A general A³: coupling reaction based on functionalized alkynes

hydroxypropargylamine; multicomponent reaction; A³-coupling

ARTIGO

A general A³-coupling reaction based on functionalized alkynes

Edison P. Wendler; Alcindo A. Dos Santos^*

Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, CP 26077, 05599-970 São Paulo - SP, Brasil

ABSTRACT

A range of hydroxypropargylpiperidones were efficiently obtained by a one-pot three-component coupling reaction of aldehydes, alkynols, and a primary amine equivalent (4-piperidone hydrochloride hydrate) in ethyl acetate using copper(I) chloride as a catalyst. The developed protocol proved to be equally efficient using a range of aliphatic aldehydes, including paraformaldehyde, and using protected and unprotected alkynols.

Keywords: hydroxypropargylamine; multicomponent reaction; A³-coupling.

INTRODUCTION

Connecting organic fragments that have desired functionalities by short and inexpensive synthetic routes is one of the most exciting and challenging tasks for organic chemists, and it requires a high level of creativity and elegance.

Recently, multicomponent reactions have been receiving significant attention, because multiple carbon-carbon and carbon- heteroatom bonds can be generated in a single step, allowing for the straightforward construction of intricate organic compounds. Recent developments in this area have been very impressive, and procedures involving seven¹ and even eight² components have been reported.

The three-component coupling of aldehydes, amines, and alkynes (A³-coupling) is a very efficient method for forming propargylamines by C-H activation.³ A³-coupling is more practical than the other methods available for preparing this class of compounds, because no moisture-sensitive stoichiometric organometallics, such as Grignard or organolithium reagents, are involved. It is also applicable to various substrates. This transformation can be catalyzed by a large number of transition-metal salts, including copper,⁴ iron,⁵ cobalt,⁶ nickel,⁷ zinc,⁸ ruthenium,⁹ silver,¹⁰ cadmium,¹¹ indium,¹² ytterbium,¹³ iridium,¹⁴ gold,¹⁵ mercury,¹⁶ bimetallic salt combinations,¹⁷ supported metals,¹⁸ andnanostructured materials.¹⁹ It is interesting to note that, although the use of various amines and aldehydes in this method has been described, the number of alkynes used has been limited. Non-functionalized alkynes, such as phenylacetylene and trimethylsilylacetylene, have been used most frequently, but the A³-coupling of alkynols, to prepare functionalized allenols, has recently been described.²⁰

In 2006, Gommermann and Knochel described the use of an A³-coupling silylated adduct in the asymmetric synthesis of (S)-(+)coniine.²¹ We know of only a few examples of unprotected alkynols being used in the A³-coupling reaction, and all of them, except for ones we have previously reported,²² have been limited to aromatic aldehydes.^23,24 A general procedure for the preparation of hydroxypropargylamines would be very desirable because these chemicals are direct precursors for alkaloids. The desired carbon skeleton could be achieved in a one-pot process using an A³-coupling-type protocol and using the correct functionalities for cyclization to form five- and six- (and higher) ring alkaloid systems.

In 2006, Carreira reported using 4-piperidone hydrochloride hydrate as a secondary amine source in an A³-coupling reaction.²⁵ The authors demonstrated that using this amine source allowed the A³-coupling adducts (tertiary amines) to be easily converted into the corresponding primary amines, in good yields, by their reaction with an amino-polystyrene resin scavenger or with a saturated ammonia-ethanolic solution. This procedure is highly compatible with chemicals containing a triple bond, and in the presence of a xypropargylamine, which can be converted into the corresponding hydroxyallylamine or the fully saturated amino alcohol, which are valuable building blocks.

Here we present a general protocol, which is complementary to the methodologies described above, for preparing hydroxypropargylamines using catalytic amounts of CuCl to promote A³-coupling by C-H activation among aliphatic aldehydes, 4-piperidone, protected and unprotected alkynols, and non-functionalized alkynes.

RESULTS AND DISCUSSION

To test the feasibility of using alkynols in the A³-coupling reaction, we screened a range of solvents, temperatures, and potential metal catalysts in the reaction of butyraldehyde (1a), 4-piperidone hydrochloride hydrate (2), and homopropargyl alcohol (3a) using 4 Å molecular sieves as a dehydrating agent (Table 1).

