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Cite this: Chem. Commun., 2014, 50, 13555 Received 3rd July 2014, Accepted 3rd September 2014 DOI: 10.1039/c4cc05090h
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A domino desulfurative coupling–acylation– hydration–Michael addition process for the synthesis of polysubstituted tetrahydro-4Hpyrido[1,2-a]pyrimidines† Zhong-Fei Yan, Zheng-Jun Quan,* Yu-Xia Da, Zhang Zhang and Xi-Cun Wang*
www.rsc.org/chemcomm
A novel method for the synthesis of the polysubstituted tetrahydro-4Hpyrido[1,2-a]pyrimidines through a domino desulfurative coupling– acylation–hydration and Michael addition sequence was established.
In past decades, by possessing high chemo- and stereoselectivity and through the construction of multiple C–C, C–O or C–N bonds in one process, domino and cascade reactions have innovated art and inspirations for organic synthesis.1 Pd-catalyzed, Cu(I) carboxylatemediated cross-coupling reactions of different organic sulfur compounds with boronic acids (so-called ‘‘Liebeskind–Srogl cross coupling reaction’’) have attracted remarkable attention in the organic synthetic community.2 Notably, the non-basic Liebeskind–Srogl reaction has been developed by Kappe3 (Scheme 1, left) and others.4 A key feature of these desulfurative C–C couplings is the requirement of both the Pd(0) catalyst and at least a stoichiometric quantity of a copper(I) carboxylate. In 2007, Liebeskind and co-workers reported the first CuI-3methylsalicylate catalyzed coupling of thiol esters with excess boronic acids under aerobic conditions without using a Pd catalyst.5 Then, a few successful examples of Pd and/or Cu, Ni catalyzed cross-coupling reactions of thioethers or thioesters with arylboronic acids were developed.6–8 Recently, we reported a multi-component domino desulfurative coupling–acylation–hydration process between dihydropyrimidinthione (DHPM),9,10 an alkyne and copper(I) carboxylate under the modified Liebeskind–Srogl conditions (Scheme 1, right),10a in which, copper(I) carboxylates act not only as desulfurative reagents but also as sources of nucleophilic carboxylates. This prompted us to study the related domino process between DHPMs, alkynes, a,b-unsaturated carboxylic acids and Cu2O, aiming at showing a straightforward access to diversely polysubstituted pyrido[1,2-a]pyrimidines11 through a domino desulfurative College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, People’s Republic of China. E-mail: [email protected], [email protected] † Electronic supplementary information (ESI) available. CCDC 942987. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c4cc05090h
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coupling–acylation–hydration and Michael addition process by using readily accessible and extensively available reaction partners (Scheme 1, right). This unprecedented transformation, involving four bond formation steps in a one-pot reaction was very efficient under mild reaction conditions. Furthermore, the Cu(I) carboxylate formed in situ from carboxylic acids and Cu2O eliminates the need for preparation of cuprous carboxylates, which are unstable and sensitive to humidity and oxidants. Initially, the reaction between DHPM (1a), acrylic acid (2a) and phenylacetylene (3a) in dioxane at 110 1C was tested in the presence of Cu2O using Pd catalysts (Table 1). To our delight, the reaction produced a novel bicycle, pyrido[1,2-a]pyrimidine 4a (69–75% yield), as the major product along with a small amount of the acyclic product 5a (5–7% yield) (entries 1–5), catalyzed by various Pd catalysts. The use of cuprous salts, such as CuI, CuBr or CuCl was not efficient for the formation of 4a, and even resulted in low conversion of 1a (entries 6–8). Generally, 2 mol% of Pd(OAc)2 and 3 mol% of DPE-Phos (bis(2-diphenylphosphinophenyl)ether) in dioxane were sufficient to achieve the major cyclization product 4a (75% yield) with a trace amount of the acyclic product 5a within 24 h at 110 1C (entry 3). Better control of the favoured cyclisation process was expected; for example, after 36 h the reaction resulted in 4a as the sole product in 77% yield (entry 9). However, shortening the reaction times to 9 h and 12 h led to the isolation of acyclic product 5a in 9% and 4% yield, respectively (entries 10 and 11). The reaction was found to proceed smoothly at longer reaction times, and it is worth noting that longer reaction times led to the conversion of 5a to 4a (entries 9–11). The copper(I) carboxylate of
Scheme 1
A desulfurative coupling–acylation–cycling domino process.
