Photoinduced Alkylation of Diazines with N-(Acyloxy)phthalimides in the Presence of Triethylamine

Dedicated to Professor Shigeru Yamago on the occasion of his 60^th birthday

Abstract

A photochemical protocol for the alkylation of diazines (pyrimidines, pyrazines, and pyridazines) with N-(acyloxy)phthalimides has been developed. The process is facilitated by the presence of triethylamine under irradiation with 427–390 nm light; this enables rapid cross-coupling reactions to construct a wide range of alkylated diazines.

Diazines (pyrimidines, pyrazines, and pyridazines), six-membered heteroarenes bearing two nitrogen atoms in the ring, are frequently employed as a core of active ingredients for the development of pharmaceutical drugs[1] and crop protection chemicals (Figure [1]).[2] Thus, operationally simple protocols that enable the facile installation of sp³-rich functionalities to diazine scaffolds are in high demand in discovery and process development endeavors.

Alkylation of six-membered electron-deficient heteroarenes such as pyridines and their derivatives with aliphatic carboxylic acids through oxidative decarboxylative generation of alkyl radicals and their addition to heteroarenes, known as the Minisci reaction, has often been adopted as the methodology of choice.[3] [4] [5] [6] The net-oxidative nature of the Minisci process inevitably necessitates the use of stoichiometric amounts of oxidants in the presence of acids. On the other hand, the installation of redox auxiliaries to carboxylic acid moieties offers a means to circumvent the redox constraints on the parent radical sources.[7–23] For example, the utilization of N-(acyloxy)phthalimides,[12] [13] [14] [15] [16] [17] [18] [19] derived from the corresponding carboxylic acids and N-hydroxyphthalimide allows the decarboxylative generation of the alkyl radicals via single-electron reduction, thus rendering the overall processes redox neutral, together with the subsequent radical addition to heteroarenes and oxidative aromatization. In this context, visible light photoredox catalysis has been actively employed to facilitate the desired redox-neutral Minisci-type alkylation of heteroarenes.[16–19] Moreover, N-(acyloxy)phthalimides have been found to function as an acceptor for the formation of electron donor–acceptor (EDA) complexes with various electron donors.[20] [21] [22] [23] As these EDA complexes typically have a charge transfer band in the visible region,[24–28] their photoexcitation under visible light irradiation induces inner-sphere single-electron transfer (SET) within the complex aggregate, allowing for the generation of alkyl radicals and their subsequent engagement in the Minisci-type alkylation of heteroarenes.

While N-(acyloxy)phthalimides have proven to be an incredibly powerful tool for the redox-neutral Minisci-type alkylation of pyridines and their derivatives (e.g., quinolines), their applications to diazines have been limited and sporadic, with only a few exceptions.[29] [30] [31] For example, Phipps and Sigman developed enantioselective alkylation of various diazines with α-amino radicals derived from the corresponding N-(acyloxy)phthalimides under the photoredox and chiral phosphoric acid dual catalysis.[30] Xiao also revealed that this dual catalysis strategy could be extended to the construction of both central and axial chirality through the alkylation of 5-arylpyrimidines with α-amino radicals.[29] In turn, Graham and Noonan reported that the decarboxylative coupling between 1-(methylthio)cyclopropane-1-carboxylic acid and 2,4-dichloropyrimidine could be promoted by using the corresponding N-(acyloxy)phthalimide under photoredox catalysis in the presence of diisopropylethylamine.[31] Herein, we report the development of a photochemical protocol for the intermolecular alkylation of diazines with N-(acyloxy)phthalimides. The reaction conditions require only triethylamine (Et₃N) as the sole additive under irradiation with 427 nm or 390 nm light, resulting in rapid alkylation of diazines with a series of N-(acyloxy)phthalimides. The discovery, reaction optimization, substrate scope, and synthetic applications of the method are described below.

We encountered an unexpected observation during the course of our investigation for the development of a scalable decarboxylative cross-coupling process of N-(acyloxy)phthalimide 1 bearing a 4-tetrahydropyran moiety with 2-chloropyrimidine (2, 5 equiv) (Table [1]). When we screened photoredox catalysts by following the report by Graham and Noonan,[31] we found that the desired cross-coupling reaction could be promoted simply in the presence of Et₃N (1 equiv) in DMSO under irradiation with 427 nm light. Surprisingly, the reaction could be completed within an hour, providing the desired alkylated pyrimidine 3 in 85% NMR yield (78% isolated yield) (entry 1). The reaction of 1 on 5 mmol scale afforded a comparable yield of 3 (74% isolated yield; entry 2). While diisopropylethylamine (i-Pr₂NEt) showed a comparable reactivity (entry 3), the use of bridge-head nitrogen bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO) and quinuclidine resulted in sluggish reaction progress, with incomplete conversion even after irradiation for 18–22 hours (entries 4 and 5). Reducing the amount of Et₃N to 0.5 equivalent did not result in a detrimental impact on the process (entry 6), whereas the use of 0.2 equivalent of Et₃N slightly slowed down the process (entry 7). The use of 3 equivalents of 2-chloropyrimidine (2) resulted in a slight decrease in the product yield (entry 8), whereas the reverse stoichiometry, employing N-(acyloxy)phthalimide 1 (5 equiv) and 2-chloropyrimidine (2; 1 equiv), was detrimental to the process efficiency (entry 9).[32] Interestingly, the process in the absence of Et₃N also took place, albeit at a much slower reaction rate (entry 10). In this case, the reaction likely proceeded via the direct photoexcitation of 1.[33] On the other hand, no reaction occurred without light irradiation (entry 11).

Table 1 Optimization of the Reaction Conditions^a

Entry	Variation from the standard conditions	Time (h)	Conversion of 1 (%)b	Yield of 3 (%)b
1	none	1	>99	85 (78)c
2	1 (5 mmol)	1.5	>99	(74)c
3	i-Pr2NEt instead of Et3N	1.5	>99	79 (68)c
4	DABCO instead of Et3N	22	65	43
5	quinuclidine instead of Et3N	18	77	54
6	Et3N (0.5 equiv)	1	>99	81
7	Et3N (0.2 equiv)	2	>99	70
8	2 (3 equiv)	1	>99	70
9	1 (5 equiv), 2 (1 equiv)	22	>99	53
10	no Et3N	22	74	48
11	no light	22	0	0

^a Reaction conditions: 1 (0.5 mmol), 2 (5 equiv), Et₃N (1 equiv), DMSO (1.5 mL, 0.33 M), irradiation with 427 nm light (Kessil lamp, 40 W), 31–34 °C (ambient temperature monitored by the IR camera), fan cooling, under Ar atmosphere, 1 h.

^{b 1}H NMR yields based on the internal standard.

^c Isolated yields in parentheses.

Contrary to the conventional Minisci-type alkylation of heteroarenes with N-(acyloxy)phthalimides under photoredox catalysis, this photochemical reaction exhibited several unique features: (a) no photocatalyst required, (b) no acid additive needed, and (c) a rapid reaction rate. Motivated by these characteristics, we investigated the scope and limitations of this method. We first explored the compatibility of alkyl groups on N-(acyloxy)phthalimides (Scheme [1]). Regarding secondary alkyl groups, the method is compatible with N-Boc-piperidine and -pyrrolidine moieties (for 4 and 5), as well as several carbocycles, such as cyclohexanes (for 6 and 7), tetrahydronaphthalene (for 8), cyclohexanone (for 9), and 2-adamantane (for 10). We found that the present protocol is also robust enough to efficiently install a series of acyclic and cyclic tertiary alkyl groups, allowing for the construction of a quaternary carbon center (for 11–14). The decarboxylative coupling of glycyrrhetinic acid derivative with 2-chloropyrimidine (2) proceeded in a diastereoselective manner (for 15). The method also proved useful for linking 2-chloropyrimidine (2) with bicylo[2.2.2]octane and bicyclo[1.1.1]pentane[34] at their bridgehead positions (for 16 and 17), although the installation of a cubane moiety displayed lower reactivity (for 18). It should be noted that the alkylation process with a primary alkyl radical was inefficient, resulting in a moderate yield of 19 after a longer reaction time.

Next, the substituent compatibility of pyrimidines was investigated using several N-(acyloxy)phthalimides as the alkylating reagents (Scheme [2]A).[35] [36] As for the effect of an additional alkyl group installed on the 2-chloropyrimidine ring, the reactions with 2-chloro-5-ethylpyrimidine and 2-chloro-4-methylpyrimidine proceeded smoothly to afford 20 and 21, respectively, in good to moderate yields within 4 hours. The present protocol was amenable to functionalize 2-bromopyrimidine (for 22 and 23), 5-bromo-2-methylpyrimidine (for 24–26), and methyl 5-bromopyrimidine-2-carboxylate (for 27), albeit after longer reaction times and with moderate efficiency. The alkylation of methyl pyrimidine-2-carboxylate and pyrimidine-2-carbonitrile resulted in the formation of C4- and C5-regioisomeric mixtures (for 28 and 29).[37] On the other hand, the functionalization of quinazoline occurred selectively at the C4 position over the C2 position, providing 30 in 62% yield.

Furthermore, we also explored the functionalization of other diazines, namely pyrazines[38] [39] [40] and pyridazines (Scheme [2]B,C). The alkylation of 2,6-dichloropyrazine (for 31–33) and 2,3-dichloropyrazine (for 34) proceeded efficiently, whereas the alkylation of 2-chloropyrazine provided a mixture of C3- and C6-adduct 35. The reaction of 2-acetylpyrazine was observed to be sluggish, providing 36 in only 21% yield after 9 hours of irradiation (Scheme [2]B). The functionalization of 3,6-dichloropyridazine with secondary and tertiary alkyl groups proceeded efficiently (for 37–40), while that with 3,6-dichloro-4-methylpyridazine resulted in moderate efficiency (35% yield of 41), presumably due to the steric hindrance from the additional methyl group (Scheme [2]C). Similarly, the installation of a π-electron-withdrawing group resulted in diminished reactivity (for 42).

To gain mechanistic insights into the present photoinduced alkylation of diazines, we conducted several experiments [Scheme [3]; also see the Supporting Information (SI) for more details]. When N-(acyloxy)phthalimide 1 was subjected to the standard reaction conditions, but in the absence of 2-chloropyrimidine (2), a reaction time of 5 hours was required to reach the full conversion of 1, resulting in the formation of alkylated phthalimides 43 and 44 in 57% combined yield, along with phthalimide 45 in 38% yield (Scheme [3]A). It is worth mentioning that recent findings by Bach demonstrated that an N-(acyloxy)phthalimide does not form an EDA aggregate with Et₃N (1 equiv) in MeCN (15 mM).[21] Similarly, our observations did not reveal a noticeable charge-transfer band in the UV-vis spectrum of a 10 mM solution of 1 and Et₃N (1 equiv) in DMSO (Scheme [3]B-i). However, at a higher concentration (100 mM), the EDA interaction between 1 and Et₃N appeared to be more obvious (Scheme [3]B-ii). Based on these findings, we hypothesize that the formation of 43 and 44 (Scheme [3]A) is triggered by the photoexcitation of this EDA aggregate I, leading to SET and subsequent mesolytic fragmentation of the resulting anion radical II, which ultimately generates alkyl radical III (Scheme [3]C). The quantum yield (Φ) of the photochemical reaction between 1 and 2 was determined to be 0.53, suggesting the involvement of productive propagative chain mechanisms alongside inefficient initiation by the photoexcitation of the weak EDA aggregate I.[41] [42] Thus, the resulting alkyl radical III adds to pyrimidine 2 to form the adduct radical IV, which likely serves as an electron donor together with deprotonation to N-(acyloxy)phthalimide 1.[43] This results in the liberation of product 3, with concomitant regeneration of alkyl radical III to propagate the chain, facilitating the rapid alkylation.[44] [45] It should be noted that the present photochemical protocol is not applicable to the alkylation of pyridines (see the SI). This highlights the unique reactivity feature of diazines, which are capable of accepting the addition of nucleophilic alkyl radicals under basic reaction conditions while maintaining redox chain propagation with N-(acyloxy)phthalimides.

