§ These authors contributed equally to this work
Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
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/H2 O (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 K2 HPO4 . 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 Studiesa
Entry
PC
Base (equiv)
Solvent
Yield (%)
1
PC1
K2 HPO4 (3)
DCE /H2 O (3:1)
83
2
PC2
K2 HPO4 (3)
DCE/H2 O (3:1)
trace
3
PC3
K2 HPO4 (3)
DCE/H2 O (3:1)
11
4
PC4
K2 HPO4 (3)
DCE/H2 O (3:1)
0
5
PC5
K2 HPO4 (3)
DCE/H2 O (3:1)
0
6
PC6
K2 HPO4 (3)
DCE/H2 O (3:1)
0
7
PC1
K2 HPO4 (3)
CH2 Cl2 /H2 O (3:1)
74
8
PC1
K2 HPO4 (3)
CHCl3 /H2 O (3:1)
9
9
PC1
K2 HPO4 (3)
H2 O
7
10
PC1
K2 HPO4 (3)
DCE
trace
11
PC1
Na2 HPO4 (3)
DCE/H2 O (3:1)
77
12
PC1
NaHCO3 (3)
DCE/H2 O (3:1)
66
13
PC1
K2 HPO4 (2)
DCE/H2 O (3:1)
71
14
PC1
K2 CO3
DCE/H2 O (3:1)
25
15
PC1
KOAc
DCE/H2 O (3:1)
24
16
PC1
K3 PO4
DCE/H2 O (3:1)
21
17
PC1
–
DCE/H2 O (3:1)
trace
18
–
K2 HPO4 (3)
DCE/H2 O (3:1)
0
19
PC1
K2 HPO4 (3)
DCE/H2 O (3:1)
0b
20
PC1
K2 HPO4 (3)
DCE/H2 O (3:1)
21c
21
PC1
K2 HPO4 (3)
DCE/H2 O (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 (λmax = 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 1 H 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
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), K2 HPO4 (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 H2 O (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 CH2 Cl2 (10 mL) and H2 O (10 mL), and the phases were separated. The aqueous layer was extracted with CH2 Cl2 (2 × 10 mL), the combined organic phases were dried (Na2 SO4 ), and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (n -pentane or n -hexane/Et2 O 20:1 to 2:1) affording the corresponding product 3 .
2-[(3R ,5R ,7R )-Adamantan-1-yl]benzo[d ]thiazole (3a)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 182.3 (Cq ), 153.3 (Cq ), 134.5 (Cq ), 125.8 (CH), 124.5 (CH), 122.8 (CH), 121.7 (CH), 43.1 (CH2 ), 40.3 (Cq ), 36.7 (CH2 ), 28.7 (CH).
MS (ESI): m /z (%) = 270 ([M + H]+ , 100).
HRMS (EI): m /z calcd for C17 H20 NS+ [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)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 181.2 (Cq ), 151.4 (Cq ), 134.6 (Cq ), 134.5 (Cq ), 127.3 (CH), 122.2 (CH), 121.4 (CH), 43.1 (CH2 ), 40.2 (Cq ), 36.7 (CH2 ), 28.7 (CH), 21.6 (CH3 ).
MS (ESI): m /z (%) = 284 ([M + H]+ , 100).
HRMS (ESI): m /z calcd for C18 H22 NS+ [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)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 179.8 (Cq ), 157.3 (Cq ), 147.8 (Cq ), 135.7 (Cq ), 123.2 (CH), 114.9 (CH), 104.4 (CH), 55.9 (CH3 ), 43.1 (CH2 ), 40.1 (Cq ), 36.7 (CH2 ), 28.7 (CH).
MS (ESI): m /z (%) = 300 ([M + H]+ , 100).
HRMS (ESI): m /z calcd for C18 H22 NOS+ [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)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 185.7 (Cq ), 155.4 (Cq ), 134.7 (Cq ), 126.8 (q, 2
J
C,F = 32.7 Hz, Cq ), 124.4 (q, 1
J
C,F = 272.0 Hz, Cq ) 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 (Cq ), 36.6 (CH2 ), 28.7 (CH).
19 F NMR (376 MHz, CDCl3 ): δ = –61.3 (s).
MS (ESI): m /z (%) = 338 ([M + H]+ , 13), 300 (100).
HRMS (EI): m /z calcd for C18 H19 F3 NS+ [M + H]+ : 338.1185; found: 338.1188.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-6-fluorobenzo[d ]thiazole (3e)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 182.0 (d, 5
J
C,F = 3.1 Hz, Cq ), 160.2 (d, 1
J
C,F = 244.2 Hz, Cq), 149.9 (d, 4
J
C,F = 1.6 Hz, Cq ), 135.5 (d, 3
J
C,F = 11.2 Hz, Cq ), 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 (Cq ), 36.6 (CH2 ), 28.7 (CH).