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Table 1
ChemComm
Optimization of reaction conditionsa,b
Entry Pd
Ligand
Cu
Time (h) Yield 4a (%) Yield 5a (%)
1 2 3 4 5 6 7 8 9 10 11 12c 13c 14d 15
PPh3 DPE-Phos DPE-Phos — — DPE-Phos DPE-Phos DPE-Phos DPE-Phos DPE-Phos DPE-Phos DPE-Phos — DPE-Phos DPE-Phos
Cu2O Cu2O Cu2O Cu2O Cu2O CuI CuCl CuBr Cu2O Cu2O Cu2O CuAC CuAC Cu2O —
24 24 24 24 24 24 24 24 36 9 12 24 24 24 24
Pd(OAc)2 Pd(PPh3)4 Pd(OAc)2 Pd(acac)2 Pd2(dba)3 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(acac)2 Pd(OAc)2 Pd(OAc)2
69 74 75 71 74 22 6 14 76 61 69 81 76 75 Trace
5 6 Trace 7 6 21 5 15 Trace 9 4 Trace Trace 6 Trace
a
Conditions: 0.25 mmol 1a, 1.5 equiv. 2a, 1.5 equiv. 3a in 2 mL solvent. Isolated yield by column chromatography. c CuAC was used instead of 2a and Cu2O. d Toluene was used as solvent. b
Scheme 2
2a (CuAC) could slightly enhance the reaction in a higher selectivity towards 4a (entries 12 and 13). On the other hand, the copper(I) carboxylates are troublesome to prepare and always unstable, sensitive to humidity and oxidants. Therefore, because the process with Cu2O and acrylic acid is more convenient to handle, and can give favorable results, we eventually used Cu2O and acrylic acid instead of copper(I) carboxylate in this one-pot operation. The use of toluene as solvent gave 4a in 75% yield, while lowering the selectivity of the transformation, with formation in 6% yield of 5a (entry 14). As expected, only trace amounts of 4a and 5a were detected without the participation of Cu2O (entry 15). Summarily, key observations included (1) a copper(I) carboxylate was not required under the one-pot reaction conditions, (2) the acyclic product 5a might have been formed first and sequentially gave the Michael addition product 4a. With the optimized conditions in hand, we examined the scope and limitations of this new domino cyclization process with respect to various DHPMs (1), terminal alkynes (3), acrylic acid (2a) and Cu2O catalyzed by Pd(OAc)2 and DPE-Phos (Scheme 2). In general, good yields were obtained under the standard reaction conditions. Both electron-rich methoxy- and diethylaminophenyl-substituted DHPMs and electron-poor fluoro-, chloro-, bromo-, and even nitrophenyl-substituted DHPMs underwent the domino reactions to deliver the products 4a–4m in moderate to good yields. Meanwhile, aryl alkynes gave exceptional selectivity for products 4a–4m with only trace acyclic products detected. A bit disappointingly, when alkyl alkynes were exposed in this transformation, the desired products 4n–4p were only achieved in lower yields (61%, 31%, 19%) with the acyclic products 5n, 5o, and 5p in 8%, 21%, and 7% yield, respectively. The related structure of compound 4b was confirmed based on X-ray crystallographic analysis.12 The process proved to be broad in scope, tolerating a variety of steric and electronic changes to both DHPMs and terminal alkyne reaction partners.
13556 | Chem. Commun., 2014, 50, 13555--13558
Scope of the DHPMs and alkyne partners.
To demonstrate the generality of this optimized protocol, we tested the a- and/or b-substituted acrylic acids as mediators and acylation reagents. Gratifyingly, the reaction of 4-Cl-, 4-Br-, 4-F-, or 2-Cl-substituted phenyl DHPM 1 with a-methylacrylic acid gave desired annulated products 4q–4u in impressive yields (Scheme 2). In contrast to a-methylacrylic acid, b-methyl-, or phenylacrylic acids are detrimental to the cyclization reaction, instead forming the acyclic products 5v–5y as the sole products (Table 2). From a mechanistic point of view, the annulation is postulated as a Michael additional process. Both the poor electrophilicity and steric hindrance of either a b-methyl or a phenyl group on the acrylic acid reduced its reactivity as a Michael receptor. In this case, the acyclic products 5v–5y would be converted into the cyclic products via a base-catalyzed intramolecular Michael addition. To our delight, treatment of compound 5v with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) at RT for 6 h led successfully to the desired cyclic product 4v in 98% yield (Table 2, entry 1). Under similar reaction conditions, 5w–y were transformed into the cyclic forms 4w–y in excellent yields of 95–98% (entries 2–4). We additionally tried to form the cyclic product in a one-pot process by adding DBU into the reaction system of 1a, b-methyl acrylic acid and 3a; however, this was unsuccessful and did not form the desired product (neither 5 nor 4 formed). On account of the mechanism studies in terms of Liebeskind– Srogl coupling,3,4 isotope-labelling experiments were conducted to gain insight into the mechanism pertaining to the key-steps in the domino process, hydration and annulation reactions. Initially, we prepared the 1,3-dideuterio-DHPM and studied the domino reaction with acrylic acid 2a and phenylacetylene 3a in the presence of Cu2O. The reaction led to formation of a-CD with deuterium located on the a-CH in the acyclic product and pyrido-ring, respectively (see the ESI† for details). On the other hand, 18O-labelling experiments were
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Table 2
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Two-step process for the synthesis of pyrido[1,2-a]pyrimidinesa
Entry
Ar
R1
R2
5/yieldb/%
4/yieldc/%
1 2 3 4
Ph Ph Ph 4-MeOC6H4
Me Me Ph Ph
Me H H H
5v/86 5w/88 5x/69 5y/58
4v/98 4w/98 4x/96 4y/95
Scheme 4
Aliphatic acids as C–N coupling partners.
a
Conditions: 1 (0.25 mmol), 2 (0.375 mmol), 3a (0.375 mmol), Cu2O (0.375 mmol), dioxane (2 mL). b Isolated yield based on the DHPM. c Isolated yield based on 5. See ESI for experimental details.
