How To Achieve High Regioselectivity in Barrier-less Nucleophilic

Jan 28, 2019 - Eshani Das* , Shyam Basak* , Anakuthil Anoop* , Santanu Chand , and ... Recently, a study has been reported from our group ( J. Org. Ch...
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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

How To Achieve High Regioselectivity in Barrier-less Nucleophilic Addition to p‑Benzynes Generated via Bergman Cyclization of Unsymmetrical Cyclic Azaenediyne? Eshani Das,*,† Shyam Basak,*,† Anakuthil Anoop,* Santanu Chand, and Amit Basak* Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India

J. Org. Chem. Downloaded from pubs.acs.org by WEBSTER UNIV on 02/12/19. For personal use only.

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ABSTRACT: Inducing high regioselectivity in nucleophilic addition to p-benzynes, first reported by Perrin and O’Connor et al. (J. Am. Chem. Soc. 2007, 129, 4795−4799) has been a challenge as the reaction involves a very fast barrier-less addition of nucleophile. On the other hand, achieving a high degree of regioselectivity is important as that will make the reaction synthetically useful. Recently, a study has been reported from our group (J. Org. Chem. 2018, 83, 7730−7740), whereby it was shown that nucleophilic addition to p-benzynes derived from unsymmetrical N-substituted cyclic enediynes proceeds with low extent of selectivity by incorporation of groups with divergent electronic characters. Herein, we report that excellent regioselectivity (>99%) can be achieved keeping an ortho alkoxy group in unsymmetrical 1,2-dialkynylbenzene in the form of a cyclic enediyne in quantitative yields. High regioselectivity (∼84%) is also shown by pyridine based enediynes where the pyridine nitrogen is in a 1,3-relationship with the impending radical center, expanding the synthetic scope of this nucleophilic addition. The regioselectivity can be explained in terms of computed electrostatic potentials which are substantially different around two radical centers arising due to the “ortho effect” (conformational alignment of lone pair of the ortho alkoxy oxygen or the nitrogen in pyridine systems).

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INTRODUCTION Enediynes, discovered in the late 80s as a group of natural products,1 have been drawing considerable attention among the scientific community because of their potent biological activities2 which originate from their ability to generate pbenzyne (believed to exist as a 1,4-benzene diradical) via a process known as cycloaromatization.3 The reaction of enediynes was originally observed by Masamune,4 and the diradical mechanism was established by Bergman. The reaction is now popularly known as Bergman cyclization (BC).5 The diradical nature of p-benzyne is responsible for abstracting H or halogen atom from suitable small molecule donors, e.g., cyclohexadiene and haloalkanes.6 Large biomolecules DNA and proteins can also act as H-donors which ultimately results in their cleavage.7 In 2007, Perrin and O’Connor8 reported for the first time that p-benzyne can also undergo nucleophilic addition. On the basis of various kinetic studies as well as isotope labeling experiments, they have proposed a mechanism involving initial rate determining formation of p-benzyne © XXXX American Chemical Society

which then undergoes rapid attack by the nucleophile, followed by protonation of the carbanion (Scheme 1). Their results have provided a new dimension to the diradical chemistry and have indicated a dual nature of reactivity of the p-benzyne intermediate.9 Scheme 1. Proposed Mechanism8 for Nucleophilic Addition to a p-Benzyne Derived from an Enediyne

Received: January 8, 2019 Published: January 28, 2019 A

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 2. Previous Studies by Das et al.10

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Recently, we have reported10 the results of nucleophilic addition to p-benzynes (Scheme 2) generated from unsymmetrical N-substituted enediynes attached with electron donor or acceptor moieties to influence the attack of the nucleophile from one side of the p-benzyne. The observed selectivity, although small, was explained on the basis of electrostatic potential difference in the vicinity of radical centers which causes differential concentration of the solvated nucleophile. This ultimately leads to some degree of selectivity. Taking a cue from our earlier work, it was realized that incorporation of a group (withdrawing or donating) at the meta or para position with respect to the impending radical centers would not produce high degree of selectivity, indicating that through-bond electronic effects will be marginal to make any substantial difference in the electrophilic character between the two radical centers. So in order to achieve high degree of selectivity in the nucleophilic addition, an electron rich group at the ortho position could be ideal as that might provide substantial difference in surface charge density near the immediate vicinity of the radical centers along with the possibility of offering steric hindrance to the approach of the nucleophile from the side of the ortho group (Figure 1). Our

RESULTS AND DISCUSSION To test this aspect of regioselectivity in nucleophilic addition, several N-substituted 10-membered unsymmetrical aryl-fused enediynes 1a−d with various alkoxy substituents at the ortho position were synthesized starting from a common intermediate 2-bromo-3-iodophenol which was prepared following a literature protocol.12a This was first O-alkylated to the 2bromo-1-iodo-3-alkoxybenzene derivatives. For the synthesis of enediynes of type I, two successive Sonogashira coupling,12b,c first with THP-protected propargyl alcohol and then with homopropargyl alcohol, were carried out. The resulting acyclic enediynes were converted into target cyclic ones by functional group modification and finally intramolecular cyclization. For the synthesis of type II enediynes, the sequence of Sonogashira couplings was reversed. The pyridine based enediyne 1e was similarly prepared starting from commercially available 2-bromo-3-iodo pyridine. The entire synthetic protocol is shown in Scheme 3. An alternative approach which could provide rapid access to the precursor for the cyclic enediynes was to employ the tosyl protected homopropargyl amine13 as the alkyne partner for Sonogashira coupling, followed by a second coupling with propargyl alcohol. The success of this strategy has been demonstrated in the case of synthesis of the isomeric pyridine based enediyne 1f (Scheme 4). The structures of all the synthesized enediynes were confirmed by extensive NMR including NOESY and HRMS studies as well as by single crystal X-ray structure14 obtained for one of the starting enediyne (as shown in Figure 2). Bergman Cyclization in the Presence of Lithium Halide. The enediynes were next subjected to Bergman cyclization by heating a DMSO solution in a sealed tube in the presence of a large excess of lithium halide (138 equiv) and pivalic acid (3 equiv) for ∼72 h following our earlier reported procedure10 (Scheme 5). Here also, the temperature of the reaction was kept at 65 °C as the enediynes were benzo fused systems15 known to undergo BC at comparatively higher temperature. After removal of DMSO under cold condition, the residue was extracted into ethyl acetate which was then evaporated off. The 1H NMR of the crude reaction products showed the formation of only one isomer in each case. Even for the pyridine based enediynes 1e and 1f, high regioselectivity (∼84%) was observed; in this case, the two regioisomers were isolated in a ratio of 1:0.19. All the cyclized products were isolated in pure form by column chromatography, and their structures were elucidated by 1H, 13C and NOESY spectral analysis. As a representative example, the NOESY spectrum and X-ray crystal structure of one halogenated product are shown in Figure 2. The results of nucleophilic addition to p-benzyne are shown in Table 1. Apart from excellent regioselectivity, the yields were nearly quantitative except for the benzyloxy enediyne 1c for which

Figure 1. Possible scenario of approach of nucleophile to ortho substituted p-benzyne.

