Letter pubs.acs.org/OrgLett
Ruthenium-Catalyzed Direct Synthesis of Semisaturated Bicyclic Pyrimidines via Selective Transfer Hydrogenation Biao Xiong,†,§ Jingxing Jiang,‡,§ Shudi Zhang,† Huanfeng Jiang,† Zhuofeng Ke,*,‡ and Min Zhang*,† †
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China School of Materials Science and Engineering, MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, Sun Yat-sen University, Guangzhou 510275, China
‡
S Supporting Information *
ABSTRACT: A new ruthenium-catalyzed direct and selective synthesis of semisaturated bicyclic pyrimidines, from αaminopyridyl alcohols and nitriles, has been demonstrated. The synthesis proceeds with an easily available catalyst system, broad substrate scope, excellent functional tolerance, and no need for high pressure H2 gas. Control experiments indicate that the reaction proceeds via successive dehydrogenative annulation and transfer hydrogenation of the less electrophilic pyridyl nucleus, and the density functional theory (DFT) study reveals the origin of such a unique selectivity.
A
Reduction reactions, in which alcohols were utilized as alternative hydrogen donors to reduce different unsaturated chemicals such as ketones,5a nitriles,5b and nitro compounds;5c (2) crosscoupling reactions between alcohols and C−C double/triple bonds contributed by the Krische group;6 (3) borrowinghydrogen reactions leading to N-alkylation and C-alkylation developed by the groups of Beller,7 Kempe,8 Fujita,9 Williams,10 and others.11 As a part of our continuous interest in creation of Nheterocycles with alcohols,12 we recently reported a synthesis of 2-alkylamino N-heteroaromatics from 2-aminoarylmethanols, alkyl nitriles, and alcohols via dehydrogenative annulation and Nalkylation processes (Scheme 1, eq 1).13 Interestingly, when we
s a significant important class of semisaturated bicyclic Nheterocycles, tetrahydropyrido-fused pyrimidines are widely distributed in numerous alkaloids and functional molecules that exhibit diverse biological and therapeutic activities. Selected agents applied for the treatment of cancer (compound 1),1a antiallergy and anti-inflammation (structure 2),1b and potent antagonist of muscarinic M3 and inhibitor of PDE IV (compound 3)1c are shown in Figure 1. However, the synthesis of such
Scheme 1. Previous Work and the New Finding Figure 1. Selected examples possessing interesting biological and therapeutical activities.
compounds mainly relies on initial construction of pyrido-fused pyrimidines followed by hydrogenation of the pyridyl ring in the presence of high pressure H2 gas.2 However, due to the thermodynamic stability and kinetic inertness of heteroaromatic ring, the development of step-economic methodologies, enabling direct and selective access to the such compounds under mild reducing conditions, has to date remained an unresolved goal. In recent years, transfer hydrogenation (TH) has emerged as an attractive tool in synthetic chemistry due to the simple experimental setups.3 By exploring alternative hydrogen donors, a number of attractive synthetic approaches have been developed in recent years, which allow effective elaboration of various functionalized products.4 In addition, due to the attractiveness of abundance and sustainability of alcohols, the utilization of such resources for TH reactions has also been elegantly explored. Representative examples mainly involve the following: (1) © 2017 American Chemical Society
replaced the alkyl nitriles with 4-methylbenzonitrile (2a), it reacted with α-aminopyridyl methanol 1a to produce a semisaturated bicyclic pyrimidine 3aa in 19% yield, exclusively (eq 2). Upon a thorough study of this new finding, we wish herein to report a ruthenium-catalyzed direct synthesis of tetrahydropyrido-fused pyrimidines from α-aminopyridyl alcohols and nitriles via selective transfer hydrogenation. Received: April 11, 2017 Published: May 5, 2017 2730
DOI: 10.1021/acs.orglett.7b01081 Org. Lett. 2017, 19, 2730−2733
Letter
Organic Letters
1a, the reactions of (2-amino-6-methylpyridin-3-yl)methanol 1b with four representative benzonitriles produced the corresponding products in relatively lower yields (Scheme 3, 3ba−3bb and
Our initial studies focused on developing a more efficient catalytic system by choosing the reaction of 1a and 2a as a model system. At the start of our work the effect of representative ruthenium precatalysts, ligands, solvents, bases, and different temperatures were evaluated (see Table S1 in Supporting Information I (SI)). An optimal yield (93%) of 3aa was obtained at 120 °C and by using 1 mol % of Ru3(CO)12, 3 mol % of Xantphos, 50 mol % of t-BuOK, and 3 equiv of methanol along with tert-amyl alcohol as the solvent. Having established the optimal reaction conditions, we then explored the generality of this synthetic protocol. First, (2aminopyridin-3-yl)methanol 1a in combination with various aryl(heteroaryl) nitriles 2 was tested. As illustrated in Scheme 2,
