Palladium-Catalyzed Synthesis of Cyclopentane-Fused Benzocyclobutenes via Tandem Directed Carbopalladation/C–H Bond Functionalization

Abstract

A new Pd-catalyzed reaction for the stereoselective synthesis of cyclopentane-fused benzocyclobutenes is described. These transformations likely proceed via carbamate-directed carbopalladation followed by intramolecular C–H activation of an alkylpalladium intermediate. The mechanistic relationship between these transformations and Pd-catalyzed reactions of γ-(n-Boc-amino)alkenes with aryl bromides that afford pyrrolidines is discussed. Differences in reactivity between Pd-amino and Pd-amido complexes appear to play a key role in the outcome of these transformations.

During the course of studies on Pd-catalyzed carboamination reactions of N-protected γ-aminoalkenes¹ we observed that the use of the weak base Cs₂CO₃ in transformations of terminal alkene substrates (e.g., 1) provided 2-benzylpyrrolidine derivatives (e.g., 2) in yields that were comparable to those obtained with the stronger base NaOtBu (eq 1).² However, when the Cs₂CO₃ conditions were employed with cyclopentene-derived substrate 3, a surprising result was obtained. As shown below, the Pd-catalyzed reaction of 3 with 4-bromobiphenyl (4) in the presence of Cs₂CO₃ did not provide the expected product 5, but instead generated benzocyclobutene derivative 6 in 72% yield and >20:1 dr (eq 3). This result is in marked contrast with the reaction of 3 with 4 in the presence of NaOtBu,^1b which affords the expected heterocycle 5 in 51% yield (eq 2).³

(1).

(2), (3).

The generation of benzocyclobutene 6 is both synthetically and mechanistically interesting.⁴ Benzocyclobutenes are widely employed as precursors to ortho-quinodimethides, which are known to undergo facile [4+2] cycloaddition reactions,⁵ and can also be employed in polymerizations.⁶ Moreover, the surprising effect of base on the reactivity of 3 raises questions about the mechanistic relationship between the reactions shown in eqs 1–3. In this Letter we describe our preliminary studies on the preparation of benzocyclobutenes via coupling of 3 with aryl bromides, and present a mechanistic hypothesis that accounts for the observed effect of base on these transformations.

To explore the scope of the Pd-catalyzed benzocyclobutene forming process, we examined reactions of 3 with various p-, m- and o-substituted aryl bromides. As shown in Table 1, reactions of p-substituted starting materials afforded products substituted exclusively at the 2-position of the aromatic ring (entries 1–4). Similarly high regioselectivity was obtained in reactions of o-substituted aryl bromides, which afforded products bearing substituents at the 5-position (entries 5–6). The regioselectivities observed in reactions of m-substituted aryl bromides were dependent on the nature of the substituent. Although the reaction of 3 with m-bromotoluene proceeded with good regioselectivity (entry 7), the coupling of 3 with m-bromoanisole afforded a 2:1 mixture of regioisomers (entry 8).

Table 1.

Synthesis of Benzocyclobutenes from 3^a

entry	ArBr	product	yield (%)b,c
1			R = CH2OAc: 74
2			R = Ph: 72
3			R = Cl: 70
4			R = OMe: 58
5			R = Me: 85
6			R = Ph: 80
7			68
8			66 (2:1)

^aConditions: 1.0 equiv 3, 1.2. equiv ArBr, 2.3 equiv Cs₂CO₃, 4 mol % Pd(OAc)₂, 8 mol % Dpe-Phos, dioxane (0.25 M), 100 °C.

^bYields refer to average isolated yields obtained in two or more experiments.

^cAll products were obtained with >20:1 dr and >20:1 regioselectivity unless otherwise noted.

The major side products formed in reactions between 3 and either electron-rich or –neutral aryl bromides were arylated cyclopentanes (7), although in many reactions trace amounts of bicyclic products 8–10 were detected by ¹H NMR analysis of the crude reaction mixtures (Fig. 1).⁷

Figure 1.

