Letter pubs.acs.org/OrgLett
Ruthenium-Catalyzed Synthesis of Fused Tricyclic 1H‑2,3Dihydropyrimido[1,2‑a]quinolines in One Step Xingyong Wang, Chulong Liu, Xiaobao Zeng, Xuesong Wang, Xinyan Wang,* and Yuefei Hu* Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China S Supporting Information *
ABSTRACT: A novel ruthenium-catalyzed intramolecular cyclization of a nitrile and an azetidine was developed to achieve a one-step synthesis of the fused tricyclic 1H-2,3dihydropyrimido[1,2-a]quinoline, which is the core skeleton for more than 100 natural pyoverdines and is also responsible for their fluorescence. yoverdines (1) are a family of fluorescent siderophores secreted by fluorescent Pseudomonas species under the conditions of iron deficiency.1 Besides their role as iron scavengers, pyoverdines also serve as regulators for some virulence factors through a transmembrane signaling system.2 More than 100 pyoverdines3 have been isolated and identified so far. Like pseudobactin4 (1a, Figure 1), they can be
P
that both compounds 3 and 4 lack the chromophore5,7 indicated that the fused tricycles and the double bond between C5 and C6 are essential. Therefore, the scaffold 2 is an attractive synthetic target for the synthesis of pyoverdine analogues and the development of novel fluorescent molecules. To our surprise, only four pioneering synthetic works5,6,8 for compound 2 have been reported in the literature. Possibly influenced by biosynthesis and incorporation studies,9 two of them used L-DOPA to construct the B-ring prior to the synthesis of the C-ring.8 In the other two, the derivatives of 3 were used as key precursors in the construction of the B-ring by oxidative cyclization.5,6 In all of these clever synthetic routes, the construction of the fused tricyclic skeleton and the introduction of the double bond between C5 and C6 represented challenging tasks. For example, 10 steps were required for the synthesis of compound 2b even though it was the simplest derivative with such a skeleton. Herein, we report a novel ruthenium-catalyzed intramolecular cyclization of a nitrile and an azetidine in the substrate 5, which led to the fused tricyclic 1H-2,3dihydropyrimido[1,2-a]quinoline 6 in one step (Scheme 1). Investigation showed that there are many methods for the synthesis of the fused tricyclic heterocyclics with a partially saturated pyrimidine ring.10 Although none of them met our requirements, the protocols for the synthesis of tetrahydropyrimidine derivatives by Lewis acid catalyzed formal 1,4-dipolar cycloaddition of a nitrile and an azetidine drew our attention
Figure 1. Pseudobactin (1a) as one of the reported pyoverdines.
considered as derivatives of 8,9-dihydroxy-1H-2,3-dihydropyrimido[1,2-a]quinoline (2a), in which a 6−19 amino acid peptide and a 4−5 carbon side chain are attached to the C2 and C5 positions, respectively. In all pyoverdine molecules, the scaffold 2a serves as a structural core and is responsible for their fluorescence. Thus, it is also called a “pyoverdine chromophore”, and such function depends heavily on its structural details. As shown in Figure 2, both compounds 2a5 and 2b6 showed strong fluorescence, which suggested that the two hydroxyls on the benzene ring and the substituents on C2 and C5 are not necessary. The fact
Scheme 1. Novel Intramolecular Cyclization in This Work
Received: May 2, 2017 Published: June 9, 2017
Figure 2. Structures of compounds 2−4. © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b01330 Org. Lett. 2017, 19, 3378−3381
Letter
Organic Letters (Scheme 2).11 They have two advantages: (a) one C−N bond, one CN bond, and one six-membered ring are formed in
Table 1. Primary Tests for Different LA Catalysts
Scheme 2. LA-Catalyzed Cycloaddition of a Nitrile and an Azetidine
one-step, and (b) two N-atoms in the pyrimidine ring come from two substrates. Unfortunately, these protocols were limited to 2-aryl-substituted N-tosylazetidines as substrates because the ring-opening of azetidine was based solely on the activation of C−N bond by the N-tosyl group.12 On the other hand, the “tert-amine effect” cyclization is a well-known strategy for the synthesis of the fused tetrahydroquinoline 10.13 As shown in Scheme 3, the vinylogous
entry
catalyst
solvent
temp (°C)
yield of 2a (%)
1 2 3 4 5 6 7 8 9 10
BF3·OEt2 BF3·OEt2 BF3·OEt2 BF3·OEt2 Ce(OTf)3 Bi(OTf)2 Zn(OTf)2 AgOTf Cu(OTf)2 AgTFA
DCM DCE DCE DCE DCE DCE DCE DCE DCE DCE
25 25 80 110 110 110 110 110 110 110
NR NR NR 10 10 20 40 60 73 90
a A solution of 5a (0.5 mmol) and catalyst (20 mol %) in solvent (2 mL) in a Schlenk tube was stirred at 25−110 °C for 12 h. bIsolated yields.
