Cyclopropanation

Abstract

A method of preparing a cyclopropane ring-bearing compound of the formula I ##STR00001##
in which R.sup.1 and R.sup.2 are independently selected from C.sub.1-C.sub.10 alkyl, optionally substituted, or R.sup.1 and R.sup.2, together with the bonds linking them to the cyclopropane ring, form a monocyclic or bicyclic ring system, which may comprise at least one hetero-atom, comprising the reaction of a compound of formula II
R.sup.1CHCHR.sup.2II
in which R.sup.1 and R.sup.2 have the significances hereinabove defined, with a compound of formula III
XCH.sub.2YIII
in which X is a nucleofuge selected from halides and pseudohalides and Y is an electrofuge selected from boranes and borates, in the presence of a metal catalyst complex selected from those useful for catalytic cyclopropanation and those useful for catalyzing Heck coupling. The method provides a particularly easy and non-hazardous method of cyclopropanation.

Claims

1. A method of preparing a cyclopropane ring-bearing compound of the formula I ##STR00018## in which R.sup.1 and R.sup.2 are independently selected from C.sub.1-C.sub.10 alkyl, optionally substituted, or R.sup.1 and R.sup.2, together with the bonds linking them to the cyclopropane ring, form a monocyclic or bicyclic ring system, which optionally comprises at least one hetero-atom, comprising the reaction of a compound of formula II
R.sup.1CHCHR.sup.2II in which R.sup.1 and R.sup.2 have the significances hereinabove defined, with a compound of formula III
XCH.sub.2YIII in which X is a nucleofuge selected from halides and pseudohalides and Y is an electrofuge selected from boranes and borates, in the presence of a metal catalyst complex selected from those useful for catalytic cyclopropanation and those useful for catalyzing Heck coupling.

2. The method according to claim 1, in which the nucleofuge is selected from halogens and pseudohalogens.

3. The method according to claim 1, in which the electrofuge is selected from trifluoroborate salts of alkali metals, and pinacol borane.

4. The method according to claim 1 in which the catalyst is a Herrmann catalyst.

Description

GENERAL PROCEDURE

(1) In the glove box, a 5 mL Young Schlenk (approximately 10 mL total volume) was equipped with a glass coated stir bar. In the glove box, base (1.5 equiv), methylenation reagent (1.5 equiv), olefin (1 equiv), and catalyst (5 mol %) were transferred to the vial. A degassed solvent mixture of a polar solvent (16 mL/mmol substrate) and a ROH solvent (2 mL/mmol substrate) were added and the Schlenk was closed. After transferring the Schlenk outside the glove box, the reaction mixture was heated to 90 C. in an oil bath and stirred for 16 h. Then the reaction mixture was rapidly cooled to 0 C. in an ice bath. Consecutively undecane (0.4 equiv) as internal standard, Et.sub.2O (45 mL/mmol substrate) and water (45 mL/mmol substrate) were then added. The phases were separated and the aqueous phase was extracted with Et.sub.2O (45 mL/mmol substrate). The combined organic phases were washed with brine (45 mL/mmol substrate), dried over MgSO.sub.4 and analyzed by GC-MS.

(2) Procedure for Standard Reaction:

(3) In the glove box, a 5 mL Young Schlenk (approximately 10 mL total volume) was equipped with a glass coated stir bar. In the glove box, K.sub.2CO.sub.3 (25.1 mg, 0.182 mmol), KBF.sub.3CH.sub.2I (43.1 mg, 0.174 mmol), norbornene (11.0 mg, 0.117 mmol), and Hermann Pd.sup.II-catalyst (2.74 mg, 0.00292 mmol, dimer so 5.0 mol % Pd.sup.II) were transferred to the vial. A degassed solvent mixture of DMF (2 mL) and H.sub.2O (0.25 mL) were added and the Schlenk was closed. After transferring the Schlenk outside the glove box, the reaction mixture was heated to 90 C. in an oil bath and stirred for 16 h. Then the reaction mixture was rapidly cooled to 0 C. in an ice bath. Consecutively undecane (10 L, 7.4 mg, 0.047 mmol) as internal standard, Et.sub.2O (5 mL/mmol substrate) and water (5 mL/mmol substrate) were then added. The phases were separated and the aqueous phase was extracted with Et.sub.2O (5 mL/mmol substrate). The combined organic phases were washed with brine (5 mL), dried over MgSO.sub.4 and analyzed by GC-MS (method: 40 C. for 2 min, then from 40 C. to 300 C. in 17 min 20 sec [ramp: 15 C./min]). The tricyclo[3.2.1.0-2,4]octane was obtained in 98% yield according to GC-MS (standardized).

