0.2
5	7e	8e	2.0	85	0.4
6	7f	8f	3.2	75	0.45
7	7g	8g	3.5	78	0.4
8	7h	8h	3.3	76	0.5

^a All the reactions were carried out using 1 (2.339 mmol), 2 (2.123 mmol), PdCl₂(PPh₃)₂ (50 mg, 0.0712 mmol), K₂CO₃ (7.380 mmol), DMF (2.5 mL), arylboronic acids 7a–h (2.546 mmol) at 80–85 °C.

^b Isolated yield.

^c Retention factor; eluent: 15% EtOAc in PE.

The possibilities for the formation of pyrimidine ring followed by Suzuki coupling in a single step were also examined. Initially, the reaction was carried out using enaminone 1, 3-bromobenzimidamide hydrochloride (2), and 3-cyano-5-fluorophenylboronic acid (7a) in the presence of PdCl₂(PPh₃)₂ and K₂CO₃ in DMF at 80–85 °C. The reaction proceeded smoothly and afforded the corresponding product 8a in 90% yield. Different types of boronic acids were examined and the obtained results are summarized in Table [4]. All the reactions were completed within 2–3.5 hours and afforded the desired products 8a–h.

The plausible mechanism of MCR may proceed via a base-catalyzed Michael addition of 3-bromobenzimidamide hydrochloride (2) to the enaminone 1 to form the intermediate 9. This intermediate sequentially undergoes cyclization, isomerization, and dehydration to give 2-(3-bromophenyl)-4-phenylpyrimidine (10), followed by Sonogashira, Heck or Suzuki coupling to afford the 4-phenyl-2-(3-alkynyl/alkenyl/aryl)phenyl-substituted pyrimidines 4, 6, and 8 as shown in Scheme [2].

In conclusion, we have developed a new MCR strategy for the synthesis of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines in high yields from enaminone 1, 3-bromobenzimidamide hydrochloride (2), and various alkynes/alkenes/arylboronic acids via a Michael addition, cyclization, isomerization, dehydration, and followed by Sonogashira/Heck/Suzuki coupling in a single pot. This MCR strategy offers several advantages like short reaction time, easy isolation of products, simple construction of substituted pyrimidine moiety, and subsequent C–C couplings for the structural elaboration of pyrimidine framework in one pot.

Scheme 2 Plausible mechanism for the formation of 4-phenyl-2-[3-(alkynyl/alkenyl/aryl)phenyl]-substituted pyrimidines

Melting points were determined using a melting point apparatus and are uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on a Varian 400 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm) and coupling constants in hertz (Hz). Standard abbreviations were used to describe the splitting pattern. High-resolution mass spectra (HRMS) were recorded on a Waters LCT Premier XE mass spectrometer equipped with electrospray ionization (ESI) source. TLC was performed on 0.25 mm Merck silica gel plates and visualized with UV light. Column chromatography was performed on silica gel. Enaminone 1 and 3-bromobenzimidamide hydrochloride (2) were prepared according to the known procedure[23] [24] and other chemicals and solvents were purchased from Sigma Aldrich and Merck and used directly. Petroleum ether (PE) used refers to the fraction boiling at 60–80 °C.

3-[3-(4-Phenylpyrimidin-2-yl)phenyl]prop-2-yn-1-ol (4a); Typical Procedure

In a 25 mL round-bottomed flask were charged enaminone 1 (0.41 g, 2.339 mmol), 3-bromobenzimidamide hydrochloride (2; 0.5 g, 2.123 mmol), DMF (2.5 mL), K₂CO₃ (1.02 g, 7.380 mmol), PdCl₂(PPh₃)₂ (50 mg, 0.0712 mmol), CuI (0.04 g, 0.21 mmol) and prop-1-yn-3-ol (3a; 0.128 g, 2.282 mmol) at r.t. Then, the reaction mixture was stirred at 70–75 °C for 2.5 h and the reaction was monitored by TLC (10% EtOAc in PE). After completion of the reaction, the mixture was concentrated under vacuum and the obtained crude product 4a was purified by column chromatography on silica gel (230–400 mesh) using EtOAc–PE (10% EtOAc–PE); yield: 486 mg (80%); off-white solid; mp 95.1–97.4 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.83 (d, J = 4.8 Hz, 1 H_arom), 8.55 (d, J = 8.4 Hz, 2 H_arom), 8.21–8.20 (m, 2 H_arom), 7.60–7.25 (m, 6 H_arom­), 4.53 (s, 2 H, OCH₂), 1.97 (br, 1 H, OH).

