Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Angew Chem Int Ed Engl. Author manuscript; available in PMC 2010 June 28.
Published in final edited form as:
PMCID: PMC2893043

Stereoselective Synthesis of Highly Substituted Cyclopentenones through [4+1] Annulations of Trialkylsilyl Vinyl Ketenes with α-Benzotriazolyl Organolithium Compounds

Cyclopentenones serve as valuable synthetic building blocks and are themselves key features in the structure of a number of prostaglandins[1] and other bioactive natural products. Popular strategies for the construction of this important ring system include the intramolecular aldol reaction, the Nazarov cyclization,[2] the Rautenstrauch rearrangement,[3] and the Pauson–Khand reaction.[4,5] Only a few general [4+1] routes to five-membered carbocycles have been reported to date, one example being the method we developed based on anion-accelerated vinylcyclopropane rearrangements.[6,7] Recently, studies by us[8] and others[9] have led to several new [4+1] approaches to the synthesis of the 2-cyclopentenone ring system. Herein, we report a new variant of our stereo-controlled [4+1] annulation strategy that provides especially efficient access to highly substituted and functionalized cyclopentenones.

As outlined in Scheme 1, our [4+1] annulation strategy is based on the reaction of nucleophilic species with leaving groups (“carbenoid reagents”) with trialkylsilyl vinyl ketenes (“TAS vinyl ketenes”).[8] The utility of vinyl ketenes as versatile intermediates in organic synthesis is now well established.[10] However, vinyl ketenes are rarely isolable species and in most applications are generated as transient intermediates which are trapped in situ in [2+2] cycloadditions. Silyl substituents have the ability to suppress the usual propensity of vinyl ketenes to undergo dimerization and [2+2] cycloaddition reactions, thus opening up new opportunities for useful synthetic transformations. For example, TAS vinyl ketenes participate as electron-rich diene components in Diels–Alder and hetero-Diels–Alder reactions leading to cyclohexenones, phenols, and oxygen and nitrogen heterocycles.[11] In the case of reactions with carbenoid reagents, addition initially furnishes dienolate intermediates, which are believed to undergo ionization and subsequent 4π electrocyclization to generate cyclopentenone rings (see below). TAS vinyl ketenes are readily available through several routes, including the photochemical Wolff rearrangement of α′-silyl-α′-diazo-α,β-unsaturated ketones used for the preparation of 1a–c in this study.[11a]

Scheme 1
Strategy for [4+1] annulation. L=leaving group.

The goal of the current investigation was to extend the scope of this [4+1] annulation strategy to include the synthesis of cyclopentenones with a much broader range of substituents at the C5 position. A variety of carbenoid reagents were screened with the aim of identifying new classes of molecules that are competent in the desired transformation and are more readily available than the diazo compounds, sulfur ylides, and stable carbenes previously employed.[8] Among the several classes of compounds examined to date, α-benzotriazolyl organolithium compounds of type 3 were best able to meet our requirements (Scheme 2). Extensive research by Katritzky and co-workers over the past two decades has demonstrated the utility of N-substituted benzotriazoles as valuable intermediates for organic synthesis.[12] Benzotriazoles of type 2 bearing a wide range of substituents are either commercially available or readily prepared in one or two steps from inexpensive starting materials and undergo metalation with n-butyllithium at −78 °C to provide access to α-benzotriazolyl organolithium derivatives of type 3. The ability of benzotriazole to function as a leaving group is also well documented and has been exploited by Katritzky and co-workers in the context of numerous useful synthetic transformations.[12]

Scheme 2
Preparation of α-benzotriazolyl organolithium compounds. Benzotriazoles 2b and 2d–f are commercially available, and the details for the preparation of 2a, 2c, and 2g–i are given in the Supporting Information.

The reaction of the benzotriazolyl carbamate 2a with TAS vinyl ketene 1a was examined to investigate the feasibility of the proposed [4+1] annulation (Scheme 3). Benzotriazole 2a was prepared in 70% overall yield as previously described by Katritzky and co-workers[13] through protection of benzylamine as its tert-butyloxycarbonyl (Boc) derivative and reaction of the crude carbamate with one equivalent of benzotriazole and one equivalent of paraformaldehyde in the presence of catalytic para-toluenesulfonic acid (toluene, reflux). Metalation of 2a with nBuLi produced the expected organolithium species, which was found to add smoothly to vinyl ketene 1a at −78°C in the desired fashion. Upon warming to room temperature, the resulting dienolate intermediate lost the benzotriazole moiety and cyclopentenone 4a formed in good yield and with greater than 96% selectivity for the trans-substituted isomer.

Scheme 3
Demonstration of the feasibility of the [4+1] annulation. Bn=benzyl.

