Enantioselective Synthesis of Triarylmethanes via Intermolecular C–H Functionalization of Cyclohexadienes with Diaryldiazomethanes

Rhodium-catalyzed C–H functionalization of cyclohexadiene derivatives with diaryldiazomethanes followed by oxidation with DDQ provides ready access to triarylmethanes. Two chiral dirhodium tetracarboxylates, Rh2(S-PTAD)4 and Rh2(S-TPPTTL)4, were found to be the optimum chiral catalysts for these transformations. This method showcases the ability of diaryldiazomethanes to perform intermolecular C–H insertion with high enantioselectivity and good yields. The method has a broad substrate scope, leading to triarylmethane products with a variety of aryl and heteroaryl substituents, including benzofuran and pyridine heterocycles.

T he metal-catalyzed reactions of transient metal carbenes have broad utility in organic synthesis. 1 The structure of the carbene has a dramatic impact on the outcome of the reaction (Scheme 1a). 2 Most of the early chemistry was conducted on acceptor and acceptor/acceptor carbenes, 3 but since then, donor/acceptor carbenes have become prominent 4 because the donor group attenuates the reactivity of the highly electrophilic carbene, enabling numerous highly selective reactions to be viable. More recent studies have explored whether donor/donor carbenes could be another class of highly selective carbenes. 5 Much of the earlier work focused on intramolecular reactions, presumably because the carbenes are less reactive than the other classes of carbenes. 5b,6 Very recently, we 5a and others 7 have shown that diarylcarbenes generated from diaryldiazomethanes are capable of enantioselective reactions, such as cyclopropanation, Si−H insertion, and B−H insertion (Scheme 1b).
The diarylcarbenes have been formally considered as donor/ donor carbenes, 2c but we have proposed it is more appropriate to consider them as donor/acceptor carbenes 4a because the two rings cannot be simultaneously in the same plane as the rhodium carbene. 5a When a ring is in the same plane as the carbene, it would behave as a donor group, but due to steric constraints, the other ring would need to be orthogonal to the carbene and then would behave as an acceptor group. This behavior is illustrated in Scheme 2, which includes the calculated values for the tilting angles for the two aryl groups in a representative diarylcarbene. Two diarylcarbene systems that strongly exhibit this behavior are those with a strong para donor on one ring and those with an ortho substituent on one ring. We have demonstrated this concept in our experimental and computational studies on rhodium-catalyzed cyclopropanation with diaryldiazomethanes. 5a In this study, we demonstrate the enantioselective reactions can be extended to C−H functionalization of cyclohexadienes, 8 leading to the enantioselective synthesis of triarylmethanes. Due to their pharmaceutical relevance, methods for their enantioselective synthesis have been extensively explored, but it is still challenging to achieve broad scope. 9 Our method extends the range of triarylmethanes that can be readily formed with high enantioselectivity.
The study began via evaluation of the C−H insertion reaction of 1,4-cyclohexadiene (2) with 4-nitro-4′-methoxydiphenyldiazomethane (1), a precursor to a prototypical diaryl carbene in which one aryl group has an electronwithdrawing group and the other has an electron-donating group. A series of chiral dirhodium catalysts were examined, and all of the catalysts generated the desired product 3 as summarized in Table 1. As expected, Rh 2 (S-DOSP) 4 gave a very low level of asymmetric induction because it requires an ester group as an acceptor group for a high degree of asymmetric induction. 10 The triaryl cyclopropane carboxylate catalyst Rh 2 (S-2-Cl-5-BrTPCP) 4 11 significantly boosted the asymmetric induction of the C−H insertion, with an ee of 79%, but the best class of catalysts was the naphthylimido-and phthalimido-derived catalysts. 12 The phthalimido-derived catalysts have interesting properties because they self-assemble into bowl-shaped structures that can be relatively rigid. 13 The naphthylimido catalyst Rh 2 (S-NTTL) 4 14 gave excellent results, generating 3 in 94% ee, but some of the phthalimido catalysts performed even better, such as Rh 2 (S-PTAD) 4 , 15 which generated 3 in 77% yield and 99% ee.
The oxidation of 1,3-cyclohexadienes to benzene derivatives is well-established. 16 Therefore, the C−H functionalization described above was expected to be a convenient asymmetric method for the construction of triarylmethanes. Confirmation that this was indeed feasible was demonstrated by conversion of 3 to triarylmethane 4 using 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) as the oxidant (Scheme 3). Most importantly, the oxidation was achieved with no racemization.
With the optimized conditions set forth, the rhodiumcatalyzed reaction with cyclohexadiene combined with DDQ oxidation was applied to a series of diaryldiazomethanes 5−9 lacking ortho substituents (Scheme 4). The combined reactions were compatible with a variety of substituents, but substrates containing a strong electron-withdrawing group such as nitro or trifluoromethyl gave the highest levels of asymmetric induction, as seen with 5 and 6. The reactions with a p-CF 3 substituent gave triarylmethane 6 in 80% yield and 85% ee, whereas the reaction with a p-chloro substrate generated 7 in 61% and 79% ee. Electron rich or electron deficient heterocyclic substrates can be incorporated into the diazo compound as illustrated in the formation of 8 and 9, although the enantioselectivity was lower in these cases (45% and 77% ee, respectively). Typical reactions were conducted on a 0.3 mmol scale, but the reaction is easily scalable, as illustrated in the formation of 4 on a 1 mmol scale in 90% yield and 99% ee.

