Organocatalyzed, Visible-Light Photoredox-Mediated, One-Pot Minisci

Note Cite This: J. Org. Chem. 2018, 83, 3000−3012

pubs.acs.org/joc

Organocatalyzed, Visible-Light Photoredox-Mediated, One-Pot Minisci Reaction Using Carboxylic Acids via N‑(Acyloxy)phthalimides Trevor C. Sherwood,* Ning Li, Aliza N. Yazdani, and T. G. Murali Dhar Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543-4000 United States S Supporting Information *

ABSTRACT: An improved, one-pot Minisci reaction has been developed using visible light, an organic photocatalyst, and carboxylic acids as radical precursors via the intermediacy of in situ-generated N-(acyloxy)phthalimides. The conditions employed are mild, demonstrate a high degree of functional group tolerance, and do not require a large excess of the carboxylic acid reactant. As a result, this reaction can be applied to drug-like scaffolds and molecules with sensitive functional groups, enabling late-stage functionalization, which is of high interest to medicinal chemistry.

T

generation of the radical was attractive as many Minisci variants involve oxidation of the radical precursor and therefore require an external oxidant to turn over the catalytic cycle. It was our hope that the use of NAPs would obviate the need for an external oxidant. We also sought to identify an organic photocatalyst to avoid the use of an expensive, metal-based catalyst, such as iridium-based complexes often used in photoredox chemistry.18,26 Finally, it was our ultimate goal to develop a one-pot Minisci protocol in which a starting carboxylic acid would undergo NAP formation in situ followed by a subsequent addition of a heteroarene and photocatalyst. Such a process would enable rapid analogue generation using a class of reagents that are abundantly available in a high level of structural diversity and avert the need for isolation of a prefunctionalized alkyl partner. From a mechanistic standpoint, we envisioned the photocatalytic cycle in Scheme 1 would be operative in our desired Minisci reaction. The NAP (1) could oxidatively quench the excited photocatalyst via single-electron transfer (SET) and undergo reductive fragmentation to generate the alkyl radical 2 in addition to CO2 and phthalimide. Radical intermediate 2 could attack a protonated heteroarene 3 to generate adduct 4, which could undergo deprotonation to generate α-amino radical 5. Intermediate 5 is well-poised to undergo SET with the oxidized form of the photocatalyst to generate protonated product 6, turning over the catalytic cycle. After extensive screening, we identified the organic photocatalyst 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN, 10, E1/2PC+/PC* = −1.04 vs SCE)27 as the optimal species for use in our photoredox-mediated Minisci reaction. As described in Table 1, entry 1, adding lepidine (8), TFA, and 10 to a solution of the NAP of cyclohexanecarboxylic acid (7) (formed in situ by mixing 7, N-hydroxyphthalimide, DMAP, and N,N′-diisopropylcarbodiimide (DIC) in DMSO) and

he Minisci reaction is well-appreciated as a way to C−H functionalize heteroarenes.1−3 This transformation classically uses an excess of carboxylic acid in conjunction with an oxidant, strong acid, and heat to functionalize at electrondeficient positions of an arene substrate. These conditions are harsh, and therefore, the functional group tolerance is low. In the ensuing decades since Minisci’s original disclosure,4 the reaction has been explored by a number of groups. Several modern versions of the Minisci reaction have been developed using photoredox chemistry employing radical precursors such as bromides,5 iodides,6 trifluoroborates,7 boronic acids,8 primary alcohols,9,10 activated amines,11 ethers,12 and peresters.13 Recently, carboxylic acids were also reported to be viable radical precursors in a metal-mediated photoredox Minisci reaction when used in 10-fold excess to the heteroarene in conjunction with an added oxidant.14 Nonphotoredoxmediated methods have also been developed, most notably the use of alkyl sulfinate salts as radical precursors.15 Many of these recently reported methods still require a large excess of the radical precursor, an added oxidant, or are limited in their scope. We sought to identify mild conditions that employed near-stoichiometric levels of a radical precursor that would be commercially available with a diverse array of incorporated functional groups. It was our aim to develop a reaction with a high functional group tolerance that could be used either as an early step in a synthetic campaign or as a latestage functionalization (LSF) approach to diversify a complex scaffold rapidly. LSF strategies are considered highly advantageous in disciplines such as medicinal chemistry wherein the ability to generate a diverse library of analogues to understand structure−activity relationship (SAR) is essential.16 To satisfy these criteria, we focused on carboxylic acids and visible-light photoredox chemistry.17,18 We were specifically inspired by the work from Okada19,20 and Overman21−24 in which N-(acyloxy)phthalimides (NAPs) are exposed to light in the presence of a photosensitizer19 or photocatalyst20−24 to generate alkyl radicals after single-electron reductive fragmentation (E1/2 = −1.26 to −1.39 V vs SCE).19,25 Reductive © 2018 American Chemical Society

Received: January 23, 2018 Published: February 8, 2018 3000

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

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The Journal of Organic Chemistry Scheme 1. Proposed Photocatalytic Cyclea

a

= −0.89 vs SCE),18 which also has a weak reduction potential in the excited state relative to the NAP substrates. Fu and Shang invoked the possibility of in situ photocatalyst reduction by DMA or another component of the reaction mixture to iridium(II) (E1/2III/II = −1.37 vs SCE), which has an appropriate potential for NAP reduction. In our reaction, in situ reduction of 10 is also conceivable to form a stronger reducing species (E1/2PC/PC− = −1.21 vs SCE)27 to reduce the NAP, possibly formed by 10 oxidizing N,N′-diisopropylurea byproduct from NAP formation, DMAP, or another component of the reaction mixture.30 Alternatively, thermodynamically unfavorable SET processes have been documented, and when such a process is coupled to a subsequent irreversible step, reactions that would seem difficult can occur.31 In our proposed catalytic cycle, irreversible decarboxylative fragmentation after SET may enable our reaction to proceed even if the potentials for photoexcited 10 and the NAP intermediate are not perfectly matched. Following up on Fu’s and Shang’s results, we attempted our one-pot procedure in DMA with 11 (entry 2) and obtained a slightly diminished 71% yield, although using DMSO as a solvent with catalyst 11 (entry 3) provided equivalent results to catalyst 10. Catalysts with higher reduction potentials in the photoexcited state were also screened, and replacing 10 in our standard conditions with Ir(ppy)3 (12, E1/2IV/III* = −1.73 vs SCE)18 provided equivalent results to both catalysts 10 and 11 (entry 4). Finally, the organic catalyst 10-phenylphenothiazine (13, E1/2PC+/PC* = −2.1 vs SCE)32,33 was attempted, but poor conversion was observed as only 7% yield of 9 was obtained (entry 5). Control reactions revealed that, in the presence of light but no photocatalyst, the reaction could still occur, though more slowly than with a photocatalyst present (entries 6 and 7). Although Fu and Shang reported that isolated NAPs did not react in the absence of a photocatalyst with visible light irradiation,28,29 our findings are in line with those reported by Overman,23 who observed slow NAP reactivity with exposure to visible light in the absence of a photocatalyst. Subsequent control reactions demonstrated that reactions run in the dark (entries 8−10) gave no product, and in the absence of NAP (entries 11 and 12), only trace amounts of product could be observed. Finally, attempts to accelerate NAP formation with the use of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) instead of DIC resulted in only 18% yield of 9, possibly due to the presence of byproducts from TBTU or interference from stoichiometric Et3N. Therefore, DIC with catalytic DMAP was selected for NAP formation. With our envisioned one-pot, organocatalyzed photoredoxmediated Minisci reaction in hand, we embarked on substrate scope exploration. As shown in Scheme 2, a wide variety of carboxylic acids could alkylate C-2 of lepidine (8) under our standard conditions employing TFA or camphor-10-sulfonic acid (CSA) to protonate the heteroarene. For electron-deficient radicals such as primary alkyl radicals and cyclopropane radical, CSA gave higher conversions than TFA. All reactions were completed in 3 h as judged by consumption of NAP intermediate unless otherwise indicated (Schemes 2 and 3). A methyl group (14) as well as small, unfunctionalized primary and secondary alkyl groups (15 − 17) could be introduced in modest to good yields. A cyclopropyl group (18) could be appended in 17% yield with an extended reaction time. Introduction of a trifluoroethyl group (19) was not

PC = photocatalyst. SET = single-electron transfer.

Table 1. Optimization for Coupling of Cyclohexanecarboxylic Acid (7) and Lepidine (8)

entry 1 2 3 4 5 6 7 8

none DMA used as a solvent none none none none none none

9 10 11 12

none none no DIC no DIC, N-hydroxyphthalimide, or DMAP TBTU, Et3N, 15 min

13 a

change to photochemistry

yield of 9 (%)a

none 1 mol % 11, DMA 1 mol % 11 1 mol % 12 1 mol % 13 no catalyst no catalyst, 24 h no catalyst, no light, 48 °C no light, rt no light, 48 °C none none

83b 71 83 83 7 28 80 NDc ND ND traced traced

none

18e

change to esterification

b

Isolated yields on a 0.25 mmol scale. Entry 1 standard conditions: run with lepidine (8, 1.0 equiv), cyclohexanecarboxylic acid (7, 1.5 equiv), N-hydroxyphthalimide (1.5 equiv), DIC (1.5 equiv), DMAP (5 mol %), TFA (2.0 equiv), and 4-CzIPN (10, 1 mol %) in DMSO (0.1 M). cND = not detected. dTrace observed by LCMS. e0.5 mmol scale. 10 = 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene. 11 = [Ir(dF(CF3)ppy)2(dtbbpy)]PF6. 12 = Ir(ppy)3. 13 = 10-phenylphenothiazine.

exposing the solution to 34 W blue LEDs (see Experimental Section) under a N2 atmosphere for 3 h without an external cooling fan (internal reaction temperatures range from 40 to 48 °C) provided 83% yield of the desired Minisci product 9. It may be somewhat surprising that 10 is a viable photocatalyst for this reaction with such a weak reducing potential in the photoexcited state relative to the NAP intermediate, but there are some possible explanations. During the course of our work, Fu, Shang, and co-workers28,29 disclosed a two-step Minisci procedure using NAPs synthesized and chromatographed in a first step followed by a second step of photoredox-mediated Minisci reaction employing DMA as a solvent and the photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (11, E1/2IV/III* 3001

