Eur. J. Org. Chem. 2008 · © WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2008 · ISSN 1434–193X
SUPPORTING INFORMATION
Title: Green, Palladium-Catalyzed Synthesis of Benzylic H-Phosphinates from Hypophosphorous Acid and Benzylic Alcohols Author(s): Laëtitia Coudray, Jean-Luc Montchamp* Ref. No.: O200800581
1. General chemistry: 1H NMR spectra were recorded on a 300-MHz spectrometer. Chemical
shifts for 1H NMR spectra are reported (in parts per million) relative to internal tetramethylsilane
(Me4Si, δ = 0.00 ppm) with CDCl3, DMSO (δ =2.50 ppm) with DMSO-d6 or H2O (δ = 4.75 ppm) in
D2O. 13C NMR spectra were recorded at 75 MHz. Chemical shifts for 13C NMR spectra are
reported (in parts per million) relative to CDCl3 (δ = 77.0 ppm) or to DMSO-d6 (δ = 39.5 ppm). 31P
NMR spectra were recorded at 121 MHz, and chemical shifts reported (in parts per million) relative
to external 85% phosphoric acid (δ = 0.0 ppm).
2. Reagents and solvents: Concentrated hypophosphorous acid was obtained by rotary evaporation
(0.5 mmHg) of the 50 wt. % aqueous solution at room temperature for 20-30 min before reaction.
Caution: overdrying H3PO2 may result in the formation of a yellow solid of high phosphorus
content that could be pyrophoric. t-AmylOH and DMF were used as received. Benzyl alcohol,
furfuryl alcohol, 2-thiophenemethanol were distilled just before reaction. Non commercial benzylic
alcohols were prepared by reduction of corresponding aldehyde or ketone by NaBH4. 1
3. 31P NMR yield measurements: The NMR yields are determined by integration of all the
resonances in the 31P NMR spectra, an approach which is valid if no phosphorus-containing gas (ie.
PH3) evolves, or if the precipitate in a heterogeneous mixture does not contain phosphorus. The
yields determined by NMR are generally accurate within ~10% of the value indicated, and are
reproducible. Isolated yields are sometimes significantly lower because of the H-phosphinate esters
are polar compounds and hydrolytically labile.
4. General procedures for the catalytic benzylation of H3PO2 with benzylic alcohols:
- Method 1 (DMF, 110°C):
A solution of concentrated H3PO2 (2 eq, 4.0 mmol) in DMF (0.2 M, 10.0 mL) was added to a
benzylic alcohol (1 eq, 2.0 mmol). Then Pd2dba3 (0.5 mol%, 0.01 mmol) and xantphos (1.1 mol%,
0.022 mmol) were added at room temperature and the reaction mixture was heated at 110°C for 17 h,
under N2.
- Method 1A: After cooling down, the reaction was filtered through Celite® and concentrated
in vacuo. The resulting solid was dissolved in ethyl acetate and extratected with 0.5 M NaHCO3
(3x). The aqueous layer is acidified to pH 1 with 10% HCl and extracted with ethyl acetate (3x).
The organic layer was washed with brine (1x) then dried over MgSO4 and concentrated to afford the
pure product as a solid.
- Method 1B (hydrophilic compounds): After cooling down, tetra-n-butyl orthosilicate (6.0
eq, 12.0 mmol) was added and the reaction mixture was heated at 110°C under N2 until completion
of the reaction (NMR monitoring on a sample of the crude mixture). After cooling down, the
reaction was filtered through Celite® and concentrated in vacuo. Purification by chromatography
over silica gel afforded the clean product as an oil.
- Method 2 (t-AmylOH, Dean Stark):
To a benzylic alcohol (1 eq, 2.0 mmol) and concentrated H3PO2 (2 eq, 4.0 mmol) dissolved in t-
AmylOH (0.2 M, 10.0 mL) were added Pd2dba3 (0.5 mol%, 0.01 mmol) and xantphos (1.1 mol%,
0.022 mmol) at room temperature. After the flask was equipped with a Dean-Stark trap (prefilled
with t-AmylOH), the reaction mixture was heated for 13-15 h, under N2.
- Method 2A: After cooling down, the reaction was filtered through Celite® and concentrated
in vacuo. The resulting solid was stirred with 2 M NaOH for 1-3 h. The aqueous layer was washed
with CH2Cl2 (3x) then it was acified with concentrated HCl to pH 1 and saturated with NaCl before
extraction with EtOAc (3x). The organic layer was washed with brine (1x) then dried over MgSO4
and concentrated.
- For solids: a wash with methanol afforded the pure product.
- For oils (precipitation step under NH3 salt form): aqueous solution 25% NH4OH (10 mL)
was added to the resulting oil. After concentration, the solid was purified by recrystalization with
CHCl3.
- Method 2B (hydrophilic compounds): After cooling down, the Dean-Stark trap was
removed then tetra-n-butyl orthosilicate (6.0 eq, 12.0 mmol) was added and the reaction mixture was
heated at reflux under N2 until completion of the reaction (NMR monitoring on a sample of the
crude mixture). After cooling down, the reaction was filtered through Celite® and concentrated in
vacuo. A purification by chromatography over silica gel afforded the clean product as an oil.
