3-Chloro-1-lithiopropene, a Functional Organolithium Reagent, and Its Reactions with Alkylboronates To Give 3-Alkylprop-1-en-3-ols

The reagent 3-chloro-1-lithiopropene (4) can be generated by treating 1-bromo-3-chloropropene with t-BuLi. It is unstable but if generated at low temperature in the presence of alkylboronic esters, such as 3, is trapped in situ to give rearrangement products 2, which on oxidation give 3-alkylprop-1-en-3-ols in good yields. The reaction works for primary, secondary, benzylic, and even tertiary alkylboronic esters, providing allylic alcohols bearing almost any alkyl group available using organoborane chemistry and incorporating all features of such groups.

) can be generated by treating 1-bromo-3-chloropropene with t-BuLi.It is unstable but if generated at low temperature in the presence of alkylboronic esters, such as 3, is trapped in situ to give rearrangement products 2, which on oxidation give 3-alkylprop-1-en-3-ols in good yields.The reaction works for primary, secondary, benzylic, and even tertiary alkylboronic esters, providing allylic alcohols bearing almost any alkyl group available using organoborane chemistry and incorporating all features of such groups.
M igration of alkyl groups from boron to carbon is important for formation of C−C bonds. 1 Depending on the reaction, trialkylboranes undergo migration of one, 2 two, 3 or all three 4 alkyl groups to a single carbon atom, usually with retention of stereochemical integrity.Furthermore, although boron is commonly removed by oxidation, the immediate product is an organoboron compound and potentially available for further elaboration.Single-migration reactions of trialkylboranes lack efficient use of alkyl groups, and migratory selectivity may be a problem.Alkyldialkoxyboranes (alkylboronate esters) are substantially less electrophilic, and only highly nucleophilic, often unstable reagents such as halomethyllithiums are sufficiently reactive. 5Even then, migration of tertalkyl groups is difficult, but in a recent investigation, we have extended the range of substrates to include quite hindered tertalkyl groups. 6eactions of 3-chloropropenylboronates such as 1 with Grignard reagents (Scheme 1a) 7 give compounds 2 with high enantiomeric excess under asymmetric catalysis. 8This important and useful reaction is limited by the availability of appropriate Grignard reagents, which are not tolerant of functionality.By contrast, organoboron derivatives tolerate many functional groups and can be generated by a range of stereospecific processes.Thus, Scheme 1b would be a more generally useful approach to compounds 2 than Scheme 1a.We now report the successful realization of this approach.
Reports of reactions like Scheme 1a 7,8 gave no examples of use of tert-alkylmagnesium reagents, so we first looked at reactions of tert-butylboronic esters and investigated both boronate ester 6 and the more hindered pinacol analogue 7. Br−Li exchange of 5 to give 4 was attempted with n-BuLi and t-BuLi; solutions were reacted with 6 or 7 and then oxidized to give 4,4-dimethylpent-1-en-3-ol (8) (Scheme 3).Yields were monitored by GC.
t-BuLi was more effective at generating 4 than n-BuLi, probably because of lower competition from other sites of attack.Generating 4 ex situ and adding it to the boronate was not successful, presumably because 4 is unstable and needs trapping immediately.Excess organolithium was deleterious, presumably because of increased competition from direct addition to the boronate, while the more hindered boronate 7 gave higher yields than 6, presumably because of lower competition from such addition.Use of 5 containing ∼5% of pentachloroacetone caused a disproportionate decrease in yield, so purity of 5 is important.However, under the most favored conditions (1.1 equiv of t-BuLi and pure 5, in situ, with 7), the yield of 8 was almost quantitative.
A representative selection of pinacol alkylboronates 3, possessing alkyl groups ranging in bulk from n-butyl to thexyl (2,3-dimethyl-2-butyl), was tested under the standard conditions (Table 1).Some products were purified from the reaction mixtures; authentic samples of others were prepared from vinylmagnesium bromide and the appropriate aldehyde, so response factors could be calculated and yields monitored by GC to provide true reaction yields (Table 1, entries 1−7).
