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Practical and User-Friendly Procedure for Michael Reactions of a-Nitroketones in Water MichaelReactionsofa-NitroketonesinWater Miranda,a Pilar López-Alvarado,a Giorgio Giorgi,a Jean Rodriguez,b Carmen Avendaño,a J. Carlos Menéndez*a Sonia a
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain E-mail:
[email protected] a Laboratoire RéSo, UMR-CNRS 6516 Réactivité en Synthèse Organique, Centre de St Jérôme, boîte D12, 13397 Marseille, cedex 20, France Received 16 July 2003
Abstract: A variety of a,b-unsaturated carbonyl derivatives gave selective Michael additions with several a-nitrocycloalkanones in water, at room temperature without any added catalyst, or in very dilute, aqueous solutions of potassium carbonate. Both preparative methods constitute new, environmentally benign and more efficient alternatives to previous procedures. Key words: Michael additions, carbanions, nucleophillic additions, nitroketones, organic reactions in water
The use of water as a reaction medium for organic reactions is receiving increasing attention, prompted by environmental concerns.1–3 Because the Michael addition is one of the most widely used methods in the formation of carbon-carbon bonds, several groups have recently focused their attention on the development of conditions that allow this reaction to be carried out in water, although the scope of the method has been rather short in terms of the range of Michael donors and acceptors employed. Thus, Feringa described that ytterbium(III) triflate catalyzes the Michael reactions of a-nitroesters with vinyl ketones and acrolein in water.4 In a related finding, Kobayashi reported that b-ketoesters react with enones in the presence of water-tolerant Lewis acids, particularly scandium tris(dodecylsulfate).5 More recently, basic conditions have been applied to related reactions, and thus Uozomi has described the use of amphiphilic resin-supported quaternary ammonium hydroxides as catalysts for Michael additions of b-ketoesters,6 and one of us has found that phosphazene bases catalyzed the reaction of the same type of substrates with a,b-unsaturated aldehydes, ketones, esters and nitriles.7 a-Nitroketones are very useful synthetic starting materials.8 In particular, ring cleavage of cyclic a-nitroketones has led to a wide range of useful polyfunctional compounds.9 a-Nitroketones are also the source of important synthetic building blocks, such as w-nitroalcohols and spiroketals,10 b-nitroalcohols11 and b-aminoalcohols,12 among others. In spite of this interest, some aspects of their chemistry, in particular their Michael reactions, have received little attention. Traditional approaches to Michael reactions have relied on the use of strongly basic SYNLETT 2003, No. 14, pp 2159–216206.1 203 Advanced online publication: 15.10.2003 DOI: 10.1055/s-2003-42096; Art ID: D17803ST © Georg Thieme Verlag Stuttgart · New York
catalysts;13 however, the high stability of an anion formed adjacent to both a nitro and a keto group renders a-nitroketones and their Michael adducts unstable under these conditions, since they tend to be opened by external nucleophiles. In fact, some recent applications of Michael adducts of a-nitroketones in basic media have been reported where these compounds are opened in a retroClaisen fashion immediately after their formation and therefore are not isolated.14 For this reason, the Michael reactions of these substrates have been conventionally carried out in organic solvents, using amine or phosphine catalysts.15 Basic alumina has also been proposed as a suitable catalyst, either suspended in diethyl ether16 or in the absence of solvent.17 Within this context, we wish to report here our studies on the Michael reaction of several a-nitrocycloalkanones18 with several structurally varied Michael acceptors in aqueous media using neutral or very mildly basic conditions, which were prompted by our interest in the synthesis of models of the CD ring system of the MDR inhibitor19 N-methylwelwitindolinone C isothiocyanate, also known as welwistatin (compound 1, Figure 1).20 H2C
Cl
H3C
H CH3
D O C
SCN A
CH3 H O
B N 1
Figure 1
CH3
Structure of welwistatin
