Hydroheteroarylation of Unactivated Alkenes Using N

Mar 30, 2017 - Xiaoshen Ma†, Hester Dang†, John A. Rose†, Paul Rablen‡, and Seth B. Herzon†§. † Department of Chemistry, Yale University,...
0 downloads 0 Views 4MB Size
Download PDF
Article pubs.acs.org/JACS

Hydroheteroarylation of Unactivated Alkenes Using N‑Methoxyheteroarenium Salts Xiaoshen Ma,† Hester Dang,† John A. Rose,† Paul Rablen,‡ and Seth B. Herzon*,†,§ †

Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, Pennsylvania 19081, United States § Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, United States ‡

S Supporting Information *

ABSTRACT: We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with Nmethoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1−2 steps from the commercial arenes or arene Noxides (25−99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50−85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertiary radicals to pyidinium salts are documented: harder secondary radicals favor C-2 addition (2−>10:1), while softer tertiary radicals favor bond formation to C-4 (4.7−>29:1). A diene possessing a 1,2-disubstituted and 2,2-disubstituted alkene undergoes hydropyridylation at the latter exclusively (61%) suggesting useful site selectivities can be obtained in polyene substrates. The methoxypyridinium salts can also be employed in dehydrogenative arylation, borono-Minisci, and tandem arylation processes. Mechanistic studies support the involvement of a radical process.

■

INTRODUCTION We recently described the cobalt-mediated intermolecular reductive coupling of unactivated alkenes and N-methoxy pyridinium salts (cf. eq 1).1 The reaction is believed to proceed by cobalt-mediated hydrogen atom transfer (HAT) to the alkene, to form the kinetically and thermodynamically favored radical intermediate. Addition of this radical to the electrondeficient N-methoxypyridinium salt, followed by aromatization, then generates the products. An evaluation of counterions revealed that the methyl sulfate salt provided the highest yields. A broad range of alkenes, from α-olefins to tetrasubstituted alkenes, are suitable substrates. The transformation connects Minisci couplings (the addition of radicals to protonated heteroarenes2) with metal-mediated HAT to alkenes.3−5

philicity provided by the methoxy substituent eliminates the need to employ acidic activation of the arene, allowing the reactions to proceed under neutral conditions. Second, the mechanistic pathway involving aromatization by methanol elimination ensures polyalkylation products are not generated. Finally, the methoxy substituent allows for quantitative activation of the hetereoarene, including highly electrondeficient substrates. As outlined below, these salts are easily prepared in high overall yield and in multigram quantities, tolerate an exceptionally broad range of substitution patterns, and are indefinitely stable on the benchtop. In this manuscript we introduce the first use of N-methoxy imidazolium, quinolium, isoquinolium, and pyridazinium derivatives in this transformation. In addition, we significantly extend the scope of the hydropyridylation reaction to include 20 discrete pyridine derivatives. We delineate several synthetically useful selectivity trends in the addition to pyridines and the hydroheteroarylation of polyene substrates. Finally we demonstrate the applications of these salts in other Minisci couplings.

Applications of N-methoxy pyridinium salts in Minisci couplings have been reported,6 and their use in this transformation presents several advantages. First, the electro© 2017 American Chemical Society

Received: March 9, 2017 Published: March 30, 2017 5998

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society

■

RESULTS AND DISCUSSION

Table 1. Synthesis of N-Methoxy Pyridinium, Quinolinium, Isoquinolinium, and Pyridazinium Saltsa

