A Brønsted Acid and Lewis Base Organocatalyst for the Aza-Morita-Baylis-Hillman Reaction

Abstract

(S)-3-[2-(Diphenylphosphino)phenyl]BINOL has been established as an efficient asymmetric bifunctional organocatalyst for the aza-Morita-Baylis-Hillman (aza-MBH) reaction. The ­Brønsted acid and Lewis base functionalities cooperate in substrate activation to promote the reaction with high enantiocontrol.

Key words

enantioselective aza-Morita-Baylis-Hillman reaction - bifunctional catalyst - Brønsted acid - Lewis base - organocatalysis

References and Notes

• 1a Asymmetric Organocatalyst - From Biomimetic Concept to Application in Asymmetric Synthesis   Berkessel A. Gröger H. Wiley-VCH; Weinheim: 2005. 
• 1b Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  43:  5138 
• 1c Seayad J. List B. Org. Biomol. Chem.  2005,  3:  719 
• For reviews see:
• 2a Shibasaki M. Sasai H. Arai T. Angew. Chem., Int. Ed. Engl.  1997,  36:  1236 
• 2b Gröger H. Chem. Eur. J.  2001,  7:  5246 
• 2c Kanai M. Kato N. Ichikawa E. Shibasaki M. Synlett  2005,  1491 
• 2d Shibasaki M. Kanai M. Funabashi K. Chem. Commun.  2002,  1989 
• 3a Somei H. Asano Y. Yoshida T. Takizawa S. Yamataka H. Sasai H. Tetrahedron Lett.  2004,  45:  1841 
• 3b Imbriglio JE. Vasbinder MM. Miller SJ. Org. Lett.  2003,  5:  3741 
• 3c Ooi T. Ohara D. Tamura M. Maruoka K. J. Am. Chem. Soc.  2004,  126:  6844 
• 3d Ishii T. Fujioka S. Sekiguchi Y. Kotsuki H. J. Am. Chem. Soc.  2004,  126:  9558 
• 3e Okino T. Hoashi Y. Takemoto Y. J. Am. Chem. Soc.  2003,  125:  12672 
• 3f Li H. Wang Y. Tang L. Deng L. J. Am. Chem. Soc.  2004,  126:  9906 
• 3g Mermerian AH. Fu GC. J. Am. Chem. Soc.  2003,  125:  4050 
• 3h Uraguchi D. Sorimachi K. Terada M. J. Am. Chem. Soc.  2004,  126:  11804 
• 3i Akiyama T. Itoh J. Yokota K. Fuchibe K. Angew. Chem. Int. Ed.  2004,  43:  1566 
• 3j Sammis GM. Danjo H. Jacobsen EN. J. Am. Chem. Soc.  2004,  126:  9928 
• 3k Matsui K. Takizawa S. Sasai H. Tetrahedron Lett.  2005,  46:  1943 
• 3l Wang J. Li H. Yu X. Zu L. Wang W. Org. Lett.  2005,  7:  4293 
• 3m Sohtome Y. Hashimoto Y. Nagasawa K. Adv. Synth. Catal.  2005,  347:  1643 
• Aza-MBH reactions are accelerated in the presence of acidic and basic catalysts. See:
• 4a Matsui K. Takizawa S. Sasai H. J. Am. Chem. Soc.  2005,  127:  3680 
• 4b Shi M. Xu Y.-M. Angew. Chem. Int. Ed.  2002,  41:  4507 
• 4c Balan D. Adolfsson H. Tetrahedron Lett.  2003,  44:  2521 
• 4d Kawahara S. Nakano A. Esumi T. Iwabuchi Y. Hatakeyama S. Org. Lett.  2003,  5:  3103 
• 4e Shi M. Chen L.-H. Chem. Commun.  2003,  1310 
• 4f Shi M. Chen L.-H. Li C.-Q. J. Am. Chem. Soc.  2005,  127:  3790 
• 4g Shi M. Li C.-Q. Tetrahedron: Asymmetry  2005,  16:  1385 
• 4h Shi M. Xu Y.-M. Shi Y.-L. Chem. Eur. J.  2005,  11:  1794 
• 4i Raheem IT. Jacobsen EN. Adv. Synth. Catal.  2005,  347:  1701 
• Asymmetric catalysts bearing metal coordination units on the axial linkage have been reported. See:
• 5a Aikawa K. Mikami K. Angew. Chem. Int. Ed.  2003,  42:  5458 
• 5b Maruoka K. Murase N. Yamamoto H. J. Org. Chem.  1993,  58:  2938 
• 5c Simonson DL. Kingsbury K. Xu M.-H. Hu Q.-S. Sabat M. Pu L. Tetrahedron  2002,  58:  8189 
• 11 Meng Y. Slaven WT. Wang D. Liu T.-J. Chow H.-F. Li C.-J. Tetrahedron: Asymmetry  1998,  9:  3693 
• 12a ten Have R. Huisman M. Meetsma A. van Leusen AM. Tetrahedron  1997,  53:  11355 
• 12b Lee KY. Lee CG. Kim JM. Tetrahedron Lett.  2003,  44:  1231 