idea to induce selectivity via ortho substitution was also inspired by the seminal work of Alabugin et al. to perturb the reactivity of enediynes via the “ortho effect”11 (tuning Bergman cyclization rate by ortho substitution). In this paper, we report the synthesis of a series of o-alkoxy substituted unsymmetrical 1,2 dialkynylbenzene in the form of cyclic enediynes 1a−d and the results of nucleophilic addition LiX (X = Cl, Br, I) to the pbenzynes derived from them. We are happy to disclose that, in all cases, we obtained only one regioisomeric halogenated derivative in excellent yields with regioselectivity >99%. We did not observe the formation of the other regioisomer in the crude 1H and 13C NMR (included in SI). In our studies, we have included pyridine based enediynes 1e,f which also showed high regioselectivity (∼84%). The origin of such high degree of selectivity has also been assessed through computational studies. B

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Synthesis of o-Substituted and Pyridine Based Enediynes (1a−e)a

a (i) Diethylcarbamoyl chloride, NaH, THF, rt, 10 h; (ii) LDA, C2H4Br2, THF, −78 °C−rt, 14 h; (iii) NaOH, EtOH, 80 °C, 7 h; (iv) alkyl/aryl halide, base, solvent; (v) 3-butyn-1-ol/THP-protected propargyl alcohol, PdCl2(PPh3)2, CuI, Et3N, rt, 10 h; (vi) THP-protected propargyl alcohol/ 3-butyn-1-ol, Pd(PPh3)4, n-BuNH2, 80 °C, 24−36 h; (vii) (a) MsCl, Et3N, DCM, 0 °C, 0.5 h; (b) NaN3, DMF, rt, 24 h; (viii) (a) PPh3, THF, H2O, rt, 24 h; (b) TsCl, Et3N, DCM, 0 °C−rt, 4 h; (ix) PPTS, EtOH, 55 °C, 12 h; (x) (a) MsCl, Et3N, DCM, 0 °C, 0.5 h; (b) K2CO3, DMF, rt, 3 h; (xi) THP-protected propargyl alcohol, PdCl2(PPh3)2, CuI, Et3N, rt, 2 h; (xii) 3-butyn-1-ol, Pd(PPh3)4, CuI, Et3N, 90 °C, 24 h.

Scheme 4. Synthesis of Pyridine Based Enediyne 1fa

(i) A, PdCl2(PPh3)2, CuI, Et3N, THF, rt, 3.5 h; (ii) propargyl alcohol, Pd(PPh3)4, CuI, Et3N-THF (4:1), 80 °C, 12 h; (iii) (a) MsCl, Et3N, DCM, 0 °C, 0.5 h; (b) K2CO3, DMF, rt, 3 h. a

C

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

Figure 2. NOESY spectra and ORTEP diagram of enediyne 1a and cyclized product 2d.

the peri position offers a route to different natural17 and nonnatural skeletons via cross-coupling reactions. Literature survey reveals the existence of several medicinally important natural products with a similar skeleton (benzo tetrahydroisoquinoline).18 The high regioselectivity observed by incorporation of an o-substituent certainly expands the scope of this reaction. The approach of the halide ion was also according to our proposed hypothesis (Figure 1). As suggested by Perrin et al.,8 the barrier-less nature of nucleophilic addition to p-benzyne was found to be true in our previous cases of unsymmetrical cyclic enediyne. Just to make sure that ortho substitution does not alter the barrier-less nature, we have carried out similar calculations and found that the nucleophilic addition remains barrier-less (computation results included in SI). Thus, this observation of exclusive regioselectivity is striking. Earlier,10 we have also shown that the N-tosyl group has no role in inducing

the isolated yield was 76% (may be due to participation of benzylic hydrogen into alternate radical initiated pathway). Inspection of the results depicted in Table 1 shows that, unlike the previously reported examples, all the enediynes 1a− d reacted with lithium bromide to give exclusively one halogenated product in very high yields. The nucleophilic addition also worked with other halides LiCl and LiI. These are the first examples of complete regioselectivity in nucleophilic addition to p-benzynes generated via Bergman cyclization and makes such addition reactions to lead to synthetically useful halo functionalized arenes.16 When we switch over to a heterosystem like pyridine based enediynes 1e and 1f, high selectivity was also observed (∼84%). This type of regioselective nucleophilic addition leads to useful synthetic intermediates. The benzotetrahydroisoquinoline as well as the corresponding pyridine fused analogues with a halogen atom at D

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 5. Reaction of Enediynes with Lithium Halides

selectivity was marginal), here the electrostatic potential significantly differs in the vicinity of two reactive radical centers (C1 and C4 as shown in Figure 3). For an example, if we consider p-benzyne generated from the ortho-methoxy enediyne 1a, the conformation of the methoxy group (as shown in Figure 4) is such that the methyl is away from the radical center, thus keeping the lone pair of oxygen in syn orientation with respect to the C1 radical center. Such spatial disposition of lone pair creates highly negative electrostatic potential close to the C1 center, thus creating a substantial and clear difference in electrostatic potential in the other side (C4 center). This fact compels the negatively charged bromide or other nucleophiles to come from the opposite side (C4 side) with respect to the ortho-methoxy group. The conformation of other p-benzynes from alkoxy substituted enediynes (1b−d) being similar, the resulting electrostatic potential map is also nearly the same (see SI). Thus, the explanation is applicable to all other p-benzynes generated from enediynes 1b−d (results included in SI). One interesting point to be noted here is that

Table 1. Experimental Results enediynes

reagent

1a 1a 1a 1b 1c 1d 1e 1f

LiBr LiCl LiI LiBr LiBr LiBr LiBr LiBr

isomeric products 2a 2a′ 2a′′ 2b 2c 2d 2e 2f

3a 3a′ 3a′′ 3b 3c 3d 3e 3f

product

combined yield (%)

only 2a only 2a′ only 2a′′ only 2b only 2c only 2d 2e:3e::1:0.19 2f:3f::1:0.19

99 95 96 90 76 99 93 96

any selectivity to halide addition. This indicates that the regioselectivity in these present systems must be originating due to the presence of the alkoxy group at the ortho position. To understand such high degree of regioselectivity, we looked at the surface electrostatic potential adjacent to two radical centers. Unlike the previously reported examples (where the difference in surface charge density causing

Figure 3. Electrostatic potential mapped over electron density (isovalue: 0.0004 e/Å3) at the [BS-B3LYP/6-31G(d,p)] level of theory for the diradical originating from 1a. The red surface indicates the electron-rich regions (negative electrostatic potential), and the blue part indicates the electron-deficient regions (positive electrostatic potential) of the molecule. (a) view from C1 side; (b) front view; (c) view from C4 side. E