The A³-coupling of 1a,2, and 3a was tested using a number of ne (Table 1, entries 2 and 3, respectively) gave comparable results to ethyl acetate (entry 10), and the latter was chosen for further study because it is more environmentally benign than the other solvents. We are aware of only two reports of ethyl acetate being used as the solvent for such a reaction, but only one substrate was described in each case.^26,27 The reaction was completed in lesser time at 70 ºC (entry 12) than at the other temperatures tested, and adduct 4a was isolated in 71% yield. When the same reaction was performed at 50 or 100 mmol scales, adduct 4a was isolated in slightly better yields (75 or 80%, respectively, entry 12). Using more CuCl did not significantly improve the yield of adduct 4a (entries 17-20), but using less catalyst caused the yield to be significantly lower under the same reaction conditions (entries 13-16). Other catalysts that have previously been used in A³-coupling reactions were also tested using our optimized conditions, but only CuBr (entry 21) talyst in further work, rather than CuBr, for economic reasons.²⁸ We reacted homopropargyl compounds 3b-e under the same condition as reported for entry 12 (3 mmol scale) to assess the influence of other functional groups on the alkyne. These substrates tolerated the reaction conditions well, allowing the corresponding adducts 4b-e to be isolated in good yields, free of exogenous byproducts (Scheme 1).

Based on these results, we applied the conditions to the reactions of other alkynols (3f-o) with 1a, and the results are summarized in Table 2.

From Table 2, it can be seen that the A³-coupling reactions using alkynols and aliphatic aldehydes gave better results than the reactions using non-functionalized alkynes (compare entries 1-7 with 8-10). Other aldehydes (1b-h) were reacted with 4-pentyn-2-ol (3f) (Table 3) to assess the scope and limitations of the protocol.

It is worth noting that adduct 4p was isolated in reasonable yield (59%) from the reaction using the equivalent of formaldehyde (paraformaldehyde, 1b) (Table 3, entry 1). Even volatile aldehydes, such as n-propanaldehyde (1c) and isobutyraldehyde (1d), were successfully converted into the corresponding A³-coupling adducts in good yields (entries 2 and 3, respectively). The yields were equally good when medium-chain 1f and long-chain 1g aldehydes were used (entries 5 and 6, respectively). Aromatic aldehydes did not give the corresponding adducts in acceptable yields, but the benzylic aldehyde 1h gave the desired adduct 4v in good yield (entry 7).

In general, aliphatic and cyclic primary, secondary, and tertiary alkynols gave the desired A³-coupling adducts in good yields without the detection of any dehydration products or other byproducts (see Tables 1-3).

As described by Carreira et al.,²⁵ 4-piperidones can be converted into the corresponding primary propargylamines by refluxing in an NH₄sence of an amine-polystyrene resin in an NH₄Cl/ethanolic solution. Using this approach, hydroxypropargyl-4-piperidones produced in our study were eventually converted into the corresponding amino alcohols.

To the best of our knowledge, there has been only one report of the synthesis of a piperidine alkaloid, (S)-(+)-coniine, from an A³-coupling adduct.²¹ The three-component reaction strategy using trimethylsilylacetylene as the alkyne component was used to produce that chemical; hence, a -CH₂CH₂OH unit had to be introduced by the methylene oxide alkylation reaction after deprotonation using n-BuLi. The strategy we have demonstrated here, i.e., using alkynols as the alkyne component, is complementary to the approach employed by Gommermann and Knochel, because no additional chain homologation is required to prepare the amino-alcohol skeleton needed for preparing cyclic alkaloids.

A tentative mechanism for the A³-coupling reaction is presented in Scheme 2, and it agrees with mechanisms proposed by other authors.²⁹

As is already known, the amines present in the reaction media are weak bases and are not sufficiently strong to deprotonate a terminal alkyne without other stimuli.³⁰ We speculate that a π-copper-alkyne ne, which would be able to be removed by a weak base, such as an amine. The iminium chloride would be concurrently produced from the aldehyde and amine. The addition of the resulting acetylide to the iminium salt would result in the formation of propargylamine, regenerating the copper ion for another cycle.

CONCLUSIONS

We have demonstrated, for the first time, a general and selective CuCl-catalyzed A3-coupling reaction for preparing hydroxypropargyl- 4-piperidones, which are valuable precursors for cyclic alkaloids. The procedure gives good yields and has short reaction times, and hydroxypropargylamines can be prepared using functionalized alkyne sources (free alcohols, silyl ethers, ethers, ketals, and tosylates). Even volatile aliphatic aldehydes were well tolerated in the procedure, and the corresponding adducts were isolated in good yields.