Tables 1 and and22 delineate the scope of the [4+1] annulation. In some cases, the desired cyclopentenone begins to appear at low temperature during the addition of the organolithium reagent, and formation of the five-membered-ring product is completed simply by warming to room temperature (Table 1). This protocol proved effective for annulations that involve carbenoid reagents with strong electron-donor substituents such as amine derivatives (entries 1 and 2) and the combination of an alkoxy moiety and a vinyl or alkynyl group (entries 3 and 4). Each of these reactions was observed to proceed with a preference for the formation of the cyclopentenone with the heteroatom substituent at C5 trans to the substituent at C4. This preference is particularly high with small R3 groups, such as hydrogen or alkynyl moieties. The latter case is synthetically significant, as the products of such reactions (e.g., 7a) undergo hydrogenation (Scheme 4) to furnish 5-alkyl-substituted cyclopentenones that cannot be produced directly under such mild conditions or with such high stereoselectivity (see below).

Scheme 4
Preparation of 5-alkyl-substituted cyclopentenones.
Table thumbnail
Table1 [4+1] Cyclopentenone annulations.[a]
Table 2
Lewis acid promoted [4+1] cyclopentenone annulations.[a]

Attempted annulation with α-benzotriazolyllithium reagents 3d–i under similar conditions did not lead to the desired cyclopentenones. Control experiments that employed benzotriazole 3d confirmed that addition to TAS vinyl ketene 1a proceeds smoothly at −78 °C in the expected manner, but cyclization of the resulting dienolate intermediate does not then occur. We therefore turned to the use of Lewis acids to promote the crucial ionization of the benzotriazole group required for five-membered-ring formation. Extensive screening studies identified ZnBr2 as particularly effective for the desired transformation.[14] Although no reaction is observed upon addition of one equivalent of ZnBr2 to the dienolate solution, efficient cyclization takes place when two or more equivalents of the Lewis acid are added at −78 °C and the reaction mixture is allowed to warm to room temperature. Under these conditions, the desired [4+1] annulation can be achieved with a variety of carbenoid reagents that bear a single heteroatom substituent such as SPh or OMe (Table 2). Cyclopentenone formation is even observed with the aryl-substituted benzotriazole 3g, although in this case elevated temperatures are required to complete the cyclization.

A notable feature of these [4+1] annulations is the high level of stereoselectivity observed in most of the reactions. Control experiments established that the stereo-chemical outcome of these [4+1] annulations is not a consequence of thermodynamic control. Specifically, equilibration experiments yielded mixtures of trans- and cis-substituted cyclopentenones with ratios significantly different from those obtained in the annulation.[15] Thus, it appears likely that the stereochemical course of the [4+1] annulation reflects a mechanism-based kinetic preference for the observed products.

Scheme 5 outlines several alternative pathways to account for the mechanism of the [4+1] annulation. Addition of the carbenoid reagent to the vinyl ketene is predicted to be highly stereoselective because of the shielding effect of the bulky trialkylsilyl group and should result in the formation of the Z-enolate 18. Direct formation of the five-membered-ring product could then result from a concerted process in which ring closure is concomitant with leaving-group departure. An alternative pathway involves ionization to produce oxidopentadienylic cation 20,[16] which should then undergo rapid conrotatory 4π-electrocyclic closure[17] to generate the cyclopentenone product.[18] Finally, the involvement of cyclopropanone intermediates of type 19 cannot be excluded, particularly in view of the finding that simple silyl ketenes react with diazomethane and trimethylsilyldiazomethane to form mono- and bis(silyl)cyclopropanones.[19]

Scheme 5
Possible mechanistic pathways for the [4+1] annulation. M=metal center, L=ligand.

The stereochemical outcome of the [4+1] annulations that we investigated previously[8] is consistent with a mechanism that involves stereospecific conrotatory electrocyclic closure of a 2-oxidopentadienylic cation. In those prior cases, we suggested that ionization of the dienolate intermediate occurs to generate a cation in which the single C1 substituent is cis to the oxy anion to minimize nonbonded interactions. A similar mechanism can account for the reactions reported herein, provided that one assumes that ionization leads to the isomer of intermediate 20 shown in Scheme 5 because of an associative interaction between the heteroatom Z and the metal (M = Zn or Li) in 18 and/or 20. Alternatively, if cyclization of 18 involves a concerted process, then the stereochemical outcome could reflect a preference for the mode of conrotation from 18 that rotates the leaving group anti to the incipient σ bond and which proceeds via the transition state in which the donor heteroatom occupies an “outside” position (“torquoselectivity”).[20]

The vinyl silane moiety incorporated in the [4+1] annulation products provides a useful handle for further synthetic transformations. Of particular interest to us was their conversion into vinyl halides, as a number of naturally occurring 2-halocyclopentenones have recently been found to exhibit potent antitumor activity.[1] In addition, the utility of 2-haloenones in a variety of transition-metal-catalyzed coupling reactions is well documented. With these ends in mind, we investigated the transformations outlined in Scheme 6 to lay the groundwork for future applications of this annulation methodology. Conversion of α-silyl cyclopentenone annulation products 11 a and 12a into iodoenone 22 proceeded smoothly by using a modification of the method of Alimardanov and Negishi.[21] Reduction of 22 with nBu3SnH then afforded 23, and Sonogashira coupling proceeded smoothly to furnish 24 with no detectable epimerization or double-bond migration in either case.

Scheme 6
Useful synthetic transformations of [4+1] annulation products. AIBN=azobisisobutyronitrile.

Further studies are underway aimed at the development of asymmetric variants of the annulation reaction and its application in the synthesis of natural products.

