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. 2016 Mar 2;138(8):2512-5.
doi: 10.1021/jacs.5b13304. Epub 2016 Feb 18.

Nitrone Cycloadditions of 1,2-Cyclohexadiene

Joyann S Barber  1 , Evan D Styduhar  1 , Hung V Pham  1 , Travis C McMahon  1 , K N Houk  1 , Neil K Garg  1
Affiliations

Nitrone Cycloadditions of 1,2-Cyclohexadiene

Joyann S Barber et al. J Am Chem Soc. .

Abstract

We report the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene, a rarely exploited strained allene. 1,2-Cyclohexadiene is generated in situ under mild conditions and trapped with nitrones to give isoxazolidine products in synthetically useful yields. The reactions occur regioselectively and exhibit a notable endo preference, thus resulting in the controlled formation of two new bonds and two stereogenic centers. DFT calculations of stepwise and concerted reaction pathways are used to rationalize the observed selectivities. Moreover, the strategic manipulation of nitrone cycloadducts demonstrates the utility of this methodology for the assembly of compounds bearing multiple heterocyclic units. These studies showcase the exploitation of a traditionally avoided reactive intermediate in chemical synthesis.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Strained intermediates 1–6, known cycloadditions of 1,2-cyclohexadiene (7), and nitrone cycloadditions of 7 described in the present study.
Figure 2
Figure 2
Scope of reaction methodology. Major diastereomer is shown. Conditions unless otherwise stated are silyl triflate (1.0 equiv), nitrone (1.0 equiv), CsF (5.0 equiv), and CH3CN (0.1 M) at 80 °C. The yields reflect the average of two isolation experiments. aNitrone (2.0 equiv) was used. bNitrone (2.0 equiv) and THF (0.1 M) at 60 °C were used.
Figure 3
Figure 3
DFT calculations (B3LYP/6-31G*) were used to examine regioselectivites and diastereoselectivities.
Figure 4
Figure 4
DFT calculations (B3LYP/6-31G*) of concerted and stepwise mechanistic pathways.
Figure 5
Figure 5
Comparison of C2 internal angle for 7 and TS1.
Figure 6
Figure 6
Strategic manipulation of nitrone cycloadducts.
See this image and copyright information in PMC

References

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