Ulgheri et al.
ee (%)
TABLE 1. Results of Hydrogenation Reaction with Respect to Catalysts and Ligands
entry
ML*
S/C
T (°C)
P (bar)
t (h)
GC yields (%)
S/R
a
b
c
d
e
f
[Rh(COD)Cl]2(S,S)-Chiraphos
[Rh(COD)Cl]2(S,S)-Chiraphos
[Rh(COD)Cl]2(S,S)-Chiraphos
[Rh(nbd)BF4](S,S)-Chiraphos
[Rh(COD)Cl]2(R)-Prophos
[Ru(II)(S)-BINAP(OAc)2]
[Ru(TFA)2(+)TMBTP]
20:1
200:1
2000:1
1000:1
100:1
100:1
100:1
50
50
50
50
50
50
50
12
12
12
12
12
12
12
24
24
24
24
24
24
24
96
70
36
11
99
22
96
90:10
90:10
90:10
60:40
50:50
72:28
90:10
80
80
80
20
0
44
80
g
and open 5 derivatives (Scheme 2). The products 4 and 5 were
obtained in different ratios varying from 80:20 to 20:80 for
different reactions. The open product 5 cyclizes spontaneously
by standing or by refluxing in toluene with pTsOH or when
injected in the GC-MS instrument. In fact, no open product was
detected by GC-MS.
Experimental Section
For general experimental procedures, see the Supporting Infor-
mation.
6-Methyl-4-phenylchromen-2-one (3). 2-Bromo-4-methylphe-
nol (1) (2.38 mL, 19.71 mmol), Et4NCl (2.18 g, 13.14 mmol), Cy2-
(Me)N (4.22 mL, 19.71 mmol), and Pd(OAc)2 (59 mg 0.26 mmol)
were added under nitrogen at room temperature to a solution of
methyl trans-cinnamate (2) (2.131 g, 13.14 mmol) in DMA (40
mL). The reaction mixture was stirred at 95 °C for 48 h, then cooled
and filtered through celite. A GC-MS of the solution showed that
the Heck adduct was obtained in 94% yield. The solution was then
diluted with Et2O and washed 3 times with H2O. The organic phase
was dried over Na2SO4, and the solvent was evaporated under
vacuum. The crude product was purified by crystallization from
Et2O/n-hexane, and the crystallization residue was purified by flash
chromatography (SiO2, n-hexane/Et2O 7:3). The pure product 3 was
obtained as pale yellow crystals (2.40 g, 77% yield): mp ) 132-
134 °C, 1H NMR (400 MHz, CDCl3) δ 7.52-7.56 (m, 3H), 7.44-
7.47 (m, 2H), 7.25-7.38 (m, 3H), 6.36 (s, 1H), 2.34 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 161.2, 155.9, 152.6, 135.6, 134.1, 133.2,
129.8, 129.1, 128.7, 126.9, 118.9, 117.3, 115.4, 21.2; MS: m/z 236
(M+, 100); Anal. Calcd for C16H12O2: C, 81.34; H, 5.12. Found:
C, 81.36; H, 5.15.
The ee of the hydrogenated intermediate 4, determined by
chiral GC and confirmed by 1H NMR experiments with a
europium(III) camphorate derivative, was strongly dependent
on the cleanliness of the glass cylinder in which the reaction
was carried out. For this reason, it was necessary to wash the
cylinder very carefully several times with 3 N HCl before the
reaction. The hydrogenation reaction was studied with different
catalysts of Rh and Ru and different chiral ligands (Table 1).
The best results were obtained by using [Rh(COD)Cl]2 with
(S,S)-Chiraphos (Table 1, entry a) and [Ru(TFA)2(+)-TMBTP]
(Table 1, entry g); in both cases, the yield was around 96%
and the ee 80%.