Synthesis of N-Methoxy Pyridinium, Quinolinium, Isoquinolinium, and Pyridazinium Salts. Six-membered N-methoxy heteroarenium (pyridine, quinoline, isoquinoline, and pyridazine) salts are accessible in high yield and one step by alkylation of the corresponding N-oxide with dimethylsulfate. All of the N-oxides employed are commercial reagents or were prepared in one step (25−93%) by oxidation with metachloroperbenzoic acid.7 In most instances, the oxidation proceeded in >70% yield, although for highly electron-deficient pyridines (such as 2-trifluoromethylpyridine) the oxidation proceeded in lower yields (25−60%). For liquid N-oxides, the alkylation typically progressed to completion with 1.10 equiv of dimethylsulfate at ambient temperature. In the case of solid Noxides, heating (40−100 °C) was employed to render the mixtures homogeneous. After cooling and removal of excess dimethyl sulfate in vacuo, the N-methoxyheteroarenium salts were obtained as viscous hydroscopic gums in high purity and nearly quantitative yields (as determined by 1H and 13C NMR analysis). These salts are bench stable for at least six months at ambient temperature when stored in a desiccator8 and have been prepared on up to 10-g scales. A broad range of pyridinium salts bearing substituents at the 2-, 3-, and 4-positions were obtained in high yield (79−99% yield, Table 1). By varying the methylation reagents, 2,6lutidine derivatives with tetrafluoroborate (2u), triflate (2v), and iodide (2w) counterions were accessible (81−84%). In addition, pyridazine (2x), quinoline (2y−2aa), and isoquinoline (2ac, 2ad) derivatives were readily prepared by this Oalkylation approach (76−99%). Although not exhaustively investigated, as demonstrated in Table 1 salts bearing a wide variety of functional groups including methyl ketone, halogen (F, Cl, Br, and I), ester, alkyl, trifluoromethyl, nitrile, aryl, and alkoxy substituents are accessible. Synthesis of N-Methoxyimidazolium Salts. We required an efficient synthetic route to N-methoxy imidazolium salts in order to evaluate their suitability in the reductive coupling. The synthesis of imidazole N-oxides can be challenging,9 however, and extensive experimentation was required to obtain a general route to the targets. Ultimately, the imidazole N-oxides were prepared in 48−99% yield by acid-mediated condensation of the oximes 3 or 4 and triazirine derivatives 5 (0.5−3.0 g scales, Scheme 1).9 The triazirine derivatives are commercially available or were prepared in one step (91−95%, 0.5−4 g scale). The oxime derivatives 4 were prepared in one step (55− 87%, 2−5 g scale). The methylation of these imidazole N-oxides with dimethylsulfate (1.10 equiv) occurs smoothly at ambient temperature to provide, after concentration, the desired Nmethoxy imidazolium methylsulfate derivatives as thick gums (Table 2). The N-methoxyimidazolium salts obtained in this way were determined to be of >95% purity (1H NMR analysis). A variety of N3-alkyl, aryl, and benzyl salts were prepared. In addition, 4-alkyl and 4-aryl imidazolium salts (7h, 7i) could be accessed by this strategy. Scope of the Alkene Component. As reported in our original communication,1 the scope of the alkene component was delineated using the hydropyridylation reaction. To facilitate analysis, N-methoxy-2,6-dimethylpyridinium methylsulfate (2b) was employed as the pyridine coupling partner (Table 3). As the pyridinium salt is readily prepared in decagram quantities and in one step from commercial materials,

a General reaction conditions: 1 (1 equiv), (CH3O)2SO2 (1.10 equiv), 24−100 °C, 1−8 h. All products were isolated as their methylsulfate (−OSO2OCH3) salts unless indicated otherwise. bMethylation conducted on a gram scale. cFor detailed reaction conditions, see Supporting Information.

5999

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society Table 3. Hydropyridylation: Alkene Scopea

Scheme 1. Synthesis of Imidazole N-Oxides 6

Table 2. Synthesis of N-Methoxyimidazolium Saltsa

a General reaction conditions: 1 (250 μmol), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), 2b (5.00 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 16 h. Yields refer to spectroscopically homogeneous materials obtained after purification by flash-column chromatography.

In general, the alkylation of 2-substituted N-methoxypyridinium methylsulfate derivatives with precursors to tertiary radicals provided the C-4 alkylation products selectively (8l−o, 27− 79%), while C-4-substituted N-methoxypyridinium methylsulfate derivatives underwent C-2 alkylation exclusively (8p−y, 37−85%). Pyridinium salts bearing C-3 substituents underwent C-6 alkylation with modest selectivities, but the yields were low (8z, 8aa, and 8ab, 31%, 23%, and 12% yields, respectively). The products shown in Table 4 also demonstrate that alkyl fluoride (8y), chloride (8x), bromide (8v, 8w), trifluoromethyl substituents (8v, 8t), Weinreb amide (8r), alcohol (8m, 8n, 8s, 8t), aryl ester (8m), aryl ketone (8o, 8w), aryl nitrile (8x), aryl fluoride (8z), aryl chloride (8u, 8v), aryl bromide (8ab), benzyl ether (8q), and aryl azide (8k) substituents are compatible with the transformation. In all cases monoalkylation products were obtained exclusively. Products 8j, 8k, 8l, 8p, 8q, 8r, 8u, 8v, 8x, 8y, 8aa, and 8ab were first disclosed in our original communication.1 Site Selectivity in the Alkylation of Pyridinium Derivatives. Further investigations into the alkylation of the unsubstituted reagent N-methoxypyridinium methylsulfate (2a) established that the site selectivity of alkylation (C-2 vs C-4) is influenced by the nature of the radical intermediate. As outlined in Table 5, tertiary radicals provide C-4 alkylation products predominantly while secondary radicals provide C-2 alkylation products selectively. All reactions in Table 5 were conducted on a 1 mmol scale to facilitate isolation of the minor regioisomer. The product 8j was formed with the lowest (4.7:1 selectivity), while, for the products 9b−9g, the corresponding C-2 isomer could not be detected by UPLC/MS analysis of the unpurified

