FULL PAPER DOI: 10.1002/ejoc.201300840
Environmentally Benign Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions of Nitrile Imines with Alkenes in Water Sureshbabu Dadiboyena[a][‡] and Ashton T. Hamme II*[a] Keywords: Green chemistry / Nitrogen heterocycles / Lewis acids / Cycloaddition / Surfactants Mild and environmentally benign Lewis acid promoted 1,3dipolar cycloaddition reactions of α-hydrazonyl chlorides with alkenes in water are reported. In the presence of Lewis acids, these α-hydrazonyl chlorides generate nitrile imines in situ, which then undergo reaction with a dipolarophile to furnish the corresponding cycloaddition product. In many cases, the required times for the completion of the Lewis acid promoted 1,3-dipolar cycloaddition reactions in water were
comparable to the equivalent reactions performed in an organic solvent. Analogous tetrahexylammonium chloride promoted 1,3-dipolar cycloaddition reactions were also performed. The comparisons between the reaction times and cycloadduct yields for the aforementioned 1,3-dipolar reactions in aqueous and organic media and the proposed role of the Lewis acid in the 1,3-dipolar cycloaddition reaction are described.
Introduction
dition reactions[8,9] have been successfully employed in aqueous media in which the Lewis acid was composed of silver[10] or lithium,[11] whereas other aqueous-based 1,3-dipolar cycloaddition reactions utilized prefabricated 1,3-dipoles.[12] Furthermore, in some cases in which 1,3-dipoles were generated in situ, micellar catalysts were often used under basic reaction conditions.[13] A number of pharmaceutical drugs such as celecoxib[14,15] and rimonabant[16] feature a pyrazole moiety[17] as the core phamacophore, and structurally similar synthetic analogues such as pyrazolines and spiropyrazolines also have potential to be biologically active. Because a 1,3dipolar cycloaddition is commonly utilized for the syntheses of the aforementioned heterocycles,[18] we report herein the results from the investigation of a mild and environmentally friendly nitrile imine based 1,3-dipolar cycloaddition methodology. This approach utilizes Lewis acids as reaction promoters in an aqueous environment at room temperature. Previous investigations have been reported to synthesize 1,3,5-trisubstituted pyrazoles and spiropyrazolines in an organic solvent.[19] As an extension of the aforementioned study, we explored the feasibility of Lewis acid promoted nitrile imine cycloadditions with various dipolarophiles in water. The Lewis acid promoted reaction of the nitrile imine that is derived from 2 or 5[20,21] with 2-methylene-1,3,3-trimethylindoline (1) in water formed pyrazole 4 or spiropyrazoline 6, respectively (see Scheme 1). The formation of either a trisubstituted pyrazole or a spiropyrazoline from these cycloaddition reactions is in accordance with earlier reports.[19] On the basis of these results, we decided to investigate and extend the application of this green methodology toward the syntheses of pyrazoles, spiropyrazolines, and pyrazolines.
The 12 principles of green chemistry[1–3] represent important guidelines for the design and development of processes to reduce and eliminate the use and generation of hazardous waste. The promotion of chemical reactions through catalysis contributes[1d–1f] significantly to the development of alternative reaction conditions by replacing organic solvents with inexpensive, safe, and nontoxic solvents such as water.[1e–1j] Although water has typically been regarded as an uncommon reaction medium by many organic chemists, water is becoming an increasingly popular medium for organic reactions.[1e,1h–1n,3,4] Chemists who make use of water as a solvent are often confronted with practical problems such as the antagonistic nature of water toward nucleophilic organic compounds and the limited solubility of the organic components. However, some chemists have taken advantage of the latter phenomenon.[1e,1l,4e,5d,5f,5g] Water is the most abundant solvent on earth and is inexpensive, nonhazardous, nontoxic,[1m–1o,5] and environmentally benign from a green chemistry point of view.[1d,1e,1m–1o] Lewis acids are historically important for promoting organic reactions,[6,7] and the vast majority of organic reactions are usually performed under anhydrous conditions, as many Lewis acids quickly decompose in the presence of water.[7a] A few Lewis acid promoted 1,3-dipolar cycload[a] Department of Chemistry and Biochemistry, College of Science, Engineering, and Technology, Jackson State University, 1400 J. R. Lynch Street, Jackson, MS 39217, USA E-mail: [email protected] http://www.jsums.edu/chemistry/ashton-t-hamme-ii/ [‡] Current address: National Institutes of Health (MIB/NIMH), Bethesda, MD 20892, USA Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201300840. Eur. J. Org. Chem. 2013, 7567–7574
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Scheme 1. Pyrazole and spiropyrazoline syntheses through a Lewis acid catalyzed 1,3-dipolar cycloaddition in water.
Results and Discussion Two electronically unique α-chlorohydrazones (unsubstituted 2, and 4-methoxy 5) were synthesized[19] to determine if the electron density of the aromatic ring affected the time of reaction completion, isolated yield, or regioselectivity of the 1,3-dipolar cycloaddition reactions. Indoline dipolarophile 1 was treated with either arylhydrazonyl chloride 2 or 5 in the presence of various Lewis acids to afford cycloaddition products 4 and 6, respectively, as crystalline solids in moderate yields. To compare aqueous to organic reaction conditions, the in situ generation of the nitrile imines was also accomplished by treating the respective hydrazonyl chlorides 2 and 5 with an excess amount of triethylamine in dry dichloromethane at room temperature through the standard nitrile imine cycloaddition protocol.[19,20] The results of the cycloaddition reaction with respect to reaction conditions, time required for reaction completion, isolated products, and isolated yields are furnished in Tables 1 and 2.
The data in Tables 1 and 2 show that when 1 and 2 or 1 and 5 were vigorously stirred at room temperature in the absence of a Lewis acid promoter in an aqueous environment, no reaction was observed according to TLC, and the starting materials were recovered almost quantitatively. Of the Lewis acids that were tested in Tables 1 and 2, Ag- and Cu-based Lewis acids consistently provided the cycloaddition products in moderate to good yields.[10a,22] To investigate this methodology further, the identical Lewis acids from Tables 1 and 2 were utilized as promoters for the cycloaddition reactions of dipolarophiles 7, 10, and 13 with the nitrile imines that are derived from hydrazonyl chlorides 2 (R = H) and 5 (R = OCH3). The data from these studies revealed that dipolarophiles 7, 10, and 13 provided the corresponding pyrazoline products in moderate to good yields depending on the employed Lewis acid promoter (see Tables 3, 4, and 5). The results of these cycloaddition reactions with respect to reaction conditions, time required for reaction completion, isolated products, and isolated yields are furnished in Tables 3, 4, and 5.
Table 1. Product and yields for the Huisgen cyclization of 1 and hydrazonyl chloride 2.
