Stereospecific Allylic Functionalization: The Reactions of Allylboronate Complexes with Electrophiles.

Allylboronic esters react readily with carbonyls and imines (π-electrophiles), but are unreactive toward a range of other electrophiles. By addition of an aryllithium, the corresponding allylboronate complexes display enhanced nucleophilicity, enabling addition to a range of electrophiles (tropylium, benzodithiolylium, activated pyridines, Eschenmoser's salt, Togni's reagent, Selectfluor, diisopropyl azodicarboxylate (DIAD), MeSX) in high regio- and stereocontrol. This protocol provides access to key new functionalities, including quaternary stereogenic centers bearing moieties such as fluorine and the trifluoromethyl group. The allylboronate complexes were determined to be 7 to 10 orders of magnitude more reactive than the parent boronic ester.

The reaction of allylmetals with electrophiles represents a cornerstone in organic synthesis.[1] The field is dominated by reactions of allylborons with carbonyls and imines (π-electrophiles) because (i) it leads to synthetically useful products with high and predictable selectivity and (ii) enantioenriched allylborons are easily available or chiral catalysts have been developed to promote the reaction.[2,3] However, reactions of allylborons with other types of electrophiles are virtually unknown; their unique reactivity with π-electrophiles stems from the simultaneous activation of both the boron atom and the carbonyl group in the closed transition state (Scheme A).[4] To address this shortcoming, more nucleophilic allylmetals have been explored, e.g., allylsilanes[5] and allylstannanes,[6] but the chiral versions are often difficult to prepare with high selectivity[7] and the latter are toxic and labile toward 1,3-transposition.

Scheme 1

Reactions of (A) Allylboronic Esters and (B) Alkylboronate Complexes; (C) This Work: The Reactivity of Allylboronate Complexes

Allylborons would be ideal reagents because they are configurationally stable, easily accessible in high ee,[3h,8] and unlike most other allylmetals do not undergo 1,3-transposition,[9] but their low nucleophilicity has limited their broader use. We considered separating the activation mode of boron by converting the allylic boronic ester into a more nucleophilic boronate complex. Previously, we have shown that the addition of an aryllithium to an alkylboronic ester creates a configurationally stable nucleophilic boronate complex that can react with electrophiles through an enantiospecific SE2inv pathway (Scheme B).[10] We reasoned that the addition of an organolithium to an allylboronic ester might also “switch on” the reactivity of these species, enabling SE2′ reactions with a much more diverse array of electrophiles (Scheme C). Herein, we report the successful realization of this strategy, providing access to an array of stereodefined tertiary and quaternary allylic products.

We began our study by investigating the tropylium cation as a model electrophile for addition to boronate complexes, selecting trisubstituted allylic boronic ester 1 to explore the formation of quaternary stereogenic centers, incorporating a reporter stereogenic center in order to assess the stereospecificity of the reaction. When the parent boronic ester 1 was subjected to the tropylium cation in THF, no reaction was observed (Table , entry 1), demonstrating the low reactivity of allylboronic esters even with highly reactive electrophiles. However, after addition of aryllithium 2, the allylboronate complex reacted readily to afford the allylation product 5, albeit with moderate regiocontrol between γ- and α-addition (87:13), and poor diastereocontrol (56:44, entry 2). The selectivity was found to be improved by lowering the reaction temperature to −78 °C, although the dr was still moderate (88:12, entry 4). In all cases, the reaction gave complete E-selectivity (>95:5). In our previous studies of boronate complexes, we had observed that electron-deficient aryllithiums improved the stereospecificity of the reaction,[10a] and they were examined here, too. Using the electron-deficient aryllithium 3 did indeed result in improved diastereocontrol (>95:5, entry 5). Interestingly, through screening various aryllithiums, we discovered that naphthyllithium (4) also gave high selectivity (entry 6), which proved beneficial in some cases with alternative electrophiles (vide infra).[11]

Table 1

Optimization of the Formation of Quaternary Stereogenic Centers with Tropylium Tetrafluoroboratea

Entry	ArLi	Temp. (°C)	Yieldb (%)	γ/αc	drc (%)
1	None	25	0
2	2	25	62	87:13	56:44
3	2	0	48	86:14	55:45
4	2	–78	52	>95:5	88:12
5	3	–78	81d	>95:5	>95:5
6	4	–78	95	>95:5	93:7

Reactions conducted with 0.10 mmol 1, 1.2 equiv ArLi and 1.2 equiv tropylium tetrafluoroborate.

1H NMR yield using 0.33 equiv of 1,3,5-trimethoxybenzene as internal standard.

dr of γ-attack product 5, determined by GC–MS.

Isolated yield.

Having identified conditions under which the allylboronate complex derived from 1 reacted with high regio- and stereoselectivity, we explored the electrophile scope in the formation of both tertiary and quaternary stereogenic centers (Scheme ). We used 3 as the standard nucleophilic activator, but if lower selectivity was observed we also tested 4. Pleasingly, the reactions of boronate complexes derived from 1 and 6 were extended to benzodithiolylium (to afford 8 and 15), activated pyridines (9 and 16)[10b] and Eschenmoser’s salt (10 and 17). In all of these C–C bond forming cases, high regio- and stereospecificity and complete E-selectivity was observed.

Scheme 2

Scope of Electrophiles added to Allylboronate Complexes

See the Supporting Information for more details; yields of isolated material; γ/α ratio and dr determined by GC–MS, 1H NMR or 19F NMR.

Tropylium tetrafluoroborate added at −78 °C.

1,3-Benzodithiolylium tetrafluoroborate added at −78 °C.

N,N-Diethylnicotinamide and Troc-Cl (Cl3CCH2OCOCl) added at −78 °C. Relative stereochemistry of dihydropyridine based on previous model,[10b] but not confirmed.