Finally, we demonstrated further derivatizations of the alkylated diazines (Scheme [4]). The alkylated 2-chloropyrimidine 3 was amenable to substitution of the C(sp²)–Cl bond with O- and N-based nucleophiles, such as propargyl alcohol (for 46), piperazine (for 47), hydrazine (for 48), and imidazole (for 49). In addition, the cross-coupling reaction with arylboronic acid could be facilitated under Pd-catalyzed reaction conditions, providing 2-arylpyrimidine 50. The iterative installation of two diazines at the bridgehead positions of the bicylo[2.2.2]octane core was also demonstrated (Scheme [4]B). The Pd-catalyzed Suzuki cross-coupling of 16 with phenylboronic acid was first conducted to prepare 2-phenylpyrimidine derivative 51. Subsequent basic hydrolysis of the methoxy carbonyl moiety of 51 afforded carboxylic acid 52, which was then transformed to N-(acyloxy)phthalimide 53 through condensation with N-hydroxyphthalimide. The photoinduced cross-coupling of 53 with 2-chloropyrimidine proceeded smoothly to give bis-pyrimidine adduct 54 in 81% yield. Likewise, the reaction of 53 with 3,6-dichloropyridazine provided pyrimidine–pyridazine hybrid 55.

This work demonstrated a facile photochemical protocol for the alkylation of diazines. Given the broad substrate scope of the present photocatalyst-free protocol in terms of diazines and N-(acyloxy)phthalimides, as well as the rapid reaction rates observed in most of the processes, we view the present method to be viable in various synthetic endeavors.

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on Bruker Avance 400 MHz and Jeol-ECA series 400 MHz spectrometers of samples in CDCl₃ [using TMS (δ = 0.00) for ¹H and CDCl₃ (δ = 77.00) for ¹³C as internal standards] and DMSO-d ₆ [using TMS (δ = 0.00) for ¹H and DMSO-d ₆ (δ = 39.52) for ¹³C as internal standard]. ¹⁹F{H} NMR (376 MHz) spectra were recorded on a Bruker Avance 400 spectrometer of samples in CDCl₃. ¹H NMR yields were measured using 1,1,2,2-tetrachloroethane (Sigma-Aldrich product number 185434) as an internal standard. HRMS was carried out on a Waters Q-Tof Premier mass spectrometer. IR spectra were recorded on a Shimadzu IR Prestige-21 FT-IR spectrometer. Flash chromatography was performed using Merck silica gel 60 with distilled solvents or basic alumina from Sigma-Aldrich (product number: 199443). Gel permeation chromatography (GPC) was performed on LaboACE LC-5060 recycling preparative HPLC. Melting points were recorded on an MPA 100 OptiMelt Automated Melting Point System and are uncorrected. The Kessil PR160 series (λ_max = 440, 427, or 390 nm) were used as the LED light source for the reactions (https://www.kessil.com/photoredox/Products.php). The ambient temperature of the reaction vessel during the photochemical reactions was measured by an infrared camera (FLIR-E6, Teledyne FLIR). Depending on the reaction time, 3–5 points were recorded and the ranges of the lowest and highest temperature were given.

Alkylation of Diazines; General Procedure

The appropriate N-(acyloxy)phthalimide (0.500 mmol, 1.0 equiv), the diazine (2.50 mmol, 5.0 equiv), freshly distilled Et₃N (70 μL, 0.502 mmol, 1.0 equiv), and anhydrous DMSO (1.5 mL) were added to a 25 mL sealed tube containing a magnetic stir bar under an argon atmosphere. The reaction mixture was stirred under irradiation of visible light (Kessil lamp, λ_max = 427 nm, 40 W, unless otherwise stated) with fan cooling. The ambient temperature was measured by an IR camera, indicating 31–34 °C. When the full conversion of the N-(acyl­oxy)phthalimide was confirmed by TLC analysis, the reaction mixture was diluted with EtOAc (40 mL) and washed with H₂O (2 × 40 mL). The aqueous layer was separated and extracted with EtOAc (2 × 40 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to afford a crude residue, which was analyzed by ¹H NMR measurement with 1,1,2,2-tetrachloroethane (84 mg, 52 μL, 0.500 mmol) as an internal standard to calculate the NMR yield(s) of the alkylation product(s). The crude material was then purified by flash column chromatography (silica gel or basic alumina).

2-Chloro-4-(tetrahydro-2H-pyran-4-yl)pyrimidine (3)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (138.6 mg, 0.503 mmol), 2-chloropyrimidine (2; 284.5 mg, 2.484 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (basic alumina, hexane/EtOAc 90:10).

Yield: 78% (82.7 mg, 0.416 mmol); white solid; mp 73–74 °C.

IR (neat): 2953, 2847, 1574 (C=N), 1537 (C=N), 1340, 1190 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.55 (d, J = 5.1 Hz, 1 H), 7.14 (d, J = 5.1 Hz, 1 H), 4.10 (ddd, J = 11.7, 4.2, 2.2 Hz, 2 H), 3.60–3.45 (m, 2 H), 2.95 (tt, J = 10.8, 4.8 Hz, 1 H), 1.90–1.84 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 176.3, 161.4, 159.6, 116.8, 67.5, 42.7, 31.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₂N₂OCl: 199.0638; found: 199.0639.

tert-Butyl 4-(2-Chloropyrimidin-4-yl)piperidine-1-carboxylate (4)

The general procedure was followed, using N-(acyloxy)phthalimide 4′ (163.7 mg, 0.437 mmol), 2-chloropyrimidine (2; 254.6 mg, 2.223 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 72% (102.2 mg, 0.343 mmol); white solid; mp 98–99 °C.

IR (neat): 3051, 2976, 2930, 1682 (C=O), 1572 (C=N), 1539 (C=N), 1427, 1167 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.54 (d, J = 5.1 Hz, 1 H), 7.12 (d, J = 5.1 Hz, 1 H), 4.35–4.18 (m, 2 H), 2.87–2.79 (m, 3 H), 1.95–1.91 (m, 2 H), 1.70 (dddd, J = 13.4, 12.8, 12.4, 4.4 Hz, 2 H), 1.47 (s, 9 H).

¹³C NMR (100 MHz, CDCl₃): δ = 176.3, 161.4, 159.6, 154.6, 117.0, 79.7, 43.8, 43.0, 30.6, 28.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₂₀N₃O₂NaCl: 320.1142; found: 320.1147.

tert-Butyl 2-(2-Chloropyrimidin-4-yl)pyrrolidine-1-carboxylate (5)

The general procedure was followed, using N-(acyloxy)phthalimide 5′ (180.5 mg, 0.501 mmol), 2-chloropyrimidine (2; 294.0 mg, 2.567 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 40% (56.2 mg, 0.195 mmol, 1 h) colorless oil.

IR (neat): 3398, 2976, 1694 (C=O), 1572 (C=N), 1393, 1189 cm^–1.

¹H NMR (400 MHz, CDCl₃) as a mixture of rotamers: δ = 8.60–8.55 (m, 1 H), 7.15 (d, J = 5.2 Hz, 1 H), 4.88 (dd, J = 8.6, 4.3 Hz, 0.4 H), 4.78 (dd, J = 8.6, 4.3 Hz, 0.6 H), 3.65–3.35 (m, 2 H), 2.46–2.32 (m, 1 H), 2.04–1.85 (m, 3 H), 1.47 (s, 3.7 H), 1.26 (s, 5.1 H).

¹³C NMR (100 MHz, CDCl₃) as a mixture of rotamers: δ = 176.3, 175.1, 161.2 (2 C, overlapped), 159.4 (2 C, overlapped), 154.12, 154.05, 116.1, 115.5, 80.2 (2 C, overlapped), 62.0, 61.5, 47.4, 47.1, 33.9, 32.5, 28.4, 28.2, 23.9, 23.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₈N₃O₂NaCl: 306.0985; found: 306.0983.

2-Chloro-4-cyclohexylpyrimidine (6)[46]

The general procedure was followed, using N-(acyloxy)phthalimide 6′ (137.4 mg, 0.503 mmol), 2-chloropyrimidine (2; 285.3 mg, 2.491 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 72% (71.5 mg, 0.364 mmol); colorless oil.

¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 5.1 Hz, 1 H), 7.12 (d, J = 5.1 Hz, 1 H), 2.68 (tt, J = 11.8, 3.4 Hz, 1 H), 2.00–1.91 (m, 2 H), 1.91–1.83 (m, 2 H), 1.80–1.72 (m, 1 H), 1.57–1.45 (m, 2 H), 1.44–1.33 (m, 2 H), 1.32–1.22 (m, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 178.4, 161.1, 159.2, 117.0, 45.7, 31.8, 25.9, 25.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₈N₃O₂NaCl: 306.0985; found: 306.0983.

2-Chloro-4-(4,4-difluorocyclohexyl)pyrimidine (7)

The general procedure was followed, using N-(acyloxy)phthalimide 7′ (157.3 mg, 0.507 mmol), 2-chloropyrimidine (2; 283.5 mg, 2.475 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 90:5:5).

Yield: 67% (78.2 mg, 0.336 mmol); white solid; mp 85–86 °C.

IR (neat): 3440, 2941, 2872, 1574 (C=N), 1535 (C=N), 1344, 1105 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.55 (d, J = 3.6 Hz, 1 H), 7.15 (d, J = 3.6 Hz, 1 H), 2.78 (tt, J = 11.6, 2.1 Hz, 1 H), 2.26–2.20 (m, 2 H), 2.08–2.05 (m, 2 H), 1.95–1.79 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 176.1, 161.4, 159.6, 122.5 (dd, J = 242.7 Hz, 239.8 Hz), 116.9, 43.4 (d, J = 1.7 Hz), 33.3 (dd, J = 25.7 Hz, 23.4 Hz), 27.8 (d, J = 9.9 Hz).

¹⁹F{¹H} NMR (100 MHz, CDCl₃): δ = –92.45 (d, J _F–F = 237.3 Hz), –101.84 (d, J _F–F = 237.3 Hz).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₂₀N₃O₂NaCl: 320.1142; found: 320.1147.

2-Chloro-4-(1,2,3,4-tetrahydronaphthalen-2-yl)pyrimidine (8)

The general procedure was followed, using N-(acyloxy)phthalimide 8′ (160.8 mg, 0.500 mmol), 2-chloropyrimidine (2; 286.1 mg, 2.498 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 62% (75.8 mg, 0.310 mmol); white solid; mp 59–60 °C.

IR (neat): 3017, 2928, 1574 (C=N), 1537 (C=N), 1342, 1186 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.54 (d, J = 5.1 Hz, 1 H), 7.18 (d, J = 5.1 Hz, 1 H), 7.16–7.09 (m, 4 H), 3.22–3.06 (m, 3 H), 3.01–2.88 (m, 2 H), 2.28–2.18 (m, 1 H), 2.01 (dddd, J = 13.2, 11.7, 10.3, 6.4, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 177.3, 161.4, 159.5, 135.6, 135.0, 129.0, 128.9, 126.1, 125.9, 117.3, 42.1, 34.4, 28.8, 28.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₃N₂NaCl: 267.0665; found: 267.0668.

4-(2-Chloropyrimidin-4-yl)cyclohexan-1-one (9)

The general procedure was followed, using N-(acyloxy)phthalimide 9′ (144.2 mg, 0.502 mmol), 2-chloropyrimidine (2; 289.0 mg, 2.523 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 2 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 59% (62.8 mg, 0.298 mmol); white solid; mp 80–81 °C.

IR (neat): 3404, 2957, 1709 (C=O), 1570 (C=N), 1535 (C=N), 1340, 1153 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.57 (d, J = 5.1 Hz, 1 H), 7.19 (d, J = 5.1 Hz, 1 H), 3.15 (tt, J = 11.6, 3.6 Hz, 1 H), 2.55–2.45 (m, 4 H), 2.32 (dddd, J = 13.6, 8.2, 6.2, 3.6, 2 H), 2.06 (dddd, J = 13.6, 12.8, 11.6, 5.6 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 209.4, 175.6, 161.4, 159.7, 117.1, 43.4, 40.3, 31.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₃N₂NaCl: 267.0665; found: 267.0668.