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Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions Table 2. Product and yields for the Huisgen cyclization of 1 and hydrazonyl chloride 5.
Table 3. Product and yields for the Huisgen cyclization of 7 with hydrazonyl chlorides 2 and 5.
These results show that under Lewis acid activation in an aqueous environment, hydrazonyl chlorides are more prone toward nitrile imine formation and subsequent 1,3-dipolar cycloaddition than the analogous reactions carried out in the absence of a Lewis acid at room temperature. Although many of the Lewis acid promoters shown in Tables 1 to 5 were effective at promoting 1,3-dipolar cycloaddition reactions with an acceptable reaction time and isolated yield, an investigation of the effect of surfactants on the reaction time and isolated yield of the Huisgen cyclization product in an aqueous environment was also performed to deterEur. J. Org. Chem. 2013, 7567–7574
mine if the reported Lewis acid methodology was comparable to a surfactant-mediated cycloaddition. Previous reports describe that the 1,3-dipolar cycloaddition reactions in aqueous media between nitrile imines and dipolarophiles were best performed by shaking a heterogeneous mixture of the reactants in the presence of a base and the surfactant tetrahexylammonium chloride (THAC), as a micellar catalyst.[3,10a] On the basis of this information, we decided to introduce THAC to the aforementioned 1,3-dipolar cycloaddition reactions and determine whether it would promote the cycloaddition reactions
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FULL PAPER Table 4. Product and yields for the Huisgen cyclization of 10 with hydrazonyl chlorides 2 and 5.
Table 5. Product and yields for the Huisgen cyclization of 13 with hydrazonyl chlorides 2 and 5.[a].
in aqueous media and provide higher isolated cycloadduct yields and faster reaction times in comparison to the silver and copper Lewis acid catalysts. The following reaction conditions were used for the cycloaddition reactions: (i) aqueous 0.1 m NaOH (method A), (ii) 80:20 mixture of 7570
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aqueous 0.1 m NaOH and THF (method B), and (iii) aqueous 0.1 m NaOH in the presence of THAC as a catalyst (method C). All the reactions were carried out with vigorous stirring of the reactants at room temperature.[3b] Methods A and B provided no cycloaddition products, but
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Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions Table 6. Tetrahexylammonium chloride-mediated Huisgen cyclization reactions.
method C furnished the desired cycloaddition products, and the time period of these reactions typically occurred between 10 and 15 h. The reaction yields along with the products for method C are provided in Table 6. The formation of the cycloadduct by applying method C provides evidence that THAC participated as a promoter of the cycloaddition reaction, and the isolated product yields and reaction times of the Lewis acid and surfactant-promoted 1,3-dipolar cycloaddition reactions in water were comparable to many of the same reactions performed in dichloromethane. On the basis of experimental evidence and previous publications,[3,5a,10a,23] the pathway that THAC and the Lewis acids follow to promote the 1,3-dipolar cycloaddition reactions may be different. In aqueous solutions, surfactants such as THAC usually promote reactions by forming micellar aggregates. However, during a 1,3-dipolar cycloaddition reaction in an organic solvent, a Lewis acid typically coordinates to the conjugated electron-withdrawing functional Eur. J. Org. Chem. 2013, 7567–7574
group of the dipolarophile or undergoes a metal insertion at the terminal end of an alkyne to increase the reactivity of the dipolarophile toward the 1,3-dipole.[24] In our examples, compound 7 is the only dipolarophile that has a conjugated electron-withdrawing group. However, because silver or copper Lewis acids were essential for all of the cycloadditions to occur in pure water at room temperature, these Lewis acids are likely to participate in the 1,3-dipolar cycloaddition reactions in a manner other than through the coordinaton to the dipolarophile. With regard to when silver carbonate was used to generate the nitrile imine from the α-chlorohydrazone, the silver could form a very strong covalent bond with a chloride ion in the aqueous solution and, thereby, drive the formation of a nitrile imine.[19–21] Although copper does not form a strong covalent bond with chloride ions in aqueous solutions, copper could potentially assist in the dissociation of the chloride ion from the α-chlorohydrazone. Upon the interaction of hydrazonyl
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Scheme 2. Proposed mechanistic rationale for the formation of a nitrile imine from 2 and copper nitrate in water.
chloride 2 with a copper-based Lewis acid, the corresponding copper-complexed intermediate 16 could form. After the loss of nitric acid, copper could then assist in the intramolecular loss of the chloride ion to form intermediate 17. The nitrile imine could then be produced from 17 by the formation of an additional C–N bond with the concomitant loss of chloride, copper, and nitrate ions as shown in the proposed mechanism in Scheme 2.[25] Other interactions between the ionic solution and the reactants that lead to the accelerated formation of cycloadducts are also possible.[26] Typically, the employment of silver carbonate provided the desired cycloaddition products in less time and higher yields than the copper-based Lewis acids, which is possibly because of the formation of the strong silver chlorine bond as well as the assistance from the carbonate ion to form the nitrile imine. However, because of the absence of insoluble silver chloride salts from the reaction mixture, the isolation of the cycloadducts from copper-based Lewis acids was less complicated. Furthermore, unlike copper Lewis acid promoted cycloadditions, silver Lewis acids could only promote the 1,3-cycloadditions in the absence of light. The regiochemical outcomes of the cycloaddition reactions were dependent on the electronic features of both the nitrile imines that were derived from 2 and 5 and alkenyl dipolarophiles 1, 7, 10, and 13 and reflects the usual frontier molecular orbital controlled nature of nitrile imine cycloaddition reactions.[27]
Conclusions In summary, the results from our study show that water is a good medium for the Lewis acid promoted generation of nitrile imines and their subsequent 1,3-dipolar cycloaddition reaction with dipolarophiles. Silver- and copperbased Lewis acids demonstrated the highest yields of isolated cycloadduct and the shortest reaction times to reach completion. Furthermore, in comparison to analogous cycloaddition reactions in organic solvents, Lewis acid and surfactant-promoted aqueous cycloaddition reactions have comparable times to reach completion, proceed at room temperature, and are more environmentally benign with moderate to good yields for the isolated products. Future studies of the application and mechanistic details of Lewis acid promoted cycloaddition reactions to synthesize other heterocyclic ring systems are in progress.
