Visible-Light-Induced Decarboxylative C–H Adamantylation of Azoles at Ambient Temperature

^§ These authors contributed equally to this work

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

The visible-light-promoted oxidant-free decarboxylative C–H adamantylation of azoles was accomplished under ambient reaction conditions. The novel acridinium photocatalyst and cobalt synergistic catalysis enabled the C–H adamantylation under oxidant-free reaction conditions. This C–H adamantylation strategy proved viable for a wide range of substituted azoles, including benzothiazole, benzoxazole, and benzimidazoles as well as caffeine derivatives, providing an expedient access to 2-adamantyl-substituted azoles.

Key words

photocatalysis - C–H functionalization - decarboxylation - cobalt - acridinium salts - oxidant-free - adamantylation - azoles

Adamantane, a strain-free molecule consisting of three fused cyclohexane rings, has attracted significant attention because of its unique structural features and properties.[1] For instance, the adamantyl moiety represents a key scaffold in several biologically active compounds[2] and clinical therapeutics.[3] The incorporation of the adamantyl group to polymers[4] and functional materials[5] significantly improves their physical properties, such as thermal stability and solubility.[6] Furthermore, the specific features of the adamantyl scaffold, including lipophilicity, steric demand, dispersion attraction, and conformational stability and rigidity expanded their presence and influence in several other important areas of research, such as supramolecular chemistry,[7] and molecular syntheses.[8] Despite the great importance of adamantyl-substituted organic compounds, the incorporation of adamantyl group into organic molecules largely relies on conventional nucleophilic substitution reactions with adamantyl halides.[8e] [9] Recently, selected examples of C–H adamantylation were reported as the part of the scope of transition-metal-catalyzed C–H alkylation protocols.[10] However, no specific methods have as of yet been reported for the C–H adamantylation of heteroarenes, in detail delineating its scope and limitations. Within our program on transition-metal-catalyzed C–H alkylation[11] and photoredox catalysis,[12] we have now devised an exceedingly mild method for the C–H adamantylation of azoles by a photoinduced[13] decarboxylative[14] C–H alkylation strategy.[15] Notable features of our approach include (i) expedient C–H adamantylation on diversely decorated azoles, (ii) non-directing group-assisted C–H functionalization, (iii) easily accessible and inexpensive 1-adamantanecarboxylic acid as reagent, (iv) visible-light-promoted C–H functionalization, (v) no stoichiometric oxidants and iridium or ruthenium photocatalysts, (vi) key mechanistic insights, and (vii) ambient reaction temperature (Scheme [1]).

Scheme 1 Visible-light-induced decarboxylative C–H adamantylation

We initiated our studies by examining suitable photocatalysts (PCs) (Figure [1]), bases, and solvents under oxidant-free conditions, using an easily accessible cobaloxime complex[16] as cocatalyst for the envisioned decarboxylative C–H adamantylation of benzothiazole (1a) with adamantanecarboxylic acid (2) (Table [1]). Thus, among a set of representative photocatalysts, 9-mesityl-10-methylacridinium perchlorate (PC1) provided optimal results in a mixture of DCE/H₂O (3:1) as the reaction medium (Table [1], entry 1). While a variety of bases could be utilized, the photoinduced C–H adamantylation was most effective in the presence of K₂HPO₄. The key importance of the photocatalyst, base, and light irradiation in the decarboxylative C–H adamantylation manifold was verified by probing the transformation in the absence of each component under otherwise identical reaction conditions (entries 17–19). Notably, the use of blue light was found beneficial to realize satisfactory yields (entries 20 and 21).

Figure 1 Photocatalysts (PCs) tested in this study

Table 1 Optimization Studies^a

Entry	PC	Base (equiv)	Solvent	Yield (%)
1	PC1	K2HPO4 (3)	DCE/H2O (3:1)	83
2	PC2	K2HPO4 (3)	DCE/H2O (3:1)	trace
3	PC3	K2HPO4 (3)	DCE/H2O (3:1)	11
4	PC4	K2HPO4 (3)	DCE/H2O (3:1)	0
5	PC5	K2HPO4 (3)	DCE/H2O (3:1)	0
6	PC6	K2HPO4 (3)	DCE/H2O (3:1)	0
7	PC1	K2HPO4 (3)	CH2Cl2/H2O (3:1)	74
8	PC1	K2HPO4 (3)	CHCl3/H2O (3:1)	9
9	PC1	K2HPO4 (3)	H2O	7
10	PC1	K2HPO4 (3)	DCE	trace
11	PC1	Na2HPO4 (3)	DCE/H2O (3:1)	77
12	PC1	NaHCO3 (3)	DCE/H2O (3:1)	66
13	PC1	K2HPO4 (2)	DCE/H2O (3:1)	71
14	PC1	K2CO3	DCE/H2O (3:1)	25
15	PC1	KOAc	DCE/H2O (3:1)	24
16	PC1	K3PO4	DCE/H2O (3:1)	21
17	PC1	–	DCE/H2O (3:1)	trace
18	–	K2HPO4 (3)	DCE/H2O (3:1)	0
19	PC1	K2HPO4 (3)	DCE/H2O (3:1)	0b
20	PC1	K2HPO4 (3)	DCE/H2O (3:1)	21c
21	PC1	K2HPO4 (3)	DCE/H2O (3:1)	15d

^a Reaction conditions: benzothiazole (1a; 0.4 mmol), 1-adamantanecarboxylic acid (2a; 1.2 mmol), photocatalyst PC (5.0 mol%), [Co(dmgH)(dmgH₂)Cl₂] (8.0 mol%), solvent (2.0 mL), 24 h under blue light irradiation (λ_max = 458 nm), yield of isolated product.

