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95:5, flow rate=0.8 mLminÀ1
, l=230 nm): tR =10.7 (minor),
Alkylation of propionaldehyde with various electrophiles
15.1 min (major).
A syringe pump was charged with a CH3CN/H2O (7:3 v/v, 2 mL) so-
lution of reagents (R1: 0.2m electrophile, 0.6m aldehyde, 0.2m
NaH2PO4·H2O; R2: 0.15m electrophile, 0.45m aldehyde, 0.15m
NaH2PO4·H2O) and was fed to the reactor at the indicated flow rate
at room temperature. Subsequently, the flow reactor was washed
with the eluent mixture (CH3CN/H2O=7:3 v/v, 2 mL) at the same
flow rate. The product at the exit of the reactor was collected at
08C in an ice bath and diluted with Et2O (3 mL). The organic layer
was separated, and the aqueous phase was extracted with Et2O
(2ꢁ1 mL). The combined organic layer was dried with Na2SO4 and
diluted with MeOH (3 mL). The crude mixture was cooled to 08C
and NaBH4 (1 mmol) was slowly added. After 1 h stirring at 08C,
the reaction was quenched with H2O (3 mL) and EtOAc (5 mL) was
added. The organic layer was separated, and the aqueous phase
was extracted with EtOAc (2ꢁ5 mL). The organic layers were recov-
ered, washed with brine (5 mL), and dried with Na2SO4. The solvent
was evaporated under reduced pressure, and the residue was
dried under high vacuum. The crude product was purified by flash
column chromatography on silica gel.
Compound 8 was purified by flash column chromatography (silica
gel, hexane/EtOAc=9:1) to afford a colorless oil. TLC: Rf =0.40
(hexane/EtOAc=8:2, stained blue with phosphomolybdic acid).
1H NMR (300 MHz, CDCl3): d=7.34–7.27 (m, 5H), 7.20 (m, 1H), 7.13
(m, 1H), 7.02 (m, 2H), 5.34 (d, 1H), 4.05 (m, 2H), 3.37–3.30 ppm (m,
1H). 13C NMR (75 MHz, CDCl3): d=139.1, 137.2, 128.8 (2C), 128.6,
128.4, 127.7 (2C), 125.6, 125.4, 122.3, 122.2, 64.4, 56.2, 54.9 ppm.
HPLC (Daicel Chiralcel OD-H column, hexane/iPrOH=9:1, flow
rate=0.8 mLminÀ1, l=230 nm): tR =19.0 (minor), 23.5 min (major).
Acknowledgements
A.P. thanks the Fondo Investimenti in Ricerca di Base (FIRB) Na-
tional Project “Multifunctional Hybrid Materials for the Develop-
ment of Sustainable Catalytic Processes”. M.B. thanks European
Cooperation in Science and Technology (COST) action CM9505
“ORCA” Organocatalysis. P.G.C. thanks Bologna University, Fonda-
zione Del Monte, and the European Commission through project
FP7–201431 (CATAFLU.OR) for financial support.
Products of aldehydes alkylation
Compounds 4–8 are known (for details see the Supporting Infor-
mation).
Keywords: alkylation · catalytic reactor · continuous flow ·
organocatalysis · stereoselectivity
Compound 4 was purified by flash column chromatography (silica
gel, hexane/EtOAc=9:1) to afford a colorless oil. TLC: Rf =0.27
(hexane/EtOAc=9:1, stained blue with phosphomolybdic acid).
1H NMR (300 MHz, CDCl3): d=7.21 (dd, 2H), 7.02 (dd, 2H), 5.13 (d,
1H), 3.70 (d, 2H), 2.17–2.09 (m, 1H), 1.06 ppm (d, 3H). 13C NMR
(75 MHz, CDCl3): d=137.7 (2C), 125.4 (2C), 122.0, 121.9, 64.8, 56.5,
43.6, 13.2 ppm. HPLC (Daicel Chiralcel OD-H column, hexane/
iPrOH=9:1, flow rate=0.8 mLminÀ1, l=230 nm): tR =8.9 (minor),
10.5 min (major).