Experimental Section General Methods: All chemicals were purchased from commercial vendors and used without purification. Analytical TLC was per7572
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formed with precoated aluminum plates (Merck silica gel 60, F254) and was visualized with UV light. Chromatography separations were carried out by using a flash column with Merck Silica Gel 60 (230–400 mesh) and ethyl acetate/hexane as the eluant. Instrumentation: IR spectra were recorded with a Nicolet Model Nexus 670 FTIR spectrophotometer. The data are presented as the frequency of absorption (cm–1), and only selected absorptions (ν˜ max) are reported. The NMR spectroscopic data (1H NMR at 300 MHz, 13C NMR at 75 MHz) were recorded in CDCl3, and the chemical shifts are reported in parts per million relative to the internal solvent signal. Data are reported as chemical shift, multiplicity [s (singlet), br. s (broad singlet), d (doublet), t (triplet), m (multiplet)], J [coupling constant in Hertz (Hz)]. All HRMS samples were analyzed by positive ion electrospray with a Bruker 12 Tesla APEX-Qe FTICR-MS with an Apollo II ion source. General Procedure for the 1,3-Dipolar Cycloaddition Reactions in Dichloromethane: To a solution of dry dichloromethane (10 mL) that contained the disubstituted alkene (3.0 mmol) and the hydrazonyl chloride (3.0 mmol) was added triethylamine (0.463 mL, 3.3 mmol). The reaction mixture was stirred at room temp. until the disappearance of the starting materials, as monitored by TLC. After the reaction was complete, the crude reaction mixture was concentrated by the removal of the solvent under reduced pressure. The crude products were purified by flash column chromatography over silica gel by using the required ratio of hexanes and ethyl acetate as the eluant. General Procedure for Lewis Acid Mediated 1,3-Dipolar Cycloaddition Reactions in Water: To a capped vial (20 dram) that contained a solution of the disubstituted alkene (3.0 mmol) and the hydrazonyl chloride (3.0 mmol) in deionized water (10 mL) was added a Lewis acid (4.5 mmol). The reaction mixture was stirred vigorously at room temp. until the disappearance of the starting materials, as monitored by TLC. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine solution and dried with anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The crude products were purified by flash column chromatography over silica gel by using the required ratio of hexanes and ethyl acetate as the eluant. When silver carbonate was used as the Lewis acid, the vessel with the reaction mixture was completely covered by aluminum foil to prevent light-induced decomposition of the silver salts. When silver carbonate was used, the reaction mixture was filtered followed by the described extraction process. General Procedure for THAC-Catalyzed Reactions: To a capped vial (20 dram) that contained a solution of the disubstituted alkene (3 mmol) and the hydrazonyl chloride (3 mmol) in a solution of NaOH (0.1 m, 10 mL) was added tetrahexylammonium chloride (10.5 mmol). The reaction mixture was vigorously stirred at room temp. until the disappearance of the starting materials, as monitored by TLC. The reaction mixture was passed through Celite, and the filtrate was extracted with dichloromethane. The extract was concentrated, and the residue was washed with brine solution and dried with anhydrous Na2SO4. The solvent was evaporated un-
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Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions der reduced pressure. The crude products were purified by flash column chromatography over silica gel by using the required ratio of hexanes and ethyl acetate as the eluant.
does not necessarily represent the official views of the National Institutes of Health.
(3-Hydroxymethyl-2,5-diphenyl-3,4-dihydro-2H-pyrazol-3-yl)methanol (11): Purification by column chromatography (hexanes/ethyl acetate, 1:1) afforded 11 as a colorless liquid. IR (KBr): ν˜ = 3378, 2962, 2873, 1713, 1600 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.61 (br. s, 2 H, CH2), 3.35 (s, 2 H, OH), 3.57 (d, J = 11.5 Hz, 2 H, CH2OH), 3.71 (d, J = 11.5 Hz, 2 H, CH2OH), 6.96 (t, J = 6 Hz, 1 H, NAr), 7.19 (s, 4 H, NAr), 7.32–7.35 (m, 3 H, Ar), 7.65–7.67 (m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.7, 64.6 (2 C), 74.5, 119.1 (2 C), 123.2, 126.2 (2 C), 128.8 (2 C), 129.1, 129.2 ( 2 C ) , 1 3 2 . 7 , 1 4 4 . 7 , 1 5 0 . 3 p p m . H R M S ( E I ) : c a l c d . fo r C17H18N2O2Na+ [M + Na]+ 305.1260; found 305.1258.