4-[(1r,3r,5r,7r)-Adamantan-2-yl]-2-chloropyrimidine (10)

The general procedure was followed, using N-(acyloxy)phthalimide 10′ (163.0 mg, 0.501 mmol), 2-chloropyrimidine (2; 284.9 mg, 2.487 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 65% (79.6 mg, 0.320 mmol); white solid; mp 126–127 °C.

IR (neat): 2912, 2853, 1572 (C=N), 1531 (C=N), 1346, 1192 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (d, J = 5.2 Hz, 1 H), 7.25 (d, J = 5.2 Hz, 1 H), 3.05–2.99 (m, 1 H), 2.61–2.60 (m, 2 H), 2.02–1.98 (m, 3 H), 1.93–1.89 (m, 2 H), 1.84–1.72 (m, 5 H), 1.66–1.61 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 176.8, 161.3, 158.9, 117.4, 49.8, 38.5, 37.4, 32.3, 30.1, 27.6, 27.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₇N₂NaCl: 271.0978; found: 271.0980.

2-Chloro-4-(tert-pentyl)pyrimidine (11)

The general procedure was followed, using redox active ester 11′ (134.4 mg, 0.514 mmol), 2-chloropyrimidine (2; 284.2 mg, 2.490 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 80% (76.1 mg, 0.412 mmol); colorless oil.

IR (neat): 2966, 1570 (C=N), 1531 (C=N), 1340, 1182 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.51 (d, J = 4.3 Hz, 1 H), 7.23 (d, J = 4.3 Hz, 1 H), 1.75 (q, J = 7.6 Hz, 2 H), 1.31 (s, 6 H), 0.72 (t, J = 7.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 181.1, 161.0, 159.1, 116.2, 41.2, 34.9, 26.3, 8.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₄N₂Cl: 185.0846; found: 185.0837.

2-Chloro-4-(1-methylcyclohexyl)pyrimidine (12)

The general procedure was followed, using N-(acyloxy)phthalimide 12′ (146.5 mg, 0.509 mmol), 2-chloropyrimidine (2; 280.7 mg, 2.451 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 0.5 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 74% (79.9 mg, 0.379 mmol); colorless oil.

IR (neat): 2930, 2857, 1570 (C=N), 1529 (C=N), 1342, 1186 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.51 (d, J = 5.3 Hz, 1 H), 7.25 (d, J = 5.3 Hz, 1 H), 2.13–2.08 (m, 2 H), 1.66–1.53 (m, 4 H), 1.48–1.42 (m, 2 H), 1.41–1.33 (m, 2 H), 1.23 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 181.4, 161.3, 159.2, 116.3, 41.4, 36.2, 28.2, 25.8, 22.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₅N₂NaCl: 233.0821; found: 233.0818.

2-Chloro-4-(3-methyloxetan-3-yl)pyrimidine (13)

The general procedure was followed, using N-(acyloxy)phthalimide 13′ (133.9 mg, 0.511 mmol), 2-chloropyrimidine (2; 284.6 mg, 2.485 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 80:20).

Yield: 62% (56.7 mg, 0.306 mmol); white solid; mp 33–34 °C.

IR (neat): 2967, 2876, 1574 (C=N), 1537 (C=N), 1427, 1342, 1180 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.62 (d, J = 3.3 Hz, 1 H), 7.21 (d, J = 3.3 Hz, 1 H), 5.01 (d, J = 7.9 Hz, 2 H), 4.65 (d, J = 7.9 Hz, 2 H), 1.76 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 176.5, 161.5, 159.8, 115.6, 81.3, 45.3, 24.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₉N₂ONaCl: 207.0301; found: 207.0291.

4-[(3r,5r,7r)-Adamantan-1-yl]-2-chloropyrimidine (14)[18]

The general procedure was followed, using N-(acyloxy)phthalimide 14′ (166.9 mg, 0.513 mmol), 2-chloropyrimidine (2; 295.7 mg, 2.582 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 81% (103.6 mg, 0.417 mmol); white solid; mp 149–150 °C.

¹H NMR (400 MHz, CDCl₃): δ = 8.51 (d, J = 5.2 Hz, 1 H), 7.19 (d, J = 5.2 Hz, 1 H), 2.14–2.11 (m, 3 H), 1.96–1.95 (m, 6 H), 1.82–1.71 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 181.2, 161.2, 159.3, 115.1, 40.9, 39.5, 36.4, 28.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₇N₂NaCl: 271.0978; found: 271.0979.

(4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-2-(2-Chloropyrimidin-4-yl)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-1,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,14b-octadecahydropicen-13(2H)-one (15)

The general procedure was followed, using N-(acyloxy)phthalimide 15′ (153.4 mg, 0.249 mmol), 2-chloropyrimidine (2; 147.5 mg, 1.288 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 76% (103.3 mg, 0.189 mmol, dr >99:1); white solid; mp 161–162 °C.

The presence of another diastereomer was ambiguous based on the ¹H NMR spectra of the crude mixture and the isolated product. The absolute stereo-configuration of the constructed quaternary carbon center of 15 was not determined.

IR (neat): 3393 (O–H), 2970, 2866, 1744 (C=O), 1651, 1568 (C=N), 1338 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.53 (d, J = 5.3 Hz, 1 H), 7.21 (d, J = 5.3 Hz, 1 H), 5.65 (s, 1 H), 3.24–3.22 (m, 1 H), 2.78 (ddd, J = 13.6, 3.6, 3.6 Hz, 1 H), 2.34 (s, 1 H), 2.36–2.26 (m, 1 H), 2.20–2.14 (m, 1 H), 2.16–2.06 (m, 1 H), 2.02–1.91 (m, 1 H), 1.90–1.80 (m, 1 H), 1.72–1.58 (m, 6 H), 1.57–1.48 (m, 2 H), 1.49–1.39 (m, 2 H), 1.37 (s, 3 H), 1.32 (s, 3 H), 1.23–1.18 (m, 1 H), 1.15 (s, 3 H), 1.14 (s, 3 H), 1.09–1.02 (m, 1 H), 1.00 (s, 3 H), 0.97–0.92 (m, 4 H), 0.81 (s, 3 H), 0.72–0.68 (m, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 200.0, 181.5, 168.8, 161.2, 159.5, 128.7, 115.3, 78.7, 61.8, 54.9, 53.4, 46.9, 45.4, 43.4, 41.3, 41.2, 39.1, 37.1, 35.8, 32.8, 32.3, 30.6, 28.5, 28.0, 27.3, 26.4, 26.3, 23.5, 21.6, 18.7, 17.5, 16.3, 15.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₄₇N₂O₂NaCl: 561.3224; found: 561.3207.

Methyl 4-(2-Chloropyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylate (16)

The general procedure was followed, using N-(acyloxy)phthalimide 16′ (181.6 mg, 0.507 mmol), 2-chloropyrimidine (2; 292.4 mg, 2.553 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 90:5:5).

Yield: 80% (113.1 mg, 0.403 mmol); white solid; mp 123–124 °C.

IR (neat): 2951, 2870, 1717 (C=O), 1572 (C=N), 1528 (C=N), 1427, 1344 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 5.2 Hz, 1 H), 7.15 (d, J = 5.2 Hz, 1 H), 3.68 (s, 3 H), 1.93 (s, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 180.0, 177.8, 161.1, 159.4, 115.7, 51.8, 39.2, 38.2, 30.0, 28.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₈N₂O₂Cl: 281.1057; found: 281.1050.

Methyl 3-(2-Chloropyrimidin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (17)

The general procedure was followed, using N-(acyloxy)phthalimide 17′ (78.7 mg, 0.250 mmol), 2-chloropyrimidine (2; 146.4 mg, 1.278 mmol), and Et₃N (35 μL, 0.251 mmol) in DMSO (0.75 mL) under irradiation with 427 nm light (Kessil lamp, 2 × 40 W) at 42–44 °C for 4 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 90:5:5).

Yield: 54% (31.9 mg, 0.134 mmol); white solid; mp 113–114 °C.

IR (neat): 2988, 1734 (C=O), 1574 (C=N), 1537 (C=N), 1339, 1211 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.55 (d, J = 5.0 Hz, 1 H), 7.13 (d, J = 5.0 Hz, 1 H), 3.73 (s, 3 H), 2.44 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 170.1, 169.8, 161.6, 159.5, 116.6, 53.2, 51.9, 41.4, 37.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₁N₂O₂NaCl: 261.0407; found: 261.0400.

Methyl 4-(2-Chloropyrimidin-4-yl)cubane-1-carboxylate (18)

The general procedure was followed, using N-(acyloxy)phthalimide 18′ (177.4 mg, 0.504 mmol), 2-chloropyrimidine (2; 285.0 mg, 2.488 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 390 nm light (Kessil lamp, 40 W) at 30–32 °C for 5 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 90:5:5).

Yield: 17% (24.3 mg, 0.088 mmol); white solid; mp 140–141 °C.

IR (neat): 2999, 1724 (C=O), 1570 (C=N), 1529 (C=N), 1190, 1176 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.54 (d, J = 5.1 Hz, 1 H), 7.09 (d, J = 5.1 Hz, 1 H), 4.33 (s, 6 H), 3.74 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.5, 172.0, 161.8, 159.3, 115.6, 59.5, 56.1, 51.6, 48.3, 46.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₁N₂O₂NaCl: 297.0407; found: 297.0404.

2-Chloro-4-(4-phenylbutyl)pyrimidine (19)

The general procedure was followed, using N-(acyloxy)phthalimide 19′ (162.1 mg, 0.501 mmol), 2-chloropyrimidine (2; 285.2 mg, 2.490 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 22 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 30% (27.5 mg, 0.112 mmol); colorless oil.

IR (neat): 3026, 2934, 2859, 1635, 1574 (C=N), 1538 (C=N), 1339, 1182 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 5.1 Hz, 1 H), 7.29–7.24 (m, 2 H), 7.20–7.15 (m, 3 H), 7.06 (d, J = 5.1 Hz, 1 H), 2.77 (t, J = 7.4 Hz, 2 H), 2.65 (t, J = 7.4 Hz, 2 H), 1.82–1.65 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.4, 161.2, 159.0, 141.9, 128.3 (2 C, overlapped), 125.8, 118.6, 37.4, 35.5, 31.0, 28.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₅N₂NaCl: 269.0821; found: 269.0820.

2-Chloro-5-ethyl-4-(tetrahydro-2H-pyran-4-yl)pyrimidine (20)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (139.4 mg, 0.506 mmol), 2-chloro-5-ethylpyrimidine (376.3 mg, 2.639 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 4 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 80:20).

Yield: 63% (72.3 mg, 0.319 mmol); colorless oil.

IR (neat): 2959, 2845, 1564 (C=N), 1541 (C=N), 1408, 1350 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.34 (s, 1 H), 4.10 (ddd, J = 12.0, 4.4, 2.4 Hz, 2 H), 3.54 (ddd, J = 12.0, 12.0, 2.0 Hz, 2 H), 3.07 (tt, J = 11.7, 4.0 Hz, 1 H), 2.68 (q, J = 7.6 Hz, 2 H), 2.12 (dddd, J = 13.0, 12.0, 11.7, 4.4 Hz, 2 H), 1.64–1.57 (m, 2 H), 1.26 (t, J = 7.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.3, 159.0, 158.9, 132.0, 67.5, 38.6, 30.8, 21.7, 14.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₇N₂ONaCl: 275.0927; found: 275.0926.

2-Chloro-4-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrimidine (21)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (137.5 mg, 0.499 mmol), 2-chloro-4-methylpyrimidine (197.7 mg, 1.537 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 4 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 42% (44.7 mg, 0.209 mmol); white solid; mp 103–104 °C.

IR (neat): 2964, 2845, 1587 (C=N), 1526 (C=N), 1115, 1084 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 6.98 (s, 1 H), 4.09 (ddd, J = 11.6, 4.0, 2.4 Hz, 2 H), 3.60–3.44 (m, 2 H), 2.89 (tt, J = 10.7, 4.5 Hz, 1 H), 2.52 (s, 3 H), 1.90–1.79 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.6, 170.7, 160.8, 116.2, 67.5, 42.5, 31.2, 24.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₃N₂ONaCl: 235.0614; found: 235.0618.

