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. Author manuscript; available in PMC: 2010 May 13.
Published in final edited form as: J Am Chem Soc. 2009 May 13;131(18):6348–6349. doi: 10.1021/ja901649s

Ligand-Controlled Access to [4+2] and [4+3]-Cycloadditions in Gold-Catalyzed Reactions of Allene-Dienes

Pablo Mauleón 1, Rachel M Zeldin 1, Ana Z González 1, F Dean Toste 1,*
PMCID: PMC2711638  NIHMSID: NIHMS112046  PMID: 19378998

Abstract

graphic file with name nihms-112046-f0001.jpg By adjusting the electronic properties of the ancilliary ligands high selectivity can be achieved for either gold(I)-catalyzed [4+2]- or [4+3]-cycloaddition reactions of diene-allenes. Triarylphosphitegold(I) complexes are employed as catalysts for a [4+2]-cycloaddition reactions leading to alkylidenecyclohexenes. Conversely, di-t-butylbiphenylphosphinegold(I)-catalyzed reactions afford cycloheptadienes via [4+3]-cycloaddition reactions.

The utility of homogenous transition metal catalysis derives, in part, from the ability to influence the outcome of the catalyzed reaction by variation of the ancillary ligands.1 We were initially attracted to LAu(I)X complexes as catalysts due to the potential of controlling reactivity2 and stereoselectivity3 by manipulating the neutral(L) and/or anionic(X)4 ligands. While these ligand effects on catalysis with cationic gold(I) complexes have been demonstrated, examples of ligand variation as a means to achieve divergent reactivity in gold-catalyzed reactions remain elusive.5,6 In this context, we were intrigued by the observation that, in sharp contrast to the selective [2+2]-cycloaddition of allenenes,7 the triphenylphosphinegold(I)-catalyzed reaction of allene-diene 1 provided a 2:1 mixture of the [4+3]8 and [4+2]9 cycloadducts (eq 1). We were, therefore, attracted to the possibility that either cycloadduct could be accessed by variation of the ligand on the gold(I) catalyst.

graphic file with name nihms-112046-f0002.jpg (1)

We hypothesized that the product selectivity in gold(I)-catalyzed cycloaddition reactions could be impacted by modulating the relative stability of the cationic transition states generated during the course of the cycloadditions. In particular fine tuning of the electronic properties of the catalyst should have a direct impact on the stability of gold(I)-carbenoid intermediate A formed in the [4+3]-cycloaddition.10 For example, we posited that the pathway leading to the [4+3]-cycloadduct could be favored by employing electron-rich σ-donor ligands that would increase the relative stability of pathway leading to A, while having significantly less impact on the formation of B.

In accord with this hypothesis, replacing Ph3P with the Takasago BRIDP ligands11 resulted in highly selective formation of the seven-membered ring (Table 1, entries 2-5). Unfortunately, these reactions, as well as that catalyzed by (IPr)gold(I), produced varying amounts of olefin isomerization to cycloheptadiene isomer 3′. The selectivity was improved to 96:4 in favor of the [4+3]-cycloadduct 3 using di-t-butylbiphenylphosphinegold(I)12 as the catalyst (entry 6). Encouraged by these results, we considered that π-acceptor ligands might decrease the relative stability of A and therefore divert the reaction to the [4+2]-cycloadduct. Gratifyingly, the use of arylphosphitegold(I)5b,13 complexes produced exclusively the formal [4+2]-cycloaddition product 2 in very good yields after 30 minutes (entries 8 and 9).

Table 1.

Ligand effects on product distributiona

graphic file with name nihms-112046-t0003.jpg
entry Ligand (L) 2 : 3 : 3′b % yieldb
1 Ph3P 67:33:0 80
2 cy-cBRIDP 22:58:20 66
3 cy-vBRIDP 17:67:16 73
4 cBRIDP 17:73:10 74
5 vBRIDP 7:87:6 80
6 IPr 7:89:4 75
7 di-t-butylbiphenylphosphine 4:96:0 89
8 Tris(2,4-di-t-butyl phenyl)phosphite 100:0:0 91
9 (PhO)3P 100:0:0 89
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a

Reaction conditions: 0.1 M allene-diene in CH2Cl2, 5 mol% LAuCl, 5 mol% AgSbF6, rt.

b

Determined by 1H NMR using 1,3,5-trinitrobenzene as internal standard.

With these results in hand, we examined the scope of the gold(I)-catalyzed cycloaddition reactions. The triarylphosphitegold(I)-catalyzed [4+2] cycloaddition showed excellent tolerance for substitution on the diene component (examples 2, 4-6 in Scheme 1). For example, a 1,1-disubstituted diene underwent the gold-catalyzed [4+2]-cycloaddition to afford cycloadduct 5 containing a quaternary carbon. Variations in the tether were also accepted, as demonstrated by the cycloaddition leading to pyrrolidine 8. In all cases the reactions were highly diastereoselective, affording exclusively the trans-fused cycloadduct.14,15 With the exception of the formation of 4, the arylphosphitegold(I)-catalyzed reaction was highly selective for the [4+2]-cycloadduct.

Scheme 1.

