Utilization of MeOH as a C1 Building Block in Tandem Three

Letter pubs.acs.org/OrgLett

Utilization of MeOH as a C1 Building Block in Tandem ThreeComponent Coupling Reaction Kaushik Chakrabarti,† Milan Maji,† Dibyajyoti Panja,† Bhaskar Paul,† Sujan Shee,† Gourab Kanti Das,‡ and Sabuj Kundu*,† †

Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India Department of Chemistry, Visva Bharati University, Santiniketan, West Bengal 731235, India

‡

S Supporting Information *

ABSTRACT: Ru(II) catalyzed tandem synthesis of α-branched methylated ketones via multicomponent reactions following the hydrogen borrowing process is described. This nonphosphine-based air and moisture stable catalyst efficiently produced various methylated ketones using methanol as a methylating agent. This system was found to be highly effective in three-component coupling between methanol, primary alcohols, and methyl ketones. A proposed catalytic cycle for the α-methylation is supported by DFT calculations as well as kinetic experiments.

M

the synthesis of similar products in two successive steps using a combination of an Ir (2 mol %) and a Rh (10 mol %) catalyst.12 Recently, a Ru catalyzed (1 mol %) analogous two-step sequential reaction using an expensive dpePhos ligand in 48 h was reported by Seayed et al.13 Although, these are remarkable advancements, a significantly higher amount of very expensive Ir and Rh metal-based catalysts, phosphine-based ligands, and sequential reactions were crucial for the success of this methodology. In order to develop more efficient and environmentally friendly methods for the synthesis of fine chemicals using alcohols as coupling partners, a more effective catalytic system consisting of relatively cheaper metals and ligands is highly desirable. In our continued interest to develop effective protocols to construct new C−C bonds via hydrogen borrowing methodology, we report a bifunctional Ru(II)-catalyzed, highly efficient three-component coupling of methanol, primary alcohols, and ketones (Scheme 1).

ulticomponent reactions (MCRs) are one of the most powerful tools in synthetic chemistry for the preparation of highly functionalized complex molecular systems.1 They can be employed as an extremely economical and efficient synthetic tactic to generate new bonds in a single step. The methyl groups can change stereoelectronic properties of molecules which can alter many biological processes, such as DNA replication, transcription, nucleosome recognition, etc.2 For example, thymine and uracil nucleobases differ structurally by only a methyl group at the 5-position of the pyrimidine ring of thymine.3 Thus, development of synthetic methodology for the selective conversion of C−H and N−H bonds to C−CH3 and N−CH3 bonds is an emerging area of research in synthetic organic chemistry. The evolution of transition-metal-based hydrogen borrowing catalysts allows for the use of sustainable feedstocks such as methanol in C−C and C−N bond formation reactions which lately has received substantial attention from the scientific community for broader applicability in green chemistry.4 However, compared with long chain alcohols, utilization of methanol is extremely challenging due to its high dehydrogenation energy.5 Inspired by the pioneering works in methanol activation by Beller,6 Grutzmacher,7 Milstein,8 and Krische,5b recently, few examples are reported for the utilization of methanol as a methylating reagent.9 Over the past decades, a variety of protocols for cross-coupling of alcohols has been developed. Although considerable progress has been achieved in α-alkylation of carbonyl compounds and βalkylation of alcohols,10 catalytic multicomponent reactions using two different alcohols and ketones remain unexplored. To the best of our knowledge, in the literature, only one such example is known for the tandem coupling of ketones, alcohols, and methanol.11 A three-component one-pot coupling of methanol, benzyl alcohol, and acetophenone was first described by the Obora group by employing an Ir-catalyst (10 mol % Ir) at 140 °C.11 At the same time, Donohoe and co-workers described © 2017 American Chemical Society

Scheme 1. Tandem Three-Component Coupling of Two Alcohols and Ketones

A Ru(II) complex bearing a phenpy-OH ligand was found to be highly effective for transfer hydrogenation of ketones and nitriles as well as β-alkylation of secondary alcohols with primary alcohols.10h,14 For that reason, to probe the utilization of methanol as a methylating agent, we started α-methylation of Received: July 11, 2017 Published: August 25, 2017 4750