¹³C NMR (400 MHz, CDCl₃): δ = 163.9, 163.7, 157.7, 137.6, 136.6, 131.8 (2 C), 131.0, 128.9 (2 C), 128.1 (2 C), 127.1 (2 C), 124.8, 114.6, 89.1, 85.5, 51.5.

HRMS (ESI): m/z (M + H)⁺ calcd for C₁₉H₁₅N₂O: 287.1184; found: 287.1173.

4-[3-(4-Phenylpyrimidin-2-yl)phenyl]but-3-yn-1-ol (4b)

Purification by column chromatography (15% EtOAc–PE) gave 4b as an off-white solid; yield: 497 mg (78%); mp 94.2–96.3 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.83 (d, J = 5.6 Hz, 1 H_arom), 8.53 (d, J = 8.4 Hz, 2 H_arom), 8.23–8.20 (m, 2 H_arom), 7.60 (d, J = 5.2 Hz, 1 H_arom), 7.55–7.53 (m, 5 H_arom), 3.86 (t, J = 6.4 Hz, 2 H, OCH₂), 2.60 (t, J = 6.8 Hz, 2 H, CH₂).

¹³C NMR (400 MHz, CDCl₃): δ = 163.9, 163.8, 157.7, 136.9, 136.8, 131.7 (2 C), 130.9, 128.9 (2 C), 128.0 (2 C), 127.1 (2 C), 126.0, 114.5, 91.4, 81.7, 61.7, 16.0.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₀H₁₇N₂O: 301.1341; found: 301.1347.

2-Methyl-4-[3-(5-phenylpyrimidin-2-yl)phenyl]but-3-yn-2-ol (4c)

Purification by column chromatography (20% EtOAc–PE) gave 4c as an off-white solid; yield: 467 mg (70%); mp 95.3–97.7 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 5.6 Hz, 1 H_arom), 8.54 (d, J = 8.8 Hz, 2 H_arom), 8.23–8.21 (m, 2 H_arom), 7.61 (d, J = 4.8 Hz, 1 H_arom), 7.62–7.54 (m, 5 H_arom), 1.50 [6 H, C(CH₃)₂].

¹³C NMR (400 MHz, CDCl₃): δ = 163.9, 163.8, 157.8, 137.4, 136.7, 131.8 (2 C), 131.0, 128.9 (2 C), 128.1 (2 C), 127.2 (2 C), 125.0, 114.6, 83.9, 66.3, 31.4, 31.0 (2 C).

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₁H₁₉N₂O: 315.1497; found: 315.1486.

5-[3-(4-Phenylpyrimidin-2-yl)phenyl]pent-4-yn-1-ol (4d)

Purification by column chromatography (15% EtOAc–PE) gave 4d as an off-white solid; yield: 533 mg (80%); mp 94.3–96.6 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.83 (d, J = 5.6 Hz, 1 H_arom), 8.52 (d, J = 8.4 Hz, 2 H_arom H), 8.23–8.20 (m, 2 H_arom), 7.60 (d, J = 5.2 Hz, 1 H_arom), 7.55–7.52 (m, 5 H_arom), 3.85 (t, J = 6.4 Hz, 2 H, OCH₂), 2.61 (t, J = 6.8 Hz, 2 H, CH₂), 1.90 (quint, J = 6.4 Hz, 2 H, CH₂).