[1] a) P. Anastas, T. C. Willimson, Green Chemistry: Frontiers in Benign Chemical Synthesis and Process, Oxford Science Publications, New York, 1998; b) A. Matlack, Introduction to Green Chemistry, 2nd ed., CRC Press, Boca Raton, 2010; c) for lectures presented at the International Symposium on Green Chemistry, see: J. H. Clark, Pure Appl. Chem. 2001, 73, 103; d) G. Centi, S. Perathoner, Catal. Today 2003, 77, 287; e) C.-J. Li, T.-H. Chan, Comprehensive Organic Reactions in Aqueous Media, 2nd ed., Wiley Interscience, Hoboken, 2007, p. 1–117; f) J. B. F. N. Engberts, M. J. Blandamer, Chem. Commun. 2001, 1701; g) G. W. V. Cave, C. L. Raston, J. L. Scott, Chem. Commun. 2001, 2159; h) U. M. Lindstrom, Chem. Rev. 2002, 102, 2751; i) S. Kobayashi, A. K. Manabe, Acc. Chem. Res. 2002, 35, 209; j) A. Lubineau, Y. Queneau, J. Org. Chem. 1987, 52, 1001; k) L. W. Bieber, M. F. da Silva, Molecules 2001, 6, 472; l) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless, Angew. Chem. 2005, 117, 3339; Angew. Chem. Int. Ed. 2005, 44, 3275; m) S. Kobayashi, K. A. Jorgensen, Cycloaddition Reactions in Organic Synthesis 1st ed., Wiley-VCH, Weinheim, Germany, 2002; n) C.-J. Li, Chem. Rev. 2005, 105, 3095; o) E. Trogu, C. Vinattieri, F. De Sarlo, F. Machetti, Chem. Eur. J. 2012, 18, 2081. [2] a) D. L. Hjersen, M. M. Kirchoff, R. L. Lankey, Corporate Environ. Strategy 2002, 9, 259; b) P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, New York, 2000, p. 1–134; c) S. E. Manahan, Green Chemistry and the Ten Commandments of Sustainability, 2nd ed., ChemChar Research, Inc. Publishers, Columbia, MO, 2006, p. 1– 394. [3] a) G. Molteni, A. Ponti, ARKIVOC (Gainesville, FL, U.S.) 2006, 49; b) G. Molteni, M. Orlandi, G. J. Broggini, J. Chem. Soc. Perkin Trans. 1 2000, 3742. [4] a) J. B. F. N. Engberts, B. L. Feringa, E. Keller, S. Otto, Recl. Trav. Chim. Pays-Bas 1996, 115, 457; b) R. A. Sheldon, A. Isabella, H. Ulf, Green Chemistry and Catalysis, Wiley-VCH, Weinheim, Germany, 2007, p. 1–475; c) T. Rispens, J. B. F. N. Engberts, J. Phys. Org. Chem. 2005, 18, 908; d) P. G. Cozzi, L. Zoli, Angew. Chem. 2008, 120, 4230; Angew. Chem. Int. Ed. 2008, 47, 4162. [5] a) A. Chatterjee, D. Maiti, P. Bhattacharya, Org. Lett. 2003, 5, 3967; b) J. Garcia-Alvarez, J. Diez, J. Gimeno, Green Chem. 2010, 12, 2127; c) R. N. Butler, W. J. Cunningham, A. G. Coyne, L. A. Burke, J. Am. Chem. Soc. 2004, 126, 11923; d) R. N. Butler, A. G. Coyne, E. M. Moloney, Tetrahedron Lett. 2007, 48, 3501; e) K. Bala, H. C. Hailes, Synthesis 2005, 3423; f) X. Wu, J. Liu, X. Li, A. Zanotti-Gerosa, F. Hancock, D. Vinci, J. Ruan, J. Xiao, Angew. Chem. 2006, 118, 6870; Angew. Chem. Int. Ed. 2006, 45, 6718; g) A. Chanda, V. V. Fokin, Chem. Rev. 2009, 109, 725; h) G. Wang, X. Liu, T. Huang, Y. Kuang, L. Lin, X. Feng, Org. Lett. 2013, 15, 76. [6] a) D. Schinzer, Selectivities in Lewis Acid Promoted Reactions, Kluwer Academic Publishers, Dordrecht, 1989; b) K. Suzuki, Pure Appl. Chem. 1994, 66, 1557. [7] a) S. Kobayashi, K. Manabe, Pure Appl. Chem. 2000, 72, 1373; b) K. B. Jensen, R. G. Hazell, K. A. Jorgensen, J. Org. Chem. 1999, 64, 2353; c) P. J. Dunn, A. B. Graham, R. Grigg, I. S. Saba, M. Thornton-Pett, Tetrahedron 2002, 58, 7701; d) B. Dugovic, L. Fisera, C. Hametner, Synlett 2004, 1569; e) E. Mernyak, J. Huber, G. Benedek, R. Pfoh, S. Ruhl, G. Schneider, J. Wolfling, ARKIVOC 2010, 101. [8] a) R. Huisgen, Angew. Chem. 1963, 75, 604; Angew. Chem. Int. Ed. Engl. 1963, 2, 565; b) R. Huisgen, Angew. Chem. 1963, 75, 742; Angew. Chem. Int. Ed. Engl. 1963, 2, 633; c) R. Huisgen, R. Grashey, R. Sauer, Chemistry of Alkenes, Interscience, London, 1964, p. 806; d) P. Caramella, P. Grunanger, in: 1,3-Dipolar Cycloaddition Chemistry (Ed.: A. Padwa), Interscience, London, 1984, vol. 1, p. 291.
[3-Hydroxymethyl-5-(4-methoxyphenyl)-2-phenyl-3,4-dihydro-2Hpyrazol-3-yl]methanol (12): Purification by column chromatography (hexanes/ethyl acetate, 1:1) afforded 12 as a colorless liquid. IR (KBr): ν˜ = 3390, 2929, 1709, 1609, 1517 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.52 (br. s, 2 H, CH2), 3.33 (s, 2 H, OH), 3.56 (d, J = 11.4 Hz, 2 H, CH2OH), 3.71 (d, J = 11.4 Hz, 2 H, CH2OH), 3.80 (s, 3 H, OCH3), 6.87 (d, J = 8.7 Hz, 2 H, Ar), 6.96 (t, J = 6.5 Hz, 1 H, NAr), 7.16–7.24 (m, 4 H, NAr), 7.60 (d, J = 8.6 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.8, 47.5 (2 C), 55.6, 72.8, 114.3 (2 C), 120.3 (2 C), 123.6, 125.2, 127.6 (2 C), 129.3 (2 C), 143.7, 147.8, 160.6 ppm. HRMS (EI): calcd. for C18H20N2O3Na+ [M + Na]+ 335.1366; found 335.1360. 5,5-Bis(chloromethyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazole (14): Purification by column chromatography (hexanes/ethyl acetate, 8:2) afforded 14 as a colorless liquid. IR (KBr): ν˜ = 3396, 3057, 2934, 1726, 1593, 1565 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.60 (s, 2 H, CH2), 3.81–3.92 (m, 4 H, CH2Cl), 7.1 (t, J = 7.5 Hz, 1 H, NAr), 7.28–7.46 (m, 7 H, Ar, NAr), 7.77 (d, J = 9.2 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.6, 47.5 (2 C), 73.1, 120.4 (2 C), 123.8, 126.0 (2 C), 128.8 (2 C), 129.2, 129.4 (2 C), 132.4, 143.4, 147.8 ppm. HRMS (EI): calcd. for C17H16Cl2N2H+ [M + H]+ 319.0763; found 319.0763. 5,5-Bis(chloromethyl)-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro1H-pyrazole (15): Purification by column chromatography (hexanes/ethyl acetate, 7:3) afforded 15 as a dark brown oil. IR (KBr): ν˜ = 3516, 3011, 2883, 2405, 1612, 1511 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.52 (s, 2 H, CH2), 3.75–3.86 (m, 7 H, OCH3, CH2Cl), 6.90 (d, J = 8.8 Hz, 2 H, Ar), 7.05 (t, J = 11 Hz, 1 H, NAr), 7.21– 7.33 (m, 4 H, NAr), 7.66 (d, J = 8.8 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.8, 47.4 (2 C), 55.5, 72.8, 114.2 (2 C), 120.2 (2 C), 123.5, 125.1, 127.5 (2 C), 129.3 (2 C), 143.6, 147.8, 160.6 ppm. HRMS (EI): calcd. for C18H18Cl2N2OH+ [M + H]+ 349.0868; found 349.0871. Supporting Information (see footnote on the first page of this article): Characterization data and copies of the 1H and 13C NMR spectra.