Our initial studies were carried out on 2-nitrocycloheptanone 2a. Because of the above mentioned low stability of a-nitroketones in basic media, we started our study using the Lewis-acid catalyzed conditions previously employed by other authors for a-nitroesters.4 However, prolonged treatment (3 d) of 2a with methyl vinyl ketone (MVK) led only to a 35% yield of the desired Michael adduct 3a, together with 49% of recovered 2a and the openchain compound 4 (47%, calculated from MVK), which can be assumed to arise from Lewis-acid catalyzed hetero Diels–Alder reaction between two molecules of MVK leading to a dihydropyran derivative, followed by hydro-
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S. Miranda et al. COCH3 O
Z O
O
NO2
NO2 NO2
i
2a
O
+ CH3 O OH
NO2
+
3a (35%)
H3C
Z
O
2a 2b 2c 2d 2e
n n=2 n=1 n=3 n=5 n=7
n 3a–k
Scheme 2
4 H 2O (47% overall)
+ H 3C
O
COCH3 H3C
O
COCH3
Scheme 1 Reagents and conditions: i. MVK, Yb(OTf)3, H2O, r.t., 3 d
lysis (Scheme 1). Compound 4 has been previously isolated from micellar aqueous reaction media containing MVK, albeit in low yield and under much harsher reaction conditions (24% of 4 after 7 d at 70 °C).21 Since this result seemed to preclude the use of water-compatible Lewis acids, we decided to attempt the use of water as the reaction medium, with no added catalyst, in the hope that the acidity of the a-nitrocarbonyl group would be enough to catalyze the reaction.22 Indeed, these conditions allowed the Michael addition of compound 2a to acrolein, methyl vinyl ketone and ethyl vinyl ketone, affording, respectively, compounds 3a–c in excellent yields and without formation of open-chain derivative (Scheme 2 and Table 1, entries 1–3). In order to test the generality of this procedure, we also examined the preparation of Michael adducts of other a-nitrocycloalcanones. Thus, treatment of commercially available a-nitrocyclohexanone 2b with acrolein in water gave compound 3d in 98% yield (entry 4). Similarly, treatment of a-nitrocyclooctanone 2c, a-nitrocyclodecanone 2d, and a-nitrocyclododecanone 2e with acrolein or MVK afforded compounds 3e–h, again in excellent yields (entries 5–8),23 although the larger nitroketones, and specially 2e, were less reactive because of their lower water solubility. In fact, 2e failed to react with acrolein under our standard aqueous conditions, and preparation of compound 3h required the addition of the cationic surfactant cetyl trimethylammonium bromide (CTAB) to the reaction medium and a longer reaction time (entry 8).
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Attempts to extend these conditions to less reactive Michael acceptors were not similarly successful. For instance, methyl acrylate gave only 30% yield of compound 3i after 7 days at room temperature (entry 9), and reflux conditions for one day led only to a slight improvement (40% yield, entry 10). These observations, coupled with the recent discovery that nitroalkanes can react as nucleophiles in aqueous sodium hydroxide, normally in the presence of cationic surfactancts,24,25 led us to attempt similar basic conditions for the reaction between 2a and MVK. Unfortunately, the only reaction product we could isolate in this case was 7-nitroheptanoic acid, from opening of 2a by the hydroxide anion. Use of dilute aqueous potassium carbonate solutions,26 on the other hand, was more satisfactory, and, after some initial attempts (entries 11, 12), we found that 0.07 M potassium carbonate at room temperature for 30 minutes led to 92% yield of compound 3b, without detection of any trace of the open chain derivative (entry 13). The optimal basic conditions thus found were then applied to other Michael acceptors (entries 14–16), with variable results. While a,b-unsaturated ketones gave excellent yields in short reaction times, only a slight improvement could be achieved in the case of methyl acrylate. In the reaction with acrolein, the yield in basic conditions was clearly inferior to the one obtained in water, owing to the formation of ring-opened products. As in the case of the non-catalyzed reactions, the addition of CTAB was found to be beneficial in some of the base-catalyzed reactions, as in the case of a,b-unsaturated nitriles and sulphones (entries 17 and 18). In conclusion, we have developed an experimentally simple and environmentally friendly protocol that allows the isolation of a variety of synthetically useful Michael adducts of a-nitroketones, generally in high to excellent yields.
Acknowledgment We thank CICYT for financial support (projects SAF 97-0143 and SAF 2000-0130). Comunidad Autónoma de Madrid is gratefully acknowledged for a predoctoral fellowship to SM, and for the support of a three-month stay of SM in Marseille. We also thank Università di Roma ‘La Sapienza’ for a fellowship to GG.