¹³C NMR (400 MHz, CDCl₃): δ = 163.8, 157.8, 137.7, 136.7, 131.8 (2 C), 131.0, 128.9 (2 C), 128.1 (2 C), 127.2 (2 C), 124.8, 114.6, 85.6, 51.6, 31.9, 14.1.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₁H₁₉N₂O: 315.1497; found: 315.1482.

2-[3-(Hex-1-ynyl)phenyl]-4-phenylpyrimidine (4e)

Purification by column chromatography (10% EtOAc–PE) gave 4e as an off-white solid; yield: 550 mg (83%); mp 109.4–111.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.82 (d, J = 5.6 Hz, 1 H_arom), 8.51 (d, J = 8.4 Hz, 2 H_arom), 8.23–8.20 (m, 2 H_arom), 7.59 (d, J = 5.2 Hz, 1 H_arom), 7.55–7.52 (m, 5 H_arom), 2.46 (t, J = 6.8 Hz, 2 H, CH₂), 1.64–1.48 (m, 4 H, 2 CH₂), 0.98 (t, J = 7.2 Hz, 3 H, CH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 162.9, 162.8, 156.7, 135.8, 135.7, 130.6 (2 C), 129.9, 127.8 (2 C), 127.0 (2 C), 126.1 (2 C), 125.4, 113.4, 91.5, 79.6, 29.7, 21.0, 18.2, 12.6.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₂H₂₁N₂: 313.1705; found: 313.1693.

2-[3-(Oct-1-ynyl)phenyl]-4-phenylpyrimidine (4f)

Purification by column chromatography (10% EtOAc–PE) gave 4f as an off-white solid; yield: 614 mg (85%); mp 113.2–115.4 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.82 (d, J = 5.6 Hz, 1 H_arom), 8.51 (d, J = 8.4 Hz, 2 H_arom), 8.23–8.20 (m, 2 H_arom), 7.59 (d, J = 5.6 Hz, 1 H_arom), 7.54–7.52 (m, 5 H_arom), 2.45 (t, J = 7.2 Hz, 2 H, CH₂), 1.67–1.44 (m, 4 H, 2 CH₂), 1.35–1.33 (m, 4 H, 2 CH₂), 0.93 (t, J = 6.8 Hz, 3 H, CH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 164.0, 163.8, 157.7, 136.8, 136.7, 131.6 (2 C), 130.9, 128.8 (2 C), 128.0 (2 C), 127.1 (2 C), 126.4, 114.4, 92.6, 80.6, 31.3, 28.67, 28.63, 22.5, 19.5, 14.0

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₄H₂₅N₂: 341.2018; found: 341.2025.

Methyl (E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylate (6a); Typical Procedure

In a 25 mL round-bottomed flask were charged enaminone 1 (0.41 g, 2.339 mmol), 3-bromobenzimidamide hydrochloride (2; 0.5 g, 2.123 mmol), DMF (2.5 mL), K₂CO₃ (1.02 g, 7.380 mmol), PdCl₂(PPh₃)₂ (50 mg, 0.0712 mmol), and methyl acrylate (5a; 0.22 g, 2.555 mmol) at r.t. Then, the mixture was stirred at 80–85 °C for 4–5 h and the reaction was monitored by TLC (10% EtOAc in PE). After completion of the reaction, the mixture was concentrated under vacuum and the obtained crude product 6a was purified by column chromatography on silica gel (230–400 mesh) using 15% EtOAc–PE; yield: 557 mg (83%); off-white solid; mp 153.2–155.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 5.2 Hz, 1 H_arom), 8.61 (d, J = 8.4 Hz, 2 H_arom), 8.23–8.21 (m, 2 H_arom), 7.79 (d, J = 16.4 Hz, 1 H, trans H), 7.68–7.54 (m, 6 H_arom), 6.56 (d, J = 16.0 Hz, 1 H, trans H), 3.83 (s, OCH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 167.2, 163.8, 163.6, 157.7, 144.2, 139.4, 136.6, 136.3, 131.0, 128.8 (2 C), 128.6 (2 C), 128.1 (2 C), 127.1 (2 C), 118.5, 114.6, 51.6.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₀H₁₇N₂O₂: 317.1290; found: 317.1287.