Note: t-AmylOH in the presence of Pd and H3PO2 can undergo elimination/hydrophosphinylation
which complicates the purification. The two components, 31P NMR δ 33.55 ppm and δ 32.45 ppm,
might be (2-methyl-butyl) phosphinic acid and (3-methyl-butyl) phosphinic acid.
5. Spectral data for the catalytic benzylation of H3PO2:
1-Naphthylmethyl-H-phosphinic acid (Table 1, entry 1).2 Method 1A, white solid (0.339 g,
82%). m.p. = 129°C, 1H NMR (DMSO-d6, 300 MHz) δ 8.12 (d, J = 7.5 Hz, 1 H), 7.93 (s, 1 H), 7.82
(d, J = 5.5 Hz, 1 H), 7.03 (d, JHP = 538.5 Hz, 1 H), 6.13-7.55 (m, 4 H), 3.60 (d, JHCP = 19.0 Hz, 2 H); 13C NMR (DMSO-d6, 75.45 MHz) δ 134.0, 132.4, 129.2 (d, JPCCC = 9.0 Hz), 128.9, 128.7 (d, JPCCC
= 7.0 Hz), 127.7, 126.6, 126.4, 126.2, 125.2, 35.4 (d, JPC = 85.0 Hz); 31P NMR (DMSO-d6, 121.47
MHz) δ 28.21 (dt, JPH = 533.5 Hz, JPCH = 19.0 Hz); HRMS (EI+) calcd. for C11H11O2P, ([M+])
206.0497, found 206.0495.
2-Naphthylmethyl-H-phosphinic acid (Table 1, entry 2). Method 1A, white solid (0.383 g, 93%).
m.p. = 136°C, 1H NMR (DMSO-d6, 300 MHz) δ 7.81-7.88 (m, 3 H), 7.74 (s, 1 H), 7.38-7.49 (m, 3
H), 6.97 (d, JHP = 532.0 Hz, 1 H), 3.24 (d, JHCP = 18.0 Hz, 2 H); 13C NMR (DMSO-d6, 75.45 MHz)
δ 133.7 (d, JPCC = 5.0 Hz), 132.4 (d, JPCCCCC = 4.0 Hz), 130.5 (d, JPCCCC = 8.0 Hz), 129.0 (d, JPCCC =
5.0 Hz), 128.7 (d, JPCCCC = 8.0 Hz), 128.5, 128.2, 128.0, 126.9, 126.3, 38.5 (d, JPC = 85.5 Hz); 31P
NMR (DMSO-d6, 121.47 MHz) δ 28.73 (dt, JPH = 532.0 Hz, JPCH = 18.0 Hz); HRMS (EI+) calcd.
for C11H11O2P, ([M+]) 206.0497, found 206.0498.
4-Chlorobenzyl-H-phosphinic acid (Table 1, entry 3). Method 1A, grey solid (0.326 g, 86%).
m.p. = 99°C, 1H NMR (CDCl3, 300 MHz) δ 7.14-7.32 (m, 4 H), 6.96 (d, JHP = 562.0 Hz, 1 H), 3.09
(d, JHCP = 18.0 Hz, 2 H); 13C NMR (CDCl3, 75.45 MHz) δ 133.6 (d, JPCCCCC = 4.5 Hz), 131.4 (d,
JPCCC = 6.0 Hz, 2 C), 129.3 (d, JPCCCC = 3.5 Hz, 2 C), 128.3 (d, JPCC = 8.0 Hz), 37.0 (d, JPC = 88.5
Hz); 31P NMR (CDCl3, 121.47 MHz) δ 35.98 (d, JPH = 562.0 Hz); HRMS (EI+) calcd. for
C7H8O2ClP, ([M+]) 189.9950, found 189.9947.
2-Furfuryl-H-phosphinic acid (Table 1, entry 4a). Method 1A, yellow oil (0.236 g, 81%). 1H
NMR (CDCl3, 300 MHz) δ 7.36 (bs, 1 H), 7.11 (d, JHP = 572.5 Hz, 1 H), 6.34 (bs, 1 H), 6.26 (bs, 1
H), 3.26 (d, JHCP = 18.5 Hz, 2 H); 13C NMR (CDCl3, 75.45 MHz) δ 144.5 (d, JPCC = 7.5 Hz), 142.9
(d, JPCCCCC = 3.0 Hz), 111.2 (d, JPCCCC = 3.0 Hz), 109.1 (d, JPCCC = 7.5 Hz), 30.5 (d, JPC = 92.5 Hz); 31P NMR (CDCl3, 121.47 MHz) δ 31.57 (d, JPH = 572.5 Hz); HRMS (EI+) calcd. for C9H15O3P,
([M+]) 146.0133, found 146.0130.