[1] For some examples of enantioenriched a-alkyl-substituted aldehydes in
total synthesis, see: a) K. C. Nicolaou, D. P. Papahatjis, D. A. Claremon,
R. L. Magolda, R. E. Dolle, J. Org. Chem. 1985, 50, 1440; b) G. S. Besra,
1372; d) A. Fꢃrstner, M. Bonnekessel, J. T. Blank, K. Radkowski, G. Seidel,
[3] a) Enantioselective Organocatalysis. Reactions and Experimental Proce-
dures (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007; b) “Asymmetric Or-
ganocatalysis” in Topics in Current Chemistry: Vol. 291 (Ed.: B. List),
Springer, Berlin, 2009.
1737; b) D. A. Evans in Asymmetric Synthesis, Vol. 3, (Ed.: J. D. Morrison),
Academic, London, 1983, p. 1.
116, 9361; b) A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky,
Compound 5 was purified by flash column chromatography (silica
gel, hexane/EtOAc=8:2) to afford a colorless oil. TLC: Rf =0.36
(hexane/EtOAc=8:2, stained blue with phosphomolybdic acid).
1H NMR (300 MHz, CDCl3): d=6.69 (m, 2H), 6.25 (m, 2H), 5.33 (m,
2H), 3.81 (dd, 1H), 3.64 (dd, 1H), 2.05 (m, 1H), 1.55 (m, 1H), 1.41
(brs, 1H), 1.11 ppm (d, 3H). 13C NMR (75 MHz, CDCl3): d=130.8
(2C), 125.0, 124.9, 124.0, 123.2, 66.5, 41.4, 37.3, 14.5 ppm. HPLC
(Daicel Chiralcel OJ-H column, hexane/iPrOH=95:5, flow rate=
0.8 mLminÀ1, l=254 nm): tR =9.8 (minor), 11.0 min (major).
Compound 6 was purified by flash column chromatography (silica
gel, CH2Cl2/MeOH=98:2) to afford a colorless oil. TLC: Rf =0.48
(CH2Cl2/MeOH=98:2). 1H NMR (300 MHz, CDCl3): d=7.18 (m, 4H),
6.69 (m, 4H), 3.92 (d, 1H), 3.61 (dd, 1H), 3.58 (d, 1H), 3.51 (dd, 1H),
2.91 (s, 6H), 2.90 (s, 6H), 2.48 (m, 1H) 0.97 ppm (d, 3H). 13C NMR
(75 MHz, CDCl3): d=149.0, 149.9 133.0 (2C), 128.6 (2C), 128.3 (2C),
113.1 (2C), 113.0 (2C), 67.2, 53.7, 40.8 (4C), 39.6, 16.4 ppm. HPLC
(Daicel Chiralcel OD-H column, hexane/iPrOH=9:1, flow rate=
0.8 mLminÀ1, l=254 nm): tR =18.4 (major), 31.7 min (minor).
ˇ
´
O. O. Grygorenko, P. S. J. Kaib, I. Komarov, A. Lee, M. Leutzsch, S. Chan-
[10] a) T. D. Beeson, A. Mastracchio, J. Hong, K. Ashton, D. W. C. MacMillan,
W. Shih, M. N. Van der Wal, R. L. Grange, D. W. C. MacMillan, J. Am. Chem.
Compound 7 was purified by flash column chromatography (silica
gel, hexane/EtOAc=9:1) to afford a colorless oil. TLC: Rf =0.28
(hexane/EtOAc=9:1, stained blue with phosphomolybdic acid).
1H NMR (300 MHz, CDCl3): d=7.23 (dd, 2H), 7.02 (dd, 2H), 5.20 (d,
1H), 3.85 (dd, 1H), 3.79 (dd, 2H), 1.94 (m, 1H), 1.30 (m, 10H),
0.89 ppm (t, 3H). 13C NMR (75 MHz, CDCl3): d=137.7, 137.6, 125.4,
125.3, 122.0 (2C), 62.4, 56.6, 47.6, 31.6, 29.3, 28.1, 27.1, 22.5,
14.0 ppm. HPLC (Daicel Chiralcel OD-H column, hexane/iPrOH=
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