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

Figure 4. Optimized syn and anti conformations of p-benzyne generated from enediyne 1a. ppm), multiplicity (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet), coupling constant (Hz), integration. Data for 13C NMR are reported as chemical shift. HRMS spectra using ESI were recorded on an ESIFTMS mass spectrometer. General Experimental Procedure. All the compounds were synthesized using our earlier reported procedure.10 The starting materials (4a−c) were synthesized using a literature known procedure.12a,22 [2-((3-(2-Bromo-3-methoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (5a). The compound 5a was synthesized by Sonogashira coupling between 2-bromo-3-iodoanisole (4a) and THP-protected propargyl alcohol in 90% yield (1.2 g). Brown gummy liquid; Rf 0.66 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.20 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.99 (t, J = 3 Hz, 1H), 4.54 (s, 2H), 3.92− 3.86 (m, 4H), 3.59−3.56 (m, 1H), 1.86−1.60 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.3, 127.9, 126.5, 125.7, 115.2, 111.9, 96.8, 90.1, 84.5, 62.3, 56.5, 54.7, 30.4, 25.5, 19.2; HRMS [ESI-TOF] calcd for C15H17BrO3H [M + H]+ 325.0439, found 325.0436. [4-(2-Methoxy-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1yl)phenyl)but-3-yn-1-ol] (6a). The compound 6a was synthesized by Sonogashira coupling between 5a and 3-butyn-1-ol in 44% yield (450 mg). Brown gummy liquid; Rf 0.17 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.97 (s, 1H), 4.53 (ABq, J = 24.8, 16.0 Hz, 2H), 3.93−3.82 (m, 6H), 3.55−3.58 (m, 1H), 2.78 (s, 2H), 1.84−1.55 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 128.6, 126.9, 124.6, 115.5, 110.7, 96.8, 95.9, 88.9, 84.9, 77.9, 62.0, 61.0, 56.2, 54.9, 30.3, 25.5, 24.7, 19.0; HRMS [ESI-TOF] calcd for C19H22O4H [M + H]+ 315.1596, found 315.1595. [2-((3-(2-(4-Azidobut-1-yn-1-yl)-3-methoxyphenyl)prop-2-yn-1yl)oxy)tetrahydro-2H-pyran] (7a). The compound 7a was synthesized from 6a via mesylation, followed by nucleophilic substitution (with NaN3) in 68% yield (290 mg). Yellow liquid; Rf 0.57 (hexane/ EtOAc, 7.8/2.2); 1H NMR (500 MHz, CDCl3) δ 7.18 (t, J = 7.9 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.97 (t, J = 3 Hz, 1H), 4.53 (ABq, J = 25.5, 15.5 Hz, 2H), 3.90−3.86 (m, 4H), 3.58−3.53 (m, 3H), 2.81 (t, J = 7.0 Hz, 2H), 1.90−1.53 (m, 6H); 13 C{1H} NMR (125 MHz, CDCl3) δ 160.1, 128.7, 127.2, 124.5, 115.2, 110.7, 96.7, 94.5, 89.02, 84.6, 62.0, 56.1, 54.8, 50.2, 30.4, 25.5, 21.1, 19.1; HRMS [ESI-TOF] calcd for C19H21N3O3Na [M + Na]+ 362.1481, found 362.1482. [N-(4-(2-Methoxy-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1yn-1-yl)phenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (8a). The compound 8a was synthesized from 7a via reduction to amine, followed by N-protection (with TsCl) in 79% yield (270 mg). White gummy solid; Rf 0.20 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 2H), 7.25−7.20 (m, 3H), 7.07 (d, J = 7.7 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 5.64 (s, 1H), 4.98 (s, 1H), 4.57−4.51 (m, 2H), 3.93 (s, 3H), 3.87 (t, J = 10.4 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.24−3.21 (m, 2H), 2.58 (t, J = 5.6 Hz, 2H), 2.38 (s, 3H), 1.84−1.55 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 160.3, 143.4, 137.6, 129.8, 128.8, 127.2, 126.5, 124.7, 115.0, 110.7, 96.7, 94.8, 89.3, 84.6, 78.7, 62.0, 56.2, 54.9, 41.8, 30.4, 25.5, 21.6, 21.0,

the crystal structure, computation and NOESY spectral analysis of respective enediynes and halogenated products suggest that the conformations (Figure 4) we are talking about is all anti (wrt alkoxy alkyl group) and syn (wrt oxygen lone pair) with the nearby radical center.19 Next, in the case of pyridine fused enediyne, the electrostatic potential difference also supports the observation. The nitrogen lone pair acted as a repulsive factor (negative electrostatic potential, see SI) to force the nucleophile to approach from the opposite side. However, unlike the previous cases (>99% regioselectivity), here besides the exclusive product another regioisomer is formed as minor product (ratio 2e:3e::1:0.19 and 2f:3f::1:0.19). This may be attributed to the geometric disposition of the nitrogen lone pair of pyridine which is actually parallel with the trajectory of attacking nucleophile, whereas, in alkoxy substituted cases, the oxygen lone pair is bent toward the nucleophile’s trajectory.

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CONCLUSION In summary, we have for the first time reported excellent regioselectivity in barrier-less nucleophilic addition20,21 to pbenzyne leading to the formation of mostly one regioisomer in near quantitative yields. This was achieved via incorporation of various alkoxy substitutions at the ortho position of a cyclic Nsubstituted enediyne. High regioselectivity was also obtained in the pyridine based system, which further broadens the scope of such reaction in heterocyclic systems. This observed selectivity has been successfully explained on the basis of electrostatic potential. Currently we are exploring other ways to induce similar selectivity and the synthetic utility of the halo functionalized cyclized products.

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EXPERIMENTAL SECTION

General Experimental Details. All reactions were performed under a nitrogen atmosphere unless otherwise stated. Glassware used in reactions was thoroughly oven-dried. All commercial grade reagents were used without further purification, and solvents were dried prior to use following a standard protocol. TLC was carried out on precoated plates (silica gel 60 F254), and the spots were visualized by exposure to UV light and/or by staining with iodine. All crude products were purified by silica gel flash column chromatography (230−400 mesh) with petroleum ether/ethyl acetate as eluent and characterized by NMR and mass spectrometry unless otherwise mentioned. Melting points were determined in open capillary tubes and are reported as uncorrected. 1H and 13C NMR spectra for all the compounds were recorded at 400/500/600 and 100/125/150 MHz (Bruker Ultrashield 400, Ascend 500, Ascend 600), respectively. The spectra were recorded in deuterochloroform (CDCl3) and deuterated dimethyl sulfoxide (DMSO-d6) as solvent at room temperature. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as internal standard (CDCl3: δH = 7.26, δC = 77.16 ppm). Data for 1H NMR are reported as follows: chemical shift (δ F