Scheme 1

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[4+2]-Cycloaddition of Allene-dienes

The phosphinegold(I)-catalyzed [4+3]-cycloaddition also showed excellent scope. The reaction also tolerated variation in the tether, allene and the alkene substituents (Scheme 2). For example, a trans,trans-1,4-disubstituted diene underwent the gold-catalyzed cycloaddition to afford cycloheptadiene 13 as a single diastereomer. Moreover, in accord with our previous observations,16 treatment of 1 with 5 mol % IPrAuCl/AgSbF6 in the presence of excess diphenylsulfoxide led to formation of trans-fused bicyclic ketone 14 in 53% yield (eq 2).

Scheme 2.

Scheme 2

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[4+3]-Cycloaddition of Allene-dienes

graphic file with name nihms-112046-f0006.jpg (2)

In contrast to the stereochemical outcome of the related [2+2]-cycloaddition reaction,7 gold(I)-catalyzed [4+2] and [4+3]-cycloaddition reactions of deuterium-labeled dienes 15 and 16 were stereospecific (eq 3). For example, di-t-butylbiphenylphosphine-gold(I)-catalyzed reaction of 15 gave 17 as a single diastereomer (for additional details see supporting information). This observation suggests that the [4+2] and [4+3]-cycloaddition reactions may proceed through concerted mechanisms;8 however, a step-wise mechanism involving generation of an allyl cation from the addition of the diene to a gold-activated allene can not be excluded.15,17

graphic file with name nihms-112046-f0007.jpg (3)

On the basis of these results, we revisited the reaction gold(I)-catalyzed of allenenes to determine whether ligand-control could be employed to divert the previously reported [2+2]-cycloaddition reaction7 towards the [3+2]-cycloaddition reaction manifold. We were pleased to find that the di-t-butylbiphenylphosphinegold(I)-catalyzed reaction of phenyl-substituted enallenes led to exclusive formation of cyclopentene cycloadducts 21 and 22 as single diastereomers in high yield (eq 4). In this case, the reaction likely proceeds via a step-wise mechanism,18 in which ligand effects stabilize the pathway proceeding through gold(I)-stabilized cation C.

graphic file with name nihms-112046-f0008.jpg (4)

In conclusion, we have demonstrated that high selectivity can be achieved for gold(I)-catalyzed intramolecular [4+2]- and [4+3]-cycloaddition reactions of diene-allenes. The studies presented herein lend further support to the hypothesis that the gold(I) complexes are capable of stabilizing adjacent carbocations, such as A and C, and that this stabilization can be modulated by adjusting the electronic properties of the ancillary ligands. Given that this class of intermediate is prevalent in gold(I)-catalyzed transformations,19 the development of reactions that take advantage of this ligand-controlled reactivity is ongoing and will be reported in due course.

Supplementary Material

1_si_001
2_si_002
3_si_003
4_si_004

Acknowledgment

We acknowledge funding from National Institute of General Medical Services support (GM073932), Merck Research Laboratories, Bristol-Myers Squibb and Novartis. P.M. thanks the Spanish MICINN for postdoctoral fellowship. We thank Lorena Riesgo for conducting preliminary experiments, Takasago for the generous donation of BRIDP ligands and Johnson Matthey for a gift of AuCl3

Footnotes

Supporting Information Available: Experimental procedures and compound characterization data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