DOI: 10.1021/acs.orglett.7b02105 Org. Lett. 2017, 19, 4750−4753

Letter

Organic Letters Scheme 3. Double Methylation of Various Ketonesa

propiophenone using complex A (Supporting Information (SI) Table 1). Among these Ru(II) complexes, the phenpy-OH ligand containing complex E displayed the best performance in the presence of KOtBu which selectively converted propiophenone to 2-methyl-1-phenylpropan-1-one (1a) in 99% yields (SI Tables 1 and 2). After optimizing the reaction conditions, we turned our attention to expanding the scope of this methodology by screening a range of ketones. Different propiophenone derivatives containing various electron-withdrawing and -donating substituents at different positions were successfully methylated in excellent yields using methanol (Scheme 2). A

a Reaction conditions: ketone (0.41 mmol), KOtBu (1.64 mmol), cat. E (1.0 mol %), MeOH (3 mL), GC yields. Isolated yields are in parentheses.

Scheme 2. Scope of Monomethylation of Ketonesa

Scheme 4. Scope of Multicomponent Reactiona

a

Reaction conditions: ketone (0.37 mmol), KOtBu (1.48 mmol), cat. E (0.5 mol %), MeOH (3 mL), GC yields. Isolated yields are in parentheses.

long chain substrate such as butyrophenone was also converted to 2-methyl-1-phenylbutan-1-one in good yield (Scheme 2, entry 8a). Challenging substrates such as phenylacetone (double methylation can be possible) and α-tetralone were regioselectively methylated at the α-position in excellent yields (Scheme 2, entries 9 and 10a). Next, a complex E catalyzed one-pot double methylation reaction of methyl ketones was investigated which is considered challenging due to poor selectivity. A number of acetophenone derivatives bearing an electron-withdrawing and -donating substituent at the different positions were successfully methylated, and the corresponding α-dimethylated ketones were isolated in excellent yields (Scheme 3, entries 11a−17a).15 2Acetylnaphthalene, cyclohexanone, and 3′,4′-(methylenedioxy)acetophenone were double methylated effectively by this method (Scheme 3, entries 18a−20a). Having successfully tested the potential of complex E in the αmethylation of ketones, we focused our attention toward catalytic tandem multicomponent coupling reactions using methanol, primary alcohols, and methyl ketones. First, acetophenone, benzyl alcohol, and methanol were tested as model substrates. Several Ru (II) complexes and bases were again screened, and complex E in the presence of KOtBu at 110 °C delivered the best results (SI Table 3). A three-component coupling reaction of methanol with both the substituted acetophenone and benzyl alcohol having common functional groups such as −Me, −OMe, and −Br proceeded smoothly, and the corresponding α-methylated ketones were selectively formed in good to excellent yields (Scheme 4, entries 22a−24a and 29a−31a, 33a). Additionally, 2acetylnaphthalene and 3′,4′-(methylenedioxy)acetophenone, 1-

a Reaction conditions: ketone (0.41 mmol), alcohol (0.41), KOtBu (1.64 mmol), cat. E (1.0 mol %), MeOH (3 mL), GC yields (isolated yields). bOne-pot sequential process. c1.5 mol % cat. E was used.

naphthylmethanol and 2-thiophenemethanol also proved to be suitable substrates in this reaction (Scheme 4, entries 25a, 27a, 32a, and 34a). To our delight, complex E displayed significantly higher reactivity compared to Obora’s system (10 mol % Ir, 15 h, 140 °C).11 One-pot α-methylation using challenging coupling partners such as 3-acetylpyridine, 1-cyclopropylethanone, 1butanol and 1-hexanol revealed moderate reactivity (Scheme 4, entries 26a, 28a, 35a, and 36a). However, these substrates required sequential routes probably due to comparable reaction rates of keto-alcohol coupling and α-methylation reactions.11 Additionally, this protocol worked smoothly with equimolar amounts of ketones and primary alcohols whereas excess amounts of coupling partner (either ketones or primary alcohol) were essential for other systems.11−13 Next, the practical relevance of this multicomponent methylation protocol was extended to gram-scale synthesis of different substituted ketones (Scheme 5a). Beckmann rearrangement is a remarkably versatile method for the synthesis of various amides which are used as building blocks in many industrial processes for the production of numerous valuable compounds.16 Hence a Beckmann rearrangement of these methy4751

