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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 May 21.
Published in final edited form as:
PMCID: PMC2732350

Regio- and Stereoselective Isomerizations of Allenamides: Synthesis of 2-Amido-Dienes and Their Tandem Isomerization–Electrocyclic Ring-Closure


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A regio- and stereoselective isomerization of allenamides is described, leading to preparations of de novo 2-amido-dienes and a tandem isomerization–6π-electron electrocyclic ring-closure.

Synthesis of conjugated dienes via an allene isomerization, while a thermodynamically favored process, is not trivial kinetically. The required 1,3-H-shift constitutes a four-electron [2π + 2σ] process that would call for an antarafacial approach if proceeding through a concerted and anti-Hückel [or Möbius] transition state.1,2 Although impossible in an allylic system, it is relatively more feasible for an allenic system because of the presence of orthogonally oriented p-orbitals of the sp-hybridized central allenic carbon [Scheme 1]. The orthogonal p-orbital at C3 [in blue] introduces a formal phase change required for an anti-Hückel transition state, or formally allows a six-electron [2π +2σ + 2π] process when the second set of allenic π-electrons becomes involved. Nevertheless, the calculated2a ΔEact value remains high at 77.7 kcal mol−1 and consequently, concerted or not, most thermal isomerizations of allenes take place at high temperatures,3,4 thereby rendering it difficult to control E/Z ratios of the resulting dienes. There are more practical approaches would involve stepwise processes promoted by acid, base, or metal, but their examples are limited and the level of stereo- and regiochemical control need to be improved.3,5

Scheme 1
Allene Isomerizations.

Given that most dienes can be prepared from an array of stereoselective transformations, synthesizing conjugated dienes from structurally more challenging allenes through a kinetically demanding and stereochemically undistinguished isomerization does not appear to be a logical first choice. However, our efforts with the chemistry of allenamides6 allowed us to envision a much greater potential in constructing amido-dienes through isomerizing allenamides79 because there are no consistent approaches for synthesizing amido-dienes.1012 Of the two major methods for preparing amido-dienes,10 the one involving acid-mediated condensations suffers from functional group tolerance with the metal-mediated amidative cross-coupling13,14 suffering from limited access to halo-dienes [Scheme 1]. In contrast, substituted allenamides are quite accessible through α-alkylations of parent allenamide15,16 or amidative cross-couplings of allenyl halides.17 Their isomerizations can prove to be an invaluable entry to amido-dienes. We communicate here a regio- and stereoselective isomerization of allenamides in the synthesis of 2-amido-dienes and a tandem isomerization–6π-electron electrocyclic ring-closure.

Screening through various thermal conditions [entries 1–7 in Table 1] including several solvents distinctly revealed that isomerization of achiral allenamide 1 was the most effective at 115 °C in CH3CN [sealed tube], leading to 2-amido-diene 218 in 78% isolated yield and 16:1 ratio [entry 4] in favor of the E-geometry [assigned later]. While there appears to be a solvent effect on the E/Z ratio [entries 5–7], we found that with the exception of HNTf2 and PTSA [entries 8–9], a range of Brønsted acids were equally effective and more facile at RT in providing 2-amido-diene 2 with excellent E/Z ratio [entries 10–13].

Table 1
Thermal vs. Acidic Conditions.

Generality of this α-isomerization could be established as shown in Table 2. Key features are: (1) An array of chiral allenamides 5–7 could be employed to construct de novo 2-amido-dienes 8–10 with comparable yields and E/Z ratios under thermal [higher temperature at 135 °C] or acidic conditions [entries 2–11]; (2) unsubstituted 2-amido-dienes 8d and 9c could also be accessed in good yields [see R = H in entries 7 and 9]; (3) allenamide 11 containing an acyclic amide is also feasible for the isomerization; and (4) a single-crystal X-ray structure of 10b was attained to unambiguously assign the E-configuration [Figure 1].

Figure 1
X-Ray Structure of 2-Amido-Diene 10b.
Table 2
Isomerization of Allenamides at the α-Position.

Although our main interest resides in identifying a useful protocol for synthesizing 2-amido-dienes given its greater scarcity,1012,19,20 we examined isomerizations of allenamides from the γ-position en route to more well-known 1-amido-dienes.21 As shown in Table 3, isomerizations of two types of γ-substituted allenamides, those with a cyclohexylidene group [see 13–16 in entries 1–13], and those with an isopropylidene group [see 17–19 in entries 14–19] led to 1-amido-dienes 20–26 exclusively as E-enamides [assigned based on the trans-olefinic proton coupling constant].