6

General Procedure for the Synthesis of (S)-1a (Scheme [2] )
To a solution of (S)-I [11] (132.0 mg, 0.3 mmol) and
2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (79.2 mg, 0.36 mmol) in THF (6 mL) were added 1 M K₂CO₃ aq (3 mL) and Pd(PPh₃)₄ (17.3 mg, 0.015 mmol). The mixture was refluxed for 12 h, and then cooled to r.t. Then, CH₂Cl₂ (5 mL) was added and the organic phase was separated. The aqueous phase was extracted twice with CH₂Cl₂ (2 × 10 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified by flash chromatography (SiO₂, EtOAc-hexane = 1:4) to give the compound (S)-II (121.9 mg, 0.3 mmol, 100%).
Compound (S)-II: orange solid; mp 58-59 °C (EtOAc-hexane). IR (neat): ν = 3354, 3039, 2915, 2830 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 8.02 (1 H, d, J = 9.2 Hz), 8.00 (1 H, s), 7.93 (1 H, d, J = 8.6 Hz), 7.89 (1 H, d, J = 8.6 Hz), 7.59 (1 H, d, J = 7.8 Hz), 7.46 (1 H, dt, J = 8.6, 1.3 Hz), 7.41-7.17 (8 H, m), 7.08 (1 H, d, J = 8.9 Hz), 3.82 (3 H, s), 3.24 (3 H, s). ¹³C NMR (67.7 MHz, CDCl₃): δ = 154.6, 153.8, 152.2, 133.8, 133.2, 131.8, 131.5, 131.3, 131.1, 129.8, 129.4, 128.8, 128.1, 127.9, 126.8, 126.6, 126.3, 125.8, 125.5, 125.3, 124.8, 123.5, 121.1, 118.2, 113.2, 61.4, 56.3. HRMS (ESI): m/z calcd for C₂₈H₂₂NaO₃: 429.1467 [M + Na]⁺; found: 429.1466. [α]_D ²⁰ -63.9 (c 0.6, CHCl₃).
To a solution of (S)-II (121.9 mg, 0.3 mmol) with pyridine (72 µL, 0.9 mmol) in CH₂Cl₂ (3 mL) was added trifluoro-methanesulfonic anhydride (100 µL, 0.6 mmol) at 0 °C. The mixture was then warmed to r.t. and was kept overnight. The mixture was quenched with H₂O and extracted with CH₂Cl₂ (2 × 10 mL). The combined organic extracts were dried (Na₂SO₄). The filtrate was evaporated in vacuo, and the residue was purified by flash chromatography (SiO₂, EtOAc-hexane = 1:4) to give (S)-III (159.9 mg, 0.297 mmol, 99%).
Compound (S)-III: orange solid; mp 42-43 °C (EtOAc-hexane). IR (neat): ν = 3056, 2917, 2833, 1389, 1182 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 7.99 (1 H, d, J = 9.2 Hz), 7.93 (1 H, s), 7.90 (1 H, d, J = 8.6 Hz), 7.85 (1 H, d, J = 7.3 Hz), 7.69-7.65 (1 H, m), 7.48-7.16 (9 H, m), 3.80 (3 H, s), 3.06 (3 H, s). ¹³C NMR (67.7 MHz, CDCl₃): δ = 154.7, 153.6, 147.6, 134.2, 133.9, 132.7, 132.5, 131.0, 130.2, 129.7, 129.2, 129.1, 128.9, 128.0, 127.7, 126.6, 125.4, 125.2, 125.1, 124.9, 123.6, 121,2. 118.8, 113.2, 60.4, 56.3. HRMS (ESI): m/z calcd for C₂₉H₂₁F₃NaO₅S: 561.0960 [M + Na]⁺; found: 561.0955. [α]_D ²⁰ -78.4 (c 0.5, CHCl₃).
To a solution of (S)-III (161.6 mg, 0.3 mmol) in DMSO (6 mL) were added Ph₂(O)PH (121.3 mg, 0.6 mmol) and DPPB (12.8 mg, 0.03 mmol) at r.t. followed by Pd(OAc)₂ (3.4 mg, 0.015 mmol) and i-Pr₂NEt (209 µL, 1.2 mmol). After the mixture was stirred for 12 h at 100 °C, it was cooled to r.t., and EtOAc (10 mL) was added. The organic phase was washed twice with H₂O, dried over Na₂SO₄ and evaporated in vacuo. The residue was purified by flash chromatography (SiO₂, EtOAc-hexane = 4:1) to give the compound (S)-IV (147.1 mg, 0.249 mmol, 83%).