^b Reaction performed in the dark.

^c 22 W CFL.

^d 2 W green LED.

With the optimized reaction conditions in hand, we probed the scope of the reaction with a range of azoles 1 (Scheme [2]). To our delight, the visible-light-enabled decarboxylative C–H adamantylation proved broadly applicable towards a range of azoles. Thus, differently substituted benzothiazoles 1a–h and benzoxazoles 1i–p were efficiently transformed into the desired adamantyl-substituted products 3a–p in satisfactory yields. Notably, the challenging benzimidazole 1q and caffeine derivatives 1r,s were successfully functionalized under identical reaction conditions.

Scheme 2 Visible-light-induced decarboxylative C–H adamantylation of azoles 1

In consideration of the unique reactivity of the photoinduced decarboxylative C–H functionalization, we were attracted to delineate its mode of action. To probe the catalyst’s working mode, we performed an intermolecular competition experiment, which revealed electron-deficient benzothiazole 1e to be preferentially converted (Scheme [3a]). Further, we investigated a SET-type regime by the use of typical radical scavengers TEMPO, galvinoxyl, and BHT (Scheme [3b]), which significantly suppressed the catalytic efficacy.

Scheme 3 Key mechanistic findings

To further elucidate the reaction mechanism of the photoinduced C–H adamantylation, we performed a series of additional experiments (Figure [2]). First, we monitored the conversion profile of the photocatalytic reaction of 1a and 2 to give 3a, which revealed the reaction being completely suppressed in the absence of light (Figure [2a]). These findings provided strong evidence for the beneficial influence of visible-light irradiation. Second, fluorescence-quenching experiments (Figure [2b–d]) revealed no quenching of the free acid 2, while both benzothiazole and the carboxylate salt quenched the excited state of acridinium photocatalyst PC1. Based on these observations, we propose the single-electron transfer to occur from PC1* to adamantane carboxylate as the key step.

Figure 2 (a) The on/off light experiments. (b) Fluorescence quenching experiments of PC1* with 2. (c) Fluorescence quenching experiments of PC1* with 1a. (d) Fluorescence quenching experiments of PC1* with adamantane carboxylate.

Scheme 4 Proposed mechanism for the decarboxylative C–H adamantylation

In light of these mechanistic findings, a plausible catalytic cycle for the photoinduced decarboxylative C–H adamantylation protocol is elaborated in Scheme [4]. The acridinium photocatalyst [Arc-Mes⁺] is initially excited to [Acr-Mes⁺]* by blue light absorption, which oxidizes the adamantane carboxylate anion to the oxygen-centered carboxyl radical. Then, decarboxylation forms the adamantyl radical. Subsequently, the [Acr-Mes^•] radical is re-oxidized to [Arc-Mes⁺] by the cobalt(III) species to complete the photocatalytic cycle. In the meantime, the attack of the adamantyl radical at the electrophilic C2 position of benzothiazole (1a) generates radical intermediate A. Upon deprotonation, reduction of the cobalt(II) species to cobalt(I) through SET from species A then delivers the adamantylated product 3a. Concurrently, the cobalt(III)-hydride species could be formed from the cobalt(I) species by capturing a proton generated in the reaction. Release of H₂ through a reaction with another proton will regenerate the cobalt(III) species.[16c] [d] [e] [f]

In summary, we have reported on the unprecedented visible-light-enabled decarboxylative C–H adamantylation of azoles at ambient reaction temperature. The oxidant-free decarboxylative adamantylation was efficiently achieved by the aid of catalytic amounts of easily available cobalt oxime complex. A range of substituted azoles, including benzothiazole, benzoxazole, and benzimidazoles as well as caffeine derivatives, were well tolerated, providing a new general strategy to access adamantyl-substituted heterocycles motifs.