Scheme 3. Variation of Aminopyridyl Alcohols
Scheme 2. Variation of Nitriles
3be−3bf), presumably because of the steric effect. In the case of (3-aminopyridin-2-yl)methanol 1c, the corresponding products were produced in a shorter time (3ca and 3cf). Substrate 1d also underwent a smooth transfer hydrogenative annulation reaction to generate the 2-aryl-4-alkyl products in high yields (3da and 3df). To gain insight into the product-forming information, the model reaction was interrupted after 1 h to analyze the reaction intermediates. Products 3aa and 2-(p-tolyl)pyrido[2,3-d]pyrimidine Int-3aa were detected in 18% and 15% yields, respectively (Scheme 4, eq 1). Then, the isolated Int-3aa was Scheme 4. Control Experiments all the reactions proceeded smoothly and furnished the desired products in good to excellent yields upon isolation (3aa−3al) by selective transfer hydrogenation of the pyridyl nucleus. Interestingly, different functional groups such as −Me, −OMe, −NMe2, −F, −Cl, −Br, −CF3, and −CN were well tolerated, and neither hydrogenation of the cyano group nor hydrogenolysis of the carbon−halogen bonds was observed, the retention of these functional groups would offer the potential for elaboration of complex molecules via further chemical transformations. Moreover, all the obtained products possess a pyrimidyl skeleton, which could act as a directing group to functionalize the 2-aryl group via C−H bond activation.14 Noteworthy, product 3al, arising from heteroaryl nitrile 2l, could serve as a hemilabile bi- or tridentate ligand that could be applied for organometallic chemistry and catalysis.15 In addition to aryl(heteroaryl) nitriles, pentanenitrile 2m was also compatible with the transformation, affording the 2-alkyl product 3am in 41% yield. And the reaction of cycloalkyl nitrile 2n and 1a gave the product 3an in 56% yield, an analogue of bioactive compound 3 shown in Figure 1. Subsequently, we surveyed the reactions of α-aminopyridyl alcohols 1 with different substitution patterns. Similar to the results described in Scheme 2, all the reactions proceeded in selective transfer hydrogenation and afforded the desired products in moderate to high yields. In comparison with substrate
combined with 5 equiv of methanol under the standard conditions, which resulted in product 3aa in almost quantitative yield (eq 2). These results indicate that Int-3aa serves as a key reaction intermediate, and the dehydrogenative annulation process proceeds much faster than the tranfer hydrogenation of the pyridyl nucleus. Based on the above-mentioned findings, a plausible reaction pathway is proposed in Scheme 5. The reaction initiates with the nucleophilic addition of amino group of 1 to the cyano group of 2, affording an amidine (Int-1). Then, the tautomerization of Int-1 followed by the ruthenium-catalyzed dehydrogenation of the alcohol unit gives an o-carbonyl amidine (Int-2) and [RuH2] species (or initial dehydrogenation of 1 to 1′ followed by an addition of −NH2 to the −CN group of 2). Further, the thermodynamically favorable intramolecular condensation of Int2 would generate the bicyclic N-heteroarene Int-3. Two cycles of 2731
DOI: 10.1021/acs.orglett.7b01081 Org. Lett. 2017, 19, 2730−2733
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Organic Letters Scheme 5. Possible Reaction Pathways
transfer hydrogenation of the pyridyl nucleus with the [RuH2] species would give rise to product 3, which is supposed to be driven by excess methanol. To reveal the origin of the unique hydrogenation selectivity, a detailed DFT study was conducted to investigate the possible pathways for the hydrogenation of 2-phenylpyrido[2,3-d]pyrimidine (Int-3ae). In comparison, the hydrogenation initiated by monohydride−ruthenium complexes is suggested to be less feasible because they are less stable (see SI II, Figure S2), and the free energies for the first hydrogenative transition states are much higher than those for dihydride active species (Figure S3, S4). Initiated from ruthenium dihydride complex A or D, the calculated potential energy surfaces (PESs) for the first hydrogenation on the pyridine ring (in red) is shown in Figure 2 (Path I/II). Hydride transfer to the ortho- or para-carbon of the
Figure 3. PESs for the first hydrogenation of the pyrimidine ring. Relative free energies are shown in kcal/mol.
