Facile conversion of chromane-6-triflate to chromane-6-alanines under Palladium conditions

Abstract

Conversion of chromane-6-triflate 5 to chromane-6-dehydroalanine 9 or 10 via its Bpin-derivative 6 followed by Suzuki coupling with protected dehydroalanine bromides 7 or 8 were reported (86%). Alternatively, a palladium-catalyzed stannation of 5 with Bu₆Sn₂ afforded the tributyltin derivative 11, and iodination (12) followed by coupling with 13 gave chromane-6-alanine 15 (75%). Either approach constitutes a conversion from chromane-6-triflate to the corresponding protected chromane-6-alanine or its dehydro analog.

In connection with a synthetic project, we were interested in synthetic access to electron-rich phenylalanine derivative 4 or their potential dehydro precursors 3 from phenols 1 or triflates 2. A structure-based search of electronic databases returned several options for relevant transformations starting from phenols, and interestingly literature also reported palladium-catalyzed coupling to build the key Ar-C bond. However, in each case, the outcome raised questions regarding overall yield or number of steps.^1–4 On the other hand, most of these reports involved investigations where rapid access to the targets using reliable methods was probably the primary consideration. We were therefore encouraged to evaluate alternative routes from 1 to 3 or 4 that might improve overall efficiency, and that would provide a vehicle for expanding structure-based retrieval of the simple synthetic transform from 1 to 3 or 4 (Scheme 1).

Scheme 1.

Suzuki coupling to dehydroamino acid derivatives

The known triflate 5⁵ was chosen as a precursor to demonstrate a Suzuki coupling approach⁶ via the corresponding pinacolboronate 6, available in 96% yield from 5 using palladium-catalyzed boronation with bis(pinacolato)diboron, [pinB]₂, following literature analogies.^7,8 Suzuki coupling of 6 with the known halogenated N-Boc dehydroamino acid derivative 7⁹ or the derived N-bis-Boc analogue 8 was then conducted in the expectation that coupling efficiency would be high in the typically well-behaved sp²-sp² mode. Indeed, good yields of both 9 and 10 were obtained under these conditions (Scheme 1).⁶ The Z-geometry assigned to 9 was confirmed by a NOESY experiment, consistent with the previously established Z-geometry of 7.^9a,c,10 In principle, enantioselective hydrogenation of 9 or 10 and analogous structures is possible using well known, high-yielding methods, and would provide access to either absolute configuration if desired.¹¹ The conversion from 5 to 9 or 10 constitutes a synthetic transform from triflates to dehydroamino acid derivatives.

An alternative version of the transform from chromane-6-triflate to a chromane-6-alanine was investigated via conversion to an intermediate aryl iodide (Scheme 2). First, the chromane-6-triflate 5 was reacted with hexabutyldistannane in the presence of Pd(Ph₃P)₄/LiCl (dioxane, 90 °C, 12h) provided intermediate tributyltin derivative 11 according to NMR assay of the crude product.¹² Filtration over alumina and removal of unreacted hexabutyldistannane under vacuum gave 11, but material recovery was modest (46%) and attempted purification by chromatography over silica gel resulted in extensive protodestannylation due to the electron-rich aryl environment.¹³ Fortunately, this complication could be avoided by performing the iodination without isolating the intermediate 11. Thus, reacting crude 11 with N-iodosuccinimide (NIS) in refluxing THF (4 days) gave the desired iodide 12 in 93% yield over the two steps from 5.^14,15 Coupling of chromane-6-iodide 12 with 13 (1.2 equiv) at RT (44 h) under the conditions developed by Jackson et al. in their initial studies¹⁷ proved relatively uneventful and gave the desired 15 in 47% yield. Using a re-optimized procedure the chromane-6-iodide 12 was used in the palladium-catalyzed Negishi coupling with the serine-derived organozinc reagent 13¹⁶ together with SPhos (14) and Pd₂dba₃ as the Palladium source at room temperature resulting 75% yield of 15 and 70% yield from triflate 5. Also, the literature procedure was slightly modified by using 2 equiv. of 13 to improve coupling efficiency with the relatively valuable iodide 12, but the other variables were not changed.¹⁶ On the other hand, an attempt to use the same procedure starting from triflate 5 in place of the iodide gave only traces of 15 (<5%). The result was a 75% yield of 15 from iodide 12¹⁸, or 70% from triflate 5 as shown in Scheme 2.

Scheme 2.

Negishi coupling to amino acid derivatives

In summary, the desired conversion from triflate 5 to amino acid derivatives 9, 10, and 15 has been demonstrated. The sp²-sp² Suzuki coupling between the boronate 6 and alkenyl bromide 7 is somewhat higher yielding compared to the sp³-sp² Negishi coupling strategy (iodide 12 with 13), but either approach offers improved efficiency compared to the literature alternatives^1–4 for analogous transformations. If the ultimate target is a protected amino ester, as represented by 15 in the current study, then either approach would involve three steps from the aryl triflate. The Suzuki coupling approach would require an enantioselective hydrogenation step¹¹ to access the chiral amino ester, but the other stages explicitly demonstrated in this report involve simple chemistry and provide the easiest access to the desired carbon framework.