2-Furfuryl-H-phosphinic acid butyl ester (Table 1, entry 4b). Method 1B (solvent :
hexanes/EtOAc, v/v, 1/1), yellow oil (0.154 g, 38%). 1H NMR (CDCl3, 300 MHz) δ 7.37 (bs, 1 H),
7.14 (d, JHP = 557.0 Hz, 1 H), 6.35 (bs, 1 H), 6.24 (m, 1 H), 3.98-4.15 (m, 2 H), 3.29 (d, JHCP = 18.0
Hz, 2 H), 1.66 (quint, J = 7.0 Hz, 2 H), 1.38 (sixtuplet, J = 7.0 Hz, 2H ), 0.93 (t, J = 7.0 Hz, 3 H); 13C NMR (CDCl3, 75.45 MHz) δ 144.4 (d, JPCC = 8.0 Hz), 142.8 (d, JPCCCCC = 3.5 Hz), 111.1 (d,
JPCCCC = 3.0 Hz), 108.9 (d, JPCCC = 7.5 Hz), 66.6 (d, JPOC = 7.0 Hz), 32.5 (d, JPOCC = 6.0 Hz), 30.0
(d, JPC = 92.0 Hz), 18.8, 13.7; 31P NMR (CDCl3, 121.47 MHz) δ 32.82 (d, JPH = 556.0 Hz); HRMS
(EI+) calcd. for C9H15O3P, ([M+]) 202.0759, found 202.0760.
3-Furfuryl-H-phosphinic acid butyl ester (Table 1, entry 5). Method 1B (solvent :
hexanes/EtOAc, v/v, 1/1), orange oil (0.149 g, 37%). 1H NMR (CDCl3, 300 MHz) δ 7.38-7.42 (m, 2
H), 7.04 (d, JHP = 545.0 Hz, 1 H), 6.37 (s, 1 H), 3.95-4.19 (dm, JHOCP = 38.5 Hz, 2 H), 3.01 (d, JHCP
= 17.5 Hz, 2 H), 1.63-1.73 (m, 2 H), 1.33-1.46 (m, 2 H), 0.94 (t, J = 7.0 Hz, 3 H); 13C NMR (CDCl3,
75.45 MHz) δ 143.7, 141.1 (d, JPCCC = 10.5 Hz), 113.1 (d, JPCC = 7.0 Hz), 111.9 (d, JPCCC = 4.5 Hz),
66.7 (d, JPOC = 7.0 Hz), 32.5 (d, JPOCC = 6.0 Hz), 26.3 (d, JPC = 92.5 Hz), 18.9, 13.7; 31P NMR
(CDCl3, 121.47 MHz) δ 37.03 (d, JPH = 545.0 Hz); HRMS (EI+) calcd. for C9H15O3P, ([M+])
202.0759, found 202.0754.
2-Thiophene-methyl-H-phosphinic acid butyl ester (Table 1, entry 6). Method 1A, yellow oil
(0.272 g, 84%). 1H NMR (CDCl3, 300 MHz) δ 12.0 (bs, 1 H), 7.20 (m, 1 H), 7.02 (d, JHP = 567.5
Hz, 1 H), 6.98 (m, 2 H), 3.36 (d, JHCP = 18.5 Hz, 2 H); 13C NMR (CDCl3, 75.45 MHz) δ 130.6 (d,
JPCC = 8.5 Hz), 127.9 (d, JPCCC = 8.0 Hz), 127.8 (d, JPCCCC = 3.5 Hz), 125.6 (d, JPCCCCC = 4.0 Hz),
31.7 (d, JPC = 92.0 Hz); 31P NMR (CDCl3, 121.47 MHz) δ 34.14 (d, JPH = 577.5 Hz); HRMS (EI+)
calcd. for C5H7O2SP, ([M+]) 161.9904, found 161.9903.
4-Hydroxybenzyl-H-phosphinic acid butyl ester (Table 1, entry 7). Method 1B (solvent :
hexanes/EtOAc, v/v, 3/7 to EtOAc 100%), lightly yellow oil (0.258 g, 57%). 1H NMR (CDCl3, 300
MHz) δ 7.05 (d, JHP = 544.5 Hz, 1 H), 7.00 (2 d, J = 8.0 Hz, 2 H), 6.67 (d, J = 8.0 Hz, 2 H), 3.94 -
4.17 (dm, JHCOP = 35.0 Hz, 2 H), 3.11 (d, JHCP = 17.0 Hz, 2 H), 1.66 (quin, J = 7.0 Hz, 2 H), 1.38
(sixtuplet, J = 7.0 Hz, 2 H), 0.92 (t, J = 7.0 Hz, 3 H); 13C NMR (CDCl3, 75.45 MHz) δ 156.4 (d,
JPCCCCC = 3.5 Hz), 131.0 (d, JPCCC = 6.5 Hz, 2 C), 119.7 (d, JPCC = 7.5 Hz), 116.5 (d, JPCCCC = 3.0
Hz, 2 C), 67.0 (d, JPOC = 8.0 Hz), 36.1 (d, JPC = 90.5 Hz), 32.6 (d, JPOCC = 6.0 Hz), 18.9, 13.8; 31P
NMR (CDCl3, 121.47 MHz) δ 37.99 (d, JPH = 544.0 Hz); HRMS (EI+) calcd. for C11H17O3P, ([M+])
228.0915, found 228.0918.
1-Pyrene-methyl-H-phosphinic acid (Table 1, entries 8a and 8b). Method 1A and 2A, lightly
brown solid (0.459 g, 82% (1A); 0.442 g, 79% (2A)). m.p. = 200°C, 1H NMR (DMSO-d6, 300
MHz) δ 7.94-8.40 (m, 9 H), 7.06 (d, JHP = 533.0 Hz, 1 H), 3.84 (d, JHCP = 19.0 Hz, 2 H); 13C NMR
(DMSO-d6, 75.45 MHz) δ 131.5, 131.1, 130.3 (d, JPCCCC = 3.0 Hz), 129.6 (d, JPCCC = 6.0 Hz),
128.1, 128.0, 127.6, 127.5 (d, JPCCC = 10.0 Hz), 126.9, 125.8, 125.6 (3 C), 124.9 (2 C), 124.5, 36.3.