also carried out to trace the oxygen atom that added to the triple bond during the hydration. The reaction between 1a, benzoic acid and 3a was performed in the presence of 18OH2 giving 18O-labeled CQO bond in the product. Meanwhile low yield of the product was observed compared to our previous study (see the ESI† for details).10a Based on these observations, the following possible mechanism is proposed (Scheme 3): the desulfurative cross-coupling step is related to the traditional Liebeskind–Srogl protocols leading to the C–C coupling product (B).3,4 Then B may undergo acylation, likely mediated by the coordination of B to the copper salt A, followed by hydration with water to deliver the acyclic product 5.10a,14 Finally, the acyclic product may subsequently undergo intramolecular Michael addition, cyclization and isomerization to produce the desired product 4. Finally, in light of the importance of the amide bond in numerous industrially important compounds, as well as a wide selection of bioactive natural products,13 aliphatic carboxylic acids were used as acylation partners (Scheme 4). When acetic acid, hexanoic acid, and 3-methylbutanoic acid were used, the coupling–hydration–acylation with DHPMs 1 and alkynes 3 in the presence of Cu2O proceeded smoothly to give the expected acyclic products 7a–h. A more sterically hindered 2,4,6triisopropylbenzoic acid successfully afforded product 7h with a yield of up to 84%. Those results showed this approach to be an efficient coupling–hydration and acylation with favorable compatibility. In conclusion, we have developed a domino process between DHPMs, alkynes, acrylic acids and Cu2O under modified Liebeskind–Srogl coupling conditions. This one-pot protocol
Scheme 3
Possible mechanism.
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led to the poly-substituted pyrido[1,2-a]pyrimidines through a sequential coupling–hydration–acylation and Michael addition cyclization. Moreover, this method of directly using acid–Cu2O mixtures rather than Cu(I) carboxylate may be applied for Liebeskind–Srogl type couplings.15 Financial support was provided by the financial support from the NSFC (No. 21362032, and 21362031), the NSF of Gansu Province (No. 1208RJYA083), and the STIE of NWNU (No. nwnu-kjcxgc-03-64).
Notes and references 1 For recent reviews, see: (a) J. Zhou, Chem. – Asian J., 2010, 5, 422; (b) L. M. Ambrosini and T. H. Lambert, ChemCatChem, 2010, 2, 1373; (c) M. Rueping, R. M. Koenigs and I. Atodiresei, Chem. – Eur. J., 2010, 16, 9350; (d) C. Zhong and X. Shi, Eur. J. Org. Chem., 2010, 2999; (e) J. E. Biggs-Houck, A. Younai and J. T. Shaw, Curr. Opin. Chem. Biol., 2010, 14, 371; ( f ) H. Pellissier, Tetrahedron, 2013, 69, 7171; (g) H. Pellissier, Chem. Rev., 2013, 113, 442; (h) A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633; (i) N. T. Patil, V. S. Shinde and B. Gajula, Org. Biomol. Chem., 2012, 10, 211; ( j) H. Clavier and H. Pellissier, Adv. Synth. Catal., 2012, 354, 3347; (k) C. De Graaff, E. Ruijter and R. V. A. Orru, Chem. Soc. Rev., 2012, 41, 3969; (l) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237; (m) Z. Zhang and J. C. Antilla, Angew. Chem., Int. Ed., 2012, 51, 117782; (n) S. Piovesana, D. M. Scarpino Schietroma and M. Bella, Angew. Chem., Int. Ed., 2011, 50, 6216; (o) L. Albrecht, H. Jiang and K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492; (p) M. Ruiz, P. Lopez-Alvarado, G. Giorgi and J. C. Menendez, Chem. Soc. Rev., 2011, 40, 3445; (q) C. Vaxelaire, P. Winter and M. Christmann, Angew. Chem., Int. Ed., 2011, 50, 3605. 2 For examples of Liebeskind–Srogl reactions, see: (a) L. S. Liebeskind and J. Srogl, J. Am. Chem. Soc., 2000, 122, 11260; (b) C. Savarin, J. Srogl and L. S. Liebeskind, Org. Lett., 2001, 3, 91; (c) Y. Yu and L. S. Liebeskind, J. Org. Chem., 2004, 69, 3554; (d) H. Yang, H. Li, R. Wittenberg, M. Egi, W. Huang and L. S. Liebeskind, J. Am. Chem. Soc., 2007, 129, 1132; (e) L. S. Liebeskind and J. Srogl, Org. Lett., 2002, 4, 979; ( f ) C. L. Kusturin, L. S. Liebeskind and W. L. Neumann, Org. Lett., 2002, 4, 983; (g) C. Kusturin, L. S. Liebeskind, H. Rahman, K. Sample, B. Schweitzer, J. Srogl and W. L. Neumann, Org. Lett., 2003, 5, 4349; (h) L. S. Liebeskind, H. Yang and H. Li, Angew. Chem., Int. Ed., 2009, 48, 1417; (i) Z. Zhang, M. G. Lindale