Catalytic reactions were carried out in pre-dried 10 mL vials under N₂ atmosphere. In cases wherein air- or moisture-sensitive reagents were used, reactions were performed under N₂ atmosphere using standard Schlenk techniques. The following substrates were prepared according to previously described procedures: Benzothiazoles 1b–h,[17] benzoxales 1l–p,[18] benzimidazole 1q,[19] [Co(dmgH)(dmgH₂)Cl₂],[20] and tetrabutylammonium adamantane carboxylate.[21] Other chemicals were obtained from commercial sources and were used without further purification, unless otherwise noted. Yields refer to isolated compounds, estimated to be >95% pure as determined by ¹H NMR spectroscopy. TLC: Merck TLC silica gel 60 F₂₅₄, TLC plates; detection under UV light at 254 nm. Chromatography: Separations were carried out on Merck Geduran^® Silica 60 (0.040–0.063 mm, 70–230 mesh ASTM) using distilled solvents. Melting points: Stuart melting point apparatus SMP3, Barloworld Scientific, the reported values are not corrected. NMR: Spectra were recorded on Varian VX 300, Varian VNMRS 300, Bruker Avance 300, Bruker Avance 400 and 500 or Varian Inova 500 and 600 spectrometers in the solvent indicated; chemical shifts (δ) are given in ppm and referenced to the residual solvent peak. All IR spectra were recorded on a Bruker ATR FT-IR Alpha device. MS: ESI-MS-spectra as well as high-resolution mass spectrometry (HRMS) were recorded with a micrOTOF (ESI-TOF-MS), Bruker Daltonik; EI-spectra were recorded with an AccuTOF (EI-TOF) instrument from Jeol. Fluorescence emission data in solution were recorded on a Jasco^® FP-8500 spectrofluorometer. The widths of excitation and emission slits were held constant at 2.5 and 5.0 nm, respectively. The scan speed was adjusted to 500 nm/min.

Visible-Light-Promoted Decarboxylative C–H Adamantylation; General Procedure

To an oven-dried 10 mL vial were added the heteroarene 1 (0.40 mmol, 1.0 equiv), 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol, 3.0 equiv), K₂HPO₄ (209 mg, 1.20 mmol, 3.0 equiv), 9-mesityl-10-methylacridinium perchlorate (8.2 mg, 5.0 mol%), and [Co(dmgH)(dmgH₂)Cl₂] (11.6 mg, 8.0 mol%). After the vial was capped with a septum, it was evacuated and refilled with N₂ for three times before DCE (1.5 mL) and H₂O (0.5 mL) were added sequentially. If the heterocyclic substrate 1 was a liquid, it was added at this point. The mixture was degassed and stirred for 24 h under visible light irradiation (Kessil A360N, see Figure S-1 in the Supporting Information). After 24 h, the mixture was diluted with CH₂Cl₂ (10 mL) and H₂O (10 mL), and the phases were separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL), the combined organic phases were dried (Na₂SO₄), and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (n-pentane or n-hexane/Et₂O 20:1 to 2:1) affording the corresponding product 3.

2-[(3R,5R,7R)-Adamantan-1-yl]benzo[d]thiazole (3a)

The general procedure was followed using benzothiazole (1a; 54.1 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 30:1) afforded 3a; yield: 89.3 mg (331 μmol, 83%); white solid; mp 103–104 °C.

IR (ATR): 2898, 2845, 1506, 1434, 1168, 999, 963, 754, 725, 680 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.00 (ddd, J = 8.2, 1.2, 0.7 Hz, 1 H), 7.86 (ddd, J = 7.2, 1.2, 0.7 Hz, 1 H), 7.44 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H), 7.32 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H), 2.18–2.12 (m, 9 H), 1.86–1.81 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 182.3 (C_q), 153.3 (C_q), 134.5 (C_q), 125.8 (CH), 124.5 (CH), 122.8 (CH), 121.7 (CH), 43.1 (CH₂), 40.3 (C_q), 36.7 (CH₂), 28.7 (CH).

MS (ESI): m/z (%) = 270 ([M + H]⁺, 100).

HRMS (EI): m/z calcd for C₁₇H₂₀NS⁺ [M + H]⁺: 270.1311; found: 270.1313.

The analytical data are in accordance with those reported in the literature.[10c]

2-[(3R,5R,7R)-Adamantan-1-yl]-6-methylbenzo[d]thiazole (3b)

The general procedure was followed using benzothiazole 1b (59.7 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 30:1) afforded 3b; yield: 60.6 mg (214 μmol, 53%); white solid; mp 132–133 °C.

IR (ATR): 2899, 2845, 1510, 1449, 1164, 1000, 835, 812, 679, 569 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 8.3 Hz, 1 H), 7.65–7.62 (m, 1 H), 7.24 (ddd, J = 8.2, 1.7, 0.6 Hz, 1 H), 2.46 (s, 3 H), 2.16–2.11 (m, 9 H), 1.83–1.80 (m, 6 H). 

¹³C NMR (101 MHz, CDCl₃): δ = 181.2 (C_q), 151.4 (C_q), 134.6 (C_q), 134.5 (C_q), 127.3 (CH), 122.2 (CH), 121.4 (CH), 43.1 (CH₂), 40.2 (C_q), 36.7 (CH₂), 28.7 (CH), 21.6 (CH₃).

MS (ESI): m/z (%) = 284 ([M + H]⁺, 100).

HRMS (ESI): m/z calcd for C₁₈H₂₂NS⁺ [M + H]⁺: 284.1467; found: 284.1471.