a General reaction conditions: 6 (1 equiv), (CH3O)2SO2 (1.10 equiv), 24 °C, 3−8 h. All products were isolated as their methylsulfate (−OSO2OCH3) salts. bReaction conducted on a 2.3-g scale.

this reagent was used in 5-fold excess in the addition reactions. Cyclic and acylic unactivated alkenes bearing 1−4 carbogenic substituents were competent substrates for the reaction (8a−8i, 47−81% yields). In all cases, only the C-4 regioisomer was observed by UPLC/MS analysis of the unpurified product mixtures. The regioselectivity in bond formation to the alkene is rationalized by HAT to generate the kinetically and thermodynamically favored alkyl radical intermediate. Pyridinium Salt Scope. Pyridine is the most common aromatic heterocycle found in FDA-approved drugs.10 Consequently, the scope of the pyridine coupling partner was extensively examined (Table 4). In addition, the scope of the alkene component was further investigated. The hydroarylation of methallyl 4-methoxybenzoate with N-methoxypyridinium methylsulfate (2a) provided a separable 4.7:1 mixture of C-4 and C-2 alkylation products; the C-4 alkylation product 8j was isolated in 66% yield after purification by flash-column chromatography (1 mmol scale). The C-4 alkylation product 8k, which contains an aryl azide substituent, was obtained in 59% yield and with 29:1 C-4/C-2 selectivity on a 1 mmol scale. 6000

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society Table 4. Hydropyridylation: Arene and Alkene Scopea

Conditions: 1 (250 μmol), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), 2 (5.00 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 16 h. In all instances, the pyridinium counterion = CH3OSO3−. Yields reported were obtained by isolation. Due to line broadening, product isomer ratios could not be determined by 1H NMR. “Single isomer” denotes instances wherein one product was observed by LC/MS analysis of the unpurified product mixture. See Supporting Information for isomer ratio determination of 8aa and 8ab. bReaction conducted on a 1 mmol scale. c52% alkene recovered. d 78% alkene recovered. a

product mixtures. The citronellol derivative 9b and the isopulegol derivative 9c were obtained in 46% and 54% yields, respectively, with exclusive bond formation to the C-4 position of the pyridine. The α-terpineol derivative 9d (67%) and the dihydroperillyl alcohol derivative 9e (26%) were obtained as single C-4 regioisomers and single diastereomers (relative stereochemistry confirmed by X-ray crystallography). This stereochemical outcome is consistent with pseudoaxial attack of the pyridinium salt on the tertiary alkyl radical intermediate. When rotenone was employed as the starting material, only C-4 alkylation products were obtained. However, the product of concomitant ketone reduction 9g was formed in 39% yield, along with the expected coupling product 9f (13%). Alkenes that serve as precursors to secondary radicals provided C-2 alkylation products with modest selectivity. For

example, replacement of a single alkenyl methyl substituent with hydrogen results in a turnover in selectivity (compare 10a and 8j; 10b and 9a). C-2 selectivity was observed for a series of α-olefins bearing various functional groups (10a−f), including two eugenol derivatives (10c, 10d). This substitution-dependent regioselectivity is also observed when coupling benzyl methallyl ether or benzyl allyl ether with 2-chloro, 2-bromo, or 2-iodopyridine derivatives (Table 6). Tertiary radical precursors formed C-4 alkylation products selectively (9i−k, 10−34:1, C-4:C-6). Secondary radical precursors formed C-6 alkylation products with modest selectivity (10g−i, 1.4−1.6:1, C-6:C-4). If the addition to the pyridinium salts is reversible, the selectivity of bulkier tertiary radicals toward the 4-position may be due to the steric encumberance of the N-methoxy 6001

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society Table 5. Regioselectivities in the Addition of Tertiary and Secondary Radicals to 2aa

Table 6. Regioselectivities in the Addition of Tertiary and Secondary Radicals to 2-Halo Pyridinium Saltsa

a

Conditions: 1 (1.00 mmol), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), 2g, 2h, or 2i (5.00 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 16 h. Isolated yields reported.