Acknowledgments The project described was supported by National Institutes of Health/National Institute of General Medical Sciences (Award Number: 5SC3GM094081-04), National Institutes of Health/ National Center for Research Resources (Award Number: G12RR013459) and National Institutes of Health/National Institute on Minority Health and Health Disparities (Award Number: G12MD007581) for the use of the Analytical and NMR CORE Facilities. The content is solely the responsibility of the authors and Eur. J. Org. Chem. 2013, 7567–7574
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FULL PAPER [9] For additional references about related 1,3-dipolar cycloadditions, see: a) S. Dadiboyena, A. Nefzi, Eur. J. Med. Chem. 2010, 45, 4697; b) S. Dadiboyena, J. Xu, A. T. Hamme II, Tetrahedron Lett. 2007, 48, 1295; c) S. Dadiboyena, A. Nefzi, Tetrahedron Lett. 2012, 53, 2096. [10] a) G. Molteni, ARKIVOC 2007, 224; b) Y. K. Lee, Y. K. Chung, J. Org. Chem. 2008, 73, 4698; c) B. Bianca Flavia, F. Mauro Comes, G. Denis, L. Erika, R. Alfredo, Synlett 2009, 2328. [11] E. McClendon, A. O. Omollo, E. J. Valente, A. T. Hamme II, Tetrahedron Lett. 2009, 50, 533. [12] R. N. Butler, A. G. Coyne, E. M. Moloney, Tetrahedron Lett. 2007, 48, 3501. [13] a) R. A. Youcef, M. D. Santos, S. Roussel, J.-P. Baltaze, N. Lubin-Germain, J. Uziel, J. Org. Chem. 2009, 74, 4318; b) G. Molteni, A. Ponti, M. Orlandi, New J. Chem. 2002, 26, 1340; c) M. Barge, S. Kamble, A. Kumbhar, G. Rashinkar, R. Salunkhe, Monatsch. Chem. 2013, DOI: 10.1007/s00706–013–0944–4; d) X. Liu, Y. Liu, Z. Zhang, F. Huang, Q. Tao, R. Ma, Y. An, L. Shi, Chem. Eur. J. 2013, 19, 7437. [14] for a review about celecoxib/Celebrex, see: S. Dadiboyena, A. T. Hamme II, Curr. Org. Chem. 2012, 16, 1390. [15] L. Oh, Tetrahedron Lett. 2006, 47, 7943. [16] a) S. R. Donohue, C. Halldin, V. W. Pike, Tetrahedron Lett. 2008, 49, 2789; b) M. Segal, Cannabinoids and Analgesia, in: Cannabinoids as Therapeutic Agents (Ed.: R. Mechoulam), CRC Press, Boca Raton, FL, 1986, p. 105–120; c) R. Lan, Q. Liu, P. Fan, S. Lin, S. R. Fernando, D. McCallion, R. Pertwee, A. Makriyannis, J. Med. Chem. 1999, 42, 769. [17] For recent reviews in the area of pyrazoles/pyrazolines, see: a) Y. L. Janin, Chem. Rev. 2012, 112, 3924; b) S. Fustero, A. Simon-Fuentes, J. F. Sanz-Cervera, Org. Prep. Proced. Int. 2009, 41, 253; c) S. Dadiboyena, Eur. J. Med. Chem. 2013, 63, 347; d) S. Dadiboyena, A. Nefzi, Eur. J. Med. Chem. 2011, 46, 5258; e) S. Chakarborty, C. Banja, S. Jena, Heterocycl. Commun. 2013, 19, 79; f) H. K. Arora, S. Jain, Der Pharmacia Lettre
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2013, 5, 340; g) M. S. Singh, S. Chowdury, RSC Adv. 2012, 2, 4547. [18] G. Broggini, G. Molteni, G. Zecchi, Heterocycles 1998, 47, 541. [19] S. Dadiboyena, E. J. Valente, A. T. Hamme II, Tetrahedron Lett. 2009, 50, 291. [20] a) S. Dadiboyena, E. J. Valente, A. T. Hamme II, Tetrahedron Lett. 2011, 52, 2536; b) S. Dadiboyena, E. J. Valente, A. T. Hamme II, Tetrahedron Lett. 2010, 51, 1341; c) M. P. Sibi, M. L. Stanley, P. C. Jasperse, J. Am. Chem. Soc. 2005, 127, 8276. [21] a) L. Basolo, E. M. Beccalli, E. Borsini, G. Broggini, M. Khansaa, M. Rigamnoti, Eur. J. Org. Chem. 2010, 1694; b) G. Broggini, I. De Marchi, M. Martinelli, G. Paladino, T. Pilati, A. Terraneo, Synthesis 2005, 2246; c) A. Singh, A. L. Loomer, G. P. Roth, Org. Lett. 2012, 14, 5266; d) K. Brahma, A. P. Sasmal, C. Chowdhury, Org. Biomol. Chem. 2011, 9, 8422. [22] P. D. Buttero, G. Molteni, T. Pilati, Tetrahedron: Asymmetry 2010, 21, 2607. [23] T. Rispens, J. B. F. N. Engberts, J. Org. Chem. 2003, 68, 8520. [24] a) A. S. Kende, M. Journet, Tetrahedron Lett. 1995, 36, 3087; b) M. J. Diego-Castro, H. C. Hailes, Chem. Commun. 1998, 1549; c) G. Broggini, G. Molteni, A. Terraneo, G. Zecchi, Heterocycles 2003, 59, 823. [25] T. Takeda, R. Sasaki, S. Yamauchi, T. Fujiwara, Tetrahedron 1997, 53, 557. [26] a) G. Molteni, P. D. Buttero, Tetrahedron 2011, 67, 7343; b) T. Lazaridis, Acc. Chem. Res. 2001, 34, 931; c) R. Breslow, Acc. Chem. Res. 1991, 24, 159. [27] a) K. N. Houk, J. Sims, R. E. Duke, R. W. Strozier, J. K. George, J. Am. Chem. Soc. 1973, 95, 7287; b) K. N. Houk, J. Sims, C. R. Watts, L. J. Luskus, J. Am. Chem. Soc. 1973, 95, 7301; c) K. N. Houk, P. Caramella, J. Am. Chem. Soc. 1976, 98, 6397. Received: June 7, 2013 Published Online: October 9, 2013
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Environmentally Benign Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions of Nitrile Imines with Alkenes in Water Sureshbabu Dadiboyena[a][‡] and Ashton T. Hamme II*[a] Keywords: Green chemistry / Nitrogen heterocycles / Lewis acids / Cycloaddition / Surfactants Mild and environmentally benign Lewis acid promoted 1,3dipolar cycloaddition reactions of α-hydrazonyl chlorides with alkenes in water are reported. In the presence of Lewis acids, these α-hydrazonyl chlorides generate nitrile imines in situ, which then undergo reaction with a dipolarophile to furnish the corresponding cycloaddition product. In many cases, the required times for the completion of the Lewis acid promoted 1,3-dipolar cycloaddition reactions in water were
comparable to the equivalent reactions performed in an organic solvent. Analogous tetrahexylammonium chloride promoted 1,3-dipolar cycloaddition reactions were also performed. The comparisons between the reaction times and cycloadduct yields for the aforementioned 1,3-dipolar reactions in aqueous and organic media and the proposed role of the Lewis acid in the 1,3-dipolar cycloaddition reaction are described.