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

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The Journal of Organic Chemistry Scheme 2. Carboxylic Acid Scopea

a

Isolated yields on a 0.25 mmol scale following the conditions from Table 1, entry 1. b(1R)-(−)-CSA (2.0 equiv) used. cND = not detected. Product also not detected when the reaction was run with 1 mol % of 11. e10:1 ratio of 24 to product with second t-Bu group; regiochemistry unassigned. f(±)-CSA (1.0 equiv) used. gTFA (1.0 equiv) used. h63% yield when run with (1R)-(−)-CSA (1.0 equiv). d

heteroarenes reacted well, although mixtures of product isomers and products with bis-alkylation were observed in some cases. 4-Methylpyridine provided 39 in 50% yield and 40 in 19% yield, and 4-chloropyridine formed 41 in 36% yield and 42 in 30% yield. Quinoline underwent functionalization at the C-2 and C-4 positions to give all three possible products 43− 45, while quinaldine formed the monoalkylated product 46 in 58% yield. Isoquinoline reacted smoothly to give 47 in 78% yield, and phthalazine and quinoxaline, each possessing multiple reactive sites, formed products 48−51 with modest yields. 4-Quinazolinone gave 55% yield of 52, and purine provided monoalkylated 53 in 59% yield along with 20% yield of an inseparable mixture of two bis-alkylated materials. 4Chloro-7-azaindole proved relatively unreactive providing 54 in a poor yield. Moving on to 5-membered heterocycles, benzimidazole formed the desired product 55 in 39% yield, and benzothiazole provided the desired product 56 in 31% yield. Unfortunately, benzoxazole proved less reactive and gave product 57 in only 5% yield. Indazole also proved recalcitrant with none of 58 isolated although trace amounts were observed by LCMS, but caffeine did afford desired product 59 in 20% yield. Lastly, nucleosides and marketed drug scaffolds were investigated as LSF substrates to demonstrate the functional group tolerance of this method as well as its utility in library synthesis for SAR development. Nebularine and peracetylated nebularine both reacted smoothly to give 60 and 61 in 73% and 61% yields, respectively, demonstrating the robustness of this method in the presence of primary and secondary hydroxyl groups. Adenosine gave only 11% yield of 62, likely due to the 6-amino group blocking the most reactive position. Nevertheless, 62 demonstrates that unprotected nucleosides with free amines can provide functionalized analogues with this method. The formation of 63 in 48% yield from quinine further demonstrates the functional group tolerance of this method, with a terminal alkene present in addition to a tertiary amine and free alcohol. Analogues of camptothecin have been of high interest due to its anticancer activity,34 and our method provides derivative 64 in 17% yield. The anticancer agent

successful, likely due to the electrophilic character of the generated radical. An allyl group (20) could not be introduced under our developed conditions with either catalyst 10 or 11, and attempts to introduce a propargyl group also proved fruitless (21). While a benzyl group (22) could be introduced in only 15% yield, the more electron-rich, indole-containing substrate 23 was produced in a slightly more useful yield of 32%. Tertiary alkyl groups worked quite well for the developed conditions as a tert-butyl group (24) and a [2.2.2]bicyclooctane group (25) were appended in 88% yield and 76% yield, respectively. However, a tertiary benzylic group could not be introduced (26). When examining alkyl partners with heteroatom-containing functional groups, a primary alkyl bromide was tolerant of the reaction conditions, providing 27 in 38% yield from the corresponding carboxylic acid. The decrease in yield of 27 relative to unfunctionalized primary alkyl substrates like 15 and 16 may be due to the formation of small amounts of byproducts from some reactivity of the primary alkyl bromide in 27. Protected, racemic glutamic acid with a free carboxylic acid side chain formed the protected non-natural amino acid derivative 28 in 28% yield, and BOC-protected glycine provided amino-methylated 29 in 67% yield. Pleasingly, an alkoxymethylated product (30) could also be obtained in 66% yield. Saturated, nitrogen-containing rings of various sizes proved to be viable coupling partners in our reaction, affording moderate yields of products 31−34. Products with tetrahydropyran (35) and tetrahydrothiopyran (36) were formed in 58% and 59% yields, respectively. In general, the success of substrates with BOC groups (28, 29, 31−33) or an oxidizable thioether functional group (36) highlights the mildness of the reaction conditions. Finally, 1-cyclohexenoic acid and benzoic acid proved unreactive as substrates (37 and 38), which may be expected given that these products would require the intermediacy of sp2-centered radicals to form. Regarding the heteroarene scope, we explored simple 5- and 6-membered rings (Scheme 3a) as well as more complex structures including nucleosides and marketed drug scaffolds (Scheme 3b). In general, substrates containing 6-membered 3002

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

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The Journal of Organic Chemistry Scheme 3. Heteroarene Scopea

a

Isolated yields on a 0.25 mmol scale following the conditions from Table 1, entry 1. bTFA (1.0 equiv) used. cAlso isolated 20% yield of inseparable isomers with a second Cy group. d0.10 mmol scale. eReactions were run at listed scales with 4-chloro-2-methylpyridine and 4(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid.

vemurafenib35 afforded the analogue 65 in 31% yield, showing a surprising preference for alkylation at C-2 of the 7-azaindole system, likely owing to the electrophilicity induced by the C-3 difluoroarylketone and possible steric shielding of C-4 and C-6 by the C-5 4-chlorophenyl group.36 By contrast, in the reaction to form 54, alkylation was only observed at C-6. In addition, imatinib, a marketed drug to treat cancer,37 underwent the Minisci reaction to give 66−71 in a combined yield of 48%. While this may seem an inefficient synthesis of any one analogue, the ability to generate multiple compounds from one reaction can be advantageous from a LSF and library design perspective, providing multiple derivatives to establish SAR. To probe the scale-dependence of our reaction, the formation of 72 was investigated on 0.25, 1.25, and 6.25 mmol scales, giving relatively consistent yields of 68%, 78%, and 73%, respectively (Scheme 3c). These reactions were run in a 2-dram vial, a 20 mL vial, and a 200 mL flask, and while the small-scale reaction was sealed, the mid- and large-scale

reactions were each affixed with a N2 balloon to accommodate the pressure build-up from CO2 generation. Furthermore, the large-scale reaction required extended time to go to completion, perhaps limited by the penetration of light due to the smaller surface area to volume ratio at this scale. In conclusion, we have developed a mild, one-pot, organocatalyzed photoredox-mediated Minisci reaction employing carboxylic acids as radical precursors, which displays a high degree of functional group tolerance. The use of an organic photocatalyst avoids elemental impurity toxicity concerns presented by iridium-based catalysts, and the one-pot procedure as well as the extensive substrate scope explored represent significant advantages over the existing photoredox Minisci variant with isolated NAPs.28,29 We believe this extension of the Minisci reaction can be used as an early step in a synthetic campaign or a tool for LSF by researchers in fields like medicinal chemistry wherein C−H functionalization is of high importance. 3003

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

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The Journal of Organic Chemistry

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or a 1.5 M aqueous solution of K2HPO4 was added until the solution reached roughly pH 8 as judged by pH paper. The organic layer was separated, washed with water (35 mL), and made slightly basic by the addition of either solid NaHCO3 or a 1.5 M aqueous solution of K2HPO4 (1.5 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford a crude solid. This crude material was purified by silica gel chromatography on a Teledyne Isco instrument unless otherwise noted. The fractions containing the desired product are isolated and concentrated. Entries 1−12 in Table 1 were run following the general procedure for the Minisci reaction using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv). The reactions were irradiated with blue light for 3 h in the photochemical portion. Reactions in entries 2−13 were run with the noted modifications to either the in situ formation of the NAP or the photochemical portion. Entries 8−10 were wrapped in foil and stirred without blue LED irradiation. Additionally, entries 8 and 10 were heated in a metal heating block. Entries 11 and 12 were run without 24 h of stirring normally allotted for in situ formation of the NAP and immediately progressed to the photochemical portion of the reaction following the listed modification for the esterification. For entry 13 in Table 1, a solution of cyclohexanecarboxylic acid (7, 96 mg, 0.75 mmol, 1.5 equiv), N-hydroxyphthalimide (122 mg, 0.75 mmol, 1.5 equiv), and triethylamine (76 mg, 0.75 mmol, 1.5 equiv) in DMSO (2.5 mL) was added to TBTU (241 mg, 0.75 mmol, 1.5 equiv). The reaction was stirred at room temperature for 15 min to form the NAP intermediate in situ. Then, a solution of lepidine (8, 72 mg, 0.50 mmol, 1.0 equiv) and TFA (114 mg, 0.077 mL, 1.0 mmol, 2.0 equiv) in DMSO (2 mL for solution formation and initial transfer +0.5 mL rinse of vial containing transferred solution of heteroarene and protic acid) was transferred to the solution containing the NAP. Then 4-CzIPN (10, 3.9 mg, 4.9 μmol, 1 mol %) was added to the reaction mixture. The solution was bubbled vigorously for 60 s with nitrogen gas, sealed, and placed between two blue Kessil brand KSH150B Grow Light LED 34 W lamps secured with gooseneck clamps. No cooling fan was used. The reaction was stirred and irradiated with blue light for 3 h. Upon completion, the workup from the general procedure was used. The crude material was purified by silica gel chromatography on a Teledyne Isco instrument to give 2-cyclohexyl-4-methylquinoline (9, 20 mg, 18% yield, 74% analytical HPLC purity). 2-Cyclohexyl-4-methylquinoline (9). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-cyclohexyl-4-methylquinoline (9, 47 mg, 83% yield) as a clear oil: LCMS tR = 0.69 min; 1H NMR (499 MHz, chloroform-d) δ 8.08−8.02 (m, 1H), 7.93 (dd, J = 8.3, 0.9 Hz, 1H), 7.65 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.48 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.16 (app d, J = 0.7 Hz, 1H), 2.88 (tt, J = 12.1, 3.4 Hz, 1H), 2.67 (d, J = 0.9 Hz, 3H), 2.05−1.96 (m, 2H), 1.92−1.85 (m, 2H), 1.82−1.75 (m, 1H), 1.62 (qd, J = 12.6, 3.1 Hz, 2H), 1.47 (qt, J = 12.9, 3.3 Hz, 2H), 1.39−1.28 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 166.6, 147.7, 144.3, 129.6, 129.0, 127.1, 125.4, 123.6, 120.3, 47.7, 32.9, 26.7, 26.2, 18.9; HRMS (ESI) m/z calcd for C16H20N [M + H+] 226.1590, found 226.1581. 2,4-Dimethylquinoline (14). The compound was prepared by the general procedure using acetic acid (23 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with 1R(−)-CSA (116 mg, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2,4dimethylquinoline (14, 10 mg, 26% yield) as a clear oil: LCMS tR = 0.50 min; 1H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 8.3, 1.0 Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.50 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.14 (app d, J = 0.8 Hz, 1H), 2.70 (s, 3H), 2.67 (d, J = 0.9 Hz, 3H); 13C NMR (101 MHz,