2-Bromo-4-(tetrahydro-2H-pyran-4-yl)pyrimidine (22)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (139.0 mg, 0.505 mmol), 2-bromopyrimidine (394.4 mg, 2.499 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 7 h. Purification was carried out by flash column chromatography (basic alumina, hexane/EtOAc 90:10).

Yield: 47% (57.8 mg, 0.237 mmol); white solid; mp 81–82 °C.

IR (neat): 2968, 2947, 2847, 1547 (C=N), 1572 (C=N), 1532 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 5.1 Hz, 1 H), 7.19 (d, J = 5.1 Hz, 1 H), 4.10 (ddd, J = 11,6, 4.4, 2.0 Hz, 2 H), 3.52 (ddd, J = 11.6, 9.6, 4.0 Hz, 2 H), 2.94 (tt, J = 11.2, 4.5 Hz, 1 H), 1.96–1.79 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 176.1, 159.3, 153.1, 117.2, 67.4, 42.6, 31.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₁N₂ONaBr: 264.9952; found: 264.9952.

4-(2-Bromopyrimidin-4-yl)cyclohexan-1-one (23)

The general procedure was followed, using N-(acyloxy)phthalimide 9′ (143.5 mg, 0.495 mmol), 2-bromopyrimidine (397.0 mg, 2.497 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 9 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 43% (54.3 mg, 0.213 mmol); white solid; mp 94–95 °C.

IR (neat): 2955, 1705 (C=O), 1556 (C=N), 1531 (C=N), 1337 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 5.1 Hz, 1 H), 7.22 (d, J = 5.1 Hz, 1 H), 3.16 (tt, J = 11.6, 3.6 Hz, 1 H), 2.62–2.43 (m, 4 H), 2.32 (dddd, 13.2, 6.4, 6.4, 3.6 Hz, 2 H), 2.10 (dddd, 13.2, 12.9, 11.6, 5.6 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 209.4, 175.5, 159.5, 153.2, 117.5, 43.4, 40.3, 31.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₁N₂ONaBr: 276.9952; found: 276.9949.

5-Bromo-2-methyl-4-(tetrahydro-2H-pyran-4-yl)pyrimidine (24)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (139.0 mg, 0.505 mmol), 5-bromo-2-methylpyrimidine (428.0 mg, 2.474 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 6 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 59% (75.6 mg, 0.296 mmol); white solid; mp 41–42 °C.

IR (neat): 2955, 2920, 2839, 1557(C=N), 1528(C=N), 1425, 1125, 1020 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 4.09 (ddd, J = 12.2, 4.8, 2.0 Hz, 2 H), 3.56 (ddd, J = 12.2, 12.2, 2.0 Hz, 2 H), 3.32 (tt, J = 11.6, 4.0 Hz, 1 H), 2.66 (s, 3 H), 2.02 (dddd, J = 13.1, 12.2, 11.6, 4.8 Hz, 2 H), 1.72 (dddd, J = 13.1, 4.0, 2.0, 2.0 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 169.2, 166.7, 158.3, 117.6, 67.6, 40.9, 30.0, 25.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₃N₂ONaBr: 279.0109; found: 279.0110.

4-(5-Bromo-2-methylpyrimidin-4-yl)cyclohexan-1-one (25)

The general procedure was followed, using N-(acyloxy)phthalimide 9′ (121.7 mg, 0.424 mmol), 5-bromo-2-methylpyrimidine (361.9 mg, 2.092 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 9 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 61% (69.7 mg, 0.259 mmol); white solid; mp 87–88 °C.

IR (neat): 3053, 2953, 2872, 1714 (C=O), 1557 (C=N), 1528 (C=N), 1423 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.63 (s, 1 H), 3.54 (tt, J = 9.6, 4.7 Hz, 1 H), 2.65 (s, 3 H), 2.63–2.44 (m, 4 H), 2.22–2.08 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 210.2, 169.2, 166.7, 158.4, 117.7, 41.4, 40.4, 30.1, 25.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₄N₂OBr: 269.0290; found: 269.0275.

5-Bromo-2-methyl-4-(3-methyloxetan-3-yl)pyrimidine (26)

The general procedure was followed, using N-(acyloxy)phthalimide 13′ (65.4 mg, 0.250 mmol), 5-bromo-2-methylpyrimidine (212.9 mg, 1.230 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 9 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 95:4:1).

Yield: 51% (31.1 mg, 0.127 mmol); colorless oil.

IR (neat): 2965, 2874, 1555 (C=N), 1418, 1028, 979 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60 (s, 1 H), 5.17 (d, J = 6.3 Hz, 2 H), 4.57 (d, J = 6.3 Hz, 2 H), 2.66 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 169.8, 166.6, 159.2, 114.8, 80.4, 46.6, 25.3, 24.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₂N₂OBr: 243.0133; found: 243.0129.

Methyl 5-Bromo-4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2-carboxylate (27)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (139.3 mg, 0.506 mmol), methyl 5-bromopyrimidine-2-carboxylate (547.4 mg, 2.822 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 7 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 40% (60.7 mg, 0.201 mmol); white solid; mp 102–103 °C.

IR (neat): 2955, 2847, 1744 (C=O), 1550 (C=N), 1416, 1201, 1163 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.88 (s, 1 H), 4.12 (ddd, J = 12.0, 4.7, 1.8 Hz, 2 H), 4.04 (s, 3 H), 3.58 (ddd, J = 12.0, 12.0, 2.3 Hz, 2 H), 3.44 (tt, J = 11.8, 3.7 Hz, 1 H), 2.12 (dddd, J = 13.4, 12.0, 11.8, 4.7 Hz, 2 H), 1.80–1.75 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 163.5, 159.2, 154.9, 123.1, 67.4, 53.4, 41.3, 29.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₃N₂O₃NaBr: 323.0007; found: 323.0007.

Methyl (tetrahydro-2H-pyran-4-yl)pyrimidine-2-carboxylates 28-C₄ and 28-C₅

The general procedure was followed, using N-(acyloxy)phthalimide 1 (72.2 mg, 0.262 mmol), methyl pyrimidine-2-carboxylate (169.1 mg, 1.224 mmol), and Et₃N (35 μL, 0.251 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 4 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10) followed by GPC; this gave 28-C₄ (21%) and 28-C₅ (6%).

Methyl 4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2-carboxylate (28-C₄)

Yield: 21% (12.2 mg, 0.055 mmol); colorless oil.

IR (neat): 3053, 2953, 2849, 1744 (C=O), 1566 (C=N), 1319, 1155 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 5.2 Hz, 1 H), 7.35 (d, J = 5.2 Hz, 1 H), 4.12 (ddd, J = 11.4, 4.8, 2.0 Hz, 2 H), 4.07 (s, 3 H), 3.55 (ddd, J = 11.4, 11.4, 2.9 Hz, 2 H), 3.11 (tt, J = 11.5, 4.3 Hz, 1 H), 1.98–1.82 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.2, 164.1, 157.9, 156.5, 119.9, 67.6, 53.5, 43.0, 31.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₅N₂O₃: 223.1083; found: 223.1081.

Methyl 5-(tetrahydro-2H-pyran-4-yl)pyrimidine-2-carboxylate (28-C₅)

Yield: 6% (3.4 mg, 0.015 mmol); colorless oil.

IR (neat): 3010, 2957, 1738 (C=O), 1564(C=N), 1329, 1163 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.80 (s, 2 H), 4.13 (ddd, J = 11.6, 4.4, 2.0 Hz, 2 H), 4.07 (s, 3 H), 3.56 (ddd, J = 11.6, 11.6, 3.5 Hz, 2 H), 2.93 (tt, J = 10.9, 5.0 Hz, 1 H), 1.93–1.81 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 163.7, 156.4, 154.9, 140.5, 67.7, 53.5, 37.1, 32.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₅N₂O₃: 223.1083; found: 223.1081.

Pyrimidine-2-carbonitriles 29-C₄ and 29-C₅

The general procedure was followed, using N-(acyloxy)phthalimide 1 (137.6 mg, 0.499 mmol), 2-cyanopyrimidine (269.0 mg, 2.559 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 4 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 80:20). Two fractions containing 29-C₄ and 29-C₅ in different ratios were obtained:

Fraction 1: overall yield: 37.8 mg (29-C₄ /29-C₅ 88:12); white solid.

Fraction 2: overall yield: 12.0 mg (29-C₄ /29-C₅ 13:87); white solid.

Yield (29-C₄ ): 37% (0.186 mmol); yield (29-C₅ ): 15% (0.078 mmol).

4-(Tetrahydro-2H-pyran-4-yl)pyrimidine-2-carbonitrile (29-C₄)

IR (neat): 3458, 2953, 2847, 1574 (C=N), 1537 (C=N), 1435, 1381 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.76 (d, J = 5.2 Hz, 1 H), 7.40 (d, J = 5.2 Hz, 1 H), 4.11 (ddd, J = 11.6, 3.3, 3.1 Hz, 2 H), 3.55 (ddd, J = 11.6, 8.6, 6.4 Hz, 2 H), 3.01 (tt, J = 9.0, 6.0 Hz, 1 H), 1.93–1.80 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 174.4, 158.0, 145.0, 120.9, 115.7, 67.4, 42.6, 31.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₂N₃O: 190.0980; found: 190.0980.

5-(Tetrahydro-2H-pyran-4-yl)pyrimidine-2-carbonitrile (29-C₅)

IR (neat): 3431, 2974, 2849, 1547(C=N), 1418 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.72 (s, 2 H), 4.13 (ddd, J = 11.6, 4.4, 2.1 Hz, 2 H), 3.59–3.51 (m, 2 H), 2.92 (tt, J = 10.4, 5.8 Hz, 1 H), 2.02–1.74 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.7, 143.5, 141.1, 115.6, 67.6, 37.3, 32.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₂N₃O: 190.0980; found: 190.0980.

4-(Tetrahydro-2H-pyran-4-yl)quinazoline (30-C₄) and 2-(Tetrahydro-2H-pyran-4-yl)quinazoline (30-C₂)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (138.1.2 mg, 0.502 mmol), quinazoline (331.5 mg, 2.547 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 3 h. Purification was carried out by flash column chromatography (silica gel, hexane/ EtOAc­/CH₂Cl₂ 90:5:5); this provided a mixture of C₄/C₂-regioisomers; overall yield: 62% (65.4 mg, 0.305 mmol; C₄/C₂ 96:4). The C₄/C₂-ratio was determined by the ¹H NMR spectrum (see SI, Figure S4). The major regioisomer 30-C₄ was isolated by GPC.

4-(Tetrahydro-2H-pyran-4-yl)quinazoline (30-C₄)

White solid; mp 109–110 °C.

IR (neat): 3040, 2957, 2860, 1614, 1557(C=N), 1499 (C=N), 1362, 1125 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.28 (s, 1 H), 8.18 (dd, J = 8.5, 1.2 Hz, 1 H), 8.07 (dd, J = 8.5, 1.4 Hz, 1 H), 7.89 (ddd, J = 8.5, 6.9, 1.4 Hz, 1 H), 7.66 (ddd, J = 8.5, 6.9, 1.2 Hz, 1 H), 4.17 (ddd, J = 11.7, 4.3, 2.1 Hz, 2 H), 3.82 (tt, J = 11.6, 3.7 Hz, 1 H), 3.69 (ddd, J = 12.7, 11.7, 2.0 Hz, 2 H), 2.23 (dddd, J = 13.7, 12.7, 11.6, 4.3 Hz, 2 H), 1.91–1.83 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.7, 154.8, 150.2, 133.4, 129.5, 127.5, 123.7, 123.1, 67.9, 38.6, 31.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₄N₂ONa: 237.1004; found: 237.1005.

3,5-Dichloro-2-(tetrahydro-2H-pyran-4-yl)pyrazine (31)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (140.8 mg, 0.511 mmol), 2,6-dichloropyrazine (380.4 mg, 2.553 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 7 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 65% (77.2 mg, 0.332 mmol); white solid; mp 86–87 °C.