The analytical data are in accordance with those reported in the literature.[22]

2-[(3R,5R,7R)-Adamantan-1-yl]-6-methoxylbenzo[d]thiazole (3c)

The general procedure was followed using benzothiazole 1c (66.1 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 25:1) afforded 3c; yield: 70.2 mg (234 μmol, 59%); white solid; mp 118–119 °C.

IR (neat): 2904, 1467, 1450, 1435, 1261, 1223, 1028, 1000, 834, 827 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.87 (dd, J = 8.9, 0.4 Hz, 1 H), 7.31 (d, J = 2.5 Hz, 1 H), 7.03 (dd, J = 8.9, 2.5 Hz, 1 H), 3.85 (s, 3 H), 2.15–2.11 (m, 9 H), 1.82–1.79 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 179.8 (C_q), 157.3 (C_q), 147.8 (C_q), 135.7 (C_q), 123.2 (CH), 114.9 (CH), 104.4 (CH), 55.9 (CH₃), 43.1 (CH₂), 40.1 (C_q), 36.7 (CH₂), 28.7 (CH).

MS (ESI): m/z (%) = 300 ([M + H]⁺, 100).

HRMS (ESI): m/z calcd for C₁₈H₂₂NOS⁺ [M + H]⁺: 300.1417; found: 300.1419.

The analytical data are in accordance with those reported in the literature.[22]

2-[(3R,5R,7R)-Adamantan-1-yl]-6-(trifluoromethyl)benzo[d]thiazole (3d)

The general procedure was followed using benzothiazole 1d (81.3 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 30:1) afforded 3d; yield: 96.3 mg (285 μmol, 71%); white solid; mp 183–184 °C.

IR (ATR): 2911, 1317, 1278, 1163, 1112, 1085, 1001, 880, 829, 681 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.15 (dq, J = 1.8, 0.7 Hz, 1 H), 8.07 (dt, J = 8.6, 0.7 Hz, 1 H), 7.68 (ddd, J = 8.6, 1.8, 0.7 Hz, 1 H), 2.19–2.14 (m, 9 H), 1.87–1.80 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 185.7 (C_q), 155.4 (C_q), 134.7 (C_q), 126.8 (q, ² J _C,F = 32.7 Hz, C_q), 124.4 (q, ¹ J _C,F = 272.0 Hz, C_q) 123.1 (CH), 122.8 (q, ³ J _C,F = 3.5 Hz, CH), 119.2 (q, ³ J _C,F = 4.2 Hz, CH) 43.1 (CH₂), 40.7 (C_q), 36.6 (CH₂), 28.7 (CH).

¹⁹F NMR (376 MHz, CDCl₃): δ = –61.3 (s).

MS (ESI): m/z (%) = 338 ([M + H]⁺, 13), 300 (100).

HRMS (EI): m/z calcd for C₁₈H₁₉F₃NS⁺ [M + H]⁺: 338.1185; found: 338.1188.

2-[(3R,5R,7R)-Adamantan-1-yl]-6-fluorobenzo[d]thiazole (3e)

The general procedure was followed using benzothiazole 1e (61.3 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 30:1) afforded 3e; yield: 62.1 mg (216 μmol, 54%); white solid; mp 107–108 °C.

IR (ATR): 2911, 2889, 1454, 1245, 1161, 1001, 915, 836, 800, 791 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.91 (ddd, J = 8.9, 4.8, 0.4 Hz, 1 H), 7.52 (ddd, J = 8.2, 2.6, 0.4 Hz, 1 H), 7.16 (ddd, J = 8.9, 8.2, 2.6 Hz, 1 H), 2.16–2.12 (m, 9 H), 1.83–1.79 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 182.0 (d, ⁵ J _C,F = 3.1 Hz, C_q), 160.2 (d, ¹ J _C,F = 244.2 Hz, Cq), 149.9 (d, ⁴ J _C,F = 1.6 Hz, C_q), 135.5 (d, ³ J _C,F = 11.2 Hz, C_q), 123.6 (d, ³ J _C,F = 9.4 Hz, CH), 114.3 (d, ² J _C,F = 24.6 Hz, CH), 107.8 (d, ³ J _C,F = 26.4 Hz, CH), 43.1 (CH₂), 40.4 (C_q), 36.6 (CH₂), 28.7 (CH).

¹⁹F NMR (376 MHz, CDCl₃): δ = –117.4 (s).

MS (ESI): m/z (%) = 288 ([M + H]⁺, 100).

HRMS (EI): m/z calcd for C₁₇H₁₉NSF⁺ [M + H]⁺: 288.1217; found: 288.1219.

2-[(3R,5R,7R)-Adamantan-1-yl]-6-chlorobenzo[d]thiazole (3f)

The general procedure was followed using benzothiazole 1f (67.9 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 30:1) afforded 3f; yield: 71.8 mg (236 μmol, 59%); white solid; mp 145–146 °C.