EXPERIMENTAL SECTION

General Information. Unless otherwise stated, reactions were run in 2-dram vials purchased from Chemglass with caps containing a pressure relief septum. Reactions were monitored by liquid chromatography/mass spectrometry (LCMS) on a Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm); solvent A water with 0.05% TFA, solvent B acetonitrile with 0.05% TFA; gradient from 2% B to 98% B over 1.0 min then 98% B for 0.5 min, flow rate 0.8 mL/ min, detection at 220 nm and low-resolution mass spectrometry detection with either Waters SQ Detector 2 with electrospray ionization (ESI) or Waters 3100 Detector with ESI. Flash column chromatography was performed on a Teledyne Isco instrument using redisep Rf silica columns and 40−63 μm silica gel from Fluka Analytical. Hexanes, EtOAc, DCM, and MeOH used for purification were purchased as UPLC grade from Sigma-Aldrich. Analytical HPLC purity and retention times, where noted, were obtained using a Shimadzu Scientific Instruments SIL-10AF HPLC with two columns: column 1 ACE Ucore Super C18 (3.0 mm × 125 mm, 2.5 μm) and column 2 ACE UCore SuperHexPh (3.0 mm × 125 mm, 2.5 μm); solvent A 95% water/5% acetonitrile with 0.05% TFA, solvent B 5% water/95% acetonitrile with 0.05% TFA; gradient from 10% B to 100% B over 12 min, held at 100% B from 12 to 15 min; flow rate 1 mL/ min; detection at 220 nm. Reaction solvents (DMSO and DMA) were purchased from Sigma-Aldrich in a Sure/Seal bottle and used without further purification. All reagents and organic building blocks were purchased from commercial suppliers and used without further purification. All yields are isolated yields for materials that are >95% pure as judged by HPLC and NMR unless otherwise stated. 1 H and 13C NMR spectra were obtained on Bruker Avance III and Avance III HD instruments at fields of 400, 500, and 700 MHz, equipped with a 5 mm BBFO Probe, Prodigy BBO Probe, and TCI Cryoprobe, respectively. All NMR spectra were obtained at room temperature unless otherwise stated. NMR spectra were internally referenced to the solvent peak.38 Chemical shifts are reported in parts per million (ppm). Data is reported in the following format: chemical shift (δ ppm), descriptor if applicable (br = broad, app = apparent), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, spt = septet), coupling constant (Hz), integration. Highresolution mass spectra (HRMS) were obtained on a ThermoFinnigan LTQ Orbitrap XL (ESI) or a ThermoFinnigan Orbitrap Exactive (ESI). General Procedure for the Minisci Reaction. The reaction was run in a 2-dram vial with a cap containing a pressure relief septum. To a solution of the carboxylic acid substrate (0.375 mmol, 1.5 equiv), Nhydroxyphthalimide (61.2 mg, 0.375 mmol, 1.5 equiv), and DMAP (1.5 mg, 0.0125 mmol, 5 mol %) in DMSO (1.25 mL) was added DIC (0.0587 mL, 0.375 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h to form the NAP intermediate in situ. Then, a solution of the heteroarene substrate (0.250 mmol, 1.0 equiv) and the appropriate protic acid [TFA (57.0 mg, 0.0383 mL, 0.500 mmol, 2.0 equiv) if the carboxylic acid substrate generates a secondary or tertiary radical; 1R-(−)-CSA (116 mg, 0.500 mmol, 2.0 equiv) if the carboxylic acid substrate generates a primary, cyclopropyl, or methyl radical] in DMSO (0.75 mL for solution formation and initial transfer +0.5 mL rinse of vial containing transferred solution of heteroarene and protic acid) was transferred to the solution containing the NAP. Then 4CzIPN (10, 1.97 mg, 2.50 μmol, 1 mol %) was added to the reaction mixture. The solution was bubbled vigorously for 60−90 s with nitrogen gas, sealed, and placed between two blue Kessil brand KSH150B Grow Light LED 34 W lamps (∼400−520 nm, more information at Kessil.com) secured with gooseneck clamps. The center of the reaction vessel was roughly 5 cm from one lamp and 7 cm from the other. No cooling fan was used, and multiple measurements show that the internal temperature rises to anywhere between 40 and 48 °C. The reaction was stirred and irradiated with blue light until completion (3−25 h) as judged by full consumption of the NAP intermediate and/or the heteroarene substrate. Upon completion, the reaction was opened to air, diluted with CH2Cl2 (35 mL), and poured into a separatory funnel containing water (35 mL), and either solid NaHCO3 3004

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

Note

The Journal of Organic Chemistry chloroform-d) δ 158.8, 147.8, 144.4, 129.3, 129.3, 126.7, 125.6, 123.7, 122.9, 25.3, 18.7; HRMS (ESI) m/z calcd for C11H12N [M + H+] 158.0964, found 158.0966. 2-Ethyl-4-methylquinoline (15). The compound was prepared by the general procedure using propionic acid (28 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with 1R-(−)-CSA (116 mg, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-ethyl-4-methylquinoline (15, 32 mg, 74% yield) as a clear oil: LCMS tR = 0.54 min; 1H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.72−7.64 (m, 1H), 7.55−7.47 (m, 1H), 7.17 (s, 1H), 2.97 (q, J = 7.6 Hz, 2H), 2.69 (s, 3H), 1.39 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, chloroform-d) δ 163.8, 147.7, 144.7, 129.4, 129.3, 126.9, 125.6, 123.7, 121.7, 32.3, 18.9, 14.2; HRMS (ESI) m/z calcd for C12H14N [M + H+] 172.1121, found 172.1121. 4-Methyl-2-propylquinoline (16). The compound was prepared by the general procedure using butyric acid (33 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with 1R-(−)-CSA (116 mg, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 4-methyl-2-propylquinoline (16, 30 mg, 64% yield) as a clear oil: LCMS tR = 0.59 min; 1H NMR (499 MHz, chloroform-d) δ 8.07−8.02 (m, 1H), 7.95 (dd, J = 8.3, 1.0 Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.50 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.14 (app d, J = 0.7 Hz, 1H), 2.93−2.87 (m, 2H), 2.68 (d, J = 0.9 Hz, 3H), 1.88−1.79 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, chloroform-d) δ 162.7, 147.9, 144.3, 129.5, 129.1, 126.9, 125.5, 123.7, 122.2, 41.4, 23.4, 18.8, 14.2; HRMS (ESI) m/z calcd for C13H16N [M + H+] 186.1277, found 186.1269. 2-Isopropyl-4-methylquinoline (17). The compound was prepared by the general procedure using isobutyric acid (33 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.250 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-isopropyl-4-methylquinoline (17, 27 mg, 58% yield) as a clear oil: LCMS tR = 0.57 min; 1H NMR (499 MHz, chloroform-d) δ 8.05 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 8.3, 1.0 Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.50 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.18 (app d, J = 0.8 Hz, 1H), 3.21 (spt, J = 6.9 Hz, 1H), 2.69 (d, J = 0.9 Hz, 3H), 1.39 (d, J = 7.1 Hz, 6H); 13C NMR (126 MHz, chloroform-d) δ 167.5, 147.7, 144.5, 129.7, 129.1, 127.2, 125.5, 123.7, 119.9, 37.4, 22.7, 19.0; HRMS (ESI) m/z calcd for C13H16N [M + H+] 186.1277, found 186.1276. 2-Cyclopropyl-4-methylquinoline (18). The compound was prepared by the general procedure using cyclopropanecarboxylic acid (32 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with 1R-(−)-CSA (116 mg, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 25 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-cyclopropyl-4-methylquinoline (18, 7.7 mg, 17% yield) as a clear oil: LCMS tR = 0.55 min; 1H NMR (499 MHz, chloroform-d) δ 7.96 (d, J = 8.4 Hz, 1H), 7.91 (dd, J = 8.3, 1.1 Hz, 1H), 7.63 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.45 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 6.99 (app d, J = 0.7 Hz, 1H), 2.65 (d, J = 0.9 Hz, 3H), 2.20 (tt, J = 8.2, 4.9 Hz, 1H), 1.16−1.11 (m, 2H), 1.10−1.04 (m, 2H); 13C NMR (126 MHz, chloroform-d) δ 163.1, 147.9, 143.9, 129.3, 129.1, 127.0, 125.1, 123.7, 120.0, 18.8, 18.1, 10.1; HRMS (ESI) m/z calcd for C13H14N [M + H+] 184.1121, found 184.1127. 2-Benzyl-4-methylquinoline (22). The compound was prepared by the general procedure using 2-phenylacetic acid (51 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column

chromatography using silica gel on a Teledyne Isco instrument to give 2-benzyl-4-methylquinoline (22, 9 mg, 15% yield, 93% analytical HPLC purity) as an off-white solid: LCMS tR = 0.66 min; 1H NMR (499 MHz, chloroform-d) δ 8.11 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 8.4, 0.9 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.53 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.35−7.27 (m, 4H), 7.25−7.21 (m, 1H), 7.07 (app d, J = 0.8 Hz, 1H), 4.31 (s, 2H), 2.62 (d, J = 0.8 Hz, 3H); 13C NMR (126 MHz, chloroform-d) δ 160.9, 147.5, 145.0, 139.4, 129.5, 129.4, 129.4, 128.8, 127.0, 126.6, 126.0, 123.8, 122.3, 45.5, 18.9; HRMS (ESI) m/z calcd for C17H16N [M + H+] 234.1277, found 234.1275. 2-((1H-Indol-3-yl)methyl)-4-methylquinoline (23). The compound was prepared by the general procedure using 2-(1H-indol-3-yl)acetic acid (66 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 24 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to obtain a solid material, which was further purified by trituration with methanol to give 2-((1H-indol-3-yl)methyl)-4methylquinoline (23, 22 mg, 32% yield) as a pale brown solid: LCMS tR = 0.68 min; 1H NMR (400 MHz, chloroform-d) δ 8.18−8.01 (m, 2H), 7.93 (dd, J = 8.3, 0.9 Hz, 1H), 7.70 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.51 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.18 (td, J = 7.6, 1.0 Hz, 1H), 7.14 (s, 1H), 7.12− 7.04 (m, 2H), 4.44 (s, 2H), 2.57 (d, J = 0.8 Hz, 3H); 13C NMR (101 MHz, chloroform-d) δ 161.4, 147.7, 144.6, 136.6, 129.6, 129.2, 127.8, 127.1, 125.7, 123.8, 122.9, 122.3, 122.1, 119.7, 119.5, 114.1, 111.2, 35.5, 18.9; HRMS (ESI) m/z calcd for C19H17N2 [M + H+] 273.1386, found 273.1386. 2-(tert-Butyl)-4-methylquinoline (24). The compound was prepared by the general procedure using pivalic acid (38 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-(tert-butyl)-4-methylquinoline (24, 44 mg, 88% yield, 10:1 ratio with a minor inseparable material containing a second tert-butyl group of unknown regiochemistry) as a clear oil: LCMS tR = 0.62 min; 1H NMR (400 MHz, chloroform-d) δ 8.06 (d, J = 8.5 Hz, 1H), 7.94 (dd, J = 8.3, 0.9 Hz, 1H), 7.66 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.49 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.35 (app d, J = 0.6 Hz, 1H), 2.69 (d, J = 0.9 Hz, 3H), 1.46 (s, 9H); 13C NMR (101 MHz, chloroform-d) δ 169.1, 147.5, 143.7, 130.1, 128.8, 126.7, 125.5, 123.5, 119.0, 38.1, 30.3, 19.1; HRMS (ESI) m/z calcd for C14H18N [M + H+] 200.1434, found 200.1425. 2-(Bicyclo[2.2.2]octan-1-yl)-4-methylquinoline (25). The compound was prepared by the general procedure using bicyclo[2.2.2]octane-1-carboxylic acid (58 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-(bicyclo[2.2.2]octan-1-yl)-4methylquinoline (25, 48 mg, 76% yield) as a white solid: LCMS tR = 0.75 min; 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.69−7.61 (m, 1H), 7.52−7.43 (m, 1H), 7.28 (s, 1H), 2.67 (s, 3H), 2.04−1.94 (m, 6H), 1.79−1.69 (m, 7H); 13C NMR (101 MHz, chloroform-d) δ 168.7, 147.6, 143.5, 130.0, 128.8, 126.7, 125.4, 123.6, 119.4, 37.8, 31.0, 26.5, 24.9, 19.1; HRMS (ESI) m/z calcd for C18H22N [M + H+] 252.1747, found 252.1748. 2-(5-Bromopentyl)-4-methylquinoline (27). The compound was prepared by the general procedure using 6-bromohexanoic acid (73 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with 1R-(−)-CSA (116 mg, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-(5-bromopentyl)-4-methylquinoline (27, 28 mg, 38% yield) as a clear oil: LCMS tR = 0.70 min; 1H NMR (499 MHz, chloroform-d) δ 8.03 (dd, J = 8.4, 0.7 Hz, 1H), 7.95 (dd, J = 8.3, 0.9 3005