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry 19.0; HRMS [ESI-TOF] calcd for C26H29NO5SNa [M + Na]+ 490.1664, found 490.1665. [N-(4-(2-(3-Hydroxyprop-1-yn-1-yl)-6-methoxyphenyl)but-3-yn1-yl)-4-methylbenzenesulfonamide] (9a). The compound 9a was synthesized from 8a via OTHP deprotection in 80% yield (150 mg). Light yellow gummy liquid; Rf 0.08 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.8 Hz, 2H), 7.26−7.20 (m, 3H), 7.08 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.64 (t, J = 5.6 Hz, 1H), 4.58 (s, 2H), 3.89 (s, 3H), 3.21 (dd, J = 11.7, 5.9 Hz, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.38 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 160.0, 143.7, 136.9, 129.9, 129.0, 127.2, 126.9, 124.9, 114.5, 110.7, 94.4, 92.2, 84.0, 78.7, 56.2, 51.5, 41.7, 21.6, 21.0; HRMS [ESITOF] calcd for C21H21NNaO4S [M + Na]+ 406.1089, found 406.1087. [1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(3-methoxy)]-1-azacyclodec-3,7-diyne] (1a). The compound 1a was synthesized from 9a via mesylation, followed by cyclization in 81% yield (80 mg). White solid; mp decomposition over 120 °C; Rf 0.40 (hexane/EtOAc, 7.8/ 2.2); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.8 Hz, 2H), 7.30− 7.25 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.15 (s, 2H), 3.89 (s, 3H), 3.58 (t, J = 4.8 Hz, 2H), 2.87 (t, J = 4.8 Hz, 2H), 2.39 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 158.1, 143.9, 135.8, 130.0, 129.7, 128.6, 127.4, 120.6, 118.3, 111.0, 102.0, 92.7, 86.8, 80.4, 56.1, 51.2, 42.2, 22.9, 21.6. HRMS [ESI-TOF] calcd for C21H19NO3SH [M + H]+ 366.1164, found 366.1160. [2-Bromo-1-ethoxy-3-iodobenzene] (4b). The compound 4b was synthesized from corresponding alcohol in 68% yield (694 mg). White gummy liquid; Rf 0.77 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.47 (dd, J = 8.1, 1.1 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 6.85−6.82 (m, 1H), 4.08 (q, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 156.4, 132.1, 129.5, 120.1, 112.6, 103.1, 65.5, 14.8. [2-((3-(2-Bromo-3-ethoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro2H-pyran] (5b). The compound 5b was synthesized by Sonogashira coupling between 4b and THP-protected propargyl alcohol in 94% yield (700 mg). Brown gummy liquid; Rf 0.68 (hexane/EtOAc, 7.8/ 2.2); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.99 (s, 1H), 4.54 (s, 2H), 4.11−4.06 (m, 2H), 3.92−3.87 (m, 1H), 3.60−3.55 (m, 1H), 1.91− 1.50 (m, 6H), 1.48−1.44 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.9, 127.8, 126.5, 125.7, 115.9, 113.3, 96.9, 89.9, 84.7, 65.2, 62.3, 54.8, 30.4, 25.5, 19.3, 14.8; HRMS [ESI-TOF] calcd for C16H19BrO3Na [M + Na]+ 361.0415, found 361.0413. [2-((3-(2-(4-Azidobut-1-yn-1-yl)-3-ethoxyphenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (7b). The compound 7b was synthesized first by Sonogashira coupling between 5b and 3-butyn-1-ol and then mesylation, followed by nucleophilic substitution (with NaN3) in 66% yield (255 mg). Brown gummy liquid; Rf 0.63 (hexane/EtOAc, 7.8/ 2.2); 1H NMR (600 MHz, CDCl3) δ 7.14 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.97 (t, J = 3.1 Hz, 1H), 4.53 (ABq, J = 23.7, 16.2 Hz, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.91− 3.86 (m, 1H), 3.59−3.52 (m, 3H), 2.80 (t, J = 7.2 Hz, 2H), 1.86− 1.56 (m, 6H), 1.44 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 159.7, 128.6, 127.1, 124.5, 115.8, 112.3, 96.7, 94.3, 88.9, 84.7, 77.6, 64.7, 62.0, 54.9, 50.3, 30.5, 25.6, 21.0, 19.2, 14.8; HRMS [ESI-TOF] calcd for C20H23N3O3Na [M + Na]+ 376.1637, found 376.1641. [N-(4-(2-Ethoxy-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn1-yl)phenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (8b). The compound 8b was synthesized from 7b via reduction to amine, followed by N-protection (with TsCl) in 80% yield (300 mg). White gummy liquid; Rf 0.27 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 8.1 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.45 (t, J = 6.0 Hz, 1H), 4.98 (t, J = 3.1 Hz, 1H), 4.56−4.50 (m, 2H), 4.13 (q, J = 6.9 Hz, 2H), 3.90−3.85 (m, 1H), 3.58−3.55 (m, 1H), 3.24 (q, J = 6.0 Hz, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 1.87−1.50 (m, 6H), 1.45 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 159.6, 143.4, 137.7, 129.8, 128.7, 127.2, 126.7, 124.5,

115.4, 112.0, 96.6, 94.4, 89.2, 84.8, 78.5, 64.7, 62.0, 54.9, 42.0, 30.4, 25.5, 21.6, 21.2, 19.0, 14.8; HRMS [ESI-TOF] calcd for C27H31NO5SNa [M + Na]+ 504.1821, found 504.1820. [N-(4-(2-Ethoxy-6-(3-hydroxyprop-1-yn-1-yl)phenyl)but-3-yn-1yl)-4-methylbenzenesulfonamide] (9b). The compound 9b was synthesized from 8b via OTHP deprotection in 85% yield (200 mg). White gummy liquid; Rf 0.08 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.78 (d, J = 7.2 Hz, 2H), 7.25 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 5.55 (s, 1H), 4.59 (s, 2H), 4.10 (q, J = 6.8 Hz, 2H), 3.22−3.20 (m, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.39 (s, 3H), 1.43 (t, J = 6.8 Hz, 3H); 13 C{1H} NMR (150 MHz, CDCl3) δ 159.4, 143.7, 137.0, 129.9, 128.9, 127.3, 127.0, 124.8, 114.9, 112.1, 94.0, 92.1, 84.2, 78.7, 64.7, 51.5, 41.7, 21.6, 21.1, 14.8; HRMS [ESI-TOF] calcd for C22H23NO4SNa [M + Na]+ 420.1245, found 420.1247. [1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(3-ethoxy)]-1-azacyclodec-3,7-diyne] (1b). The compound 1b was synthesized from 9b via mesylation, followed by cyclization in 70% yield (152 mg). White solid; mp 107−109 °C; Rf 0.43 (hexane/EtOAc, 7.8/2.2)1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.16−4.11 (m, 4H), 3.60−3.55 (m, 3H), 2.90−2.84 (m, 3H), 2.39 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 157.4, 143.9, 135.8, 130.0, 129.7, 128.4, 127.4, 120.5, 118.7, 112.4, 101.7, 92.4, 87.0, 80.6, 64.6, 51.2, 42.2, 23.0, 21.6, 14.8; HRMS [ESI-TOF] calcd for C22H21NO3SH [M + H]+ 380.1320, found 380.1319. [1-(Benzyloxy)-2-bromo-3-iodobenzene] (4c). The compound 4c was synthesized from corresponding alcohol in 71% yield (1 g). White gummy liquid; Rf 0.80 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.50−7.45 (m, 3H), 7.40 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.1 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.14 (s, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 156.0, 136.2, 132.6, 129.5, 128.8, 128.2, 127.1, 120.4, 113.1, 103.2, 71.3. [2-((3-(3-(Benzyloxy)-2-bromophenyl)prop-2-yn-1-yl)oxy)tetrahydro-2H-pyran] (5c). The compound 5c was synthesized by Sonogashira coupling between 4c and THP-protected propargyl alcohol in 92% yield (900 mg). Brown gummy liquid; Rf 0.66 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.48−7.46 (m, 2H), 7.41−7.30 (m, 2H), 7.32 (t, J = 7.1 Hz, 1H), 7.20−7.10 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 5.16 (s, 2H), 5.00 (s, 1H), 4.56 (s, 2H), 3.91 (t, J = 9.9 Hz, 1H), 3.60−3.56 (m, 1H), 1.87−1.60 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 155.6, 136.5, 128.7, 128.1, 127.8, 127.1, 126.7, 126.2, 116.2, 113.9, 97.0, 90.2, 84.6, 71.2, 62.3, 54.8, 30.5, 25.6, 19.3; HRMS [ESI-TOF] calcd for C21H21BrO3Na [M + Na]+ 423.0572, found 423.0575. [2-((3-(2-(4-Azidobut-1-yn-1-yl)-3-(benzyloxy)phenyl)prop-2-yn1-yl)oxy)tetrahydro-2H-pyran] (7c). The compound 7c was synthesized first by Sonogashira coupling between 5c and 3-butyn-1-ol and then mesylation, followed by nucleophilic substitution (with NaN3) in 50% yield (145 mg). Yellow liquid; Rf 0.63 (hexane/EtOAc, 7.8/2.2); 1 H NMR (400 MHz, CDCl3) δ 7.50−7.30 (m, 5H), 7.15−7.05 (m, 2H), 6.85 (d, J = 8.1 Hz, 1H), 5.15 (s, 2H), 4.99 (s, 1H), 4.60−4.50 (m, 2H), 3.88 (t, J = 10.0 Hz, 1H), 3.59−3.56 (m, 1H), 3.52 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 1.87−1.57 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 159.4, 136.9, 128.6, 128.6, 128.0, 127.1, 127.1, 124.9, 116.1, 113.0, 96.6, 94.6, 89.0, 84.6, 77.5, 70.7, 62.0, 54.8, 50.2, 30.4, 25.5, 21.0, 19.1; HRMS [ESI-TOF] calcd for C25H25N3O3K [M + K]+ 454.1533, found 454.1530. [N-(4-(2-(Benzyloxy)-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop1-yn-1-yl)phenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (8c). The compound 8c was synthesized from 7c via reduction to amine, followed by N-protection (with TsCl) in 68% yield (111 mg). Yellow gummy liquid; Rf 0.27 (hexane/EtOAc, 7.8/2.2); 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2H), 7.40−7.30 (m, 5H), 7.20 (d, J = 8.1 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 5.48 (t, J = 6.0 Hz, 1H), 5.21 (s, 2H), 4.99 (t, J = 3.1 Hz, 1H), 4.58−4.51 (m, 2H), 3.90−3.85 (m, 1H), 3.59−3.56(m, 1H), 3.22 (q, J = 6.3 Hz, 2H), 2.61 (t, J = 6.1 Hz, 2H), 2.36 (s, 3H), 1.86−1.54 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) G