Scheme 3. “tert-Amine Effect” Cyclization (n = 1−3)
Table 2. Tests for Different Transition-Metal Catalysts
structure of 7 plays a crucial role in this strategy,14 in which the cyclic amine in 8 is activated by EWG groups through a conjugated chain. Then a sigmatropic hydrogen 1,5-shift occurs to form the intermediate 9 with an endocyclic CN double bond. Significantly, this activation remains efficient even when the conjugated chain length is up to eight carbons.15 Recognizing that if compound 5 was used as a substrate it would be difficult to form an endocyclic CN double bond by 1,5-[H]-shift because the azetidine is a four-membered cyclic amine, we reasoned that the azetidine might be opened in an intramolecular formal 1,4-dipolar cycloaddition with the nitrile to yield the desired 6. Thus, the model substrate 5a was synthesized from ofluorobenzaldehyde in two easy steps14c (see the SI), and its cycloaddition was tested. As shown in Table 1, 5a was recovered in almost quantitative yield when it was treated with BF3·OEt2 at 25 °C in DCM or DCE following the reported conditions11d (entries 1 and 2). Pleasingly, the desired 6a was isolated when the reaction was carried out at 110 °C (entries 3 and 4), and its yield could be increased by using other Lewis acid catalysts (entries 5−7). It seemed that the catalysts with soft-metals showed higher catalytic activity (entries 8 and 9), which implied that these catalysts could be playing dual roles as a Lewis acid and as a transition-metal catalyst, respectively. The fact that AgTFA gave the highest yield of 6a strongly indicated that the transition-metal catalyst could be playing a major role (entry 10, compared to entry 8). As shown in Table 2, further tests were made using different transition-metal catalysts (entries 1−8). To our delight, 6a was obtained in 95% yield when 10 mol % of RuCl2(PPh3)3 was used as a catalyst (entry 8). A similar excellent result was obtained with 5 mol % of RuCl2(PPh3)3 when the reaction was run for 24 h (entry 9). Although comparable yields of 6a (80− 85%) were obtained in PrCN, DMF, or DMSO, entry 9 was assigned as the standard conditions due to the convenience of DCE.
entry
catalyst (mol %)
time (h)
yield of 2a (%)
1 2 3 4 5 6 7 8 9 10
Pd(OAc)2/bpy (10) Co(acac)2 (10) Rh2(oct)4 (10) AuCl3 (10) CoCl2 (10) PdCl2(PPh3)2 (10) MoCl5 (10) RuCl2(PPh3)3 (10) RuCl2(PPh3)3 (5) RuCl2(PPh3)3 (4)
12 12 12 12 12 12 12 12 24 24
10 20 45 45 50 60 70 95 95 91
a
A solution of 5a (0.5 mmol) and catalyst (4−10 mol %) in DCE (2 mL) in a Schlenk tube was stirred at 110 °C for 12−24 h. bIsolated yields.
