Regioselective Synthesis of Optically Active Trifluoromethyl Group Substituted Allylic Amines by Palladium-Catalyzed Allylic Amination

Abstract

We succeeded in the regioselective synthesis of chiral trifluoromethyl group substituted allylic amines from chiral allyl acetate using two types of palladium catalysts. Furthermore, we found that the kinetic resolution had occurred during the isomerization step from the γ-type product to the α-type product by the [Pd(C₃H₅)(cod)]BF₄/(S)-BINAP catalyst.

palladium catalyst - allylic amination - trifluoromethyl group - chiral allylic amine - kinetic resolution

References and Notes

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Selected examples of transition-metal-catalyzed allylic aminations of allylic esters: for [Pd]

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For [Ir]:

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For [Rh]:

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3j Evans PA. Robinson JE. Nelson JD. J. Am. Chem. Soc.  1999,  121:  12214 

For [Ru]:

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3l Matsushima Y. Onitsuka K. Kondo T. Mitsudo T. Takahashi S. J. Am. Chem. Soc.  2001,  123:  10405 

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Examples of allylic substitutions of fluorinated allyl substrates:

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Examples of net retention mechanism in the palladium-catalyzed allylic substitutions:

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8

We observed the racemization of allylic amines took place by palladium catalysts. For example, the ee of (R)-4a decreased from 88% to 80% by Pd(OAc)₂/DPPE at 60 ˚C for 12 h, and the ee of (S)-3a also decreased from 98% to 13% by [Pd(C₃H₅)(cod)]BF₄/(S)-BINAP at 100 ˚C for 12 h.

9

We also confirmed the reaction with 10 mol% of [Pd(C₃H₅)(cod)]BF₄/BIPHEP [2,2′-bis(diphenyl-phosphino)-1,1′-biphenyl] gave an α-product with 96% regioselectivity at 60 ˚C, but the ee decreased to 66%.

10

Typical Procedure for the [Pd(C ₃ H ₅ )(cod)]BF ₄ /( S )-BINAP-Catalyzed Allylic Amination of ( S )-1 with 2a To a solution of [Pd(C₃H₅)(cod)]BF₄ (7.0 mg, 0.021 mmol), (S)-BINAP (12.8 mg, 0.021 mmol), (S)-1,1,1-trifluoro-4-phenylbut-3-en-2-yl acetate [(S)-1, 50 mg, 0.21 mmol] in dioxane (1.0 mL) was added morpholine (2a) and stirred at r.t. for 5 min and 40 ˚C for 12 h. The reaction mixture was quenched with brine and H₂O (1 mL), then extracted with EtOAc (3 × 2 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The NMR yield (95%, trioxane as an internal standard) and ratio of 3a and 4a was determined by ^¹H NMR of the crude materials.
Analytical Data of 3a
[α]_D ^²6 +69.2 [c 1.37, CHCl₃; 99% ee (S)]. The enantiomeric purity was determined to be 99% ee by HPLC analysis with a Daicel CHIRALPAK AD-H [hexane-2-PrOH (99:1), flow: 1.0 mL/min, 254 nm, 35 ˚C, t _major = 11.2 min, t _minor = 13.0 min]. ^¹H NMR (500 MHz, CDCl₃): δ = 2.71-2.80 (m, 4 H), 3.60 (quin, J = 8.2 Hz, 1 H), 3.72 (t, J = 4.6 Hz, 4 H), 6.18 (dd, J = 8.2, 16.0 Hz, 1 H), 6.72 (d, J = 16.0 Hz, 1 H), 7.28-7.42 (m, 5 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 50.4, 67.2, 68.6 (q, J _CF = 27.5 Hz), 118.5, 125.7 (q, J _CF = 285.0 Hz), 126.7, 128.5, 128.7, 135.7, 137.5. ^¹9F NMR (470 MHz, CDCl₃): δ = 92.0 (d, J = 8.2 Hz). HRMS (EI): m/z calcd for C₁₄H₁₆F₃NO: 271.1184; found: 271.1195.

11

The absolute configuration of (S)-3a and (R)-4a were determined by the comparison of the X-ray crystallographic analysis of the products from the reaction of (S)-4-(4-chlorophenyl)-1,1,1-trifluorobut-3-en-2-yl acetate with 1-phenylpiperazine. See details in the Supporting Information.

Selected examples of kinetic resolution in the palladium-catalyzed allylic substitutions of disubstituted symmetrical or monosubstituted allylic esters:

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Examples of kinetic resolution in the palladium-catalyzed allylic substitutions of 1,3-disubstituted unsymmetrical allylic esters:

13a Hayashi T. Yamamoto A. Ito Y.
J. Chem. Soc., Chem. Commun.  1986,  1090 

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14

Calculated by ee_P and ee_S. S = ln[(1 - c)(1 + ee_P)]/ln[(1 - c) (1 - ee_P)]. c = ee_S/(ee_S + ee_P).

15 Kagan HB. Fiaud JC. Top. Stereochem.  1988,  18:  249