Scheme 2. Atomic Charges and LUMO of N-Methoxypyridinium Ion

rationalized by charge and frontier molecular orbital arguments. The Mulliken, Hirshfeld, and Natural Population Analysis (NPA) atomic charges about the pyridine ring were calculated at the B3LYP/aug-cc-pVTZ level of theory. By all three methods, the C-2 positions were determined to have a higher positive charge than the C-4 position (see Scheme 2 and the Supporting Information). By comparison, the LUMO of 2a was determined to have a higher coefficient at C-4 than C-2. Thus, if the addition is irreversible, we reason that electrostatic interactions favor C-2 alkylation by secondary radicals, while frontier orbital interactions favor C-4 alkylation by softer (higher energy SOMO) tertiary radicals. Similar models have been used to rationalize the addition of two-electron nucleophiles to N-alkylpyridinium salts, with harder nucleo-

a

Conditions: 1 (1.00 mmol), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), 2a (5.00 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 16 h. Yields reported were obtained by isolation. bn/d = not detected. c Relative stereochemistry determined by X-ray analysis; see Supporting Information.

substituent. Alternatively, if the addition to the pyridinium ion is irreversible, the selectivities in the alkylation of 2a can be 6002

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society philes favoring addition to the more-polarized 2-position and softer nucleophiles favoring addition to the 4-position, which has a higher LUMO coefficient.11 To date, we have only observed a single exception to the selectivity trends outlined in Tables 5 and 6. When using allyl boronic acid pinacol ester as the substrate, the C-4 alkylation product 9h was obtained (Scheme 3). This exception is attributed to the electron-donating ability of the C−B bond, which increases the energy of the SOMO of the secondary radical, rendering it more tertiary-like.

Table 7. Hydroheteroarylation with NMethoxypyridiazinium, -Quinolinium, and -Isoquinolinium Derivativesa

Scheme 3. Hydropyridylation of Allyl Pinacol Borane Provides the C-4-Alkylation Product 9h Selectively

Alkylation of Pyridazinium, Quinolinium, and Isoquinolinium Derivatives. A large variety of other sixmembered N-methoxyheteroarenium salts can be employed in the reductive coupling protocol (Table 7). The pyridazine derivatives 11a and 11b were obtained in 51% and 34% yields, respectively, with exclusive C-4 selectivity. When using pmethoxybenzyl allyl ether as the coupling partner, the C-4 alkylation product 11c was obtained in 22% yield and with 4.7:1 C-4:C-6 selectivity. When 2,2-disubstituted alkenes were coupled with N-methoxyquinolinium derivatives, C-2 alkylation products were formed exclusively (c.f., 11d, 39%; 11e, 49%). Existing substitution at the C-2 position of the quinolinium salt directed alkylation to the 4-position (11f, 41%). The irgasan derivative 11g was obtained in 63% yield using N-methoxybenzo[h]quinolinium methylsulfate (2ab). When using Nmethoxyisoquinolinium methylsulfate as the heteroarene source (2ac), the C-3 alkylation product 11h was obtained in 26% yield. The estrone derivative 11i was prepared in 51% yield. Alkylation of N-Methoxyimidazolium Salts. Imidazoles are electron-rich heterocycles, and the addition of alkyl radicals to these species is rare.2i,j We prepared N-methoxyimidazolium salts and examined their reactivity in the alkene addition reaction. When 3-methoxy-1-methyl-1H-imidazol-3-ium methylsulfate (7a) was employed as the heteroarene source, secondary and tertiary radical intermediates afforded the reductive coupling products 12a and 12b in 51% and 41% yields, respectively, and with exclusive C-2 selectivity (Table 8). A variety of N3 substituents are compatible with the reaction including n-butyl (12c, 33%), benzyl protecting groups (benzyl: 12d, 21%; p-methoxybenzyl: 12e, 49%; and p-fluorobenzyl: 12f, 45%), and aryl substituents (p-bromophenyl: 12g, 73%; ptrifluoromethylphenyl: 12h, 59%). Alkyl halides (12g), aryl halides (12f, 12g), carbamates (12c, 12d), alcohols (12h), trifluoromethyl substituents (12h), and ethers (12i) are compatible with the addition. N-Methoxyimidazolium derivatives bearing C-5 substituents also afforded C-2 alkylation products (12i and 12j, 62% and 47% yields, respectively). Currently, the hydroimidazolylation is limited to C-2 alkylation of imidazoles (Scheme 4). Attempted coupling of the 2-substituted imidazolium salt 14 with prenyl pmethoxybenozate 13 resulted in production of the reduction product 16 (72%); the desired alkylation product 15 was not

a Conditions: alkene (250 μmol), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), heterocyclic salt (5.00 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 48 h. In all instances, the heteroarenium counterion = CH3OSO3−.