(d, JPC = 84.5 Hz); 31P NMR (DMSO-d6, 121.47 MHz) δ 27.59 (dt, JPH = 533.0 Hz, JPCH = 19.0 Hz);
HRMS (EI+) calcd. for C17H13O2P, ([M+]) 280.0653, found 280.0648.
Piperonyl-H-phosphinic acid (Table 1, entry 9). Method 2A, white solid (0.212 mg, 53%). m.p.
= 124°C, 1H NMR (DMSO-d6, 300 MHz) δ 6.73-7.68 (m, 2 H), 6.60-6.64 (m, 1 H), 6.79 (d, JHP =
532.5 Hz, 1 H), 5.90 (s, 3 H), 2.92 (d, JHCP = 18.0 Hz, 2 H); 13C NMR (DMSO-d6, 75.45 MHz) δ
147.9 (d, JPCCCC = 3.5 Hz), 146.6 (d, JPCCCCC = 3.5 Hz), 126.0 (d, JPCC = 7.5 Hz), 123.4 (d, JPCCC =
7.0 Hz), 110.8 (d, JPCCC = 6.0 Hz), 108.9 (d, JPCCCC = 3.5 Hz), 101.5, 37.8 (d, JPC = 86.5 Hz); 31P
NMR (DMSO-d6, 121.47 MHz) δ 29.77 (dt, JPH = 532.5 Hz, J = 18.0 Hz); HRMS (EI+) calcd. for
C8H9O4P, ([M+]) 200.0238, found 200.0234.
Benzyl-H-phosphinic acid butyl ester (Table 1, entry 10).3 Method 2B, lightly yellow oil (0.356
mg, 56%). 1H NMR (CDCl3, 300 MHz) δ 7.23-7.36 (m, 5 H), 7.04 (d, JHP = 544.5 Hz, 1 H), 3.89 -
4.14 (dm, JHCOP = 42.5 Hz, 2 H), 3.21 (d, JHCP = 18.5 Hz, 2 H), 1.63 (quin, J = 8.0 Hz, 2 H), 1.34
(sixtuplet, J = 8.0 Hz, 2 H), 0.90 (t, J = 8.0 Hz, 3 H); 13C NMR (CDCl3, 75.45 MHz) δ 129.8 (d, JPCC
= 6.0 Hz), 129.8 (d, JPCCC = 6.5 Hz, 2 C), 128.9 (d, JPCCCC = 3.0 Hz, 2 C), 127.2 (d, JPCCCCC = 3.5
Hz), 66.5 (d, JPOC = 7.0 Hz), 37.0 (d, JPC = 88.5 Hz), 32.3 (d, JPOCC = 6.0 Hz), 18.7, 13.5; 31P NMR
(CDCl3, 121.47 MHz) δ 38.03 (d, JPH = 544.0 Hz); HRMS (EI+) calcd. for C11H17O2P, ([M+])
212.0966, found 212.0966.
2-Methylbenzyl-H-phosphinic acid ammonium salt (Table 1, entry 11). Method 2A, white solid
(0.153 mg, 41%). m.p. = 139°C, 1H NMR (H2O, 300 MHz) δ 7.04-7.13 (m, 4 H), 6.78 (dt, JHP =
514.5 Hz, J = 2.0 Hz, 1 H), 2.88 (dd, JHCP = 18.5 Hz, J = 2.0 Hz, 2 H), 2.18 (s, 3 H); 13C NMR
(CDCl3, 75.45 MHz) δ 137.1 (d, JPCCC = 5.5 Hz), 132.2 (d, JPCC = 7.0 Hz), 130.5, 130.4 (d, JPCCC =
6.0 Hz), 126.8 (d, JPCCCC = 4.0 Hz), 126.3 (d, JPCCCC = 3.0 Hz), 37.2 (d, JPC = 84.0 Hz), 19.5; 31P
NMR (CDCl3, 121.47 MHz) δ 28.40 (dt, JPH = 514.5 Hz, J = 18.5 Hz); HRMS (EI+) calcd. for
C8H11O2P, ([M+]) 170.0497, found 170.0493.
3-Methylbenzyl-H-phosphinic acid ammonium salt (Table 1, entry 12). Method 2A, white solid
(0.219 g, 54%). m.p. = 136°C, 1H NMR (H2O, 300 MHz) δ 7.09-7.14 (m, 1 H), 6.89-6.98 (m, 3 H),
6.74 (dt, JHP = 516.5 Hz, J = 2.0 Hz, 1 H), 2.77 (dd, JHCP = 18.0 Hz, J = 2.0 Hz, 2 H), 2.16 (s, 3 H); 13C NMR (CDCl3, 75.45 MHz) δ 139.0 (d, JPCCCC = 3.0 Hz), 133.5 (d, JPCC = 7.0 Hz), 130.3 (d,
JPCCC = 5.5 Hz), 128.9 (d, JPCCCCC = 3.0 Hz), 127.1 (d, JPCCCC = 4.0 Hz), 126.6 (d, JPCCC = 6.0 Hz),
39.6 (d, JPC = 84.0 Hz), 20.5; 31P NMR (CDCl3, 121.47 MHz) δ 29.92 (dt, JPH = 516.5 Hz, J = 18.0
Hz); HRMS (EI+) calcd. for C8H11O2P, ([M+]) 170.0497, found 170.0500.
