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J Am Chem Soc. Author manuscript; available in PMC 2016 Jun 9.

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Nitrone Cycloadditions of 1,2-Cyclohexadiene

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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.

The synthesis of heterocycles and natural product scaffolds remains a vital area of study.^1,2 One approach to construct such important compounds involves the use of strained intermediates such as benzyne, hetarynes, and cyclic alkynes (1–6, Figure 1).³ Although initially viewed as undesirably reactive species several decades ago, these intermediates can now be used to prepare medicinally privileged scaffolds and stereochemically complex natural products.^3,4 Likewise, our understanding of the structure and reactivity of arynes and cyclic alkynes has evolved considerably.^3,4

Strained intermediates 1–6, known cycloadditions of 1,2-cyclohexadiene (7), and nitrone cycloadditions of 7 described in the present study.

A less well-studied class of highly strained intermediates is cyclic allenes, such as 1,2-cyclohexadiene (7, Figure 1). 1,2-Cyclohexadiene (7) was first reported by Wittig in 1966⁵ but has seen little synthetic use since, especially compared with its aryne and alkyne counterparts. Seminal efforts include theoretical studies⁶ and the two C–C bond forming reactions: [2 + 2]^6a,c,7 and [4 + 2]^{6a,d,7c–e,8} cycloadditions to form products such as 8 and 9, respectively. These transformations hint at the potential utility of 7 as a versatile synthetic building block, but no other cycloadditions involving 7 have been reported.

We now report the first dipolar cycloadditions of 1,2-cyclohexadiene, which allow for a facile entryway to isoxazolidine products (Figure 1, 7 + 10 → 11). The resulting products contain significant sp³-character⁹ and are obtained with high regio- and diastereoselectivities. Computational studies suggest that stepwise and concerted reaction pathways are operative in the cycloadditions and predict the observed selectivity trends.

We initiated our study toward the trapping of 1,2-cyclohexadiene (7) by first accessing a suitable precursor that could allow for allene generation in situ. Encouraged by Guitián's synthesis of a trimethylsilyltriflate precursor to 7,^7e which was used in Diels–Alder cycloadditions, we prepared the new triethylsilyltriflate species 12,¹⁰ which proved more readily accessible and could be obtained in gram quantities.¹¹ We initially surveyed the reaction of silyltriflate 12 with 5 equiv of commercially available nitrone 13 using different fluoride sources at ambient temperature (Table 1). Although the use of TBAF gave low yields of cycloadduct 14 (entry 1), KF/18-crown-6 gave more promising results (entry 2). Additionally, the use of CsF cleanly gave product 14 in modest yield, although the remainder of the mass was unreacted silyl triflate 12 (entry 3). In all cases, it should be noted that 14 was formed regioselectively and in approximately 9:1 dr, with the major product being the endo isomer (14a). For practical reasons, we elected to further pursue the use of CsF and ultimately found that the reaction proceeded smoothly at elevated temperatures and higher concentration (entries 4 and 5) to give cycloadduct 14 in 4 h (entry 5; compared with 3 d for entry 3). Finally, to probe the necessary stoichiometry, we tested the cycloaddition using just 1 equiv of nitrone 13. We were delighted to find that cycloadduct 14 could be formed in comparable yields under these conditions (entry 6).

Table 1

Optimization of Nitrone Cycloaddition

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entry	conditions	temp (°C)	concn (M)	equiv of 13	yield, % (14a/14b dr)a
1	TBAF, THF	23	0.025	5.0	35 (10.8:1)
2	KF, 18-crown-6, CH3CN	23	0.025	5.0	77 (12.1:1)
3	CsF, CH3CN	23	0.025	5.0	41 (13.5:1)
4	CsF, CH3CN	80	0.025	5.0	90 (9.5:1)
5	CsF, CH3CN	80	0.1	5.0	92 (9.3:1)
6	CsF, CH3CN	80	0.1	1.0	84 (8.5:1)

Having identified suitable reaction conditions, we assessed the scope of the methodology by varying the nitrone component and evaluating isolated yields and diastereoselectivities (Figure 2). All reactions were performed using CsF at 80 °C and either 1 or 2 equiv of the nitrone trapping agent, as indicated.¹² In addition to the parent experiment, which gave 14 in 88% yield and roughly 9:1 dr, we were delighted to find that nitrones derived from acetaldehyde and pivaldehyde could be employed to give products 15 and 16, respectively. Nitrones derived from aldehydes bearing heterocycles were also tested. As shown by the formation of products 17–21, furan, thiophene, thiazole, quinoline,¹³ and indole heterocycles are tolerated in this methodology. Finally, several nitrones prepared from ketone or cyclic amine precursors were tested, resulting in isoxazolidines 22–24.¹⁴

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. ^a Nitrone (2.0 equiv) was used. ^b Nitrone (2.0 equiv) and THF (0.1 M) at 60 °C were used.

DFT calculations were performed to assess mechanistic aspects of the 1,2-cyclohexadiene/nitrone cycloaddition.¹⁵ We investigated both the regio- and diastereoselectivity of the cycloaddition. Although Diels–Alder and (2 + 2) cycloadditions of 1,2-cyclohexadiene (7) have been studied computationally, no reports of (3 + 2) cycloadditions of 7 are available. We assessed pathways that could lead to either of two possible constitutional isomers, in addition to all possible stereoisomers, as summarized in Figure 3. Cycloaddition via pathway A would give diastereomers 25 and 26, whereas pathway B would furnish 14a and 14b. Previous reports with linear allenes indicate the plausibility of both pathways. However, consistent with our experimental results, computations show that pathway A is disfavored for the reaction of 7 and nitrone 13.¹⁶ The lower energy pathway involves attack of the central allene carbon (C2) on the nitrone, with attack of the nitrone oxygen on C1 (pathway B).

