Metal-Free Denitrogenative C–C Couplings of Pyridotriazoles with

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Metal-Free Denitrogenative C−C Couplings of Pyridotriazoles with Boronic Acids To Afford α‑Secondary and α‑Tertiary Pyridines Chao Dong, Xin Wang, Zibo Pei, and Ruwei Shen* State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, Nanjing 211800, China

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S Supporting Information *

ABSTRACT: Pyridotriazoles are utilized as robust building blocks to access α-secondary and α-tertiary pyridines via the development of a simple yet practically useful metal-free denitrogenative C−C crosscoupling with boronic acids. The reaction shows a high level of functional tolerance, broad substrate scope, and facile scalability. The synthetic potential of the method is demonstrated by the strurctural modification of a bioactive molecule and concise synthesis of pheniramine analogs.

T

he transition-metal-free (TM-free) cross-coupling reaction of diazo compounds with organoborons is an important method for C−C bond formation.1 In general, the reaction can be described as a net transformation involving nucleophilic attack of the diazo compound to an organoboron reagent to form a tetra-coordinated boron intermediate, followed by 1,2-migration of a substituent from boron to carbon with the elimination of nitrogen (Figure 1a). This chemistry was known as early as the 1960s;2 however, the involvement of highly toxic and unstable diazo compounds as well as the use of some not-readily available organoborons restricted the application of the method, and only in recent times has the transformation begun evolving into an effective synthetic method for practical use.3−6 For example, Barluenga and Valdés reported the elegant use of tosylhydrazones as diazo surrogates7 that smoothly couple with boronic acids in the presence of a base for C−C bond formation (Figure 1b).3,8 Wang et al. developed a series of arylation of α-diazocarbonyl compounds with boroxines or boronic acids.4 Recently a TMfree protocol involving in situ diazotizion of α-aminoesters and α-aminoacetonitriles for deaminative coupling has been achieved for the synthesis of α-aryl esters and nitriles (Figure 1c).4b On the other hand, pyridotriazoles 1 receive increasing interest as valuable building blocks in organic synthesis due to their easy availability and rich chemical properties.9,10 These compounds have shown to present a tautomeric equilibrium with the corresponding 2-pyridyl diazo species 1′ in solution,11 and thus can be regarded as “masked” diazo compounds (as depicted in Figure 1d). Several useful transformations of synthetic potentials have been developed accordingly, in particular, with the assistance of transition metal catalysts.12−15 For example, Gevorgyan et al. developed the Rh- and Cucatalyzed denitrogenative cyclizations of pyridotriazoles with alkynes or nitriles to provide effective ways to many valuable azacycles.12 Straassert and Glorius reported the Rh-catalyzed C−H bond activation and subsequent cyclization with pyridotriazoles as carbene precursors to access novel © XXXX American Chemical Society

Figure 1. Background of the work.

fluorescent scaffolds.13 Recently, Hu reported the Rh-catalyzed formal [4 + 1]-cycloaddition of pyridotriazoles with propargyl alcohols to produce 2-pyridyl 2,5-dihydrofurans,14a and we have reported the Cu-catalyzed denitrogenative C−P couplings Received: April 16, 2019

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DOI: 10.1021/acs.orglett.9b01334 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

effective solvents (Table 1, entries 10−12). Noteworthy, this reaction is not sensitive to moisture or air, and could be performed without the protection of an inert atmosphere. Indeed, a scale-up reaction performed in an AR grade dioxane under air still afforded 3aa in high yield (79%, 1.034 g) (Table 1, entry 2). The results summarized in Scheme 1 show a remarkably broad scope with respect to boronic acids. A variety of

with phosphorus nucleophiles for the synthesis of phosphorylated pyridines.14b However, the reactivity of pyridotriazoles toward organoborons, to the best of our knowledge, has not been explored. We reason that pyridotriazole may also act as a diazo precursor to couple with a suitable organoboron reagent under TM-free conditions. Such a transformation would be an appealing and flexible method to access α-secondary and αtertiary pyridines, which are targets of current interest for synthetic chemists16,17 due to their wide occurrence as critical structural elements in many pharmaceuticals, therapeutic agents, agrochemicals, and natural products (Figure 1e).18 In this context, we report here the first cross-coupling of pyridotriazoles 1 with boronic acids 2 to afford a collection of substituted pyridines 3 (Figure 1d). The reaction features simple reaction conditions, a high level of functional tolerance, a broad substrate scope, and facile scalability. Application of the method to the synthesis of medicinally relevant products is also described (vide infra). Pyridotriazole 1a, prepared via the condensation of 2-acetyl6-bromopyridine with hydrazine hydrate followed by oxidation by PhI(OAc)2,19 was initially chosen as a model substrate to investigate the reaction with various organoboron species (Table 1). When a mixture of 1a and phenylboronic acid (2a)