observed. Current efforts are aimed at modulating the imidazolium salt to permit C-4 or C-5 alkylation. Mechanistic Experiments. Several experiments were conducted to probe the mechanism of this transformation. First, we examined the hydropyridylation of citronellol (17) with the pyridine 2a in the presence of excess TEMPO (Scheme 5). Under these conditions, the conversion of substrate was significantly diminished and the TEMPO adduct 18 was obtained in 16% yield, along with 79% of 17. The 6003

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society Table 8. Hydroheteroarylation with N-Methoxyimidazolium Methylsulfate Derivativesa

Scheme 4. Attempted Coupling of the 2-Substituted NMethoxyimidazolium Salt 14

Scheme 5. Synthesis of the TEMPO Adduct 18

Scheme 6. Reductive Cyclization of the Diene 19

Scheme 7. Reductive Cyclization of 19 Using Et3SiD, 2a−d11, and CD2Cl2

Conditions: 1 (250 μmol), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), 7 (5.00 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 12 h. In all instances, the imidazolium counterion = CH3OSO3−. a

6). The low yield of the cyclohydropyridylation product 20 may derive from the steric hindrance of the neopentyl alkyl radical intermediate, which slows addition to the pyridinium salt. We have previously shown that the hydrogen atom in the HAT step using the Co(acac)2−Et3SiH system derives from silane.4s To determine the source of the second hydrogen atom in 21 (Scheme 6), we repeated the reaction using Et3SiD, 2ad11, and CD2Cl2 as solvent (Scheme 7). Under these conditions the reduction product 21-d was formed in 68% yield and with >95% monodeuteration at one of the methyl substituents. These results suggest that the second hydrogen atom in 21-d derives from the acetylacetone ligands on the cobalt complex, tert-butylhydroperoxide (TBHP), or byproducts derived from decomposition of TBHP.

hydropyridylation product 9b was not observed. Boger and coworkers have reported the formation of TEMPO adducts in their iron-based alkene hydrofunctionalization protocol.4r The results herein are consistent with this report and support the intermediacy of an alkyl radical intermediate. The basis for the reduced conversion of 17 is not clear but may be due to inhibition of the HAT step by TEMPO. When the diene 19 was employed in the hydropyridylation, the cyclization product 20 and the reductive cyclization product 21 were obtained in 9% and 88% yield, respectively (Scheme 6004

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society

intermediate.4w By comparison, the hydropyridylation of 22 displayed much higher selectivity: the products derived from functionalization of the 2,2-disubstituted alkene were formed in 61% combined yield, and the products of functionalization of the 1,2-disubstituted alkene were not detected (Scheme 9B). The C-4 alkylation product 24 was formed with 5.6:1 selectivity, which was expected based on the trends discussed above. Although further experimentation is required to delineate the full scope of these selectivity trends, this result suggests that the selective hydroheteroarylation of complex polyene substrates is possible and is preparatively useful. N-Methoxyheteroarenium Salts As Limiting Reagents. As the functionalized alkenes in the preceding discussion were typically prepared by multistep sequences, the N-methoxyheteroarenium salts were used in excess. However, it was of interest to determine the efficiency of the transformation using an excess of the alkene. The yields of selected examples under alkene- and arene-limiting conditions are summarized in Table 9. Generally, the yields of product were slightly lower using the arenium salt as the limiting reagent, with the exception of the pyridazine derivative 11c, which was formed in low yield when the arene was used as the limiting reagent. These results

Based on our mechanistic studies and a large amount of literature precedence,3d,4e,12 the mechanism shown in Scheme 8 Scheme 8. Working Mechanism of the Hydropyridylation Reaction

is proposed. A cobalt(III) hydride intermediate (A) may be generated from the reaction of Co(acac)2, Et3SiH, and TBHP. Hydrogen atom transfer from A to the alkene would generate the alkyl radical B and regenerate the cobalt(II) species. Addition of the alkyl radical B to the pyridinium salt would form the radical cation C. Finally, electron transfer to the radical cation, followed by elimination of methanol, would generate the observed products. Site-Selective Hydropyridylation. We recently reported that the HAT reduction of 2,2-disubstituted and trisubstituted alkenes was faster than monosubstituted and 1,2-disubstituted alkenes, and alkynes (Scheme 9A).4w For example, the 2,2disubstituted alkene in 22 was reduced with 8:1 selectivity over the adjacent 1,2-disubstituted alkene using 1,4-dihydrobenzene (DHB) as a hydrogen atom source. This selectivity was rationalized on the basis of the kinetic and thermodynamic preference for formation of the more-substituted radical