DOI: 10.1021/acs.orglett.7b02105 Org. Lett. 2017, 19, 4750−4753

Letter

Organic Letters

For a better understanding of the mechanism of α-methylation of propiophenone, we have performed DFT calculations. The reaction pathway consists of three key steps: (a) dehydrogenation of methanol, (b) aldol condensation, and (c) hydrogenation of the CC bond. Two probable pathways (outersphere and innersphere) are possible for the dehydrogenation and hydrogenation steps. In the outersphere mechanism,17 the base-mediated activation18 of the precatalyst E generated the intermediate I1out in which the hydroxyl hydrogen of methanol remained in a Hbonded state with the pyridone oxygen (Figure 1). Next, methanol was dehydrogenated in I1out through a concerted seven-membered transition state TS1out (18.59 [14.07 kcal/ mol]) resulting in the transfer of hydroxyl hydrogen to the pyridone oxygen and Cα−H to the Ru center.17b As a result, Ru− H intermediate I2out (−3.64 [12.02] kcal/mol) was formed. Afterward, aldol condensation between formaldehyde (generated from methanol dehydrogenation) and propiophenone produced the α,β-unsaturated ketone (2-methyl-1-phenylprop2-en-1-one). At the final stage of this catalytic cycle, the CC bond of the α,β-unsaturated ketone was hydrogenated by the cooperative transfer of the Ru−H and O−H of the 2hydroxypyridine ligand scaffold of complex I2out via TS2out (27.74 [26.07] kcal/mol) and subsequently formed intermediate I3out (−3.56 [−5.87] kcal/mol). Then I3out was smoothly converted to I1out which again participated in another catalytic cycle (Figure 1). On the other hand, in the innersphere mechanism,19 methoxycomplex I1in was formed from the precatalyst E in the presence of base (SI Figure 1). In this molecule, the hydrogen of the 2hydroxypyridine unit was H-bonded with the methoxy-oxygen (SI Figure 1). Next, an acetonitrile molecule was dissociated to afford the intermediate I2in (20.33 [35.14] kcal/mol) followed by β-H elimination via a four-membered transition state TS1in (23.74 [37.79] kcal/mol) generating I3in (19.82 [35.67] kcal/ mol).19b Afterward, aldol condensation took place which produced the α,β-unsaturated ketone. The CC bond of the α,β-unsaturated ketone was reduced by the Ru−H (I4in) through TS2in (54.01 [67.23] kcal/mol) and produced intermediate I5in which finally resulted in the desired methylated ketone and the active complex I2in (SI Figure 1). Significantly higher energy barriers for the dissociation of the CH3CN from I1in and

Scheme 5. (a) Gram Scale Multicomponent Reaction; (b) Beckmann Rearrangement of the Methylated Ketones; (c) Kinetic Experiments with Possible Intermediates

lated compounds (3a, 6a, 22a, and 23a) was carried out to expand the applicability of this methodology further which selectively yielded the corresponding alkylated acetanilide derivatives efficiently (Scheme 5b). To understand the mechanism of the α-methylation of propiophenone using methanol, kinetic experiments were carried out. Under the optimized conditions, probable intermediate Q was smoothly transformed to desired product 1a. Following similar reaction conditions, in the presence of methanol-d4, complex E selectively converted compound Q and propiophenone to the deuterated products S and T, respectively (Scheme 5c).

Figure 1. Calculated Gibbs free energies and enthalpies (kcal/mol) for α-methylation of propiophenone following outersphere pathway (Hybrid functional, B3LYP was used with the LANL2DZ basis set for Ru and 6-31G** basis set for nonmetal elements). 4752