References

  • 1.(a) van Leeuwen PWNM. Homogenous Catalysis: Understanding the Art. Kluwer Academic Publishers; Dordrecht: 2004. Chapter 1. [Google Scholar]; (b) van Leeuwan PWNM.Chem. Rev 2000100274111749304 [Google Scholar]; (c) Tolman CA. Chem. Rev. 1977;77:313. [Google Scholar]
  • 2.(a) Teles Angew. Chem. Int. Ed. 1998;37:1415. doi: 10.1002/(SICI)1521-3773(19980605)37:10<1415::AID-ANIE1415>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]; (b) Gorin DJ, Sherry BD, Toste FD. Chem. Rev. 2008;108:3351. doi: 10.1021/cr068430g. For a review of ligand effects in Au-catalysis see: [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.(a) Ito Y, Sawamura M, Hayashi T. J. Am. Chem. Soc. 1986;108:6405. [Google Scholar]; (b) Widenhoefer RA. Chem. Eur. J. 2008;14:5382. doi: 10.1002/chem.200800219. For a review on stereoselective Au-catalysis see: [DOI] [PubMed] [Google Scholar]
  • 4.(a) LaLonde RL, Sherry BD, Kang EJ, Toste FD. J. Am. Chem. Soc. 2007;129:2452. doi: 10.1021/ja068819l. [DOI] [PubMed] [Google Scholar]; (b) Hamilton GL, Kang EJ, Mba M, Toste FD. Science. 2007;317:496. doi: 10.1126/science.1145229. [DOI] [PubMed] [Google Scholar]
  • 5.(a) Lemière G, Gandon V, Agenet N, Goddard J-P, de Kozak A, Aubert C, Fensterbank L, Malacria M. Angew. Chem. Int. Ed. 2006;45:7596. doi: 10.1002/anie.200602189. [DOI] [PubMed] [Google Scholar]; (b) Gorin DJ, Watson IDG, Toste FD. J. Am. Chem. Soc. 2008;130:3736. doi: 10.1021/ja710990d. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Xia Y, Dudnik AS, Gevorgyan V, Li Y. J. Am. Chem. Soc. 2008;130:6940. doi: 10.1021/ja802144t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.For selected examples of ligand-controlled divergent reactivity, see: Trost BM, Rhee YH. J. Am. Chem. Soc. 2002;124:2528. doi: 10.1021/ja011840w.Makino T, Itoh K. J. Org. Chem. 2005;69:395. doi: 10.1021/jo035551x.Kezuka S, Okado T, Niou E, Takeuchi R. Org. Lett. 2005;7:1711. doi: 10.1021/ol050085e.Gray BL, Schreiber SL. J. Comb. Chem. 2007;9:1028. doi: 10.1021/cc7001028.Walczak MAA, Wipf P. J. Am. Chem. Soc. 2008;120:6924. doi: 10.1021/ja802906k.
  • 7.Luzung MR, Mauleón P, Toste FD. J. Am. Chem. Soc. 2007;129:12402. doi: 10.1021/ja075412n. [DOI] [PubMed] [Google Scholar]
  • 8.Pt-catalyzed [4+3]: Trillo B, Fernando L, Gulías M, Castedo L, Mascareñas JL. Angew. Chem. Int. Ed. 2008;47:951. doi: 10.1002/anie.200704566.During the preparation of this manuscript a related NHCAu(I)-catalyzed [4+3] cycloaddition was reported: Trillo B, López F, Monteserrat S, Ujaque G, Castedo L, Lledós A, Mascareñas Chem. Eur. J. 2009;15:3336. doi: 10.1002/chem.200900164.
  • 9.Rh-catalyzed [4+2]:Wender PA, Jenkins TE, Shigeaki S. J. Am. Chem. Soc. 1995;117:1843.
  • 10.The choice of ligand has been shown to have an impact on the reactivity of Rh-carbenoid intermediates: Padwa A, Austin DJ, Price AT, Semones MA, Doyle MP, Protopopova MA, Winchester WR, Tran A. J. Am. Chem. Soc. 1993;115:8669.Mehía-Oneto JM, Padwa A. Tetrahedron Lett. 2004;45:9115. and references therein.
  • 11.Suzuki K, Hori Y, Nishikawa T, Kobayashi T. Adv. Synth. Catal. 2007;349:2089. [Google Scholar]
  • 12.Nieto-Oberhuber C, López S, Echavarren AM. J. Am. Chem. Soc. 2005;127:6178. doi: 10.1021/ja042257t. [DOI] [PubMed] [Google Scholar]
  • 13.López S, Herrero-Gómez E, Pérez-Galán P, Nieto-Oberhuber C, Echavarren AM. Angew. Chem., Int. Ed. 2006;45:6029–6032. doi: 10.1002/anie.200602448. [DOI] [PubMed] [Google Scholar]
  • 14.Established by X-ray analysis of [4+2]-cycloadduct 7 (see supporting information).
  • 15.The formal intramolecular [4+2]-cycloaddition of allyl cations and dienes also provides the endo-cycloadduct: Gassman PG, Singleton DA. J. Am. Chem. Soc. 1984;106:6085.Gassman PG, Singelton DA. J. Org. Chem. 1986;51:3075.
  • 16.Witham CA, Mauleón P, Shapiro ND, Sherry BD, Toste FD. J. Am. Chem. Soc. 2007;129:5838. doi: 10.1021/ja071231+. [DOI] [PubMed] [Google Scholar]
  • 17.This would require rapid trapping of the allyl cation. For excellent discussion of stereochemical course of allyl cation cycloadditions see: Hoffman HMR. Angew. Chem. Int. Ed. 1984;23:1.
  • 18.(a) Giguere RJ, Tassely SM, Rose MI, Krishnamurthy VV. Tetrahedron Lett. 1990;31:4577. [Google Scholar]; (b) Harmata M. Tetrahedron. 1997;53:6235. [Google Scholar]
  • 19.(a) Fürstner A, Davies PW. Angew. Chem., Int. Ed. 2007;46:2. doi: 10.1002/anie.200604335. [DOI] [PubMed] [Google Scholar]; (b) Hashmi ASK. Chem. Rev. 2007;107:31. [Google Scholar]; (c) Gorin DJ, Toste FD. Nature. 2007;446:395. doi: 10.1038/nature05592. [DOI] [PubMed] [Google Scholar]; (d) Jiménez-Núñez E, Echavarren AM. Chem. Rev. 2008;108:3326. doi: 10.1021/cr0684319. (a) [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1_si_001
NIHMS112046-supplement-1_si_001.pdf (5.2MB, pdf)
2_si_002
NIHMS112046-supplement-2_si_002.cif (33.1KB, cif)
3_si_003
NIHMS112046-supplement-3_si_003.cif (17.3KB, cif)
4_si_004
NIHMS112046-supplement-4_si_004.cif (16.7KB, cif)

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