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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron Lett. Author manuscript; available in PMC 2010 July 15.
Published in final edited form as:
Tetrahedron Lett. 2009 July 15; 50(28): 4067–4070.
doi:  10.1016/j.tetlet.2009.04.102
PMCID: PMC2699673
NIHMSID: NIHMS114043

1,3-Dipolar cycloaddition of arynes with azomethine imines: synthesis of 1,2-dihydropyrazolo[1,2-a]indazol-3(9H)-ones

Abstract

A [3+2] 1,3-dipolar cycloaddition reaction of arynes with stable azomethine imines has been developed. The reaction rapidly assembles tricyclic pyrazoloindazolone derivatives in moderate yields under mild reaction conditions.

1,3-Dipolar cycloadditions have been recognized as a powerful tool for the synthesis of 5-membered ring heterocycles.1 In addition to traditional dipolarophiles, such as alkynes and alkenes, arynes readily undergo 1,3-dipolar cycloadditions to afford various heterocycles.25 Although the initial success with arynes was reported long ago,6 at that time the benzyne was generated using hazardous diazotized anthranilic acid as the benzyne precursor. Recent studies have demonstrated that benzynes can be conveniently generated from o-(trimethylsilyl)phenyl triflates (1) under mild, non-hazardous, fluoride-promoted conditions.7 Arynes generated from these modern aryne precursors have been successfully applied to 1,3-dipolar cycloaddition reactions of diazo compounds to generate indazoles,2 azides to generate benzotriazoles,3 and nitrones to generate dihydrobenzo[d]isoxazoles.4 With our continuing interest in aryne chemistry, especially aryne annulation chemistry, we wish to report that azomethine imines (2)8 smoothly react with arynes generated from o-(trimethylsilyl)phenyl triflates under mild reaction conditions to furnish the corresponding 1,2-dihydropyrazolo[1,2-a]indazol-3(9H)-ones (3).

Azomethine imines (2), easily prepared via condensation of 3-pyrazolidinone9 with various aldehydes,10 are isolable and stable compounds. They have been shown to react with a variety of dipolarophiles.8,10a,10b The reactivity of benzyne with this specific 1,3-dipole has been briefly examined using the hazardous benzyne precursor diazotized anthranilic acid.6,11 This prompted us to re-investigate the reactivity of this dipole with a more modern benzyne precursor under fluoride-promoted conditions. To our surprise, this approach was intentionally “excluded from consideration” in the previous investigation,11 because of the belief that benzynes generated in this way involve the “intermediate ortho-substituted phenyl anion”, which has “demonstrated ability” “to add to the iminium bond”. Herein, we wish to report our preliminary results in the [3+2] dipolar cycloaddition of azomethine imines 2 with o-(trimethylsilyl)phenyl triflates as the benzyne precursors under fluoride-promoted conditions (Scheme 1).

Scheme 1
General reaction of benzynes with azomethine imines.

We started by optimizing the reaction conditions using an unsubstituted benzyne precursor (1a, X = H) and an azomethine imine derived from 4-methoxybenzaldehyde (2a, R = 4-MeOC6H4) (Table 1). Although this reaction was promising, it was not particularly clean. Somewhat surprisingly, unlike previous analogous [3+2] cycloadditions we have examined,24 the yield seemed not to be very dependent on the reaction conditions when 1.0 equiv of 1a was used (entries 1–3). Regardless of the fluoride source, solvent, and temperature, the desired product 3a (X = H, R = 4-MeOC6H4) was obtained in moderate yields with incomplete conversion, and the best result, a 55% yield, was obtained when using TBAF (tetrabutylammonium fluoride) as the fluoride source (entry 3). In an attempt to drive the reaction to completion, higher loadings of the benzyne precursor 1a were employed (entries 4–9). While we did observe higher conversion, and most reactions were complete, the yields of the desired product actually dropped (compare entry 4 with entry 3). After examining a number of reaction conditions, none gave a yield higher than 55%. Crude 1H NMR spectral analysis revealed that the reaction mixture is even dirtier than those performed using a 1:1 stoichiometry. Varying the temperature, diluting the reaction mixture, or performing portionwise addition of 1a (not shown) all resulted in significantly lower yields. We have conducted a control experiment in which we allowed the isolated product 3a to react with the benzyne precursor 1a under the usual reaction conditions. We observed a nearly identical crude 1H NMR spectrum to that obtained in the reaction mixture of 2a with excess 1a. Clearly, the lower yield employing a higher loading of 1a was at least in part caused by some reaction of the benzyne with 3a. Unfortunately, the reaction between 1a and 3a, or excess 1a with 2a, gave such a complex mixture that no useful information could be obtained.12