Scheme 1. Scope of Boronic Acidsa

Table 1. Examinations on Reaction Conditionsa

run Ph[B] 1 2 3 4 5 6

2a 2a 3a 4a 5a 6a

solvent

yield (%)b

run

Ph[B]

solvent

yield (%)b

dioxane dioxane dioxane dioxane dioxane dioxane

84 79c 0 0 0 50d (70)e

7 8 9 10 11 12

2a 2a 2a 2a 2a 2a

DCE toluene MeCN DMSO DMF MeOH

77 72 74 trace trace 0

a

Unless otherwise noted, 1 (0.20 mmol and , 2 (2.5 equiv) were heated in dioxane (1 mL) at 100 °C. Isolated yields are given. b5 mmol scale. cDeduced from 1H NMR.

a Unless otherwise noted, a mixture of 1a (0.2 mmol) and 2a−5a (2.5 equiv) or 6a (1 equiv) in a solvent (1 mL) in a screw-capped tube was heated at 100 °C for 8 h. bIsolated yields. c5 mmol scale using AR grade dioxane (10 mL, AR, 99%, containing 10 ppm BHT as stabilizer). dReaction time: 4 h. eWater (3.0 equiv) was added.

commercially available arylboronic acids 2 bearing electrondonating or -withdrawing groups at different positions of the phenyl ring smoothly coupled with 1a to give the corresponding products in good to high yields. The reaction exhibits a high level of functional group tolerance. Halogen atoms, hydroxyl, hydroxymethyl, carbonyl (aldehyde, ketone and amide), cyano, amino, trifluoromethoxy, methylthio, and sulfonyl functionalities were all tolerated (3af−3at, 50%− 84%). The reaction also allows the use of heterocyclecontaining boronic acids to afford bis(heterocycle)methanes (3au−3az, 48%−80%), which may be promising privileged scaffolds for drug discovery.21 Furthermore, the reaction is applicable to the construction of C(sp3)−C(sp3) bonds by using alkylboronic acids as coupling partners (3aA−3aC, 60%−64%). Particularly, the challenging secondary−secondary alkyl coupled products 3aD and 3aE were also obtained in acceptable yields when secondary alkylboronic acids were used. However, the reactions of alkenylboronic acids gave a mixture of products, i.e., the normal coupling products and the CC bond migrated products (3aF/3aF′, 3aG/3aG′).

was stirred in dioxane at 100 °C for 8 h, the coupling product 3aa was obtained in 84% yield (Table 1, entry 1). Boronic esters PhBPin (3a) and PhBNep (4a) as well as PhBF3K (5a) are however unreactive probably due to the low electrophilicity of boron in these compounds (Table 1, entries 3−5).6e In contrast, phenylboroxine (6a) showed higher reactivity, but the reaction gave 3aa in low yield togather with some unidentified byproducts. It was interesting to find that the presence of water facilitated the reaction of 1a with 6a to give improved yield (Table 1, entry 6). But regardless, we did not attempt further improvement on this reaction considering that boronic acids are more easily available than boroxines.20 The coupling reaction of 1a and 2a could also be performed in DCE, toluene, or MeCN to afford 3aa in good yields (Table 1, entries 7−9), but DMSO, DMF, and MeOH were not B

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Organic Letters A number of pyridotriazoles were also examined to broaden the reaction scope, and the results are summaried in Scheme 2.

Scheme 3. Derivation of Estrone

Scheme 2. Scope of Pyridotriazolesa

reaction as a tool for structural modification of bioactive molecules by the incorporation of pyridine units. Moreover, the reaction was successfully applied to the synthesis of the antihistamine chlorpheniramine and analogs. As shown in Scheme 4, the β-amino ketone 9 was obtained in Scheme 4. Concise and Metal-Free Synthesis of Chlorpheniramine and Analogs

Reaction conditions: (a) vinylMgCl, THF, 0 °C, 1 h; Me2NH in THF, rt, 1 h; (b) hydrazine hydrate, MeOH, rt, overnight; (c) PhI(OAc)2, CH2Cl2, rt, 2 h; (d) boronic acid, dioxane, 130 °C. For experimetnal details, see the Supporting Information. a

a Unless otherwise noted, a mixture of 1 (0.20 mmol) and 2 (2.5−3.0 equiv) in dioxane (1 mL) was heated at 100 °C. Isolated yields are given. bThe reaction was performed at 130 °C in a sealed tube.