IR (ATR): 2898, 2844, 1514, 1435, 1259, 1097, 999, 802, 768, 680 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.88 (dd, J = 8.7, 0.4 Hz, 1 H), 7.81 (dd, J = 2.1, 0.4 Hz, 1 H), 7.38 (dd, J = 8.7, 2.1 Hz, 1 H), 2.16–2.11 (m, 9 H), 1.84–1.79 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 182.8 (C_q), 151.9 (C_q), 135.8 (C_q), 130.4 (C_q), 126.6 (CH), 123.5 (CH), 121.3 (CH), 43.1 (CH₂), 40.4 (C_q), 36.6 (CH₂), 28.7 (CH).

MS (ESI): m/z (%) = 304 ([M + H]⁺, 100).

HRMS (ESI): m/z calcd for C₁₇H₁₉ClNS⁺ [M + H]⁺: 304.0921; found: 304.0924.

The analytical data are in accordance with those reported in the literature.[22]

2-[(3R,5R,7R)-Adamantan-1-yl]-6-bromobenzo[d]thiazole (3g)

The general procedure was followed using benzothiazole 1g (85.6 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 30:1) afforded 3g; yield: 75.1 mg (216 μmol, 54%); white solid; mp 182–183 °C.

IR (ATR): 2907, 2847, 1438, 1269, 1086, 1000, 860, 814, 804, 682 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.97 (dd, J = 2.0, 0.4 Hz, 1 H), 7.82 (dd, J = 8.7, 0.4 Hz, 1 H), 7.52 (dd, J = 8.7, 2.0 Hz, 1 H), 2.16–2.11 (m, 9 H), 1.83–1.78 (m, 6 H).

¹³C NMR (76 MHz, CDCl₃): δ = 182.9 (C_q), 152.2 (C_q), 136.3 (C_q), 129.2 (CH), 124.2 (CH), 123.9 (CH), 118.0 (C_q), 43.0 (CH₂), 40.4 (C_q), 36.6 (CH₂), 28.6 (CH).

MS (ESI): m/z (%) = 348 ([M + H]⁺, 100; ⁷⁹Br).

HRMS (ESI): m/z calcd for C₁₇H₁₉ ⁷⁹BrNS⁺ [M + H]⁺: 348.0416; found: 348.0420.

Ethyl 2-[(3R,5R,7R)-Adamantan-1-yl]benzo[d]thiazole-6-carboxylate (3h)

The general procedure was followed using benzothiazole 1h (82.9 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 15:1) afforded 3h; yield: 60.0 mg (176 μmol, 44%); white solid; mp 131–133 °C.

IR (ATR): 2899, 1707, 1272, 1231, 1106, 1001, 850, 772, 730, 681 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.58 (dd, J = 1.7, 0.6 Hz, 1 H), 8.12 (dd, J = 8.6, 1.7 Hz, 1 H), 8.00 (dd, J = 8.6, 0.6 Hz, 1 H), 4.41 (q, J = 7.1 Hz, 2 H), 2.16–2.12 (m, 9 H), 1.84–1.80 (m, 6 H), 1.41 (t, J = 7.1 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 186.0 (C_q), 166.4 (C_q), 156.3 (C_q), 134.4 (C_q), 127.1 (CH), 126.7 (C_q), 123.9 (CH), 122.4 (CH), 61.3 (CH₂), 43.0 (CH₂), 40.7 (C_q), 36.6 (CH₂), 28.6 (CH), 14.5 (CH₃).

MS (ESI): m/z (%) = 342 [M + H]⁺ (100).

HRMS (EI): m/z calcd for C₂₀H₂₄NO₂S⁺ [M + H]⁺: 342.1522; found: 342.1524.

2-[(3R,5R,7R)-Adamantan-1-yl]benzo[d]oxazole (3i)

The general procedure was followed using benzoxazole 1i (48.0 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-hexane/EtOAc 10:1) afforded 3i; yield: 56.0 mg (221 μmol, 55%); white solid; mp 99–100 °C.

IR (ATR): 2907, 2852, 1560, 1455, 1264, 1240, 1044, 736, 704 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.70–7.56 (m, 1 H), 7.46–7.35 (m, 1 H), 7.28–7.13 (m, 2 H), 2.15–1.97 (m, 9 H), 1.74 (t, J = 3.0 Hz, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.9 (C_q), 150.5 (C_q), 141.2 (C_q), 124.2 (CH), 123.9 (CH), 119.7 (CH), 110.3 (CH), 40.2 (CH₂), 36.5 (CH₂), 36.0 (C_q), 27.9 (CH).

MS (ESI): m/z (%) = 254 ([M + H]⁺, 100), 276 ([M + Na]⁺, 15).

HRMS (ESI): m/z calcd for C₁₇H₂₀NO⁺ [M + H]⁺: 254.1539; found: 254.1540.

The analytical data are in accordance with those reported in the literature.[10b]

2-[(3R,5R,7R)-Adamantan-1-yl]-5-methylbenzo[d]oxazole (3j)

The general procedure was followed using 5-methylbenzoxazole 1j (53.3 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-hexane/EtOAc 10:1) afforded 3j; yield: 61.0 mg (228 μmol, 57%); white solid; mp 94–96 °C.