N,N-Dimethylmethyleneiminium iodide added at −78 °C.

Ate complex solution added to solution of 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one in THF at −78 °C.

Dimethyl(methylthio)sulfonium tetrafluoroborate added at −78 °C.

Diisopropyl azodicarboxylate added at −78 °C.

Ate complex solution in MeCN added to solution of Selectfluor in MeCN at −40 °C, and the reaction maintained at −40 °C for 16 h.

1H NMR yield using 0.33 equiv of 1,3,5-trimethoxybenzene as internal standard due to product instability.

The allylboronate complex derived from 6 could also be trifluoromethylated using Togni’s reagent as an electrophilic source of CF3, providing access to 11 in 50% yield, >95:5 γ/α and 90:10 dr. In comparison to alternative allylmetal species, Gouverneur and co-workers have reported the trifluoromethylation of analogous allylsilanes, which proceeds with similar selectivity under photoredox catalysis.[12] It is of particular note that the allylboronate complex from 1 could also be trifluoromethylated in 59% yield, >95:5 γ/α and >95:5 dr (18). Trifluoromethylation of an allylmetal to form a quaternary stereogenic center has, to the best of our knowledge, not previously been reported.

Electrophiles that create new carbon–heteroatom bonds could also be utilized in conjunction with the allylboronate complexes, enabling formation of C–S, C–N and C–F bonds at tertiary (12–14) and quaternary stereocenters (19–21). The electrophilic fluorination of boronate complexes[10c] provides access to medicinally relevant chiral allylic fluorides which are otherwise challenging to obtain from allylmetals.[13] Though allylsilanes are known to undergo successful stereospecific fluorination,[14] access to enantioenriched acyclic tertiary allylfluorides from an allylmetal has not previously been reported. Pleasingly, the reaction of 1 with aryllithium 4, and subsequent fluorination with Selectfluor in MeCN at −40 °C, was found to afford allylfluoride 21 in 76% yield, >95:5 γ/α and >95:5 dr. To determine the absolute configuration and demonstrate that there were no matched/mismatched effects in operation, we also synthesized the alternative diastereomer of fluoride 14 from the opposite anti diastereomer of 6.[15]

We next chose to develop the fluorination of allylboronate complexes because of the importance of incorporating fluorine stereoselectively into organic molecules (Scheme ). It was found that changing the alkyl substituent at R1 to either a sterically bulky iso-propyl (22) or a benzyl group (23) afforded the desired allylfluorides in high yield and selectivity. Fluorination of allylboronates derived from cyclic alkenes also occurred in good yield, albeit with slightly reduced regioselectivities (24 and 25). Pleasingly, the reaction tolerated a range of functional groups including carbamates (25), tert-butyl esters (26) and tert-butyldiphenylsilyl protected alcohols (27). Owing to the facile synthesis of the starting allylboronic esters through lithiation–borylation between a vinylboronic ester and alkylbenzoate,[3k,16] an array of allylfluorides can now be formed with high selectivity.

Scheme 3

Scope of the Fluorination Reaction

All boronic esters have dr >95:5. Yields of isolated material; γ/α ratio and dr determined by GCMS or 19F NMR.

To quantify the change of nucleophilicity of the allyl moiety upon addition of an organolithium to an allylboronic ester (28), we measured the kinetics of the reactions of allylboron compounds 28–32 with benzhydrylium ions 33, following previously published methods (Figures and 2).[17]Figure demonstrates that the measured second-order rate constants correlate linearly with the electrophilicity parameters E of the reference benzhydrylium ions, which allows us to employ eq for calculating the nucleophilicity parameters N and susceptibilities sN of 28–32.

Figure 1

Correlation of second-order rate constants k2 for reactions of allylboron compounds 28–32 (for structures, see Figure ) with benzhydrylium ions 33 (see Supporting Information) toward electrophilicity parameters E of benzyhdrylium ions.

Figure 2

Comparison of nucleophilicity parameters N (susceptibility parameters sN in parentheses) of allylmetal reagents. Boronate complexes and allyltrifluoroborate determined in CH3CN, other nucleophiles in CH2Cl2.

Although Figure shows the relative reactivities of the allylboron compounds somewhat depend on the nature of the electrophiles (because of the different slopes (sN) of the correlation lines), a rough ordering of the nucleophilic reactivities is given by their N parameters (Figure ), which correspond to the negative intercepts on the abscissa (log k2 = 0) of the correlation lines in Figure . Addition of an aryllithium to allylboronic ester 28 increases the nucleophilicity by 7 to 10 orders of magnitude.[18] Thus, the anionic allylboronate complexes 30–32 are significantly more nucleophilic than allylsilanes, allylstannanes and allyltrifluoroborate 29, all of which are more nucleophilic than the parent boronic ester 28. The previously reported N parameter of benzylboronate complex 34,[19] which reacts in an SE2 mode with electrophiles, is two logarithmic units smaller than of 30. In line with this ordering, allylboronates 30–32 react with high γ-selectivity (SE2′), in preference to reaction at the α-position (SE2).

In conclusion, by addition of an aryllithium, we have converted weakly nucleophilic allylic boronic esters into potent nucleophiles that now react with a broad range of carbon- and heteroatom-based electrophiles with very high γ-selectivity and essentially complete stereospecificity. Indeed, the addition of an aryllithium to form a boronate complex increases the nucleophilicity of the stable boronic ester by 7 to 10 orders of magnitude. Importantly, this process provides access to a broad array of functionalities, including quaternary all-carbon stereocenters and allylic fluoro- and trifluoromethyl moieties. We envisage the continued application of boronate complexes[10e] will provide access to an array of new enantioenriched functionalities that are otherwise difficult to obtain.