85% yield from a one-pot reaction of commercially available Nmethoxy-N-methylpicolinamide (8), vinylmagnesium chloride, and dimethylamine. Condensation of 9 with hydrazine hydrate at room temerature followed by oxidation by PhI(OAc)2 gave pyridotriazole 10 in 77% yield. The couplings of 10 with (4chlorophenyl)boronic acid delivered chlorpheniramine 11a in 75% yield. Clearly, this TM-free synthetic route is highly promising for the concise synthesis of these pheniramine analogs considering the commercial availability of a wide variety of arylboronic acids. Three analogs 11b, 11c, and 11d were provided in good yields by reactions of 10 with the corresponding boronic acids. Finally, a putative mechanism for the reaction is proposed (Scheme 5). Pyridotriazole 1 decomposes under the reaction conditions to produce small amounts of the ring-opening diazo intermediate 1′,11 which reacts with boronic acid 2 to generate 2-picolylboronic acid B via a boronate intermediate A. B undergoes protodeboronation to give the product 3 (Path a). Since phenylboroxine is also reactive, we consider that another pathway may occur in the reaction (Path b). Boronic acid is in equilibrium with the corresponding boroxine under the reaction conditions. A similar process involving nucleophilic attack of the diazo species 1′ to boroxine generating intermediate C, followed by denitrogenative 1,2-migration of R3 from boron to carbon, takes place to furnish intermediate D. Rapid hydrolysis of D gave the product 3. The detailed reaction pathway however remains to be further elucidated.22 In conclusion, we have reported a highly effective C−C cross-coupling reaction of pyridotriazoles and organoboronic

Pyridotriazole 1b (R1 = R2 = H) smoothly reacted with boronic acids to produce 3ba, 3bg, 3bi, and 3bk in good to high yields. 6- or 7-Methyl pyridotriazoles 1c and 1d also efficiently coupled with 2a to furnish 3ca and 3da in high yields. 4-Methyl pyridotriazole 1e was less reactive, and the reaction performed at 130 °C for 20 h produced 3ea in diminished yield. 7-Aryl-substituted pyridotriazoles 1f−1h proved to be good substrates to produce 3fa−3ha in high yields. Although pyridotriazoles 1i (R1 = 6-Br, R2 = Me) and 1j (R1 = 5-Cl, R2 = Me) showed low reactivity, high yields of 3ia and 3ja were attained when the reactions were performed at 130 °C. Notably, 7-methoxy pyridotriazole 1k showed high reactivity, and the products 3ka and 3kC were obtained in 85% and 75% yield in 5 h. The hydroxy-containing substrates 1l and 1m could also be used to produce 3la and 3ma in moderate yields. It is clear that the substitution R2 also affects the reaction. The products 3na, 3on, 3pp, and 3qs were obtained in moderate to good yields when R2 was an alkyl group. Unfortunately, pyridotriazoles 1r (R1 = H, R2 = Ph) and 1s (R1 = H, R2 = CO2Et) did not react under the same conditions to provide 3ra and 3sa. To illustrate the value of the present reaction, several synthetic applications of the reaction were performed. As shown in Scheme 3, the reaction of estrone-derived arylboronic acid 2H with 1k smoothly produced the estrone derivative 7 in 78% yield, indicating the potential use of the C