IR (ATR): 2902, 2849, 1561, 1452, 1261, 1181, 1044, 923, 796 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.48–7.42 (m, 1 H), 7.32 (d, J = 8.2 Hz, 1 H), 7.06 (dd, J = 8.2, 1.7 Hz, 1 H), 2.43 (s, 3 H), 2.15–2.09 (m, 9 H), 1.79 (t, J = 3.2 Hz, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 172.9 (C_q), 148.6 (C_q), 141.4 (C_q), 133.5 (C_q), 125.2 (CH), 119.6 (CH), 109.6 (CH), 40.3 (CH₂), 36.6 (CH₂), 36.1 (C_q), 28.1 (CH), 21.5 (CH₃).

MS (EI) m/z (%) = 267 ([M]⁺, 100), 135 (60).

HRMS (ESI): m/z calcd for C₁₈H₂₂NO⁺ [M + H]⁺: 268.1696; found: 268.1702.

2-[(3R,5R,7R)-Adamantan-1-yl]-5-chlorobenzo[d]oxazole (3k)

The general procedure was followed using 5-chlorobenzoxazole 1k (61.4 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-hexane/EtOAc 10:1) afforded 3k; yield: 68.0 mg (236 μmol, 59%); white solid; mp 115–116 °C.

IR (ATR): 2906, 2851, 1557, 1451, 1264, 1044, 801, 739, 704 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.63 (d, J = 2.1 Hz, 1 H), 7.37 (d, J = 8.6 Hz, 1 H), 7.23 (dd, J = 8.6, 2.1 Hz, 1 H), 2.19–2.08 (m, 9 H), 1.83–1.76 (m, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 174.3 (C_q), 149.0 (C_q), 142.3 (C_q), 129.3 (C_q), 124.5 (CH), 119.7 (CH), 110.9 (CH), 40.2 (CH₂), 36.5 (CH₂), 36.3 (C_q), 28.0 (CH).

MS (EI): m/z (%) = 287 ([M]⁺, 100), 135 (90).

HRMS (ESI): m/z calcd for C₁₇H₁₉ClNO⁺ [M + H]⁺: 288.1150; found: 288.1155.

2-[(3R,5R,7R)-Adamantan-1-yl]-5-(tert-butyl)benzo[d]oxazole (3l)

The general procedure was followed using benzoxazole 1l (66.1 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 20:1) afforded 3l; yield: 56.0 mg (182 μmol, 45%); white solid; mp 159–160 °C.

IR (ATR): 2906, 2849, 1561, 1480, 1452, 1272, 1041, 924, 800 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.74 (dd, J = 2.0, 0.6 Hz, 1 H), 7.39 (dd, J = 8.6, 0.6 Hz, 1 H), 7.34 (dd, J = 8.6, 2.0 Hz, 1 H), 2.15–2.13 (m, 6 H), 2.12–2.10 (m, 3 H), 1.81 (t, J = 2.9 Hz, 6 H), 1.36 (s, 9 H).

¹³C NMR (126 MHz, CDCl₃): δ = 173.2 (C_q), 148.5 (C_q), 147.5 (C_q), 141.2 (C_q), 121.9 (CH), 116.4 (CH), 109.5 (CH), 40.5 (CH₂), 36.7 (CH₂), 36.3 (C_q), 35.0 (C_q), 32.0 (CH₃), 28.2 (CH).

MS (ESI): m/z (%) = 332 ([M + Na]⁺, 2), 310 ([M + H]⁺, 100).

HRMS (EI): m/z calcd for C₂₁H₂₈NO [M + H]⁺: 310.2165; found: 310.2168.

2-[(3R,5R,7R)-Adamantan-1-yl]-5-bromobenzo[d]oxazole (3m)

The general procedure was followed using benzoxazole 1m (79.2 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol). After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 20:1) afforded 3m; yield: 56.1 mg (169 μmol, 42%); white solid; mp 135–136 °C.

IR (ATR): 2905, 2849, 1555, 1444, 1253, 1040, 907, 871, 798, 682 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.80 (d, J = 1.9 Hz, 1 H), 7.38 (dd, J = 8.4, 1.9 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 2.14–2.11 (m, 9 H), 1.84–1.77 (m, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 174.2 (C_q), 150.0 (C_q), 143.0 (C_q), 127.3 (CH), 122.8 (CH), 116.7 (C_q), 111.6 (CH), 40.3 (CH₂), 36.6 (CH₂), 36.4 (C_q), 28.1 (CH).

MS (ESI): m/z (%) = 334 ([M + H]⁺, 97; ⁸¹Br), 332 ([M + H]⁺, 100; ⁷⁹Br).

HRMS (ESI): m/z calcd for C₁₇H₁₉ ⁷⁹BrNO⁺ [M + H]⁺: 332.0645; found: 332.0648.

2-[(3R,5R,7R)-Adamantan-1-yl]-6-methylbenzo[d]oxazole (3n)

The general procedure was followed using benzoxazole 1n (53.3 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 20:1) afforded 3n; yield: 53.0 mg (198 μmol, 50%); white solid; mp 112–114 °C.