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry δ 159.3, 143.4, 137.6, 136.8, 129.8, 128.8, 128.0, 127.2, 127.0, 125.0, 115.9, 113.0, 96.6, 94.8, 89.3, 84.7, 78.3, 70.7, 61.9, 54.9, 41.9, 30.4, 25.5, 21.6, 21.2, 19.0; HRMS [ESI-TOF] calcd for C32H33NO5SNa [M + Na]+ 566.1977, found 566.1981. [N-(4-(2-(Benzyloxy)-6-(3-hydroxyprop-1-yn-1-yl)phenyl)but-3yn-1-yl)-4-methylbenzenesulfonamide] (9c). The compound 9c was synthesized from 8c via OTHP deprotection in 76% yield (60 mg). Yellow gummy liquid; Rf 0.07 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 2H), 7.41−7.01 (m, 9H), 6.86 (d, J = 8.0 Hz, 1H), 5.54 (s, 1H), 5.17 (s, 2H), 4.60 (s, 2H), 3.22−3.21 (m, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.39 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 159.3, 143.7, 137.0, 136.8, 129.9, 128.8, 128.7, 128.1, 127.3, 127.1, 127.0, 125.3, 115.6, 113.1, 94.4, 92.3, 84.1, 78.7, 70.8, 51.6, 41.8, 21.6, 21.1; HRMS [ESI-TOF] calcd for C27H25NO4SNa [M + Na]+ 482.1402, found 482.1401. [1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(3-benzyloxy)]-1-azacyclodec-3,7-diyne] (1c). The compound 1c was synthesized from 9c via mesylation, followed by cyclization in 75% yield (41 mg). Yellow gummy liquid; Rf 0.60 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.9 Hz, 2H), 7.44−7.28 (m, 7H), 7.10 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.21 (s, 2H), 4.15 (s, 2H), 3.62−3.55 (m, 2H), 2.92−2.85 (m, 2H), 2.39 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 157.2, 143.9, 136.8, 135.8, 130.0, 129.8, 128.8, 128.4, 128.0, 127.4, 127.1, 120.9, 119.1, 113.3, 102.0, 92.6, 86.9, 80.5, 70.8, 51.2, 42.2, 23.0, 21.6; HRMS [ESI-TOF] calcd for C27H23NO3SH [M + H]+ 442.1477, found 442.1476. [4-(2-Bromo-3-methoxyphenyl)but-3-yn-1-ol] (5d). The compound 5d was synthesized by Sonogashira coupling between 2bromo-3-iodo anisole (4a) and 3-butyn-1-ol in 91% yield (519 mg). Brown gummy liquid; Rf 0.31 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.20 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 3.89 (s, 3H), 3.85 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 156.3, 127.9, 127.0, 125.4, 115.3, 111.5, 91.8, 81.7, 61.1, 56.5, 24.2; HRMS [ESI-TOF] calcd for C11H11BrO2H [M + H]+ 255.0021, found 255.0022. [4-(3-Methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1yl)phenyl)but-3-yn-1-ol] (6d). The compound 6d was synthesized by Sonogashira coupling between 5d and THP-protected propargyl alcohol in 41% yield (360 mg). Brown gummy liquid; Rf 0.17 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 5.03 (s, 1H), 4.58 (ABq, J = 22.8, 15.6, 2H), 3.91−3.84 (m, 4H), 3.82 (t, J = 5.8 Hz, 2H), 3.58−3.55 (m, 1H), 2.71 (t, J = 5.8 Hz, 2H), 1.86− 1.53 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 160.3, 129.2, 128.1, 124.1, 114.6, 110.3, 96.5, 93.1, 91.6, 81.4, 81.2, 61.9, 61.0, 56.1, 55.2, 30.3, 25.5, 24.3, 19.0; HRMS [ESI-TOF] calcd for C19H22O4H [M + H]+ 315.1596, found 315.1598. [2-((3-(2-(4-Azidobut-1-yn-1-yl)-6-methoxyphenyl)prop-2-yn-1yl)oxy)tetrahydro-2H-pyran] (7d). The compound 7d was synthesized from 6d via mesylation, followed by nucleophilic substitution (with NaN3) in 59% yield (210 mg). Brown liquid; Rf 0.54 (hexane/ EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.04 (s, 1H), 4.64−4.54 (m, 2H), 3.91−3.86 (m, 4H), 3.58−3.50 (m, 3H), 2.76 (t, J = 7.1 Hz, 2H), 1.87−1.55 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 160.3, 129.1, 127.7, 124.3, 114.7, 110.5, 96.4, 93.4, 90.1, 81.2, 81.0, 61.9, 56.1, 55.0, 50.0, 30.5, 25.6, 20.8, 19.1; HRMS [ESITOF] calcd for C19H21N3O3Na [M + Na]+ 362.1481, found 362.1481. [N-(4-(3-Methoxy-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1yn-1-yl)phenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (8d). The compound 8d was synthesized from 7d via reduction to amine, followed by N-protection (with TsCl) in 96% yield (245 mg). Yellow gummy liquid; Rf 0.20 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 2H), 7.23−7.17 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 5.45 (t, J = 5.1 Hz, 1H), 5.06 (s, 1H), 4.60 (s, 2H), 3.88−3.85 (m, 4H), 3.59−3.56 (m, 1H), 3.23−3.20 (m, 2H), 2.59 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 1.84−1.57