EXPERIMENTAL

All reagents were purchased from Aldrich. Thin layer chromatography (TLC) was performed using silica gel 60 F₂₅₄ precoated plates, and the chemicals were made visible using vanillin as a coloring reagent (using 1.0 g vanillin in a 99:1 CH₃CO₂H / H₂SO₄ solution). Gas chromatography (GC) was performed using a Shimadzu^® GC2014 instrument equipped with a DB-5 column (30 m length, 0.25 mm id, 0.25 µm film) and a flame ionization detector (FID). All new compounds were characterized by NMR, IR, EI-MS, and ESI-HRMS spectroscopy. The ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a Bruker^® DRX 400 spectrometer using tetramethylsilane (TMS) as the internal standard. Chemical shifts are reported in parts per million (ppm, δ) downfield of TMS. The IR spectra were recorded using a Bomen Hartmann & Braun^® MB-Series Model Arid-Zone^® instrument. Low-resolution mass spectra were recorded using a Shimadzu^® QP 5000 mass spectrometer after gas chromatographic separation using an HP-5MS GC column (30 m length, 0.25 mm id, 0.25 µm film). High-resolution mass spectra were recorded using a Bruker^® Daltonics MicroTOF Ic LC/MS instrument from direct injections of the pure samples.

General procedure for the synthesis of hydroxypropargylamine derivatives

CuCl (0.009 g, 0.1 mmol), 4 Å molecular sieves (0.300 g), 4-piperidone hydrochloride monohydrate (0.169 g, 1.1 mmol), and EtOAc (2 mL) were added, in that order, to a 10-mL round-bottomed flask. The mixture was stirred at 70 ºC and then triethylamine (0.110 g, 0.15 mL, 1.1 mmol), alkynol (2.0 mmol), and the appropriate freshly distilled aldehyde (1.0 mmol) were added. The reaction mixture was stirred, and the progress of the reaction was monitored by GC-FID or TLC. The reaction mixture was passed through a short pad of Celite^® in a column and eluted with EtOAc (3 × 5 mL). A saturated NH₄Cl solution (10 mL) was added to the organic phase, and the mixture was stirred vigorously for 20 min, separated, and the organic phase was treated with HCl (15 mL, 10% v/v) in a separatory funnel. The coupling products, neutralized with a saturated NaHCO₃ solution (3 × 10 mL) and extracted again with EtOAc (4 × 10 mL). The organic phases were combined, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography using the appropriate eluent.

SUPPLEMENTARY MATERIAL

The ¹H NMR, ¹³C NMR, IR, EI-MS, and EI-HRMS spectra, and the corresponding spectral data, for all of the newly synthesized compounds are available as supplementary material.

ACKNOWLEDGMENTS

The authors thank the São Paulo Research Foundation (FAPESP no. 2011/11613-8, 2011/17228-6 and 05/59572-7), Coordination for the Improvement of Higher Education Personnel (CAPES no. 23038.000497/2010-14), and the Brazilian National Council for Scientific and Technological Development (CNPq no. 57.5417/20080) for financial support. The authors are also grateful for the financial and structural support offered by the University of São Paulo through the NAP-CatSinQ (Research Core in Catalysis and Chemical Synthesis). The authors also thank Prof. Dr. P. H. C. Camargo for revising this manuscript. E. P. Wendler is grateful to CAPES for scholarship funding and the Federal University of São Carlos for providing access to their facilities.

REFERENCES

1. Dömling, A.; Ugi, I.; Angew. Chem. Int. Ed. 1993,32,563; Dömling, A.; Herdtweck, E.; Ugi, I.; Acta Chem. Scand. 1998,52,107; Brauch, S.; Gabriel, L.; Westermann, B.; Chem. Commun. 2010,46,3387.

2. Elders, N.; Van der Born, D.; Hendrickx, L. J. D.; Timmer, B. J. J.; Krause, A.; Janssen, E.; de Kanter, F. J. J.; Ruijter, E.; Orru, R. V. A.; Angew. Chem. Int. Ed. 2009,48,5856.

3. (Authors available only in japanese); Jpn. Kokai Koho Patent JP 58069845 A, 1983; Youngman, M. A.; Dax, S. L.; Tetrahedron Lett. 1997,38,6347.