All but one of the standard reactions (i.e., entries 1−6) provided very good of the desired products 9, none of which contained allylic rearrangement isomers 10, which have been recorded in earlier reports. 7Reaction of the 2,2dimethylpropane-1,3-diol ester of n-butylboronic acid did give some rearranged product (78:22 mixture of (E/Z)-10:9), but no rearranged products were observed with 2,2-dimethyl-1,3propanediol esters of more hindered alkylboronic acids or with pinacol boronates of less hindered alkylboronic acids.
As 5 isomerizes to give a mixture of E and Z isomers in the presence of light, 13 samples had been kept cold and in the dark.In order to check whether precursor 5 needed to be stereochemically pure, a sample was exposed to daylight for several hours to convert it into an E/Z mixture and then subjected to a standard reaction with 3 (R = cyclohexyl).The yield of 9 (R = cyclohexyl) (Table 1, entry 5) was similar to those obtained for other examples with pure (E)-5, so synthesis of 1-bromo-3-chloropropene need not be stereoselective.
The most hindered pinacol alkylboronic ester (thexyl, entry 7) gave a significantly lower yield than the other alkylboronates When subjected to the standard conditions, 11 gave 36% of 9 (R = thexyl, entry 8), while 12 gave 99% (entry 9).Similar subtlety was observed in reactions with BrCH 2 Li, where yields of the corresponding products from 1 (R = thexyl), 11, and 12 were 35, 80, and 71%. 6For best results in the present reaction, therefore, it is important that the boronate be sufficiently hindered to inhibit direct reaction between the added organolithium and the boronate or its complex with 4, but not be so hindered to limit its ability to capture 4, allowing decomposition of 4 to compete.Pinacol alkylboronates are evidently satisfactory up to the hindrance level of a t-butyl group, but for thexyl, the somewhat less hindered 2,2dimethylpropane-1,3-diol boronate is optimal.To find where the limits of the method lie, standard conditions were applied to alkylboronates incorporating highly hindered tert-alkyl groups obtained by use of reactions of trialkylboranes with dichloromethyl methyl ether (DCME, Table 2).
The results were similar to those with bromomethyllithium as reagent. 6With very hindered triethylmethyl-and trioctylmethylboronates, modest but usable yields of the expected products were formed even without optimization of individual reactions.However, with extremely hindered dicyclohexyl(2phenylethenyl)methyl-and tricyclopentylmethylboronates, none of the desired products were formed (even with the ethylene glycol boronate in the latter case).Therefore, the   upper limit of steric hindrance for this methodology has been identified.Several products 9/14 were isolated by column chromatography from reactions in Tables 1 and 2 (see Supporting Information).Yields of isolated products were typically 5−20% lower than indicated by GC because of losses during separation.However, additional fractions containing the desired product mixed with other materials were available, and higher yields of isolated product could be achieved if necessary.
The new methodology is very general, being applicable to alkylboronates with alkyl groups of widely different bulk and potentially possessing functionality incompatible with Grignard or organolithium reagents.To test the ability of the method to tolerate functionality, and to demonstrate applicability to compounds of synthetic interest, we synthesized 15 (Scheme 4). 14The crude product (91% yield) was a mixture (85:15) of 15 and 16, which was separated by column chromatography.
Reaction of 15 with 4 under the standard conditions led to hydroxy ester 17 (96% yield by GC), which was purified by column chromatography.Lactone 18 (100% yield) was obtained by reflux of a benzene solution of 17 with ptoluenesulfonic acid monohydrate (PTSA) for 4 h (Scheme 5). 15It is unlikely that 17 or 18 could be obtained easily by reacting 1 according to Scheme 1a with Grignard reagent 19 because of the lack of stability of such a reagent, and comparable reactions have not been demonstrated with more stable organozinc reagents.Hydroxy esters typified by 17 and lactone 18 have been used in syntheses of prostaglandins, 16 insect pheromones, 17 and other natural products. 18While there are efficient routes to compound 18, 19 the present approach is very short and demonstrates the synthetic potential of the new process.