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K.; Ellis, D.; Klute, W.; Ryckmans, T. ChemMedChem 2012, 7, 233. (e) Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. J. Org. Chem. 2014, 79, 328. (f) Vernekar, S. K. V.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z. J. Med. Chem. 2015, 58, 651. (g) Wegener, A.; Miller, K. A. J. Org. Chem. 2017, 82, 11655. (4) (a) Peng, C.; Zhang, W.; Yan, G.; Wang, J. Org. Lett. 2009, 11, 1667. (b) Wu, G.; Deng, Y.; Wu, C.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 10510. (c) Wu, G.; Deng, Y.; Wu, C.; Wang, X.; Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2014, 2014, 4477. (5) (a) Battilocchio, C.; Feist, F.; Hafner, A.; Simon, M.; Tran, D. N.; Allwood, D. M.; Blakemore, D. C.; Ley, S. V. Nat. Chem. 2016, 8, 360. (b) Tran, D. N.; Battilocchio, C.; Lou, S. B.; Hawkins, J. M.; Ley, S. V. Chem. Sci. 2015, 6, 1120. (c) Kupracz, L.; Kirschning, A. J. Flow Chem. 2013, 3, 11. (6) For other examples, also see: (a) Wang, D.; de Wit, M. J. M.; Szabó, K. J. J. Org. Chem. 2018, 83, 8786. (b) Ghorai, J.; Anbarasan, P. J. Org. Chem. 2015, 80, 3455. (c) Argintaru, O. A.; Ryu, D.; Aron, I.; Molander, G. A. Angew. Chem., Int. Ed. 2013, 52, 13656. (d) Li, X.; Feng, Y.; Lin, L.; Zou, G. J. Org. Chem. 2012, 77, 10991. (e) Elkin, P. K.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.; Arkhipov, D. E.; Korlyukov, A. A.; Tartakovsky, V. A. Tetrahedron Lett. 2011, 52, 5259. (7) For recent reviews on reactions of tosylhydrazones, see: (a) Xia, Y.; Wang, J. Chem. Soc. Rev. 2017, 46, 2306. (b) Xia, Y.; Qiu, D.; Wang, J. Chem. Rev. 2017, 117, 13810. (c) Xiao, Q.; Zhang, Y.; Wang, J. Acc. Chem. Res. 2013, 46, 236. (d) Barluenga, J.; Valdés, C. Angew. Chem., Int. Ed. 2011, 50, 7486. (e) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012, 41, 560. (f) Arunprasath, D.; Bala, B. D.; Sekar, G. Adv. Synth. Catal. 2019, 361, 1172. (8) (a) For the Pd-catalyzed reaction of tosylhydrazones with boronic acids, see: Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun. 2010, 46, 1724. (b) For a related Rh-catalyzed reaction of 1-sulfonyl-1,2,3-triazoles with boronic acids, see: Selander, N.; Worrell, B. T.; Chuprakov, S.; Velaparthi, S.; Fokin, V. V. J. Am. Chem. Soc. 2012, 134, 14670. (9) For reviews, see: (a) Chattopadhyay, B.; Gevorgyan, V. Angew. Chem., Int. Ed. 2012, 51, 862. (b) Abarca, B.; Ballesteros-Garrido, R. Top. Heterocycl. Chem. 2014, 40, 325. (c) Jones, G.; Abarca, B. Adv. Heterocycl. Chem. 2010, 100, 195. (10) For synthesis of pyridotriazoles, see: Hirayama, T.; Ueda, S.; Okada, T.; Tsurue, N.; Okuda, K.; Nagasawa, H. Chem. - Eur. J. 2014, 20, 4156 and references therein . (11) (a) Abarca, B.; Alkorta, I.; Ballesteros, R.; Blanco, F.; Chadlaoui, M.; Elguero, J.; Mojarrad, F. Org. Biomol. Chem. 2005, 3, 3905. (b) L’abbé, G.; Godts, F.; Toppet, S. J. Chem. Soc., Chem. Commun. 1985, 589, 589. (c) Regitz, M.; Arnold, B.; Danion, D.; Schubert, H.; Fusser, G. Bull. Soc. Chim. Belg. 1981, 90, 615. (d) L’abbé, G. Bull. Soc. Chim. Belg. 1990, 99, 281. (e) For a recent experimental and computational study on the equilibrium, see: Aylward, N.; Winter, H.-W.; Eckhardt, U.; Wentrup, C. J. Org. Chem. 2016, 81, 667. (12) (a) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 4757. (b) Chuprakov, S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463. (c) Helan, V.; Gulevich, A. V.; Gevorgyan, V. Chem. Sci. 2015, 6, 1928. (d) Shi, Y.; Gevorgyan, V. Chem. Commun. 2015, 51, 17166. (e) Shi, Y.; Gulevich, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2014, 53, 14191. (f) Roy, S.; Kumar Das, S.; Chattopadhyay, B. Angew. Chem., Int. Ed. 2018, 57, 2238. (13) Kim, J. H.; Gensch, T.; Zhao, D.; Stegemann, L.; Strassert, C. A.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54, 10975. (14) (a) Lv, X.; Yang, H.; Shi, T.; Xing, D.; Xu, X.; Hu, W. Adv. Synth. Catal. 2019, 361, 1265. (b) Shen, R.; Dong, C.; Yang, J.; Han, L.-B. Adv. Synth. Catal. 2018, 360, 4252. (15) For other reports, also see: (a) Joshi, A.; Chandra Mohan, D.; Adimurthy, S. J. Org. Chem. 2016, 81, 9461. (b) Adam, R.; Abarca, B.; Ballesteros, R. Synthesis 2017, 49, 5059. (c) Moon, Y.; Kwon, S.; Kang, D.; Im, H.; Hong, S. Adv. Synth. Catal. 2016, 358, 958. (d) Liu, S.; Sawicki, J.; Driver, T. G. Org. Lett. 2012, 14, 3744. (e) Joshi, A.;

Scheme 5. Proposed Mechanism

acids to provide a new method for the synthesis of a collection of substituted pyridines in good to high yields. The reaction has significant features for practical use, such as operational simplicity, easy scale-up, and metal/additive-free conditions. As demonstrated by its application to the concise synthesis of medicinally relevant molecules and structural modification of the bioactive product, this method should be useful to access valuable pyridine derivatives with biological activities. Further work on the reaction mechanism and expanding the scope of the method will be pursued.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01334. Experimental details and copies of 1H and 13C NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ruwei Shen: 0000-0002-8834-3256 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the NSFC (21302095), Jiangsu Provincial NSF (BK20130924), and Nanjing Tech University is acknowledged.

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REFERENCES

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