LETTER Table 1 Entry
Michael Reactions of a-Nitroketones in Water
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Results of the Michael Additions to a-Nitrocycloalkanones Z
n
Product
Conditions
Yield (%)
1
CHO
2
3a
H2O, r.t., 8 h
85
2
COCH3
2
3b
H2O, r.t., 4 d
93
3
COCH2CH3
2
3c
H2O, r.t., 4 d
85
4
CHO
1
3d
H2O, r.t., 14 h
98
5
CHO
3
3e
H2O, r.t., 14 h
99
6
COCH3
3
3f
H2O, r.t., 4 d
98
7
CHO
5
3g
H2O, r.t., 37 h
99
8
CHO
7
3h
H2O, r.t., CTAB (10%), 5 d
99
9
CO2CH3
2
3i
H2O, r.t., 7 d
30
10
CO2CH3
2
3i
H2O, reflux, 1 d
40
11
COCH3
2
3b
KHCO3 (0.07 M in H2O), r.t., 3 h
76
12
COCH3
2
3b
K2CO3 (0.035 M in H2O), r.t., 4 h
65
13
COCH3
2
3b
K2CO3 (0.07 M in H2O), r.t., 30 min
92
14
COCH2CH3
2
3c
K2CO3 (0.07 M in H2O), r.t., 1 h
80
15
CO2CH3
2
3i
K2CO3 (0.07 M in H2O), r.t., 45 min
49
16
CHO
2
3a
K2CO3 (0.07 M in H2O), r.t., 30 min
55
17
CN
2
3j
K2CO3 (0.07 M in H2O), r.t., CTAB (10%), 3 h
60
18
SO2C6H5
2
3k
K2CO3 (0.07 M in H2O), r.t., CTAB (10%), 3 h
77
References (1) (a) Li, C.-J. Chem. Rev. 1993, 93, 2023. (b) Chan, T. H.; Li, C.-J. Can. J. Chem. 1994, 72, 1181. (c) Lubineau, A.; Augé, J.; Queneau, Y. Synthesis 1994, 741. (d) Li, C.-J.; Chan, T. H. Organic Reactions in Aqueous Media; Wiley: New York, 1997. (e) Organic Synthesis in Water; Grieco, P. A., Ed.; Blacky Academic and Professional: London, 1998. (f) Lubineau, A.; Augé, J. Topics in Current Chemistry, In Modern Solvents in Organic Synthesis, Vol. 206; Knochel, P., Ed.; Springer-Verlag: Berlin, Heidelberg, 1999, 1. (2) Ribe, S.; Wipf, P. Chem. Commun. 2001, 299. (3) Ludwig, R. Angew. Chem. Int. Ed. 2001, 40, 1808. (4) Keller, E.; Feringa, B. L. Synlett 1997, 842. (5) Mori, Y.; Kakumoto, K.; Manabe, K.; Kobayashi, S. Tetrahedron Lett. 2000, 41, 3107. (6) Shibatomi, K.; Nakahashi, T.; Uozomi, Y. Synlett 2000, 1643. (7) Bensa, D.; Brunel, J.-M.; Buono, G.; Rodriguez, J. Synlett 2001, 715. (8) Fischer, R. H.; Witz, H. M. Synthesis 1980, 261. (9) For a review, see: Ballini, R. Synlett 1999, 1009. (10) (a) Rosini, G.; Ballini, R.; Marotta, E. Tetrahedron 1989, 45, 5935. (b) Ballini, R.; Petrini, M.; Rosini, G. Tetrahedron 1990, 46, 7531. (11) Ballini, R.; Bosica, G.; Marcantoni, E.; Vita, P.; Bartoli, G. J. Org. Chem. 2000, 65, 5845.
(12) Barrett, A. G. M.; Spilling, C. D. Tetrahedron Lett. 1988, 29, 5733. (13) (a) Bergman, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10, 1795. (b) Jung, M. E.; Semmelhack, M. F. Comprehensive Organic Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 1–67. (14) (a) Ballini, R.; Papa, F.; Abate, C. Eur. J. Org. Chem. 1999, 87. (b) Ballini, R.; Barboni, L.; Bosica, G. J. Org. Chem. 2000, 65, 6261. (c) Ballini, R.; Barboni, L.; Bosica, G.; Filippone, P.; Peretti, S. Tetrahedron 2000, 56, 4095. (15) (a) Cookson, R. C.; Ray, P. S. Tetrahedron Lett. 1982, 23, 3521. (b) Yurdakul, A.; Gurtner, C.; Jung, E.-S.; LorenziRiatsch, A.; Linden, A.; Guggisberg, A.; Bienz, S.; Hesse, M. Helv. Chim. Acta 1998, 81, 1373. (c) Ballini, R.; Barboni, L.; Bosica, L.; Fiorini, D. Synthesis 2002, 2725. (16) (a) Rosini, G.; Ballini, R.; Marotta, E. Tetrahedron 1989, 45, 5935. (b) Ballini, R.; Petrini, M.; Rosini, G. Tetrahedron 1990, 46, 7531. (17) Rosini, G.; Marotta, E. Synthesis 1986, 237. (18) These starting materials were prepared in two steps, by transformation of commercially available cycloalkanones into the enol acetates and subsequent treatment of the latter compounds with acetyl nitrate. Representative Procedure: To a solution of cycloheptanone (10 g, 90 mmol) in isopropenyl acetate (85 mL) was added p-toluenesulfonic acid (2.9 g, 15 mmol). The reacting mixture was refluxed for 24 h in an oil bath at 100 °C, and then it was cooled and diluted with Et2O Synlett 2003, No. 14, 2159–2162