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

Note

The Journal of Organic Chemistry Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.50 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.13 (app d, J = 0.7 Hz, 1H), 3.41 (t, J = 6.8 Hz, 2H), 2.96−2.90 (m, 2H), 2.67 (d, J = 0.9 Hz, 3H), 1.96−1.89 (m, 2H), 1.88−1.80 (m, 2H), 1.60−1.52 (m, 2H); 13C NMR (126 MHz, chloroform-d) δ 162.2, 147.9, 144.4, 129.5, 129.2, 126.9, 125.6, 123.7, 122.1, 39.1, 33.9, 32.8, 29.2, 28.2, 18.8; HRMS (ESI) m/z calcd for C15H19NBr [M + H+] 292.0695, found 292.0696. Methyl 2-((tert-Butoxycarbonyl)amino)-4-(4-methylquinolin-2yl)butanoate (28). The compound was prepared by the general procedure using (±)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5oxopentanoic acid [98 mg, 0.38 mmol, 1.5 equiv, prepared by mixing (+)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (49 mg, 0.19 mmol, 0.75 equiv) and (−)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (49 mg, 0.19 mmol, 0.75 equiv)] and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with (±)-CSA (58 mg, 0.25 mmol, 1.0 equiv) used in the photochemical portion and was irradiated with blue light for 4 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument and repurified by reverse-phase preparative HPLC using ammonium acetate buffer, and the fractions containing the desired material were concentrated. The material was further purified by trituration with deuterated chloroform to remove salts. The organic solution was concentrated, and flash column chromatography using silica gel on a Teledyne Isco instrument gave methyl 2-((tert-butoxycarbonyl)amino)-4-(4-methylquinolin-2-yl)butanoate (28, 25 mg, 28% yield) as a clear oil: LCMS tR = 0.69 min; 1H NMR (400 MHz, chloroformd) δ 8.06 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 8.3, 0.8 Hz, 1H), 7.67 (ddd, J = 8.3, 7.0, 1.4 Hz, 1H), 7.51 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.13 (s, 1H), 6.20−5.75 (m, 1H), 4.48−4.18 (m, 1H), 3.71 (s, 3H), 3.02 (t, J = 7.5 Hz, 2H), 2.67 (d, J = 0.7 Hz, 3H), 2.41−2.30 (m, 1H), 2.30−2.17 (m, 1H), 1.44 (s, 9H); 13C NMR (101 MHz, chloroform-d) δ 173.3, 160.8, 155.8, 147.6, 144.9, 129.4, 129.4, 127.0, 125.9, 123.7, 122.3, 79.8, 53.8, 52.4, 34.8, 31.5, 28.5, 18.8; HRMS (ESI) m/z calcd for C20H27N2O4 [M + H+] 359.1965, found 359.1959. tert-Butyl ((4-Methylquinolin-2-yl)methyl)carbamate (29). The compound was prepared by the general procedure using N-(tertbutoxycarbonyl)glycine (66 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 μL, 0.25 mmol, 1.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give tert-butyl ((4-methylquinolin-2yl)methyl)carbamate (29, 46 mg, 67% yield) as a white solid. Following the general procedure using 1R-(−)-CSA (58 mg, 0.25 mmol, 1.0 equiv) in the photochemical portion (3 h) and identical purification procedure gave tert-butyl ((4-methylquinolin-2-yl)methyl)carbamate (29, 43 mg, 63% yield) as a white solid: LCMS tR = 0.67 min; 1H NMR (499 MHz, chloroform-d) δ 8.05 (d, J = 8.4 Hz, 1H), 7.97 (dd, J = 8.3, 0.9 Hz, 1H), 7.70 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.54 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.19 (s, 1H), 6.06−5.56 (m, 1H), 4.64−4.48 (m, 2H), 2.69 (d, J = 0.7 Hz, 3H), 1.50 (s, 9H); 13C NMR (126 MHz, chloroform-d) δ 156.9, 156.2, 147.4, 145.1, 129.6, 129.5, 127.5, 126.2, 123.9, 120.6, 79.6, 46.2, 28.6, 18.9; HRMS (ESI) m/z calcd for C16H21N2O2 [M + H+] 273.1598, found 273.1600. 2-((Benzyloxy)methyl)-4-methylquinoline (30). The compound was prepared by the general procedure using 2-(benzyloxy)acetic acid (62 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-((benzyloxy)methyl)-4-methylquinoline (30, 44 mg, 66% yield) as a yellow oil: LCMS tR = 0.73 min; 1H NMR (499 MHz, chloroform-d) δ 8.07 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.55 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.50 (s, 1H), 7.45−7.40 (m, 2H), 7.40−7.35 (m, 2H), 7.34− 7.28 (m, 1H), 4.83 (s, 2H), 4.69 (s, 2H), 2.72 (s, 3H); 13C NMR (126 MHz, chloroform-d) δ 158.8, 147.5, 145.1, 138.1, 129.7, 129.4, 128.6,

128.0, 127.9, 127.7, 126.2, 123.8, 120.2, 74.0, 73.2, 19.0; HRMS (ESI) m/z calcd for C18H18NO [M + H+] 264.1383, found 264.1381. tert-Butyl 3-(4-Methylquinolin-2-yl)azetidine-1-carboxylate (31). The compound was prepared by the general procedure using 1-(tertbutoxycarbonyl)azetidine-3-carboxylic acid (75 mg, 0.37 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 μL, 0.25 mmol, 1.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give tert-butyl 3-(4-methylquinolin-2-yl)azetidine-1-carboxylate (31, 29 mg, 39% yield) as a clear oil: LCMS tR = 0.71 min; 1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J = 8.4 Hz, 1H), 7.96 (dd, J = 8.3, 0.8 Hz, 1H), 7.69 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.53 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.26 (s, 1H), 4.43−4.34 (m, 2H), 4.27 (dd, J = 8.6, 5.9 Hz, 2H), 4.00 (tt, J = 8.8, 5.9 Hz, 1H), 2.70 (d, J = 0.7 Hz, 3H), 1.48 (s, 9H); 13C NMR (101 MHz, chloroform-d) δ 161.0, 156.7, 147.6, 145.3, 129.8, 129.5, 127.3, 126.2, 123.8, 120.1, 79.6, 54.7 (br), 35.9, 28.6, 18.9; HRMS (ESI) m/z calcd for C18H23N2O2 [M + H+] 299.1754, found 299.1751. tert-Butyl 3-(4-Methylquinolin-2-yl)pyrrolidine-1-carboxylate (32). The compound was prepared by the general procedure using 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (81 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 μL, 0.25 mmol, 1.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give tert-butyl 3-(4-methylquinolin-2-yl)pyrrolidine-1-carboxylate (32, 33 mg, 42% yield) as a clear oil: LCMS tR = 0.71 min; 1H NMR (499 MHz, chloroform-d) δ 8.04 (br d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.69 (br t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.16 (app d, J = 0.5 Hz, 1H), 3.95−3.82 (m, 1H), 3.75−3.59 (m, 3H), 3.52−3.40 (m, 1H), 2.71−2.67 (m, 3H), 2.40−2.21 (m, 2H), 1.49 (br s, 4H), 1.48 (br s, 5H); 13C NMR (126 MHz, chloroform-d) δ 161.1, 161.0, 154.8, 147.7, 145.0, 129.7, 129.4, 127.3, 126.0, 123.8, 120.8, 79.4, 51.3, 51.0, 47.1, 46.3, 46.2, 45.9, 32.4, 31.7, 28.7, 19.0 (five extra carbon signals attributed to tert-butyl carbamate rotamers); HRMS (ESI) m/z calcd for C19H25N2O2 [M + H+] 313.1911, found 313.1915. tert-Butyl 4-(4-Methylquinolin-2-yl)piperidine-1-carboxylate (33). The compound was prepared by the general procedure using 1-(tertbutoxycarbonyl)piperidine-4-carboxylic acid (86 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 μL, 0.25 mmol, 1.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give tert-butyl 4-(4-methylquinolin-2-yl)piperidine-1-carboxylate (33, 51 mg, 62% yield) as a clear oil: LCMS tR = 0.75 min; 1H NMR (499 MHz, chloroform-d) δ 8.02 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.67 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.54−7.47 (m, 1H), 7.14 (s, 1H), 4.52−4.05 (br m, 2H), 3.00 (tt, J = 12.0, 3.7 Hz, 1H), 2.97−2.79 (br m, 2H), 2.68 (s, 3H), 1.96 (br d, J = 12.5 Hz, 2H), 1.89−1.77 (m, 2H), 1.48 (s, 9H); 13C NMR (126 MHz, chloroform-d) δ 164.4, 154.9, 147.7, 144.8, 129.6, 129.3, 127.2, 125.8, 123.7, 120.1, 79.5, 45.6, 44.2 (br), 31.7, 28.6, 19.0; HRMS (ESI) m/z calcd for C20H27N2O2 [M + H+] 327.2067, found 327.2068. 4-Methyl-2-(1-phenylpiperidin-4-yl)quinoline (34). The compound was prepared by the general procedure using 1-phenylpiperidine-4-carboxylic acid (77 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 24 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 4-methyl-2-(1phenylpiperidin-4-yl)quinoline (34, 21 mg, 28% yield) as a white solid that darkened on standing: LCMS tR = 0.60 min; 1H NMR (499 MHz, chloroform-d) δ 8.05 (d, J = 8.4 Hz, 1H), 7.97 (dd, J = 8.3, 0.9 Hz, 1H), 7.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.52 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.31−7.27 (m, 2H), 7.22 (app d, J = 0.7 Hz, 1H), 7.04−6.99 3006

