Diisopropyl (Dichloromethyl)boronate1

[63360-99-5]  · C7H15BCl2O2  · Diisopropyl (Dichloromethyl)boronate  · (MW 212.91)

(reacts with RLi to form a-chloroalkyl boronic esters;2 chiral 1,2-diol ester derivatives react highly stereoselectively with RLi to form chiral a-chloroalkyl boronic esters1)

Physical Data: bp 65 °C/10 mmHg,2 50-52 °C/5 mmHg;3 n25D 1.4208.2

Form Supplied in: commercially available as pure liquid.

Preparative Method: addition of LDA to CH2Cl2 and triisopropyl borate in THF at -78 °C, then anhydrous HCl, filtration, and fractional distillation.3

Handling, Storage, and Precautions: is hydrolyzed to (dichloromethyl)boronic acid on contact with atmospheric moisture, and should be stored well sealed under nitrogen. It can be transferred and weighed in air without difficulty. The toxicity is unknown, but it should be regarded as a typical reactive alkyl halide.

Reagent Preparation.

The first preparation of diisopropyl (dichloromethyl)boronate was from preformed Cl2CHLi, generated from BuLi and CH2Cl2 in THF at -100 °C, which was treated with B(OMe)3 and worked up with aqueous acid and ether to yield crude (dichloromethyl)boronic acid, which was esterified with 2-propanol (60%).2

The most efficient method reported is the dropwise addition of Lithium Diethylamide to a vigorously stirred solution of CH2Cl2 and Triisopropyl Borate in THF with the internal temperature kept strictly below 0 °C with an ice-salt bath, followed by vacuum distillation of the diethylamine and THF, treatment with diethyl ether, anhydrous HCl, filtration under an inert atmosphere, and distillation of diisopropyl (dichloromethyl)boronate (69%) (eq 1).3 The preparation works equally well at -78 °C with Lithium Diisopropylamide in place of LiNEt2 (yield 70%), except that diisopropylamine is not as easily removed by distillation as diethylamine, and the voluminous amine salt is a nuisance to filter.

Diol Esters.

1,2-Diols or 1,3-diols react rapidly and irreversibly with diisopropyl (dichloromethyl)boronate4,5 or (dichloromethyl)boronic acid.2,6 For example, transesterification with (R,R)-2,3-butanediol readily yields [4R-(4a,5b)]-2-(dichloromethyl)-4,5-dimethyl-1,3,2-dioxaborolane (1) (eq 2).4 The 1,3,2-dioxaborolanes can be purified by vacuum distillation,2-6 and the (4S)-4,5-dicyclohexyl derivative can be recrystallized.7

a-(Chloroalkyl)boronic Esters.

Diisopropyl (dichloromethyl)boronate reacts with organolithium reagents to form a-(chloroalkyl)boronic esters, which can be oxidized to aldehydes or treated with a second mole of RLi to form s-alkylboronic esters.2

1,3,2-Dioxaborolanes are generally easier to handle than diisopropyl boronic esters and have been employed in all of the more recent chemistry of this type.1 For example, 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with vinylmagnesium chloride yields 2-(1-chloroallyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (eq 3).8 The 2-(dibromomethyl) analog behaved similarly.8

2-(Dichloromethyl)-1,3,2-dioxaborolanes and -1,3,2-dioxaborinanes have been reduced with Tri-n-butylstannane to the corresponding 2-chloromethyl derivatives,5 though better routes to these compounds now exist (see Pinacol (Chloromethyl)boronate).

The most useful 1,2-diol esters are those having C2 symmetry, systematically named (4a,5b)-2-(dichloromethyl)-4,5-dialkyl-1,3,2-dioxaborolanes. With Grignard or lithium reagents these yield [2(S*),4a,5b]-2-(1-chloroalkyl)-4,5-dialkyl-1,3,2-dioxaborolanes.1,4 For example, [4R-(4a,5b)]-2-(dichloromethyl)-4,5-dimethyl-1,3,2-dioxaborolane (1) with n-Butyllithium yields intermediate borate (2), which rearranges at rt in the presence of Zinc Chloride to form {4R-[2(S*),4a,5b]}-(1-chloropentyl)-4,5-dimethyl-1,3,2-dioxaborolane (3) (eq 4).4 Diastereomeric excesses (de's) in this reaction as well as those with other lithium or Grignard reagents are generally ~90%.4

Higher stereoselectivities were obtained with larger 4,5-substituents on the dioxaborolane (eq 5). [4S-(4a,5b)]-4,5-Diisopropyl-2-(dichloromethyl)-1,3,2-dioxaborolane (4a) of ~95-98% ee and a series of Grignard or lithium reagents yielded (aS)-a-chloroethyl boronic esters (5a) in &egt;92-94% ee and de.9 The measurement technique was inadequate to establish the true de's, which later work suggests may be 98-99% (see Alternative Route below).