Interestingly, when dissolving a crude mixture of the hydro-
genated lactone in warm CH3OH and then cooling, a few
milligrams (20% yield) of white crystals of the S enantiomer
were obtained with ee >98%,16 as determined by chiral GC
analysis. The hydrogenated lactone (S)-4 with ee 80% was then
(S)-6-Methyl-4-phenylchroman-2-one (4). A glass cylinder
placed in a stainless steel autoclave was charged with 6-methyl-
4-phenylchromen-2-one (3) (1 g, 4.2 mmol), [Rh(COD)Cl]2
(10.45 mg, 0.2 mmol), S,S-Chiraphos (18.08 mg, 0.4 mmol), CH3-
OH (10 mL), and 4 N NaOH (2.1 mL). The autoclave was
pressurized to 12 bar with hydrogen, the reaction mixture was stirred
at 50 °C for 24 h and then was cooled to room temperature, and
the residual gas was released. The solvent was removed under
vacuum, and the crude product dissolved in H2O was acidified to
pH ) 1-2 with a solution of 6 N HCl and extracted with CH2Cl2
(30 mL × 3). The organic phases were dried over Na2SO4 and
filtered through celite, and the solvent was removed under vacuum.
Chiral GC of the crude product (DetTBuSilâCDX 25 m column,
carrier gas N2, T1 ) 100 °C, initial isotherm time ) 1, heating
rate ) 2, Tfinal ) 200 °C, final isotherm time ) 10, flow ) 2, N2
pressure ) 30 psi) showed that the hydrogenated product was
obtained in 96% yield and that the enantiomeric ratio S/R 90:10,
80% ee, was enriched in the enantiomer which has the lower
retention time, and to which the absolute S configuration was
attributed (S enantiomer, retention time ) 46.12 min; R enantiomer,
retention time ) 48.55 min; retention time of 6-methyl-4-phenyl-
_
reduced to lactol 6 with DIBALH in toluene at 25 °C. The
reaction was followed by GC-MS and was quenched when 89%
of lactol 6 was observed together with 4% of the over-reduction
product and 7% of the starting material. The crude product 6
was then submitted to reductive amination with (i-Pr)2NH, Pd/C
in CH3OH, to give (S)-tol in 73% isolated yield for the two
steps as a colorless oil. The desired product was so obtained in
47% overall isolated yield and 80% ee. Following the same
procedure but using (R,R)-Chiraphos as the chiral ligand, (R)-
tol was obtained in 45% overall yield and 81% ee. The (S)-tol
was converted to D-tartrate salt, and the [R]D was measured to
assign the absolute configuration by comparing the obtained
value with the data reported in the literature.1 The [R]D of the
(S)-tol D-tartrate salt recovered was in accordance with literature
reported data for the product with ee >98%.
In conclusion, we have developed a short and efficient four-
step enantioselective synthesis of (S)- and (R)-tol that could
easily be used on an industrial scale. The target products were
obtained in high yield and enantioselectively by an asymmetric
hydrogenation of a coumarin intermediate, easily synthesized
by a Heck reaction from inexpensive commercially available
starting materials. Moreover, we also realized a very simple
synthesis of a coumarin derivative that represent a useful and
short approach to the synthesis of many other coumarins.
1
chromen-2-one ) 53.05 min). The H NMR CDCl3 of the crude
product showed a mixture of closed and open reaction products 4
and 5. The open form 5 was cyclized either by standing or by
refluxing for 4 h in toluene in the presence of a catalytic amount
of pTsOH acid. After complete cyclization of 5 to 4, the crude
product mixture was purified by flash chromatography (SiO2,
hexane/Et2O 7:3) to give 850 mg of 4 as a white solid (84% yield).
The crude mixture of products 4 and 5 was dissolved in warm CH3-
OH and then cooled to give 170 mg (20% yield) of white needles
of product S, with ee >98% (retention time ) 46.12 min), as
(16) Yield of the highly enantiomerically pure hydrogenated product (ee
>98%) could be improved by studying the crystallization conditions also
according to: Mughal, R. K.; Davey, R. J.; Black, S. N. Cryst. Growth
Des. 2007, 7, 225.
20
determined by chiral GC analysis: [R]D -2.8 (c 1.44, CHCl3),
mp ) 103-105 °C, 1H NMR (CDCl3, 400 MHz) δ 7.38-7.28 (m,
3H), 7.18-7.00 (m, 4H),6.78 (bs, 1H), 4.30 (t, J ) 6.4 Hz, 1H),
6058 J. Org. Chem., Vol. 72, No. 16, 2007