- Email: [email protected]
Spontaneous and diastereoselective aldol reactions of cyclic β-amino ketones in the presence of water
Tetrahedron Letters 52 (2011) 5680–5683
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Spontaneous and diastereoselective aldol reactions of cyclic b-amino ketones in the presence of water Ryszard Lazny ⇑, Aneta Nodzewska, Iwona Tomczuk Institute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-399 Bialystok, Poland
a r t i c l e
i n f o
Article history: Received 21 April 2011 Revised 9 August 2011 Accepted 19 August 2011 Available online 26 August 2011 Keywords: Aldol reaction Reaction in water Tropinone Granatanone
a b s t r a c t Direct aldol reactions of 4-methyl-1-piperidone, tropinone and granatanone (pseudopelletierine) take place spontaneously in the presence of water without any catalyst or additional reagents. The anti/syndiastereoselectivity of the aqueous aldol reaction depends on the amount of water used. The synselectivity of the reaction is probably due to the thermodynamic control. Excellent atom economy and low E factors together with anti-selectivity as high as 98:2 for the tropinone aldol were obtained. Ó 2011 Elsevier Ltd. All rights reserved.
The aldol reaction, owing to its ability to install two adjacent stereocenters, is a powerful C–C bond forming transformation.1 In recent years, organocatalyzed aldol reactions have been studied intensively.2,3 Newer methods for direct aldol reactions typically utilize activated reagents and/or catalysts.1 The catalysts used include Lewis acids, Lewis bases, and metal complexes.4 The enamine-catalyzed aldol reaction often uses secondary amine catalysts, most prominently those derived from proline, and to a lesser extent, primary amines, amino acids, etc.5 Non-enamine organocatalysis is less common, and typically uses anhydrous or neat conditions. Examples include the use of cinchona alkaloid derivatives,6 DBU, and DIPEA7 as catalysts. To the best of our knowledge, the only reported aldol reaction in water, catalyzed by a tertiary amine (pyridine) was the addition of dihydroxyacetone to glyceraldehyde (a general base-catalyzed process).8,9 Performing the aldol reaction in aqueous media may offer several advantages such as reduction of waste, simpler procedures, reduction of cost, and high selectivity.10 A base-catalyzed (Na2CO3) crossed-aldol reaction in water has been reported,11 as has a related aldol condensation giving enones via aqueous hydroxide catalysis12 and a DBU-water complex.13 Herein, we disclose our findings on the spontaneous, diastereoselective aldol reaction of heterocyclic b-aminoketones in the presence of water without a catalyst. During our research on organocatalytic reactions we found that the aldol reaction of tropinone with benzaldehyde occurred spontaneously in the presence of water, and under some conditions, was
diastereoselective and high yielding. Surprisingly, the reaction proceeds without catalysts or any additional reagents and can provide, depending on the conditions and time, the aldol diastereomer 1 or its previously unknown isomer 2, selectively (Scheme 1). So far, the only diastereomer characterized was exo,anti-1, accessible synthetically via deprotonation with LDA or similar bases under anhydrous conditions.14–16 Aldols of tropinone synthesized by deprotonation are important intermediates for the synthesis of biologically active tropane derivatives.17 Some of them were used by us,16,18 and others19 for the syntheses of several tropane alkaloids. Unexpectedly, under optimized conditions, the diastereoselective aldol reaction of tropinone took place in water or in the presence of small amounts of water. As is evident from Table 1, the diastereoselectivity depended on the amount of water added. Under relatively high dilution, excellent anti selectivity was obtained and the product could be isolated by filtration. Under optimal conditions (entry 8) the tropinone dissolved in water and reacted with benzaldyhyde ‘on-water’. As no additional reagents or catalysts are needed, this process is characterized by excellent
N
E-mail address: [email protected] (R. Lazny). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.08.107
PhCHO
H
OH
N
Ph +
O
H
OH Ph
N
water, rt Me tropinone
⇑ Corresponding author. Tel.: +48 85 745 7834; fax: +48 85 745 7589.
O
O
Me
exo, anti 1
Me
exo, syn 2
Scheme 1. Aldol reaction of tropinone and benzaldehyde in the presence of water.
5681
R. Lazny et al. / Tetrahedron Letters 52 (2011) 5680–5683 Table 1 Dependence of diastereoselectivity on the amount of water used for the reaction of tropinone (2 mmol) with benzaldehyde (1 mmol) Entry 1 2 3 4 5 6 7 8 9 10 11 a b c d e f g
Water (equiv) 0 0.45 0.89 4.4 7.1 29 66 139 139 278 555
Conversiona [%] (isolated yield [%])
Water (mL)
Ratio of 1:2b
c
0 0.0080 0.016 0.080 0.13 0.53 1.2 2.5 2.5 5.0 10.0
N.P.c 11:89 10:90 24:76 30:70 37:63 82:18 98:2 33:67 95:5 94:6
N.P. P53d P95d (yield 84e) P95 P95 P95 P95 P98 (yield 75f) P52g P95 P84
Conversion of aldol products was determined by 1H NMR spectroscopy. The ratio was determined by means of 1H NMR spectroscopy of the crude product. No product observed after 7 days. Reaction time: 3 days.23 Yield of product isolated by evaporation of volatiles and vacuum drying. Yield of product isolated by filtration. An excess of aldehyde was used: tropinone (1 mmol), benzaldehyde (2 mmol). The reaction gave several additional by-products.
