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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2010 August 20.
Published in final edited form as:
PMCID: PMC2805901

Olefinic-Amide and Olefinic-Lactam Cyclizations


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Olefinic-amide and olefinic-lactam cyclization reactions that result in the generation of cyclic enamides are described.

Small molecules that contain electron rich olefins (enol ethers and enamides) are both valuable in their own right and are interesting precursors to more elaborate substrates.1,2 Over the past few years we have been interested in the generation and use of cyclic enol ethers and have recently described their synthesis from olefinic-ester and olefinic-lactone cyclizations using an in situ generated Ti reagent that is presumed to be a Ti ethylidene.3 Although the corresponding olefinic-amide cyclizations would be synthetically useful,4 to the best of our knowledge there are only two reports of related reactions that employ amides. Takeda has described Ti(II) promoted cyclizations of dithianes having pendant amides and,5 in work more closely related to that proposed here, Bennasar and co-workers have successfully carried out two-step olefinic-amide cyclizations to enamides.6 The Bennasar chemistry involves the initial conversion of amides into mixtures of cyclic and acyclic enamides using dimethyltitanocene followed by the conversion of the acyclic enamides into the corresponding cyclic enamides using the 2nd generation Grubbs catalyst.7 With a limited number of substrates they observed a mixture of cyclic and acyclic products from the dimethyltitanocene reaction. Representative of their results was the generation of indole 2 in 40% overall yield from olefinic-amide 1. In addition to synthesizing indoles, they also generated dihydroquinolines and dihydroisoquinolines using this chemistry. More problematic was the use of the two-step protocol to generate 7-membered ring substrates as olefin isomerization competed with cyclization. With some substrates they were able to overcome this problem by adding dihydroquinone to the reaction mixture.8

When combined with our experience with olefinic-ester and olefinic-lactone cyclizations, the Bennasar chemistry outlined above peaked our interest in studying olefinic-amide and olefinic-lactam cyclization reactions. Described here is the successful use of in situ generated titanium ethylidenes in this context.

In order to compare the titanium ethylidene reagent with Bennasar’s two-step protocol, we decided to initially examine the cyclization of aromatic substrates 4-6. Concerned about the potential reaction of carbonyl protecting groups with the titanium reagent, i.e. Boc, CBz, etc., we opted to initially avoid this potential problem by employing a Ts group in this capacity. As illustrated in Table 1, the cyclization of ene-amide 5 gave a 78% yield of dihydroquinoline 8C (entry 2). Bennasar’s two-step protocol on a related substrate resulted in a 41% overall yield. The cyclization to indole 7C was also successful giving it in 70% yield vs. 40% overall using the two-step procedure (entry 1 and Scheme 1). Finally, the use of ene-amide 6 resulted in a 58% yield of 7-membered ring substrate 9C along with 18% of the corresponding acyclic enamide 9A. Bennasar’s procedure was more competitive here; they were able to isolate a 50% overall yield of the seven-membered ring substrate along with 7% of the corresponding dihydroquinoline from olefin isomerization and cyclization. Olefin isomerization does not appear to be a problem with the titanium reagent.

Scheme 1
Bennasar and Co-Workers Synthesis of Indole 2 via RCM.
Table 1
Olefinic-Amide Cyclizations to Benzyl Fused Enamides

Having established the viability of the olefinic-amide cyclizations to aromatic substrates, we next explored the cyclization of non-aromatic olefinic-lactams. When ε-caprolactam substrates 10, 11, and 12 were subjected to the titanium ethylidene reagent we isolated cyclic enamides 14C, 15C, and 16C, as the exclusive products (Table 2, entries 1-3). Noteworthy because it is unlikely that this substrate could be formed from an acyclic olefinic-enamide cyclization was that this chemistry was successful in the generation of 4-membered ring substrate 14C.9,10 As with the aromatic substrate 6, lactam 13 gave a mixture of the cyclized seven-membered enamide 17C and an uncyclized product (entry 4).

Table 2
Olefinic-Lactam Cyclizations

Not surprisingly enamide 14C was not stable to SiO2 chromatography. For characterization purposes, we converted 14C into cyclobutanone 18 by subjecting it to aqueous acid.11 Additionally, bromoaminal 19 was generated from the treatment of 14C with NBS in MeOH.12

The lactam cyclizations are not limited to ε-caprolactam substrates. Cyclic enamides 22C and 23C were the major products from the cyclization of 2-pyrrolidinone 20 and δ-valerolactam 21, respectively (entries 2 and 3, Table 3). In contrast to the cyclization of ε-caprolactam substrate 12 to give 16C however, these reactions did result in the formation of small amounts of acyclic enamide.

Table 3
Olefinic-Lactam Cyclizations

As a final test of the methodology, we examined the cyclization of methyl and ethyl substituted amides 24 and 25 (Scheme 3) When these substrates were subjected to the titanium ethylidene reagent, cyclic enamide was isolated in synthetically useful quantities but as a mixture with the corresponding acyclic enamides. As a mechanistic test, we did not observe the formation of 26C when we resubjected acyclic enamide 26A to the reaction conditions. This is consistent with the notion that cyclic enamide results from an olefin-metathesis, carbonyl-olefination pathway.13

Scheme 3
Olefinic-Amide Cyclizations

In summary, we have demonstrated that titanium ethylidenes can be utilized in olefinic-amide and olefinic-lactam cyclization reactions and that the efficiency of the reaction depends somewhat on the nature of the substrate. We plan to continue examining the scope of olefinic-carbonyl cyclizations and their use in total synthesis efforts.

Scheme 2
Enamide Derivatization

Supplementary Material




We are grateful to the National Institutes of Health, General Medical Sciences (GM56677) for support of this work. We would like to thank the support staff at the University of Utah and especially Dr. Peter Flynn (NMR) and Dr. Jim Muller (mass spectrometry) for help in obtaining data.


Supporting Information Available. Experimental procedures and spectroscopic data for all new compounds. This material is available free of charge via the Internet at


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