PDF icon Download PDF
Synlett 2009(1): 109-111  
DOI: 10.1055/s-0028-1087390
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Daniel Sälinger, Reinhard Brückner*
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg, Germany
Fax: +49(761)2036100; e-Mail: reinhard.brueckner@organik.chemie.uni-freiburg.de;
Further Information

Publication History

Received 2 October 2008
Publication Date:
12 December 2008 (online)

   Permissions and Reprints All articles of this category
Preview

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.

Key words

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

17

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

19

(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.

21

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

22

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] ].

23

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].

25

Simplified Synthesis of Diamine 10²4
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.

26

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 (δA = 3.33 ppm, δB = 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 (δA = 4.97 ppm, δB = 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 (mc, 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).