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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Am Chem Soc. Author manuscript; available in PMC 2010 August 26.
Published in final edited form as:
PMCID: PMC2763378

Gold-Catalyzed [3+3]-Annulation of Azomethine Imines with Propargyl Esters

The reactions of alkenyl Fischer carbenes 1 with 1,3-dipoles typically proceed via a concerted-asynchronous [3+2] cycloaddition (eq 1). Considering the orbitals involved in these transformations, the isolobal analogy allows the comparison of the reactivity of 1 to that of Lewis-acid complexed acrylates.1 In contrast, the LUMO of alkenyl metal-carbenoids of type 2 may be approximated as singlet vinylcarbenes (eq 2).2,3 Given this analogy, a [3+3]-cycloaddition between 1,3-dipoles and carbenoids of type 2 would be predicted. Unfortunately, free electrophilic vinylcarbenes undergo rapid rearrangement to cyclopropenes and intermolecular cycloadditions of these species are typically low yielding.4,5 This problem has been circumvented through the use of alkenyl metal-carbenoids 2, which are typically generated in situ from metal-catalyzed diazo decomposition;6 however, cycloaddition reactions of 1,3-dipoles with carbenoids7 of type 2 have yet to be reported. We report herein a gold(III)-catalyzed [3+3]-cycloaddition8 of propargyl esters and azomethine imines, which is proposed to proceed via stepwise cycloaddition with a gold(III)-carbenoid intermediate of type 2.9,10,11

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Beginning with our previously optimized reaction conditions,9d we were delighted to find that bicyclic [3+3] cycloadduct 5a was formed in 90% yield and with 6:1 cis:trans diastereoselectivity in the Au(III)-catalyzed reaction of ylide 4a with propargyl ester 3a (Table 1, entry 1).12,13 While varying the solvent failed to provide an increase in the diastereoselectivity (entries 2–4), lowering the temperature to 0 °C improved the ratio of cis:trans to 8:1 (entry 5).14 Other Au(III)-chloride salts also catalyzed the reaction with only slightly diminished yields (entries 6–7); however, Au(III) bromide and various Au(I) catalysts failed to provide any of the desired product (entries 8–9).15

Table 1
Reaction optimization.

With optimal conditions in hand (entry 5), the substrate scope of the gold-catalyzed [3+3]-cycloaddition reaction was examined. As demonstrated in the reaction of β-phenyl substituted azomethine imine 4a, substitution of the β-position of the pyrazolidinone generally provides bicyclic product 5a with high cis selectivity (vida infra). Alkyl substituents are also tolerated at this position (Table 2, entries 1–2), with larger substituents giving increased selectivity (20:1 for tert-butyl versus 8:1 for methyl). Remarkably, even an alkynyl substituent is sufficient to provide high selectivity (7:1, entry 3). Moreover, this reaction was readily extended to the synthesis of tetracycle (eq 3). Following the initial [3 + 3] cycloaddition of azomethine imine 4p, the alkyne was deprotected with TBAF and subjected to Au(I)-catalyzed hydroarylation conditions to deliver 7.16

Table 2
Azomethine imine scope.

The azomethine imine can also be substituted at the α-position, although in this case the product (5e) was formed with 1.3:1 cis:trans diastereoselectivity (entry 4). On the other hand, the cycloaddition of azomethine imine 4f, having both α- and β-substituents, remained highly selective (10:1, entry 5). Finally, the backbone need not be substituted (entry 7), but can also accommodate quaternary carbons in either position (entries 8–9).

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The aldehyde-derived substituent of the azomethine imine can also be varied. Both electron-rich and electron-deficient aryl groups are well tolerated in the gold(III)-catalyzed cycloaddition (entries 10–11). Ortho-substituted aryl groups are also accommodated (entries 12–13), but provide the cycloadducts with significantly lower diastereoselectivity. Finally, the cycloaddition reaction of ylides derived from aliphatic aldehydes generally proceeded in lower yield (entry 14).

An additional stereocenter is generated when secondary propargyl esters are employed (eqs 4, 5). In this case, regardless of whether the cycloaddition is concerted or stepwise (as depicted),17 the high 1,2-cis diastereoselectivity can be rationalized as resulting from the cis-imine geometry and the preferred trans geometry of the proposed gold-carbenoid intermediate.9d,18 To gain further insight into the origin of the 1,2-cis stereoselectivity, secondary propargyl ester 8c was reacted with tert-butyl substituted azomethine imine 4c (eq 5).19 In this case, a 2:1 mixture of diastereomers with respect to the pyrazolidinone substituent, and favoring the 1,3-trans isomer of 9c, was formed.20 Furthermore, the high diastereoselectivity in the gold-catalyzed reactions of 3a can be rationalized by minimization of unfavorable steric interactions between the propargyl ester methyl groups and the β-substituent in the ring closing transition state (eq 6). These result suggests that the diastereoselectivity is determined during ring closing, rather than in the formation of allylgold intermediate 10.13

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In conclusion, we have developed a gold(III)-catalyzed synthesis of diazabicycles from readily available starting materials.21 This report represents the first example of a formal cycloaddition between alkenyl metal carbenoids and 1,3-dipoles. In contrast to the previously reported cycloadditions,9d,10f this reaction highlights the difference in the reactivity of alkenyl Fischer carbenes and the alkenyl Au-carbenoids generated from the rearrangement of propargyl esters. Further studies exploring and exploiting this difference are ongoing and will be reported in due course.

Supplementary Material






We gratefully acknowledge NIHGMS (RO1 GM073932), Bristol-Myers Squibb, and Novartis for funding, and Johnson Matthey for the generous donation of AuCl3. Y.S. thanks the China Scholarship Council (Grant no. [2008]3019) for a predoctoral fellowship.


