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. Author manuscript; available in PMC: 2015 Apr 2.
Published in final edited form as: Tetrahedron Lett. 2014 Feb 24;55(14):2208–2211. doi: 10.1016/j.tetlet.2014.02.052

Synthesis and Tautomerism of Spiro-Pyrazolines

Sureshbabu Dadiboyena 1,†, Edward J Valente 2, Ashton T Hamme II 1,*
PMCID: PMC4036741  NIHMSID: NIHMS576774  PMID: 24882890

Abstract

An experimental study on the synthesis, tautomerism and acid promoted structural changes of spiro-pyrazolines is described. The target was achieved through a [3+2]-dipolar cycloaddition of an alkene with nitrile imines generated in situ and was isolated in high yield. The synthesized cycloadduct displayed a tendency to exhibit an imine-enamine type of tautomerism as evidenced by X-ray crystal and NMR studies. Furthermore, addition of an acid resulted in the transformation of an imine tautomer to an enamine. The current report constitutes a first formal observation of this kind of tautomerism observed in spiro-indoline pyrazolines.

Keywords: Spiro-isoxazolines; Spiro-pyrazolines; 1,3-Dipolar Cycloaddition; Tautomerism; Heterocycles; Indolines; Regioselectivity

1. Introduction

Spiro-isoxazolines1-3 and spiro-pyrazolines4,5 are of recurring interest to the chemists engaged in the drug-discovery areas of natural product synthesis and heterocyclic methodology development. These compounds incorporate useful isoxazole6 or pyrazole7 based motifs in their core structures and are junctioned to another carbocyclic/heterocyclic ring at one carbon atom. When compared to spiro-isoxazolines, spiro-pyrazolines, isosterically equivalent to spiro-isoxazolines where the nitrogen replaces the oxygen, are structurally rigid and present the flexibility for possible synthetic and biological property exploration.5 In addition to the synthesis of pyrazoles and pyrazoline derivatives, tautomerism is another area of equal interest due to their high application potential in biological systems, chemical reactivity, and molecular recognition.8-10 Although, the importance of tautomerism (imine-enamine) has been described very well for pyrazole related ring systems,9-11 it's rarely observed in analogous spiro-pyrazolines. As of today, only three reports exist on the structural changes observed in spiro-pyrazolines.12

Our long standing interest in this area resulted in the establishment of efficient strategies for the construction of architecturally complex natural product analogues and bioactive heterocycles of synthetic and biological interest.5,6d,7g,13,14 In addition to methodology development, we are also equally interested in assessing structural and biological applications for spiro-pyrazolines. Recently, we demonstrated the construction of 1,3,5-trisubstituted pyrazoles on the basis of the 1,3-dipolar cycloaddition protocol, which was then followed by an unforeseen ring fragmentation/elimination.14 We observed that the placement of an electron-rich or electron-deficient substituents of the aromatic ring at ortho-, meta-, and para-positions is crucial for the identity of the final product (pyrazole or spiro-pyrazoline). Additionally, we also postulated a mechanism based on the occurrence of an imine-enamine type of tautomerism and the factors leading to pyrazole formation rather than the anticipated spiro-pyrazoline (Scheme 1). Based on these observations, we decided to extend the investigation of this protocol for the preparation of a spiro-pyrazoline with an electron rich para-methoxy group on the aromatic ring. Herein, we present results from our ongoing research highlighting the first imine-enamine type of tautomerism observed in spiroindoline-pyrazolines.

Scheme 1.

Scheme 1

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Pyrazole synthesis from the spiro-pyrazoline intermediate 3.

2. Results and discussion

During our studies toward synthesizing spiro-pyrazolines, we discovered that when 1,3,3-trimethy-2-methylenelindoline (1) was used as the dipolarophile, spiro-pyrazoline 6 was the only product isolated. The cycloaddition process7g,14-16 leading to the desired spiro-pyrazoline 617 formation occurred with complete regiochemical integrity and in good isolated yield (Scheme 2). While assessing the NMR spectrum of the synthesized spiro-pyrazoline 6, we observed an inconsistency with respect to the diastereotopic methylene protons. The inconsistency with the methylene protons suggested the need for a detailed NMR study in selected solvents and data comparision of the reported spiro-pyrazolines. The spiro-pyrazoline 6 was subjected to NMR studies in chloroform-d and benzene-d6 solvents.18 The 1H NMR spectra clearly evidenced the spiro-pyrazoline to exist as imine 6 and enamine tautomer 7 in benzene-d6 and chloroform-d solvents respectively. The enamine tautomer 7 (CDCl3) displayed the enamine (CH=C-NH) proton (multiplet) peak at δ 4.15-4.17 ppm, and the imine tautomer (C6D6) 6 displayed the desired diastereotopic proton (C=N-CH2−) doublets at δ 3.00 and 3.4 ppm (Scheme 3).