Ethyl (E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylate (6b)

Purification by column chromatography (15% EtOAc–PE) gave 6b as an off-white solid; yield: 546 mg (78%); mp 106.5–108.7 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 5.2 Hz, 1 H_arom), 8.60 (d, J = 8.4 Hz, 2 H_arom), 8.23–8.20 (m, 2 H_arom), 7.76 (d, J = 16.4 Hz, 1 H, trans H), 7.67 (d, J = 8.4 Hz, 2 H_arom), 7.62 (d, J = 4.8 Hz, 1 H_arom), 7.56–7.53 (m, 3 H_arom), 6.54 (d, J = 16.0 Hz, 1 H, trans H), 4.29 (q, J = 6.8 Hz, 2 H, OCH₂), 1.36 (t, J = 6.8 Hz, 3 H, CH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 166.7, 163.7, 163.6, 157.7, 143.8, 139.3, 136.6, 136.4, 130.9, 128.8 (2 C), 128.6 (2 C), 128.1 (2 C), 127.0 (2 C), 119.0, 114.6, 60.4, 14.2.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₁H₁₉N₂O₂: 331.1447; found: 331.1455.

tert-Butyl (E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylate (6c)

Purification by column chromatography (15% EtOAc–PE) gave 6c as an off-white solid; yield: 608 mg (80%); mp 94.8–97.1 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 5.2 Hz, 1 H_arom), 8.59 (d, J = 8.8 Hz, 2 H_arom), 8.24–8.20 (m, 2 H_arom), 7.68–7.53 (m, 7 H_arom­ and trans H), 6.49 (d, J = 16.0 Hz, 1 H, trans H), 1.55 (s, 9 H, t-C₄H₉).

¹³C NMR (400 MHz, CDCl₃): δ = 166.1, 163.8, 163.8, 157.8 (2 C), 142.9, 139.1, 136.7, 131.0, 128.9 (2 C), 128.6 (2 C), 128.0 (2 C), 127.1 (2 C), 121.0, 114.6, 80.5, 28.1 (3 C).

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₃H₂₃N₂O₂: 359.1760; found: 359.1761.

(E)-4-[3-(4-Phenylpyrimidin-2-yl)phenyl]but-3-en-2-one (6d)

Purification by column chromatography (10% EtOAc–PE) gave 6d as an off-white solid; yield: 497 mg (78%); mp 173.1–175.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 5.6 Hz, 1 H_arom), 8.62 (d, J = 8.4 Hz, 2 H_arom), 8.24–8.21 (m, 2 H_arom), 7.70 (d, J = 8.4 Hz, 1 H_arom), 7.63–7.61 (m, 1 H_arom), 7.57–7.53 (m, 3 H_arom and trans H), 6.83 (d, J = 16.0 Hz, 1 H, trans H), 2.42 (s, 3 H, CH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 198.1, 163.7, 163.5, 157.7, 142.6, 139.6, 136.5, 136.3, 131.0, 128.8 (2 C), 128.6 (2 C), 128.3 (2 C), 127.7, 127.0 (2 C), 114.7, 27.4.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₀H₁₇N₂O: 301.1341; found: 301.1349.

(E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylonitrile (6e)

Purification by column chromatography (20% EtOAc–PE) gave 6e as an off-white solid; yield: 487 mg (81%); mp 204.1–206.4 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 5.6 Hz, 1 H_arom), 8.63 (d, J = 8.0 Hz, 2 H_arom), 8.23–8.21 (m, 2 H_arom), 7.64–7.54 (m, 6 H_arom­), 7.48 (d, J = 16.4 Hz, 1 H, trans H), 6.00 (d, J = 16.8 Hz, 1 H, trans H).