atom economy and a very low Sheldon’s E factor (environmental impact measure).20–22 The anti isomer 1 was obtained from the dilute aqueous mixture and usually deposited from the mixture as a sticky solid. Interestingly, in some runs no solid product was obtained. In such cases virtually no syn:anti selectivity was observed. However, ‘seeding’ such reaction mixtures that showed high conversion (typically ca. 90%), with ca. 10 mg of pure anti isomer resulted unfailingly in deposition of a solid, virtually 95% pure (by NMR) anti isomer in ca. 75% yield. Conversion of saturated ca. 1:1 mixtures of syn and anti isomers into solid anti isomers by ‘seeding’ with the anti isomer and stirring suggests strongly that the anti selectivity results from isomer equilibration via a retroaldol reaction and preferential crystallization of the more stable crystalline anti form. The anti isomer has a noticeably higher melting point and is much easier to crystallize then the syn counterpart. The remaining aqueous filtrate can be recharged with substrates and used for preparing the next batch of the anti aldol. Reversing the ratio of reactants gave lower conversion and stereoselectivity (entry 9 vs 8). It has been pointed out by Blackmond et al. that the disposal of organics-contaminated water is often an expensive and underestimated issue.24 As the aqueous phase in the reaction of tropinone and benzaldehyde can be recycled easily, and does not have to be disposed of, this process may offer a green chemistry advantage.25,26 Under dry, neat conditions, the reaction was too slow to be quantified (Table 1, entry 1). Conversely, the addition of substoichiometric amounts of water allowed the reaction to proceed in a reasonable time frame (entries 2 and 3) favoring the exo,syn isomer 2. The optimal amount of water, ca. 0.89 mol equiv gave excellent conversion (95%) and very good syn selectivity (syn:anti ca. 90:10). Pure syn isomer was obtained by evaporation of the reaction mixture with toluene and vacuum drying, followed by trituration with hexane and slow crystallization from diethyl ether. We have tested this procedure on other cyclic ketones: granatanone (5) reacted with benzaldehyde under the same conditions. Using optimal amount of water (0.45 equiv, 0.0080 mL), the reaction reached 95% conversion in 7 days (anti:syn 11:89, with some by-products). Disappointingly, reaction under high dilution conditions (2.5 mL) gave poor conversion (52%) and poor anti selectivity (anti:syn 57:43). The analogous reactions of N-methyl-4-piperidone, regardless of the amount of water and ratio of substrates, were plagued by lack of diastereoselectivity (typically syn:anti 53:47), low conversions, and the formation of by-products (mostly hemiacetals of the formed aldols, analogous with observations on cyclohexanone derivatives27).
O
O
OH
4-nitrobenzaldehyde water, rt
N Me
NO 2
N Me
3
6
O
O
H
OH
4-nitrobenzaldehyde water, rt
N
Me (CH 2) n
N
Me (CH2 )n
4, n = 2: tropinone 5, n = 3: granatanone
NO 2
7, n = 2 8, n = 3
Scheme 2. Aldol reactions of cyclic b-amino ketones.
Table 2 Aldol reactions of b-amino ketones with 4-nitrobenzaldehyde in the presence of watera
a b c d e f
Entry
Product
Time
Water (mL)
Conversionb[%] (yield [%])
anti:sync
1 2 3 4 5 6 7 8 9 10 11 12
6 6 6 6 7 7 7 7 8 8 8 8
2h 20 h 2h 20 d 2h 20 h 2h 7d 2h 20 h 2h 3d
2.5 2.5 0.016 0.016 2.5 2.5 0.016 0.016 2.5 2.5 0.016 0.016
20 28 16 98 (88)d 85 98 (95)e N.P.f 98 (75)d 92 98 (93)e N.P.f 95
43:57 41:59 47:53 9:91 63:37 64:36 N.P.f 22:78 49:51 5:95 N.P.f 20:80
2 mmol of ketone, 1 mmol of aldehyde, 2.5 mL of H2O, 48 h. Conversion of aldol products determined by 1H NMR spectroscopy. The ratio was determined by 1H NMR spectroscopy. Yield of product isolated by evaporation of volatiles and vacuum drying. Yield of products isolated by filtration. No product observed.
To our satisfaction, reactions with 4-nitrobenzaldehyde worked well for 3-granatanone, tropinone and in a limited way for N-methyl-4-piperidone (Scheme 2). The results are shown in Table 2. The reaction of tropinone in excess water gave, in a short time, a mixture of solid products with moderate anti selectivity (entries 5
5682
R. Lazny et al. / Tetrahedron Letters 52 (2011) 5680–5683 Table 3 Aldol reactions of tropinone with various aldehydes in the presence of watera Entry 1 2 3 4 5 6 7 8 9 10 11e 12e a b c d e
Aldehyde p-CF3–C6H4CHO p-CF3–C6H4CHO p-F–C6H4CHO p-F–C6H4CHO p-Cl–C6H4CHO p-Cl–C6H4CHO m-MeO–C6H4CHO m-MeO–C6H4CHO 1-Naphthaldehyde 1-Naphthaldehyde PhCHO p-NO2–C6H4CHO
Water (mL) 2.5 0.016 2.5 0.016 2.5 0.016 2.5 0.016 2.5 0.016 2.5 2.5
Time b
48 h 14 d 48 hb 14 d 48 hb 14 d 48 hb 14 d 48 hb 14 d 48 h 48 h
Conversionc [%] (yield [%])
anti:synd
89 98 50 82 75 96 53 78 40 55 65 98
45:55 16:84 46:54 20:80 45:55 14:86 38:62 10:90 33:67 5:95 95:5 65:35
(81) (66) (82) (70) (50)
2 mmol of ketone, 1 mmol of aldehyde. Yield of product isolated by evaporation of volatiles and vacuum drying. Extension of the time did not improve the conversion. Conversion of aldol products was determined by 1H NMR spectroscopy. The ratio was determined by 1H NMR spectroscopy. 1.1 mmol of ketone, 1 mmol of aldehyde.