Scheme 2.

Scheme 2

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Spiro-pyrazoline isolated from 1,3-dipolar cycloaddition.

Scheme 3.

Scheme 3

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Enamine-imine tautomerism exhibited by spiro-pyrazoline in chloroform-d and benzene-d6 solvents.

Additional DEPT-135 studies in benzene-d6 solvent concluded the methylene peak at δ 39.8 ppm facing downward demonstrating the occurance of spiro-pyrazoline as the imine 6. Furthermore, the observed methylene peak was absent when the study was repeated in chloroform-d. This type of observed tautomerism is the first of its kind and to our knowledge, only Toth's research group has documented similar results exhibited by spirochromone-pyrazolines.12 The existence of a spiro-pyrazoline as imine 6 and enamine 7 tautomers in chloroform and benzene solvents is depicted in Figure 1 where the imine tautomer is slightly yellow in C6D6. However, the enamine tautomer exists as a reddish-pink colored compound in CDCl3.

Figure 1.

Figure 1

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Spiro-pyrazoline existence as imine (left: benzene) and enamine (right: chloroform) tautomer.

Gratifyingly, the existence of spiropyrazoline 6 as a crystalline solid enabled us to perform X-ray studies to reveal compound's regio-structural features.19-21 Compound 6 (C26H27N3O) was unambiguously confirmed by the X-ray structural analysis and revealed the presence of –CH2-group at C15 carbon position, which provided the necessary evidence to show that the compound exists in the form of an imine (CH2-C=N) tautomer as a major conformer in the solid state. The ORTEP rendition of the crystal structure of 6 is as shown in Figure 2.

Figure 2.

Figure 2

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Thermal ellipsoid plot of spiro-pyrazoline 6.

Our next idea was to spectroscopically observe any structural changes that the spiro-pyrazoline would undergo from imine to enamine, or enamine to imine, in the presence of a proton source. We hypothesized that an acidic environment would provide a proton source in C6D6 that would change the favored tautomer from the imine to the analogous enamine. Previous reports described the addition of an trifluoroacetic acid (TFA) resulted in structural changes and indicated the transformation from an imine to an enamine.12c On the basis of this information, we decided to introduce TFA to the aforementioned NMR study in order to determine whether TFA would trigger any structural changes of spiro-pyrazoline 6 in chloroform-d and benzene-d6 solvents.22 Upon addition of TFA, the desired structural changes were observed and clearly the anticipated transformation from imine 6 to enamine 7, that is in accordance with literature precedent, was observed.23 The two characteristic doublets at δ 3.00 and 3.4 ppm that were characterisitic of the diastereotopic protons (C=N-CH2−) observed before TFA addition completely disappeared, and an extra peak toward NH proton appeared at δ 1.59 ppm. However, no potential change in tautomerism was observed when TFA was added to sample 7 that was dissolved in chloroform-d. The most likely reason for the aforementioned behavior is attributed to the relative stability and extended conjugation of one tautomer over the other under acidic conditions. However, the acidic nature of CDCl3 or commercial triflouroacetic acid that served as a proton source to bring the anticipated transformation remains inconclusive at this stage. The acid promoted imine-enamine tautomerism of the spiro-pyrazoline is shown in Scheme 4.

Scheme 4.

Scheme 4

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TFA promoted structural transformation of spiro-pyrazoline 6 in benzene-d6 and chloroform-d solvents.

