A new enzymatic approach to (R)-Tamsulosin hydrochloride

Article abstract of DOI:10.1016/j.tetasy.2007.01.012

An enantioselective baker's yeast mediated approach to the pharmacologically active (R)-enantiomer of Tamsulosin hydrochloride is reported.

Full text of DOI:10.1016/j.tetasy.2007.01.012

Tetrahedron: Asymmetry 18 (2007) 488–492
A new enzymatic approach to (R)-Tamsulosin hydrochloride
Daniela Acetti, Elisabetta Brenna* and Claudio Fuganti
Dipartimento di Chimica, Materiali ed Ingegneria Chimica del Politecnico, Via Mancinelli 7, I-20131 Milano, Italy
Received 9 January 2007; accepted 13 January 2007
Available online 7 February 2007
Abstract—An enantioselective baker’s yeast mediated approach to the pharmacologically active (R)-enantiomer of Tamsulosin hydro-
chloride is reported.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, an enzymatic approach was patented:8 derivative
(R)-8 was obtained by lipase-mediated esterification of
racemic 5 with ethyl chloroacetate. Reaction of (R)-8 first
with chlorosulfonic acid, then with NH4OH, gave interme-
diate (R)-9. This latter was treated with the potassium salt
of 2-ethoxyphenol, followed by NaBH4–BF3ÆEt2O reduc-
tion, to afford (R)-1.
Nine of the top 10 drugs contain a chiral active ingredient,
and for six of them this ingredient is a single enantiomer
small molecule.1 The demand of enantiopure chiral inter-
mediates as well as finished products for pharmaceutical
applications is growing rapidly. A typical target value for
the enantiomeric purity is 99.5%.2 High values of enantio-
and diastereoselectivity can be reached by biocatalytic pro-
cesses.3 Furthermore, rapid screening and optimisation of
enzymatic activity, along with available, easy-to-use en-
zymes are now making biocatalysis a handy tool for chiral
synthesis.
Most of the known synthetic sequences to (R)-1 make use
of amine 5, which is actually p-methoxyamphetamine. This
latter compound is included in the Green List9 of psycho-
tropic substances under international control, compiled
by the International Narcotics Control Board (INCB).
We have devised a synthetic approach to pharmacologi-
cally active (R)-1, which does not involve the manipulation
of amine 5, and which is based on an enantioselective bio-
catalysed reaction. We report herein on this new synthetic
route.
Tamsulosin hydrochloride (R)-1ÆHCl is the international
non-proprietary name of (ꢀ)-(R)-5-[2-[[2-(o-ethoxyphen-
oxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide hy-
drochloride (Scheme 1), and is employed in the symp-
tomatic treatment of benign prostatic hyperplasia. It was
first developed by Yamanouchi Pharmaceuticals4 and is
currently marketed as a single enantiomer. The preparation
of (R)-1,4,5 is based on the reaction of (R)-2 with an o-eth-
oxyphenoxy derivative, that is, compounds 3,4b,c,5b or 4.5a
Intermediate (R)-2 could be prepared by functionalisation
of amine (R)-54b,c,5a or by the reaction of ketone 6 with
amine (R)-7,5b followed by imine reduction and concomi-
tant debenzylation. Amine (R)-2 was also prepared by
the classical resolution of the corresponding racemic mix-
ture by employing tartaric acid as the resolving agent.6
Classical resolution of racemic Tamsulosin was attempted
using (+)-camphor-10-sulfonic acid.7
2. Results and discussion
According to our previous experience,10 incubation of anis-
aldehyde with very actively fermenting baker’s yeast, in the
presence of glucose, yielded after 72 h a 7:3 mixture of ani-
sic alcohol, and of diol 10 (Scheme 2). Extraction of the
reaction mixture with hexane allowed the removal of most
of the anisic alcohol. Subsequent extraction with ethyl ace-
tate gave a residue from which diol (1R,2S)-10 could be
recovered by crystallisation from hexane. The relative ste-
1
reochemistry of diol 10 was assigned on the basis of H
NMR spectroscopy,11 and the absolute configuration is
known.11c Hydrogenolysis of (1R,2S)-10 gave alcohol (S)-
11 (ee >99% by chiral GC of the corresponding acetate).