and 6). The drop in selectivity may be explained based on the high crystallization tendency of both isomers of the p-nitro derivative. Similar to the reaction with benzaldehyde, the reaction with ‘one drop of water’ showed significant syn selectivity but required extended time (entry 8). Interestingly, granatanone reacted with 4-nitrobenzaldehyde giving preferentially the syn product regardless of the amount of water used. It was possible, however, to observe that the initially formed anti isomer transformed into the syn form as the reaction time was increased. The syn selectivity improved from 49:51 to 5:95 over an additional 18 h (entries 9 and 10). Again, the reaction of N-methyl-4-piperidone was less encouraging, showing very good syn selectivity with a minimal amount of water used and formation of a solid product (entry 4). As with granatanone, conversion of the initially formed anti isomer into the syn product was evident. At higher dilution, loss of diastereoselectivity and chemoselectivity was apparent from the analysis of the complex reaction mixture obtained which contained several unidentified by-products. A short study of the scope of aldehyde acceptors suitable for reaction with tropinone as a representative donor (Table 3) showed that the reactivity was fairly general as judged from the good to reasonable conversions (except for more sterically hindered naphthaldehyde). It is clear that the reactions in the presence of minimal amounts of water were syn-selective and gave both high conversion and fairly good diastereoselectivities.23 A single crystallization of the aldol products improved the diastereoselectivity to very high levels. However, no anti selectivity was obtained in excess water in cases where selective precipitation of the solid product did not occur. Although the optimal ratio of ketone to aldehyde was found to be 2:1, reactions with ratios close to 1:1 were also possible especially for reactive acceptors (entries 11 and 12). The aqueous reactions were limited to non-enolizable aldehydes because of the self-aldol reaction of enolizable aldehydes. The conditions were not suitable for other aldehydes such as formaldehyde, furfural, or a,b-unsaturated aldehydes (e.g., crotonaldehyde) due to uncontrollable side reactions leading to complex mixtures. Pivaldehyde was too sterically hindered as an acceptor. The promoting role of water is intriguing but may, at least partly, be explained in line with Houk’s proposition for aldol reactions in water28 and general base-catalyzed enolization or formation of an amine water complex.13 As a tentative explanation of the observed selectivity (and more importantly the observed conversion of anti isomers into syn isomers) it can be suggested that the studied reactions represent a rarely reported case of thermodynamically-controlled stereoselective processes. We inferred
H
H O Me
N
H
H H
O
1 (anti ) destabilized
Ph
H O
Ph Me
N
H H H H
O
2 (syn) more stable
Figure 1. Hydrogen bonding stabilized conformers of aldol products 1 and 2. Destabilizing steric interactions marked in red.
that the syn isomers are more stable and therefore dominate in the equilibrating reaction mixture (Fig. 1). Theoretical calculations confirmed higher stability of the hydrogen bond stabilized syn isomer.29 However, the equilibration of syn/anti isomers combined with selective precipitation of the anti form, forming more stable crystals, was responsible for the excellent anti selectivity in the case of aldol 1. It is noteworthy that under such conditions diastereoselectivity up to 98:2 was obtained. In conclusion, we have reported the first diastereoselective (up to 98:2) aldol reaction of ketones in the presence of water without additional reagents or a catalyst. The syn/anti selectivity can be controlled by the amount of water added and precipitation of the solid product. This new syn-selective synthetic procedure using substoichiometric amounts of water is complementary to known methods that typically favor the formation of anti diastereomers from cyclic ketone metal enolates30 in accord with the Zimmerman–Traxler model31 and by use of organocatalysis.2,3 The preliminary results although somewhat limited in scope open up access to otherwise hard to obtain on larger scale (tropinone), or unknown (piperidone, grantanone) products of considerable synthetic utility.32 The rationalization of stereoselectivity will necessitate further experimental and computational study. It seems, from observations collected so far, that the highly diastereoselective aldol reaction of cyclic b-amino ketones in the presence of water is reversible and controlled thermodynamically. This is a rarely utilized approach to stereocontrol that may open exciting and, thus far, unexplored possibilities for performing aldol reactions both on laboratory and industrial scale in accord with the green chemistry standards. Acknowledgments The work was supported by the University of Bialystok (BST-125) and the Ministry of Science and Higher Education (Grant No. N N250 546939). We also thank Dr. L. Siergiejczyk for the
R. Lazny et al. / Tetrahedron Letters 52 (2011) 5680–5683