3. Conclusions

In summary, the p-methoxyphenyl spiro-pyrazoline was synthesized via [3+2]-dipolar cycloaddition of the indoline dipolarophile with the corresponding hydrazonyl chloride. The synthesized spiro-pyrazolines exhibited imine-enamine type of tautomerism as evidenced by Xray crystal and NMR studies. Furthermore, evidence of the imine-enamine tautomerism in our spiro-pyrazolines provides credence for the tautomerism based mechanistic postulation for the spiro-pyazoline ring fragmentation that leads to the corresponding pyrazole.

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 does not necessarily represent the official views of the National Institutes of Health.

Footnotes

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References

  • 1.(a) Berquist PR, Wells RJ. Chemotaxonomy of the Porifera: The Development and Current Status of the Field. In: Scheuer PJ, editor. Marine Natural Products: Chemical and Biological Perspectives. Vol. 5. Academic Press; New York: 1993. pp. 1–50. [Google Scholar]; (b) Faulkner DJ. Nat Prod Rep. 1998:113. doi: 10.1039/a815113y. [DOI] [PubMed] [Google Scholar]
  • 2.(a) Berquist PR, Wells RJ. In: Marine Natural Products. Scheuer PJ, editor. V. Academic Press; New York: 1983. Chapter 1. [Google Scholar]; (b) Smietana M, Gouverneur V, Mioskowski C. Tetrahedron Lett. 1999;40:1291. [Google Scholar]
  • 3.(a) Adamo MFA, Chimichi S, De Sio F, Donati D, Sarti-Fantoni P. Tetrahedron Lett. 2002;43:4157. [Google Scholar]; (c) Harburn JJ, Rath NP, Spilling CD. J Org Chem. 2005;70:6398. doi: 10.1021/jo050846r. [DOI] [PubMed] [Google Scholar]; (d) Adamo MFA, Donati D, Duffy EF, Sarti-Fantoni P. J Org Chem. 2005;70:8395. doi: 10.1021/jo051181w. [DOI] [PubMed] [Google Scholar]; (e) Savage GP. Curr Org Chem. 2010;14:1478. [Google Scholar]; (f) Dadiboyena S. Curr Org Synth. 2013;13:661. [Google Scholar]; (g) Marsini MA, Huang Y, Van De Water R, Pettus TRR. Org Lett. 2007;9:3229. doi: 10.1021/ol0710257. [DOI] [PMC free article] [PubMed] [Google Scholar]; (h) Wasserman HH, Wang J. J Org Chem. 1998;63:5581. [Google Scholar]; (i) Boehlow TR, Harburn JJ, Spilling CD. J Org Chem. 2001;66:3111. doi: 10.1021/jo010015v. [DOI] [PubMed] [Google Scholar]; (j) Forrester AR, Thomson RH, Woo SO. Liebigs Ann Chem. 1978:66. [Google Scholar]; (k) Murakata M, Yamada K, Hoshino O. J Chem Soc, Chem Commun. 1994:443. [Google Scholar]; (l) Singh V, Yadav GP, Maulik PR, Batra S. Tetrahedron. 2008;64:2979. [Google Scholar]
  • 4.(a) Singh A, Roth GP. Organic Lett. 2011;13:2118. doi: 10.1021/ol200547m. [DOI] [PubMed] [Google Scholar]; (b) Dawood KM, Fuchigami T. J Org Chem. 2005;70:7537. doi: 10.1021/jo0507587. [DOI] [PubMed] [Google Scholar]; (c) Singh V, Singh V, Batra S. Eur J Org Chem. 2008:5446. [Google Scholar]; (d) Dawood K. Tetrahedron. 2005;61:5229. [Google Scholar]; (d) Dadiboyena S. Eur J Med Chem. 2013;63:347. doi: 10.1016/j.ejmech.2013.01.059. [DOI] [PubMed] [Google Scholar]; (e) Kerbel A, Vebrel J, Roche M, Laude B. Tetrahedron Lett. 1990;31:4145. [Google Scholar]; (f) Jedlovska E, Levai A, Toth G, Balazs B, Fisera L. J Heterocycl Chem. 1999;36:1087. [Google Scholar]