4-Methylbenzyl-H-phosphinic acid ammonium salt (Table 1, entry 13). Method 2A, white solid
(0.243 g, 65%). m.p. = 168°C, 1H NMR (H2O, 300 MHz) δ 6.99-7.58 (m, 4 H), 6.71 (dt, JHP = 515.5
Hz, J = 2.0 Hz, 1 H), 2.75 (dd, JHCP = 17.5 Hz, J = 2.0 Hz, 2 H), 2.14 (d, J = 2.0 Hz, 3 H); 13C NMR
(CDCl3, 75.45 MHz) δ 136.5 (d, JPCCCCC = 3.0 Hz), 130.3 (d, JPCC = 7.0 Hz), 129.6 (d, JPCCC = 6.0
Hz, 2 C), 129.5 (d, JPCCCC = 3.0 Hz, 2 C), 39.2 (d, JPC = 83.0 Hz), 20.2; 31P NMR (CDCl3, 121.47
MHz) δ 27.96 (dt, JPH = 515.5 Hz, J = 17.5 Hz); HRMS (EI+) calcd. for C8H11O2P, ([M+]) 170.0497,
found 170.0498.
3-(Benzyloxycarbonylamino)benzyl-H-phosphinic acid (Table 1, entry 14). Method 2A, white
solid (0.482 g, 79%). m.p. = 157°C, 1H NMR (DMSO-d6, 300 MHz) δ 9.77 (bs, 1 H), 7.20-7.40 (m,
8 H), 6.89 (d, JHP = 532.0 Hz, 1 H), 6.86 (d, J = 6.5 Hz, 1 H), 5.13 (s, 2 H), 3.02 (d, JHCP = 18.5 Hz,
2 H); 13C NMR (CDCl3, 75.45 MHz) δ 153.1, 138.9, 136.4, 132.3 (d, JPCC = 3.0 Hz), 128.6, 128.2 (2
C), 127.8 (3 C), 123.8, 119.2, 116.3, 65.4, 37.7 (d, JPC = 90.0 Hz); 31P NMR (CDCl3, 121.47 MHz) δ
25.09 (d, JPH = 532.0 Hz); HRMS (EI+) calcd. for C15H16O4NP, ([M+]) 305.0817, found 305.0811.
4-Phenylbenzyl-H-phosphinic acid (Table 1, entry 15).4 Method 2A, white solid (0.306 g, 66%).
m.p. = 132°C, 1H NMR (DMSO-d6, 300 MHz) δ 7.57-7.64 (m, 4 H), 7.41-7.46 (m, 2 H),7.30-7.35
(m, 3 H), 6.92 (d, JHP = 531.0 Hz, 1 H), 3.11 (d, JHCP = 18.5 Hz, 2 H); 13C NMR (CDCl3, 75.45
MHz) δ 140.6, 139.0 (d, JPCCCCC = 4.0 Hz), 132.1 (d, JPCC = 7.5 Hz), 131.0 (d, JPCCC = 6.0 Hz, 2 C),
129.6 (2 C), 128.0, 127.4 (d, JPCCC = 3.0 Hz, 2 C), 127.2 (2 C), 38.2 (d, JPC = 85.0 Hz); 31P NMR
(DMSO-d6, 121.47 MHz) δ 28.69 (dt, JPH = 531.0 Hz, JPCH = 18.5 Hz).
3-Methoxybenzyl-H-phosphinic acid ammonium salt (Table 1, entry 16). Method 2A, white
solid (0.130 g, 32%). m.p. = 126°C, 1H NMR (H2O, 300 MHz) δ 7.16 (t, J = 8.0 Hz, 1 H), 6.77 (dt,
JHP = 518.5 Hz, J = 1.5 Hz, 1 H), 6.72-6.75 (m, 3 H), 3.68 –s, 3 H), 2.80 (d, JHCP = 18.0 Hz, 2 H); 13C NMR (CDCl3, 75.45 MHz) δ 159.1 (d, JPCCCC = 3.0 Hz), 135.3 (d, JPCC = 7.0 Hz), 130.0 (d,
JPCCCC = 3.0 Hz), 122.5 (d, JPCCC = 5.5 Hz), 115.1 (d, JPCCC = 6.0 Hz), 112.2 (d, JPCCCCC = 3.5 Hz),
55.4, 39.7 (d, JPC = 83.0 Hz); 31P NMR (CDCl3, 121.47 MHz) δ 29.31 (dt, JPH = 518.5 Hz, J = 18.0
Hz); HRMS (EI+) calcd. for C8H11O3P, ([M+]) 186.0446, found 186.0443.