assistance in recording NMR spectra, and Dr. A. Ratkiewicz for DFT calculations. References and notes 1. Mahrwald, R. Aldol Reactions; Springer: Heidelberg, 2009. 2. Enantioselective Organocatalysis: Reactions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. 3. Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: from Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005. 4. Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004. 5. Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632. 6. Paradowska, J.; Rogozinska, M.; Mlynarski, J. Tetrahedron Lett. 2009, 50, 1639– 1641. 7. Markert, M.; Mulzer, M.; Schetter, B.; Mahrwald, R. J. Am. Chem. Soc. 2007, 129, 7258–7259. 8. Gutsche, C. D.; Buriks, R. S.; Nowotny, K.; Grassner, H. J. Am. Chem. Soc. 1962, 84, 3775–3777. 9. Gutsche, C. D.; Redmore, D.; Buriks, R. S.; Nowotny, K.; Grassner, H.; Armbruster, C. W. J. Am. Chem. Soc. 1967, 89, 1235–1245. 10. Mlynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502–1511. 11. Wang, G.-W.; Zhang, Z.; Dong, Y.-W. Org. Process Res. Dev. 2003, 8, 18–21. 12. Jung, D. I.; Song, J. H.; Lee, D. H.; Kim, Y. H.; Lee, Y. G.; Hahn, J. T. Bull. Korean Chem. Soc. 2006, 27, 1493–1496. 13. Cota, I.; Chimentao, R.; Sueiras, J.; Medina, F. Catal. Commun. 2008, 9, 2090– 2094. 14. Majewski, M.; Zheng, G.-Z. Can. J. Chem. 1992, 70, 2618–2626. 15. Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 1993, 58, 533–534. 16. Majewski, M.; Lazny, R. J. Org. Chem. 1995, 60, 5825–5830. 17. Pollini, G. P.; Benetti, S.; De Risi, C.; Zanirato, V. Chem. Rev. 2006, 106, 2434– 2454. 18. Sienkiewicz, M.; Wilkaniec, U.; Lazny, R. Tetrahedron Lett. 2009, 50, 7196– 7198. 19. Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773–4775. 20. Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233–1246. 21. Sheldon, R. A. Chem. Commun. 2008, 3352–3365. 22. Sheldon, R. A.; Arends, I.; Hanefeld, U. Green Chemistry and Catalysis; WileyVCH: Weinheim, 2007.
5683
23. Typical procedure for the reaction with substoichiometric amounts of water: Preparation of 2: Benzaldehyde (0.102 ml, 1 mmol) was added to a mixture of tropinone (0.278 g, 2 mmol) and H2O (0.016 mL, 0.89 mmol). The reaction mixture was then stirred at room temperature for 72 h or until NMR monitoring showed satisfactory conversion (conversion P95%, isomer ratio anti:syn 10:90 base on integration of signals at 5.23 and 5.01 ppm). The mixture was taken up in toluene (1 mL) and evaporated under vacuum (repeated three times). The residue was triturated with hexane to give 2 (0.206 g, 84%). Analytical sample was slowly crystallized from Et2O. Mp 81– 83 °C (decomp.); Rf: 0.40 (5% MeOH/CH2Cl2); 1H NMR (CDCl3, 400 MHz): 7.47– 7.22 (m, 5H), 7.35 (br s, 1H), 5.01 (d, J = 2.6 Hz, 1H, (CH(OH)Ph), 3.51–3.43 (m, 1H, CH–N), 3.25–3.18 (m, 1H, CH–N), 2.98 (ddd, J = 17.0 Hz, 5.2 Hz, 1.7 Hz, 1H, ax-CH2–C@O), 2.43 (app dt, J = 17.0 Hz, 1.7 Hz, 1H, eq-CH2–C@O), 2.39–2.37 (m, 1H, CH–CH(OH)Ph), 2.37 (s, 3H, CH3–N), 2.20–2.03 (m, 2H), 1.70–1.61 (m, 1H), 1.42–1.35 (m, 1H); 13C NMR (CDCl3, 100 MHz): 210.7 (C@O), 143.7, 128.3, 126.9, 125.5, 75.7 (CH–OH), 63.1 (CH–CH(OH)–Ph), 61.2 (2 CH–N), 50.3 (CH2– C@O), 40.4 (CH3–N), 26.8 (CH2), 26.4 (CH2); IR (CHCl3) mmax 2956, 2883, 1709, 1602, 1451, 1109, 1077, 1064 cm 1; HRMS (ESI): 268.1325 (M++Na) calcd for C15H19NO2Na 268.1313. 24. Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798–3800. 25. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998. 26. Anastas, P. T.; Zimmerman, J. B. Environ. Sci. Technol. 2003, 37, 94A–101A. 27. Emer, E.; Galletti, P.; Giacomini, D. Eur. J. Org. Chem. 2009, 3155–3160. 28. Zhang, X.; Houk, K. N. J. Org. Chem. 2005, 70, 9712–9716. 29. DFT calculations at B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) levels showed the syn isomer 2 to be more stable in the gas phase than anti isomer 1 by ca.1.25 kcal/mol. The syn isomer is more stable despite the apparent axial disposition of the Ph group in the second six-membered ring that is formed by internal H-bonding. In this flattened ring containing one hydrogen and one oxygen atom typical destabilizing 1,3-diaxial interactions are minimized. In the anti isomer the strong destabilizing interaction of the apparent equatorial Ph group with the CH2 next to carbonyl is likely responsible for the destabilization. 30. Heathcock, C. H. In Comprehensive Organic Synthesis; Pergamon: Oxford, 1991; Vol. 2, p 181. 31. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–1923. 32. All new compounds gave satisfactory analytical data.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Spontaneous and diastereoselective aldol reactions of cyclic b-amino ketones in the presence of water Ryszard Lazny ⇑, Aneta Nodzewska, Iwona Tomczuk Institute of Chemistry, University of Bialystok, ul. Hurtowa 1, 15-399 Bialystok, Poland
a r t i c l e
i n f o
Article history: Received 21 April 2011 Revised 9 August 2011 Accepted 19 August 2011 Available online 26 August 2011 Keywords: Aldol reaction Reaction in water Tropinone Granatanone
a b s t r a c t Direct aldol reactions of 4-methyl-1-piperidone, tropinone and granatanone (pseudopelletierine) take place spontaneously in the presence of water without any catalyst or additional reagents. The anti/syndiastereoselectivity of the aqueous aldol reaction depends on the amount of water used. The synselectivity of the reaction is probably due to the thermodynamic control. Excellent atom economy and low E factors together with anti-selectivity as high as 98:2 for the tropinone aldol were obtained. Ó 2011 Elsevier Ltd. All rights reserved.