To generalize the scope of our method, different substrates were tested. As shown in Scheme 4, satisfactory results were obtained for all products 6a−r. Under the standard conditions, 6a−e,l,r were synthesized in 83−95% yields. In other cases, the results were influenced significantly by both the electronic and steric effects of the substituents on the benzene rings. Luckily, these problems could be overcome simply by using higher temperatures and/or longer times. For example, 6f−i,k,m−q were smoothly synthesized at 120 °C. The nitro-substitued product 6j was synthesized in 81% yield at 130 °C for 60 h. The structure of 6n indicated that only the o-azetidine underwent cycloaddition regioselectively. When the benzene ring was replaced by a pyridine ring, similar excellent results were obtained for 6r. A large-scale synthesis (5 g) was tested to give 6a in 96% yield. As shown in Scheme 5, the importance of our method was enhanced greatly by the synthesis of 6s−v, which contain potentially important groups (for example, two methoxyl groups on the A ring, one double bond between C5 and C6, and substituents on the B and C rings, respectively). As was expected, 5w−z in which one nitrile of 5a was replaced by a sulfonyl group gave the desired products 6w−z in excellent yields. The structure of 6z was confirmed by a single-crystal Xray diffraction analysis. 3379
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Organic Letters Scheme 4. Synthesis of the Products 6a−r
Scheme 6. Effect of EWG Groups and Vinylogous Structure
by two factors: (a) the ester and keto groups have weaker electron-withdrawing ability than a nitrile, and (b) they can be enolized to form the Ru complex 13, by which the catalyst may partially lose catalytic activity. These hypotheses are in full agreement with the results reported in the references17 and also were confirmed by further experiments in which the desired 15 was obtained in 42% yield from 14. To our surprise, 6a could also be obtained in 82% yield from compound 16 (Scheme 7). Since the nitrile is not conjugated Scheme 7. Effect of Vinylogous Structure
Scheme 5. Synthesis of the Products 6s−z
with the benzene ring in 16, this result suggested the exciting possibility that the azetidine might be opened directly by the Ru catalyst without the vinylogy.18 To our disappointment, substrates 17−19 were recovered in almost quantitative yields when they were treated under the same conditions. All of these results indicated that the Ru-catalyzed ring opening of the azetidine was induced by the vinylogy. The conversion of 16 into 6a may arise from the fact that 5a is formed initially as an intermediate, even though it was not isolated from this reaction (see the SI). Thus, a possible mechanism is proposed for our method as shown in Scheme 8. The compound 5a initially coordinates with the ruthenium to form the complex 20,19 by which the vinylogy may be enhanced. Since the C−N bond in azetidine is highly polarized, ruthenium may easily carry out an oxidative Scheme 8. Proposed Mechanism
Importantly, no reactions occurred when 11 and 12 were used as the substrates16 even when prolonged reaction times (144 h) were used. As shown in Scheme 6, this may be caused 3380
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Organic Letters addition to form a ruthena-cyclopentane intermediate 21.20 Then, an intramolecular nitrile insertion into the Ru−N bond occurs to give a tricyclic intermediate 22. Finally, the intermediate 22 undergoes a reductive elimination of ruthenium to give the desired 6a. In summary, a novel ruthenium-catalyzed intramolecular cyclization of a nitrile and an azetidine was developed by which the fused tricyclic 1H-2,3-dihydropyrimido[1,2-a]quinolines were synthesized in one step. The vinylogy plays a crucial role in achieving a long-distance activation of the azetidine ring by which the ring opening of azetidine without N-Ts and 2-aryl substitution occurred efficiently. Since the method can be easily performed on a large scale, it is expected to have broad implications in the synthesis of pyoverdine analogues and development of structurally novel fluorescent molecules. The modification works for the groups on B and C rings are also in progress.