6. Catalytic bisbenzylation of H3PO2: Preparation of bis(1-naphthylmethyl)-phosphinic acid 2
(Scheme 1, molecule 2):
To 1-naphthylmethyl alcohol (0.632 g, 4.0 mmol, 2 eq) and concentrated H3PO2 (0.132 g, 2.0 mmol,
1 eq) dissolved in t-AmylOH (0.2 M, 10.0 mL) were added Pd2dba3 (0.0092 g, 0.01 mmol, 0.5
mol%) and xantphos (0.0127 g, 0.022 mmol, 1.1 mol%) at room temperature. After the flask was
equipped with a Dean-Stark trap (prefilled with t-AmylOH), the reaction mixture was heated for 16
h, under N2. After cooling down, the reaction was concentrated in vacuo. The resulting solid was
washed with EtOAc to afford a grey solid (0.540 g, 78%). m.p. = 210°C (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 8.13 (m, 2 H), 7.89 (s, 2 H), 7.79 (m, 2 H), 7.40-7.51 (m, 8 H),
3.63 (d, JHCP = 16.0 Hz, 4 H); 13C NMR (DMSO-d6, 75.45 MHz) δ 134.1 (2 C), 132.8 (d, JPCCCC =
4.5 Hz, 2 C), 130.7 (d, JPCCC = 10.0 Hz, 2 C), 129.0 (d, JPCCC = 6.5 Hz, 2 C), 128.9 (2 C), 127.4 (d,
JPCCCCC = 3.5 Hz, 2 C), 126.3 (2 C), 126.2 (2 C), 126.1 (d, JPCCCC = 3.5 Hz, 2 C), 126.0 (2 C), 34.7
(d, JPC = 85.5 Hz, 2 C); 31P NMR (DMSO-d6, 121.47 MHz) δ 41.17 (s); HRMS (EI+) calcd. for
C22H19O2P, ([M+]) 346.1123, found 346.1127.
7. Catalytic benzylation of H-phosphinic acids: Preparation of (1-naphthylmethyl)-phenyl-
phosphinic acid (Scheme 1, molecule 3):
To 1-naphthylmethyl alcohol (0.316 g, 2.0 mmol, 1 eq) and phenyl-H-phosphinic acid (0.284 g, 2.0
mmol, 1 eq) dissolved in t-AmylOH (0.2 M, 10.0 mL) were added Pd2dba3 (0.0092 g, 0.01 mmol,
0.5 mol%) and xantphos (0.0127 g, 0.022 mmol, 1.1 mol%) at room temperature. The resulting
solution was heated at reflux for 17 h, under N2. After cooling down, the reaction was filtered and
concentrated in vacuo. The residue was dissolved in EtOAc and extracted with 0.5 M NaHCO3
(3x). The aqueous layer was acidified to pH 1 with 10% HCl and extracted with EtOAc (3x). The
organic layer was washed with brine (1x) then dried over MgSO4 and concentrated to afford an oil.
The addition of hexanes to the oil afforded after filtration the pure phosphinic acid 3 as a white solid
(0.400 g, 71%). m.p. = 163°C. 1H NMR (DMSO-d6, 300 MHz) δ 8.05 (d, J = 9.5 Hz, 1 H), 7.84 (dd, J = 9.0 Hz, J = 2.5 Hz, 1 H),
7.73 (d, J = 8.5 Hz, 1 H), 7.59-7.66 (m, 2 H), 7.31-7.52 (m, 7 H), 7.22 (dd, J = 6.5 Hz, J = 3.5 Hz, 1
H), 3.70 (d, JHCP = 17.5 Hz, 2 H); 13C NMR (DMSO-d6, 75.45 MHz) δ 134.7 (d, JPC = 126.5 Hz),
134.0 (d, JPCC = 2.5 Hz), 132.7 (d, JPCCCC = 4.5 Hz), 132.2 (d, JPCCCC = 2.5 Hz), 131.8 (d, JPCC = 9.5
Hz, 2 C), 130.4 (d, JPCCC = 8.5 Hz), 129.0 (d, JPCCC = 6.5 Hz), 128.8 (d, JPCCC = 12.0 Hz, 2 C),
128.8, 127.4 (d, JPCCCCC = 3.5 Hz), 126.1 (2 C), 125.8 (2 C), 35.8 (d, JPC = 92.0 Hz); 31P NMR
(DMSO-d6, 121.47 MHz) δ 33.58 (s); HRMS (EI+) calcd. for C17H15O2P, ([M+]) 282.0810, found
282.0806.