The aldol reaction, owing to its ability to install two adjacent stereocenters, is a powerful C–C bond forming transformation.1 In recent years, organocatalyzed aldol reactions have been studied intensively.2,3 Newer methods for direct aldol reactions typically utilize activated reagents and/or catalysts.1 The catalysts used include Lewis acids, Lewis bases, and metal complexes.4 The enamine-catalyzed aldol reaction often uses secondary amine catalysts, most prominently those derived from proline, and to a lesser extent, primary amines, amino acids, etc.5 Non-enamine organocatalysis is less common, and typically uses anhydrous or neat conditions. Examples include the use of cinchona alkaloid derivatives,6 DBU, and DIPEA7 as catalysts. To the best of our knowledge, the only reported aldol reaction in water, catalyzed by a tertiary amine (pyridine) was the addition of dihydroxyacetone to glyceraldehyde (a general base-catalyzed process).8,9 Performing the aldol reaction in aqueous media may offer several advantages such as reduction of waste, simpler procedures, reduction of cost, and high selectivity.10 A base-catalyzed (Na2CO3) crossed-aldol reaction in water has been reported,11 as has a related aldol condensation giving enones via aqueous hydroxide catalysis12 and a DBU-water complex.13 Herein, we disclose our findings on the spontaneous, diastereoselective aldol reaction of heterocyclic b-aminoketones in the presence of water without a catalyst. During our research on organocatalytic reactions we found that the aldol reaction of tropinone with benzaldehyde occurred spontaneously in the presence of water, and under some conditions, was
diastereoselective and high yielding. Surprisingly, the reaction proceeds without catalysts or any additional reagents and can provide, depending on the conditions and time, the aldol diastereomer 1 or its previously unknown isomer 2, selectively (Scheme 1). So far, the only diastereomer characterized was exo,anti-1, accessible synthetically via deprotonation with LDA or similar bases under anhydrous conditions.14–16 Aldols of tropinone synthesized by deprotonation are important intermediates for the synthesis of biologically active tropane derivatives.17 Some of them were used by us,16,18 and others19 for the syntheses of several tropane alkaloids. Unexpectedly, under optimized conditions, the diastereoselective aldol reaction of tropinone took place in water or in the presence of small amounts of water. As is evident from Table 1, the diastereoselectivity depended on the amount of water added. Under relatively high dilution, excellent anti selectivity was obtained and the product could be isolated by filtration. Under optimal conditions (entry 8) the tropinone dissolved in water and reacted with benzaldyhyde ‘on-water’. As no additional reagents or catalysts are needed, this process is characterized by excellent
N
E-mail address: [email protected] (R. Lazny). 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.08.107
PhCHO
H
OH
N
Ph +
O
H
OH Ph
N
water, rt Me tropinone
⇑ Corresponding author. Tel.: +48 85 745 7834; fax: +48 85 745 7589.
O
O
Me
exo, anti 1
Me
exo, syn 2
Scheme 1. Aldol reaction of tropinone and benzaldehyde in the presence of water.
5681
R. Lazny et al. / Tetrahedron Letters 52 (2011) 5680–5683 Table 1 Dependence of diastereoselectivity on the amount of water used for the reaction of tropinone (2 mmol) with benzaldehyde (1 mmol) Entry 1 2 3 4 5 6 7 8 9 10 11 a b c d e f g
Water (equiv) 0 0.45 0.89 4.4 7.1 29 66 139 139 278 555
Conversiona [%] (isolated yield [%])
Water (mL)
Ratio of 1:2b
c
0 0.0080 0.016 0.080 0.13 0.53 1.2 2.5 2.5 5.0 10.0
N.P.c 11:89 10:90 24:76 30:70 37:63 82:18 98:2 33:67 95:5 94:6
N.P. P53d P95d (yield 84e) P95 P95 P95 P95 P98 (yield 75f) P52g P95 P84
Conversion of aldol products was determined by 1H NMR spectroscopy. The ratio was determined by means of 1H NMR spectroscopy of the crude product. No product observed after 7 days. Reaction time: 3 days.23 Yield of product isolated by evaporation of volatiles and vacuum drying. Yield of product isolated by filtration. An excess of aldehyde was used: tropinone (1 mmol), benzaldehyde (2 mmol). The reaction gave several additional by-products.