We could obtain this alcohol also by baker’s yeast reduc-
tion12 of ketone 12: after 72 h incubation time we could
*
Corresponding author. Fax: +39 02 23993080; e-mail: elisabetta.
brenna@polimi.it
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.01.012

D. Acetti et al. / Tetrahedron: Asymmetry 18 (2007) 488–492
489
H
H2NO2S
H3CO
N
O
EtO
(R)-1
NH2
H2NO2S
H3CO
NH2
OR
H3CO
OEt
(R)-2
3
4
R = CH2CH2Br
R = CH2CH(OEt)2
(R)-5
H
N
X
O
H2NO2S
H3CO
Cl
NH2
O
H3CO
6
(R)-7
(R)-8 X= H
(R)-9 X = SO2NH2
Scheme 1.
OH
CHO
OH
ii
OH
i
O
iii
H3CO
H3CO
H3CO
H3CO
(1R,2S)-10
(S)-11
12
Scheme 2. Reagents and conditions: (i) baker’s yeast, glucose, water, rt, 72 h; (ii) H2, Pd/C, HClO4, EtOH; (iii) baker’s yeast, glucose, water, rt, 72 h.
recover alcohol (S)-11 in 27% yield showing ee = 98% (chi-
ral GC of the corresponding acetate).
with ammonium hydroxide in THF. Acetate (S)-14 was
recovered, and hydrolysed to afford alcohol (S)-15. Treat-
ment with mesyl chloride in pyridine, and reaction with so-
dium azide in DMF gave azide (R)-16. Hydrogenation of
the azide group, imine formation by the reaction with alde-
Alcohol (S)-11 was converted into acetyl derivative (S)-13
(Scheme 3), and treated first with chlorosulfonic acid, then
H2NO2S
OAc
iii
ii
OAc
OH
i
H3CO
H3CO
H3CO
(S)-11
(S)-15
(S)-13
(S)-14
H
H2NO2S
H2NO2S
N3
N
H2NO2S
H3CO
OH
O
v
iv
EtO
H3CO
H3CO
(R)-16
(R)-1
O
O
O
vi
O
O
18
17
Scheme 3. Reagents and conditions: (i) Ac2O, pyridine; (ii) ClSO3H; then NH4OH in THF; (iii) KOH, MeOH; (iv) CH3SO2Cl, pyridine; then NaN3 in
DMF; (v) H2, Pd/C, EtOH and aldehyde 17; (vi) O3, MeOH–CH2Cl2; then NaBH4.

490
D. Acetti et al. / Tetrahedron: Asymmetry 18 (2007) 488–492
hyde 17 and imine reduction were conducted one pot in the
same reaction vessel.
tion with hexane allowed the recovery of most anisic alco-
hol (26.3 g, 52%). Ethyl acetate extraction, performed after
filtration on a Celite pad, gave a residue from which com-
pound (1R,2S)-10 was obtained as a white solid (16.1 g,
Aldehyde 17 was obtained by ozonolysis of derivative 18,
prepared by reaction of the sodium salt of o-ethoxyphenol
with allyl bromide. After the final workup the hydrochlo-
ride of enantiopure (R)-1 was recovered.
21%) by crystallisation from hexane: mp 98 ꢁC;
24
½aꢁD ¼ ꢀ26:7 (c 1.0, CHCl3) [lit.11c for (1R,2S)-10 ee =
98% [a]D = ꢀ26.2 (c 1.30, CHCl3); Ref. 10 [a]D = ꢀ22.4
1
(c 1.0, EtOH)]; H NMR11 (400 MHz, CDCl3): d 7.28 (d,
2H, J = 8.6 Hz, aromatic hydrogens), 6.90 (d, 2H, 8.6 Hz,
aromatic hydrogens), 4.59 (d, 1H, J = 4.6 Hz, ArCHOH),
3.98 (m, 1H, CH3CHOH), 3.81 (s, 3H, OCH3), 1.10 (3H,
d, J = 6.2 Hz, CH3CH); 13C NMR11a,1b (100.6 MHz,
CDCl3): d 159.1, 132.5, 127.8, 113.6, 77.1, 71.2, 55.7, 17.2.