and L. S. Liebeskind, J. Am. Chem. Soc., 2011, 133, 6403; ( j) H. Li, A. He, J. R. Falck and L. S. Liebeskind, Org. Lett., 2011, 13, 3682; (k) K. M. Lovell, T. Vasiljevik, J. J. Araya, A. Lozama, K. M. Prevatt-Smith, V. W. Day, C. M. Dersch, R. B. Rothman, E. R. Butelman, M. J. Kreek and T. E. Prisinzano, Bioorg. Med. Chem., 2012, 20, 3100; (l) G. Bouscary-Desforges, A. Bombrun, J. K. Augustine, G. Bernardinelli and A. Quattropani, J. Org. Chem., 2012, 77, 4586; (m) S. Dahbi and P. Bisseret, Eur. J. Org. Chem., 2012, 3579; (n) M. Cernova, R. Pohl, B. Klepetarova and M. Hocek, Synlett, 2012, 1305; (o) G. Bouscary-Desforges, A. Bombrun, J. K. Augustine, G. Bernardinelli and A. Quattropani, J. Org. Chem., 2012, 77, 243. ´ 3 (a) A. Lengar and C. O. Kappe, Org. Lett., 2004, 6, 771; (b) H. Prokopcova and C. O. Kappe, Adv. Synth. Catal., 2007, 349, 448; (c) C. O. Kappe, J. Org. Chem., 2007, 72, 4440. ¨t, A. P. Rauter and 4 (a) S. Silva, B. Sylla, F. Suzenet, A. Tatiboue P. Rollin, Org. Lett., 2008, 10, 853; (b) V. P. Mehta, A. Sharma and
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7 8 9
10
E. Van der Eycken, Org. Lett., 2008, 10, 1147; (c) X. Guinchard and E. Roulland, Org. Lett., 2009, 11, 4700. J. M. Villalobos, J. Srogl and L. S. Liebeskind, J. Am. Chem. Soc., 2007, 129, 15734. ´ and C. O. Kappe, Angew. Chem., Int. Ed., 2008, (a) H. Prokopcova ´ and C. O. Kappe, Angew. Chem., Int. Ed., 47, 3674; (b) H. Prokopcova 2009, 48, 2276. (a) A. Henke and J. Srogl, Chem. Commun., 2011, 47, 4282; (b) Y. Dong, M. Wang, J. Liu, W. Ma and Q. Liu, Chem. Commun., 2011, 47, 73802. (a) A. C. Wotal and D. J. Weix, Org. Lett., 2012, 14, 1476; (b) C. I. Someya, M. Weidauer and S. Enthaler, Catal. Lett., 2013, 143, 424. For reviews on the DHPMs, see: (a) C. O. Kappe, Tetrahedron, 1993, 49, 6937; (b) C. O. Kappe, Acc. Chem. Res., 2000, 33, 879; (c) C. O. Kappe and A. Stadler, Org. React., 2004, 63, 1; (d) D. Dallinger, A. Stadler and C. O. Kappe, Pure Appl. Chem., 2004, 76, 1017; (e) L. Z. Gong, X. H. Chen and X. Y. Xu, Chem. – Eur. J., 2007, 13, 8920; ( f ) M. A. Kolosov and V. D. Orlov, Mol. Diversity, 2009, 13, 5; ( g) Z.-J. Quan, Z. Zhang, Y.-X. Da and X.-C. Wang, Chin. J. Org. Chem., 2009, 29, 876; (h) C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 10432. Our previous work on the DHPM derivatives: (a) Z.-J. Quan, W.-H. Hu, X.-D. Jia, Z. Zhang, Y.-X. Da and X.-C. Wang, Adv. Synth. Catal., 2012, 354, 2939; (b) Z.-J. Quan, Y. Lv, Z.-J. Wang, Z. Zhang, Y.-X. Da and X.-C. Wang, Tetrahedron Lett., 2013, 54, 1884; (c) Z.-J. Quan, W.-H. Hu, Z. Zhang, X.-D. Jia, Y.-X. Da and X.-C. Wang, Adv. Synth. Catal., 2013, 355, 891; (d) Z.-J. Quan, Y. Lv, F.-Q. Jing, X.-D. Jia, C.-D. Huo and X.-C. Wang, Adv. Synth. Catal., 2014, 356, 325.
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ChemComm 11 For examples of pyrido[1,2-a]pyrimidines, see: (a) G. C. B. Harriman, S. Chi, M. Zhang, A. Crowe, R. A. Bennett and I. Parsons, Tetrahedron Lett., 2003, 44, 3659; (b) R. L. Smith, R. J. Barette and E. Sanders-Bush, J. Pharmacol. Exp. Ther., 1995, 275, 1050; (c) F. Awouters, J. Vermeire, F. Smeyers, P. Vermote, R. Van Beek and C. J. E. Niemegeers, Drug Dev. Res., 1986, 8, 95; (d) Y. Yanagihara, H. Kasai, T. Kawashima and T. Shida, Jpn. J. Pharmacol., 1988, 48, 91. 12 CCDC 942987 for 4b. 13 For recent reviews about amide bond formations, see: (a) V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480, 471; (b) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011, 40, 3405; (c) R. M. Lanigan and T. D. Sheppard, Eur. J. Org. Chem., 2013, 7453. 14 The alternative pathway involves an ester intermediate D. The addition of acid into the C–C triple bond of C–C coupling product B generates an ester intermediate D, followed by O to N transacylation leading to the N-acylated products. The ester intermediates were unable to be isolated, though a similar conjugate addition of acid into the C–C ¨thig and triple bond of alkynes was reported, see: O. V. Maltsev, A. Po L. Hintermann, Org. Lett., 2014, 16, 1282.
15 The reaction between 1a and phenylboronic acid in the presence of thiophenecarboxylic acid and Cu2O under the catalytic conditions has been evaluated and the desulfurative coupling product 83 was obtained in 72% yield (see the ESI† for details).