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

Note

The Journal of Organic Chemistry (m, 2H), 6.86 (tt, J = 7.3, 1.0 Hz, 1H), 3.91−3.83 (m, 2H), 3.08−3.00 (m, 1H), 2.96−2.87 (m, 2H), 2.70 (d, J = 0.8 Hz, 3H), 2.16−2.04 (m, 4H); 13C NMR (126 MHz, chloroform-d) δ 164.8, 152.0, 147.8, 144.8, 129.7, 129.3, 129.2, 127.3, 125.8, 123.8, 120.1, 119.6, 116.8, 50.4, 45.6, 31.9, 19.0; HRMS (ESI) m/z calcd for C21H23N2 [M + H+] 303.1856, found 303.1855. 4-Methyl-2-(tetrahydro-2H-pyran-4-yl)quinoline (35). The compound was prepared by the general procedure using tetrahydro-2Hpyran-4-carboxylic acid (49 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 4-methyl-2-(tetrahydro-2Hpyran-4-yl)quinoline (35, 33 mg, 58% yield) as a white solid: LCMS tR = 0.53 min; 1H NMR (499 MHz, chloroform-d) δ 8.04 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.71−7.63 (m, 1H), 7.53−7.47 (m, 1H), 7.17 (s, 1H), 4.12 (dd, J = 11.1, 3.9 Hz, 2H), 3.59 (td, J = 11.7, 1.9 Hz, 2H), 3.12 (tt, J = 11.9, 3.9 Hz, 1H), 2.69 (s, 3H), 2.06−1.96 (m, 2H), 1.94−1.87 (m, 2H); 13C NMR (126 MHz, chloroform-d) δ 164.3, 147.7, 144.8, 129.6, 129.2, 127.2, 125.8, 123.7, 120.0, 68.2, 44.5, 32.4, 19.0; HRMS (ESI) m/z calcd for C15H18NO [M + H+] 228.1383, found 228.1381. 4-Methyl-2-(tetrahydro-2H-thiopyran-4-yl)quinoline (36). The compound was prepared by the general procedure using tetrahydro2H-thiopyran-4-carboxylic acid (55 mg, 0.38 mmol, 1.5 equiv) and lepidine (8, 36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 4-methyl-2-(tetrahydro-2Hthiopyran-4-yl)quinoline (36, 36 mg, 59% yield) as a white solid: LCMS tR = 0.63 min; 1H NMR (499 MHz, chloroform-d) δ 8.02 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.66 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.49 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.14 (s, 1H), 2.96−2.85 (m, 3H), 2.77−2.70 (m, 2H), 2.67 (s, 3H), 2.32−2.23 (m, 2H), 2.10−1.98 (m, 2H); 13C NMR (126 MHz, chloroform-d) δ 165.0, 147.7, 144.8, 129.6, 129.2, 127.2, 125.8, 123.7, 120.0, 47.2, 33.6, 29.0, 19.0; HRMS (ESI) m/z calcd for C15H18NS [M + H+] 244.1154, found 244.1154. 2-Cyclohexyl-4-methylpyridine (39) and 2,6-Dicyclohexyl-4methylpyridine (40). The compounds were prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and 4-methylpyridine (23 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and were irradiated with blue light for 3 h in the photochemical portion. The products were purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-cyclohexyl-4-methylpyridine (39, 22 mg, 50% yield) as a colorless oil and 2,6-dicyclohexyl-4-methylpyridine (40, 12 mg, 19% yield) as a white solid. Data for 39: LCMS tR = 0.61 min; 1H NMR (400 MHz, chloroform-d) δ 8.38 (d, J = 5.0 Hz, 1H), 6.96 (s, 1H), 6.91 (d, J = 5.0 Hz, 1H), 2.65 (tt, J = 11.7, 3.4 Hz, 1H), 2.32 (s, 3H), 1.99−1.89 (m, 2H), 1.89−1.81 (m, 2H), 1.78−1.70 (m, 1H), 1.57− 1.46 (m, 2H), 1.46−1.34 (m, 2H), 1.34−1.20 (m, 1H); 13C NMR (101 MHz, chloroform-d) δ 166.4, 148.9, 147.5, 122.2, 122.0, 46.6, 33.1, 26.8, 26.3, 21.2; HRMS (ESI) m/z calcd for C12H18N [M + H+] 176.1434, found 176.1435. Data for 40: LCMS tR = 0.83 min; 1H NMR (400 MHz, chloroform-d) δ 6.77 (s, 2H), 2.72−2.57 (m, 2H), 2.29 (s, 3H), 2.01−1.89 (m, 4H), 1.88−1.78 (m, 4H), 1.78−1.69 (m, 2H), 1.53−1.34 (m, 8H), 1.34−1.18 (m, 2H); 13C NMR (101 MHz, chloroform-d) δ 165.7, 147.3, 118.7, 46.7, 33.3, 26.8, 26.4, 21.3; HRMS (ESI) m/z calcd for C18H28N [M + H+] 258.2216, found 258.2215. 4-Chloro-2-cyclohexylpyridine (41) and 4-Chloro-2,6-dicyclohexylpyridine (42). The compounds were prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and 4-chloropyridine, HCl (38 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (28 mg, 19 μL, 0.25 mmol, 1.0 equiv) used in the photochemical portion and were irradiated with blue light for 3 h in the photochemical portion. The products were purified by flash

column chromatography using silica gel on a Teledyne Isco instrument to give 4-chloro-2-cyclohexylpyridine (41, 18 mg, 36% yield) as a colorless oil and 4-chloro-2,6-dicyclohexylpyridine (42, 21 mg, 30% yield) as a white solid. Data for 41: LCMS tR = 0.72 min; 1H NMR (400 MHz, chloroform-d) δ 8.42 (d, J = 5.4 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 5.4, 2.0 Hz, 1H), 2.69 (tt, J = 11.7, 3.3 Hz, 1H), 1.99−1.91 (m, 2H), 1.90−1.82 (m, 2H), 1.79−1.72 (m, 1H), 1.56− 1.34 (m, 4H), 1.33−1.21 (m, 1H); 13C NMR (101 MHz, chloroformd) δ 168.4, 150.1, 144.5, 121.6, 121.6, 46.5, 32.9, 26.6, 26.1; HRMS (ESI) m/z calcd for C11H15NCl [M + H+] 196.0888, found 196.0896. Data for 42: LCMS tR = 0.97 min; 1H NMR (400 MHz, chloroform-d) δ 6.95 (s, 2H), 2.66 (tt, J = 11.5, 3.4 Hz, 2H), 1.99−1.91 (m, 4H), 1.87−1.79 (m, 4H), 1.78−1.70 (m, 2H), 1.51−1.34 (m, 8H), 1.33− 1.20 (m, 2H); 13C NMR (101 MHz, chloroform-d) δ 167.5, 144.3, 118.3, 46.6, 33.0, 26.6, 26.2; HRMS (ESI) m/z calcd for C17H25NCl [M + H+] 278.1670, found 278.1675. 4-Cyclohexylquinoline (43), 2-Cyclohexylquinoline (44), and 2,4Dicyclohexylquinoline (45). The compounds were prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and quinoline (32 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.1 equiv) used in the photochemical portion and were irradiated with blue light for 3 h in the photochemical portion. The products were purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 4-cyclohexylquinoline (43, 6.3 mg, 12% yield) as a clear oil, 2cyclohexylquinoline (44, 5.9 mg, 11% yield) as a clear oil, and 2,4dicyclohexylquinoline (45, 19 mg, 26% yield) as a clear oil. Data for 43: LCMS tR = 0.70 min; 1H NMR (499 MHz, chloroform-d) δ 8.84 (d, J = 4.6 Hz, 1H), 8.14−8.08 (m, 2H), 7.69 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.56 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.28 (d, J = 4.7 Hz, 1H), 3.39−3.28 (m, 1H), 2.07−1.98 (m, 2H), 1.98−1.89 (m, 2H), 1.89− 1.83 (m, 1H), 1.61−1.50 (m, 4H), 1.41−1.30 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 153.6, 150.5, 148.5, 130.5, 128.9, 127.1, 126.3, 123.2, 117.6, 39.0, 33.7, 27.1, 26.4; HRMS (ESI) m/z calcd for C15H18N [M + H+] 212.1434, found 212.1435. Data for 44: LCMS tR = 0.65 min; 1H NMR (499 MHz, chloroform-d) δ 8.08 (d, J = 8.5 Hz, 1H), 8.05 (app d, J = 8.5 Hz, 1H), 7.77 (dd, J = 8.1, 1.2 Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.47 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 2.93 (tt, J = 12.0, 3.4 Hz, 1H), 2.06−1.99 (m, 2H), 1.94−1.86 (m, 2H), 1.83−1.76 (m, 1H), 1.63 (qd, J = 12.6, 3.1 Hz, 2H), 1.48 (qt, J = 12.9, 3.3 Hz, 2H), 1.39−1.29 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 167.0, 147.9, 136.5, 129.4, 129.1, 127.6, 127.1, 125.7, 119.7, 47.8, 33.0, 26.7, 26.3; HRMS (ESI) m/z calcd for C15H18N [M + H+] 212.1434, found 212.1435. Data for 45: LCMS tR = 0.91 min; 1H NMR (499 MHz, chloroform-d) δ 8.06 (dd, J = 8.4, 0.8 Hz, 1H), 8.03 (app d, J = 8.4 Hz, 1H), 7.64 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.47 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.20 (s, 1H), 3.35−3.24 (m, 1H), 2.88 (tt, J = 12.1, 3.4 Hz, 1H), 2.07−1.98 (m, 4H), 1.97−1.82 (m, 5H), 1.82−1.74 (m, 1H), 1.70−1.42 (m, 8H), 1.41−1.30 (m, 2H); 13C NMR (126 MHz, chloroform-d) δ 166.7, 153.5, 148.2, 130.0, 128.7, 125.8, 125.3, 122.9, 115.9, 48.0, 39.1, 33.8, 33.0, 27.1, 26.7, 26.5, 26.3; HRMS (ESI) m/z calcd for C21H28N [M + H+] 294.2216, found 294.2217. 4-Cyclohexyl-2-methylquinoline (46). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and 2-methylquinoline (36 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 4-cyclohexyl-2-methylquinoline (46, 33 mg, 58% yield) as a clear oil: LCMS tR = 0.72 min; 1H NMR (499 MHz, chloroform-d) δ 8.05−7.99 (m, 2H), 7.63 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.47 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H), 7.15 (s, 1H), 3.34−3.21 (m, 1H), 2.71 (s, 3H), 2.05−1.96 (m, 2H), 1.96−1.87 (m, 2H), 1.87− 1.81 (m, 1H), 1.59−1.46 (m, 4H), 1.38−1.28 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 158.9, 153.4, 148.2, 129.6, 128.9, 125.3, 125.2, 122.9, 118.4, 38.9, 33.7, 27.0, 26.4, 25.6; HRMS (ESI) m/z calcd for C16H20N [M + H+] 226.1590, found 226.1588. 3007

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

Note

The Journal of Organic Chemistry 1-Cyclohexylisoquinoline (47). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and isoquinoline (32 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.1 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 1-cyclohexylisoquinoline (47, 41 mg, 78% yield) as a clear oil: LCMS tR = 0.64 min; 1H NMR (499 MHz, chloroform-d) δ 8.48 (d, J = 5.6 Hz, 1H), 8.22 (br d, J = 8.4 Hz, 1H), 7.82−7.76 (m, 1H), 7.66−7.60 (m, 1H), 7.60−7.54 (m, 1H), 7.49−7.45 (m, 1H), 3.61−3.51 (m, 1H), 2.04−1.89 (m, 4H), 1.89−1.77 (m, 3H), 1.59−1.48 (m, 2H), 1.44− 1.34 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 165.8, 142.0, 136.5, 129.6, 127.6, 126.9, 126.4, 124.8, 119.0, 41.7, 32.7, 27.0, 26.4; HRMS (ESI) m/z calcd for C15H18N [M + H+] 212.1434, found 212.1432. 1-Cyclohexylphthalazine (48) and 1,4-Dicyclohexylphthalazine (49). The compounds were prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and phthalazine (33 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and were irradiated with blue light for 3 h in the photochemical portion. The products were purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 1-cyclohexylphthalazine (48, 14 mg, 26% yield, 92% analytical HPLC purity) as a clear oil and 1,4-dicyclohexylphthalazine (49, 35 mg, 47% yield) as a yellow solid. Data for 48: LCMS tR = 0.64 min; 1H NMR (499 MHz, chloroform-d) δ 9.40 (s, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.97−7.93 (m, 1H), 7.93−7.85 (m, 2H), 3.51 (tt, J = 11.4, 3.5 Hz, 1H), 2.10−2.02 (m, 2H), 2.02−1.92 (m, 4H), 1.87−1.80 (m, 1H), 1.59−1.48 (m, 2H), 1.46−1.36 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 163.7, 150.2, 132.4, 131.8, 127.3, 126.8, 125.2, 123.6, 40.9, 32.5, 27.0, 26.3; HRMS (ESI) m/z calcd for C14H17N2 [M + H+] 213.1386, found 213.1384. Data for 49: LCMS tR = 0.81 min; 1H NMR (499 MHz, chloroform-d) δ 8.20−8.13 (m, 2H), 7.88−7.82 (m, 2H), 3.46 (tt, J = 11.3, 3.5 Hz, 2H), 2.09−2.01 (m, 4H), 2.01−1.91 (m, 8H), 1.85−1.78 (m, 2H), 1.58−1.46 (m, 4H), 1.44−1.33 (m, 2H); 13C NMR (126 MHz, chloroform-d) δ 162.0, 131.3, 125.1, 124.4, 40.6, 32.5, 27.1, 26.4; HRMS (ESI) m/z calcd for C20H27N2 [M + H+] 295.2169, found 295.2166. 2-Cyclohexylquinoxaline (50) and 2,3-Dicyclohexylquinoxaline (51). The compounds were prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and quinoxaline (33 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and were irradiated with blue light for 24 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-cyclohexylquinoxaline (50, 15 mg, 28% yield) as a tan oil and 2,3dicyclohexylquinoxaline (51, 8 mg, 11% yield) as a brown oil. Data for 50: LCMS tR = 1.07 min; 1H NMR (499 MHz, chloroform-d) δ 8.77 (s, 1H), 8.10−8.02 (m, 2H), 7.77−7.67 (m, 2H), 2.97 (tt, J = 12.0, 3.5 Hz, 1H), 2.08−2.01 (m, 2H), 1.97−1.90 (m, 2H), 1.84−1.78 (m, 1H), 1.72 (qd, J = 12.6, 3.2 Hz, 2H), 1.48 (qt, J = 12.9, 3.3 Hz, 2H), 1.41− 1.31 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 161.3, 145.1, 142.3, 141.6, 129.9, 129.2, 129.2, 129.0, 45.2, 32.5, 26.5, 26.0; HRMS (ESI) m/z calcd for C14H17N2 [M + H+] 213.1386, found 213.1395. Data for 51: Analytical HPLC column 2 tR = 12.62 min; 1H NMR (499 MHz, chloroform-d) δ 8.00−7.96 (m, 2H), 7.64−7.59 (m, 2H), 3.09 (tt, J = 11.1, 3.8 Hz, 2H), 1.97−1.90 (m, 4H), 1.90−1.77 (m, 10H), 1.53−1.34 (m, 6H); 13C NMR (126 MHz, chloroform-d) δ 159.8, 141.0, 128.8, 128.5, 41.9, 32.6, 26.9, 26.1; HRMS (ESI) m/z calcd for C20H27N2 [M + H+] 295.2169, found 295.2166. 2-Cyclohexyl-4-quinazolinone (52). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and 4-quinazolinone (37 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco

instrument to give 2-cyclohexyl-4-quinazolinone (52, 32 mg, 55% yield) as a white solid: LCMS tR = 0.70 min; 1H NMR (400 MHz, chloroform-d) δ 10.96 (br s, 1H), 8.28 (br d, J = 7.2 Hz, 1H), 7.80− 7.73 (m, 1H), 7.73−7.64 (m, 1H), 7.46 (br t, J = 7.0 Hz, 1H), 2.78− 2.63 (m, 1H), 2.06 (br d, J = 11.5 Hz, 2H), 2.00−1.86 (m, 2H), 1.85− 1.66 (m, 3H), 1.55−1.33 (m, 3H); 13C NMR (101 MHz, chloroformd) δ 163.8, 160.0, 149.6, 134.8, 127.5, 126.5, 126.4, 121.0, 45.0, 30.7, 26.1, 25.9; HRMS (ESI) m/z calcd for C14H17N2O [M + H+] 229.1335, found 229.1333. 6-Cyclohexylpurine (53). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and purine (30 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 6-cyclohexylpurine (53, 30 mg, 59% yield) as a white solid. Also we obtained two inseparable isomers each incorporating a second cyclohexyl group at two different positions in an unequal ratio; regiochemistry not confirmed (14 mg, 20% yield) as a white solid. Data for 53: LCMS tR = 0.56 min; 1H NMR (400 MHz, chloroform-d) δ 12.54 (br s, 1H), 8.98 (s, 1H), 8.27 (s, 1H), 3.61−3.44 (m, 1H), 2.08−1.98 (m, 2H), 1.97−1.86 (m, 4H), 1.86−1.77 (m, 1H), 1.59− 1.32 (m, 3H); 13C NMR (101 MHz, chloroform-d) δ 167.2 (br), 152.1, 151.8 (br), 141.9, 131.5 (br), 42.2, 31.5, 26.4, 26.1; HRMS (ESI) m/z calcd for C11H15N4 [M + H+] 203.1291, found 203.1290. 4-Chloro-6-cyclohexyl-7-azaindole (54). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and 4-chloro-7-azaindole (38 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument and repurified by reverse-phase preparative HPLC using ammonium acetate buffer, and the fractions containing the desired material were concentrated. The material was further purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 4-chloro-6-cyclohexyl-7-azaindole (54, 3 mg, 5% yield) as a white solid with a faint purple hue: LCMS tR = 0.94 min; 1H NMR (499 MHz, chloroform-d) δ 10.39 (br s, 1H), 7.30 (dd, J = 3.3, 1.7 Hz, 1H), 7.03 (s, 1H), 6.57 (dd, J = 3.4, 1.3 Hz, 1H), 2.78 (tt, J = 12.0, 3.4 Hz, 1H), 2.05−1.98 (m, 2H), 1.93−1.86 (m, 2H), 1.82−1.76 (m, 1H), 1.58 (qd, J = 12.6, 3.1 Hz, 2H), 1.45 (qt, J = 12.9, 3.3 Hz, 2H), 1.36−1.27 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 161.0, 148.3, 137.2, 124.9, 118.1, 114.2, 99.7, 46.5, 33.5, 26.8, 26.2; HRMS (ESI) m/z calcd for C13H16N2Cl [M + H+] 235.0997, found 235.0994. 2-Cyclohexylbenzimidazole (55). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and benzimidazole (30 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 5 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-cyclohexylbenzimidazole (55, 20 mg, 39% yield) as an off-white solid: LCMS tR = 0.59 min; 1H NMR (499 MHz, methanol-d4) δ 7.51−7.45 (m, 2H), 7.19−7.14 (m, 2H), 2.89 (tt, J = 12.0, 3.6 Hz, 1H), 2.11−2.03 (m, 2H), 1.91−1.84 (m, 2H), 1.81−1.74 (m, 1H), 1.66 (qd, J = 12.5, 3.2 Hz, 2H), 1.46 (qt, J = 12.8, 3.3 Hz, 2H), 1.39− 1.29 (m, 1H); 13C NMR (126 MHz, methanol-d4) δ 160.8, 139.2 (br), 123.1, 115.3 (br), 39.8, 32.8, 27.2, 27.0; HRMS (ESI) m/z calcd for C13H17N2 [M + H+] 201.1386, found 201.1388. 2-Cyclohexylbenzothiazole (56). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and benzothiazole (34 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-cyclohexylbenzothiazole (56, 17 mg, 31% yield) as a pale yellow 3008

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

Note

The Journal of Organic Chemistry solid: LCMS tR = 1.12 min; 1H NMR (400 MHz, chloroform-d) δ 7.97 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.47−7.41 (m, 1H), 7.37−7.30 (m, 1H), 3.11 (tt, J = 11.6, 3.6 Hz, 1H), 2.26−2.15 (m, 2H), 1.94−1.84 (m, 2H), 1.81−1.73 (m, 1H), 1.65 (qd, J = 12.3, 3.2 Hz, 2H), 1.45 (qt, J = 12.6, 3.1 Hz, 2H), 1.38−1.26 (m, 1H); 13C NMR (101 MHz, chloroform-d) δ 177.7, 153.3, 134.7, 125.9, 124.6, 122.7, 121.7, 43.6, 33.6, 26.2, 25.9; HRMS (ESI) m/z calcd for C13H16NS [M + H+] 218.0998, found 218.0995. 2-Cyclohexylbenzoxazole (57). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and benzoxazole (30 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 2-cyclohexylbenzoxazole (57, 2.6 mg, 5% yield, 89% analytical HPLC purity) as a tan oil: LCMS tR = 1.08 min; 1H NMR (499 MHz, chloroform-d) δ 7.71−7.66 (m, 1H), 7.51−7.44 (m, 1H), 7.31−7.27 (m, 2H), 2.96 (tt, J = 11.4, 3.6 Hz, 1H), 2.22−2.14 (m, 2H), 1.91− 1.84 (m, 2H), 1.78−1.66 (m, 3H), 1.48−1.38 (m, 2H), 1.38−1.28 (m, 1H); 13C NMR (126 MHz, chloroform-d) δ 170.6, 150.7, 141.3, 124.5, 124.2, 119.7, 110.4, 38.1, 30.6, 25.9, 25.8; HRMS (ESI) m/z calcd for C13H16NO [M + H+] 202.1226, found 202.1230. 8-Cyclohexyl-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (59). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and caffeine (49 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) and extra DMSO (1 mL) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give 8-cyclohexyl-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (59, 14 mg, 20% yield) as a white solid: LCMS tR = 0.86 min; 1H NMR (400 MHz, chloroform-d) δ 3.92 (s, 3H), 3.57 (s, 3H), 3.39 (s, 3H), 2.70 (tt, J = 11.7, 3.4 Hz, 1H), 1.95−1.81 (m, 4H), 1.80−1.63 (m, 3H), 1.46−1.28 (m, 3H); 13C NMR (101 MHz, chloroform-d) δ 158.1, 155.6, 151.9, 148.3, 107.2, 36.0, 31.5, 31.1, 29.9, 28.0, 26.1, 25.7; HRMS (ESI) m/z calcd for C14H21N4O2 [M + H+] 277.1659, found 277.1653. (2R,3R,4S,5R)-2-(6-Cyclohexyl-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (60). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and nebularine (63 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion, irradiated with blue light for 3 h in the photochemical portion, and purified by reverse-phase preparative HPLC using TFA buffer, and the desired fractions were concentrated. The obtained material was free-based using ion-exchange resin and concentrated to give (2R,3R,4S,5R)-2-(6-cyclohexyl-9H-purin-9-yl)-5(hydroxymethyl)tetrahydrofuran-3,4-diol (60, 61 mg, 73% yield) as a white solid: LCMS tR = 0.60 min; 1H NMR (400 MHz, methanol-d4) δ 8.81 (s, 1H), 8.69 (s, 1H), 6.12 (d, J = 5.8 Hz, 1H), 4.75 (t, J = 5.4 Hz, 1H), 4.37 (dd, J = 4.9, 3.6 Hz, 1H), 4.17 (q, J = 3.0 Hz, 1H), 3.93−3.86 (m, 1H), 3.82−3.73 (m, 1H), 3.52−3.40 (m, 1H), 1.99− 1.77 (m, 7H), 1.63−1.46 (m, 2H), 1.46−1.36 (m, 1H); 13C NMR (101 MHz, methanol-d4) δ 167.7, 153.1, 151.7, 145.6, 133.3, 90.7, 87.7, 75.7, 72.3, 63.1, 42.9, 32.3, 27.3, 27.0; HRMS (ESI) m/z calcd for C16H23N4O4 [M + H+] 335.1714, found 335.1712. (2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(6-cyclohexyl-9H-purin-9-yl)tetrahydrofuran-3,4-diyl Diacetate (61). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (95 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-cyclohexyl-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (61, 70 mg, 61% yield) as a colorless oil: LCMS tR = 0.87 min;