3. Conclusions
A simple approach to Tamsulosin hydrochloride 1 is re-
ported. No hallucinogen substances were involved and
high enantiomeric purity was obtained by means of a
baker’s yeast-mediated reaction. The optically active key
intermediate (S)-11 (ee >99%) could be synthesised by
hydrogenolysis of diol 10, prepared in turn by an enantio-
selective bio-catalysed reaction. Alcohol (S)-11 was also
accessible in 98% ee by baker’s yeast reduction of ketone
12. Crystalline diol 10 could be isolated and purified very
easily without the use of column chromatography. The
method shows great advantages for a practical application:
it combines highly stereoselective baker’s yeast-mediated
reactions with unexceptional organic synthesis procedures,
to afford the pharmacologically active enantiomer of
Tamsulosin.
4.3. (S)-1-(4-Methoxyphenyl)propan-2-ol (S)-11
Compound (1R,2S)-10 (15.9 g, 0.087 mol) was treated with
H2 at atmospheric pressure and room temperature, in eth-
anol (100 mL) in the presence of HClO4 (1 mL), using Pd/
C 5% (0.800 g) as a catalyst. After the usual workup, the
crude product was purified by column chromatography
on a silica gel column (hexane/AcOEt 9:1) to afford (S)-
11 (12.5 g, 86%): ee >99% (chiral GC of the corresponding
24
acetate); ½aꢁD ¼ þ32:6 (c 1.1, CHCl3) [Ref. 12a ee = 95%,
[a]D = +27 (c 4.4; CHCl3); Ref. 12b ee = 94%, [a]D =
1
+30.9 (c 1, CHCl3)]; H NMR12 (400 MHz, CDCl3): d
7.12 (d, 2H, J = 8.7 Hz, aromatic hydrogens), 6.85 (d,
2H, 8.6 Hz, aromatic hydrogens), 3.97 (m, 1H, CHOH),
3.79 (s, 3H, OCH3), 2.73 (dd, 1H, J = 13.5, 4.8 Hz, ArCH),
2.62 (dd, 1H J = 13.5, 7.9 Hz, ArCH), 1.22 (3H, d,
J = 6.2 Hz, CH3CH); 13C NMR (100.6 MHz, CDCl3): d
157.8, 130.4, 130.0, 113.6, 68.6, 54.9, 44.5, 22.3; GC–MS:
tR = 15.62 min, m/z (%) 166 (M+, 18), 121 (100), 107
(10). Compound (S)-11 (1.36 g, 27%) was also obtained
by baker’s yeast12a (50 g) incubation (72 h, rt) of ketone
12 (5.00 g, 0.030 mol) in the presence of glucose in tap
water. After the usual workup alcohol (S)-11 was recovered
with ee = 98% (chiral GC of the corresponding acetate).
4. Experimental
4.1. General
GC–MS analyses were performed on a HP 6890 gas-
chromatograph equipped with a 5973 mass-detector, using
a HP-5MS column (30 m · 0.25 mm · 0.25 lm). The fol-
lowing temperature program was employed: 60ꢁ (1 min)/
6ꢁ/min/150ꢁ (1 min)/12ꢁ/min/280ꢁ (5 min). 1H and 13C
NMR spectra were recorded on a Bruker ARX 400 spec-
1
trometer (400 MHz H, 100.6 MHz 13C), in CDCl3 solu-
tion at rt unless otherwise stated, using TMS as an
internal standard; J values are given in Hertz. All the chro-
matographic separations were carried out on silica gel col-
umns. Chiral GC: DANI-HT-86.10 gas chromatograph;
enantiomer excesses determined on a Chirasil-DEX-CB
column with the following temp. program; 50 ꢁC (3 min)–
3.5 ꢁC/min–180 ꢁC (5 min); tR in min (S)-13-tR =
22.89 min, (R)-13-tR = 23.32 min. Optical rotations were
measured on a Dr. Kernchen Propol digital automatic
polarimeter. The ESI spectrum was acquired on a Bruker
Esquire 3000 plus instrument. Ketone 12 was prepared
by Dakin West reaction starting from 4-methoxyphenyl
acetic acid according to Ref. 13.