Table 1
Reaction optimization (Scheme 1, X = H, R = 4-MeOC6H4)a

Understanding this unanticipated event, we performed a series of reactions with various loadings of 1a (entries 10–14). As the loading of 1a decreased, the conversion of 2a also decreased, but the yield of 3a actually increased, and the reaction got increasingly cleaner. The best result, a 53% yield, was obtained at a near 1:1 ratio of 1a:2a (entry 14), which was comparable to the result reported in entry 3. In a final attempt, we used TBAT (tetrabutylammonium difluorotriphenylsilicate) as an alternative, soluble fluoride source,13 and, to our pleasure, 3a was obtained in a much improved 72% yield (entry 15).14 We therefore used this fluoride and procedure as our standard conditions for further studies.15

A couple of different benzyne precursors were next screened in the reaction with azomethine imine 2a using these standard conditions (Table 2). It was observed that electron-rich benzynes were generated somewhat more slowly and longer reaction times were needed. Even after 2 days, the crude 1H NMR spectra of these reactions still showed unreacted benzyne precursors. Nonetheless, the substituted benzynes still reacted with the azomethine imines smoothly to afford the desired products in moderate yields. An unsymmetrical 3-methoxybenzyne, generated from precursor 1d (entry 3), showed good regioselectivity in this cycloaddition, although related cycloadditions with other dipoles have given exclusively one regioisomer.2,3

Table 2
Reaction scope of different benzyne precursorsa

Additional azomethine imines have been tested using benzyne precursor 1a under the standard reaction conditions (Table 3). The reaction tolerates a broad range of functional groups, including a halide (entry 2), an ester (entry 3), and an acetal (entry 4). Substitution in the ortho position did not affect the cycloaddition (entry 4). A variety of azomethine imines derived from heterocyclic aldehydes also worked in this cycloaddition, including pyridyl (entry 5), furyl (entry 6), and pyrrolyl (entry 7). Azomethine imines derived from aliphatic aldehydes, such as cyclohexanecarboxaldehyde (entry 8) and 1-cyclohexene-1-carboxaldehyde (entry 9), proceeded as well, giving the desired adduct in 70% and 55% yields respectively. In most cases, the reaction afforded the tricyclic adduct in moderate yields.16 However, the yields of the product significantly dropped as the solubility of the azomethine imines in MeCN decreased (entries 4, 6, and 7). In these cases, running the same reaction in DCM may give a marginal improvement in the yield.17 A gem-dimethyl group on the pyrazolidinone moiety was found to significantly improve the yield of the reaction (entries 10–12). For instance, azomethine imine 2g derived from 5-methylfurfuraldehyde without the gem-dimethyl afforded the product 3j in only a 29% yield (entry 6). However, azomethine imine 2l derived from the same aldehyde, but bearing the gem-dimethyl moiety, resulted in a dramatic increase in yield to 71% (entry 11). We believe that the improved yields in these cases (also compare entry 12 with entry 8) due to the gem-dimethyl group largely arise from the increased solubility of these azomethine imines in the solvent.

Table 3
Reaction scope of different azomethine iminesa

In conclusion, we have developed a method for the [3+2] dipolar cycloaddition of arynes using modern aryne precursors with stable azomethine imines under mild reaction conditions. The reaction provides tricyclic 1,2-dihydropyrazolo[1,2-a]indazol-3(9H)-ones in moderate to good yields. More applications of arynes in dipolar cycloaddition reactions are currently underway in our laboratory.

Acknowledgments

We thank the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Center of Excellence in Chemical Methodology and Library Development (P50 GM069663) for their generous financial support. We also thank Mr. Donald C. Rogness for his help in preparation of the aryne precursors.