DOI: 10.1021/acs.orglett.7b02105 Org. Lett. 2017, 19, 4750−4753

Letter

Organic Letters

Frost, J. R.; Christensen, K. E.; Stevenson, N. G.; Donohoe, T. J. J. Am. Chem. Soc. 2017, 139, 2577−2580. (5) (a) Tani, K.; Iseki, A.; Yamagata, T. Chem. Commun. 1999, 18, 1821−1822. (b) Moran, J.; Preetz, A.; Mesch, R. A.; Krische, M. J. Nat. Chem. 2011, 3, 287−290. (6) Nielsen, M.; Alberico, E.; Baumann, W.; Drexler, H.-J.; Junge, H.; Gladiali, S.; Beller, M. Nature 2013, 495, 85−89. (7) Rodríguez-Lugo, R. E.; Trincado, M.; Vogt, M.; Tewes, F.; SantisoQuinones, G.; Grützmacher, H. Nat. Chem. 2013, 5, 342−347. (8) Khusnutdinova, J. R.; Garg, J. A.; Milstein, D. ACS Catal. 2015, 5, 2416−2422. (9) (a) Campos, J.; Sharninghausen, L. S.; Manas, M. G.; Crabtree, R. H. Inorg. Chem. 2015, 54, 5079−5084. (b) Oku, T.; Arita, Y.; Tsuneki, H.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 7368−7377. (c) Dang, T. T.; Ramalingam, B.; Seayad, A. M. ACS Catal. 2015, 5, 4082−4088. (d) Del Zotto, A.; Baratta, W.; Sandri, M.; Verardo, G.; Rigo, P. Eur. J. Inorg. Chem. 2004, 2004, 524−529. (e) Paul, B.; Shee, S.; Chakrabarti, K.; Kundu, S. ChemSusChem 2017, 10, 2370−2374. (f) Quan, X.; Kerdphon, S.; Andersson, P. G. Chem. - Eur. J. 2015, 21, 3576−3579. (g) Natte, K.; Neumann, H.; Beller, M.; Jagadeesh, R. V. Angew. Chem., Int. Ed. 2017, 56, 6384−6394. (10) (a) Obora, Y. ACS Catal. 2014, 4, 3972−3981. (b) Huang, F.; Liu, Z.; Yu, Z. Angew. Chem., Int. Ed. 2016, 55, 862−875. (c) Wang, D.; Zhao, K.; Xu, C.; Miao, H.; Ding, Y. ACS Catal. 2014, 4, 3910−3918. (d) Xu, C.; Goh, L. Y.; Pullarkat, S. A. Organometallics 2011, 30, 6499−6502. (e) Musa, S.; Ackermann, L.; Gelman, D. Adv. Synth. Catal. 2013, 355, 3077−3080. (f) Schlepphorst, C.; Maji, B.; Glorius, F. ACS Catal. 2016, 6, 4184−4188. (g) Roy, B. C.; Chakrabarti, K.; Shee, S.; Paul, S.; Kundu, S. Chem. - Eur. J. 2016, 22, 18147−18155. (h) Chakrabarti, K.; Paul, B.; Maji, M.; Roy, B. C.; Shee, S.; Kundu, S. Org. Biomol. Chem. 2016, 14, 10988−10997. (11) Ogawa, S.; Obora, Y. Chem. Commun. 2014, 50 (19), 2491−2493. (12) (a) Chan, L. K. M.; Poole, D. L.; Shen, D.; Healy, M. P.; Donohoe, T. J. Angew. Chem., Int. Ed. 2014, 53, 761−765. (b) Shen, D.; Poole, D. L.; Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.; Donohoe, T. J. Angew. Chem., Int. Ed. 2015, 54, 1642−1645. (13) Dang, T. T.; Seayad, A. M. Adv. Synth. Catal. 2016, 358, 3373− 3380. (14) Paul, B.; Chakrabarti, K.; Kundu, S. Dalton Trans. 2016, 45, 11162−11171. (15) Compared to the monomethylation, the double methylation reaction requuired double the catalyst loading and slightly and elevated temperature (100 °C). (16) (a) Blatt, A. H. Chem. Rev. 1933, 12, 215−260. (b) Mahajan, P. S.; Humne, V. T.; Tanpure, S. D.; Mhaske, S. B. Org. Lett. 2016, 18, 3450− 3453. (c) Nace, H. R.; Watterson, A. C. J. Org. Chem. 1966, 31, 2109− 2115. (17) (a) Alberico, E.; Lennox, A. J. J.; Vogt, L. K.; Jiao, H.; Baumann, W.; Drexler, H.-J.; Nielsen, M.; Spannenberg, A.; Checinski, M. P.; Junge, H.; Beller, M. J. Am. Chem. Soc. 2016, 138, 14890−14904. (b) Zeng, G.; Sakaki, S.; Fujita, K.-i.; Sano, H.; Yamaguchi, R. ACS Catal. 2014, 4, 1010−1020. (c) Xu, R.; Chakraborty, S.; Bellows, S. M.; Yuan, H.; Cundari, T. R.; Jones, W. D. ACS Catal. 2016, 6, 2127−2135. (d) Sonnenberg, J. F.; Wan, K. Y.; Sues, P. E.; Morris, R. H. ACS Catal. 2017, 7, 316−326. (18) de Boer, S. Y.; Korstanje, T. J.; La Rooij, S. R.; Kox, R.; Reek, J. N. H.; van der Vlugt, J. I. Organometallics 2017, 36, 1541−1549. (19) (a) Hale, L. V. A.; Malakar, T.; Tseng, K.-N. T.; Zimmerman, P. M.; Paul, A.; Szymczak, N. K. ACS Catal. 2016, 6, 4799−4813. (b) Li, H.; Wang, X.; Huang, F.; Lu, G.; Jiang, J.; Wang, Z.-X. Organometallics 2011, 30, 5233−5247.