¹³C NMR (400 MHz, CDCl₃): δ = 166.5, 162.9, 162.7, 158.6, 138.4, 138.0, 137.2, 136.1, 131.2, 129.0 (2 C), 128.3 (2 C), 127.9 (2 C), 127.1 (2 C), 123.5, 115.1.

HRMS (ESI): m/z (M + H)⁺ calcd for C₁₉H₁₄N₃: 284.1188; found: 284.1181.

(E)-3-[3-(4-Phenylpyrimidin-2-yl)phenyl]acrylamide (6f)

Purification by column chromatography (25% EtOAc–PE) gave 6f as an off-white solid; yield: 467 mg (73%); mp 195.3–197.6 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.98 (d, J = 5.2 Hz, 1 H_arom), 8.57 (d, J = 8.0 Hz, 2 H_arom), 8.37–8.36 (m, 2 H_arom), 8.04 (d, J = 5.6 Hz, 1 H_arom), 7.76 (d, J = 8.4 Hz, 2 H_arom), 7.62–7.60 (m, 4 H_arom), 7.19 (br, 1 H, NH),7.52 (d, J = 16.4 Hz, 1 H, trans H), 6.76 (d, J = 16 Hz, 1 H, trans H).

¹³C NMR (400 MHz, CDCl₃): δ = 174.7, 162.9, 162.4, 158.2, 149.4, 147.8, 139.4, 135.9, 135.5, 130.9, 128.7 (2 C), 128.1, 127.7, 126.8 (2 C), 118.1, 115.0, 97.7.

HRMS (ESI): m/z (M + H)⁺ calcd for C₁₉H₁₆N₃O: 302.1293; found: 302.1296.

5-Fluoro-3′-(4-phenylpyrimidin-2-yl)biphenyl-3-carbonitrile (8a); Typical Procedure

In a 25 mL round-bottomed flask were charged enaminone 1 (0.41 g, 2.339 mmol), 3-bromobenzimidamide hydrochloride (2; 0.5 g, 2.123 mmol), DMF (2.5 mL), K₂CO₃ (1.02 g, 7.380 mmol), PdCl₂(PPh₃)₂ (50 mg, 0.0712 mmol), and 3-cyano-5-fluorophenylboronic acid (7a; 0.42 g, 2.546 mmol) at r.t. The reaction mixture was then stirred at 80–85 °C for 2 h and the reaction was monitored by TLC (15% EtOAc in PE). After completion of the reaction, the mixture was concentrated under vacuum and the obtained crude product 8a was purified by column chromatography on silica gel (230–400 mesh) using 15% EtOAc–PE; yield: 671 mg (90%); off-white solid; mp 152.5–154.6 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.87 (d, J = 5.2 Hz, 1 H_arom), 8.69 (d, J = 8.0 Hz, 2 H_arom), 8.26–8.23 (m, 2 H_arom), 7.76 (s, 1 H_arom), 7.70 (d, J = 8.4 Hz, 2 H_arom), 7.66 (d, J = 5.2 Hz, 2 H_arom) 7.63–7.55 (m, 3 H_arom), 7.37–7.35 (m, 1 H_arom).

¹³C NMR (400 MHz, CDCl₃): δ = 164.1, 163.7 (d, J = 34.4 Hz, ArCF), 161.2, 157.7 (2 C), 144.4, 139.5, 139.5, 138.3, 136.5, 131.1 (2 C), 129.1, 128.9, 127.1 (2 C), 127.1, 126.75, 126.71, 119.0, 118.8, 115.3, 114.8.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₃H₁₅FN₃: 352.1250; found: 352.1255.