Footnotes

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References

1. (a) Padwa A. 1,3-Dipolar Cycloaddition Chemistry. John Wiley & Sons; New York: 1984. (b) Padwa A, Pearson WH. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and Natural Products. Wiley; New York, Chichester: 2002.
2. Liu Z, Shi F, Martinez PDG, Raminelli C, Larock RC. J Org Chem. 2008;73:219–226. [PubMed] (b) Jin T, Yamamoto Y. Angew Chem, Int Ed. 2007;46:3323–3325. [PubMed]
3. Shi F, Waldo JP, Chen Y, Larock RC. Org Lett. 2008;10:2409–2412. [PubMed]
4. (a) Wu QC, Li BS, Lin WQ, Shi CQ, Chen YW, Chen YX. Hecheng Huaxue (Chin J Synth Chem) 2007;15:292–295. (b) Lu C, Larock RC. manuscript in preparation. (c) Kivrak A, Larock RC. manuscript in preparation.For a closely related example of pyridine N-oxides, see: (d) Raminelli C, Liu Z, Larock RC. J Org Chem. 2006;71:4689–4691. [PubMed]
5. For a recent comprehensive review of aryne chemistry, see Chen Y, Larock RC. In: Modern Arylation Methods. Ackermann L, editor. Wiley-VCH; Weinheim: 2009. pp. 401–473.
6. Huisgen R, Knorr R. Naturwissenschaften. 1962;48:716.
7. (a) Himeshima Y, Sonoda T, Kobayashi H. Chem Lett. 1983:1211–1214. (b) Peña D, Cobas A, Pérez D, Guitian E. Synthesis. 2002:1454–1458.
8. Schantl JG. In: Science of Synthesis. Padwa A, editor. Vol. 27. Georg Thieme Verlag; Stuttgart, New York: 2004. pp. 731–824.
9. Perri ST, Slater SC, Toske SG, White JD. J Org Chem. 1990;55:6037–6047.
10. Shintani R, Fu GC. J Am Chem Soc. 2003;125:10778–10779. [PubMed] (b) Suárez A, Downey CW, Fu GC. J Am Chem Soc. 2005;127:11244–11245. [PubMed] (c) Dorn H, Otto A. Angew Chem, Int Ed Engl. 1968;7:214–215.
11. Taylor EC, Sobieray DM. Tetrahedron. 1991;47:9599–9620.
12. We have observed that different side-products were obtained under different reaction conditions.
13. (a) Pilcher AS, DeShong P. J Org Chem. 1996;61:6901–6905. [PubMed]For other examples utilizing TBAT as the fluoride source in benzyne chemistry, see: (b) Gilmore CD, Allan KM, Stoltz BM. J Am Chem Soc. 2008;130:1558–1559. [PubMed] (c) Hayes ME, Shinokubo H, Danheiser RL. Org Lett. 2005;7:3917–3920. [PubMed]
14. Representative procedure (entry 15, Table 1): An oven-dried 1-dram vial equipped with a stirrer bar was charged with 110 mg of 1a (1.05 equiv) and 72 mg of 2a (0.35 mmol), followed by 3.5 mL of dry MeCN. The mixture was briefly stirred and 235 mg of TBAT (1.25 equiv) was added in one portion. The vial was sealed, wrapped with Parafilm® and stirred at room temperature for 1 day. The resultant mixture was poured into an aqueous solution of NaHCO3 and extracted three times with DCM. The combined DCM extracts were dried over MgSO4, evapoated, and the residue was purified by column chromatography (1:1 to 1:1.5 hexanes/EtOAc) to afford 71 mg of product 3a (72%) as a slightly yellow solid; mp 154–156 °C; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.6 Hz, 2 H), 7.30 (t, J = 7.7 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 6.94 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 7.5 Hz, 1 H), 5.10 (s, 1 H), 3.83 (s, 3 H), 3.55–3.60 (m, 1 H), 3.02–3.18 (m, 2 H), 2.79–2.85 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 162.5, 159.8, 135.3, 133.7, 130.2, 129.6, 128.6, 124.8, 123.7, 114.2, 112.7, 74.0, 55.3, 52.0, 36.7; HRMS (EI): calcd for C17H16N2O2 280.1212, found 280.1216. NOTE: Most products exhibit air-sensitivity presumably through oxidation of the methine C–H bond in the central 5-membered ring. Solid samples can be stored well, but most samples in solution readily decompose. All of the work-up, purification, and characterization should be performed as quickly as possible, and storing samples as solutions should be avoided.
15. At least in the case of TBAT, running the reaction with a higher loading of 1a for a shortened reaction time did not improve the yield.
16. It should be pointed out that the azomethine imine derived from N-methyl 3-indolecarboxaldehyde reacted with 1a to afford exclusively a 1:2 adduct in quantitative yield. We have not yet been able to unambiguously assign the structure of this product.
17. Most azomethine imines are more soluble in DCM than in acetonitrile. Reactions in DCM are cleaner, but slower. After 1d of reaction time, the benzyne precursors were not generally fully consumed. These reactions were not further optimized in terms of reaction time and mixed solvents.