(m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.4, 143.4, 137.6, 129.8, 129.2, 127.7, 127.3, 124.1, 114.7, 110.5, 96.3, 93.5, 90.4, 81.5, 81.3, 61.8, 56.1, 55.1, 41.9, 30.4, 29.8, 25.6, 21.0, 18.9; HRMS [ESITOF] calcd for C26H29NO5SNa [M + Na]+ 490.1664, found 490.1664. [N-(4-(2-(3-Hydroxyprop-1-yn-1-yl)-3-methoxyphenyl)but-3-yn1-yl)-4-methylbenzenesulfonamide] (9d). The compound 9d was synthesized from 8d via OTHP deprotection in 80% yield (150 mg). White gummy liquid; Rf 0.07 (hexane/EtOAc, 7.8/2.2); 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.9 Hz, 2H), 7.24−7.18 (m, 3H), 6.95 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.61 (t, J = 5.2 Hz, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.23−3.18 (m, 2H), 2.58 (t, J = 5.8 Hz, 2H), 2.39 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 160.4, 143.7, 137.1, 129.9, 129.2, 127.3, 124.0, 114.6, 110.5, 96.4, 90.1, 82.0, 80.5, 56.1, 51.8, 41.7, 21.6, 20.9; HRMS [ESI-TOF] calcd for C21H21NO4SNa [M + Na]+ 406.1089, found 406.1086. [1-[4-Methylphenylsulfonyl]-[5,6]-[benz-(6-methoxy)]-1-azacyclodec-3,7-diyne] (1d). The compound 1d was synthesized from 9d via mesylation, followed by cyclization in 82% yield (91 mg). White solid; mp decomposition over 164 °C; Rf 0.37 (hexane/EtOAc, 7.8/ 2.2); 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 8.1 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.20 (s, 2H), 3.88 (s, 3H), 3.59 (t, J = 5.1 Hz, 2H), 2.81 (t, J = 5.1 Hz, 2H), 2.39 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 158.1, 143.9, 136.0, 130.8, 130.0, 129.2, 127.5, 120.9, 117.4, 110.5, 98.3, 96.3, 84.1, 83.4, 56.1, 51.1, 42.6, 22.4, 21.6; HRMS [ESI-TOF] calcd for C21H19NO3SH [M + H]+ 366.1164, found 366.1161. [2-Bromo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine] (5e). The compound 5e was synthesized by Sonogashira coupling between 2-bromo-3-iodo pyridine (commercially available) and THP-protected propargyl alcohol in 85% yield (1.09 g). Brown gummy liquid; Rf 0.80 (hexane/EtOAc, 3/2); 1H NMR (400 MHz, CDCl3) δ 8.30−8.28 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.24−7.21 (m, 1H), 4.96 (s, 1H), 4.54 (s, 2H), 3.89 (t, J = 9.2 Hz, 1H), 3.59− 3.56 (m, 1H), 1.86−1.60 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.8, 144.6, 141.3, 123.3, 122.2, 97.1, 93.1, 82.4, 62.3, 54.7, 30.4, 25.5, 19.2.; HRMS [ESI-TOF] calcd for C13H14BrNO2H [M + H]+ 296.0286, found 296.0288. [4-(3-(3-((Tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin2-yl)but-3-yn-1-ol] (6e). The compound 6e was synthesized by Sonogashira coupling between 5e and 3-butyn-1-ol in 82% yield (891 mg). 1H NMR (600 MHz, CDCl3) δ 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 7.72 (dd, J = 7.9, 1.6 Hz, 1H), 7.17 (dd, J = 7.9, 4.8 Hz, 1H), 4.97 (t, J = 3.2 Hz, 1H), 4.54 (ABq, J = 30.6, 16.0 Hz, 2H), 3.89−3.84 (m, 3H), 3.60−3.56 (m, 1H), 2.91 (s, 1H), 2.76 (t, J = 5.9 Hz, 2H), 1.86−1.56 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 148.9, 145.4, 139.4, 122.3, 122.0, 96.8, 92.3, 91.7, 82.6, 81.0, 62.0, 60.8, 54.8, 30.3, 25.5, 24.2, 18.9; HRMS [ESI-TOF] calcd for C17H19NO3H [M + H]+ 286.1443, found 286.1443. [2-(4-Azidobut-1-yn-1-yl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine] (7e). The compound 7e was synthesized from 6e via mesylation, followed by nucleophilic substitution (with NaN3) in 58% yield (402 mg). Yellow liquid; Rf 0.60 (hexane/EtOAc, 3/2); 1H NMR (600 MHz, CDCl3) δ 8.48 (dd, J = 4.8, 1.5 Hz, 1H), 7.73 (dd, J = 7.9, 1.5 Hz, 1H), 7.17 (dd, J = 7.9, 4.8 Hz, 1H), 4.96 (t, J = 3.2 Hz, 1H), 4.55 (q, J = 16.0 Hz, 2H), 3.90−3.86 (m, 1H), 3.60− 3.55 (m, 3H), 2.79 (t, J = 7.1 Hz, 2H), 1.81−1.55 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 148.9, 145.0, 139.4, 122.5, 122.1, 96.8, 91.9, 90.4, 82.3, 81.1, 62.0, 54.7, 49.7, 30.4, 25.5, 20.6, 19.0; HRMS [ESI-TOF] calcd for C17H18N4O2H [M + H]+ 311.1508, found 311.1505. [4-Methyl-N-(4-(3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn1-yl)pyridin-2-yl)but-3-yn-1-yl)benzenesulfonamide] (8e). The compound 8e was synthesized from 7e via reduction to amine, followed by N-protection (with TsCl) in 90% yield (356 mg). White gummy liquid; Rf 0.29 (hexane/EtOAc, 3/2); 1H NMR (600 MHz, CDCl3) δ 8.46 (dd, J = 4.8, 1.1 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.74 (dd, J = 7.9, 1.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 7.9, 4.8 Hz, 1H), 5.65 (t, J = 6.1 Hz, 1H), 4.99 (t, J = 3.1 Hz, 1H), H