Compound (S)-IV: white solid; mp 77-78 °C (EtOAc-hexane). IR (neat): ν = 3055, 2932, 2844, 1438, 1158 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 7.96 (1 H, d, J = 9.2 Hz), 7.75 (1 H, s), 7.85-7.04 (22 H, m), 7.54 (1 H, d, J = 7.5 Hz), 6.99 (1 H, d, J = 8.1 Hz), 3.78 (3 H, s), 2.99 (3 H, s). ¹³C NMR (67.7 MHz, CDCl₃): δ = 154.6, 153.6, 144.6, 134.1, 133.9, 133.8, 133.5, 133.3, 133.2, 133.2, 133.1, 132.0, 131.9, 131.6, 131.5, 131.4, 131.4, 131.3, 131.2, 131.0, 130.9, 130.9, 129.4, 129.3, 129.2, 128.8, 128.8, 128.3, 128,1, 128.0, 127.9, 127.7, 127.4, 127.4, 126.4, 126.2, 126.2, 125.9,124.9, 124.2, 123.4, 113.6, 60.1, 56.8. ³¹P NMR (162 MHz, CDCl₃): δ = 29.37, 28.95. HRMS (ESI): m/z calcd for C₄₀H₃₁NaO₅P: 613.1909 [M + Na]⁺; found: 613.1898. [α]_D ²⁰ -64.3 (c 0.4, CHCl₃).
To a solution of (S)-IV (177.2 mg, 0.3 mmol) in CH₂Cl₂ (3 mL) was added BBr₃ (0.9 mL, 0.9 mmol, 1 M in CH₂Cl₂) at 0 °C and the resulting solution was stirred for 30 min. The reaction mixture was quenched with H₂O and extracted with CH₂Cl₂ (2 × 10 mL). The combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo. The residue was purified by flash chromatography (SiO₂, EtOAc-hexane = 1:4) to give the compound (S)-V (153.6 mg, 0.273 mmol, 91%).
(S)-V: white solid; mp 149-150 °C (EtOAc-hexane). IR (neat): ν = 3356, 3053, 2912, 2853, 1448, 1166 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 7.89 (1 H, d, J = 8.9 Hz), 7.84 (1 H, d, J = 7.8 Hz), 7.80-6.98 (22 H, m). ¹³C NMR (67.7 MHz, CDCl₃): δ = 153.3, 150.9, 143.1, 134.0, 133.3, 133.0, 132.8, 132.7, 132.3, 132.1, 132.0, 131.8, 131.7, 131.5, 131.4, 131.2, 130.8, 130.6, 129.8, 129.8, 128.6, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.7, 127.0, 126.9, 126.8, 126.2, 126.0, 124.9, 124.8, 123.1, 122.8, 119.6, 115.0, 112.9. ³¹P NMR (162 MHz, CDCl₃): δ = 31.17. HRMS (ESI): m/z calcd for C₃₈H₂₇NaO₅P: 585.1596 [M + Na]⁺; found: 585.1615. [α]_D ²⁰ +86.4 (c 0.6, CHCl₃).
To a solution of (S)-V (112.5 mg, 0.2 mmol) and Et₃N (279 µL, 2.0 mmol) in toluene (6.7 mL) was added HSiCl₃ (404 µL, 4.0 mmol) at 0 °C. After being stirred at 50 °C for 12 h, the mixture was cooled to r.t., diluted with EtOAc and then quenched with a small amount of sat. aq NaHCO₃. The resulting suspension was filtered through Celite^® and the solid was washed with EtOAc (2 × 10 mL). The combined organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc-hexane = 1:4) to give the compound (S)-1a (65.6 mg, 0.12 mmol, 60%).
Compound (S)-1a: white solid; mp 105-106 °C (EtOAc-hexane). IR (neat): ν = 3370, 3050, 2902, 2824, 1444 cm^-1. ¹H NMR (270 MHz, CDCl₃): δ = 7.96 (1 H, d, J = 9.2 Hz), 7.88 (1 H, d, J = 7.3 Hz), 7.80-6.98 (23 H, m), 5.18 (1 H, br s). ¹³C NMR (67.7 MHz, CDCl₃): δ = 152.8, 150.2, 149.7, 143.1, 142.7, 133.8, 133.6, 133.5, 133.3, 132.0, 131.9, 130.9, 129.2, 129.2, 129.2, 128.9, 128.8, 128.6, 128.4, 128.3, 128.2, 128.1, 126.9, 126.9, 125.2, 124.7, 123.8, 123.6, 118.1, 111.8, 111.7. ³¹P NMR (162 MHz, CDCl₃): δ = -10.46, -11.71. HRMS (ESI): m/z calcd for C₃₈H₂₇NaO₂P: 569.1646 [M + Na]⁺; found: 569.1631. [α]_D ²⁰ -73.2 (c 0.6, CHCl₃).