Introduction
dition reactions[8,9] have been successfully employed in aqueous media in which the Lewis acid was composed of silver[10] or lithium,[11] whereas other aqueous-based 1,3-dipolar cycloaddition reactions utilized prefabricated 1,3-dipoles.[12] Furthermore, in some cases in which 1,3-dipoles were generated in situ, micellar catalysts were often used under basic reaction conditions.[13] A number of pharmaceutical drugs such as celecoxib[14,15] and rimonabant[16] feature a pyrazole moiety[17] as the core phamacophore, and structurally similar synthetic analogues such as pyrazolines and spiropyrazolines also have potential to be biologically active. Because a 1,3dipolar cycloaddition is commonly utilized for the syntheses of the aforementioned heterocycles,[18] we report herein the results from the investigation of a mild and environmentally friendly nitrile imine based 1,3-dipolar cycloaddition methodology. This approach utilizes Lewis acids as reaction promoters in an aqueous environment at room temperature. Previous investigations have been reported to synthesize 1,3,5-trisubstituted pyrazoles and spiropyrazolines in an organic solvent.[19] As an extension of the aforementioned study, we explored the feasibility of Lewis acid promoted nitrile imine cycloadditions with various dipolarophiles in water. The Lewis acid promoted reaction of the nitrile imine that is derived from 2 or 5[20,21] with 2-methylene-1,3,3-trimethylindoline (1) in water formed pyrazole 4 or spiropyrazoline 6, respectively (see Scheme 1). The formation of either a trisubstituted pyrazole or a spiropyrazoline from these cycloaddition reactions is in accordance with earlier reports.[19] On the basis of these results, we decided to investigate and extend the application of this green methodology toward the syntheses of pyrazoles, spiropyrazolines, and pyrazolines.
The 12 principles of green chemistry[1–3] represent important guidelines for the design and development of processes to reduce and eliminate the use and generation of hazardous waste. The promotion of chemical reactions through catalysis contributes[1d–1f] significantly to the development of alternative reaction conditions by replacing organic solvents with inexpensive, safe, and nontoxic solvents such as water.[1e–1j] Although water has typically been regarded as an uncommon reaction medium by many organic chemists, water is becoming an increasingly popular medium for organic reactions.[1e,1h–1n,3,4] Chemists who make use of water as a solvent are often confronted with practical problems such as the antagonistic nature of water toward nucleophilic organic compounds and the limited solubility of the organic components. However, some chemists have taken advantage of the latter phenomenon.[1e,1l,4e,5d,5f,5g] Water is the most abundant solvent on earth and is inexpensive, nonhazardous, nontoxic,[1m–1o,5] and environmentally benign from a green chemistry point of view.[1d,1e,1m–1o] Lewis acids are historically important for promoting organic reactions,[6,7] and the vast majority of organic reactions are usually performed under anhydrous conditions, as many Lewis acids quickly decompose in the presence of water.[7a] A few Lewis acid promoted 1,3-dipolar cycload[a] Department of Chemistry and Biochemistry, College of Science, Engineering, and Technology, Jackson State University, 1400 J. R. Lynch Street, Jackson, MS 39217, USA E-mail: [email protected] http://www.jsums.edu/chemistry/ashton-t-hamme-ii/ [‡] Current address: National Institutes of Health (MIB/NIMH), Bethesda, MD 20892, USA Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201300840. Eur. J. Org. Chem. 2013, 7567–7574
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Scheme 1. Pyrazole and spiropyrazoline syntheses through a Lewis acid catalyzed 1,3-dipolar cycloaddition in water.
Results and Discussion Two electronically unique α-chlorohydrazones (unsubstituted 2, and 4-methoxy 5) were synthesized[19] to determine if the electron density of the aromatic ring affected the time of reaction completion, isolated yield, or regioselectivity of the 1,3-dipolar cycloaddition reactions. Indoline dipolarophile 1 was treated with either arylhydrazonyl chloride 2 or 5 in the presence of various Lewis acids to afford cycloaddition products 4 and 6, respectively, as crystalline solids in moderate yields. To compare aqueous to organic reaction conditions, the in situ generation of the nitrile imines was also accomplished by treating the respective hydrazonyl chlorides 2 and 5 with an excess amount of triethylamine in dry dichloromethane at room temperature through the standard nitrile imine cycloaddition protocol.[19,20] The results of the cycloaddition reaction with respect to reaction conditions, time required for reaction completion, isolated products, and isolated yields are furnished in Tables 1 and 2.
The data in Tables 1 and 2 show that when 1 and 2 or 1 and 5 were vigorously stirred at room temperature in the absence of a Lewis acid promoter in an aqueous environment, no reaction was observed according to TLC, and the starting materials were recovered almost quantitatively. Of the Lewis acids that were tested in Tables 1 and 2, Ag- and Cu-based Lewis acids consistently provided the cycloaddition products in moderate to good yields.[10a,22] To investigate this methodology further, the identical Lewis acids from Tables 1 and 2 were utilized as promoters for the cycloaddition reactions of dipolarophiles 7, 10, and 13 with the nitrile imines that are derived from hydrazonyl chlorides 2 (R = H) and 5 (R = OCH3). The data from these studies revealed that dipolarophiles 7, 10, and 13 provided the corresponding pyrazoline products in moderate to good yields depending on the employed Lewis acid promoter (see Tables 3, 4, and 5). The results of these cycloaddition reactions with respect to reaction conditions, time required for reaction completion, isolated products, and isolated yields are furnished in Tables 3, 4, and 5.
Table 1. Product and yields for the Huisgen cyclization of 1 and hydrazonyl chloride 2.
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Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions Table 2. Product and yields for the Huisgen cyclization of 1 and hydrazonyl chloride 5.
Table 3. Product and yields for the Huisgen cyclization of 7 with hydrazonyl chlorides 2 and 5.
These results show that under Lewis acid activation in an aqueous environment, hydrazonyl chlorides are more prone toward nitrile imine formation and subsequent 1,3-dipolar cycloaddition than the analogous reactions carried out in the absence of a Lewis acid at room temperature. Although many of the Lewis acid promoters shown in Tables 1 to 5 were effective at promoting 1,3-dipolar cycloaddition reactions with an acceptable reaction time and isolated yield, an investigation of the effect of surfactants on the reaction time and isolated yield of the Huisgen cyclization product in an aqueous environment was also performed to deterEur. J. Org. Chem. 2013, 7567–7574
mine if the reported Lewis acid methodology was comparable to a surfactant-mediated cycloaddition. Previous reports describe that the 1,3-dipolar cycloaddition reactions in aqueous media between nitrile imines and dipolarophiles were best performed by shaking a heterogeneous mixture of the reactants in the presence of a base and the surfactant tetrahexylammonium chloride (THAC), as a micellar catalyst.[3,10a] On the basis of this information, we decided to introduce THAC to the aforementioned 1,3-dipolar cycloaddition reactions and determine whether it would promote the cycloaddition reactions
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FULL PAPER Table 4. Product and yields for the Huisgen cyclization of 10 with hydrazonyl chlorides 2 and 5.