Although we oxidized the intermediate (1-alkylallyl)boronates (like 2) to substituted allylic alcohols 9/14/17, they are also available for other types of transformations, such as reactions with aldehydes 7,8,20 or protodeboronation. 21oducts like 2 are potentially available (Scheme 6) by use of 3-chloro-3-lithiopropene (20), accessible by deprotonation of allyl chloride with LDA. 22We therefore mixed 1 (R = Bn) with allyl chloride and LDA (to generate 20) under the conditions developed for reactions of 4. Compound 9 (R = Bn) was obtained in 40% yield (by GC), showing that this approach is much less efficient than use of 4. Of course, not all reactions of 4 and 20 will give identical products, so the new reagent is important for other reasons, too.
In conclusion, the novel organolithium reagent 4 has been generated from 1-bromo-3-chloropropene and t-BuLi at −78 °C.In the presence of pinacol alkylboronates (3), it is trapped to form complexes that rearrange to (α-alkylallyl)boronates 2, in good yields except for ones with extremely hindered alkyl groups, which require less hindered diol units.Direct oxidation of 2, without isolation, gives the corresponding allylic alcohols 9 in good yields.

■ EXPERIMENTAL SECTION
General Experimental Details.Melting point determinations were performed by the open capillary method and are reported uncorrected. 1 H and 13 C NMR chemical shifts (δ) are reported in parts per million (ppm) relative to TMS, and coupling constants J are reported to the nearest 0.1 Hz.C, CH, CH 2 ,o rC H 3 13 C signals are assigned from DEPT-90 and 135 spectra.In a number of cases, carbon atoms attached to boron gave very broad peaks in 13 C NMR spectra, and these could not always be distinguished.Hydrogen atoms attached to these carbons were not always observed in 1 H NMR spectra.Lowand high-resolution mass spectra were recorded on a time-of-fight mass spectrometer using electron impact (EI).High-resolution mass spectra were recorded only for new compounds.IR spectra were recorded on a FT-IR spectrometer as a thin film (liquid samples) or applied as a solution in chloroform, and the chloroform was allowed to evaporate (solid samples).Column chromatography was carried out using 60A (35−70 μm) silica.GC determinations were performed using a gas chromatograph fitted with a ZB-5 column (30 m, 0.32 mm inner diameter, 1.0 μm film thickness).The carrier gas was He at 69.3 kPa, and a split injection mode was used.The oven temperature was increased from 70 to 260 °Ca t6°C min −1 and then held for 4 min.Authentic samples of products were used to determine response factors relative to tetradecane, a known amount of which was added to reaction mixtures to allow quantification of product yields.