Table 9. Comparison of the Yields of Hydroheteroarylation Products Using the Arene or Alkene As Limiting Reagenta

Scheme 9. Site-Selective Reduction (A) and Hydropyridylation (B) of the 2,2-Disubstituted Alkene in 22

a

Alkene limiting conditions: alkene (1 equiv), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), heterocyclic salt (5.00 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 12−48 h. In all instances, the heteroarenium counterion = CH3OSO3−. bArene limiting conditions: alkene (3.00 equiv), Co(acac)2 (1.00 equiv), TBHP (1.00 equiv), heterocyclic salt (1 equiv), Et3SiH (5.00 equiv), CH2Cl2 (0.2 M), 24 °C, 12−48 h. In all instances, the heteroarenium counterion = CH3OSO3−. 6005

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society indicate that an excess of either the arene or alkene lead to synthetically useful yields of product. Further Applications. To demonstrate the preparative utility of our hydroheteroarylation protocol, the hydropyridylation of terpineol (26) was conducted on a 1.5-g (10 mmol) scale to provide the product 9d in 69% yield (Scheme 9), which is comparable to the yield on a 1 mmol scale (67%, Table 5). The hydropyridylation product 9d was further functionalized using the powerful borono-Minisci coupling of Baran and co-workers, to afford 27 in 42% yield (Scheme 10).2i

Scheme 12. Pyrimidinium, Pyrazinium, Benzopyrazinium, and Thiazolium Derivatives That Failed To Afford the Desired Products

ligands with various heteroatoms can significantly alter the HAT-activities of the cobalt center.4s Finally, in certain instances, such as products 8aa and 8ab (Table 4), low conversions of alkene were observed, and starting material was recovered. However, in many instances the low-yielding reactions reported herein led to complex mixtures of products that could not be further characterized due to line broadening in the 1H NMR spectra of the unpurified product mixtures. In conclusion, we have delineated the synthesis and applications of imidazole, pyridine, quinoline, isoquinoline, and pyridazine-based hetereoarenium salts in a novel reductive addition to unactivated alkenes. The scope of the reaction is broad, and the reagents are readily prepared on multigram scales. Further efforts will focus on extending the scope of heteroarenes that can be employed in this chemistry.

Scheme 10. Gram-Scale Hydropyridylation of Terpineol (26) and Functionalization by the Borono-Minisci Reaction.2i

■

Unsurprsingly, N-methoxyheteroarenium salts described in this work can also be utilized in other Minisci processes. The light-induced dehydrogenative coupling between tetrahydrofuran (28) and the 2,6-lutidine derivative 2b proceeded in 45% yield (Scheme 11A).13 Alternatively, the N-methoxypyridinium

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b02388. X-ray crystallography data for 2b (CIF) X-ray crystallography data for 2j (CIF) X-ray crystallography data for a derivative of 9d (CIF) X-ray crystallography data for a derivative of 9e (CIF) Detailed experimental procedures and characterization data for all new compounds (PDF)

Scheme 11. (A) Light-Induced Dehydrogenative Coupling Using the Heteroarenium Salt 2b; (B) Acid-Free BoronoMinisci Coupling Using the Heteroarenium Salt 2a

■

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Seth B. Herzon: 0000-0001-5940-9853 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Dr. Brandon Mercado is gratefully acknowledged for X-ray crystallography of compounds 2b, 2j, and derivatives of 9d and 9e. Financial support from the National Science Foundation (CHE-1151563) is gratefully acknowledged.

salt 2a was a competent partner in Baran’s borono-Minisci coupling (Scheme 11B).2i,k The C-4 alkylation product was not detected. The ability to conduct these reactions under neutral conditions, using a quantitatively activated arene coupling partner, may present advantages in certain situations. In addition, because methanol elimination is a requiste for coupling, these processes should not result in overalkylation, and site selectivities are generally high. Limitations of the Reaction. When employing pyrimidinium, pyrazinium, benzopyrazinium, and thiazolium derivatives (Scheme 12) in the hydroheteroarylation conditions, the desired C−C coupling products were not observed. The problems in utilizing these substrates may derive from coordination of the additional heteroatom to the cobalt center. This result is consistent with our previous observations that

