High-Yielding Large-Scale Syntheses of Enantiomerically Pure NOBIN and a NOBIN-Based Enantiomerically Pure NHC Precursor

Abstract

The MOM-protected monotriflate derived from enantiomerically pure (S)-BINOL rendered (S)-NOBIN (67% over 5 steps) and an (S)-configured NHC precursor (55% over 5 steps) on 10 gram and 5 gram scales, respectively. The C-N bond formation was realized by OTf → NHBn and OTf → NH-CH₂-CH₂-NH-mesityl exchanges, respectively.

BINOL - Buchwald-Hartwig amination - imidazolinium chloride - ligand synthesis - N-heterocyclic carbene - NOBIN

References and Notes

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First resolution:

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<A NAME="RG32508ST-17">17</A>

Enantiopure BINOL: 5 g ca. 50 ı [(R)-BINOL, ABCR; (S)-BINOL, AlfaAesar), 1 kg ca. 900 $ [(R)- or (S)-BINOL, AK Scientific).

<A NAME="RG32508ST-18">18</A> Ooi T. Ohmatsu K. Maruoka K. J. Am. Chem. Soc.  2007,  129:  2410 

<A NAME="RG32508ST-19">19</A>

(S)-BINOL monotriflate (5.59 g, 13.4 mmol) was dissolved in CH₂Cl₂ (35 mL) and CH₂(OMe)₂ (35 mL). Then P₄O₁₀ (3.93 g, 13.8 mmol, 1.03 equiv) was added within 1 h in 2 portions. The mixture was stirred at r.t. for 7 h, poured into aq NH₃ (35%, 30 mL), and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic phases were dried over MgSO₄. Evaporation of the solvent under reduced pressure and flash chromatography on SiO₂ (eluent: cyclohexane-EtOAc, 95:5) provided the MOM-protected (S)-BINOL monotriflate 5 ^¹8 (5.90 g, 95%) as a colorless oil. It crystallized slowly when transferred into a refrigerator.

<A NAME="RG32508ST-20">20</A> Acetalization method: Paleo MR. Aurrecoechea N. Jung K.-Y. Rapoport H. J. Org. Chem.  2003,  68:  130 

<A NAME="RG32508ST-21">21</A>

See: http://www.epa.gov/ttn/atw/hlthef/chlo-eth.html.

<A NAME="RG32508ST-22">22</A>

A suspension of benzylamine 6 (15.9 g, 38.0 mmol) and Pd (10% on C, 2.04 g, 1.99 mmol, 5 mol%) in EtOAc (70 mL) was heated under H₂ (1 atm) at 60 ˚C for 3 h. After filtration through Celite, the solvent was removed under reduced pressure. The residue was dissolved in CH₂Cl₂ (100 mL) and MeOH (100 mL). Concentrated H₂SO₄ (6.0 mL) was added and the mixture refluxed for 2 h. Saturated aq NaHCO₃ (100 mL) was added after cooling. The mixture was extracted with CH₂Cl₂ (3 × 50 mL). The combined organic phases were dried over MgSO₄. Evaporation of the solvent under reduced pressure provided (S)-NOBIN (1; 9.19 g, 85%) as a faintly yellow solid (pure as judged by ^¹H NMR). Recrystallization from toluene rendered rounded white needles (8.84 g, 82%). On a smaller scale (3.29 g of benzylamine 6) the yield of recrystallized 1 was 1.97 g [88%; cf. footnote (e) of Scheme  [¹] ].

<A NAME="RG32508ST-23">23</A>

Enantiopure NOBIN: 1 g ca. 500 ı [(R)- or (S)-NOBIN, ABCR], 10 g ca. 1500 $ [(R)-NOBIN], 50 g ca. 4000 $ [(S)-NOBIN, both Shanghai FWD Chemicals].

<A NAME="RG32508ST-24">24</A> Perillo I. Caterina MC. López J. Salerno A. Synthesis  2004,  851 

<A NAME="RG32508ST-25">25</A>

Simplified Synthesis of Diamine 10^²4
A suspension of 2-bromoethylamine hydrobromide (7; 8.24 g, 40.2 mmol) and mesitylamine (9; 16.0 g, 119 mmol, 2.94 equiv) in toluene (160 mL) was refluxed for 23 h. After cooling, aq NaOH (20%, 120 mL) was added. The mixture was extracted with EtOAc (3 × 120 mL). The combined organic phases were dried over MgSO₄. Evaporation of the solvent under reduced pressure and flash chromatography on SiO₂ (eluent: EtOAc, then EtOAc-MeOH, 1:1 + 1% Et₃N) provided 10 (6.39 g, 89%) as a deep red oil.

<A NAME="RG32508ST-26">26</A>

The following conditions were adapted from a related transformation:^¹8 Cs₂CO₃ (7.51 g, 23.0 mmol, 1.30 equiv) was dried in vacuo with a heat gun for 30 min. After
cooling, Pd(OAc)₂ (395 mg, 1.76 mmol, 9.90 mol%),
(o-Ph₂PC₆H₄)₂O (1.89 g, 3.51 mmol, 20 mol%), and a solution of the MOM-protected monotriflate 5 (8.22 g, 17.8 mmol) and the diamine 10 (4.09 g, 22.9 mmol, 1.29 equiv) in toluene (9 mL) were added. The suspension was degassed and stirred at 115 ˚C for 14 h. Filtration through Celite, evaporation of the solvent under reduced pressure, and flash chromatography on SiO₂ (eluent: cyclohexane-EtOAc, 90:10 → 80:20) provided the diamine 12 (7.79 g, 89%) as a reddish-brown sticky solid. ^¹H NMR (400 MHz, CDCl₃, TMS): δ = 1.91 (s, 2 × o-CH₃), 2.17 (s, p-CH₃), 2.95 (ddd, ^³ J = ^³ J = 5.5 Hz, ^³ J = 2.2 Hz, NCH₂), 3.12 (s, OCH₃), AB signal (δ_A = 3.33 ppm, δ_B = 3.39 ppm, J _AB = 13.0 Hz, in addition split by J _A = J _B = 5.7 Hz, NCH₂), 3.85 (br s, 2 × NH), AB signal (δ_A = 4.97 ppm, δ_B = 5.02 ppm, J _AB = 6.8 Hz, OCH₂O), 6.71 (s, 2 × mesityl-H), 6.94-6.97 (m, ArH), 7.11-7.19 (m_c, 2 × ArH), 7.21-7.23 (m, 2 × ArH), 7.24-7.27 (m, ArH), 7.35 (ddd, ^³ J = 8.1 Hz, ^³ J = 5.8 Hz, ^³ J = 2.3 Hz, ArH), 7.55 (d, ^³ J = 9.1 Hz, ArH), 7.76-7.78 (m, ArH), 7.86 (d, ^³ J = 8.1 Hz, ArH), 7.87 (d, ^³ J = 8.9 Hz, ArH), 7.95 (d, ^³ J = 9.0 Hz, ArH). HRMS (EI, 70 eV): m/z calcd for C₃₃H₃₄N₂O₂ [M⁺]: 490.262028; found: 490.262202 (+0.4 ppm). [α]_D ^²0 -75 (c 1.05, CHCl₃).