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(20 mL). The solution was washed with sat. aq NaHCO3 (2 × 30 mL) and brine (2 × 30 mL). The organic layer was dried (Na2SO4) and evaporated, yielding 1-cycloheptenyl acetate (14.08 g, 100%), as a dark brown oil. To a solution of this compound in CH2Cl2 (30 mL) at 0 °C was successively added acetic anhydride (28.26 mL, 30.55 g, 295.7 mmol) and 96% sulfuric acid (0.5 mL). A mixture of glacial acetic acid (2.25 mL, 2.39 g, 40.8 mmol) and 65% nitric acid (6.75 mL) was then added dropwise. After stirring for an additional time of 3 h, the reacting mixture was diluted with CH2Cl2 (30 mL) and washed with brine (2 × 20 mL), and sat. aq NaHCO3 (3 × 20 mL, until no effervescence was observed). The organic layer was dried (Na2SO4) and evaporated and the residue was chromato-graphed on silica gel, eluting with 10:1 petroleum ether–ethyl acetate, yielding 7.482 g (54%) of compound 2a, as a pale yellow viscous oil. IR (NaCl): 1721 (C=O), 1158 and 1375 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): d = 5.34 (dd, 1 H, J = 9.5 and 3.9 Hz, H-2), 2.80–2.50 (m, 2 H, H-7), 2.40–2.20 (m, 1 H, H-3), 2.20–2.00 (m, 2 H, H-5,3), 2.00–1.75 (m, 2 H, H-6,4), 1.75–1.50 (m, 2 H, H-6,4), 1.50–1.25 (m, 1 H, H-5). 13 C NMR (63 MHz, CDCl3): d = 201.7 (C-1), 94.1 (C-2), 41.7 (C-7), 29.1 (C-5), 29.0 (C-3), 26.6 (C-4), 24.2 (C-6). Anal. Calcd. for C7H11NO3 (M = 157): C, 53.50; H, 7.00; N, 8.92. Found: C, 53.37; H, 7.06; N, 8.85. (19) For a review of MDR inhibitors, see: Avendaño, C.; Menéndez, J. C. Curr. Med. Chem. 2002, 9, 159.
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(20) (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.; Moore, R. E. Mol. Pharmacol. 1995, 47, 241. (b) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994, 116, 9935. (c) Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996, 49, 288. (21) (a) Bassetti, M.; Cerichelli, G.; Floris, B. Gazz. Chim. Ital. 1991, 121, 527. (b) The rationalization given in this reference for the formation of 4 differs from the one proposed in Scheme 1. (22) For a similar effect with 1,3-diones, see: Crispin, D. J.; Vanstone, A. E.; Whitehurst, J. S. J. Chem. Soc. C 1970, 10. (23) Representative Procedure: To a vigorously stirred dispersion of a-nitrocycloheptanone 2a (150 mg, 0.96 mmol) in H2O (5 mL) was added acrolein (2.4 mmol, 2.5 equiv). The mixture was stirred at r.t. for 8 h, and the aqueous phase was then extracted with Et2O (3 × 10 mL), which was dried (Na2SO4) and evaporated, yielding 172 mg (85%) of 3-(1¢-nitro-2¢-oxocycloheptyl)-propanal (3a), as a pale yellow, viscous liquid. IR (NaCl): 1721 (C=O), 1542 and 1347 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): d = 9.77 (s, 1 H, CHO), 2.80–1.40 (m, 14 H). 13C NMR (63 MHz, CDCl3): d = 202.5 (C-2¢), 199.7 (C-1), 98.4 (C-1¢), 41.2 (C3¢), 38.3 (C-2), 35.1 (C-5¢), 29.3 (C-7¢), 28.6 (C-6¢), 25.5 (C4¢), 24.4 (C-2). Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09; N, 6.57. Found: C, 56.59; H, 7.29; N, 6.49. (24) (a) Ballini, R.; Bosica, G. Tetrahedron Lett. 1996, 44, 8027. (b) Ballini, R.; Bosica, G. Eur. J. Org. Chem. 1998, 355. (25) Ballini, R.; Bosica, G. J. Org. Chem. 1997, 62, 425. (26) For a similar effect of K2CO3 in the Michael reactions of 1,3diones, see ref.21