IR (neat): 3053, 2961, 2849, 1516 (C=N), 1420, 1301 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.48 (s, 1 H), 4.11 (ddd, J = 11.6, 4.4, 1.8 Hz, 2 H), 3.58 (ddd, J = 12.2, 12.0, 2.4 Hz, 2 H), 3.39 (tt, J = 11.6, 3.8 Hz, 1 H), 1.97 (dddd, J = 13.2, 12.2, 11.6, 4.4 Hz, 2 H), 1.80–1.75 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 155.7, 146.1, 144.8, 141.9, 67.7, 38.7, 30.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁N₂OCl₂: 233.0248; found: 233.0240.

4-(3,5-Dichloropyrazin-2-yl)cyclohexan-1-one (32)

The general procedure was followed, using N-(acyloxy)phthalimide 9′ (145.2 mg, 0.506 mmol), 2,6-dichloropyrazine (376.7 mg, 2.529 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 3 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 80:20).

Yield: 48% (59.1 mg, 0.243 mmol); white solid; mp 96–97 °C.

IR (neat): 2963, 2945, 2899, 1709 (C=O), 1421, 1153 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.47 (s, 1 H), 3.62 (tt, J = 11.2, 3.7 Hz, 1 H), 2.63–2.46 (m, 4 H), 2.30–2.19 (m, 2 H), 2.19–2.03 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 209.8, 155.3, 146.2, 145.1, 141.9, 40.5, 39.2, 30.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₁N₂OCl₂: 245.0248; found: 245.0240.

3,5-Dichloro-2-(3-methyloxetan-3-yl)pyrazine (33)

The general procedure was followed, using N-(acyloxy)phthalimide 13′ (64.1 mg, 0.245 mmol), 2,6-dichloropyrazine (188.6 mg, 1.266 mmol), and Et₃N (35 μL, 0.251 mmol) in DMSO (0.75 mL) under irradiation with 427 nm light (Kessil lamp, 2 × 40 W) at 40–42 ℃ for 9 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 41% (21.8 mg, 0.100 mmol); colorless oil.

IR (neat): 2965, 2876, 1508 (C=N), 1420, 1311, 1292, 1144 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (s, 1 H), 5.13 (d, J = 6.3 Hz, 2 H), 4.59 (d, J = 6.3 Hz, 2 H), 1.82 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.1, 145.5, 144.7, 141.6, 80.2, 44.5, 24.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₉N₂OCl₂: 219.0092; found: 219.0087.

2,3-Dichloro-5-(tetrahydro-2H-pyran-4-yl)pyrazine (34)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (136.8 mg, 0.497 mmol), 2,3-dichloropyridazine (385.0 mg, 2.586 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 2 × 40 W) at 40–43 °C for 4 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 90:5:5).

Yield: 68% (79.2 mg, 0.340 mmol); colorless oil.

IR (neat): 2970, 2924, 1643, 1537(C=N), 1450 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.20 (s, 1 H), 4.10 (ddd, J = 11.6, 4.4, 2.1 Hz, 2 H), 3.54 (ddd, J = 12.7, 11.6, 2.8 Hz, 2 H), 3.01 (tt, J = 11.2, 4.6 Hz, 1 H), 2.07–1.82 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.7, 148.3, 142.3, 141.4, 67.7, 39.2, 30.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁N₂OCl₂: 233.0248; found: 233.0241.

(Tetrahydro-2H-pyran-4-yl)pyrazines 35-C₃ and 35-C₆

The general procedure was followed, using N-(acyloxy)phthalimide 1 (139.8 mg, 0.508 mmol), 2-chloropyrazine (278.4 mg, 2.431 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 3 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

2-Chloro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (35-C₃)

Yield: 44% (44.1 mg, 0.224 mmol); colorless oil.

IR (neat): 3049, 2955, 2843, 1522 (C=N), 1445, 1394, 1123, 1089 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.47 (d, J = 2.5 Hz, 1 H), 8.22 (d, J = 2.5 Hz, 1 H), 4.12 (ddd, J = 11.3, 4.8, 1.8 Hz, 2 H), 3.59 (ddd, J = 12.1, 11.3, 2.1 Hz, 2 H), 3.42 (tt, J = 11.6, 3.7 Hz, 1 H), 2.00 (dddd, J = 13.6, 12.1, 11.6, 4.8 Hz, 2 H), 1.85–1.75 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.7, 148.3, 142.3, 141.4, 67.7, 39.2, 30.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₁N₂OClNa: 221.0458; found: 221.0428.

2-Chloro-6-(tetrahydro-2H-pyran-4-yl)pyrazine (35-C₆)

Yield: 23% (23.4 mg, 0.117 mmol); colorless oil.

IR (neat): 2953, 2920, 2845, 1516 (C=N), 1402, 1386, 1178 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (s, 1 H), 8.39 (s, 1 H), 4.11 (ddd, J = 11.7, 4.5, 2.1 Hz, 2 H), 3.54 (ddd, J = 11.7, 11.6, 2.6 Hz, 2 H), 3.00 (tt, J = 11.6, 4.2 Hz, 1 H), 2.16–1.78 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 148.8, 142.4, 140.5, 67.7, 40.7, 31.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₁N₂OClNa: 221.0458; found: 221.0422.

1-[5-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yl]ethan-1-one (36)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (137.2 mg, 0.498 mmol), 1-(pyrazin-2-yl)ethan-1-one (315.9 mg, 2.587 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 9 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 21% (20.1 mg, 0.104 mmol); colorless oil.

IR (neat): 2953, 2845, 1697(C=O), 1572 (C=N), 1361 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.16 (s, 1 H), 8.53 (s, 2 H), 4.13 (ddd, J = 11.4, 3.2 Hz, 2 H), 3.63–3.53 (m, 2 H), 3.11 (tt, J = 11.7, 3.9 Hz, 1 H), 2.71 (s, 3 H), 2.05–1.93 (m, 2 H), 1.92–1.84 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 199.2, 162.9, 145.9, 142.8, 141.7, 67.7, 41.4, 31.6, 25.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₄N₂O₂Na: 229.0953; found: 229.0950.

3,6-Dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridazine (37)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (139.4 mg, 0.506 mmol), 3,6-dichloropyridazine (370.0 mg, 2.484 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 3 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 77% (90.6 mg, 0.386 mmol); white solid; mp 119–120 °C.

IR (neat): 3051, 2957, 2845, 1556 (C=N), 1387, 1346 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.38 (s, 1 H), 4.13 (ddd, J = 12.0, 4.4, 1.2 Hz, 2 H), 3.61–3.55 (m, 2 H), 3.15 (tt, J = 11.9, 2.4 Hz, 1 H), 1.92–1.84 (m, 2 H), 1.79–1.69 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.4, 156.3, 146.5, 127.2, 67.5, 37.5, 31.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₀N₂OCl₂Na: 255.0068; found: 255.0069.

4-(3,6-Dichloropyridazin-4-yl)cyclohexan-1-one (38)

The general procedure was followed, using N-(acyloxy)phthalimide 9′ (142.9 mg, 0.497 mmol), 3,6-dichloropyridazine (373.3 mg, 2.506 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 4 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 80:20).

Yield: 74% (90.2 mg, 0.368 mmol); white solid; mp 129–130 °C.

IR (neat): 2983, 2945, 1717 (C=O), 1564 (C=N), 1349, 1139 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.40 (s, 1 H), 3.40 (tt, J = 12.1, 3.1 Hz, 1 H), 2.63–2.55 (m, 4 H), 2.39–2.30 (m, 2 H), 1.97–1.78 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 208.2, 156.3, 146.1 (2 C, overlapped), 126.9, 40.5, 38.3, 31.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₀N₂OCl₂Na: 255.0068; found: 255.0069.

3,6-Dichloro-4-(3-methyloxetan-3-yl)pyridazine (39)

The general procedure was followed, using N-(acyloxy)phthalimide 13′ (65.9 mg, 0.252 mmol), 3,6-dichloropyridazine (194.5 mg, 1.306 mmol), and Et₃N (35 μL, 0.251 mmol) in DMSO (0.75 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 8 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 55% (30.4 mg, 0.139 mmol); white solid; mp 105–106 °C.

IR (neat): 3044, 2960, 2876, 1566 (C=N), 1454, 1337 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.15 (s, 1 H), 5.03 (d, J = 6.3 Hz, 2 H), 4.62 (d, J = 6.3 Hz, 2 H), 1.85 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 156.3, 154.3, 146.9, 126.9, 80.4, 43.0, 25.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₉N₂OCl₂: 219.0092; found: 219.0086.

Methyl 4-(3,6-dichloropyridazin-4-yl)bicyclo[2.2.2]octane-1-carboxylate (40)

The general procedure was followed, using N-(acyloxy)phthalimide 16′ (72.1 mg, 0.202 mmol), 3,6-dichloropyridazine (151.0 mg, 1.014 mmol), and Et₃N (28 μL, 0.201 mmol) in DMSO (0.6 mL) under irradiation with 427 nm light (Kessil lamp, 2 × 40 W) at 41–44 °C for 6 h. Purification was carried out by flash column chromatography (silica gel, hexane/acetone 95:5).

Yield: 56% (35.7 mg, 0.113 mmol); white solid; mp 113–114 °C.

IR (neat): 3054, 2951, 2874, 2305, 1720 (C=O), 1556 (C=N), 1342 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.39 (s, 1 H), 3.69 (s, 3 H), 2.10–2.06 (m, 6 H), 1.98–1.94 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 177.3, 156.4, 155.7, 149.3, 128.2, 51.9, 38.3, 36.1, 27.8, 27.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₇N₂O₂Cl₂: 219.0092; found: 315.0665.

3,6-Dichloro-4-methyl-5-(tetrahydro-2H-pyran-4-yl)pyridazine (41)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (109.4 mg, 0.397 mmol), 3,6-dichloro-4-methylpyridazine (374.2 mg, 2.295 mmol), and Et₃N (60 μL, 0.430 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 3 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 80:20).

Yield: 35% (34.1 mg, 0.139 mmol); white solid; mp 114–115 °C.

IR (neat): 2957, 2841, 1516 (C=N), 1296, 1246 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.14 (ddd, J = 12.2, 4.0, 1.3 Hz, 2 H), 3.55–3.49 (m, 3 H), 2.57 (s, 3 H), 2.39–2.50 (m, 2 H), 1.55–1.59 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.3, 156.2, 142.6, 138.3, 68.1, 38.8, 28.1, 17.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₂N₂OCl₂Na: 269.0224; found: 269.0223.

Methyl 5-(tetrahydro-2H-pyran-4-yl)pyridazine-4-carboxylate (42)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (138.5mg, 0.503 mmol), methyl pyridazine-4-carboxylate (349.4 mg, 2.529 mmol), and Et₃N (70 μL, 0.502 mmol) in DMSO (1.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 22 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 80:20).

Yield: 21% (22.5 mg, 0.106 mmol); white solid; mp 87–88 °C.

IR (neat): 2957, 2850, 1734 (C=O), 1555 (C=N), 1437, 1117 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.41 (s, 1 H), 9.35 (s, 1 H), 4.12 (ddd, J = 11.8, 4.4, 1.2 Hz, 2 H), 4.00 (s, 3 H), 3.78 (tt, J = 12.0, 3.6 Hz, 1 H), 3.58 (ddd, J = 11.8, 11.8, 2.4 Hz, 2 H), 1.93 (dddd, J = 12.6, 12.0, 11.8, 4.4 Hz, 2 H), 1.82–1.75 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 165.0, 151.3, 149.4, 144.0, 126.4, 67.8, 53.0, 35.5, 32.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₁₅N₂O₃: 223.1085; found: 223.1085.