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(10) Remennikov, G. Y. J. Heterocycl. Chem. 2017, DOI: 10.1002/ jhet.2852. (11) (a) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2009, 50, 1105. (b) Ghorai, M. K.; Das, K.; Kumar, A.; Das, A. Tetrahedron Lett. 2006, 47, 5393. (c) Yadav, V. K.; Sriramurthy, V. J. Am. Chem. Soc. 2005, 127, 16366. (d) Bhanu Prasad, B. A.; Bisai, A.; Singh, V. K. Org. Lett. 2004, 6, 4829. (12) Bertolini, F.; Crotti, S.; Bussolo, V. D.; Macchia, F.; Pineschi, M. J. Org. Chem. 2008, 73, 8998. (13) For selected recent references, see: (a) Kang, Y. K.; Kim, S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847. (b) Zhou, G.; Zhang, J. Chem. Commun. 2010, 46, 6593. (c) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 11, 129. (d) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2009, 131, 13226. (e) Kaval, N.; Dehaen, W.; Mátyus, P.; Van der Eycken, E. Green Chem. 2004, 6, 125. (14) For selected reviews and early references, see: (a) Meth-Cohn, O. Adv. Heterocycl. Chem. 1996, 65, 1 (a review). (b) Nijhuis, W. H. N.; Verboom, W.; El-Fadl, A. A.; van Hummel, G. J.; Reinhoudt, D. N. J. Org. Chem. 1989, 54, 209. (c) Nijhuis, W. H. N.; Verboom, W.; ElFadl, A. A.; Harkema, S.; Reinhoudt, D. N. J. Org. Chem. 1989, 54, 199. (d) Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N. J. Am. Chem. Soc. 1987, 109, 3136. (e) Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S. J. Org. Chem. 1984, 49, 269. (15) (a) Földi, Á . A.; Ludányi, K.; Bényei, A. C.; Mátyus, P. Synlett 2010, 2010, 2109. (b) Dunkel, P.; Túrós, G.; Bényei, A.; Ludányi, K.; Mátyus, P. Tetrahedron 2010, 66, 2331. (16) Compounds 11 and 12 usually have the required E-isomer only; see: (a) Maadi, A. E.; Matthiesen, C. L.; Ershadi, P.; Baker, J.; Herron, D. M.; Holt, E. M. J. Chem. Crystallogr. 2003, 33, 757. (b) TexierBoullet, F.; Foucaud, A. Tetrahedron Lett. 1982, 23, 4927. (17) Dell’Amico, L.; Rassu, G.; Zambrano, V.; Sartori, A.; Curti, C.; Battistini, L.; Pelosi, G.; Casiraghi, G.; Zanardi, F. J. Am. Chem. Soc. 2014, 136, 11107 and references cited therein. (18) Selected reviews for the vinylogy: (a) Casiraghi, G.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (b) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929. (c) Fuson, R. C. Chem. Rev. 1935, 16, 1. (19) Selected references and references cited therein: (a) Medina, S.; Domı ́nguez, G.; Pérez-Castells, J. Org. Lett. 2012, 14, 4982. (b) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. (c) Yamamoto, Y.; Kinpara, K.; Nishiyama, H.; Itoh, K. Adv. Synth. Catal. 2005, 347, 1913. (d) Varela, J. A.; Castedo, L.; Saá, C. J. Org. Chem. 2003, 68, 8595. (20) Selected references and references cited therein: (a) Li, T.; Xu, F.; Li, X.; Wang, C.; Wan, B. Angew. Chem., Int. Ed. 2016, 55, 2861. (b) Li, T.; Yan, H.; Li, X.; Wang, C.; Wan, B. J. Org. Chem. 2016, 81, 12031.
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01330. Experimental details, characterization, 1H and 13C NMR spectra for all products (PDF) X-ray crystallogrphic data for 6z (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Yuefei Hu: 0000-0002-7030-0418 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by NNSFC (Nos. 21372142 and 21472107).
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REFERENCES
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NOTE ADDED AFTER ASAP PUBLICATION Compound 12 in Scheme 6 was corrected June 23, 2017.
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