intermediate H or K. A recoordination of carbon monoxide to the metal center of complex H/K leads to the amido intermediate I/ L, which is endergonic by 22.3 or 25.0 kcal/mol. Intermediate I/L then undergoes a reductive elimination to IM-3/IM-4 with an activation free energy of 9.3 or 39.1 kcal/mol, respectively. As we can see, the free energy of the rate-determining transition state is 23.7 kcal/mol (TS5) for Path III and is 26.3 kcal/mol (TS8) for Path IV, which is much higher than that of the first hydrogenation on the pyridine ring (Figure 2). For the second hydrogenation of the pyridyl and the pyrimidyl rings, please see Figures S5−S10. The above detailed DFT studies reveal the origin of the selectivity in the hydrogenation of 2-phenylpyrido[2,3-d]pyrimidine (Int-3ae). Very interestingly, although the pyrimidyl nucleus is more electrophilic than the pyridine ring, the hydrogenation on the pyridine ring (Path I/II) is obviously preferred, as compared with the hydrogenation on the pyrimidine ring (Path III/IV). In Path III, the conjugated effect between the heterocycle and phenyl ring has to be broken after the hydride addition. In addition, the phenyl group on the pyrimidine ring has more steric hindrance resulting in a disfavored Path III. In Path IV, although the hydride addition is feasible (ΔG‡ = 12.2 kcal/ mol), the process L → TS8 → IM-4 in Path IV is difficult due to the geometry of the transition state structure (TS8, ΔG‡ = 39.1 kcal/mol). Different from other reductive elimination TS structures (TS2, TS4, or TS6), there is no adjacent N atoms to direct and stabilize the Ru center of TS8. Therefore, the threemembered ring transition state TS8 is highly strained resulting in a difficult hydrogenation of the pyrimidyl ring through Path IV. In contrast, the hydride transfer transition state on pyridine ring is less hindered (TS1/TS3). Furthermore, the five-membered reductive elimination transition state on the pyridine ring is more accessible, due to the directing and stabilization effect of the adjacent N atom of the pyrimidyl ring, which leads to the selective hydrogenation of 2-phenylpyrido[2,3-d]pyrimidine on its pyridyl ring (Figure 4). In summary, we have developed a new method for direct and selective synthesis of tetrahydropyrido-fused pyrimidines from ortho-aminopyridyl methanols and nitriles. The synthesis proceeds with an easily available catalyst system, broad substrate scope, excellent functional tolerance, and no need for high pressure H2 gas. Control experiments indicate that the reaction proceeds via successive dehydrogenative annulation and transfer hydrogenation of the less-electrophilic pyridyl nucleus, and the DFT study revealed the origin of such a unique selectivity. The work of this paper has allowed the potential for further design of new reactions to construct semisaturated fused N-heterocycles
Figure 2. PESs for the first hydrogenation of the pyridine ring. Relative free energies are shown in kcal/mol.
pyridyl ring occurs via transition state TS1 (Path I) or TS3 (Path II), with activation free energies of 17.8 or 13.3 kcal/mol, respectively. The formed five-coordinated intermediate B or E will recombine with a CO ligand to six-coordinated intermediate C or F, which is lower by 29.1 or 27.7 kcal/mol, respectively. Then, the amido species C or F experiences a reductive elimination to the first hydrogenation intermediate IM-1 or IM-2, regenerating the Ru(0) precatalyst, via transition state TS2 or TS4 (9.7 or 9.9 kcal/mol, respectively). Transition states TS2 and TS4 are close to each other in free energy and are lower than the transition state of the first step, TS1 or TS3. As a result, Path II is relatively more favored for the first hydrogenation on the pyridine ring, since TS3 is lower than TS1 by 4.3 kcal/mol. On the other hand, the PESs for the first hydrogenation on pyrimidine ring (in blue) is shown in Figure 3 (Path III/IV). Starting from complex G or J, the hydride attacks the carbon-2 or carbon-4 of the pyrimidyl ring via transition state TS5 or TS7 (23.7 or 12.2 kcal/mol, respectively), to form five-coordinated 2732
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Figure 4. Origin of the selective hydrogenation of Int-3ae.
that are inaccessible or challenging to prepare with the conventional methods.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01081. Experimental procedures and spectral data (PDF) DFT study (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Huanfeng Jiang: 0000-0002-4355-0294 Zhuofeng Ke: 0000-0001-9064-8051 Min Zhang: 0000-0002-7023-8781 Author Contributions §
B.X. and J.X.J. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Funds of National Key Research and Development Program of China (2016YFA0602900), “1000 Youth Talents Plan”, Science Foundation for Distinguished Young Scholars of Guangdong Province (2014A030306018, 2015A030306027), and the National Natural Science Foundation of China (21472052, 21473261, and 21673301) are acknowledged. Computing facilities were supported in part by the Guangdong Province Key Laboratory of Computational Science and the Guangdong Province Computational Science Innovative Research Team, the Joint Funds of NSFC-Guangdong for Supercomputing Applications, and the National Supercomputing Center in Guangzhou.
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REFERENCES
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