19 F NMR (376 MHz, CDCl3 ): δ = –117.4 (s).
MS (ESI): m /z (%) = 288 ([M + H]+ , 100).
HRMS (EI): m /z calcd for C17 H19 NSF+ [M + H]+ : 288.1217; found: 288.1219.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-6-chlorobenzo[d ]thiazole (3f)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 182.8 (Cq ), 151.9 (Cq ), 135.8 (Cq ), 130.4 (Cq ), 126.6 (CH), 123.5 (CH), 121.3 (CH), 43.1 (CH2 ), 40.4 (Cq ), 36.6 (CH2 ), 28.7 (CH).
MS (ESI): m /z (%) = 304 ([M + H]+ , 100).
HRMS (ESI): m /z calcd for C17 H19 ClNS+ [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)
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/Et2 O 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 .
1 H 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).
13 C NMR (76 MHz, CDCl3 ): δ = 182.9 (Cq ), 152.2 (Cq ), 136.3 (Cq ), 129.2 (CH), 124.2 (CH), 123.9 (CH), 118.0 (Cq ), 43.0 (CH2 ), 40.4 (Cq ), 36.6 (CH2 ), 28.6 (CH).
MS (ESI): m /z (%) = 348 ([M + H]+ , 100; 79 Br).
HRMS (ESI): m /z calcd for C17 H19
79 BrNS+ [M + H]+ : 348.0416; found: 348.0420.
Ethyl 2-[(3R ,5R ,7R )-Adamantan-1-yl]benzo[d ]thiazole-6-carboxylate (3h)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 186.0 (Cq ), 166.4 (Cq ), 156.3 (Cq ), 134.4 (Cq ), 127.1 (CH), 126.7 (Cq ), 123.9 (CH), 122.4 (CH), 61.3 (CH2 ), 43.0 (CH2 ), 40.7 (Cq ), 36.6 (CH2 ), 28.6 (CH), 14.5 (CH3 ).
MS (ESI): m /z (%) = 342 [M + H]+ (100).
HRMS (EI): m /z calcd for C20 H24 NO2 S+ [M + H]+ : 342.1522; found: 342.1524.
2-[(3R ,5R ,7R )-Adamantan-1-yl]benzo[d ]oxazole (3i)
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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 172.9 (Cq ), 150.5 (Cq ), 141.2 (Cq ), 124.2 (CH), 123.9 (CH), 119.7 (CH), 110.3 (CH), 40.2 (CH2 ), 36.5 (CH2 ), 36.0 (Cq ), 27.9 (CH).
MS (ESI): m /z (%) = 254 ([M + H]+ , 100), 276 ([M + Na]+ , 15).
HRMS (ESI): m /z calcd for C17 H20 NO+ [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)
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 .
1 H 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).
13 C NMR (126 MHz, CDCl3 ): δ = 172.9 (Cq ), 148.6 (Cq ), 141.4 (Cq ), 133.5 (Cq ), 125.2 (CH), 119.6 (CH), 109.6 (CH), 40.3 (CH2 ), 36.6 (CH2 ), 36.1 (Cq ), 28.1 (CH), 21.5 (CH3 ).
MS (EI) m /z (%) = 267 ([M]+ , 100), 135 (60).
HRMS (ESI): m /z calcd for C18 H22 NO+ [M + H]+ : 268.1696; found: 268.1702.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-5-chlorobenzo[d ]oxazole (3k)
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 .
1 H 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).
13 C NMR (126 MHz, CDCl3 ): δ = 174.3 (Cq ), 149.0 (Cq ), 142.3 (Cq ), 129.3 (Cq ), 124.5 (CH), 119.7 (CH), 110.9 (CH), 40.2 (CH2 ), 36.5 (CH2 ), 36.3 (Cq ), 28.0 (CH).
MS (EI): m /z (%) = 287 ([M]+ , 100), 135 (90).
HRMS (ESI): m /z calcd for C17 H19 ClNO+ [M + H]+ : 288.1150; found: 288.1155.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-5-(tert -butyl)benzo[d ]oxazole (3l)
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/Et2 O 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 .
1 H 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).
13 C NMR (126 MHz, CDCl3 ): δ = 173.2 (Cq ), 148.5 (Cq ), 147.5 (Cq ), 141.2 (Cq ), 121.9 (CH), 116.4 (CH), 109.5 (CH), 40.5 (CH2 ), 36.7 (CH2 ), 36.3 (Cq ), 35.0 (Cq ), 32.0 (CH3 ), 28.2 (CH).