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Cite this: Chem. Commun., 2014, 50, 13555 Received 3rd July 2014, Accepted 3rd September 2014 DOI: 10.1039/c4cc05090h
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A domino desulfurative coupling–acylation– hydration–Michael addition process for the synthesis of polysubstituted tetrahydro-4Hpyrido[1,2-a]pyrimidines† Zhong-Fei Yan, Zheng-Jun Quan,* Yu-Xia Da, Zhang Zhang and Xi-Cun Wang*
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A novel method for the synthesis of the polysubstituted tetrahydro-4Hpyrido[1,2-a]pyrimidines through a domino desulfurative coupling– acylation–hydration and Michael addition sequence was established.
In past decades, by possessing high chemo- and stereoselectivity and through the construction of multiple C–C, C–O or C–N bonds in one process, domino and cascade reactions have innovated art and inspirations for organic synthesis.1 Pd-catalyzed, Cu(I) carboxylatemediated cross-coupling reactions of different organic sulfur compounds with boronic acids (so-called ‘‘Liebeskind–Srogl cross coupling reaction’’) have attracted remarkable attention in the organic synthetic community.2 Notably, the non-basic Liebeskind–Srogl reaction has been developed by Kappe3 (Scheme 1, left) and others.4 A key feature of these desulfurative C–C couplings is the requirement of both the Pd(0) catalyst and at least a stoichiometric quantity of a copper(I) carboxylate. In 2007, Liebeskind and co-workers reported the first CuI-3methylsalicylate catalyzed coupling of thiol esters with excess boronic acids under aerobic conditions without using a Pd catalyst.5 Then, a few successful examples of Pd and/or Cu, Ni catalyzed cross-coupling reactions of thioethers or thioesters with arylboronic acids were developed.6–8 Recently, we reported a multi-component domino desulfurative coupling–acylation–hydration process between dihydropyrimidinthione (DHPM),9,10 an alkyne and copper(I) carboxylate under the modified Liebeskind–Srogl conditions (Scheme 1, right),10a in which, copper(I) carboxylates act not only as desulfurative reagents but also as sources of nucleophilic carboxylates. This prompted us to study the related domino process between DHPMs, alkynes, a,b-unsaturated carboxylic acids and Cu2O, aiming at showing a straightforward access to diversely polysubstituted pyrido[1,2-a]pyrimidines11 through a domino desulfurative College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, People’s Republic of China. E-mail: [email protected], [email protected] † Electronic supplementary information (ESI) available. CCDC 942987. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/ c4cc05090h
This journal is © The Royal Society of Chemistry 2014
coupling–acylation–hydration and Michael addition process by using readily accessible and extensively available reaction partners (Scheme 1, right). This unprecedented transformation, involving four bond formation steps in a one-pot reaction was very efficient under mild reaction conditions. Furthermore, the Cu(I) carboxylate formed in situ from carboxylic acids and Cu2O eliminates the need for preparation of cuprous carboxylates, which are unstable and sensitive to humidity and oxidants. Initially, the reaction between DHPM (1a), acrylic acid (2a) and phenylacetylene (3a) in dioxane at 110 1C was tested in the presence of Cu2O using Pd catalysts (Table 1). To our delight, the reaction produced a novel bicycle, pyrido[1,2-a]pyrimidine 4a (69–75% yield), as the major product along with a small amount of the acyclic product 5a (5–7% yield) (entries 1–5), catalyzed by various Pd catalysts. The use of cuprous salts, such as CuI, CuBr or CuCl was not efficient for the formation of 4a, and even resulted in low conversion of 1a (entries 6–8). Generally, 2 mol% of Pd(OAc)2 and 3 mol% of DPE-Phos (bis(2-diphenylphosphinophenyl)ether) in dioxane were sufficient to achieve the major cyclization product 4a (75% yield) with a trace amount of the acyclic product 5a within 24 h at 110 1C (entry 3). Better control of the favoured cyclisation process was expected; for example, after 36 h the reaction resulted in 4a as the sole product in 77% yield (entry 9). However, shortening the reaction times to 9 h and 12 h led to the isolation of acyclic product 5a in 9% and 4% yield, respectively (entries 10 and 11). The reaction was found to proceed smoothly at longer reaction times, and it is worth noting that longer reaction times led to the conversion of 5a to 4a (entries 9–11). The copper(I) carboxylate of
Scheme 1
A desulfurative coupling–acylation–cycling domino process.