4.4. (S)-1-(4-Methoxyphenyl)propan-2-yl acetate (S)-13
Alcohol (S)-11 (12.3 g, 0.074 mol) was treated with acetic
anhydride (20 mL) in pyridine solution (30 mL). After the
usual workup, acetate (S)-13 was recovered by column
chromatography, eluting with hexane–ethyl acetate 9:1
24
(13.8 g, 90%): ee >99% (chiral GC); ½aꢁD ¼ þ7:5 (c 1.1,
1
CHCl3); H NMR (400 MHz, CDCl3): d 7.10 (m, 2H, aro-
matic hydrogens), 6.82 (m, 2H, aromatic hydrogens), 5.06
(m, 1H, CHOAc), 3.78 (s, 3H, OCH3), 2.85 (dd, 1H,
J = 13.8, 6.5 Hz, ArCH), 2.69 (dd, 1H, J = 13.8, 6.5 Hz,
ArCH), 1.99 (s, 3H, OAc), 1.20 (3H, d, J = 6.2 Hz,
CH3CH); 13C NMR (100.6 MHz, CDCl3): d 170.3, 158.2,
130.2, 129.6, 113.6, 71.5, 55.0, 41.2, 21.1, 19.2; GC–MS:
tR = 18.53 min, m/z (%) 208, (M+, 2), 148 (100), 121 (81).
4.2. (1R,2S)-1-(4-Methoxyphenyl)propane-1,2-diol
(1R,2S)-10
4.5. (S)-1-(3-(Chlorosulfonyl)-4-methoxyphenyl)propan-2-yl
acetate
Anisaldehyde (50.0 g, 0.368 mol) was added in ethanolic
solution (50 mL) to a suspension of fermenting baker’s
yeast (500 g) in tap water (1.5 L), in the presence of glucose
(200 g). The reaction was stirred at room temperature for
72 h, to give a final 7:3 mixture of anisic alcohol and diol
10. After the addition of acetone (500 mL), a first extrac-
Compound (S)-13 (13.5 g, 0.065 mol) was added to chloro-
sulfonic acid (80 g) at ꢀ10 ꢁC. The reaction mixture was
stirred at 0 ꢁC for 1 h, then poured into ice water, and ex-
tracted with ethyl acetate. The organic phase was washed

D. Acetti et al. / Tetrahedron: Asymmetry 18 (2007) 488–492
491
with a saturated aqueous sodium hydrogen carbonate solu-
4.8. (S)-1-(4-Methoxy-3-sulfamoylphenyl)propan-2-yl
methanesulfonate
tion, dried (Na2SO4) and concentrated under reduced pres-
sure. The residue was employed without any further
purification (16.9 g, 85%) (chemical purity by GC–MS
Compound (S)-15 (9.20 g, 0.037 mol) was dissolved in pyr-
idine (30 mL) and methanesulfonyl chloride (5.48 g,
0.0481 mol) was added at 0 ꢁC. After 2 h at room temper-
ature the reaction mixture was poured into ice water and
extracted with ethyl acetate. The organic phase was dried
(Na2SO4) and concentrated under reduced pressure to give
the title compound (10.5 g, 88%) which was employed
24
1
94%): ½aꢁD ¼ þ2:7 (c 0.99, CHCl3); H NMR (400 MHz,
CDCl3): d 7.79 (d, 1H, J = 2.1 Hz, H–C(2) aromatic), d
7.51 (dd, 1H, J = 8.3, 2.1 Hz, H–C(6) aromatic), 7.05 (d,
1H, J = 8.3 Hz, H–C(5) aromatic), 5.07 (m, 1H, CHOAc),
4.04 (s, 3H, OCH3), 2.88 (dd, 1H, J = 13.9, 7.2 Hz, ArCH),
2.80 (dd, 1H, J = 13.9, 5.5 Hz, ArCH), 1.98 (s, 3H,
CH3COO), 1.21 (3H, d, J = 6.2 Hz, CH3CH); 13C NMR
(100.6 MHz, CDCl3): 170.2, 155.9, 137.9, 131.5, 130.3,
130.0, 113.2, 70.6, 56.5, 40.8, 21.0, 19.4. GC–MS:
tR = 25.44 min, m/z (%) 271 (M+ꢀ35, 7), 246 (100), 219
(15), 148 (23), 90 (38).
without any further purification (chemical purity by GC–
24
MS 92%): ½aꢁD ¼ þ10:7 (c 0.77, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.77 (d, 1H, J = 2.4 Hz, H–C(2) aro-
matic), 7.42 (dd, 1H, J = 8.3, 2.4 Hz, H–C(6) aromatic),
7.01 (d, 1H, J = 8.3 Hz, H–C(5) aromatic), 5.14 (br s,
2H, NH2), 4.92 (m, 1H, CHOSO2), 4.00 (s, 3H, OCH3),
2.99 (dd, 1H, J = 14.2, 7.2 Hz, ArCH), 2.92 (dd, 1H,
J = 14.2, 5.2 Hz, ArCH), 2.81 (s, 1H, OSO2CH3), 1.43
(3H, d, J = 6.6 Hz, CH3CH); GC–MS: tR = 28.12 min,
m/z (%) 228 (M+ꢀ95, 100), 200 (50), 148 (37).