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

2H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 155.0, 143.9, 133.5, 132.1, 132.1, 131.0, 130.0, 127.9, 127.1, 125.4, 122.2, 121.3, 118.9, 104.4, 55.8, 49.9, 43.7, 30.0, 21.7; HRMS [ESI-TOF] calcd for C21H20BrNO3SH [M + H]+ 446.0426, found 446.0406. [10-Chloro-6-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2a′). The compound 2a′ was synthesized from 1a in the presence of LiCl, under Bergman cyclization condition in 95% yield (18 mg). White solid; mp 193−195 °C; Rf 0.40 (hexane/EtOAc, 4/1); 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.79−7.76 (m, 3H), 7.42 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 4.48 (s, 2H), 3.98 (s, 3H), 3.42 (t, J = 5.6 Hz, 2H), 3.14 (t, J = 5.6 Hz, 2H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.1, 143.9, 133.5, 131.6, 130.8, 130.0, 129.1, 128.9, 127.9, 126.9, 125.3, 120.5, 116.2, 104.5, 55.8, 47.0, 43.7, 29.9, 21.7; HRMS [ESITOF] calcd for C21H20ClNO3SH [M + H]+ 402.0931, found 402.0931. [10-Iodo-6-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2a′′). The compound 2a′′ was synthesized from 1a in the presence of LiI, under Bergman cyclization condition in 96% yield (24 mg). White solid; mp 201−203 °C; Rf 0.40 (hexane/EtOAc, 4/1); 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 7.9 Hz, 2H), 6.82 (d, J = 7.7 Hz, 1H), 4.41 (s, 2H), 3.99 (s, 3H), 3.40 (t, J = 5.7 Hz, 2H), 3.13 (t, J = 5.7 Hz, 2H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.9, 143.9, 134.9, 134.7, 133.6, 132.4, 130.0, 127.9, 127.3, 125.0, 124.2, 122.6, 104.4, 103.4, 55.9, 55.9, 43.8, 30.0, 21.7; HRMS [ESI-TOF] calcd for C21H20INOK [M + K]+ 468.0227, found 468.0244. [10-Bromo-6-ethoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2b). The compound 2b was synthesized from 1b in the presence of LiBr, under Bergman cyclization condition in 90% yield (28 mg). White solid; mp 200−202 °C; Rf 0.44 (hexane/EtOAc, 4/ 1); 1H NMR (600 MHz, CDCl3) δ 8.02 (s, 1H), 7.79−7.76 (m, 3H), 7.40 (t, J = 8.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 4.46 (s, 2H), 4.19 (q, J = 6.9 Hz, 2H), 3.41 (t, J = 5.8 Hz, 2H), 3.16 (t, J = 5.8 Hz, 2H), 2.41 (s, 3H), 1.54 (t, J = 6.9 Hz, 3H); 13 C{1H} NMR (150 MHz, CDCl3) δ 154.3, 143.9, 133.7, 132.2, 132.0, 130.9, 130.0, 127.9, 127.2, 125.6, 122.2, 121.5, 118.7, 105.2, 64.2, 49.9, 43.7, 30.0, 21.7, 14.9; HRMS [ESI-TOF] calcd for C22H22BrNO3SH [M + H]+ 460.0582, found 460.0580. [6-(Benzyloxy)-10-bromo-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2c). The compound 2c was synthesized from 1c in the presence of LiBr, under Bergman cyclization condition in 76% yield (14 mg). White semi-solid; Rf 0.46 (hexane/EtOAc, 4/1) 1H NMR (600 MHz, CDCl3) δ 8.06 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 7.3 Hz, 2H), 7.44−7.32 (m, 6H), 6.89 (d, J = 7.5 Hz, 1H), 5.23 (s, 2H), 4.46 (s, 2H), 3.41 (t, J = 5.4 Hz, 2H), 3.14 (t, J = 5.4 Hz, 2H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 154.1, 143.9, 136.8, 133.5, 132.2, 132.2, 131.1, 130.0, 128.8, 128.3, 127.9, 127.7, 127.1, 125.6, 122.2, 121.5, 119.2, 105.8, 70.6, 49.9, 43.7, 30.0, 21.7; HRMS [ESI-TOF] calcd for C27H24BrNO3SH [M + H]+ 522.0739, found 522.0734. [5-Bromo-9-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2d). The compound 2d was synthesized from 1d in the presence of LiBr, under Bergman cyclization condition in 99% yield (19 mg). White solid; mp 197−199 °C; Rf 0.37 (hexane/EtOAc, 4/ 1); 1H NMR (600 MHz, CDCl3) δ 7.98 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 8.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 4.43 (s, 2H), 3.99 (s, 3H), 3.45 (t, J = 6.2 Hz, 2H), 3.14 (t, J = 6.2 Hz, 2H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 155.2, 144.0, 133.6, 132.6, 132.5, 130.6, 129.9, 128.0, 127.3, 125.3, 124.6, 119.3, 119.3, 104.3, 55.9, 48.6, 44.3, 31.2, 21.6; HRMS [ESI-TOF] calcd for C21H20BrNO3SH [M + H]+ 446.0426, found 446.0424. [5-Bromo-7-tosyl-6,7,8,9-tetrahydropyrido[3,4-g]quinolone] (2e). The compound 2e was synthesized from 1e in the presence of LiBr, under Bergman cyclization condition in 82% yield (10.9 mg). White semi-solid; Rf 0.43 (hexane/EtOAc, 3.4/1.6); 1H NMR (600 MHz, CDCl3) δ 8.87 (dd, J = 4.1, 1.4 Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 8.5, 4.1 Hz,

4.57 (ABq, J = 21.0, 16.2 Hz, 2H), 3.90−3.86 (m, 1H), 3.60−3.58 (m, 1H), 3.24 (q, J = 6.3 Hz, 2H), 2.63 (t, J = 6.3 Hz, 2H), 2.37 (s, 3H), 1.86−1.54 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 148.9, 145.0, 143.5, 139.5, 137.5, 129.8, 127.2, 122.4, 122.2, 96.8, 92.1, 90.9, 82.5, 81.3, 61.9, 54.8, 41.6, 30.3, 25.5, 21.6, 21.1, 18.9; HRMS [ESITOF] calcd for C24H26N2O4SH [M + H]+ 439.1692, found 439.1691. [N-(4-(3-(3-Hydroxyprop-1-yn-1-yl)pyridin-2-yl)but-3-yn-1-yl)-4methylbenzenesulfonamide] (9e). The compound 9e was synthesized from 8e via OTHP deprotection in 75% yield (191 mg). Yellow liquid; Rf 0.11 (hexane/EtOAc, 3/2); 1H NMR (600 MHz, CDCl3) δ 8.47 (d, J = 4.3 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.27−7.19 (m, 3H), 5.67 (t, J = 5.5 Hz, 1H), 4.62 (s, 2H), 3.31 (brs, 1H), 3.24−3.20 (m, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.39 (s, 3H); 13 C{1H} NMR (150 MHz, CDCl3) δ 149.0, 144.6, 143.9, 139.6, 136.9, 130.0, 127.2, 122.5, 122.3, 95.0, 90.6, 81.8, 81.7, 51.4, 41.4, 21.7, 21.0; HRMS [ESI-TOF] calcd for C19H18N2O3SH [M + H]+ 355.1116, found 355.1117. [1-[4-Methylphenylsulfonyl]-[5,6]-[N-3-pyridinyl]-1-azacyclodec3,7-diyne] (1e). The compound 1e was synthesized from 9e via mesylation, followed by cyclization in 65% yield (36 mg). Colorless gummy solid; Rf 0.46 (hexane/EtOAc, 3/2); 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.1 Hz, 1H), 7.75 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.17−7.11 (m, 1H), 4.18 (s, 2H), 3.58 (t, J = 4.6 Hz, 2H), 2.86 (t, J = 4.6 Hz, 2H), 2.39 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 149.1, 148.3, 144.1, 135.7, 134.8, 130.1, 127.4, 125.4, 121.6, 100.2, 94.8, 85.3, 82.8, 51.0, 42.3, 22.4, 21.7; HRMS [ESI-TOF] calcd for C19H16N2O2SH [M + H]+ 337.1011, found 337.1011. [N-(4-(2-Bromopyridin-3-yl)but-3-yn-1-yl)-4-methylbenzenesulfonamide] (9f). The compound 9f was synthesized by Sonogashira coupling between 2-bromo-3-iodo pyridine (commercially available) and tosyl-protected homopropargylamine (A) in 83% yield (300 mg). Light brown gummy liquid; Rf 0.20 (hexane/EtOAc, 4/1); 1H NMR (600 MHz, CDCl3) δ 8.28 (dd, J = 4.8, 1.9 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.64 (dd, J = 7.6, 1.9 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.21 (dd, J = 7.6, 4.8 Hz, 1H), 5.08 (t, J = 6.2 Hz, 1H), 3.24 (q, J = 6.4 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.41 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 148.6, 144.6, 143.8, 141.0, 137.1, 129.9, 127.2, 123.3, 122.3, 94.0, 79.8, 41.7, 21.7, 21.1; HRMS [ESI-TOF] calcd for C16H15BrN2O2SH [M + H]+ 379.0116, found 379.0114. [N-(4-(2-(3-Hydroxyprop-1-yn-1-yl)pyridin-3-yl)but-3-yn-1-yl)-4methylbenzenesulfonamide] (9f′). The compound 9f′ was synthesized by Sonogashira coupling between 9f and propargylalcohol in 50% yield (130 mg). Brown gummy liquid; Rf 0.11 (hexane/EtOAc, 1/1); 1H NMR (600 MHz, CDCl3) δ 8.49 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.28−7.26 (m, 2H), 7.18 (dd, J = 7.9, 4.8 Hz, 1H), 5.56 (t, J = 6.0 Hz, 1H), 4.62 (s, 2H), 3.24−3.21 (m, 2H), 3.15 (brs, 1H), 2.64 (t, J = 5.9 Hz, 2H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 148.7, 144.7, 143.8, 139.0, 137.1, 129.9, 127.2, 122.6, 122.4, 93.4, 92.0, 83.8, 79.5, 51.4, 41.6, 21.6, 21.2; HRMS [ESI-TOF] calcd for C19H18N2O3SH [M + H]+ 355.1116, found 355.1118. [1-[4-Methylphenylsulfonyl]-[5,6]-[N-6-pyridinyl]-1-azacyclodec3,7-diyne] (1f). The compound 1f was synthesized from 9f′ via mesylation, followed by cyclization in 77% yield (30 mg). Colorless gummy solid; Rf 0.14 (hexane/EtOAc, 4/1); 1H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.59 (dd, J = 7.8, 1.5 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.17 (dd, J = 7.8, 4.9 Hz, 1H), 4.18 (s, 2H), 3.59−3.56 (m, 2H), 2.88−2.84 (m, 2H), 2.40 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 148.3, 147.7, 144.2, 135.5, 135.1, 130.1, 127.5, 126.6, 122.2, 100.5, 94.3, 85.9, 81.7, 51.1, 42.1, 22.6, 21.7; HRMS [ESI-TOF] calcd for C19H16N2O2SH [M + H]+ 337.1011, found 337.1009. [10-Bromo-6-methoxy-2-tosyl-1,2,3,4-tetrahydrobenzo[g]isoquinoline] (2a). The compound 2a was synthesized from 1a in the presence of LiBr, under Bergman cyclization condition in 99% yield (23 mg). White semi-solid; Rf 0.41 (hexane/EtOAc, 4/1) 1H NMR (600 MHz, CDCl3) δ 8.00 (s, 1H), 7.80−7.77 (m, 3H), 7.42 (t, J = 8.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 7.6 Hz, 1H), 4.46 (s, 2H), 3.98 (s, 3H), 3.41 (t, J = 5.8 Hz, 2H), 3.14 (t, J = 5.8 Hz, I