IR (ATR): 2908, 2849, 1566, 1451, 1263, 1234, 1040, 919, 809, 602 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.55 (d, J = 8.1 Hz, 1 H), 7.29–7.27 (m, 1 H), 7.11–7.08 (m, 1 H), 2.46 (s, 3 H), 2.16–2.10 (m, 9 H), 1.83–1.79 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 172.6 (C_q), 150.9 (C_q), 139.1 (C_q), 134.7 (C_q), 125.2 (CH), 119.1 (CH), 110.7 (CH), 40.4 (CH₂), 36.6 (CH₂), 36.2 (C_q), 28.1 (CH), 21.8 (CH₃).

MS (ESI): m/z (%) = 290 ([M + Na]⁺, 9), 268 ([M + H]⁺, 100).

HRMS (EI): m/z calcd for C₁₈H₂₂NO [M + H]⁺: 268.1696; found: 268.1697.

2-[(3R,5R,7R)-Adamantan-1-yl]-6-chlorobenzo[d]oxazole (3o)

The general procedure was followed using benzoxazole 1o (50.2.1 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 10:1) afforded 3o; yield: 52.5 mg (182 μmol, 46%); white solid; mp 150–152 °C.

IR (ATR): 2915, 2851, 1609, 1564, 1460, 1039, 819, 800, 702, 599 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.58 (dd, J = 8.5, 0.4 Hz, 1 H), 7.50–7.46 (m, 1 H), 7.26 (dd, J = 8.5, 2.0 Hz, 1 H), 2.16–2.10 (m, 9 H), 1.84–1.78 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 173.8 (C_q), 150.9 (C_q), 140.2 (C_q), 130.0 (C_q), 124.7 (CH), 120.3 (CH), 111.2 (CH), 40.3 (CH₂), 36.6 (CH₂), 36.3 (C_q), 28.0 (CH).

MS (ESI): m/z (%) = 288 ([M + H]⁺, 60).

HR MS (EI): m/z calcd for C₁₇H₁₉ClNO [M + H]⁺: 288.1150; found: 288.1153.

tert-Butyl 2-[(3R,5R,7R)-Adamantan-1-yl]benzo[d]oxazole-6-carboxylate (3p)

The general procedure was followed using benzoxazole 1p (87.7 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 10:1) afforded 3p; yield: 52.8 mg (161 μmol, 40%); white solid; mp 116–118 °C.

IR (ATR): 2904, 1710, 1291, 1268, 1244, 1154, 1044, 943, 777 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.12 (dd, J = 1.5, 0.6 Hz, 1 H), 7.98 (dd, J = 8.3, 1.5 Hz, 1 H), 7.67 (dd, J = 8.3, 0.6 Hz, 1 H), 2.17–2.10 (m, 9 H), 1.83–1.79 (m, 6 H), 1.60 (s, 9 H).

¹³C NMR (101 MHz, CDCl₃): δ = 175.6 (C_q), 165.5 (C_q), 150.3 (C_q), 145.0 (C_q), 128.6 (C_q), 125.8 (CH), 119.1 (CH), 112.0 (CH), 81.3 (C_q), 40.2 (CH₂), 36.5 (CH₂), 36.5 (C_q), 28.4 (CH₃), 28.0 (CH).

MS (ESI): m/z (%) = 354 ([M + H]⁺, 100), 298 (14).

HR-MS (EI): m/z calcd for C₂₂H₂₈NO₃ [M + H]⁺: 354.2064; found: 354.2064.

2-[(3R,5R,7R)-Adamantan-1-yl]-1-phenyl-1H-benzo[d]imidazole (3q)

The general procedure was followed using 1-phenylbenzimidazole 1q (78.0 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-hexane/EtOAc 10:2) afforded 3q; yield: 80.0 mg (244 μmol, 61%); white solid; mp 185–187 °C.

IR (ATR): 2904, 2850, 1498, 1454, 1375, 1264, 737, 700 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.78 (dt, J = 8.0, 0.9 Hz, 1 H), 7.55–7.51 (m, 3 H), 7.37–7.33 (m, 2 H), 7.21 (ddd, J = 8.2, 7.1, 1.2 Hz, 1 H), 7.10 (ddd, J = 8.2, 7.1, 1.2 Hz, 1 H), 6.71 (dt, J = 8.0, 0.9 Hz, 1 H), 2.05 (d, J = 2.9 Hz, 6 H), 2.00–1.89 (m, 3 H), 1.69–1.54 (m, 6 H).

¹³C NMR (126 MHz, CDCl₃): δ = 161.1 (C_q), 141.2 (C_q), 140.0 (C_q), 138.2 (C_q), 129.3 (CH), 129.3 (CH), 129.2 (CH), 122.3 (CH), 121.9 (CH), 119.0 (CH), 109.9 (CH), 41.4 (CH₂), 37.7 (C_q), 36.5 (CH₂), 28.4 (CH).

MS (EI) m/z (%) = 328 ([M]⁺, 70), 327 (100), 271 (30).