atom economy and a very low Sheldon’s E factor (environmental impact measure).20–22 The anti isomer 1 was obtained from the dilute aqueous mixture and usually deposited from the mixture as a sticky solid. Interestingly, in some runs no solid product was obtained. In such cases virtually no syn:anti selectivity was observed. However, ‘seeding’ such reaction mixtures that showed high conversion (typically ca. 90%), with ca. 10 mg of pure anti isomer resulted unfailingly in deposition of a solid, virtually 95% pure (by NMR) anti isomer in ca. 75% yield. Conversion of saturated ca. 1:1 mixtures of syn and anti isomers into solid anti isomers by ‘seeding’ with the anti isomer and stirring suggests strongly that the anti selectivity results from isomer equilibration via a retroaldol reaction and preferential crystallization of the more stable crystalline anti form. The anti isomer has a noticeably higher melting point and is much easier to crystallize then the syn counterpart. The remaining aqueous filtrate can be recharged with substrates and used for preparing the next batch of the anti aldol. Reversing the ratio of reactants gave lower conversion and stereoselectivity (entry 9 vs 8). It has been pointed out by Blackmond et al. that the disposal of organics-contaminated water is often an expensive and underestimated issue.24 As the aqueous phase in the reaction of tropinone and benzaldehyde can be recycled easily, and does not have to be disposed of, this process may offer a green chemistry advantage.25,26 Under dry, neat conditions, the reaction was too slow to be quantified (Table 1, entry 1). Conversely, the addition of substoichiometric amounts of water allowed the reaction to proceed in a reasonable time frame (entries 2 and 3) favoring the exo,syn isomer 2. The optimal amount of water, ca. 0.89 mol equiv gave excellent conversion (95%) and very good syn selectivity (syn:anti ca. 90:10). Pure syn isomer was obtained by evaporation of the reaction mixture with toluene and vacuum drying, followed by trituration with hexane and slow crystallization from diethyl ether. We have tested this procedure on other cyclic ketones: granatanone (5) reacted with benzaldehyde under the same conditions. Using optimal amount of water (0.45 equiv, 0.0080 mL), the reaction reached 95% conversion in 7 days (anti:syn 11:89, with some by-products). Disappointingly, reaction under high dilution conditions (2.5 mL) gave poor conversion (52%) and poor anti selectivity (anti:syn 57:43). The analogous reactions of N-methyl-4-piperidone, regardless of the amount of water and ratio of substrates, were plagued by lack of diastereoselectivity (typically syn:anti 53:47), low conversions, and the formation of by-products (mostly hemiacetals of the formed aldols, analogous with observations on cyclohexanone derivatives27).
O
O
OH
4-nitrobenzaldehyde water, rt
N Me
NO 2
N Me
3
6
O
O
H
OH
4-nitrobenzaldehyde water, rt
N
Me (CH 2) n
N
Me (CH2 )n
4, n = 2: tropinone 5, n = 3: granatanone
NO 2
7, n = 2 8, n = 3
Scheme 2. Aldol reactions of cyclic b-amino ketones.
Table 2 Aldol reactions of b-amino ketones with 4-nitrobenzaldehyde in the presence of watera
a b c d e f
Entry
Product
Time
Water (mL)
Conversionb[%] (yield [%])
anti:sync
1 2 3 4 5 6 7 8 9 10 11 12
6 6 6 6 7 7 7 7 8 8 8 8
2h 20 h 2h 20 d 2h 20 h 2h 7d 2h 20 h 2h 3d
2.5 2.5 0.016 0.016 2.5 2.5 0.016 0.016 2.5 2.5 0.016 0.016
20 28 16 98 (88)d 85 98 (95)e N.P.f 98 (75)d 92 98 (93)e N.P.f 95
43:57 41:59 47:53 9:91 63:37 64:36 N.P.f 22:78 49:51 5:95 N.P.f 20:80
2 mmol of ketone, 1 mmol of aldehyde, 2.5 mL of H2O, 48 h. Conversion of aldol products determined by 1H NMR spectroscopy. The ratio was determined by 1H NMR spectroscopy. Yield of product isolated by evaporation of volatiles and vacuum drying. Yield of products isolated by filtration. No product observed.
To our satisfaction, reactions with 4-nitrobenzaldehyde worked well for 3-granatanone, tropinone and in a limited way for N-methyl-4-piperidone (Scheme 2). The results are shown in Table 2. The reaction of tropinone in excess water gave, in a short time, a mixture of solid products with moderate anti selectivity (entries 5
5682
R. Lazny et al. / Tetrahedron Letters 52 (2011) 5680–5683 Table 3 Aldol reactions of tropinone with various aldehydes in the presence of watera Entry 1 2 3 4 5 6 7 8 9 10 11e 12e a b c d e
Aldehyde p-CF3–C6H4CHO p-CF3–C6H4CHO p-F–C6H4CHO p-F–C6H4CHO p-Cl–C6H4CHO p-Cl–C6H4CHO m-MeO–C6H4CHO m-MeO–C6H4CHO 1-Naphthaldehyde 1-Naphthaldehyde PhCHO p-NO2–C6H4CHO
Water (mL) 2.5 0.016 2.5 0.016 2.5 0.016 2.5 0.016 2.5 0.016 2.5 2.5
Time b
48 h 14 d 48 hb 14 d 48 hb 14 d 48 hb 14 d 48 hb 14 d 48 h 48 h
Conversionc [%] (yield [%])
anti:synd
89 98 50 82 75 96 53 78 40 55 65 98
45:55 16:84 46:54 20:80 45:55 14:86 38:62 10:90 33:67 5:95 95:5 65:35
(81) (66) (82) (70) (50)
2 mmol of ketone, 1 mmol of aldehyde. Yield of product isolated by evaporation of volatiles and vacuum drying. Extension of the time did not improve the conversion. Conversion of aldol products was determined by 1H NMR spectroscopy. The ratio was determined by 1H NMR spectroscopy. 1.1 mmol of ketone, 1 mmol of aldehyde.