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Table 1
ChemComm
Optimization of reaction conditionsa,b
Entry Pd
Ligand
Cu
Time (h) Yield 4a (%) Yield 5a (%)
1 2 3 4 5 6 7 8 9 10 11 12c 13c 14d 15
PPh3 DPE-Phos DPE-Phos — — DPE-Phos DPE-Phos DPE-Phos DPE-Phos DPE-Phos DPE-Phos DPE-Phos — DPE-Phos DPE-Phos
Cu2O Cu2O Cu2O Cu2O Cu2O CuI CuCl CuBr Cu2O Cu2O Cu2O CuAC CuAC Cu2O —
24 24 24 24 24 24 24 24 36 9 12 24 24 24 24
Pd(OAc)2 Pd(PPh3)4 Pd(OAc)2 Pd(acac)2 Pd2(dba)3 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(acac)2 Pd(OAc)2 Pd(OAc)2
69 74 75 71 74 22 6 14 76 61 69 81 76 75 Trace
5 6 Trace 7 6 21 5 15 Trace 9 4 Trace Trace 6 Trace
a
Conditions: 0.25 mmol 1a, 1.5 equiv. 2a, 1.5 equiv. 3a in 2 mL solvent. Isolated yield by column chromatography. c CuAC was used instead of 2a and Cu2O. d Toluene was used as solvent. b
Scheme 2
2a (CuAC) could slightly enhance the reaction in a higher selectivity towards 4a (entries 12 and 13). On the other hand, the copper(I) carboxylates are troublesome to prepare and always unstable, sensitive to humidity and oxidants. Therefore, because the process with Cu2O and acrylic acid is more convenient to handle, and can give favorable results, we eventually used Cu2O and acrylic acid instead of copper(I) carboxylate in this one-pot operation. The use of toluene as solvent gave 4a in 75% yield, while lowering the selectivity of the transformation, with formation in 6% yield of 5a (entry 14). As expected, only trace amounts of 4a and 5a were detected without the participation of Cu2O (entry 15). Summarily, key observations included (1) a copper(I) carboxylate was not required under the one-pot reaction conditions, (2) the acyclic product 5a might have been formed first and sequentially gave the Michael addition product 4a. With the optimized conditions in hand, we examined the scope and limitations of this new domino cyclization process with respect to various DHPMs (1), terminal alkynes (3), acrylic acid (2a) and Cu2O catalyzed by Pd(OAc)2 and DPE-Phos (Scheme 2). In general, good yields were obtained under the standard reaction conditions. Both electron-rich methoxy- and diethylaminophenyl-substituted DHPMs and electron-poor fluoro-, chloro-, bromo-, and even nitrophenyl-substituted DHPMs underwent the domino reactions to deliver the products 4a–4m in moderate to good yields. Meanwhile, aryl alkynes gave exceptional selectivity for products 4a–4m with only trace acyclic products detected. A bit disappointingly, when alkyl alkynes were exposed in this transformation, the desired products 4n–4p were only achieved in lower yields (61%, 31%, 19%) with the acyclic products 5n, 5o, and 5p in 8%, 21%, and 7% yield, respectively. The related structure of compound 4b was confirmed based on X-ray crystallographic analysis.12 The process proved to be broad in scope, tolerating a variety of steric and electronic changes to both DHPMs and terminal alkyne reaction partners.
13556 | Chem. Commun., 2014, 50, 13555--13558
Scope of the DHPMs and alkyne partners.
To demonstrate the generality of this optimized protocol, we tested the a- and/or b-substituted acrylic acids as mediators and acylation reagents. Gratifyingly, the reaction of 4-Cl-, 4-Br-, 4-F-, or 2-Cl-substituted phenyl DHPM 1 with a-methylacrylic acid gave desired annulated products 4q–4u in impressive yields (Scheme 2). In contrast to a-methylacrylic acid, b-methyl-, or phenylacrylic acids are detrimental to the cyclization reaction, instead forming the acyclic products 5v–5y as the sole products (Table 2). From a mechanistic point of view, the annulation is postulated as a Michael additional process. Both the poor electrophilicity and steric hindrance of either a b-methyl or a phenyl group on the acrylic acid reduced its reactivity as a Michael receptor. In this case, the acyclic products 5v–5y would be converted into the cyclic products via a base-catalyzed intramolecular Michael addition. To our delight, treatment of compound 5v with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) at RT for 6 h led successfully to the desired cyclic product 4v in 98% yield (Table 2, entry 1). Under similar reaction conditions, 5w–y were transformed into the cyclic forms 4w–y in excellent yields of 95–98% (entries 2–4). We additionally tried to form the cyclic product in a one-pot process by adding DBU into the reaction system of 1a, b-methyl acrylic acid and 3a; however, this was unsuccessful and did not form the desired product (neither 5 nor 4 formed). On account of the mechanism studies in terms of Liebeskind– Srogl coupling,3,4 isotope-labelling experiments were conducted to gain insight into the mechanism pertaining to the key-steps in the domino process, hydration and annulation reactions. Initially, we prepared the 1,3-dideuterio-DHPM and studied the domino reaction with acrylic acid 2a and phenylacetylene 3a in the presence of Cu2O. The reaction led to formation of a-CD with deuterium located on the a-CH in the acyclic product and pyrido-ring, respectively (see the ESI† for details). On the other hand, 18O-labelling experiments were
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Table 2
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Two-step process for the synthesis of pyrido[1,2-a]pyrimidinesa
Entry
Ar
R1
R2
5/yieldb/%
4/yieldc/%
1 2 3 4
Ph Ph Ph 4-MeOC6H4
Me Me Ph Ph
Me H H H
5v/86 5w/88 5x/69 5y/58
4v/98 4w/98 4x/96 4y/95
Scheme 4
Aliphatic acids as C–N coupling partners.
a
Conditions: 1 (0.25 mmol), 2 (0.375 mmol), 3a (0.375 mmol), Cu2O (0.375 mmol), dioxane (2 mL). b Isolated yield based on the DHPM. c Isolated yield based on 5. See ESI for experimental details.