8. One pot, two steps benzylation-oxidation 5 of H3PO2: Preparation of (1-naphthylmethyl)-
phosphonic acid 6 (Scheme 1, molecule 4):
To 1-naphthylmethyl alcohol (0.316 g, 2.0 mmol, 1 eq) and concentrated H3PO2 (0.264 g, 4.0 mmol,
2 eq) dissolved in DMF (0.2 M, 10.0 mL) were added Pd2dba3 (0.0092 g, 0.01 mmol, 0.5 mol%) and
xantphos (0.0127 g, 0.022 mmol, 1.1 mol%) at room temperature. The resulting solution was heated
at 110°C, for 15 h under N2 then opened to air for a additional 8 h. After cooling down, the reaction
was concentrated in vacuo. The residue was dissolved in EtOAc and washed with brine (3x). The
organic layer was dried over MgSO4 and concentrated to afford an oil. The addition of CHCl3 to the
oil afforded after filtration the pure phosphonic acid as a white solid (0.333 g, 75%). m.p. = 209°C. 1H NMR (DMSO-d6, 300 MHz) δ 8.12 (d, J = 9.0 Hz, 1 H), 7.87 (m, 1 H), 7.76 (m, 1 H), 7.41-7.50
(m, 4 H), 3.43 (d, JHCP = 22.0 Hz, 2 H); 13C NMR (DMSO-d6, 75.45 MHz) δ 134.1 (d, JPCC = 2.5
Hz), 132.5 (d, JPCCCC = 5.0 Hz), 131.5 (d, JPCCC = 9.0 Hz), 128.8 (d, JPCCC = 4.0 Hz), 128.8, 127.2
(d, JPCCCCC = 4.0 Hz), 126.3, 126.1, 126.1 (d, JPCCCC = 3.5 Hz), 125.8, 33.0 (d, JPC = 132.0 Hz); 31P
NMR (DMSO-d6, 121.47 MHz) δ 21.93 (st, JPCH = 22.0 Hz); HRMS (EI+) calcd. for C11H11O3P,
([M+]) 222.0446, found 222.0441.
9. Procedure for the asymmetric benzylation of H3PO2:
- Benzylation of H3PO2 with 1-(2-naphthyl)ethanol (Equation 2):
To 1-(2-naphthyl)ethanol (0.344 g, 2.0 mmol, 1 eq) and concentrated H3PO2 (0.264 g, 4.0 mmol, 2
eq) dissolved in t-AmylOH (0.2 M, 10.0 mL) were added Pd2dba3 (0.0183 g, 0.02 mmol, 1 mol%)
and xantphos (0.0255 g, 0.044 mmol, 2.2 mol%) at room temperature. After the flask was equipped
with a Dean-Stark trap (prefilled with t-AmylOH), the reaction mixture was heated for 16 h, under
N2. After cooling down, the reaction was filtered and concentrated in vacuo. The residue was
dissolved in EtOAc and extracted with 0.5 M NaHCO3 (3x). The aqueous layer was acidified to pH
1 with 10% HCl and extracted with EtOAc. The organic layer was washed with brine (1x) then
dried over MgSO4 and concentrated to afford a white solid (0.440 g, 100%, 89:11 branched : linear).
- Hydrophosphinylation of 2-vinylnaphthalene with H3PO2:
To 2-vinylnaphthalene (0.318 g, 2.0 mmol, 1 eq) and concentrated H3PO2 (0.264 g, 4.0 mmol, 2 eq)
dissolved in t-AmylOH (0.2 M, 10.0 mL) were added Pd2dba3 (0.0183 g, 0.02 mmol, 1 mol%) and
xantphos (0.0255 g, 0.044 mmol, 2.2 mol%) at room temperature. After the flask was equipped with
a Dean-Stark trap (prefilled with t-AmylOH), the reaction mixture was heated for 16 h, under N2.
After cooling down, the reaction was filtered and concentrated in vacuo. The residue was dissolved
in EtOAc and extracted with 0.5 M NaHCO3 (3x). The aqueous layer was acidified to pH 1 with
10% HCl and extracted with EtOAc. The organic layer was washed with brine (1x) then dried over
MgSO4 and concentrated to afford a white solid (0.315 g, 72%, 78:22 branched : linear).
- Spectral data:
- 1-(2-Naphthyl)ethyl-H-phosphinic acid (Branched isomer) 1H NMR (CDCl3, 300 MHz) δ 7.25-7.81 (m, 7 H), 6.88 (d, JHP = 548.0 Hz, 1 H), 3.21 (dq, JHCP =
24.5 Hz, J = 7.5 Hz, 1 H), 1.59 (d, JHCCP = 19.0 Hz, J = 7.5 Hz, 3 H); 13C NMR (CDCl3, 75.45 MHz)
δ 133.4 (d, JPCCCC = 5.5 Hz), 133.3 (d, JPCC = 7.5 Hz), 132.6 (d, JPCCCCC = 2.5 Hz), 128.3 (d, JPCCCC
= 2.5 Hz), 127.8, 127.6, 127.4 (d, JPCCC = 8.0 Hz), 126.7 (d, JPCCC = 5.0 Hz), 126.2, 126.0, 40.6 (d,
JPC = 89.5 Hz), 12.4; 31P NMR (CDCl3, 121.47 MHz) δ 41.10 (d, JPH = 548.0 Hz); HRMS (EI+)
calcd. for C12H13O2P, ([M+]) 220.0653, found 220.0657.
- 2-(2-Naphthyl)ethyl-H-phosphinic acid (Linear isomer) 1H NMR (CDCl3, 300 MHz) δ 7.25-7.81 (m, 7 H), 7.00 (d, JHP = 548.0 Hz, 1 H), 2.94-3.04 (m, 2 H),
2.00-2.11 (m, 2 H); 31P NMR (CDCl3, 121.47 MHz) δ 37.39 (d, JPH = 548.0 Hz); HRMS (EI+) calcd.
for C12H13O2P, ([M+]) 220.0653, found 220.0657.