MS (ESI): m /z (%) = 332 ([M + Na]+ , 2), 310 ([M + H]+ , 100).
HRMS (EI): m /z calcd for C21 H28 NO [M + H]+ : 310.2165; found: 310.2168.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-5-bromobenzo[d ]oxazole (3m)
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/Et2 O 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 .
1 H 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).
13 C NMR (126 MHz, CDCl3 ): δ = 174.2 (Cq ), 150.0 (Cq ), 143.0 (Cq ), 127.3 (CH), 122.8 (CH), 116.7 (Cq ), 111.6 (CH), 40.3 (CH2 ), 36.6 (CH2 ), 36.4 (Cq ), 28.1 (CH).
MS (ESI): m /z (%) = 334 ([M + H]+ , 97; 81 Br), 332 ([M + H]+ , 100; 79 Br).
HRMS (ESI): m /z calcd for C17 H19
79 BrNO+ [M + H]+ : 332.0645; found: 332.0648.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-6-methylbenzo[d ]oxazole (3n)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 172.6 (Cq ), 150.9 (Cq ), 139.1 (Cq ), 134.7 (Cq ), 125.2 (CH), 119.1 (CH), 110.7 (CH), 40.4 (CH2 ), 36.6 (CH2 ), 36.2 (Cq ), 28.1 (CH), 21.8 (CH3 ).
MS (ESI): m /z (%) = 290 ([M + Na]+ , 9), 268 ([M + H]+ , 100).
HRMS (EI): m /z calcd for C18 H22 NO [M + H]+ : 268.1696; found: 268.1697.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-6-chlorobenzo[d ]oxazole (3o)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 173.8 (Cq ), 150.9 (Cq ), 140.2 (Cq ), 130.0 (Cq ), 124.7 (CH), 120.3 (CH), 111.2 (CH), 40.3 (CH2 ), 36.6 (CH2 ), 36.3 (Cq ), 28.0 (CH).
MS (ESI): m /z (%) = 288 ([M + H]+ , 60).
HR MS (EI): m /z calcd for C17 H19 ClNO [M + H]+ : 288.1150; found: 288.1153.
tert -Butyl 2-[(3R ,5R ,7R )-Adamantan-1-yl]benzo[d ]oxazole-6-carboxylate (3p)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 175.6 (Cq ), 165.5 (Cq ), 150.3 (Cq ), 145.0 (Cq ), 128.6 (Cq ), 125.8 (CH), 119.1 (CH), 112.0 (CH), 81.3 (Cq ), 40.2 (CH2 ), 36.5 (CH2 ), 36.5 (Cq ), 28.4 (CH3 ), 28.0 (CH).
MS (ESI): m /z (%) = 354 ([M + H]+ , 100), 298 (14).
HR-MS (EI): m /z calcd for C22 H28 NO3 [M + H]+ : 354.2064; found: 354.2064.
2-[(3R ,5R ,7R )-Adamantan-1-yl]-1-phenyl-1H -benzo[d ]imidazole (3q)
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 .
1 H 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).
13 C NMR (126 MHz, CDCl3 ): δ = 161.1 (Cq ), 141.2 (Cq ), 140.0 (Cq ), 138.2 (Cq ), 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 (Cq ), 36.5 (CH2 ), 28.4 (CH).
MS (EI) m /z (%) = 328 ([M]+ , 70), 327 (100), 271 (30).
HRMS (ESI): m /z calcd for C23 H25 N2
+ [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)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 159.6 (Cq ), 155.8 (Cq ), 151.9 (Cq ), 147.2 (Cq ), 108.2 (Cq ), 40.0 (CH2 ), 36.9 (Cq ), 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 C18 H25 N4 O2
+ [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)
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/Et2 O 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 .
1 H 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).
13 C NMR (101 MHz, CDCl3 ): δ = 160.8 (Cq ), 155.4 (Cq ), 151.9 (Cq ), 147.8 (Cq ), 107.6 (Cq ), 95.3 (CH2 ), 73.1 (CH), 55.2 (CH3 ), 52.4 (CH2 ), 41.4 (CH2 ), 37.6 (Cq ), 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 C22 H32 N4 O4 Na+ [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 1 H/19 F NMR spectroscopy using 4-fluoroanisole as internal standard (14.5 mg, 0.115 mmol).
Reaction in the Presence of Radical Scavengers
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/Et2 O 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
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).