and 6). The drop in selectivity may be explained based on the high crystallization tendency of both isomers of the p-nitro derivative. Similar to the reaction with benzaldehyde, the reaction with ‘one drop of water’ showed significant syn selectivity but required extended time (entry 8). Interestingly, granatanone reacted with 4-nitrobenzaldehyde giving preferentially the syn product regardless of the amount of water used. It was possible, however, to observe that the initially formed anti isomer transformed into the syn form as the reaction time was increased. The syn selectivity improved from 49:51 to 5:95 over an additional 18 h (entries 9 and 10). Again, the reaction of N-methyl-4-piperidone was less encouraging, showing very good syn selectivity with a minimal amount of water used and formation of a solid product (entry 4). As with granatanone, conversion of the initially formed anti isomer into the syn product was evident. At higher dilution, loss of diastereoselectivity and chemoselectivity was apparent from the analysis of the complex reaction mixture obtained which contained several unidentified by-products. A short study of the scope of aldehyde acceptors suitable for reaction with tropinone as a representative donor (Table 3) showed that the reactivity was fairly general as judged from the good to reasonable conversions (except for more sterically hindered naphthaldehyde). It is clear that the reactions in the presence of minimal amounts of water were syn-selective and gave both high conversion and fairly good diastereoselectivities.23 A single crystallization of the aldol products improved the diastereoselectivity to very high levels. However, no anti selectivity was obtained in excess water in cases where selective precipitation of the solid product did not occur. Although the optimal ratio of ketone to aldehyde was found to be 2:1, reactions with ratios close to 1:1 were also possible especially for reactive acceptors (entries 11 and 12). The aqueous reactions were limited to non-enolizable aldehydes because of the self-aldol reaction of enolizable aldehydes. The conditions were not suitable for other aldehydes such as formaldehyde, furfural, or a,b-unsaturated aldehydes (e.g., crotonaldehyde) due to uncontrollable side reactions leading to complex mixtures. Pivaldehyde was too sterically hindered as an acceptor. The promoting role of water is intriguing but may, at least partly, be explained in line with Houk’s proposition for aldol reactions in water28 and general base-catalyzed enolization or formation of an amine water complex.13 As a tentative explanation of the observed selectivity (and more importantly the observed conversion of anti isomers into syn isomers) it can be suggested that the studied reactions represent a rarely reported case of thermodynamically-controlled stereoselective processes. We inferred
H
H O Me
N
H
H H
O
1 (anti ) destabilized
Ph
H O
Ph Me
N
H H H H
O
2 (syn) more stable
Figure 1. Hydrogen bonding stabilized conformers of aldol products 1 and 2. Destabilizing steric interactions marked in red.
that the syn isomers are more stable and therefore dominate in the equilibrating reaction mixture (Fig. 1). Theoretical calculations confirmed higher stability of the hydrogen bond stabilized syn isomer.29 However, the equilibration of syn/anti isomers combined with selective precipitation of the anti form, forming more stable crystals, was responsible for the excellent anti selectivity in the case of aldol 1. It is noteworthy that under such conditions diastereoselectivity up to 98:2 was obtained. In conclusion, we have reported the first diastereoselective (up to 98:2) aldol reaction of ketones in the presence of water without additional reagents or a catalyst. The syn/anti selectivity can be controlled by the amount of water added and precipitation of the solid product. This new syn-selective synthetic procedure using substoichiometric amounts of water is complementary to known methods that typically favor the formation of anti diastereomers from cyclic ketone metal enolates30 in accord with the Zimmerman–Traxler model31 and by use of organocatalysis.2,3 The preliminary results although somewhat limited in scope open up access to otherwise hard to obtain on larger scale (tropinone), or unknown (piperidone, grantanone) products of considerable synthetic utility.32 The rationalization of stereoselectivity will necessitate further experimental and computational study. It seems, from observations collected so far, that the highly diastereoselective aldol reaction of cyclic b-amino ketones in the presence of water is reversible and controlled thermodynamically. This is a rarely utilized approach to stereocontrol that may open exciting and, thus far, unexplored possibilities for performing aldol reactions both on laboratory and industrial scale in accord with the green chemistry standards. Acknowledgments The work was supported by the University of Bialystok (BST-125) and the Ministry of Science and Higher Education (Grant No. N N250 546939). We also thank Dr. L. Siergiejczyk for the