DFT calculations (B3LYP/6-31G*) were used to examine regioselectivites and diastereoselectivities.

To explain the observed diastereoselectivities, we compared the possible transition states for the formation of both endo and exo products 14a and 14b (Figure 4). First examining a concerted reaction mechanism, we found that the activation energy for the endo reaction is 14.5 kcal/mol (TS1), which presents a plausible pathway for the formation of 14a. A concerted exo transition state could not be explicitly located; instead diradical transition state TS2 always resulted, suggesting the concerted exo reaction is higher in energy. As we do observe exo product 14b, we proceeded to examine the stepwise mechanism through TS2. We found that diradical 27 can be formed via initial formation of the C–C bond; an intrinsic reaction coordinate scan and a nonzero S ² value confirms the diradical nature of this process. From diradical 27, cyclization furnishes 14a or 14b (via TS3a or TS3b); the formation of 14a is favored by 1.2 kcal/mol, which correlates to the observed 10:1 ratio of products. Therefore, we propose that both stepwise and concerted mechanisms for cycloaddition are in competition, a phenomenon we have previously observed in our studies on Diels–Alder reactions with allenes,^17,18 which are known to be very reactive and form relatively stable allylic radical intermediates.

DFT calculations (B3LYP/6-31G*) of concerted and stepwise mechanistic pathways.

Regardless of the reaction mechanism, the 1,3-dipolar cycloaddition of 1,2-cyclohexadiene occurs quickly with mild heating. The low ~15 kcal/mol barriers for these reactions, compared with the >30 kcal/mol barriers for cycloaddition with linear allenes,^17,18 can be attributed to the predistortion of 7 into geometries near those of the transition states for cycloadditions. The optimized structures of 1,2-cyclohexadiene (7) and TS1 (concerted pathway) are shown in Figure 5. Of note, the C1–C2–C3 angle is nearly identical in both cases (132.8° vs 129.8°).¹⁹ Thus, only 3° contraction is necessary to reach the transition state geometry. In contrast, linear allenes must bend by more than 30° in order to reach their optimal transition state geometries (see SI for details). Examples of distortion-accelerated reactions are known²⁰ and explain the facility of these reactions with 1,2-cyclohexadiene.

Comparison of C2 internal angle for 7 and TS1.

The nitrone cycloaddition of 1,2-cyclohexadiene (7), when used sequentially with other transformations, provides new and unique strategies for preparing compounds bearing multiple heterocyclic units (Figure 6). For example, isoxazolidine 28 was synthesized via a nitrone cycloaddition from 12. Next, palladium-catalyzed Suzuki–Miyaura cross-coupling²¹ with boronic acid 29 afforded product 30 in 65% yield. Of note, 30 contains three distinct heterocycles (i.e., a furan, pyridine, and isoxazolidine). In another example, we questioned if silyltriflate 12 could be used as a building block for the assembly of polycyclic fused heterocycles, such as 33. Nitrone cycloaddition with 31 furnished isoxazolidine 32. Subsequent N–O bond cleavage,²² followed by S_NAr cyclization²³ gave tricycle 33. The conversion of 12 to 33 allows for the facile construction of three new bonds and two stereogenic centers. Moreover, the two synthetic applications shown in Figure 6 showcase how the unusual intermediate cyclohexadiene (7), despite its high reactivity, can be used to access varying types of polycyclic heterocycles in a controlled way.

Strategic manipulation of nitrone cycloadducts.

In summary, we have discovered the first 1,3-dipolar cycloadditions of 1,2-cyclohexadiene. The transformation involves in situ generation of the strained intermediate under mild conditions, and trapping with nitrones to give isoxazolidine products in synthetically useful yields. The reactions occur regioselectively, with a notable endo preference, thus resulting in the controlled formation of two new bonds and two stereogenic centers. DFT calculations suggest that stepwise and concerted reaction pathways are operative in the cycloadditions and predict the observed selectivity trends. Moreover, the strategic manipulation of nitrone cycloadducts demonstrates the utility of this methodology for the assembly of compounds bearing multiple heterocyclic units. These studies are expected to prompt the further exploitation of traditionally avoided reactive intermediates in chemical synthesis.

Supplementary Material

supporting info

Acknowledgments

The authors are grateful to the NIH-NIGMS (R01 GM090007 for N.K.G.), the NSF (CHE-1361104 for K.N.H.), Bristol–Myers Squibb, the A. P. Sloan Foundation, the Dreyfus Foundation, the University of California, Los Angeles, the Foote Family (H.V.P. and E.D.S.), and the Chemistry–Biology Interface training program (J.S.B., USPHS National Research Service Award 5T32GM008496-20) for financial support. These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631). Computations were performed with resources made available from the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575), as well as the UCLA Institute of Digital Research and Education (IDRE).

Footnotes

Notes

The authors declare no competing financial interest.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.5b13304.

Detailed experimental and computational procedures, compound characterization, Cartesian coordinates, electronic energies, entropies, enthalpies, Gibbs free energies, and lowest frequencies of the calculated structures (PDF)

References

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