4. For recently described three-component copper catalyzed reactions, see: Zhang, Q.; Chen, J-X.; Gao, W-X.; Ding, J-C.; Wu, H-Y.; Appl. Organometal. Chem. 2010,24,809; Peshkov, V. A.; Pereshivko, O. P.; Donets, P. A.; Mehta, V. P.; Van der Eycken, E. V.; Eur. J. Org. Chem. 2010, 4861; Bariwal, J. B.; Ermolat'ev, D. S.; Glasnov, T. N.; Van Hecke, K.; Mehta, V. P.; Van Meervelt, L.; Kappe, C. O.; Van der Eycken, E. V.; Org. Lett. 2010,12,2774; Li, P.; Pereshivko, O. P.; Peshkov, V. A.; Van der Eycken, E. V.; Org. Lett. 2010,12,2638; Nandakumar, A.; Muralidharan, D.; Perumal, P. T.; Tetrahedron Lett. 2011,52,1644; Luz, I.; Llabrés i Xamena, F. X.; Corma, A.; J. Catal. 2012,285,285.

5. Chen, W-W.; Nguyen, R. V.; Li, C-J.; Tetrahedron Lett. 2009,50,2895; Patil, S. S.; Patil, S. V.; Bobade, V. D.; Synlett 2011,2379.

6. Chen, W-W.; Bi, H-P.; Li, C-J.; Synlett 2010,475.

7. Namitharan, K.; Pitchumani, K.; Eur. J. Org. Chem. 2010,411; Samai, S.; Nandi, G. C.; Singh, M. S.; Tetrahedron Lett. 2010,51,5555.

8. Kantan, M. L.; Balasubrahmanyam, V.; Shiva Kumar, K. B.; Venkanna, G. T.; Tetrahedron Lett. 2007,48,7332.

9. Sinha, P.; Raghuvanshi, D. S.; Singh, K. N.; Mishra, L.; Polyhedron 2012,31,227.

10. Reddy, K. M.; Babu, N. S.; Suryanarayana, I.; Prasad, P. S. S.; Lingaiah N.; Tetrahedron Lett. 2006,47,7563; Huang, B.; Yao, X.; Li, C-J.; Adv. Synth. Catal. 2006,348,1528; He, T.; Zha, Z.; Pan, C.; Wang, Z.; Synth. Comm. 2007,37,849; Li, Z.; Wei, C.; Chen, L.; Varma, R. S.; Li, C-J.; Tetrahedron Lett. 2004,45,2443.

11. Raghuvanshi, D. S.; Singh, K. N.; Synlett 2011,373.

12. Zhang, Y.; Li, P.; Wang, M.; Wang, L.; J. Org. Chem. 2009,74,4364.

13. Kumar, A.; Rao, V. K.; Synlett 2011,2157.

14. Fischer, C.; Carreira, E. M.; Org. Lett. 2001,3,4319; Sakagushi, S.; Kubo, T.; Ishii, Y.; Angew. Chem. Int. Ed. 2001,40,2534.

15. Lo, V.; K-Y.; Liu, Y.; Wong, M-K.; Che, C-M.; Org. Lett. 2006,8,1529; Wei, C.; Li, C-J.; J. Am. Chem. Soc. 2003,125,9584; Abahmane, L.; Köhler, J. M.; Grob, G. A.; Chem. Eur. J. 2011,17,3005; Kung, K. K-Y.; Li, G-L.; Zou, L.; Chong, H-C.; Leung, Y-C.; Wong, K-H.; Lo, V. K-Y.; Che, C-M.; Wong, M-K.; Org. Biomol. Chem. 2012,10,925.

16. Li, P-H.; Wang, L.; Chin. J. Chem. 2005,23,1076.

17. Chernyak, N.; Gevorgyan, V.; Angew. Chem. Int. Ed. 2010,49,2743; Chernyak, D.; Chernyak, N.; Gevorgyan, V.; Adv. Synth. Catal. 2010,352,961; Aliaga, M. J.; Ramón, D. J.; Yus, M.; Org. Biomol. Chem. 2010,8,43; Zhang, K.; Huang, Y.; Chen, R.; Tetrahedron Lett. 2010,51,5463; Li, C-J.; Wei, C.; Chem. Commun. 2002,268.