Table 5. Product and yields for the Huisgen cyclization of 13 with hydrazonyl chlorides 2 and 5.[a].
in aqueous media and provide higher isolated cycloadduct yields and faster reaction times in comparison to the silver and copper Lewis acid catalysts. The following reaction conditions were used for the cycloaddition reactions: (i) aqueous 0.1 m NaOH (method A), (ii) 80:20 mixture of 7570
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aqueous 0.1 m NaOH and THF (method B), and (iii) aqueous 0.1 m NaOH in the presence of THAC as a catalyst (method C). All the reactions were carried out with vigorous stirring of the reactants at room temperature.[3b] Methods A and B provided no cycloaddition products, but
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Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions Table 6. Tetrahexylammonium chloride-mediated Huisgen cyclization reactions.
method C furnished the desired cycloaddition products, and the time period of these reactions typically occurred between 10 and 15 h. The reaction yields along with the products for method C are provided in Table 6. The formation of the cycloadduct by applying method C provides evidence that THAC participated as a promoter of the cycloaddition reaction, and the isolated product yields and reaction times of the Lewis acid and surfactant-promoted 1,3-dipolar cycloaddition reactions in water were comparable to many of the same reactions performed in dichloromethane. On the basis of experimental evidence and previous publications,[3,5a,10a,23] the pathway that THAC and the Lewis acids follow to promote the 1,3-dipolar cycloaddition reactions may be different. In aqueous solutions, surfactants such as THAC usually promote reactions by forming micellar aggregates. However, during a 1,3-dipolar cycloaddition reaction in an organic solvent, a Lewis acid typically coordinates to the conjugated electron-withdrawing functional Eur. J. Org. Chem. 2013, 7567–7574
group of the dipolarophile or undergoes a metal insertion at the terminal end of an alkyne to increase the reactivity of the dipolarophile toward the 1,3-dipole.[24] In our examples, compound 7 is the only dipolarophile that has a conjugated electron-withdrawing group. However, because silver or copper Lewis acids were essential for all of the cycloadditions to occur in pure water at room temperature, these Lewis acids are likely to participate in the 1,3-dipolar cycloaddition reactions in a manner other than through the coordinaton to the dipolarophile. With regard to when silver carbonate was used to generate the nitrile imine from the α-chlorohydrazone, the silver could form a very strong covalent bond with a chloride ion in the aqueous solution and, thereby, drive the formation of a nitrile imine.[19–21] Although copper does not form a strong covalent bond with chloride ions in aqueous solutions, copper could potentially assist in the dissociation of the chloride ion from the α-chlorohydrazone. Upon the interaction of hydrazonyl
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Scheme 2. Proposed mechanistic rationale for the formation of a nitrile imine from 2 and copper nitrate in water.
chloride 2 with a copper-based Lewis acid, the corresponding copper-complexed intermediate 16 could form. After the loss of nitric acid, copper could then assist in the intramolecular loss of the chloride ion to form intermediate 17. The nitrile imine could then be produced from 17 by the formation of an additional C–N bond with the concomitant loss of chloride, copper, and nitrate ions as shown in the proposed mechanism in Scheme 2.[25] Other interactions between the ionic solution and the reactants that lead to the accelerated formation of cycloadducts are also possible.[26] Typically, the employment of silver carbonate provided the desired cycloaddition products in less time and higher yields than the copper-based Lewis acids, which is possibly because of the formation of the strong silver chlorine bond as well as the assistance from the carbonate ion to form the nitrile imine. However, because of the absence of insoluble silver chloride salts from the reaction mixture, the isolation of the cycloadducts from copper-based Lewis acids was less complicated. Furthermore, unlike copper Lewis acid promoted cycloadditions, silver Lewis acids could only promote the 1,3-cycloadditions in the absence of light. The regiochemical outcomes of the cycloaddition reactions were dependent on the electronic features of both the nitrile imines that were derived from 2 and 5 and alkenyl dipolarophiles 1, 7, 10, and 13 and reflects the usual frontier molecular orbital controlled nature of nitrile imine cycloaddition reactions.[27]
Conclusions In summary, the results from our study show that water is a good medium for the Lewis acid promoted generation of nitrile imines and their subsequent 1,3-dipolar cycloaddition reaction with dipolarophiles. Silver- and copperbased Lewis acids demonstrated the highest yields of isolated cycloadduct and the shortest reaction times to reach completion. Furthermore, in comparison to analogous cycloaddition reactions in organic solvents, Lewis acid and surfactant-promoted aqueous cycloaddition reactions have comparable times to reach completion, proceed at room temperature, and are more environmentally benign with moderate to good yields for the isolated products. Future studies of the application and mechanistic details of Lewis acid promoted cycloaddition reactions to synthesize other heterocyclic ring systems are in progress.
Experimental Section General Methods: All chemicals were purchased from commercial vendors and used without purification. Analytical TLC was per7572
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formed with precoated aluminum plates (Merck silica gel 60, F254) and was visualized with UV light. Chromatography separations were carried out by using a flash column with Merck Silica Gel 60 (230–400 mesh) and ethyl acetate/hexane as the eluant. Instrumentation: IR spectra were recorded with a Nicolet Model Nexus 670 FTIR spectrophotometer. The data are presented as the frequency of absorption (cm–1), and only selected absorptions (ν˜ max) are reported. The NMR spectroscopic data (1H NMR at 300 MHz, 13C NMR at 75 MHz) were recorded in CDCl3, and the chemical shifts are reported in parts per million relative to the internal solvent signal. Data are reported as chemical shift, multiplicity [s (singlet), br. s (broad singlet), d (doublet), t (triplet), m (multiplet)], J [coupling constant in Hertz (Hz)]. All HRMS samples were analyzed by positive ion electrospray with a Bruker 12 Tesla APEX-Qe FTICR-MS with an Apollo II ion source. General Procedure for the 1,3-Dipolar Cycloaddition Reactions in Dichloromethane: To a solution of dry dichloromethane (10 mL) that contained the disubstituted alkene (3.0 mmol) and the hydrazonyl chloride (3.0 mmol) was added triethylamine (0.463 mL, 3.3 mmol). The reaction mixture was stirred at room temp. until the disappearance of the starting materials, as monitored by TLC. After the reaction was complete, the crude reaction mixture was concentrated by the removal of the solvent under reduced pressure. The crude products were purified by flash column chromatography over silica gel by using the required ratio of hexanes and ethyl acetate as the eluant. General Procedure for Lewis Acid Mediated 1,3-Dipolar Cycloaddition Reactions in Water: To a capped vial (20 dram) that contained a solution of the disubstituted alkene (3.0 mmol) and the hydrazonyl chloride (3.0 mmol) in deionized water (10 mL) was added a Lewis acid (4.5 mmol). The reaction mixture was stirred vigorously at room temp. until the disappearance of the starting materials, as monitored by TLC. The reaction mixture was extracted with ethyl acetate, and the organic phase was washed with brine solution and dried with anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The crude products were purified by flash column chromatography over silica gel by using the required ratio of hexanes and ethyl acetate as the eluant. When silver carbonate was used as the Lewis acid, the vessel with the reaction mixture was completely covered by aluminum foil to prevent light-induced decomposition of the silver salts. When silver carbonate was used, the reaction mixture was filtered followed by the described extraction process. General Procedure for THAC-Catalyzed Reactions: To a capped vial (20 dram) that contained a solution of the disubstituted alkene (3 mmol) and the hydrazonyl chloride (3 mmol) in a solution of NaOH (0.1 m, 10 mL) was added tetrahexylammonium chloride (10.5 mmol). The reaction mixture was vigorously stirred at room temp. until the disappearance of the starting materials, as monitored by TLC. The reaction mixture was passed through Celite, and the filtrate was extracted with dichloromethane. The extract was concentrated, and the residue was washed with brine solution and dried with anhydrous Na2SO4. The solvent was evaporated un-
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Lewis Acid Promoted [2+3] Dipolar Cycloaddition Reactions der reduced pressure. The crude products were purified by flash column chromatography over silica gel by using the required ratio of hexanes and ethyl acetate as the eluant.