7

Results of the aza-MBH reaction of 2a with 3a catalyzed by 1a using various solvents (0.5 M; substrate concentration of 3a) at 0 °C for 20 h: CH₂Cl₂ (36% yield, 45% ee), toluene (24% yield, 56% ee), MeCN (38% yield, 48% ee), DMF (34% yield, 21% ee), MeOH (22% yield, 21% ee).

8

Results of the aza-MBH reaction of 2a with 3a catalyzed by organocatalysts 1d-i in t-BuOMe (0.05 M; substrate concentration of 3a) at -20 °C for 144 h: 1d (no reaction), 1e (71% yield, 88% ee), 1f (80% yield, 86% ee), 1g (no reaction), 1h (14% yield, 73% ee), 1i (29% yield, 77% ee).

9

General Experimental Procedure (Table 2) To a solution of organocatalyst 1a (2.7 mg, 0.005 mmol, 10 mol%) in t-BuOMe (1.0 mL) were added 2 (0.15 mmol) and imine 3 [12] (0.05 mmol) at -20 °C. The mixture was stirred until the reaction had reached completion by monitoring with TLC analysis. The mixture was directly purified by flash column chromatography (SiO₂, EtOAc-hexane = 1:2) to give the corresponding adduct 4. All products were characterized by ¹H NMR, ¹³C NMR, MS, and IR spectroscopy. Absolute configurations of 5 were determined by comparing the assign of the optical rotations with those in the literature. [4]

10

The aza-MBH reaction of 2a with 3a was performed in t-BuOMe (0.05M; substrate concentration of 3a) at 0 °C; 6a: no reaction; 6b: (S)-4a, 86 h, 5% yield, 63% ee; 6c: (R)-4a, 48 h, 95% yield, 61% ee.