Scheme 3. Stereoretentive Oxidation to Triarylmethane 4
Organic Letters pubs.acs.org/OrgLett Letter lized from the mixture, and the relative and absolute configurations of 11a could be determined by X-ray crystallography. Major diastereomer 11a was produced with a higher level of asymmetric induction (86% ee) compared to that of minor diastereomer 11b (52% ee). The two diastereomers could barely be separated by chromatography. Hence, the combined mixture was oxidized by DDQ to form triarylmethane 12 in 77% ee. This value matches the expected calculated value assuming that both 11a and 11b are generated with the same sense of asymmetric induction and that the oxidation of 11a and 11b to 12 occurs without a loss of the asymmetric induction. The absolute configuration of 12 is assigned as R because it is derived from 11a of known absolute configuration. The absolute configurations of all of the other triarylmethanes are tentatively assigned by analogy to 12.
The C−H functionalization of 1-methyl-1,4-cyclohexadiene could be applied to a variety of diaryldiazomethanes as illustrated in Scheme 6. A diastereomeric mixture of the C−H insertion products was generated, and these were directly oxidized with DDQ to form the desired triarylmethanes 13−15 in 51−89% yields and 75−93% ee. Once again, the highest enantioselectivity was obtained using the 4-nitro-4′-methoxydiaryldiazomethane in which the electronic differentiation between the donor and the acceptor group is most pronounced. In this case, 15 was formed in 93% ee. A catalyst screen of the reaction to afford 15 revealed that Rh 2 (S-PTAD) 4 remained the optimal catalyst (see the Supporting Information and Table 1).
In our previous studies, 5a addition of an o-chloro substituent was found to enhance diastereoselectivity in the case of cyclopropanation of styrene. We employed a catalyst screen on 2-chloro-4-nitrodiphenyldiazomethane to verify if enhanced enantioselectivity of the final triarylmethane product could be obtained using some of the other bowl-shaped catalysts ( Table  2). 17 While Rh 2 (S-PTAD) 4 was found to give the desired product in 74% ee (entry 1), Rh 2 (S-TPPTTL) 4 18 gave a significant increase to 88% ee. Rh 2 (S-TPPTTL) has been previously shown to give superior asymmetric induction in cyclopropanation reactions with ortho-substituted aryldiazoacetates, 19 and similar characteristics are observed here in the reaction with ortho-substituted diaryldiazomethanes.

Organic Letters
pubs.acs.org/OrgLett Letter derived from diaryldiazomethanes having an electron-donating group, an electron-withdrawing group, and an o-chloro group, were generated with the highest levels of enantioselectivity (98% and 91% ee, respectively). These trends are consistent with our understanding that diaryl diazo compounds that closely model that of a donor/acceptor diazo compound through electronic and steric properties give the higher levels of asymmetric induction. The reaction could be also extended to various substituted cyclohexadienes, resulting in the formation of 23−25. In addition to the 1-methyl-substituted cyclohexadiene, three other substituted 1,4-cyclohexadiene derivatives were shown to produce triarylmethane products. The formation of 25 is an interesting transformation because the C−H functionalization was site selective, favoring by a 12:1 ratio insertion α to the methyl group versus insertion α to the isopropyl group in γ-terpene.
In conclusion, we have developed a facile enantioselective synthesis of triarylmethanes using rhodium-catalyzed C−H functionalization of cyclohexadienes with diaryldiazomethanes. Our system allows a variety of diaryl precursors to be incorporated into new triarylmethane scaffolds with high enantioselectivity, a previously difficult task with current literature methods. This method can tolerate a variety of electron rich and poor aryl substituents and bulky o-chloro substituents and is compatible with two heterocycles. Furthermore, the diaryl system, previously used for mainly intermolecular reactions, now has been shown to have the ability to perform C−H functionalization on activated systems, which broadens their synthetic potential.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its online Supporting Information.
Complete experimental procedures and compound characterization (PDF)  The triarylmethane compound could not be resolved using chiral HPLC. The ee value is estimated from the analysis of the C−H insertion intermediate. The ee value was assigned on the basis of the analysis shown in Scheme 5 and the crystal structure of 11a. b The ee value is an estimated value due to the imperfect resolution of peaks in the HPLC spectrum. c For the reaction, 0.30 mmol of diazo was inversely added to a solution of Rh 2 (S-PTAD) 4 and 4 equiv of the cyclohexadiene substrate in 1 mL of CHCl 3 .