HRMS (ESI): m/z calcd for C₂₃H₂₅N₂ ⁺ [M + H]⁺: 329.2012; found: 329.2018.

8-[(3R,5R,7R)-Adamantan-1-yl]-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (3r)

The general procedure was followed using caffeine (1r; 77.6 mg, 0.40 mmol) and 1-adamantanecarboxylic acid (2; 180 mg, 1.20 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 1:1) afforded 3r; yield: 80.4 mg (245 μmol, 61%); white solid; mp 263–264 °C.

IR (ATR): 2895, 1700, 1660, 1539, 1426, 1361, 1223, 982, 743 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.15 (s, 3 H), 3.54 (s, 3 H), 3.37 (s, 3 H), 2.16–2.08 (m, 9 H), 1.81–1.74 (m, 6 H).

¹³C NMR (101 MHz, CDCl₃): δ = 159.6 (C_q), 155.8 (C_q), 151.9 (C_q), 147.2 (C_q), 108.2 (C_q), 40.0 (CH₂), 36.9 (C_q), 36.6 (CH₂), 34.5 (CH₃), 29.7 (CH₃), 28.3 (CH), 28.0 (CH₃).

MS (ESI): m/z (%) = 329 ([M + H]⁺, 100).

HRMS (EI): m/z calcd for C₁₈H₂₅N₄O₂ ⁺ [M + H]⁺: 329.1972; found: 329.1969.

The analytical data are in accordance with those reported in the literature.[23]

8-[(3R,5R,7R)-Adamantan-1-yl]-7-[2-(methoxymethoxy)propyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (3s)

The general procedure was followed using substrate 1s (85.0 mg, 0.30 mmol) and 1-adamantanecarboxylic acid (2; 162 mg, 0.90 mmol) for 48 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 10:1) afforded 3s; yield: 53.5 mg (129 μmol, 43%); white solid; mp 147–148 °C.

IR (ATR): 2890, 1165, 1536, 1426, 1382, 1137, 1105, 1035, 743 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.55–4.46 (m, 2 H), 4.41 (dd, J = 14.0, 3.6 Hz, 1 H), 4.28–4.22 (m, 2 H), 3.56 (s, 3 H), 3.38 (s, 3 H), 3.01 (s, 3 H), 2.25–2.06 (m, 9 H), 1.80–1.75 (m, 6 H), 1.27 (d, J = 6.3 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃): δ = 160.8 (C_q), 155.4 (C_q), 151.9 (C_q), 147.8 (C_q), 107.6 (C_q), 95.3 (CH₂), 73.1 (CH), 55.2 (CH₃), 52.4 (CH₂), 41.4 (CH₂), 37.6 (C_q), 36.6 (CH₂), 29.7 (CH₃), 28.5 (CH), 28.1 (CH₃), 18.4 (CH₃).

MS (ESI): m/z (%) = 439 ([M + Na]⁺, 100), 417 ([M + H]⁺, 99).

HRMS (ESI): m/z calcd for C₂₂H₃₂N₄O₄Na⁺ [M + Na]⁺: 439.2316; found: 439.2319.

Competition Experiment

The general procedure was followed using benzothiazoles 1e (61.3 mg, 0.40 mmol) and 1b (59.7 mg, 0.40 mmol) as well as 1-adamantanecarboxylic acid (2; 72.0 mg, 0.40 mmol). After aqueous workup and removal of the remaining solvent, the crude mixture was analyzed by ¹H/¹⁹F NMR spectroscopy using 4-fluoroanisole as internal standard (14.5 mg, 0.115 mmol).

Reaction in the Presence of Radical Scavengers

The general procedure was followed using benzothiazole (1a; 54.1 mg, 0.40 mmol), 1-adamantanecarboxylic acid (2; 216 mg, 1.20 mmol) and radical scavengers (1–3 equiv) for 24 h. After aqueous workup, purification by column chromatography on silica gel (n-pentane/Et₂O 10:1) yielded 3a.

On/Off Plot

According to the general procedure, five independent reactions were set up and placed in front of the blue LEDs. The reaction mixtures were sequentially stirred under visible light irradiation and in the absence of light. Every 2 h a reaction vial was removed from the setup and workup was performed according to the general procedure. After a total of 10 h, the obtained isolated yields were plotted with respect to the reaction time.

Fluorescence Quenching Experiments

Sample solutions were prepared in DCE with [Acr-Mes]⁺(ClO₄)⁻ concentration of c = 1.6 × 10^–7 M and varying concentrations of the respective quencher (added to each sample from a stock solution). The sample solutions were degassed prior to measurement by sparging with N₂. Stern–Volmer experiments were conducted with a fixed excitation wavelength of 430 nm and detection at 518 nm (emission maximum). Plotting of the I₀/I value against the concentration of the potential quencher resulted in the graphs (Figures [2b]–d).

Acknowledgment

Generous supports by the Alexander von Humboldt Foundation (fellowship to P.G.) and the DFG (Gottfried-Wilhelm-Leibniz prize to L. A.) are gratefully acknowledged.

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