Supporting Information Available: Experimental procedures, compound characterization data (PDF), and X-ray structure data (CIF). This data is available free of charge at


1. (a) Barluenga J, Rodrígues F, Fañanás FJ, Flórez J. Topics Organomet Chem. 2004;13:59. (b) Barluenga J, Santamaria J, Tomás M. Chem Rev. 2004;104:2259. [PubMed] (c) Sierra MA, Fernández I, Cossío FP. Chem Commun. 2008:4671. [PubMed]
2. (a) Davies HML, Clark DM, Alligood DB, Elband GR. Tetrahedron. 1987;43:4265. (b) Davies HML, Hu B. Tetrahedron Lett. 1992;33:453.
3. For descriptions of singlet vinylcarbene, see: (a) Hoffmann R, Zeiss GD, Van Dine GW. J Am Chem Soc. 1968;90:1485. (b) Davis JH, Goddard WA, III, Bergman RG. J Am Chem Soc. 1977;99:2427. (c) Sevin A, Arnaud-Danon L. J Org Chem. 1981;46:2346. (d) Yoshimine M, Pacansky J, Honjou N. J Am Chem Soc. 1989;111:2785.
4. (a) Bertrand G, editor. Carbene Chemistry: From Fleeting Intermediates to Powerful Reagents. FontisMedia; Lausanne, Dekker, New York: 2002. (b) Moss RA, Platz MS, Jones M Jr, editors. Reactive Intermediate Chemistry. Wiley-Interscience; Hoboken, NJ: 2004.
5. Nucleophilic singlet vinylcarbenes react as 3-carbon units in cycloadditions with olefins, see: Boger DL, Wysocki RJ. J Org Chem. 1988;53:3408.
6. (a) Davies HML. Curr Org Chem. 1998;2:463. (b) Davies HML, Walji AM. In: Modern Rhodium-Catalyzed Organic Reactions. Evans PA, editor. Wiley-VCH; Weinheim, Germany: 2005. p. 301.
7. For the first use of the term carbenoid as a “description of intermediates which exhibit reactions qualitatively similar to those of carbenes without necessarily being free divalent carbon species,” see: Closs GL, Moss RA. J Am Chem Soc. 1964;86:4042.
8. For examples of formal [3 + 3] cycloaddition reactions of azomethine imines, see: (a) Shintani R, Hayashi T. J Am Chem Soc. 2006;128:6330. [PubMed] (b) Chan A, Scheidt KA. J Am Chem Soc. 2007;129:5334. [PubMed] (c) Perreault C, Goudreau SR, Zimmer LE, Charette AB. Org Lett. 2008;10:689. [PubMed]
9. For examples of gold-catalyzed intermolecular cycloaddition reactions using propargyl esters, see: (a) Johansson MJ, Gorin DJ, Staben ST, Toste FD. J Am Chem Soc. 2005;127:18002. [PubMed] (b) Gorin DJ, Dubé P, Toste FD. J Am Chem Soc. 2006;128:14480. [PubMed] (c) Gorin DJ, Watson IDG, Toste FD. J Am Chem Soc. 2008;130:3736. [PubMed] (d) Shapiro ND, Toste FD. J Am Chem Soc. 2008;130:9244. [PubMed]
10. For additional examples of gold-catalyzed intermolecular cycloaddition reactions, see: (a) Ito Y, Sawamura M, Hayashi T. J Am Chem Soc. 1986;108:6405. (b) Asao N, Takahashi K, Lee S, Kasahara T, Yamamoto Y. J Am Chem Soc. 2002;124:12650. [PubMed] (c) Kusama H, Miyashita Y, Takaya J, Iwasawa N. Org Lett. 2006;8:289. [PubMed] (d) Melhado AD, Luparia M, Toste FD. J Am Chem Soc. 2007;129:12638. [PubMed] (e) Zhang G, Huang X, Zhang L. J Am Chem Soc. 2008;130:1814. [PubMed] (f) Zhang G, Zhang L. J Am Chem Soc. 2008;130:12598. [PubMed]
11. (a) Fürstner A, Davies PW. Angew Chem, Int Ed. 2007;46:3410. [PubMed] (b) Hashmi ASK. Chem Rev. 2007;107:3180. [PubMed] (c) Gorin DJ, Toste FD. Nature. 2007;446:395. [PubMed] (d) Shen HC. Tetrahedron. 2008;64:7847. (e) Jiménez-Núñez E, Echavarren AM. Chem Rev. 2008;108:3326. [PubMed]
12. The major isomer was assigned to be cis by X-ray crystallography (see supporting information).
13. Similar cis-selectivity has been observed, see: reference 8. (a) Suárez A, Downey CW, Fu GC. J Am Chem Soc. 2005;127:11244. [PubMed] (b) Bonin M, Chauveau A, Micouin L. Synlett. 2006;15:2549.
14. Employing a different propargyl ester (acetate or pivolate) provided no change in selectivity.
15. HCl, PtCl2, PdCl2(PPh3)2, [IrCl(cod)]2, and [RuCl2(CO)3]2 failed to promote this reaction.
16. Nevado C, Echavarren AM. Chem Eur J. 2005;11:3155. [PubMed]
17. Additional evidence for a stepwise mechanism was obtained in the reaction of azomethine imine 11, which furnished enamine 12 after ring fragmentation and tautomerization.
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18. Witham CA, Mauleón P, Shapiro ND, Sherry BD, Toste FD. J Am Chem Soc. 2007;129:5838. [PubMed]
19. This substrate combination was chosen to aid in characterization of the products. Nearly identical selectivites were observed in reactions employing either 8a or 8c.
20. The configuration of the minor isomer was confirmed by X-ray crystallography (see supporting information).
21. For further synthetic transformations of the diazabicycles, see the supporting information.