- Determination of the enantioselectivity of the benzylation:
1-(2-Naphthyl)ethyl-H-phosphinic acid (5 mg) was dissolved in CDCl3 (0.5 mL) and R-(+)-1-
phenylethylamine (2 drops) were added. Then by 31P NMR, the enantiomeric excess was
determinated by height and by integration.
31P NMR data (CDCl3 + R-(+)-1phenylethylamine, 300 MHz):
Starting material Linear isomer Branched isomer: Integration percent, height, shift
ee%
Racemic
1-(2-Naphthyl)ethanol
10% 43%, 124.4, 30.53 ppm
46%, 124.6, 30.33 ppm
3%
R-(+)
1-(2-Naphthyl)ethanol*
11% 10%, 15.7, 30.48 ppm
79%, 125.7, 30.25 ppm
77%
2-Vinylnaphthalene 22% 38%, 65.6, 28.84 ppm
41%, 71.4, 29.67 ppm
3%
*R-(+)-1-(2-Naphthyl)ethanol (from Aldrich, R/S ≥ 98.5:1.5)
- Determination of the absolute configuration: Preparation of 1-(2-naphthyl)ethylphosphonic
acid 7:
To the chiral 1-(2-naphthyl)ethyl-H-phosphinic acid (0.227 g, 1.03 mmol, 1 eq) in DMF (0.15 M, 7
mL) were added Pd2dba3 (0.0094 g, 0.0103 mmol, 1 mol%) and xantphos (0.0124 g, 0.0216 mmol,
2.2 mol%) at room temperature. The resulting solution was heated at 110°C, opened to air for 23 h.
After cooling down, the reaction was filtered and concentrated in vacuo. The residue was dissolved
in EtOAc and extracted with 0.5 M NaHCO3 (3x). The aqueous layer was acidified to pH 1 with
10% HCl and extracted with EtOAc. The organic layer was washed with brine (1x) then dried over
MgSO4 and concentrated to afford a white solid (0.147 g, 61%, 89:11 branched : linear) 1H NMR (CDCl3, 300 MHz) δ 7.75-7.842 (m, 4 H), 7.43-7.48 (m, 3 H), 3.15 (dq, JHCP = 21.5 Hz, J
= 7.5 Hz, 1 H), 1.49 (dd, JHCCP = 17.5 Hz, J = 7.5 Hz, 3 H); 13C NMR (DMSO-d6, 75.45 MHz) δ
138.8 (d, JPCC = 8.0 Hz), 133.6, 132.5, 128.2 (d, JPCCC = 5.0 Hz), 128.1, 128.0, 127.8, 127.2 (d, JPCCC
= 8.0 Hz), 126.6, 126.0, 39.6 (d, JPC = 124.0 Hz), 16.8 (d, JPCC = 4.5 Hz); 31P NMR (DMSO-d6,
121.47 MHz) δ 25.99 (s, 11%), 25.65 (s, 89%); HRMS (EI+) calcd. for C12H13O3P, ([M+]) 236.0602,
found 236.0598. [α]D = - 11.106° (c 0.9, MeOH).
Comparing the specific rotation of the 1-(2-naphthyl)ethylphosphonic acid and the literature data
([α]D = -3.7 (c 1.2, MeOH) for the (R)-1-phenylethylphosphonic acid 8), the absolute configuration
(S) was assigned to 1-(2-naphthyl)ethyl-H-phosphinic acid. Therefore the reaction proceeds with
overall inversion of configuration.
10. References:
1) (a) Zeynizadeh, B.; Behyar, T. Bull. Chem. Soc. Jpn. 2005, 78, 307-315. (b) Hu, A.; Ngo, H. L.;
Lin, W. Org. Lett. 2004, 6, 2937-2940.
2) Kuimov, V.A.; Gusarova, N.K.; Malysheva, S.F.; Sukhov, B.G.; Smetannikov, Y.V.; Tarasova,
N.P.; Gusarov, A.V.; Trofimov, B.A. Russ. J. Gen. Chem. 2006, 76, 708.
3) (a) Abrunhosa-Thomas, I.; Ribière, P.; Adcock, A.C.; Montchamp, J.-L. Synthesis 2006, 2, 325.
(b) Bravo-Altamirano, K.; Huang, Z. ; Montchamp, J.-L. Tetrahedron 2005, 61, 6315. (c) Huang, Z.;
Bravo-Altamirano, K. ; Montchamp, J.-L. C.R. Chimie 2004, 7, 763.
4) Bianchini, G.; Aschi, M.; Cavicchio, G.; Crucianelli, M.; Preziuso, S.; Gallina, C.; Nastari, A.;
Gavuzzo, E.; Mazza, F. Bioorg. Med. Chem., 2005, 13, 4740.
5) Bravo-Altamirano, K.; Montchamp, J.-L. Tetrahedron Lett. 2007, 48, 5755.
6) Katritzky, A.R.; Pilarski, B. Org. Prep. Proced. Int. 1990, 22, 209.
7) Gulyukina, N. S.; Dolgina, T.M.; Bondarenko, G. N.; Beletskaya, I. P.; Bondarenko, N. A.;
Henry, J.-C.; Lavergne, D.; Ratovelomanana-Vidal, V.; Genet, J.-P. Russ. J. Org. Chem. 2002, 38,
573.
8) Bennani, Y.L.; Hanessian, S. Tetrahedron 1996, 52, 13837.
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