  • 5.Dadiboyena S, Hamme AT., II Tetrahedron Lett. 2011;52:2536. doi: 10.1016/j.tetlet.2011.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.For isoxazoles, see: Waldo JP, Larock RC. Org Lett. 2005;23:5203. doi: 10.1021/ol052027z.Grecian S, Fokin VV. Angew Chem, Int Ed. 2008;47:8285. doi: 10.1002/anie.200801920.Crossley JA, Browne DL. J Org Chem. 2010;75:5414. doi: 10.1021/jo1011174.Dadiboyena S, Xu J, Hamme AT., II Tetrahedron Lett. 2007;48:1295. doi: 10.1016/j.tetlet.2006.12.005.Dadiboyena S, Nefzi A. Tetrahedron Lett. 2012;53:2096. doi: 10.1016/j.tetlet.2012.02.041.Dadiboyena S, Nefzi A. Eur J Med Chem. 2010;45:4697. doi: 10.1016/j.ejmech.2010.07.045.Lee CC, Fitzmaurice RJ, Caddick S. Org Biomol Chem. 2009;7:4349. doi: 10.1039/b911098d.
  • 7.For pyrazoles, see: Browne DL, Helm MD, Plant A, Harrity JPA. Angew Chem Int Ed. 2007;46:8656. doi: 10.1002/anie.200703767.Browne Dl, Viva JF, Plant A, Gomez-Bengoa E, Harrity JPA. J Am Chem Soc. 2009;131:7762. doi: 10.1021/ja902460n.Deng X, Mani NS. Org Lett. 2008;10:1307. doi: 10.1021/ol800200j.Dadiboyena S, Hamme AT., II Curr Org Chem. 2012;16:1390.Dadiboyena S, Nefzi A. Eur J Med Chem. 2011;46:5258. doi: 10.1016/j.ejmech.2011.09.016.Janin YL. Chem Rev. 2012;112:3924. doi: 10.1021/cr200427q.Dadiboyena S, Valente EJ, Hamme AT., II Tetrahedron Lett. 2010;51:1341. doi: 10.1016/j.tetlet.2010.01.017.Browne DL, Harrity JPA. Tetrahedron. 2010;66:553.Oh L. Tetrahedron Lett. 2006;47:7943.
  • 8.(a) Zheng Z, Yu Z, Luo N, Han X. J Org Chem. 2006;71:9695. doi: 10.1021/jo061725+. [DOI] [PubMed] [Google Scholar]; (b) Dardonville C, Elguero J, Rozas I, Fernandez-Castano C, Foces-Foces C, Sobrados I. New J Chem. 1998:1421. [Google Scholar]; (c) Kwiakowsky JS, Pullman B. Adv Heterocycl Chem. 1975;18:199. [Google Scholar]
  • 9.(a) Sanguinet L, Pozzo J. J Phy Chem B. 2005;109:11139. doi: 10.1021/jp0442450. [DOI] [PubMed] [Google Scholar]; (b) Guimon C, Pfister-Guillouzo G, Begtrup M. Can J Chem. 1983;61:1197. [Google Scholar]; (c) Abdel-Wahab BF, Dawood KM. Arkivoc. 2012:491. [Google Scholar]
  • 10.Elguero J, Marzin C, Katrizky AR, Linda P. The Tautomerism of Heterocycles. Academic Press; New York: 1976. [Google Scholar]
  • 11.Hadda TB, Ali MA, Masand V, Gharby S, Fergoung T, Warad I. Med Chem Res. 2013;22:1438. [Google Scholar]
  • 12.(a) Toth G, Levai A, Dinya Z, Snatzke G. Tetrahedron. 1991;47:8119. [Google Scholar]; (b) Toth G, Levai A, Szollosy A, Duddeck H. Tetrahedron. 1993;49:863. [Google Scholar]; (c) Toth G, Levai A, Duddeck H. Mag Res Chem. 1992;30:235. [Google Scholar]
  • 13.(a) Ellis ED, Xu J, Valente EJ, Hamme AT., II Tetrahedron Lett. 2009;50:5516. doi: 10.1016/j.tetlet.2009.07.095. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) McClendon E, Omollo AO, Valente EJ, Hamme AT., II Tetrahedron Lett. 2009;50:533. doi: 10.1016/j.tetlet.2008.11.053. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Dadiboyena S, Hamme AT., II Eur J Org Chem. 2013:7567. doi: 10.1002/ejoc.201300840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Dadiboyena S, Valente EJ, Hamme AT. Tetrahedron Lett. 2009;50:291. doi: 10.1016/j.tetlet.2008.10.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.(a) Huisgen R. Angew Chem, Int Ed Engl. 1963;2:565. [Google Scholar]; (b) Huisgen R. Angew Chem, Int Ed Engl. 1963;2:633. [Google Scholar]