H NMR (400 MHz, chloroform-d) δ 8.91 (s, 1H), 8.16 (s, 1H), 6.23 (d, J = 5.2 Hz, 1H), 5.98 (t, J = 5.4 Hz, 1H), 5.69 (t, J = 5.1 Hz, 1H), 4.50−4.43 (m, 2H), 4.41−4.34 (m, 1H), 3.45 (tt, J = 11.7, 3.3 Hz, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.03−1.75 (m, 7H), 1.57−1.31 (m, 3H); 13C NMR (101 MHz, chloroform-d) δ 170.4, 169.7, 169.5, 167.2, 152.8, 150.6, 142.0, 132.5, 86.6, 80.5, 73.2, 70.7, 63.2, 42.0, 31.4, 31.4, 26.4, 26.0, 20.9, 20.7, 20.5; HRMS (ESI) m/z calcd for C22H29N4O7 [M + H+] 461.2031, found 461.2032. (2R,3R,4S,5R)-2-(6-Amino-2-cyclohexyl-9H-purin-9-yl)-5(hydroxymethyl)tetrahydrofuran-3,4-diol (62). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and adenosine (67 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion, irradiated with blue light for 3 h in the photochemical portion, and purified by reverse-phase preparative HPLC using ammonium acetate buffer, and the desired fractions were concentrated to give (2R,3R,4S,5R)-2-(6-amino-2cyclohexyl-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol (62, 10 mg, 11% yield) as a white solid: LCMS tR = 0.53 min; 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 5.93 (d, J = 6.5 Hz, 1H), 4.84−4.80 (m, 1H), 4.35 (dd, J = 4.9, 2.2 Hz, 1H), 4.19−4.15 (m, 1H), 3.95−3.85 (m, 1H), 3.75 (dd, J = 12.5, 2.4 Hz, 1H), 2.77− 2.62 (m, 1H), 1.92−1.60 (m, 7H), 1.50−1.24 (m, 3H); 13C NMR (101 MHz, methanol-d4) δ 170.6, 157.4, 150.8, 141.9, 119.4, 91.4, 88.2, 75.0, 72.9, 63.7, 33.2, 33.1, 27.5, 27.4, 27.2; HRMS (ESI) m/z calcd for C16H24N5O4 [M + H+] 350.1823, found 350.1821; key NOE correlation singlet at 8.19 ppm correlates with doublet at 5.93 ppm. (R)-(2-Cyclohexyl-6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methanol (63). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and quinine (81 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give (R)-(2-cyclohexyl-6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methanol (63, 49 mg, 48% yield) as a white solid. Proton and carbon NMR spectra match the spectroscopic data previously reported in the literature.8,39 Data for 63: LCMS tR = 0.64 min; 1H NMR (400 MHz, chloroform-d) δ 7.95 (br d, J = 9.1 Hz, 1H), 7.47 (s, 1H), 7.30 (br d, J = 8.8 Hz, 1H), 7.20 (br s, 1H), 5.80−5.66 (m, 1H), 5.58 (br s, 1H), 5.03−4.85 (m, 2H), 3.88 (s, 3H), 3.49 (br s, 1H), 3.20−3.04 (m, 2H), 2.89−2.76 (m, 1H), 2.75−2.60 (m, 2H), 2.35− 2.20 (m, 1H), 1.94 (br d, J = 11.8 Hz, 2H), 1.89−1.65 (m, 6H), 1.64− 1.18 (m, 8H); 13C NMR (101 MHz, chloroform-d) δ 164.1, 157.3, 147.7, 144.0, 142.1, 131.4, 125.2, 121.1, 116.8, 114.5, 101.5, 72.6, 60.1, 57.4, 55.8, 47.5, 43.5, 40.2, 33.0, 33.0, 28.1, 27.8, 26.7, 26.2, 21.6; HRMS (ESI) m/z calcd for C26H35N2O2 [M + H+] 407.2693, found 407.2695. (S)-11-Cyclohexyl-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (64). The compound was prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and camptothecin (87 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 20 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give a solid material that was further purified via trituration with methanol to give (S)-11-cyclohexyl-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H)-dione (64, 18 mg, 17% yield) as a yellow solid. Proton NMR spectrum matches the spectroscopic data previously reported in the literature.8 Data for 64: LCMS tR = 0.96 min; 1H NMR (400 MHz, chloroform-d) δ 8.34− 8.17 (m, 2H), 7.79 (td, J = 7.6, 1.1 Hz, 1H), 7.69−7.62 (m, 2H), 5.76 (d, J = 16.3 Hz, 1H), 5.42 (s, 2H), 5.34−5.26 (m, 1H), 3.88−3.50 (m, 2H), 2.01 (br d, J = 10.5 Hz, 4H), 1.96−1.81 (m, 4H), 1.64−1.52 (m, 3H), 1.51−1.39 (m, 1H), 1.04 (t, J = 7.4 Hz, 3H); HRMS (ESI) m/z calcd for C26H27N2O4 [M + H+] 431.1965, found 431.1973. 1

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DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

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The Journal of Organic Chemistry

1.49−1.35 (m, 2H), 1.34−1.13 (m, 3H); 13C NMR (101 MHz, chloroform-d) δ 165.9, 165.6, 160.4, 158.5, 154.8, 150.5, 150.0, 142.7, 137.8, 136.7, 134.1, 133.7, 131.0, 129.5, 127.1, 124.5, 121.7, 115.9, 113.3, 113.0, 62.6, 55.2, 53.2, 46.1, 39.6, 33.9, 26.5, 26.0, 17.8; HRMS (ESI) m/z calcd for C35H43N7O [M + 2H]2+ 288.6759, found 288.6760; key NOE correlations doublet at 6.82 ppm correlates with multiplet at 3.03−2.91 ppm, doublet at 6.82 ppm correlates with singlet at 8.58 ppm. Data for 68: analytical HPLC column 1 tR = 4.75 min; 1H NMR (400 MHz, chloroform-d) δ 9.14 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 1.8 Hz, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.39 (dd, J = 8.2, 2.2 Hz, 1H), 7.86 (br s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 8.2, 2.0 Hz, 1H), 7.29−7.25 (m, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 5.3 Hz, 1H), 7.01 (s, 1H), 3.57 (s, 2H), 2.77 (tt, J = 11.7, 3.2 Hz, 1H), 2.50 (br s, 8H), 2.34 (s, 3H), 2.31 (s, 3H), 1.97 (br d, J = 11.3 Hz, 2H), 1.92−1.83 (m, 2H), 1.81−1.73 (m, 1H), 1.56 (qd, J = 12.4, 2.2 Hz, 2H), 1.50−1.37 (m, 2H), 1.36−1.28 (m, 1H); 13C NMR (101 MHz, chloroform-d) δ 169.0, 165.5, 163.2, 160.7, 158.9, 148.0, 142.6, 138.0, 136.7, 135.4, 134.1, 131.0, 130.3, 129.5, 127.2, 124.4, 121.3, 115.4, 113.3, 108.3, 62.7, 55.2, 53.2, 46.7, 46.1, 32.9, 26.7, 26.2, 17.8; HRMS (ESI) m/z calcd for C35H43N7O [M + 2H]2+ 288.6759, found 288.6759; key NOE correlations doublet at 7.15 ppm correlates with doublet of doublets at 8.39 ppm and doublet at 7.15 ppm correlates with doublet at 9.14. Data for 69: analytical HPLC column 1 tR = 5.05 min; 1H NMR (400 MHz, chloroform-d) δ 8.55 (d, J = 5.3 Hz, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.78 (s, 1H), 7.49 (dd, J = 8.2, 2.1 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 5.2 Hz, 1H), 7.02 (s, 1H), 6.68 (d, J = 5.0 Hz, 1H), 3.58 (s, 2H), 2.76− 2.44 (m, 8H), 2.43−2.36 (m, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 2.29− 2.20 (m, 1H), 1.91−1.03 (m, 20H); 13C NMR (101 MHz, chloroformd) δ 167.5, 165.6, 162.8, 160.4, 158.0, 154.1, 149.5, 142.5, 137.9, 136.7, 134.1, 132.3, 131.1, 129.5, 127.2, 124.4, 118.8, 115.8, 113.8, 113.2, 62.5, 55.1, 53.6, 52.9, 45.8, 43.4, 41.0, 34.0, 33.7, 32.7, 32.5, 29.8, 26.6, 26.5, 26.0, 26.0, 17.8, 14.3; HRMS (ESI) m/z calcd for C41H53N7O [M + 2H]2+ 329.7150, found 329.7150. Data for 70: analytical HPLC column 1 tR = 6.12 min; 1H NMR (400 MHz, chloroform-d) δ 8.47 (d, J = 5.1 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.79 (br s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.2, 1.8 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.82 (d, J = 5.1 Hz, 1H), 3.57 (s, 2H), 3.06− 2.93 (m, 1H), 2.72 (tt, J = 11.5, 3.3 Hz, 1H), 2.52 (br s, 8H), 2.33 (s, 6H), 2.11−1.10 (m, 20H); 13C NMR (101 MHz, chloroform-d) δ 167.8, 166.8, 165.5, 162.6, 160.3, 158.0, 142.6, 138.0, 137.3, 136.7, 134.2, 131.0, 130.0, 129.5, 127.1, 124.0, 117.9, 115.4, 112.9, 112.8, 62.6, 55.1, 53.0, 46.5, 45.9, 42.4, 32.9, 32.8, 26.7, 26.6, 26.4, 26.1, 17.8; HRMS (ESI) m/z calcd for C41H53N7O [M + 2H]2+ 329.7150, found 329.7151; key NOE correlation doublet at 7.64 ppm correlates with doublet at 6.82 ppm. Data for 71: analytical HPLC column 1 tR = 5.83 min; 1H NMR (400 MHz, chloroform-d) δ 8.53−8.48 (m, 1H), 8.51 (s, 1H) 8.30 (d, J = 2.0 Hz, 1H), 7.84−7.77 (m, 2H), 7.80 (s, 1H), 7.53 (dd, J = 8.2, 2.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.82 (d, J = 5.1 Hz, 1H), 3.57 (s, 2H), 2.97 (tt, J = 11.9, 3.0 Hz, 1H), 2.73 (tt, J = 11.8, 3.3 Hz, 1H), 2.51 (br s, 8H), 2.32 (s, 6H), 2.01−1.17 (m, 20H); 13C NMR (101 MHz, chloroform-d) δ 167.5, 166.3, 165.6, 160.3, 158.3, 155.1, 149.4, 142.6, 137.9, 136.7, 134.1, 131.3, 131.0, 129.5, 127.2, 124.3, 118.9, 115.7, 113.1, 113.0, 62.6, 55.2, 53.1, 46.8, 46.0, 39.7, 34.0, 33.1, 26.7, 26.6, 26.2, 26.1, 17.8; HRMS (ESI) m/z calcd for C41H53N7O [M + 2H]2+ 329.7150, found 329.7153; key NOE correlation singlet at 8.51 ppm correlates with doublet at 6.82 ppm. Procedure for the Substrate Run on 0.25, 1.25, and 6.25 mmol Scales: Methyl 4-(4-chloro-6-methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (72). 0.25 mmol Scale. The compound was prepared by the general procedure using 4(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (80 mg, 0.38 mmol, 1.5 equiv) and 4-chloro-2-methylpyridine (32 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (58 mg, 39 μL, 0.51 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a