Table 3
Isomerization of Allenamides at the γ-Position.

A keen observation here for the γ-isomerization is that acidic conditions appear to be more effective in general with the exception of 17 [entry 15]. In addition, thermal isomerizations at the γ-position required higher temperatures and/or longer reaction times than those of α-isomerizations. This difference prompted us to explore a possible regioselective isomerization. As shown in Scheme 2, when heating allenamides 27a and 27b, containing both α- and γ-substituents, at 135 °C in CH3CN, isomerizations occurred exclusively at the α-position, leading to 2-amido-dienes 28a and 28b22 in 71% and 94% yields, respectively, all in favor of the E-enamide [assigned by NOE18]. Isomerization of allenamide 27c took place at RT when in contact with silica gel but again α-isomerization was favored. This regioselective isomerization are both mechanistically intriguing23 and should be great synthetic value in constructing highly substituted 2-amido-dienes.

Scheme 2
Regioselective α-Isomerizations.

The E-selectivity23 attained from α-isomerization provides an excellent platform for the following important pericyclic transformation. As shown in Scheme 3, isomerization of α-allylated allenamide 29 under acidic conditions afforded 3-amido-triene 30 in 86% yield. With the E-selectivity, triene 30 is perfectly suited for a thermal 6π-electron electrocyclic ring-closure24 to give cyclic diene 31. Although only in 35% yield,25 examples of cyclic 2-amido-dienes such as 31 are more rare.26 Allenamide 32a provided a good example of synthesizing cyclic 2-amido-diene 34a via acid-promoted α-isomerization followed by ring-closure. Allenamide 32b demonstrated that the thermal isomerization could be arrested with the gem-dimethyl group in triene 33b impeding the ring-closure. Unfortunatedly, attempted ring-closure of 32b at 200 °C led to an unidentified product instead of 34b.

Scheme 3
3-Amido-Trienes and Pericyclic Ring-Closure.

At last, this process could be rendered in tandem under thermal conditions to access cyclic 2-amido-dienes 34a, 37, and 38 in good overall yields directly from respective allenamides 32a, 35, and 36 [Scheme 4]. It is noteworthy that these 6π-electron pericyclic ring-closures mostly took place at 135 °C, which implies an accelerated process. This feature is consistent with related ring-closures of 1,3,5-hexatrienes bearing a C3-donating group.27,28

Scheme 4
A Tandem α-Isomerization–Pericyclic Ring-Closure.

We have described here a regio- and stereoselective isomerization of allenamides, leading to preparations of de novo 2-amido-dienes and a tandem isomerization–6π-electron electrocyclic ring-closure. Studies involving applications of these dienes and this new tandem process as well as mechanistic understanding of this allene-isomerization are underway.

Supplementary Material


Supporting Information Available:

Experimental procedures as well as NMR spectra, characterizations, and X-ray structural files are available for all new compounds and free of charge via Internet




Authors thank NIH [GM066055] for support and Dr. Victor Young [University of Minnesota] for X-ray structural analysis.


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22. There appears to be ~% of 1-amido-diene from γ-isomerization.
23. Without detailed studies, a rationale for lowering of the thermal activation barrier of 1,3-H-shift is the stabilization of the bi-radical intermediate provided by the nitrogen atom, assuming a radical intermediate is considered electron deficient. Based on the this model, this stabilization is direct when isomerizations take place at the α-position [see i], and "vinylogous" for isomerizations at the γ-position [see ii]. Thus, thermal isomerizations at the α-position were faster than at the γ-position.
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As one reviewer suggested, it is also possible that the nitrogen atom mediates a polarized transition sate in which an increasing charge density at the β-carbon could develop, leading to an N-acyl iminium ion-like character with the migrating hydrogen behaving more like a proton. This charged transition state instead of a neutral one should possess a lower thermal activation barrier for the 1,3-H-shift. Finally, a rationale for the E-selectivity from the thermal α-isomerization is that the pro-Z-TS experiences a greater allylic strain than the pro-E-TS during the 1,3-H-shift, although we cannot rule out equilibration from Z- to E-enamide after the initial isomerization.
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