Side products

Although the benzocyclobutene-forming reactions proceeded smoothly with many aryl bromides, the Pd-catalyzed coupling of 3 with the electron-poor substrate 3-bromobenzotrifluoride afforded a 26:39:23 mixture of 11:8:9 (eq 4);⁸ upon purification 11 was obtained in 24% yield. In addition, the Pd-catalyzed reaction of 3 with 1-bromo-2-methylnaphthalene proceeded slowly and in low conversion (ca. 40%) to afford 5-aryl azabicyclo[3.3.0]octane 12 in 26% isolated yield (eq 5).⁹

(4).

(5).

The dependence of base on the outcome of Pd-catalyzed reactions of 3 with aryl bromides (eqs 2–3) likely results from differences in reactivity of palladium amino complexes vs. palladium amido complexes.¹⁰ As shown in Scheme 1, oxidative addition of the aryl bromide to Pd(0) generates 13, which can bind the carbamate to provide 14. In the presence of a base, amino complex 14 can potentially be converted to amido complex 18. However, with the weak base Cs₂CO₃ this process should be relatively slow due to the low solubility of Cs₂CO₃,¹⁰ and the equilibrium between 14 and 18 may favor 14. In contrast, when the relatively strong, soluble base NaOtBu is employed, the conversion of 14 to 18 is relatively fast, and the equilibrium favors amido complex 18.^10,11

Scheme 1.

The benzocyclobutene products formed when Cs₂CO₃ is used as base are likely generated via directed carbopalladation^12,13 of amino complex 14 to provide the sterically hindered alkylpalladium intermediate 15, which lacks β-hydrogen atoms syn to the metal. Intramolecular aryl C–H bond activation^4,14 of 15 provides 16 and an equivalent of HBr, which is neutralized by Cs₂CO₃ Complex 16 is then converted to benzocyclobutene 17 via C–C bond-forming reductive elimination.^4,15 The arylated cyclopentane side product 7 may result from competing protonation of the Pd–C bond(s) of 15 or 16. The conversion of the electron-poor m-bromobenzotrifluoride to a mixture of 11, 8, and 9 is likely due to enhancement of the N–H proton acidity of 14 when the complex bears an electron-withdrawing aryl substituent, which would shift the 14/18 equilibrium toward 18.

Under conditions that facilitate rapid and/or thermodynamically favorable formation of amido complex 18, the reactions likely proceed via syn-amidopalladation as described previously to generate 19,¹ which is converted to 8 via C–C bond-forming reductive elimination. Alternatively, 19 can also be transformed to 9 or 10 via β-hydride elimination/reinsertion processes.^1a,c

The differences in reactivity observed between substrates bearing terminal alkenes (e.g., 1) and cycloalkene substrate 3 may be due either to the influence of alkene size on the position of the 18/19 equilibrium, the influence of substrate sterics on the rate of C–C bond-forming reductive elimination from 19, or the influence of alkene substitution on the relative rates of alkene insertion into the Pd–C bond of 14 vs. the Pd–N bond of 18. In addition, the fact that Pdcatalyzed reactions of 3 with aryl halides lacking o-hydrogen atoms are converted to azabicyclooctanes (e.g., 12) in the presence of Cs₂CO₃ suggests that the carbopalladation of 14 is either reversible,¹⁶ or very slow with bulky aryl groups. Our current data do not allow us to differentiate between these possibilities.

In conclusion, we have developed a new transformation for the conversion of 3 to cyclopentane-fused benzocyclobutenes via an unprecedented sequence of heteroatom directed carbopalladation followed by intramolecular aryl C–H bond activation. These are the first examples of reactions that exploit directed carbopalladation for the generation and functionalization of alkylpalladium intermediates that lack syn-β-hydrogen atoms. Importantly, the results described above illustrate that differences in reactivity between Pd-amino and Pd-amido complexes can be exploited to allow the construction of strikingly different products from common starting materials. Further studies on the scope of this method and applications of these concepts are currently underway.

Supplementary Material

1File003. Supporting Information Available.

Experimental procedures and characterization data for new compounds and x-ray crystal structure of 6 (34 pages). This material is available free of charge via the Internet at http://pubs.acs.org.