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

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1H), 7.34 (d, J = 8.3 Hz, 2H), 4.48 (s, 2H), 3.44 (t, J = 5.9 Hz, 2H), 3.21 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 151.4, 147.4, 144.1, 136.8, 135.1, 133.4, 131.3, 130.0, 128.6, 127.9, 126.7, 122.2, 121.6, 49.6, 43.4, 29.9, 21.7; HRMS [ESI-TOF] calcd for C19H17BrN2O2SH [M + H]+ 417.0272, found 417.0273. [10-Bromo-7-tosyl-6,7,8,9-tetrahydropyrido[3,4-g]quinolone] (3e). The compound 3e was synthesized from 1e in the presence of LiBr, under Bergman cyclization condition in 14% yield (2.1 mg). White semi-solid; Rf 0.24 (hexane/EtOAc, 3.4/1.6); 1H NMR (600 MHz, CDCl3) δ 9.00 (dd, J = 4.2, 1.5 Hz, 1H), 8.08 (dd, J = 8.3, 1.5 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.52 (s, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H), 4.45 (s, 2H), 3.47 (t, J = 6.2 Hz, 2H), 3.24 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 151.4, 144.6, 144.2, 136.1, 136.0, 133.2, 132.4, 130.0, 128.0, 127.7, 127.0, 124.4, 122.0, 48.2, 44.0, 31.3, 21.7; HRMS [ESITOF] calcd for C19H17BrN2O2SH [M + H]+ 417.0272, found 417.0268. [5-Bromo-8-tosyl-6,7,8,9-tetrahydropyrido[4,3-g]quinolone] (2f). The compound 2f was synthesized from 1f in the presence of LiBr, under Bergman cyclization condition in 83% yield (22.4 mg). White semi-solid; Rf 0.20 (DCM/EtOAc, 9.7/0.3); 1H NMR (600 MHz, CDCl3) δ 8.87 (d, J = 4.1 Hz, 1H), 8.53 (d, J = 8.6 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.45 (dd, J = 8.6, 4.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 4.46 (s, 2H), 3.46 (t, J = 6.2 Hz, 2H), 3.17 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 151.2, 147.2, 144.2, 135.3, 135.1, 133.1, 132.8, 130.0, 128.0, 127.1, 126.4, 124.0, 122.3, 48.4, 44.1, 31.0, 21.7; HRMS [ESI-TOF] calcd for C19H17BrN2O2SH [M + H]+ 417.0272, found 417.0276. [10-Bromo-8-tosyl-6,7,8,9-tetrahydropyrido[4,3-g]quinolone] (3f). The compound 3f was synthesized from 1f in the presence of LiBr, under Bergman cyclization condition in 16% yield (4.3 mg). White semi-solid; Rf 0.54 (DCM/EtOAc, 9.7/0.3); 1H NMR (600 MHz, CDCl3) δ 9.03−8.99 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.57 (s, 1H), 7.45 (dd, J = 8.2, 4.1 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 4.55 (s, 2H), 3.47 (t, J = 5.9 Hz, 2H), 3.21 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 151.2, 144.2, 144.1, 136.0, 134.4, 133.9, 133.4, 130.0, 127.9, 126.6, 124.5, 122.1, 50.0, 43.4, 29.7, 21.7; HRMS [ESI-TOF] calcd for C19H17BrN2O2SH [M + H]+ 417.0272, found 417.0271.

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ACKNOWLEDGMENTS DST is acknowledged for an SERB grant (SB/S1/OC-94/ 2013) and for the JC Bose Fellowship to A.B. which supported this research. E.D. is grateful to IIT Kharagpur for a senior research fellowship. The authors also thank Mr. Biswajit Roy for his helpful suggestion in the synthetic part.

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ASSOCIATED CONTENT

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00060. 1 H, 13C, 2D (NOESY) NMR spectra of the synthesized compounds and X-ray crystallographic data, Cartesian coordinates of optimized geometry, and other computational details (PDF) Crystallographic data for 2d (CIF) Crystallographic data for 1a (CIF) Crystallographic data for 1d (CIF)

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REFERENCES

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[email protected] (E.D.). [email protected] (S.B.). [email protected] (A.A.). [email protected] (A.B.).

ORCID

Anakuthil Anoop: 0000-0002-8116-5506 Amit Basak: 0000-0003-4041-2846 Author Contributions †

These authors contributed equally.

Notes

The authors declare no competing financial interest. J

DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

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DOI: 10.1021/acs.joc.9b00060 J. Org. Chem. XXXX, XXX, XXX−XXX