(Tetrahydro-2H-pyran-4-yl)isoindoline-1,3-diones 43 and 44

N-(Acyloxy)phthalimide 1 (1.816 mmol, 1.0 equiv), freshly distilled Et₃N (0.26 mL, 1.865 mmol, 1.0 equiv), and anhydrous DMSO (5.5 mL) were added to a 25 mL sealed tube containing a magnetic stir bar under an argon atmosphere. The reaction mixture was stirred with irradiation of visible light (Kessil lamp, λ_max = 427 nm, 40 W). The ambient temperature was measured by an IR camera, indicating 31–34 °C. Full conversion of N-(acyloxy)phthalimide 1 was confirmed by TLC analysis within 5 h. Then the reaction mixture was diluted with EtOAc­ (40 mL) and washed with H₂O (2 × 40 mL). The aqueous layer was separated and extracted with EtOAc (2 × 40 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to afford a crude residue, which was analyzed by ¹H NMR measurement with 1,1,2,2-tetrachloroethane (30.5 mg, 0.181 mmol) as an internal standard to calculate the NMR yields of the products (43, 27%; 44, 30%; 45, 38%). The crude material was then purified by flash column chromatography (silica gel) and GPC.

4-(Tetrahydro-2H-pyran-4-yl)isoindoline-1,3-dione (43)

Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10), followed by GPC.

Yield: 9% (52.3 mg, 0.161 mmol); white solid; mp 179–180 °C.

IR (neat): 3412 (N–H), 1766 (C=O), 1421, 1069 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.73 (dd, J = 7.2, 2.0 Hz, 1 H), 7.69 (dd, J = 7.2, 7.2 Hz, 1 H), 7.65 (dd, J = 7.2, 2.0 Hz, 1 H), 7.56 (br s, NH), 4.10 (ddd, J = 11.6, 5.2, 1.6 Hz, 2 H), 4.00 (tt, J = 11.7, 4.2 Hz, 1 H), 3.64 (ddd, J = 11.6, 11,2, 2.4 Hz, 2 H), 1.92–1.76 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.5, 167.5, 146.5, 134.6, 133.3, 132.2, 128.2, 121.5, 68.1, 35.3, 32.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄NO₃: 232.0974; found: 232.0971.

5-(Tetrahydro-2H-pyran-4-yl)isoindoline-1,3-dione (44)

The general procedure was followed, using N-(acyloxy)phthalimide 1 (503.2 mg, 1.816 mmol) and Et₃N (0.26 mL, 1.865 mmol) in DMSO (5.5 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–34 °C for 5 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 15% (88.1 mg, 0.272 mmol); white solid; mp 189–190 °C.

IR (neat): 3418 (N–H), 2855, 1732 (C=O), 1435 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.81 (d, J = 7.8 Hz, 1 H), 7.79 (br s, NH), 7.74 (s, 1 H), 7.61 (dd, J = 7.8, 1.6 Hz, 1 H), 4.12 (ddd, J = 10.9, 4.4, 1.7 Hz, 2 H), 3.56 (ddd, J = 11.5, 10.9, 2.8 Hz, 2 H), 2.94 (tt, J = 11.2, 4.9 Hz, 1 H), 1.92–1.77 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 168.0, 167.8, 153.3, 133.3, 132.9, 130.8, 123.9, 121.9, 68.0, 42.0, 33.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄NO₃: 232.0974; found: 232.0971.

X-ray crystallography: Recrystallization from MeOH gave a single crystal of 44, which was analyzed by X-ray crystallographic analysis. CCDC 2265818 (44) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

2-(Prop-2-yn-1-yloxy)-4-(tetrahydro-2H-pyran-4-yl)pyrimidine (46)

To a 25 mL sealed tube containing a magnetic stir bar, propargyl alcohol (0.30 mL, 5.20 mmol, 5.0 equiv) in THF (6.0 mL) was treated with NaH (60% w/w dispersion in mineral oil; 123.4 mg, 3.085 mmol, 3.0 equiv) at 0 °C; the suspension was stirred for 15 min at the same temperature. To the suspension was added a solution of 3 (200.7 mg, 1.013 mmol, 1.0 equiv) in THF (4.0 mL) and the reaction mixture was stirred at 50 °C for 3 h. The reaction was quenched with H₂O and the organic materials were extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give a crude residue, which was purified by flash column chromatography (silica gel, hexane/EtOAc 90:10); this provided 46.

Yield: 87% (191.8 mg, 0.880 mmol); colorless oil.

IR (neat): 3287(alkyne C-H), 3254, 2951, 2847, 2124 (C≡C), 1584 (C=N), 1408, 1350, 1024 (C–O) cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 5.1 Hz, 1 H), 6.86 (d, J = 5.1 Hz, 1 H), 5.02 (d, J = 2.4 Hz, 2 H), 4.09 (ddd, J = 11.6, 4.8, 2.4 Hz, 2 H), 3.53 (ddd, J = 11.6, 9.2, 3.6 Hz, 2 H), 2.88 (tt, J = 10.6, 5.2 Hz, 1 H), 2.46 (t, J = 2.4 Hz, 1 H), 2.07–1.78 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.5, 164.0, 159.2, 112.7, 78.5, 74.4, 67.6, 54.7, 42.5, 31.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₅N₂O₂: 219.1134; found: 219.1123.

2-[4-(Pyridin-2-yl)piperazin-1-yl]-4-(tetrahydro-2H-pyran-4-yl)pyrimidine (47)

To a 25 mL sealed tube containing a magnetic stir bar and 3 (198.0 mg, 0.997 mmol, 1.0 equiv) in toluene (2 mL) were added 1-(2-pyridyl)piperazine (0.30 mL, 1.970 mmol, 1.7 equiv) and i-Pr₂NEt (0.30 mL, 1.764 mmol, 1.7 equiv). The reaction mixture was stirred at 110 °C for 24 h. After the volatile materials had been removed in vacuo, the resulting residue was diluted with H₂O (40 mL) and the organic materials were extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated. The crude material was purified by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 85:10:5); this provided 47.

Yield: 95% (309.2 mg, 0.947 mmol); colorless oil.

IR (neat): 3399, 2945, 2845, 1593 (C=N), 1574 (C=N), 1556 (C=N), 1438, 1240 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.25 (d, J = 5.1 Hz, 1 H), 8.22 (dd, J = 5.1, 2.0 Hz, 1 H), 7.50 (ddd, J = 8.8, 7.1, 2.0 Hz, 1 H), 6.70–6.67 (m, 1 H), 6.65–6.62 (m, 1 H), 6.40 (d, J = 5.1 Hz, 1 H), 4.08 (ddd, J = 11.5, 4.4, 2.0 Hz, 2 H), 3.99–3.93 (m, 4 H), 3.66–3.61 (m, 4 H), 3.52 (ddd, J = 11.5, 11.5, 2.7 Hz, 2 H), 2.74 (tt, J = 11.3, 4.3 Hz, 1 H), 1.96–1.78 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 161.7, 159.5, 157.7, 148.0, 137.5, 113.4, 107.3, 107.1, 67.8, 45.0, 43.4, 42.8, 31.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₄N₅O: 326.1981; found: 326.1981.

N-[4-(Tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]morpholin-4-amine (48)

4-Aminomorpholine (0.17 mL, 1.763 mmol, 1.7 equiv) and i-Pr₂NEt (0.30 mL, 1.764 mmol, 1.7 equiv) were added to a 25 mL sealed tube containing a magnetic stir bar and 3 (198.3 mg, 0.999 mmol, 1.0 equiv) in 1,4-dioxane (2 mL); the reaction mixture was stirred at 100 °C for 24 h. After the volatile materials had been removed in vacuo, the resulting residue was diluted with H₂O (40 mL) and the organic materials were extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, and concentrated. The crude material was purified by flash column chromatography (silica gel, hexane/EtOAc 80:20); this provided 48.

Yield: 73% (190.7 mg, 0.729 mmol); white solid; mp 89–90 °C.

IR (neat): 3440 (N–H), 2880

¹H NMR (400 MHz, CDCl₃): δ = 8.24 (d, J = 5.1 Hz, 1 H), 6.41 (d, J = 5.1 Hz, 1 H), 4.07 (ddd, J = 11.5, 4.3, 2.1 Hz, 2 H), 3.84–3.73 (m, 8 H), 3.51 (ddd, J = 11.5, 11.2, 2.8 Hz, 2 H), 2.72 (tt, J = 11.2, 4.4 Hz, 1 H), 1.94–1.75 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 173.1, 161.8, 157.7, 107.5, 67.8, 66.8, 44.2, 42.7, 31.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₂₁N₄O₂: 265.1665; found: 265.1687.

2-(1H-Imidazol-1-yl)-4-(tetrahydro-2H-pyran-4-yl)pyrimidine (49)

In a 25 mL sealed tube containing a magnetic stir bar, imidazole (87.6 mg, 1.287 mmol, 1.5 equiv) in THF (1.5 mL) was treated with NaH (60% w/w dispersion in mineral oil; 68.3 mg, mmol, 1.7 equiv) at 0 °C and the suspension was stirred for 1 h at the same temperature. To the suspension was added a solution of 3 (161.2 mg, 0.806 mmol, 1.0 equiv) in THF (1.0 mL) and the reaction mixture was stirred at 80 °C for 9 h. The reaction was quenched with H₂O and the organic materials were extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give a crude residue, which was purified by flash column chromatography (basic alumina, hexane/EtOAc 50:50); this provided 49.

Yield: 61% (112.3 mg, 0.492 mmol); white solid; mp 94–95 °C.

IR (neat): 3398, 3136, 2953, 2849, 1587 (C=N), 1479, 1433 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.63 (s, 1 H), 8.59 (d, J = 5.1 Hz, 1 H), 7.91 (s, 1 H), 7.17 (s, 1 H), 7.07 (d, J = 5.1 Hz, 1 H), 4.13 (ddd, J = 11.6, 3.9, 2.2 Hz, 2 H), 3.57 (ddd, J = 11.6, 10.0, 4.0 Hz, 2 H), 2.96 (tt, J = 10.7, 5.0 Hz, 1 H), 2.05–1.88 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.0, 158.8, 154.6, 136.2, 130.6, 116.5, 116.1, 67.6, 42.6, 31.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₅N₄O: 231.1246; found: 231.1248.

3-[4-(Tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]benzonitrile (50)

A solution of Na₂CO₃ (537.5 mg, 5.071 mmol, 5.0 equiv) in H₂O (2.5 mL) was added to a mixture of 3 (204.4 mg, 1.030 mmol, 1.0 equiv), (3-cyanophenyl)boronic acid (221.0 mg, 1.504 mmol, 1.5 equiv), and PdCl₂(PPh₃)₂ (7.8 mg, 0.011 mmol, 1 mol%) in 1,4-dioxane (2.5 mL) in a 25 mL sealed tube containing a magnetic stir bar. The reaction mixture was stirred at 90 °C for 12 h. The mixture was then diluted with H₂O (40 mL) and the organic materials were extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The resulting crude material was purified by flash column chromatography (silica gel, CH₂Cl₂); this provided 50.

Yield: 73% (200.8 mg, 0.752 mmol); white solid; mp 98–99 °C.

IR (neat): 3073, 2951, 2845, 2229 (C≡N), 1585 (C=N), 1548 (C=N), 1391 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.81 (s, 1 H), 8.74 (d, J = 5.1 Hz, 1 H), 8.72 (m, 1 H), 7.75 (ddd, J = 7.8, 1.6, 1.2 Hz, 1 H), 7.60 (dd, J = 8.0, 7.8, Hz, 1 H), 7.13 (d, J = 5.1 Hz, 1 H), 4.14 (ddd, J = 11.6, 4.4, 2.0 Hz, 2 H), 3.59 (ddd, J = 11.6, 10.0, 3.2 Hz, 2 H), 3.00 (tt, J = 11.2, 4.4 Hz, 1 H), 2.07–1.89 (m, 4 H).

¹³C NMR (100 MHz, CDCl₃): δ = 172.9, 162.0, 157.5, 138.9, 133.5, 132.2, 131.8, 129.2, 118.6, 117.2, 112.6, 67.6, 42.7, 31.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₆N₃O: 266.1293; found: 266.1293.

Methyl 4-(2-phenylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylate (51)

The procedure used for the synthesis of 50 was followed to prepare 51, using 16 (447.6 mg, 1.594 mmol, 1.0 equiv), phenylboronic acid (258.3 mg, 2.119 mmol, 1.5 equiv), PdCl₂(PPh₃)₂ (12.1 mg, 0.017 mmol, 1 mol%), and Na₂CO₃ (872.5 mg, 8.232 mmol, 5.0 equiv) in 1,4-dioxane (4 mL) and H₂O (4 mL) at 90 °C for 6 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 81% (417.8 mg, 1.291 mmol); white solid; mp 92–93 °C.