  • 16.General Procedures for the 1,3-Dipolar Cycloaddition: A solution of the 1,3,3-trimethy-2-methylenelindoline (3 mmol) and the hydrazonyl chloride (3 mmol) in 10 mL of either dry chloroform or dichloromethane was treated with triethylamine (334 mg, 3.3 mmol). The reaction mixture was stirred at rt until the disappearance of the starting materials, as evidenced by TLC. After the reaction was complete, a minimum amount of silica gel was added, and the solvent was evaporated under reduced pressure. The crude products were purified by flash column chromatography over silica gel using hexanes-ethyl acetate (8:2) ratio as an eluant system.
  • 17.Representative NMR data of 5′-(4-methoxyphenyl)-1,3,3-trimethyl-2′-phenyl-2′,4′-dihydrospiro[indoline-2,3′-pyrazole] (6): After column chromatography, this compound was obtained as light purple solid (Yield: 68%, 0.81g), mp 112-115°C; IR (CaF2, CCl4) ν 2969, 2933, 1603, 1514, 1428 cm-1. 1H NMR (imine form 6, C6D6): δ 1.10 (s, 3H), 1.29 (s, 3H), 2.25 (s, 3H), 3.03 (d, J = 18.2 Hz, 1H), 3.32 (s, 3H), 3.40 (d, J = 18.2 Hz, 1H), 6.09 (d, J = 7.6 Hz, 1H), 6.73 (t, J = 7.3 Hz, 1H), 6.76-6.94 (m, 4H), 7.03-7.22 (m, 5H), 7.72 (d, J = 8.8 Hz, 2H); 13C NMR: δ 29.1, 31.3, 39.8, 55.1, 100.6, 104.8, 114.6, 118.6, 118.8, 120.8, 121.8, 126.2, 127.5, 129.8, 141.8, 147.3, 150.8, 153.2, 160.8; (Enamine form 7, CDCl3): δ 1.67 (s, 6H), 2.70 (d, J = 5Hz, 3H), 3.85 (s, 3H), 4.14 (br s, 1H), 6.39 (t, J = 7.8Hz, 1H), 6.51 (d, J = 8Hz, 1H), 6.66 (d, J = 8 Hz, 1H), 6.72 (s, 1H), 6.79 (d, J = 7.8 Hz, 2H), 6.93-7.21 (m, 6H), 7.82 (d, J = 8.8 Hz, 2H); 13C NMR: δ 28.9, 31.1, 38.1, 55.6, 100.6, 110.7, 114.3, 116.7, 125.9, 126.1, 127.2, 128.1, 128.2, 128.2, 128.7, 129.5, 140.4, 147.3, 150.7, 152.8, 159.8; HRMS (EI): m/z calcd for C26H27N3O (MNa+): 420.2046; found: 420.2040.
  • 18.NMR study: ∼4-5mg of spiro-pyrazoline was dissolved in 0.5mL of the selected solvent.
  • 19.Sheldrick GM. SHELXS86. In: Crystallographic Computing 3. Sheldrick GM, Kruger C, Goddard R, editors. Oxford University Press; 1985. pp. 175–189. [Google Scholar]
  • 20.Sheldrick GM. SHELX97 [Includes SHELXS97, SHELXL97, CIFTAB] Programs for Crystal Structure Analysis (Release 97-2) Institüt für Anorganische Chemie der Universität; Tammanstrasse 4, D-3400 Göttingen, Germany: 1998. [Google Scholar]
  • 21.Structural information for spiro-pyrazoline (6) has been deposited with the CCDC as 701051, available free of charge from www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CambridgeCrystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033).
  • 22.The study was carried out in NMR tubes. Commercial TFA and NMR solvents were utilized without any purification.
  • 23.When 2-3 drops of commercial TFA was added dropwise to chloroform-d and benzene-d6 samples containing the spiro-pyrazoline, the tautomerism from imine 6 to enamine 7 was clearly observed in benzene-d6. Admixtures of C6D6 and CDCl3 weren't performed as part of this study.

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