also carried out to trace the oxygen atom that added to the triple bond during the hydration. The reaction between 1a, benzoic acid and 3a was performed in the presence of 18OH2 giving 18O-labeled CQO bond in the product. Meanwhile low yield of the product was observed compared to our previous study (see the ESI† for details).10a Based on these observations, the following possible mechanism is proposed (Scheme 3): the desulfurative cross-coupling step is related to the traditional Liebeskind–Srogl protocols leading to the C–C coupling product (B).3,4 Then B may undergo acylation, likely mediated by the coordination of B to the copper salt A, followed by hydration with water to deliver the acyclic product 5.10a,14 Finally, the acyclic product may subsequently undergo intramolecular Michael addition, cyclization and isomerization to produce the desired product 4. Finally, in light of the importance of the amide bond in numerous industrially important compounds, as well as a wide selection of bioactive natural products,13 aliphatic carboxylic acids were used as acylation partners (Scheme 4). When acetic acid, hexanoic acid, and 3-methylbutanoic acid were used, the coupling–hydration–acylation with DHPMs 1 and alkynes 3 in the presence of Cu2O proceeded smoothly to give the expected acyclic products 7a–h. A more sterically hindered 2,4,6triisopropylbenzoic acid successfully afforded product 7h with a yield of up to 84%. Those results showed this approach to be an efficient coupling–hydration and acylation with favorable compatibility. In conclusion, we have developed a domino process between DHPMs, alkynes, acrylic acids and Cu2O under modified Liebeskind–Srogl coupling conditions. This one-pot protocol
Scheme 3
Possible mechanism.
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led to the poly-substituted pyrido[1,2-a]pyrimidines through a sequential coupling–hydration–acylation and Michael addition cyclization. Moreover, this method of directly using acid–Cu2O mixtures rather than Cu(I) carboxylate may be applied for Liebeskind–Srogl type couplings.15 Financial support was provided by the financial support from the NSFC (No. 21362032, and 21362031), the NSF of Gansu Province (No. 1208RJYA083), and the STIE of NWNU (No. nwnu-kjcxgc-03-64).
Notes and references 1 For recent reviews, see: (a) J. Zhou, Chem. – Asian J., 2010, 5, 422; (b) L. M. Ambrosini and T. H. Lambert, ChemCatChem, 2010, 2, 1373; (c) M. Rueping, R. M. Koenigs and I. Atodiresei, Chem. – Eur. J., 2010, 16, 9350; (d) C. Zhong and X. Shi, Eur. J. Org. Chem., 2010, 2999; (e) J. E. Biggs-Houck, A. Younai and J. T. Shaw, Curr. Opin. Chem. Biol., 2010, 14, 371; ( f ) H. Pellissier, Tetrahedron, 2013, 69, 7171; (g) H. Pellissier, Chem. Rev., 2013, 113, 442; (h) A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633; (i) N. T. Patil, V. S. Shinde and B. Gajula, Org. Biomol. Chem., 2012, 10, 211; ( j) H. Clavier and H. Pellissier, Adv. Synth. Catal., 2012, 354, 3347; (k) C. De Graaff, E. Ruijter and R. V. A. Orru, Chem. Soc. Rev., 2012, 41, 3969; (l) H. Pellissier, Adv. Synth. Catal., 2012, 354, 237; (m) Z. Zhang and J. C. Antilla, Angew. Chem., Int. Ed., 2012, 51, 117782; (n) S. Piovesana, D. M. Scarpino Schietroma and M. Bella, Angew. Chem., Int. Ed., 2011, 50, 6216; (o) L. Albrecht, H. Jiang and K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492; (p) M. Ruiz, P. Lopez-Alvarado, G. Giorgi and J. C. Menendez, Chem. Soc. Rev., 2011, 40, 3445; (q) C. Vaxelaire, P. Winter and M. Christmann, Angew. Chem., Int. Ed., 2011, 50, 3605. 2 For examples of Liebeskind–Srogl reactions, see: (a) L. S. Liebeskind and J. Srogl, J. Am. Chem. Soc., 2000, 122, 11260; (b) C. Savarin, J. Srogl and L. S. Liebeskind, Org. Lett., 2001, 3, 91; (c) Y. Yu and L. S. Liebeskind, J. Org. Chem., 2004, 69, 3554; (d) H. Yang, H. Li, R. Wittenberg, M. Egi, W. Huang and L. S. Liebeskind, J. Am. Chem. Soc., 2007, 129, 1132; (e) L. S. Liebeskind and J. Srogl, Org. Lett., 2002, 4, 979; ( f ) C. L. Kusturin, L. S. Liebeskind and W. L. Neumann, Org. Lett., 2002, 4, 983; (g) C. Kusturin, L. S. Liebeskind, H. Rahman, K. Sample, B. Schweitzer, J. Srogl and W. L. Neumann, Org. Lett., 2003, 5, 4349; (h) L. S. Liebeskind, H. Yang and H. Li, Angew. Chem., Int. Ed., 2009, 48, 1417; (i) Z. Zhang, M. G. Lindale and