Synthesis of Boronate Esters.Boronate esters 3 where R = Bn and 4-MeOBn were purchased from Sigma-Aldrich and TCI, respectively, and used without further purification.Boronate esters 3 where R = Bu, i-Pr, and cyclohexyl were prepared from the reaction of their corresponding boronic acids with pinacol in pentane in 73, 36, and 32% yields, respectively.Boronate ester 3 where R = tert-Bu was prepared by the literature method from pinacolborane and tert-BuMgCl in 40% yield. 24Boronate ester 3 where R = thexyl was prepared by the method previously described from the monohydroboration of 2,3-dimethyl-2-butene and subsequent reaction with pinacol, while boronate esters 11 and 12 were also prepared as described previously. 6oronate esters 13 were prepared by the DCME reaction with the appropriate trialkylboranes.The procedure for preparation of 13 (R C = c-Hex, R D = PhCHCH) is typical.Characterization details of the other boronate esters 13 can be found in our previous publication. 6oronate Ester 13 (R C = c-Hex, R D = PhCHCH): Dicyclohexylborane was prepared by the dropwise addition of cyclohexene (2.12 mL, 20.9 mmol) to borane dimethyl sulfide complex (10 M, 1.00 mL, 10.0 mmol).The mixture was stirred at room temperature for 2 h, dry THF (10 mL) was added, then the mixture was kept at 0 °C during the dropwise addition of phenylacetylene (1.15 mL, 10.5 mmol).The mixture was stirred for 1 h at 0 °C and 1 h at room temperature then recooled to 0 °C.Dichloromethyl methyl ether (1.36 mL, 15.0 mmol) was added dropwise, followed by a freshly prepared solution of lithium triethylcarboxide (dropwise addition of n-BuLi (1.6 M in hexanes, 9.38 mL, 15.0 mmol) to a solution of 3-ethyl-3-pentanol (2.12 mL, 15.0 mmol) in THF (10 mL)) dropwise via a cannula over a 20 min period.The ice bath was removed and the mixture left to stir for a further 1 h.2,2-Dimethyl-1,3-propanediol (1.57g, 15.0 mmol) in dry THF (5 mL) was added and the reaction mixture left to stir overnight at room temperature.The crude product following workup was separated by column chromatography on silica (petroleum ether) to give pure Reactions of Alkylboronic Esters with 5 and tert-BuLi: General Procedure.A mixture of the appropriate boronic ester 3, 11, 12,o r13 (1 equiv), 1-bromo-3-chloroprop-1-ene (5, 1.1 equiv), and dry THF in a dry 50 mL round-bottomed flask equipped with a magnetic stirrer bar and septum was cooled to −78 °C, and t-BuLi in hexanes (1.1 equiv) was added dropwise with vigorous stirring, and the mixture was stirred for an additional 30 min.The cooling bath was removed and the reaction mixture left to warm to 20 °C over 3 h.An accurately weighed amount of tetradecane (∼0.2 mL) was added as a standard to enable GC determination of the amount of desired product formed following workup.The reaction mixture was cooled to 0 °C, then oxidized by dropwise addition of excess NaOH (0.6 g in 5 mL of H 2 O), followed by hydrogen peroxide (30% by weight, 3 mL).Once the initial exothermic reaction subsided, the cooling bath was removed and the mixture left to stir overnight at room temperature.Diethyl ether (10 mL) was added, the aqueous layer saturated with sodium chloride, and a small aliquot taken from the organic phase for GC analysis.The mixture was extracted with diethyl ether (2 × 25 mL).The extract was washed with water (10 mL) and brine (10 mL), then dried over MgSO 4 to give a crude product containing the desired 3-alkylprop-1-en-3-ol 9 or 14, which was estimated by GC.In some cases (see below), mixtures were separated by column chromatography on silica (prewashed with 3% triethylamine in petroleum ether, petroleum ether/ethyl acetate 95:5 through 85:15) to provide the pure products.

3 .
Our experience with halomethyllithium reactions led us to suspect poorer capture of 4 b yt h em o r eh i n d e r e d alkylboronate, allowing competitive decomposition of 4.T o try to overcome this, we synthesized the less hindered thexylboronates 11 and 12 from thexylborane and the corresponding diols.

99 a
Yield by GC with tetradecane as standard.b E/Z 5 used.c Boronic ester 11 or 12 used instead of 3 (R = thexyl).
mp 117.5−118.5 °C).Synthesis of (E)-3-Bromoprop-2-en-1-ol:10 A two-necked roundbottomed flask equipped with a magnetic stirrer bar, septum, and septum-capped dropping funnel was assembled hot and flushed with N 2 .(E)-3-Bromoacrylic acid (8.00 g, 53 mmol) was dissolved in dry diethyl ether (40 mL) and transferred via syringe to the dropping funnel.Powdered LiAlH 4 (4.02 g, 106 mmol) was transferred quickly to the reaction flask, and dry diethyl ether (40 mL) was added.The reaction mixture was cooled in an ice bath, and the solution of 3bromoacrylic acid was added dropwise via the dropping funnel with