IR (neat): 3447, 2949, 2868, 1730 (C=O), 1566 (C=N), 1543, 1427, 1381 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.67 (d, J = 5.3 Hz, 1 H), 8.51–8.44 (m, 2 H), 7.48–7.46 (m, 3 H), 7.07 (d, J = 5.3 Hz, 1 H), 3.68 (s, 3 H), 1.97 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 178.1, 175.9, 163.6, 157.1, 138.0, 130.4, 128.4, 128.1, 114.9, 51.7, 39.3, 37.9, 30.0, 28.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₃N₂O₂: 323.1759; found: 323.1759.

4-(2-Phenylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylic Acid (52) and 1,3-Dioxoisoindolin-2-yl 4-(2-Phenylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylate (53)

To a 100 mL sealed tube containing a magnetic stir bar and 51 (351.7 mg, 1.090 mmol, 1.0 equiv) in THF (7 mL) and MeOH (7mL) was added an aqueous NaOH solution (44.0 mg, 1.10 mmol in 7 mL of H₂O), and the reaction mixture was stirred at 70 °C for 3 h. Volatile materials were removed in vacuo before 1 M aqueous HCl was added until the pH became 3–4; then the organic materials were extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo, providing carboxylic acid 52, which was used in the next step without further purification.

Yield: 96% (323.7 mg, 1.049 mmol); white solid; mp >200 °C.

DIC (0.20 mL, 1.291 mmol, 1.1 equiv) was added to a mixture of 52 (323.7 mg, 1.049 mmol, 1.0 equiv), DMAP (13.8 mg, 0.113 mmol, 0.1 equiv), and N-hydroxyphthalimide (183.9 mg, 1.127 mmol, 1.1 equiv) in CH₂Cl₂ (10 mL) in a 100 mL round bottom flask containing a magnetic stir bar; the reaction mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated in vacuo. The resulting crude material was purified by flash column chromatography (silica gel, hexane/EtOAc 70:30); this gave 53; yield: 76% (363.1 mg, 0.797 mmol); white solid; mp 158–159 °C. It was further purified by recrystallization (CH₂Cl₂) before use.

4-(2-Phenylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylic Acid (52)

IR (neat): 3044, 2945, 2866, 1566 (C=N), 1545 (C=N), 1425, 1144 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.10 (br s, COOH), 8.78 (d, J = 5.3 Hz, 1 H), 8.46–8.37 (m, 2 H), 7.58–7.48 (m, 3 H), 7.38 (d, J = 5.3 Hz, 1 H), 1.96–1.91 (m, 6 H), 1.90–1.81 (m, 6 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 178.6, 175.9, 162.4, 157.7, 137.5, 130.6, 128.6, 127.7, 115.8, 38.3, 37.6, 29.6, 28.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₂₁N₂O₂: 309.1603; found: 309.1599.

1,3-Dioxoisoindolin-2-yl 4-(2-phenylpyrimidin-4-yl)bicyclo[2.2.2]octane-1-carboxylate (53)

IR (neat): 3053, 2957, 2305, 1780 (C=O), 1746(C=O), 1566(C=N), 1427 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.70 (d, J = 5.2 Hz, 1 H), 8.50–8.47 (m, 2 H), 7.88 (dd, J = 5.5, 3.1 Hz, 2 H), 7.78 (dd, J = 5.5, 3.1 Hz, 2 H), 7.50–7.47 (m, 3 H), 7.11 (d, J = 5.2 Hz, 1 H), 2.23–2.18 (m, 6 H), 2.11–2.06 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.4, 173.5, 163.7, 162.0, 157.3, 138.9, 134.7, 130.5, 129.0, 128.5, 128.2, 123.9, 114.9, 39.0, 37.8, 29.7, 28.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₄N₃O₄: 454.1767; found: 454.1765.

2-Chloro-4-[4-(2-phenylpyrimidin-4-yl)bicyclo[2.2.2]octan-1-yl]pyrimidine (54)

The general procedure was followed, using N-(acyloxy)phthalimide 53 (45.52 mg, 0.100 mmol), 2-chloropyrimidine (2; 61.4 mg, 0.536 mmol), and Et₃N (14 μL, 0.100 mmol) in DMSO (0.30 mL) under irradiation with 427 nm light (Kessil lamp, 40 W) at 31–33 °C for 1 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc/CH₂Cl₂ 90:5:5).

Yield: 81% (30.2 mg, 0.081 mmol); white solid; mp 158–159 °C.

IR (neat): 3044, 2945, 2866, 1566 (C=N), 1545, 1425, 1144 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.70 (d, J = 5.2 Hz, 1 H), 8.53 (d, J = 5.2 Hz, 1 H), 8.50–8.47 (m, 2 H), 7.51–7.48 (m, 3 H), 7.22 (d, J = 5.2 Hz, 1 H), 7.13 (d, J = 5.2 Hz, 1 H), 2.15–2.04 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 180.4, 175.9, 163.7, 161.1, 159.4, 157.2, 138.0, 130.5, 128.5, 128.2, 115.8, 114.9, 38.9, 38.5, 30.6, 30.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₂N₄Cl: 377.1533; found: 377.1534.

3,6-Dichloro-4-[4-(2-phenylpyrimidin-4-yl]bicyclo[2.2.2]octan-1-yl)pyridazine (55)

The general procedure was followed, using N-(acyloxy)phthalimide 53 (46.6 mg, 0.107 mmol), 3,6-dichloropyrimidine (76.8 mg, 0.516 mmol), and Et₃N (14 μL, 0.100 mmol) in DMSO (0.30 mL) under irradiation with 427 nm light (Kessil lamp, 2 × 40 W) at 41–42 °C for 8 h. Purification was carried out by flash column chromatography (silica gel, hexane/EtOAc 90:10).

Yield: 59% (26.1 mg, 0.063 mmol); colorless oil.

IR (neat): 3392, 2944, 2866, 1566 (C=N), 1382, 1184 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.72 (d, J = 5.2 Hz, 1 H), 8.50–8.47 (m, 2 H), 7.52–7.46 (m, 3 H), 7.44 (s, 1 H), 7.13 (d, J = 5.2 Hz, 1 H), 2.23–2.12 (m, 12 H).

¹³C NMR (100 MHz, CDCl₃): δ = 175.3, 163.8, 157.4, 156.4, 155.9, 149.6, 137.9, 130.6, 128.5, 128.2, 128.2, 114.8, 37.7, 36.8, 30.0, 28.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₁N₄Cl₂: 411.1143; found: 411.1143.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1 https://njardarson.lab.arizona.edu/content/top-pharmaceuticals-poster
• 2 https://www-acs-org.accesdistant.sorbonne-universite.fr/content/dam/acsorg/events/drug-discovery/slides/2019-09-19-recent-crop-protection-poster.pdf
• 3 Minisci F, Bernardi R, Bertini F, Galli R, Perchinummo M. Tetrahedron 1971; 27: 3575
  CrossrefPubMedSearch in Google Scholar
• 4 Minisci F, Fontana F, Vismara E. J. Heterocycl. Chem. 1990; 27: 79-96
  CrossrefSearch in Google Scholar
• 5 Duncton MA. J. Med. Chem. Commun. 2011; 2: 1135
  CrossrefPubMedSearch in Google Scholar
• 6 Proctor RS. J, Phipps RJ. Angew. Chem. Int. Ed. 2019; 58: 13666
  CrossrefPubMedSearch in Google Scholar
• 7 Sun AC, McAtee RC, McClain EJ, Stephenson CR. J. Synthesis 2019; 51: 1063
  Thieme ConnectPubMedSearch in Google Scholar
• 8 McClain EJ, Wortman AK, Stephenson CR. J. Chem. Sci. 2022; 13: 12158
  CrossrefPubMedSearch in Google Scholar
• 9 Sun AC, McClain EJ, Beatty JW, Stephenson CR. J. Org. Lett. 2018; 20: 3487
  CrossrefPubMedSearch in Google Scholar
• 10 Beatty JW, Douglas JJ, Miller R, McAtee RC, Cole KP, Stephenson CR. J. Chem 2016; 1: 456
  CrossrefPubMedSearch in Google Scholar
• 11 Beatty JW, Douglas JJ, Cole KP, Stephenson CR. J. Nat. Commun. 2015; 6: 7919
  CrossrefPubMedSearch in Google Scholar
• 12 Okada K, Okamoto K, Morita N, Okubo K, Oda M. J. Am. Chem. Soc. 1991; 113: 9401
  CrossrefSearch in Google Scholar
• 13 Okada K, Okamoto K, Oda M. J. Am. Chem. Soc. 1988; 110: 8736
  CrossrefPubMedSearch in Google Scholar
• 14 Karmakar S, Silamkoti A, Meanwell NA, Mathur A, Gupta AK. Adv. Synth. Catal. 2021; 363: 3693
  CrossrefSearch in Google Scholar
• 15 Murarka S. Adv. Synth. Catal. 2018; 360: 1735
  CrossrefPubMedSearch in Google Scholar
• 16 Proctor RS. J, Davis HJ, Phipps RJ. Science 2018; 360: 419
  CrossrefPubMedSearch in Google Scholar
• 17 Sherwood TC, Li N, Yazdani AN, Dhar TG. M. J. Org. Chem. 2018; 83: 3000
  CrossrefPubMedSearch in Google Scholar
• 18 Cheng W.-M, Shang R, Fu M.-C, Fu Y. Chem. Eur. J. 2017; 23: 2537
  CrossrefPubMedSearch in Google Scholar
• 19 Cheng W.-M, Shang R, Fu Y. ACS Catal. 2017; 7: 907
  CrossrefSearch in Google Scholar
• 20 Fu M.-C, Shang R, Zhao B, Wang B, Fu Y. Science 2019; 363: 1429
  CrossrefPubMedSearch in Google Scholar
• 21 Bosque I, Bach T. ACS Catal. 2019; 9: 9103
  CrossrefSearch in Google Scholar
• 22 de Pedro Beato E, Spinnato D, Zhou W, Melchiorre P. J. Am. Chem. Soc. 2021; 143: 12304
  CrossrefPubMedSearch in Google Scholar
• 23 Sharique M, Majhi J, Dhungana RK, Kammer LM, Krumb M, Lipp A, Romero E, Molander GA. Chem. Sci. 2022; 13: 5701
  CrossrefPubMedSearch in Google Scholar
• 24 Tasnim T, Ayodele MJ, Pitre SP. J. Org. Chem. 2022; 87: 10555
  CrossrefPubMedSearch in Google Scholar
• 25 Yang Z, Liu Y, Cao K, Zhang X, Jiang H, Li J. Beilstein J. Org. Chem. 2021; 17: 771
  CrossrefPubMedSearch in Google Scholar
• 26 Crisenza GE. M, Mazzarella D, Melchiorre P. J. Am. Chem. Soc. 2020; 142: 5461
  CrossrefPubMedSearch in Google Scholar
• 27 Yuan Y.-q, Majumder S, Yang M.-h, Guo S.-r. Tetrahedron Lett. 2020; 62: 151506
  CrossrefSearch in Google Scholar
• 28 Lima CG. S, Lima TM, Duarte M, Jurberg ID, Paixão MW. ACS Catal. 2016; 6: 1389
  CrossrefSearch in Google Scholar
• 29 Liang D, Chen J.-R, Tan L.-P, He Z.-W, Xiao W.-J. J. Am. Chem. Soc. 2022; 144: 6040
  CrossrefPubMedSearch in Google Scholar
• 30 Reid JP, Procter RS. J, Sigman MS, Phipps RJ. J. Am. Chem. Soc. 2019; 141: 19178
  CrossrefPubMedSearch in Google Scholar
• 31 Graham MA, Noonan G, Cherryman JH, Douglas JJ, Gonzalez M, Jackson LV, Leslie K, Liu Z.-q, McKinney D, Munday RH, Parsons CD, Whittaker DT. E, Zhang E.-x, Zhang J.-w. Org. Process Res. Dev. 2021; 25: 57
  CrossrefSearch in Google Scholar
• 32 2-Chloropyrimidine (2) ($3.9/g:https://www.sigmaaldrich.com/US/en/product/aldrich/193291) is much cheaper than N-(acyloxy)phthalimide 1 ($65/g: https://www.combi-blocks.com/cgi-bin/find.cgi?JP-4977)
• 33 Yoon UC, Mariano PS. Acc. Chem. Res. 2001; 34: 523
  CrossrefPubMedSearch in Google Scholar
• 34 Anderson JM, Measom ND, Murphy JA, Poole DL. Angew. Chem. Int. Ed. 2021; 60: 24754
  CrossrefPubMedSearch in Google Scholar
• 35 Wu C, Ying T, Yang X, Su W, Dushkin AV, Yu J. Org. Lett. 2021; 23: 6423
  CrossrefPubMedSearch in Google Scholar
• 36 Shore DG. M, Wasik KA, Lyssikatos JP, Estrada AA. Tetrahedron Lett. 2015; 56: 4063
  CrossrefSearch in Google Scholar
• 37 O’Hara F, Blackmond DG, Baran PS. J. Am. Chem. Soc. 2013; 135: 12122
  CrossrefPubMedSearch in Google Scholar
• 38 Xie X, Zhang Y, Hao J, Wan W. Org. Biomol. Chem. 2020; 18: 400
  CrossrefPubMedSearch in Google Scholar
• 39 Huang Q, Qin L, Zard SZ. Tetrahedron 2018; 74: 5804
  CrossrefSearch in Google Scholar
• 40 Bohman B, Berntsson B, Dixon RC. M, Stewart CD, Barrow RA. Org. Lett. 2014; 16: 2787
  CrossrefPubMedSearch in Google Scholar
• 41 Buzzetti L, Crisenza GE. M, Melchiorre P. Angew. Chem. Int. Ed. 2019; 58: 3730
  CrossrefPubMedSearch in Google Scholar
• 42 Wortman AK, Stephenson CR. J. Chem 2023; 9: 2390
  CrossrefPubMedSearch in Google Scholar
• 43 The process from radical intermediate IV to product 3 could be mediated by the radical anion of 3 (formed by deprotonation before SET). We observed an irreversible reduction wave of 3 in the CV measurement (see the SI) and determined the reduction potential of 3 as E _1/2 = –2.06 V vs. SCE. As the reduction potentials of N-(acyloxy)phthalimide 1 is –1.29 V vs. SCE (see the SI), the radical anion of 3 could potentially function as an electron carrier to N-(acyloxy)phthalimide 1 to facilitate the proposed chain propagation. On the other hand, hydrodechlorination of 2-chloropyrimidine (2) (E _1/2 = –1.75 V vs. SCE) and 3 was not observed at all.
• 44 Studer A, Curran DP. Angew. Chem. Int. Ed. 2011; 50: 5018
  CrossrefPubMedSearch in Google Scholar
• 45 The alkylation of other diazines especially with the reaction time longer than 5 h (Scheme 3) could also be facilitated by the non-chain redox mechanism.
• 46 Huang C.-Y, Li J, Li C.-J. Nat. Commun. 2021; 12: 4010
  CrossrefPubMedSearch in Google Scholar