R. Lazny et al. / Tetrahedron Letters 52 (2011) 5680–5683
assistance in recording NMR spectra, and Dr. A. Ratkiewicz for DFT calculations. References and notes 1. Mahrwald, R. Aldol Reactions; Springer: Heidelberg, 2009. 2. Enantioselective Organocatalysis: Reactions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. 3. Berkessel, A.; Gröger, H. Asymmetric Organocatalysis: from Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: Weinheim, 2005. 4. Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004. 5. Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632. 6. Paradowska, J.; Rogozinska, M.; Mlynarski, J. Tetrahedron Lett. 2009, 50, 1639– 1641. 7. Markert, M.; Mulzer, M.; Schetter, B.; Mahrwald, R. J. Am. Chem. Soc. 2007, 129, 7258–7259. 8. Gutsche, C. D.; Buriks, R. S.; Nowotny, K.; Grassner, H. J. Am. Chem. Soc. 1962, 84, 3775–3777. 9. Gutsche, C. D.; Redmore, D.; Buriks, R. S.; Nowotny, K.; Grassner, H.; Armbruster, C. W. J. Am. Chem. Soc. 1967, 89, 1235–1245. 10. Mlynarski, J.; Paradowska, J. Chem. Soc. Rev. 2008, 37, 1502–1511. 11. Wang, G.-W.; Zhang, Z.; Dong, Y.-W. Org. Process Res. Dev. 2003, 8, 18–21. 12. Jung, D. I.; Song, J. H.; Lee, D. H.; Kim, Y. H.; Lee, Y. G.; Hahn, J. T. Bull. Korean Chem. Soc. 2006, 27, 1493–1496. 13. Cota, I.; Chimentao, R.; Sueiras, J.; Medina, F. Catal. Commun. 2008, 9, 2090– 2094. 14. Majewski, M.; Zheng, G.-Z. Can. J. Chem. 1992, 70, 2618–2626. 15. Bunn, B. J.; Simpkins, N. S. J. Org. Chem. 1993, 58, 533–534. 16. Majewski, M.; Lazny, R. J. Org. Chem. 1995, 60, 5825–5830. 17. Pollini, G. P.; Benetti, S.; De Risi, C.; Zanirato, V. Chem. Rev. 2006, 106, 2434– 2454. 18. Sienkiewicz, M.; Wilkaniec, U.; Lazny, R. Tetrahedron Lett. 2009, 50, 7196– 7198. 19. Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773–4775. 20. Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233–1246. 21. Sheldon, R. A. Chem. Commun. 2008, 3352–3365. 22. Sheldon, R. A.; Arends, I.; Hanefeld, U. Green Chemistry and Catalysis; WileyVCH: Weinheim, 2007.
5683
23. Typical procedure for the reaction with substoichiometric amounts of water: Preparation of 2: Benzaldehyde (0.102 ml, 1 mmol) was added to a mixture of tropinone (0.278 g, 2 mmol) and H2O (0.016 mL, 0.89 mmol). The reaction mixture was then stirred at room temperature for 72 h or until NMR monitoring showed satisfactory conversion (conversion P95%, isomer ratio anti:syn 10:90 base on integration of signals at 5.23 and 5.01 ppm). The mixture was taken up in toluene (1 mL) and evaporated under vacuum (repeated three times). The residue was triturated with hexane to give 2 (0.206 g, 84%). Analytical sample was slowly crystallized from Et2O. Mp 81– 83 °C (decomp.); Rf: 0.40 (5% MeOH/CH2Cl2); 1H NMR (CDCl3, 400 MHz): 7.47– 7.22 (m, 5H), 7.35 (br s, 1H), 5.01 (d, J = 2.6 Hz, 1H, (CH(OH)Ph), 3.51–3.43 (m, 1H, CH–N), 3.25–3.18 (m, 1H, CH–N), 2.98 (ddd, J = 17.0 Hz, 5.2 Hz, 1.7 Hz, 1H, ax-CH2–C@O), 2.43 (app dt, J = 17.0 Hz, 1.7 Hz, 1H, eq-CH2–C@O), 2.39–2.37 (m, 1H, CH–CH(OH)Ph), 2.37 (s, 3H, CH3–N), 2.20–2.03 (m, 2H), 1.70–1.61 (m, 1H), 1.42–1.35 (m, 1H); 13C NMR (CDCl3, 100 MHz): 210.7 (C@O), 143.7, 128.3, 126.9, 125.5, 75.7 (CH–OH), 63.1 (CH–CH(OH)–Ph), 61.2 (2 CH–N), 50.3 (CH2– C@O), 40.4 (CH3–N), 26.8 (CH2), 26.4 (CH2); IR (CHCl3) mmax 2956, 2883, 1709, 1602, 1451, 1109, 1077, 1064 cm 1; HRMS (ESI): 268.1325 (M++Na) calcd for C15H19NO2Na 268.1313. 24. Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem., Int. Ed. 2007, 46, 3798–3800. 25. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, 1998. 26. Anastas, P. T.; Zimmerman, J. B. Environ. Sci. Technol. 2003, 37, 94A–101A. 27. Emer, E.; Galletti, P.; Giacomini, D. Eur. J. Org. Chem. 2009, 3155–3160. 28. Zhang, X.; Houk, K. N. J. Org. Chem. 2005, 70, 9712–9716. 29. DFT calculations at B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) levels showed the syn isomer 2 to be more stable in the gas phase than anti isomer 1 by ca.1.25 kcal/mol. The syn isomer is more stable despite the apparent axial disposition of the Ph group in the second six-membered ring that is formed by internal H-bonding. In this flattened ring containing one hydrogen and one oxygen atom typical destabilizing 1,3-diaxial interactions are minimized. In the anti isomer the strong destabilizing interaction of the apparent equatorial Ph group with the CH2 next to carbonyl is likely responsible for the destabilization. 30. Heathcock, C. H. In Comprehensive Organic Synthesis; Pergamon: Oxford, 1991; Vol. 2, p 181. 31. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–1923. 32. All new compounds gave satisfactory analytical data.