N-(3-(5-(4-Chlorophenyl)-2-cyclohexyl-1H-pyrrolo[2,3-b]pyridine3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (65). The compound was prepared by the general procedure on a 0.10 mmol scale using cyclohexanecarboxylic acid (7, 19 mg, 0.15 mmol, 1.5 equiv) and vemurafenib (49 mg, 0.10 mmol, 1.0 equiv) as substrates with TFA (22 mg, 15 μL, 0.20 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. The product was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give N-(3-(5-(4-chlorophenyl)-2-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-3carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (65, 18 mg, 31% yield) as a white solid: LCMS tR = 1.08 min; 1H NMR (499 MHz, acetone-d6) δ 11.68 (br s, 1H), 8.73 (br s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 7.90 (app br s, 1H), 7.79 (td, J = 9.0, 5.8 Hz, 1H), 7.63−7.59 (m, 2H), 7.52−7.48 (m, 2H), 7.32−7.24 (m, 1H), 3.29−3.17 (m, 1H), 3.15−3.09 (m, 2H), 1.95 (br d, J = 12.3 Hz, 2H), 1.88−1.75 (m, 6H), 1.75−1.68 (m, 1H), 1.35−1.18 (m, 3H), 0.96 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz, acetone-d6) δ 181.5, 157.4, 157.1 (dd, J = 246.3, 7.4 Hz), 152.9 (dd, J = 248.6, 8.7 Hz), 148.9, 143.7, 138.6, 133.9, 131.4, 130.0, 129.6, 128.7 (d, J = 8.3 Hz), 127.0, 123.6 (dd, J = 12.9, 3.7 Hz), 121.7 (t, J = 23.9 Hz), 120.2, 113.2 (dd, J = 22.5, 4.1 Hz), 112.1, 54.9, 38.0, 32.6, 27.3, 26.4, 18.0, 13.0; HRMS (ESI) m/z calcd for C29H29N3O3F2SCl [M + H+] 572.1581, found 572.1581. Key NOE correlations: doublet at 8.56 ppm correlates with multiplet from 7.63− 7.59 ppm and apparent broad singlet at 7.90 ppm correlates with multiplet from 7.63−7.59 pp. Key HMBC correlations: 1H signal (8.56 ppm, d, J = 2.3 Hz, 1H) correlates with 13C signal at 127.0 ppm and 1 H signal (1.95 ppm, br d, J = 12.3 Hz, 2H) correlates with 13C signal at 157.4 ppm. Products 66−71. The compounds were prepared by the general procedure using cyclohexanecarboxylic acid (7, 48 mg, 0.37 mmol, 1.5 equiv) and imatinib (123 mg, 0.25 mmol, 1.0 equiv) as substrates with TFA (57 mg, 38 μL, 0.50 mmol, 2.0 equiv) used in the photochemical portion and was irradiated with blue light for 3 h in the photochemical portion. Purified by reverse-phase HPLC using TFA buffer. Isolated fractions were neutralized with saturated aqueous sodium bicarbonate solution and concentrated to give N-(3-((4-(2-cyclohexylpyridin-3yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1yl)methyl)benzamide (66, 18 mg, 13% yield) as a pale yellow solid, N(3-((4-(4-cyclohexylpyridin-3-yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (67, 17 mg, 12% yield) as a pale yellow solid, N-(3-((4-(6-cyclohexylpyridin-3yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1yl)methyl)benzamide (68, 12 mg, 8% yield, 92% analytical HPLC purity) as a pale yellow solid, N-(3-((4-(2,4-dicyclohexylpyridin-3yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4-((4-methylpiperazin-1yl)methyl)benzamide (69, 4 mg, 2% yield) as a yellow oil, N-(3-((4(2,6-dicyclohexylpyridin-3-yl)pyrimidin-2-yl)amino)-4-methylphenyl)4-((4-methylpiperazin-1-yl)methyl)benzamide (70, 10 mg, 6% yield, 94% analytical HPLC purity) as a yellow solid, N-(3-((4-(4,6dicyclohexylpyridin-3-yl)pyrimidin-2-yl)amino)-4-methylphenyl)-4((4-methylpiperazin-1-yl)methyl)benzamide (71, 11 mg, 7% yield, 93% analytical HPLC purity) as a yellow solid. Data for 66: analytical HPLC column 1 tR = 4.22 min; 1H NMR (400 MHz, chloroform-d) δ 8.65 (dd, J = 4.7, 1.5 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 7.85−7.77 (m, 3H), 7.75 (dd, J = 7.8, 1.5 Hz, 1H), 7.49− 7.39 (m, 3H), 7.24−7.17 (m, 2H), 7.01 (s, 1H), 6.82 (d, J = 5.0 Hz, 1H), 3.58 (s, 2H), 3.08−2.97 (m, 1H), 2.77−2.42 (m, 8H), 2.38 (s, 3H), 2.33 (s, 3H), 1.86−1.63 (m, 5H), 1.39−1.15 (m, 5H); 13C NMR (101 MHz, chloroform-d) δ 167.2, 165.5, 163.7, 160.4, 158.3, 150.0, 142.4, 137.9, 137.4, 136.7, 134.2, 133.2, 131.0, 129.5, 127.1, 124.2, 120.9, 115.6, 113.0, 112.8, 62.5, 55.0, 52.7, 45.7, 42.4, 32.8, 26.5, 26.0, 17.8; HRMS (ESI) m/z calcd for C35H43N7O [M + 2H]2+ 288.6759, found 288.6757. Data for 67: analytical HPLC column 1 tR = 4.45 min; 1 H NMR (400 MHz, chloroform-d) δ 8.60−8.55 (m, 1H), 8.58 (s, 1H) 8.52 (d, J = 5.0 Hz, 1H), 8.30 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H), 7.80 (br d, J = 8.1 Hz, 2H), 7.50 (dd, J = 8.2, 1.5 Hz, 1H), 7.44 (br d, J = 8.1 Hz, 2H), 7.29 (d, J = 5.3 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.01 (s, 1H), 6.82 (d, J = 5.0 Hz, 1H), 3.56 (s, 2H), 3.03−2.91 (m, 1H), 2.72−2.36 (m, 8H), 2.33 (s, 3H), 2.31 (s, 3H), 1.88−1.66 (m, 5H), 3010

DOI: 10.1021/acs.joc.8b00205 J. Org. Chem. 2018, 83, 3000−3012

Note

The Journal of Organic Chemistry

HRMS (ESI) m/z calcd for C16H21NO2Cl [M + H+] 294.1255, found 294.1257.

Teledyne Isco instrument to give methyl 4-(4-chloro-6-methylpyridin2-yl)bicyclo[2.2.2]octane-1-carboxylate (72, 50 mg, 68% yield) as a white solid. 1.25 mmol Scale. The reaction was run in a 20 mL vial with a cap containing a pressure relief septum. To a stirred solution of 4(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (398 mg, 1.88 mmol, 1.5 equiv), N-hydroxyphthalimide (306 mg, 1.88 mmol, 1.5 equiv), and DMAP (7.7 mg, 0.063 mmol, 5 mol %) in DMSO (6.25 mL) was added DIC (0.29 mL, 1.86 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h for an in situ NAP formation. Then, a solution of 4-chloro-2-methylpyridine (159 mg, 1.25 mmol, 1.0 equiv) and TFA (283 mg, 0.19 mL, 2.48 mmol, 2.0 equiv) in DMSO (4 mL for solution formation and initial transfer +2.25 mL rinse of vial containing transferred solution) was transferred to the solution containing the NAP. Then, 4-CzIPN (10, 9.9 mg, 0.013 mmol, 1 mol %) was added to the reaction mixture. The solution was bubbled vigorously for 180 s with nitrogen gas, sealed, and affixed with a balloon containing nitrogen gas. The reaction vessel was placed above a stir plate between two blue Kessil brand KSH150B Grow Light LED 34 W lamps secured with gooseneck clamps. The center of the reaction vessel was roughly 5 cm from one lamp and 7 cm from the other. No cooling fan was used. The reaction was stirred and irradiated with blue light for 3 h. Upon completion, the reaction was opened to air, diluted with CH2Cl2 (60 mL), and poured into a separatory funnel containing water (50 mL). A 1.5 M aqueous K2HPO4 solution was added until the solution reached roughly pH 8 as judged by pH paper. The organic layer was separated, washed with water (50 mL), washed again with water (50 mL), and made slightly basic by the addition of a 1.5 M aqueous K2HPO4 solution (1.5 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford a crude yellow solid. This crude material was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give methyl 4(4-chloro-6-methylpyridin-2-yl)bicyclo[2.2.2]octane-1-carboxylate (72, 285 mg, 78% yield) as an off-white solid. 6.25 mmol Scale. The reaction was run in a 200 mL flask using a standard rubber septum. To a stirred solution of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1.99 g, 9.38 mmol, 1.5 equiv), N-hydroxyphthalimide (1.53 g, 9.38 mmol, 1.5 equiv), and DMAP (38.5 mg, 0.32 mmol, 5 mol %) in DMSO (31 mL) was added DIC (1.46 mL, 9.37 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h for an in situ NAP formation. Then, a solution of 4-chloro-2-methylpyridine (797 mg, 6.25 mmol, 1.0 equiv) and TFA (1.43 g, 0.96 mL, 12.5 mmol, 2.0 equiv) in DMSO (20 mL for solution formation and initial transfer +11 mL rinse of vial containing transferred solution) was transferred to the solution containing the NAP. Then, 4-CzIPN (10, 49 mg, 0.062 mmol, 1 mol %) was added to the reaction mixture. The solution was bubbled vigorously for 8 min with nitrogen gas, sealed, and affixed with a balloon containing nitrogen gas. The reaction vessel was placed above a stir plate between two blue Kessil brand KSH150B Grow Light LED 34 W lamps secured with gooseneck clamps. The center of the reaction vessel was roughly 6 cm from each lamp. No cooling fan was used, and the internal temperature was measured to be 45 °C at completion. The reaction was stirred and irradiated with blue light for 24 h. Upon completion, the reaction was opened to air, diluted with CH2Cl2 (250 mL), and poured into a separatory funnel containing water (250 mL) and a 1.5 M aqueous K2HPO4 solution (50 mL). The solution reached roughly pH 8 as judged by pH paper. The aqueous layer was extracted with DCM (3 × 50 mL). The combined organic extracts were washed with water (3 × 250 mL) that had been made slightly basic by the addition of a 1.5 M aqueous K2HPO4 solution (1.5 mL) added to each wash. The organic layer was dried (Na2SO4), filtered, and concentrated to afford a crude yellow solid. This crude material was purified by flash column chromatography using silica gel on a Teledyne Isco instrument to give methyl 4-(4-chloro-6-methylpyridin-2-yl)bicyclo[2.2.2]octane1-carboxylate (72, 1.33 g, 73% yield) as an off-white solid: LCMS tR = 0.78 min; 1H NMR (499 MHz, DMSO-d6) δ 7.21 (d, J = 1.5 Hz, 1H), 7.19 (d, J = 1.3 Hz, 1H), 3.59 (s, 3H), 2.43 (s, 3H), 1.87−1.82 (m, 6H), 1.82−1.77 (m, 6H); 13C NMR (126 MHz, DMSO-d6) δ 177.3, 168.5, 158.6, 143.1, 120.3, 116.8, 51.5, 38.7, 37.3, 29.9, 28.1, 24.0;

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00205. Spectral data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: (609)-252-3341. ORCID

Trevor C. Sherwood: 0000-0003-3070-6373 T. G. Murali Dhar: 0000-0003-0738-1021 Author Contributions

All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Linping Wang and Robert Langish for assistance with HRMS and Janet Caceres Cortes, Purnima Khandelwal, and Xiaohua Stella Huang for assistance with NMR characterization. We also thank Yingru Zhang for assistance with purification of select compounds. We are grateful to Christopher Jamison in BMS Chemical and Synthetic Development for providing us with the 4-CzIPN photocatalyst. We would like to thank Andrew Dilger for helpful discussions. We are grateful to William (Rick) Ewing for serving as chair of the summer intern program at Bristol-Myers Squibb supporting Aliza N. Yazdani.

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REFERENCES

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