L. S. Liebeskind, J. Am. Chem. Soc., 2011, 133, 6403; ( j) H. Li, A. He, J. R. Falck and L. S. Liebeskind, Org. Lett., 2011, 13, 3682; (k) K. M. Lovell, T. Vasiljevik, J. J. Araya, A. Lozama, K. M. Prevatt-Smith, V. W. Day, C. M. Dersch, R. B. Rothman, E. R. Butelman, M. J. Kreek and T. E. Prisinzano, Bioorg. Med. Chem., 2012, 20, 3100; (l) G. Bouscary-Desforges, A. Bombrun, J. K. Augustine, G. Bernardinelli and A. Quattropani, J. Org. Chem., 2012, 77, 4586; (m) S. Dahbi and P. Bisseret, Eur. J. Org. Chem., 2012, 3579; (n) M. Cernova, R. Pohl, B. Klepetarova and M. Hocek, Synlett, 2012, 1305; (o) G. Bouscary-Desforges, A. Bombrun, J. K. Augustine, G. Bernardinelli and A. Quattropani, J. Org. Chem., 2012, 77, 243. ´ 3 (a) A. Lengar and C. O. Kappe, Org. Lett., 2004, 6, 771; (b) H. Prokopcova and C. O. Kappe, Adv. Synth. Catal., 2007, 349, 448; (c) C. O. Kappe, J. Org. Chem., 2007, 72, 4440. ¨t, A. P. Rauter and 4 (a) S. Silva, B. Sylla, F. Suzenet, A. Tatiboue P. Rollin, Org. Lett., 2008, 10, 853; (b) V. P. Mehta, A. Sharma and
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10
E. Van der Eycken, Org. Lett., 2008, 10, 1147; (c) X. Guinchard and E. Roulland, Org. Lett., 2009, 11, 4700. J. M. Villalobos, J. Srogl and L. S. Liebeskind, J. Am. Chem. Soc., 2007, 129, 15734. ´ and C. O. Kappe, Angew. Chem., Int. Ed., 2008, (a) H. Prokopcova ´ and C. O. Kappe, Angew. Chem., Int. Ed., 47, 3674; (b) H. Prokopcova 2009, 48, 2276. (a) A. Henke and J. Srogl, Chem. Commun., 2011, 47, 4282; (b) Y. Dong, M. Wang, J. Liu, W. Ma and Q. Liu, Chem. Commun., 2011, 47, 73802. (a) A. C. Wotal and D. J. Weix, Org. Lett., 2012, 14, 1476; (b) C. I. Someya, M. Weidauer and S. Enthaler, Catal. Lett., 2013, 143, 424. For reviews on the DHPMs, see: (a) C. O. Kappe, Tetrahedron, 1993, 49, 6937; (b) C. O. Kappe, Acc. Chem. Res., 2000, 33, 879; (c) C. O. Kappe and A. Stadler, Org. React., 2004, 63, 1; (d) D. Dallinger, A. Stadler and C. O. Kappe, Pure Appl. Chem., 2004, 76, 1017; (e) L. Z. Gong, X. H. Chen and X. Y. Xu, Chem. – Eur. J., 2007, 13, 8920; ( f ) M. A. Kolosov and V. D. Orlov, Mol. Diversity, 2009, 13, 5; ( g) Z.-J. Quan, Z. Zhang, Y.-X. Da and X.-C. Wang, Chin. J. Org. Chem., 2009, 29, 876; (h) C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 10432. Our previous work on the DHPM derivatives: (a) Z.-J. Quan, W.-H. Hu, X.-D. Jia, Z. Zhang, Y.-X. Da and X.-C. Wang, Adv. Synth. Catal., 2012, 354, 2939; (b) Z.-J. Quan, Y. Lv, Z.-J. Wang, Z. Zhang, Y.-X. Da and X.-C. Wang, Tetrahedron Lett., 2013, 54, 1884; (c) Z.-J. Quan, W.-H. Hu, Z. Zhang, X.-D. Jia, Y.-X. Da and X.-C. Wang, Adv. Synth. Catal., 2013, 355, 891; (d) Z.-J. Quan, Y. Lv, F.-Q. Jing, X.-D. Jia, C.-D. Huo and X.-C. Wang, Adv. Synth. Catal., 2014, 356, 325.
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ChemComm 11 For examples of pyrido[1,2-a]pyrimidines, see: (a) G. C. B. Harriman, S. Chi, M. Zhang, A. Crowe, R. A. Bennett and I. Parsons, Tetrahedron Lett., 2003, 44, 3659; (b) R. L. Smith, R. J. Barette and E. Sanders-Bush, J. Pharmacol. Exp. Ther., 1995, 275, 1050; (c) F. Awouters, J. Vermeire, F. Smeyers, P. Vermote, R. Van Beek and C. J. E. Niemegeers, Drug Dev. Res., 1986, 8, 95; (d) Y. Yanagihara, H. Kasai, T. Kawashima and T. Shida, Jpn. J. Pharmacol., 1988, 48, 91. 12 CCDC 942987 for 4b. 13 For recent reviews about amide bond formations, see: (a) V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480, 471; (b) C. L. Allen and J. M. J. Williams, Chem. Soc. Rev., 2011, 40, 3405; (c) R. M. Lanigan and T. D. Sheppard, Eur. J. Org. Chem., 2013, 7453. 14 The alternative pathway involves an ester intermediate D. The addition of acid into the C–C triple bond of C–C coupling product B generates an ester intermediate D, followed by O to N transacylation leading to the N-acylated products. The ester intermediates were unable to be isolated, though a similar conjugate addition of acid into the C–C ¨thig and triple bond of alkynes was reported, see: O. V. Maltsev, A. Po L. Hintermann, Org. Lett., 2014, 16, 1282.
15 The reaction between 1a and phenylboronic acid in the presence of thiophenecarboxylic acid and Cu2O under the catalytic conditions has been evaluated and the desulfurative coupling product 83 was obtained in 72% yield (see the ESI† for details).
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