hydrogenation of alkene via TS2in suggested that the innersphere pathway was less favored than the outersphere one. In conclusion, for the first time a cooperative Ru(II) catalyzed tandem three-component coupling of ketones, alcohols, and methanol was developed. Remarkably, a series of functionalized acetophenone, benzyl alcohol derivatives, and methanol were efficiently coupled in a tandem manner which furnished the corresponding α-methylated ketones under mild reaction conditions. The synthetic utility of this reaction was further extended by regioselectively transforming these final ketone products to the acetanilide derivatives. For α-methylation of ketones using methanol as a methylating agent, the catalyst loading was reduced to 0.5 mol % at 85 °C which can be even further reduced to 0.1 mol % at 120 °C. Various kinetic experiments and detailed DFT calculations were carried out to understand the catalytic cycle and the superior reactivity of the bifunctional catalyst E. Notably, employment of a simple air and moisture stable nonphosphine-based Ru(II) catalyst makes this tandem three-component coupling protocol highly attractive.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02105. General procedure for the α-methylation experiment, multicomponent reaction, optimization details, DFT calculations, characterization data and NMR spectra of the products (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sabuj Kundu: 0000-0002-4227-294X Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We are grateful to the Science and Engineering Research Board (SERB), India and Council of Scientific & Industrial Research (CSIR) and DST-INSPIRE for financial support. K.C. and B.P. thank UGC-India, M.M. and S.S. thank CSIR-India, and D.P. thanks IITK for fellowship.

■

REFERENCES

(1) (a) Touré, B. B.; Hall, D. G. Chem. Rev. 2009, 109, 4439−4486. (b) Jose Climent, M.; Corma, A.; Iborra, S. RSC Adv. 2012, 2, 16−58. (c) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50, 6234−6246. (d) Ganem, B. Acc. Chem. Res. 2009, 42, 463−472. (e) D’Souza, D. M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095−1108. (2) Saenger, W. Principles of Nucleic Acid Structure; Springer: New York, 1984. (3) (a) Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183− 2192. (b) Barreiro, E. J.; Kümmerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111, 5215−5246. (4) (a) Gunanathan, C.; Milstein, D. Science 2013, 341, 1229712. (b) Yang, Q.; Wang, Q.; Yu, Z. Chem. Soc. Rev. 2015, 44, 2305−2329. (c) Elangovan, S.; Neumann, J.; Sortais, J.-B.; Junge, K.; Darcel, C.; Beller, M. Nat. Commun. 2016, 7, 12641. (d) Frost, J. R.; Cheong, C. B.; Akhtar, W. M.; Caputo, D. F. J.; Stevenson, N. G.; Donohoe, T. J. J. Am. Chem. Soc. 2015, 137, 15664−15667. (e) Akhtar, W. M.; Cheong, C. B.; 4753

DOI: 10.1021/acs.orglett.7b02105 Org. Lett. 2017, 19, 4750−4753