■

REFERENCES

(1) Ma, X.; Herzon, S. B. J. Am. Chem. Soc. 2016, 138, 8718. (2) (a) Minisci, F. Synthesis 1973, 1973, 1. (b) Minisci, F.; Fontana, F.; Vismara, E. J. Heterocycl. Chem. 1990, 27, 79. (c) Murphy, J. A.; Sherburn, M. S. Tetrahedron Lett. 1990, 31, 1625. (d) Murphy, J. A.; Sherburn, M. S. Tetrahedron 1991, 47, 4077. (e) Artis, D. R.; Cho, I.S.; Jaime-Figueroa, S.; Muchowski, J. M. J. Org. Chem. 1994, 59, 2456. (f) Togo, H.; Taguchi, R.; Yamaguchi, K.; Yokoyama, M. J. Chem. Soc., Perkin Trans. 1 1995, 2135. (g) Yamazaki, O.; Togo, H.; Matsubayashi, S.; Yokoyama, M. Tetrahedron Lett. 1998, 39, 1921. (h) Duncton, M.

6006

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007

Article

Journal of the American Chemical Society

2015, 348, 886. (y) Kuo, J. L.; Hartung, J.; Han, A.; Norton, J. R. J. Am. Chem. Soc. 2015, 137, 1036. (z) Dao, H. T.; Li, C.; Michaudel, Q.; Maxwell, B. D.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 8046. (aa) Obradors, C.; Martinez, R. M.; Shenvi, R. A. J. Am. Chem. Soc. 2016, 138, 4962. (ab) Crossley, S. W. M.; Martinez, R. M.; GuevaraZuluaga, S.; Shenvi, R. A. Org. Lett. 2016, 18, 2620. (ac) Green, S. A.; Matos, J. L. M.; Yagi, A.; Shenvi, R. A. J. Am. Chem. Soc. 2016, 138, 12779. (ad) Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutiérrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 2484. (5) For selected applications of HAT in the synthesis and functionalization of complex bioactive natural products, see refs 4h, 4l, and the following: (a) Barker, T. J.; Duncan, K. K.; Otrubova, K.; Boger, D. L. ACS Med. Chem. Lett. 2013, 4, 985. (b) Leggans, E. K.; Duncan, K. K.; Barker, T. J.; Schleicher, K. D.; Boger, D. L. J. Med. Chem. 2013, 56, 628. (c) Allemann, O.; Brutsch, M.; Lukesh, J. C.; Brody, D. M.; Boger, D. L. J. Am. Chem. Soc. 2016, 138, 8376. (6) (a) Katz, R. B.; Mistry, J.; Mitchell, M. B. Synth. Commun. 1989, 19, 317. (b) Biyouki, M. A. A.; Smith, R. A. J.; Bedford, J. J.; Leader, J. P. Synth. Commun. 1998, 28, 3817. For applications of pyridine Noxides in Minisci couplings, see: (c) Dyall, L. K.; Pausacker, K. H. J. Chem. Soc. 1961, 18. (7) Itoh, T.; Nagano, T.; Hirobe, M. Chem. Pharm. Bull. 1986, 34, 2013. (8) In certain instances the salts can be recrystallized from acetone under argon. (9) For a review of the syntheses of imidazole and benzimidazole Noxides, see: Nikitina, G. V.; Pevzner, M. S. Chem. Heterocycl. Compd. 1993, 29, 127. (10) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257. (11) Fleming, I. Molecular Orbitals and Organic Chemical Reactions, reference edition; John Wiley & Sons, Ltd: United Kingdom, 2010; p 184. (12) Tokuyasu, T.; Kunikawa, S.; Masuyama, A.; Nojima, M. Org. Lett. 2002, 4, 3595. (13) Lipp, A.; Lahm, G.; Opatz, T. J. Org. Chem. 2016, 81, 4890.