(4) tricyclo[3.2.1.02,4]octane (compared to authentic sample, identical fragmentation pattern [GC-MS])retention time: 5.81 min, area: 20343140, correction factor: 1.304/1.00 tricyclo[3.2.1.0-2,4]octane/undecane;

(5) undecaneretention time: 8.65 min, area: 15889470.

(6) The results are set forth in the following tables. Table 1 shows the screening of catalysts using norborene as the test olefin, and Table 2 shows the optimization of solvent, additives, and the electrofuge/nucleofuge combinations. Table 3 shows results for olefins other than norbornene.

(7) TABLE-US-00001 TABLE 1 Screening of catalysts for the methylenation of norbornene..sup.a entry catalyst yield remaining 1.sup.b 1 none 0% 80% 2 Pd.sup.0(PPh.sub.3).sub.4 6% 71% 3.sup.c Pd.sup.0(dba).sub.2 + IPr 2% 81% 4 Pd.sup.0(IPr).sub.2 37% 45% 5 Pd.sup.0(P(tBu).sub.3).sub.2 85% 15% 6 Pd.sup.II-Herrmann 98% 0% 7 Pd.sup.IIIPrCl.sub.2-dimer 88% 4% .sup.aConditions: scale 0.117 mmol 1, 0.06 M concentration of 1. .sup.bStandardized GC-yield and recovery of 1. .sup.cPd.sup.0(dba).sub.2 (5 mol %) and IPr ligand (6 mol %) were used.

(8) TABLE-US-00002 TABLE 2 Optimization of norbornene methylenation using the Herrmann (4) and Pd.sup.0(P(tBu).sub.3).sub.2 (5) catalysts..sup.a # cat XCH.sub.2B base DMF/H.sub.2O yield.sup.b rem. 1.sup.b 1 4 ICH.sub.2BF.sub.3K (2) K.sub.2CO.sub.3 8/1 98% 0% 2 5 ICH.sub.2BF.sub.3K (2) K.sub.2CO.sub.3 8/1 85% 15% 3 4 ICH.sub.2BF.sub.3K (2) K.sub.2CO.sub.3 DMF only 25% 56% 4 5 ICH.sub.2BF.sub.3K (2) K.sub.2CO.sub.3 DMF only 47% 42% 5 4 ICH.sub.2BF.sub.3K (2) none 8/1 24% 54% 6 5 ICH.sub.2BF.sub.3K (2) none 8/1 35% 52% 7 4 ICH.sub.2BF.sub.3K (2) none DMF only 1% 73% 8 5 ICH.sub.2BF.sub.3K (2) none DMF only 87% 7% 9.sup.c 4 ICH.sub.2BF.sub.3K (2) K.sub.2CO.sub.3 8/1 38% 37% 10.sup.c 5 ICH.sub.2BF.sub.3K (2) K.sub.2CO.sub.3 8/1 66% 17% 11 5 BrCH.sub.2BF.sub.3K none DMF only 7% 73% 12 5 ICH.sub.2B(OR).sub.2.sup.d CsF.sup.e DMF only 70% 16% 13 5 ICH.sub.2B(OR).sub.2.sup.d K.sub.2CO.sub.3 + CsF.sup.e 8/1 92% 8% .sup.aConditions: scale 0.117 mmol 1, 0.06 M concentration of 1. .sup.bStandardized GC-yield and recovery of 1. .sup.cBefore addition of 1 and the catalyst the B-reagent 2 was preactivated at 90 C. for 30 min. .sup.d2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used. .sup.e3.0 equiv of CsF was used.

(9) TABLE-US-00003 TABLE 3 Methylenation of several electron-rich olefins using Herrmann catalyst 4..sup.a # substrate cyclopropane.sup.b -H elimination product.sup.b remaining 7.sup.b 1 0 58% 2 43% 3 39% .sup.aConditions: scale 0.113-0.117 mmol, 0.06 M concentration of 7. .sup.bStandardized GC-yield and recovery of 7. .sup.cA mixture of several olefins was obtained.