2-(4′-Methoxybiphenyl-3-yl)-4-phenylpyrimidine (8b)

Purification by column chromatography (10% EtOAc–PE) gave 8b as an off-white solid; yield: 610 mg (85%); mp 159.2–161.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 5.6 Hz, 1 H_arom), 8.63 (d, J = 8.4 Hz, 2 H_arom), 8.26–8.23 (m, 2 H_arom), 7.71 (d, J = 8.8 Hz, 2 H_arom), 7.65–7.62 (m, 2 H_arom), 7.60 (d, J = 5.6 Hz, 2 H_arom), 7.57–7.54 (m, 2 H_arom), 7.02 (d, J = 8.8 Hz 2 H_arom), 3.87 (s, 3 H, OCH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 164.3, 163.8, 159.4, 157.7, 142.9, 136.8, 136.0, 132.9, 130.9, 128.8 (2 C), 128.7 (2 C), 128.1 (2 C), 127.1 (2 C), 126.6 (2 C), 116.0, 114.2 (2 C), 55.2.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₃H₁₉N₂O: 339.1497; found: 339.1506.

2-(3′-Methoxybiphenyl-3-yl)-4-phenylpyrimidine (8c)

Purification by column chromatography (10% EtOAc–PE) gave 8c as an off-white solid; yield: 574 mg (80%); mp 158.2–160.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 5.2 Hz, 1 H_arom), 8.65 (d, J = 8.8 Hz, 2 H_arom), 8.26–8.23 (m, 2 H_arom), 7.75 (d, J = 8.0 Hz, 2 H_arom), 7.61 (d, J = 5.6 Hz, 1 H_arom), 7.56–7.54 (m, 3 H_arom), 7.39 (t, J = 8.0 Hz, 1 H_arom), 7.29–7.21 (m, 3 H_arom), 3.89 (s, 3 H, OCH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 164.2, 163.8, 159.9, 157.8 (2C), 143.1, 142.1, 136.9, 130.9, 129.8, 128.9 (2 C), 128.7 (2 C), 127.2 (2 C), 127.1 (2 C), 119.6, 114.4, 113.0, 112.8, 55.3.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₃H₁₉N₂O: 339.1497; found: 339.1503

[3′-(4-Phenylpyrimidin-2-yl)biphenyl-3-yl]methanol (8d)

Purification by column chromatography (20% EtOAc–PE) gave 8d as an off-white solid; yield: 531 mg (74%); mp 123.1–125.7 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 5.6 Hz, 1 H_arom), 8.66 (d, J = 8.8 Hz, 2 H_arom), 8.27–8.24 (m, 2 H_arom), 7.77 (d, J = 8.8 Hz, 2 H_arom), 7.70 (s, 1 H_arom), 7.64–7.61 (m, 2 H_arom), 7.58–7.56 (m, 3 H_arom), 7.48 (t, J = 7.6 Hz, 1 H_arom), 7.39 (d, J = 7.6 Hz, 1 H_arom), 4.80 (s, 2 H, OCH₂).

¹³C NMR (400 MHz, CDCl₃): δ = 163.9, 163.5, 157.3 (2 C), 142.7, 141.1, 140.4, 136.4, 136.3, 130.6 (2 C), 128.6, 128.5, 128.3, 126.8 (2 C), 126.0 (2 C), 125.8, 125.3 (2 C), 114.1, 64.8.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₃H₁₉N₂O: 339.1497; found: 339.1504.

4-Phenyl-2-[4′-(trifluoromethyl)biphenyl-3-yl]pyrimidine (8e)

Purification by column chromatography (15% EtOAc–PE) gave 8e as an off-white solid; yield: 679 mg (85%); mp 188.1–190.3 °C.

¹H NMR (400 MHz, CDCl₃): δ =  8.88 (d, J = 5.2 Hz, 1 H_arom), 8.70 (d, J = 8.4 Hz, 2 H_arom), 8.27–8.25 (m, 2 H_arom), 7.81–7.73 (m, 6 H_arom­), 7.65 (d, J = 5.6 Hz, 1 H_arom), 7.59–7.56 (m, 3 H_arom).