does not necessarily represent the official views of the National Institutes of Health.
(3-Hydroxymethyl-2,5-diphenyl-3,4-dihydro-2H-pyrazol-3-yl)methanol (11): Purification by column chromatography (hexanes/ethyl acetate, 1:1) afforded 11 as a colorless liquid. IR (KBr): ν˜ = 3378, 2962, 2873, 1713, 1600 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.61 (br. s, 2 H, CH2), 3.35 (s, 2 H, OH), 3.57 (d, J = 11.5 Hz, 2 H, CH2OH), 3.71 (d, J = 11.5 Hz, 2 H, CH2OH), 6.96 (t, J = 6 Hz, 1 H, NAr), 7.19 (s, 4 H, NAr), 7.32–7.35 (m, 3 H, Ar), 7.65–7.67 (m, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.7, 64.6 (2 C), 74.5, 119.1 (2 C), 123.2, 126.2 (2 C), 128.8 (2 C), 129.1, 129.2 ( 2 C ) , 1 3 2 . 7 , 1 4 4 . 7 , 1 5 0 . 3 p p m . H R M S ( E I ) : c a l c d . fo r C17H18N2O2Na+ [M + Na]+ 305.1260; found 305.1258.
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[3-Hydroxymethyl-5-(4-methoxyphenyl)-2-phenyl-3,4-dihydro-2Hpyrazol-3-yl]methanol (12): Purification by column chromatography (hexanes/ethyl acetate, 1:1) afforded 12 as a colorless liquid. IR (KBr): ν˜ = 3390, 2929, 1709, 1609, 1517 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.52 (br. s, 2 H, CH2), 3.33 (s, 2 H, OH), 3.56 (d, J = 11.4 Hz, 2 H, CH2OH), 3.71 (d, J = 11.4 Hz, 2 H, CH2OH), 3.80 (s, 3 H, OCH3), 6.87 (d, J = 8.7 Hz, 2 H, Ar), 6.96 (t, J = 6.5 Hz, 1 H, NAr), 7.16–7.24 (m, 4 H, NAr), 7.60 (d, J = 8.6 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.8, 47.5 (2 C), 55.6, 72.8, 114.3 (2 C), 120.3 (2 C), 123.6, 125.2, 127.6 (2 C), 129.3 (2 C), 143.7, 147.8, 160.6 ppm. HRMS (EI): calcd. for C18H20N2O3Na+ [M + Na]+ 335.1366; found 335.1360. 5,5-Bis(chloromethyl)-1,3-diphenyl-4,5-dihydro-1H-pyrazole (14): Purification by column chromatography (hexanes/ethyl acetate, 8:2) afforded 14 as a colorless liquid. IR (KBr): ν˜ = 3396, 3057, 2934, 1726, 1593, 1565 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.60 (s, 2 H, CH2), 3.81–3.92 (m, 4 H, CH2Cl), 7.1 (t, J = 7.5 Hz, 1 H, NAr), 7.28–7.46 (m, 7 H, Ar, NAr), 7.77 (d, J = 9.2 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.6, 47.5 (2 C), 73.1, 120.4 (2 C), 123.8, 126.0 (2 C), 128.8 (2 C), 129.2, 129.4 (2 C), 132.4, 143.4, 147.8 ppm. HRMS (EI): calcd. for C17H16Cl2N2H+ [M + H]+ 319.0763; found 319.0763. 5,5-Bis(chloromethyl)-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro1H-pyrazole (15): Purification by column chromatography (hexanes/ethyl acetate, 7:3) afforded 15 as a dark brown oil. IR (KBr): ν˜ = 3516, 3011, 2883, 2405, 1612, 1511 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.52 (s, 2 H, CH2), 3.75–3.86 (m, 7 H, OCH3, CH2Cl), 6.90 (d, J = 8.8 Hz, 2 H, Ar), 7.05 (t, J = 11 Hz, 1 H, NAr), 7.21– 7.33 (m, 4 H, NAr), 7.66 (d, J = 8.8 Hz, 2 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 41.8, 47.4 (2 C), 55.5, 72.8, 114.2 (2 C), 120.2 (2 C), 123.5, 125.1, 127.5 (2 C), 129.3 (2 C), 143.6, 147.8, 160.6 ppm. HRMS (EI): calcd. for C18H18Cl2N2OH+ [M + H]+ 349.0868; found 349.0871. Supporting Information (see footnote on the first page of this article): Characterization data and copies of the 1H and 13C NMR spectra.
Acknowledgments The project described was supported by National Institutes of Health/National Institute of General Medical Sciences (Award Number: 5SC3GM094081-04), National Institutes of Health/ National Center for Research Resources (Award Number: G12RR013459) and National Institutes of Health/National Institute on Minority Health and Health Disparities (Award Number: G12MD007581) for the use of the Analytical and NMR CORE Facilities. The content is solely the responsibility of the authors and Eur. J. Org. Chem. 2013, 7567–7574
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![Phosphine-catalyzed [3+2] cycloaddition reactions of azomethine imines with electron-deficient alkenes: a facile access to dinitrogen-fused heterocycles.](/assets/img/hold.png)