Supplementary Material

Supporting Information


We thank the National Institutes of Health (GM 28273) and Merck Research Laboratories for generous financial support.


Supporting information for this article is available on the WWW under or from the author.


[1] Review: Roberts SM, Santoro MG, Sickle ES. J. Chem. Soc. Perkin Trans. 1. 2002:1735..
[2] a) Habermas KL, Denmark SE, Jones TK. Org. React. 1994;45:1. b) Tius MA. Acc. Chem. Res. 2003;36:284. [PubMed]
[3] a) Rautenstrauch V. J. Org. Chem. 1984;49:950.; for a recent gold(I)-catalyzed variant, see: b) Shi X, Gorin DJ, Toste FD. J. Am. Chem. Soc. 2005;127:5802. [PubMed].
[4] a) Schore NE. Org. React. 1991;40:1. b) Brummond KM, Kent JL. Tetrahedron. 2000;56:3263.
[5] For a review of transition-metal-mediated routes to cyclopentenones, see: Gibson SE, Lewis SE, Mainolfi N. J. Organomet. Chem. 2004;689:3873..
[6] Danheiser RL, Bronson JJ, Okano K. J. Am. Chem. Soc. 1985;107:4579. and references therein.
[7] For other recent examples, see: Spino C, Rezaei H, Dupont-Gaudet K, Bélanger F. J. Am. Chem. Soc. 2004;126:9926. and references therein. [PubMed].
[8] a) Loebach JL, Bennett DM, Danheiser RL. J. Am. Chem. Soc. 1998;120:9690.; b) Dalton AM, Zhang Y, Davie CP, Danheiser RL. Org. Lett. 2002;4:2465. [PubMed]; for the extension of this strategy to include reactions of nucleophilic carbenes, see: c) Rigby JH, Wang Z. Org. Lett. 2003;5:263. [PubMed].
[9] For examples, see: a) Murakami M, Itami K, Ito Y. J. Am. Chem. Soc. 1999;121:4130.; b) Gagnier SV, Larock RC. J. Am. Chem. Soc. 2003;125:4804. [PubMed].
[10] Dudley GB, Takaki KS, Cha DD, Danheiser RL. Org. Lett. 2000;2:3407. and references therein. [PubMed]
[11] a) Loebach JL, Bennett DM, Danheiser RL. J. Org. Chem. 1998;63:8380. b) Bennett DM, Okamoto I, Danheiser RL. Org. Lett. 1999;1:641. [PubMed]
[12] Reviews: a) Katritzky AR, Lan X, Yang JZ, Denisko OV. Chem. Rev. 1998;98:409. [PubMed]; b) Katritzky AR, Manju K, Singh SK, Meher NK. Tetrahedron. 2005;61:2555..
[13] Katritzky AR, Luo Z, Fang Y, Steel PJ. J. Org. Chem. 2001;66:2858. [PubMed]
[14] Other Lewis acids that promote the desired reaction in good yield include BF3·OEt2, AlCl3, Cu(OTf)2, TiCl4, and SnCl4.
[15] For example, exposure of 9a to KOtBu in THF (RT, 19 h) afforded a 91:9 mixture of 9a and the corresponding cis isomer, and similar reaction of 11a produced a 62:38 mixture of trans- and cis-substituted cyclopentenones; exposure of 12a to methanesulfonic acid (MeOH, RT, 32 h) afforded a 70:30 mixture of trans/cis isomers.
[16] Depending on the reaction conditions, this intermediate may be a free zwitterionic species or could still be associated with the metal center.
[17] Pentadienyl cation electrocyclic ring closures are involved in the mechanism of the Nazarov cyclization; for reviews, see: reference [2a] and Denmark SE. In: Comprehensive Organic Synthesis. Trost BM, Fleming I, editors. Vol. 5. Pergamon; Oxford: 1991. p. 751..
[18] For the formation of cyclopentenones through the base-induced cyclization of α′-chloro-β′,γ′-unsaturated ketone enolate and enamine derivatives, see: Mathew J. J. Org. Chem. 1991;56:713.. Although it was proposed that these cyclizations proceed by an “intramolecular abnormal SN2′” mechanism, we believe these reactions more likely involve the cyclization of an oxidopentadienylic cation analogous to 20. For a related transformation which involves a benzotriazolyl moiety in place of chloride as the leaving group, see: Katritzky AR, Zhang G, Jiang J. J. Org. Chem. 1995;60:7605..
[19] Zaitseva GS, Lutsenko IF, Kisin AV, Baukov Yu. I., Lorberth J. J. Organomet. Chem. 1988;345:253. and references therein.
[20] Theoretical studies predict that electron-donor groups prefer an “outside” position and electron-withdrawing groups an “inside” position in the electrocyclic closure of pentadienylic cations; see: a) Kallel EA, Houk KN. J. Org. Chem. 1989;54:6006.; b) Faza ON, López CS, Álvarez R, de Lera ÁR. Chem. Eur. J. 2004;10:4324. [PubMed].
[21] Alimardanov A, Negishi E.-i. Tetrahedron Lett. 1999;40:3839.