Corresponding Author

Publication History

Received: 06 September 2023

Accepted after revision: 27 September 2023

Accepted Manuscript online:
27 September 2023

Article published online:
06 November 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 https://njardarson.lab.arizona.edu/content/top-pharmaceuticals-poster
• 2 https://www-acs-org.accesdistant.sorbonne-universite.fr/content/dam/acsorg/events/drug-discovery/slides/2019-09-19-recent-crop-protection-poster.pdf
• 3 Minisci F, Bernardi R, Bertini F, Galli R, Perchinummo M. Tetrahedron 1971; 27: 3575
  CrossrefPubMedSearch in Google Scholar
• 4 Minisci F, Fontana F, Vismara E. J. Heterocycl. Chem. 1990; 27: 79-96
  CrossrefSearch in Google Scholar
• 5 Duncton MA. J. Med. Chem. Commun. 2011; 2: 1135
  CrossrefPubMedSearch in Google Scholar
• 6 Proctor RS. J, Phipps RJ. Angew. Chem. Int. Ed. 2019; 58: 13666
  CrossrefPubMedSearch in Google Scholar
• 7 Sun AC, McAtee RC, McClain EJ, Stephenson CR. J. Synthesis 2019; 51: 1063
  Thieme ConnectPubMedSearch in Google Scholar
• 8 McClain EJ, Wortman AK, Stephenson CR. J. Chem. Sci. 2022; 13: 12158
  CrossrefPubMedSearch in Google Scholar
• 9 Sun AC, McClain EJ, Beatty JW, Stephenson CR. J. Org. Lett. 2018; 20: 3487
  CrossrefPubMedSearch in Google Scholar
• 10 Beatty JW, Douglas JJ, Miller R, McAtee RC, Cole KP, Stephenson CR. J. Chem 2016; 1: 456
  CrossrefPubMedSearch in Google Scholar
• 11 Beatty JW, Douglas JJ, Cole KP, Stephenson CR. J. Nat. Commun. 2015; 6: 7919
  CrossrefPubMedSearch in Google Scholar
• 12 Okada K, Okamoto K, Morita N, Okubo K, Oda M. J. Am. Chem. Soc. 1991; 113: 9401
  CrossrefSearch in Google Scholar
• 13 Okada K, Okamoto K, Oda M. J. Am. Chem. Soc. 1988; 110: 8736
  CrossrefPubMedSearch in Google Scholar
• 14 Karmakar S, Silamkoti A, Meanwell NA, Mathur A, Gupta AK. Adv. Synth. Catal. 2021; 363: 3693
  CrossrefSearch in Google Scholar
• 15 Murarka S. Adv. Synth. Catal. 2018; 360: 1735
  CrossrefPubMedSearch in Google Scholar
• 16 Proctor RS. J, Davis HJ, Phipps RJ. Science 2018; 360: 419
  CrossrefPubMedSearch in Google Scholar
• 17 Sherwood TC, Li N, Yazdani AN, Dhar TG. M. J. Org. Chem. 2018; 83: 3000
  CrossrefPubMedSearch in Google Scholar
• 18 Cheng W.-M, Shang R, Fu M.-C, Fu Y. Chem. Eur. J. 2017; 23: 2537
  CrossrefPubMedSearch in Google Scholar
• 19 Cheng W.-M, Shang R, Fu Y. ACS Catal. 2017; 7: 907
  CrossrefSearch in Google Scholar
• 20 Fu M.-C, Shang R, Zhao B, Wang B, Fu Y. Science 2019; 363: 1429
  CrossrefPubMedSearch in Google Scholar
• 21 Bosque I, Bach T. ACS Catal. 2019; 9: 9103
  CrossrefSearch in Google Scholar
• 22 de Pedro Beato E, Spinnato D, Zhou W, Melchiorre P. J. Am. Chem. Soc. 2021; 143: 12304
  CrossrefPubMedSearch in Google Scholar
• 23 Sharique M, Majhi J, Dhungana RK, Kammer LM, Krumb M, Lipp A, Romero E, Molander GA. Chem. Sci. 2022; 13: 5701
  CrossrefPubMedSearch in Google Scholar
• 24 Tasnim T, Ayodele MJ, Pitre SP. J. Org. Chem. 2022; 87: 10555
  CrossrefPubMedSearch in Google Scholar
• 25 Yang Z, Liu Y, Cao K, Zhang X, Jiang H, Li J. Beilstein J. Org. Chem. 2021; 17: 771
  CrossrefPubMedSearch in Google Scholar
• 26 Crisenza GE. M, Mazzarella D, Melchiorre P. J. Am. Chem. Soc. 2020; 142: 5461
  CrossrefPubMedSearch in Google Scholar
• 27 Yuan Y.-q, Majumder S, Yang M.-h, Guo S.-r. Tetrahedron Lett. 2020; 62: 151506
  CrossrefSearch in Google Scholar
• 28 Lima CG. S, Lima TM, Duarte M, Jurberg ID, Paixão MW. ACS Catal. 2016; 6: 1389
  CrossrefSearch in Google Scholar
• 29 Liang D, Chen J.-R, Tan L.-P, He Z.-W, Xiao W.-J. J. Am. Chem. Soc. 2022; 144: 6040
  CrossrefPubMedSearch in Google Scholar
• 30 Reid JP, Procter RS. J, Sigman MS, Phipps RJ. J. Am. Chem. Soc. 2019; 141: 19178
  CrossrefPubMedSearch in Google Scholar
• 31 Graham MA, Noonan G, Cherryman JH, Douglas JJ, Gonzalez M, Jackson LV, Leslie K, Liu Z.-q, McKinney D, Munday RH, Parsons CD, Whittaker DT. E, Zhang E.-x, Zhang J.-w. Org. Process Res. Dev. 2021; 25: 57
  CrossrefSearch in Google Scholar
• 32 2-Chloropyrimidine (2) ($3.9/g:https://www.sigmaaldrich.com/US/en/product/aldrich/193291) is much cheaper than N-(acyloxy)phthalimide 1 ($65/g: https://www.combi-blocks.com/cgi-bin/find.cgi?JP-4977)
• 33 Yoon UC, Mariano PS. Acc. Chem. Res. 2001; 34: 523
  CrossrefPubMedSearch in Google Scholar
• 34 Anderson JM, Measom ND, Murphy JA, Poole DL. Angew. Chem. Int. Ed. 2021; 60: 24754
  CrossrefPubMedSearch in Google Scholar
• 35 Wu C, Ying T, Yang X, Su W, Dushkin AV, Yu J. Org. Lett. 2021; 23: 6423
  CrossrefPubMedSearch in Google Scholar
• 36 Shore DG. M, Wasik KA, Lyssikatos JP, Estrada AA. Tetrahedron Lett. 2015; 56: 4063
  CrossrefSearch in Google Scholar
• 37 O’Hara F, Blackmond DG, Baran PS. J. Am. Chem. Soc. 2013; 135: 12122
  CrossrefPubMedSearch in Google Scholar
• 38 Xie X, Zhang Y, Hao J, Wan W. Org. Biomol. Chem. 2020; 18: 400
  CrossrefPubMedSearch in Google Scholar
• 39 Huang Q, Qin L, Zard SZ. Tetrahedron 2018; 74: 5804
  CrossrefSearch in Google Scholar
• 40 Bohman B, Berntsson B, Dixon RC. M, Stewart CD, Barrow RA. Org. Lett. 2014; 16: 2787
  CrossrefPubMedSearch in Google Scholar
• 41 Buzzetti L, Crisenza GE. M, Melchiorre P. Angew. Chem. Int. Ed. 2019; 58: 3730
  CrossrefPubMedSearch in Google Scholar
• 42 Wortman AK, Stephenson CR. J. Chem 2023; 9: 2390
  CrossrefPubMedSearch in Google Scholar
• 43 The process from radical intermediate IV to product 3 could be mediated by the radical anion of 3 (formed by deprotonation before SET). We observed an irreversible reduction wave of 3 in the CV measurement (see the SI) and determined the reduction potential of 3 as E _1/2 = –2.06 V vs. SCE. As the reduction potentials of N-(acyloxy)phthalimide 1 is –1.29 V vs. SCE (see the SI), the radical anion of 3 could potentially function as an electron carrier to N-(acyloxy)phthalimide 1 to facilitate the proposed chain propagation. On the other hand, hydrodechlorination of 2-chloropyrimidine (2) (E _1/2 = –1.75 V vs. SCE) and 3 was not observed at all.
• 44 Studer A, Curran DP. Angew. Chem. Int. Ed. 2011; 50: 5018
  CrossrefPubMedSearch in Google Scholar
• 45 The alkylation of other diazines especially with the reaction time longer than 5 h (Scheme 3) could also be facilitated by the non-chain redox mechanism.
• 46 Huang C.-Y, Li J, Li C.-J. Nat. Commun. 2021; 12: 4010
  CrossrefPubMedSearch in Google Scholar

• Supplementary Material