Pinacol (Chloromethyl)boronate1

[83622-42-8]  · C7H14BClO2  · Pinacol (Chloromethyl)boronate  · (MW 176.45)

(precursor to allylic boronic esters for stereoselective reactions with aldehydes to form homoallylic alcohols;2 precursor to heterosubstituted methylboronates1)

Alternate Name: 2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Physical Data: bp 81 °C/14 mmHg; 1H NMR d 1.22 (s, CH3), 2.77 (s, CH2Cl).3

Preparative Method: addition of BuLi to stirred ClCH2Br and B(OMe)3 in THF at -78 °C followed by Me3SiCl yields ClCH2B(OMe)2, which is transesterified with pinacol.4

Handling, Storage, and Precautions: (halomethyl)boronic esters are lachrymators and must be handled in a fume hood. As usual with reactive alkyl halides, skin contact should be avoided.

Reagent Preparation.

The first efficient preparation of (chloromethyl)boronic esters was via reduction of (dichloromethyl)boronic esters with Tri-n-butylstannane.3

The most economical route to pinacol (chloromethyl)boronate (1) is the addition of n-Butyllithium to a vigorously stirred solution of bromochloromethane and Trimethyl Borate in THF cooled with a dry ice-acetone bath. After quenching with Chlorotrimethylsilane, the product is treated with pinacol and distilled (73-85%) (eq 1).4

Diisopropyl (chloromethyl)boronate has been made via a similar route from Chloroiodomethane, Triisopropyl Borate, and butyllithium, followed by quenching with ethereal HCl and distillation (84%).5 Yields have been higher with ICH2Cl than with BrCH2Cl in our laboratory. The diisopropyl ester is easily transesterified with a variety of diols.1,6

An especially convenient preparation of diisopropyl (bromomethyl)boronate has been reported recently.7 Dibromomethane is used in place of chloroiodomethane in the foregoing procedure, there is no halide exchange during workup, and 85% yields are routinely obtained on a 2-mol scale.

For some purposes, especially reactions with enolates, pinacol (chloromethyl)boronate (1) is not reactive enough in SN2 displacements.5,8 The chloride is easily displaced by Sodium Iodide in acetone to produce pinacol (iodomethyl)boronate.3 It remains to be investigated how the bromo analog will compare in reactivity with the chloro and iodo compounds.

Allylic Boronic Esters.

A major use of pinacol (chloromethyl)boronate (1) and related compounds has been for the synthesis of allylic boronic esters (2),2 which react diastereoselectively with aldehydes to form homoallylic alcohols. The configuration of the double bond is retained in the synthesis (eq 2),2 and the required alkenylmetallic reagents are often easily prepared in high isomeric purity, for example, via organocopper chemistry.9

Major byproducts limiting yields in the synthesis of (Z)-allylic boronic esters (3) were found to include alkenylboronic ester (4) and alkene (5) (eq 3).10,11 When (Z)-1-propenylmagnesium bromide was used in place of the lithium reagent, formation of alkenylboronic ester (4) was reduced below 1%.11 When (E)-1-lithiopropene was used, the (E) analog of (4) was not a problem. However, either of the simple crotylboronates was more efficiently prepared via reaction of lithiated (Z)- or (E)-2-butene with FB(OMe)2.11

Reaction With Enolates.

Pinacol (iodomethyl)boronate (6) reacts with ester, ketone, or amide enolates to form g-boryl carbonyl compounds (eqs 4 and 5).4,8 The iodo boronic ester (6) has been found superior to the less reactive chloro compound (1) for this purpose. Intramolecular interaction of the boron atom with the carbonyl oxygen provides stereocontrol in subsequent reactions of the products.4

Dibutyl (iodomethyl)boronate and pinacol (chloromethyl)boronate (1) alkylate malonic ester anions.12 Pinacol (iodomethyl)boronate (6) also alkylates secondary and tertiary amines.13

Zinc Derivative.

Pinacol (iodomethyl)boronate (6) reacts with activated zinc to form the zinc reagent (7).14 The zinc reagent is in turn converted to a cuprate, which reacts with electrophiles, for example as illustrated in eq 6.14

Homologs and Related Reagents.

a-Haloalkylboronic esters constitute a broadly useful class of reagents for making C-C bond connections with organometallics, especially for asymmetric synthesis1 (see also Diisopropyl (Dichloromethyl)boronate).

a,a-Disubstituted allylic boronic esters are readily prepared from pinacol (1-bromo-1-methylethyl)boronate (8) and alkenyllithiums (eq 7).11

a-Bromoalkyl boronic esters react diastereoselectively with t-butyl lithiopropionate (eq 8).15 Diastereomeric excesses were 88-96%, enantiomeric excesses >98% (R = i-Pr, Bu).

1. (a) Matteson, D. S. ACR 1988, 21, 294. (b) Matteson, D. S. CRV 1989, 89, 1535. (c) Matteson, D. S. T 1989, 45, 1859. (d) Matteson, D. S. The Chemistry of the Metal-Carbon Bond; Hartley, F.; Patai, S., Eds; Wiley: New York, 1987; Vol. 4, pp 307-409.
2. Wuts, P. G. M.; Thompson, P. A.; Callen, G. R. JOC 1983, 48, 5398.
3. Wuts, P. G. M.; Thompson, P. A. JOM 1982, 234, 137.
4. Whiting, A. TL 1991, 32, 1503.
5. Sadhu, K. M.; Matteson, D. S. OM 1985, 4, 1687.
6. Matteson, D. S.; Kandil, A. A. TL 1986, 27, 3831.
7. Michnick, T. J.; Matteson, D. S. SL 1991, 631.
8. Matteson, D. S.; Beedle, E. C. TL 1987, 28, 4499.
9. Hoffmann, R. W.; Schlapbach, A. LA 1990, 1243.
10. Roush, W. R.; Peseckis, S. M.; Walts, A. E. JOC 1984, 49, 3429.
11. Roush, W. R.; Adam, M. A.; Walts, A. E.; Harris, D. J. JACS 1986, 108, 3422.
12. (a) Matteson, D. S.; Cheng, T. C. JOC 1968, 33, 3055. (b) Kinder, D. H.; Ames, M. M. JOC 1987, 52, 2452.
13. Matteson, D. S.; Majumdar, D. JOM 1979, 170, 259.
14. Knochel, P. JACS 1990, 112, 7431.
15. Matteson, D. S.; Michnick, T. J. OM 1990, 9, 3171.

Donald S. Matteson

Washington State University, Pullman, WA, USA

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