4.6. (S)-1-(4-Methoxy-3-sulfamoylphenyl)propan-2-yl ace-
tate (S)-14
Chlorosulfonyl compound (16.5 g, 0.054 mol) was dis-
solved in THF (50 mL), and a concentrated aqueous
ammonia solution (200 mL) was added. The mixture was
stirred at room temperature for 1 h, then diluted with water
and extracted with ethyl acetate. The organic phase was
dried (Na2SO4), and the residue was crystallised from
methanol to give compound (S)-14 (12.2 g, 79%): mp
4.9. (R)-5-(2-Azidopropyl)-2-methoxybenzenesulfonamide
(R)-16
A solution of sodium azide (4.10 g, 0.063 mol) and of the
mesyl derivative (10.2 g, 0.032 mol) in DMF (20 mL) was
heated at 40 ꢁC for 2 h. The reaction mixture was poured
into water and extracted with ethyl acetate. The organic
phase was dried (Na2SO4) and concentrated under reduced
pressure. After column chromatography (hexane/ethyl ace-
24
1
94 ꢁC; ½aꢁD ¼ þ7:6 (c 0.99, CHCl3); H NMR (400 MHz,
CDCl3): d 7.71 (d, 1H, J = 2.1 Hz, H–C(2) aromatic),
7.36 (dd, 1H, J = 8.6, 2.1 Hz, H–C(6) aromatic), 6.98 (d,
1H, J = 8.6 Hz, H–C(5) aromatic), 5.20 (br s, 2H, NH2),
5.04 (m, 1H, CHOAc), 3.99 (s, 3H, OCH3), 2.86 (dd, 1H,
J = 14.2, 7.3 Hz, ArCH), 2.75 (dd, 1H, J = 14.2, 5.5 Hz,
ArCH), 1.98 (s, 3H, CH3COO), 1.21 (3H, d, J = 6.2 Hz,
CH3CH); 13C NMR (100.6 MHz, CDCl3): d 170.5, 154.6,
134.9, 130.1, 129.8, 128.9, 112.2, 71.0, 56.4, 40.9, 21.0,
19.3. GC–MS: tR = 26.96 min, m/z (%) 227 (M+ꢀ60,
100), 200 (17), 120 (20), 90 (25). Anal. Calcd for
C12H17NO5S: C, 50.16; H, 5.96; N, 4.87; S, 11.16. Found:
C, 50.21; H, 5.89; N, 4.81; S, 11.09.
tate 7:3), compound (R)-16 was recovered (5.44g, 63%):
24
½aꢁD ¼ ꢀ26:4 (c 0.95, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.70 (d, 1H, J = 2.4 Hz, H–C(2) aromatic), 7.37
(dd, 1H, J = 8.3, 2.4 Hz, H–C(6) aromatic), 7.00 (d, 1H,
J = 8.3 Hz, H–C(5) aromatic), 5.35 (br s, 2H, NH2), 3.98
(s, 3H, OCH3), 3.66 (m, 1H, CHN3), 2.72 (m, 2H, ArCH2),
1.25 (3H, d, J = 6.6 Hz, CH3CH); 13C NMR (100.6 MHz,
CDCl3): d 154.7, 134.9, 130.1, 129.8, 128.6, 112.2, 58.6,
56.3, 41.1, 18.8; GC–MS: tR = 27.13 min, m/z (%) 270
(M+, 1), 242 (93), 200 (71), 120 (90), 90 (100). Anal. Calcd
for C10H14N4O3S: C, 44.43; H, 5.22; N, 20.73; S, 11.86.
Found: C, 44.36; H, 5.15; N, 20.66; S, 11.94.