A higher de, &egt;99%, has been reported for conversion of [4S-(4a,5b)]-2-(dichloromethyl)-4,5-dicyclohexyl-1,3,2-dioxaborolane (4b) via the (aS)-a-chloroethyl boronic ester (5b) (eq 5) to the (Z)-(aR)-a-methyl-2-butenyl boronic ester (6) (eq 6).7


The more easily accessible 4,5-diphenyl analog of (4) does not yield satisfactory diastereoselection (62-72% de).10 Problems have been encountered in the attempted utilization of this chemistry for the preparation of a-chloroallylic boronic esters. Although vinylmagnesium chloride with (1) yielded 73% of (aS)-a-chloroallylboronic ester of >82% de,10 attempted use of 1-propenylmagnesium halides led to allylic rearrangement of the initially formed a-chlorocrotylboronic esters if zinc chloride was used or led to low de's if it was not.11 An unrelated enantioselective synthesis of a-halocrotylboronic esters was devised.11,12

Alternative Route.

It is important to note that the C2 symmetry of [4R-(4a,5b)]-2-(dichloromethyl)-4,5-dimethyl-1,3,2-dioxaborolane (1) makes both faces of the boron atom equivalent, and that there is only one diastereomer of the derived borate complex (2). Thus the mode of assembly of (2) does not matter, and the reaction of [4R-(4a,5b)]-2-butyl-4,5-dimethyl-1,3,2-dioxaborolane (7) with Dichloromethyllithium (eq 7) yields the same intermediate (2) as that from (1) and butyllithium in (eq 4) and produces (3) in similar yield and diastereomeric purity.4

The use of [4S-(4a,5b)]-2-alkyl-4,5-diisopropyl-1,3,2-dioxaborolanes (8) in this alternative route has led to s-alkylboronic esters (10) of 99.8% de (eq 8).13 It was shown that the de was enhanced in the reaction of the chloro intermediate (9) with R2MgX. It should be noted that (9) (eq 8) is the same as (5a) (eq 5). In addition to the conversion of (9) to (10) by organometallic reagents, useful products are obtained from (9) with a variety of other nucleophiles.1,14

With chiral dioxaborolanes that lack C2 symmetry, the two faces of the boron atom are nonequivalent, and entirely different results may be obtained depending on the route to the borate intermediate. Pinanediol derived from either enantiomer of a-pinene is a relatively inexpensive and effective chiral director. Reaction of dichloromethyllithium with (S)-pinanediol alkylboronates (11) leads to borates (12), which rearrange in the presence of zinc chloride to a-chloroalkylboronic esters (13) having de's in the 97-99% range (eq 9).15 This chemistry provides a broadly useful method of asymmetric synthesis.1,16

In contrast, reactions of pinanediol dichloromethylboronate (14) with alkylmagnesium halides yield borate intermediates (15) diastereomeric to (12), which rearrange to gross mixtures of diastereomers (13) and (16) (eq 10).6 Accordingly, (14) is not useful for asymmetric synthesis.

Dimethyl (1,1-dichloroethyl)boronate, CH3CCl2B(OMe)2, has been prepared3 and converted to the pinanediol ester.17 Pinanediol (1,1-dichloroethyl)boronate does not yield useful asymmetric inductions, and the alternative route via pinanediol boronates (11) and (1,1-dichloroethyl)lithium did so only when R = Ph.17 Pinanediol (1,1-dichloroethyl)boronate has been converted to the (1-chlorovinyl)boronate.18

Related Reagents.

Dichloromethyllithium; Pinacol (Chloromethyl)boronate.

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. (e) Matteson, D. S. Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1992; Vol. 11, pp 409-427.
2. Rathke, M. W.; Chao, E.; Wu, G. JOM 1976, 122, 145.
3. Matteson, D. S.; Hurst, G. D. OM 1986, 5, 1465.
4. Sadhu, K. M.; Matteson, D. S.; Hurst, G. D.; Kurosky, J. M. OM 1984, 3, 804.
5. Wuts, P. G. M.; Thompson, P. A. JOM 1982, 234, 137.
6. Tsai, D. J. S.; Jesthi, P. K.; Matteson, D. S. OM 1983, 2, 1543.
7. (a) Ditrich, K.; Bube, T.; Stürmer, R.; Hoffmann, R. W. AG 1986, 98, 1016; AG(E) 1986, 25, 1028. (b) Hoffmann, R. W.; Ditrich, K.; Köster, G.; Stürmer, R. CB 1989, 122, 1783.
8. Hoffmann, R. W.; Landmann, B. CB 1986, 119, 1039.
9. Matteson, D. S.; Kandil, A. A. TL 1986, 27, 3831.
10. Hoffmann, R. W.; Landmann, B. CB 1986, 119, 2013.
11. Hoffmann, R. W.; Dresely, S. AG 1986, 98, 186; AG(E) 1986, 25, 189.
12. (a) Hoffmann, R. W.; Dresely, S.; Lanz, J. W. CB 1988, 121, 1501. (b) Hoffmann, R. W.; Dresely, S. S 1988, 103.
13. Tripathy, P. B.; Matteson, D. S. S 1990, 200.
14. Matteson, D. S.; Michnick, T. J. OM 1990, 9, 3171.
15. Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. JACS 1986, 108, 810.
16. Matteson, D. S.; Kandil, A. A.; Soundararajan, R. JACS 1990, 112, 3964.
17. Matteson, D. S.; Hurst, G. D. HC 1990, 1, 65.
18. Matteson, D. S.; Beedle, E. C. HC 1990, 1, 135.

Donald S. Matteson

Washington State University, Pullman, WA, USA

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