18. Wang, M.; Li, P.; Wang, L.; Eur. J. Org. Chem. 2008, 2255; Fodor, A.; Kiss, A.; Debreczeni, N.; Hell, Z.; Gresits, I.; Org. Biomol. Chem. 2010,8,4575; Li, P.; Wang, L.; Zhang, Y.; Wang, M.; Tetrahedron Lett. 2008,49,6650; Sreedhar, B.; Reddy, P. S.; Krishna, C. S. V.; Babu, P. V.; Tetrahedron Lett. 2007,48,7882; Patil, M. K.; Keller, M.; Reddy, B. M.; Pale, P.; Sommer, J.; Eur. J. Org. Chem. 2008, 4440; Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Sreedhar, B.; Tetrahedron Lett. 2004,45,7319; Yong, G-P.; Tian, D.; Tong, H-W.; Liu, S-M.; J. Mol. Catal. A-Chem. 2010,323,40; Li, Y.; Chen, X.; Song, Y.; Fang, L.; Zou, G.; Dalton Trans. 2011,40,2046; Maggi, R.; Bello, A.; Oro, C.; Sartori, G.; Soldi, L.; Tetrahedron 2008,64,1435.

19. Kidwai, M.; Banasal, V.; Kumar, A.; Mozumdar, S.; Green Chem. 2007,9,742; Li, P.; Wang. L.; Tetrahedron 2007,63,5455; Kantam, M. L.; Yadav, J.; Laha, S.; Jha, S.; Synlett 2009, 1791; Bhatte, K. D.; Sawant, D. N.; Deshmukh, K. M.; Bhanage, B. M.; Catal. Commun. 2011,16,114; Kidwai, M.; Bansal, V.; Mishra, N. K.; Kumar, A.; Mozumdar, S.; Synlett 2007, 1581; Layek, K.; Chakravarti, R.; Kantam, M. L.; Maheswaran, H.; Vinu, A.; Green Chem. 2011,13,2878; Sreedhar, B.; Kumar, A. S.; Reddy, P. S.; Tetrahedron Lett. 2010,51,1891.

20. Kuang, J.; Luo, H.; Ma, S.; Adv. Synth. Catal. 2012,354,933; Ye, J.; Li, S.; Chen, B.; Fan, W.; Kuang, J.; Liu, J.; Liu, Y.; Miao, B.; Wan, B.; Wang, B.; Xie, X.; Yu, Q.; Yuan, W.; Ma, S.; Org. Lett. 2012,14,1346.

21. Gommermann, N.; Knochel, P.; Chem. Eur. J. 2006,12,4380.

22. Melgar, G. Z.; Wendler, E. P.; Dos Santos, A. A.; Porto, A. L. M.; Tetrahedron Asymm. 2010,21,2271.

23. Wei, C.; Mague, J. T.; Li, C-J.; Proc. Natl. Acad. Sci. USA 2004,101,5749; Yadav, J. S.; Reddy, B. V. S.; Naveenkumar, V.; Rao, R. S.; Nagaiah, K.; New J. Chem. 2004,28,335; Shi, L.; Tu, Y-Q.; Wang, M.; Zhang, F-M.; Fan, C-A.; Org. Lett. 2004,6,1001.

24. Ramu, E.; Varala, R.; Sreelatha, N.; Adapa, S. R.; Tetrahedron Lett. 2007,48,7184.

25. Aschwanden, P.; Stephenson, R. J.; Carreira, E. M.; Org. Lett. 2006,8,2437; Carreira, E. M.; WIPO Patent WO 2005121157 A1, 2005.

26. Bisai, A.; Singh, V. K.; Org. Lett. 2006,8,2405.

27. Zeng, T.; Chen, W-W.; Cirtiu, C. M.; Moores, A.; Song, G.; Li, C-J.; Green Chem. 2010,12,570.

28. Prices from Sigma-Aldrich Catalog 2009-2010: CuCl (97%) = 0.06 US$/g; CuBr (98%) = 0.25 US$/g.

29. Bariwal, J. B.; Ermolat'ev, D. S.; Van der Eycken, E. V.; Chem. Eur. J. 2010,16,3281; Feng, H.; Ermolat'ev, D. S.; Song, G.; Van der Eycken, E. V.; Org. Lett. 2012,14,1942.

30. Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V.; Chem. Soc. Rev. 2012,41,3790.

Recebido em 15/1/13; aceito em 16/4/13; publicado na web em 17/7/13

Supplementary Information

The supplementary material is available in pdf: [Supplementary material]

Datas de Publicação

• Publicação nesta coleção
  04 Out 2013
• Data do Fascículo
  2013

Histórico

• Recebido
  15 Jan 2013
• Aceito
  16 Abr 2013