¹³C NMR (400 MHz, CDCl₃): δ =  164.0, 163.9, 157.8 (2 C), 144.1, 141.7, 137.7, 136.8, 131.0 (2 C), 128.9 (2 C), 128.9 (2 C), 127.4 (2 C), 127.3 (2 C), 127.2 (2 C), 125.7, 125.7, 114.6.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₃H₁₆F₃N₂: 377.1266; found: 377.1276

2-(4′-Chlorobiphenyl-3-yl)-4-phenylpyrimidine (8f)

Purification by column chromatography (10% EtOAc–PE) gave 8f as an off-white solid; yield: 544 mg (75%); mp 150.2–152.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.87 (d, J = 5.2 Hz, 1 H_arom), 8.68 (d, J = 8.4 Hz, 2 H_arom), 8.27–8.25 (m, 2 H_arom), 7.72 (d, J = 8.4 Hz, 2 H_arom), 7.63–7.56 (m, 6 H_arom), 7.45 (d, J = 8.0 Hz, 2 H_arom).

¹³C NMR (400 MHz, CDCl₃): δ =  164.1, 163.8, 157.8 (2 C), 141.9, 138.9, 137.1, 136.8, 133.7, 130.9 (2 C), 128.9, 128.9, 128.8, 128.7 (2 C), 128.3, 127.1 (2 C), 127.0 (2 C), 114.5.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₂H₁₆ClN₂: 343.1002; found: 343.1015

2-[3-(2-Methoxypyridin-4-yl)phenyl]-4-phenylpyrimidine (8g)

Purification by column chromatography (25% EtOAc–PE) gave 8g as an off-white solid; yield: 561 mg (78%); mp 126.4–128.5 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.85 (d, J = 5.6 Hz, 1 H_arom), 8.66 (d, J = 8.4 Hz, 2 H_arom), 8.49 (d, J = 2.4 Hz, 1 H_arom), 8.25–8.23 (m, 2 H_arom), 7.89 (d, J = 8.8 Hz, 1 H_arom), 7.68 (d, J = 8.4 Hz, 2 H_arom), 7.61 (d, J = 5.6 Hz, 1 H_arom), 7.56–7.54 (m, 3 H_arom), 6.86 (d, J = 8.8 Hz, 1 H_arom), 4.0 (s, 3 H, OCH₃).

¹³C NMR (400 MHz, CDCl₃): δ = 164.0, 163.7, 163.6, 157.7 (2 C), 145.0 (2 C), 139.8, 137.2, 136.7, 130.8, 129.3, 128.8 (2 C), 128.8 (2 C), 127.0 (2 C), 126.4 (2 C), 114.3, 110.7, 53.4.

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₂H₁₈N₃O: 340.1450; found: 340.1461.

2-(3′,4′-Dichlorobiphenyl-3-yl)-4-phenylpyrimidine (8h)

Purification by column chromatography (10% EtOAc–PE) gave 8h as an off-white solid; yield: 606 mg (76%); mp 121.3–123.7 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.86 (d, J = 5.2 Hz, 1 H_arom), 8.66 (d, J = 8.4 Hz, 2 H_arom), 8.26–8.23 (m, 2 H_arom), 7.76 (d, J = 2.0 Hz, 1 H_arom), 7.69 (d, J = 8.4 Hz, 2 H_arom), 7.64 (d, J = 5.2 Hz, 1 H_arom), 7.56–7.51 (m, 5 H_arom).

¹³C NMR (400 MHz, CDCl₃): δ = 164.1, 163.9, 157.6 (2 C), 155.3, 140.7, 140.5, 137.4, 136.6, 132.9, 131.7, 131.1, 130.7, 130.7 (2 C), 128.9, 128.9, 128.9, 127.2, 127.0, 126.3 (2 C).

HRMS (ESI): m/z (M + H)⁺ calcd for C₂₂H₁₅Cl₂N₂: 377.0612; found: 377.0624.

Acknowledgment

The authors thank Dr. A. K. Roy, Dr. K. V. Raghu, Dr. V. Dahanukar, and the analytical group of Dr. Reddy’s Laboratories, Hyderabad, India for spectral data, and CSIR, Human Resources Development Group, Govt. of India, New Delhi for providing financial assistance [No. 01(2391)/10/EMR-II].

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