A. J.; Estiarte, M. A.; Johnson, R. J.; Cox, M.; O’Mahony, D. J. R.; Edwards, W. T.; Kelly, M. G. J. Org. Chem. 2009, 74, 6354. (i) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 13194. (j) Duncton, M. A. J. MedChemComm 2011, 2, 1135. (k) Molander, G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13, 1852. (l) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 14411. (m) Nagib, D. A.; MacMillan, D. W. Nature 2011, 480, 224. (n) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494. (o) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. (p) Zhou, Q.; Ruffoni, A.; Gianatassio, R.; Fujiwara, Y.; Sella, E.; Shabat, D.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 3949. (q) Antonchick, A. P.; Burgmann, L. Angew. Chem., Int. Ed. 2013, 52, 3267. (r) Wu, X.; See, J. W. T.; Xu, K.; Hirao, H.; Roger, J.; Hierso, J.-C.; Zhou, J. Angew. Chem., Int. Ed. 2014, 53, 13573. (s) Gianatassio, R.; Kawamura, S.; Eprile, C. L.; Foo, K.; Ge, J.; Burns, A. C.; Collins, M. R.; Baran, P. S. Angew. Chem., Int. Ed. 2014, 53, 9851. (t) DiRocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.; Tudge, M. Angew. Chem., Int. Ed. 2014, 53, 4802. (u) Prier, C. K.; MacMillan, D. W. Chem. Sci. 2014, 5, 4173. (v) He, L.; Natte, K.; Rabeah, J.; Taeschler, C.; Neumann, H.; Brückner, A.; Beller, M. Angew. Chem., Int. Ed. 2015, 54, 4320. (w) Jin, J.; MacMillan, D. W. C. Nature 2015, 525, 87. (x) Fang, L.; Chen, L.; Yu, J.; Wang, L. Eur. J. Org. Chem. 2015, 2015, 1910. (y) Paul, S.; Guin, J. Chem. - Eur. J. 2015, 21, 17618. (z) Tang, R.-J.; Kang, L.; Yang, L. Adv. Synth. Catal. 2015, 357, 2055. (aa) Cuthbertson, J. D.; MacMillan, D. W. Nature 2015, 519, 74. (ab) McCallum, T.; Barriault, L. Chem. Sci. 2016, 7, 4754. (3) For reviews, see: (a) Eisenberg, D. C.; Norton, J. R. Isr. J. Chem. 1991, 31, 55. (b) Gansäuer, A.; Shi, L.; Otte, M.; Huth, I.; Rosales, A.; Sancho-Sanz, I.; Padial, N.; Oltra, J. E. Hydrogen Atom Donors: Recent Developments. Radicals in Synthesis III; Springer: Berlin, Heidelberg, 2012; Vol. 320, p 93. (c) Hoffmann, R. W. Chem. Soc. Rev. 2016, 45, 577. (d) Crossley, S. W. M.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. Chem. Rev. 2016, 116, 8912. (e) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692. (4) For key primary references, see: (a) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 18, 573. (b) Kato, K.; Mukaiyama, T. Chem. Lett. 1992, 21, 1137. (c) Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676. (d) Waser, J.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 8294. (e) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693. (f) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4519. (g) Choi, J.; Tang, L.; Norton, J. R. J. Am. Chem. Soc. 2007, 129, 234. (h) Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008, 130, 420. (i) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 5758. (j) Choi, J.; Pulling, M. E.; Smith, D. M.; Norton, J. R. J. Am. Chem. Soc. 2008, 130, 4250. (k) Hartung, J.; Pulling, M. E.; Smith, D. M.; Yang, D. X.; Norton, J. R. Tetrahedron 2008, 64, 11822. (l) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131, 4904. (m) Gaspar, B.; Carreira, E. M. J. Am. Chem. Soc. 2009, 131, 13214. (n) Taniguchi, T.; Goto, N.; Nishibata, A.; Ishibashi, H. Org. Lett. 2010, 12, 112. (o) Girijavallabhan, V.; Alvarez, C.; Njoroge, F. G. J. Org. Chem. 2011, 76, 6442. (p) Leggans, E. K.; Barker, T. J.; Duncan, K. K.; Boger, D. L. Org. Lett. 2012, 14, 1428. (q) Li, G.; Han, A.; Pulling, M. E.; Estes, D. P.; Norton, J. R. J. Am. Chem. Soc. 2012, 134, 14662. (r) Barker, T. J.; Boger, D. L. J. Am. Chem. Soc. 2012, 134, 13588. (s) King, S. M.; Ma, X.; Herzon, S. B. J. Am. Chem. Soc. 2014, 136, 6884. (t) Iwasaki, K.; Wan, K. K.; Oppedisano, A.; Crossley, S. W.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 1300. (u) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.-M.; Baran, P. S. Nature 2014, 516, 343. (v) Crossley, S. W. M.; Barabé, F.; Shenvi, R. A. J. Am. Chem. Soc. 2014, 136, 16788. (w) Ma, X.; Herzon, S. B. Chem. Sci. 2015, 6, 6250. (x) Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.; Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S. Science 6007

DOI: 10.1021/jacs.7b02388 J. Am. Chem. Soc. 2017, 139, 5998−6007