4.7. (S)-5-(2-Hydroxypropyl)-2-methoxybenzenesulfonamide
(S)-15
4.10. (R)-5-(2-(2-(2-Ethoxyphenoxy)ethylamino)propyl)-2-
methoxybenzenesulfonamide hydrochloride (R)-1
Compound (S)-14 (12.0 g, 0.042 mol) was treated with
KOH (3.51 g, 0.062 mol) in methanol (50 mL). After the
usual workup, compound (S)-15 was obtained as a white
solid (9.36 g, 91%); mp 168–170 ꢁC; [a]D = +24.1 (c 1,
A solution of azide (5.20 g, 0.019 mol) in ethanol (80 mL)
was treated with H2 in the presence of Pd/C (0.500 mg)
as a catalyst. After 1 h at room temperature, the hydrogen
flux was stopped and aldehyde 17 (5.07 g, 0.0285 mol) was
added. The reaction mixture was stirred at room tempera-
ture for 1 h, then hydrogen was supplied again for 2 h.
After the usual workup, the residue was treated with HCl
ethanolic. The solid recovered by filtration was crystallised
1
MeOH); H NMR (400 MHz, DMSO-d6): d 7.57 (d, 1H,
J = 2.0 Hz, H–C(2) aromatic), 7.37 (dd, 1H, J = 8.2,
2.1 Hz, H–C(6) aromatic), 7.09 (d, 1H, J = 8.2 Hz, H–
C(5) aromatic), 6.95 (br s, 2H, NH2), 4.52 (d, 1H,
J = 4.5 Hz, OH), 3.87 (s, 3H, OCH3), 3.78 (m, 1H,
CHOH), 2.63 (dd, 1H, J = 13.7, 6.5, ArCH), 2.58 (dd,
1H, J = 13.7, 6.1 Hz, ArCH), 1.04 (3H, d, J = 6.2 Hz,
CH3CH); 13C NMR (100.6 MHz, DMSO-d6): d 154.2,
134.4, 131.1, 130.7, 128.1, 112.3, 67.1, 56.0, 43.9, 22.9;
GC–MS: tR = 26.45 min, m/z (%) 245 (M+, 5), 200 (22),
120 (100), 90 (85). Anal. Calcd for C10H15NO4S: C,
48.97; H, 6.16; N, 5.71; S, 13.07. Found: C, 49.05; H,
6.23; N, 5.80; S, 13.15.
from methanol to give (R)-1 HCl (2.30 g, 27%): mp 227–
24
229 ꢁC, ½aꢁD ¼ ꢀ4:1 (c 0.45, MeOH) [lit.4b,c [a]D = ꢀ4.0
1
(c 0.35, MeOH)]; H NMR (400 MHz, DMSO-d6): d 7.64
(d, 1H, J = 2.2 Hz, aromatic), 7.45 (dd, 1H, J = 8.4,
2.2 Hz, aromatic), 7.18 (d, 1H, J = 8.4 Hz, aromatic),
7.07 (dd, J = 8.0, 1.6 Hz, aromatic), 7.04 (br s, 2H,
SO2NH2), 7.03 (dd, J = 8.0, 1.6 Hz, aromatic), 6.97 (dt,
J = 7.8, 1.7 Hz, aromatic), 6.90 (dt, J = 7.8, 1.7 Hz, aro-

492
D. Acetti et al. / Tetrahedron: Asymmetry 18 (2007) 488–492
matic), 4.31 (t, J = 5.3 Hz, OCH2CH2), 4.03 (q, J = 7.0 Hz,
OCH2CH3), 3.89 (s, 3H, OCH3), 3.54 (m, 1H, CHN), 3.41
(m, 2H, NCH2), 3.30 (dd, 1H, J = 13.2, 3.5 Hz, ArCH),
2.70 (dd, 1H, J = 13.2, 10.8 Hz, ArCH), 1.27 (3H, d,
J = 6.9 Hz, CH3CH), 1.16 (d, 3H, J = 6.5 Hz, CH3); ESI
MS: m/z 409 (M+(1)+1).
14.6; GC–MS: tR = 14.26 min, m/z (%) 180 (M+, 100),
152 (20), 121 (50), 109 (90). Anal. Calcd for C10H12O3:
C, 66.65; H, 6.71. Found: C, 66.58; H, 6.65.
References
4.11. 1-(Allyloxy)-2-ethoxybenzene 18
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nouchi Pharmaceutical Co., U.S. Patent 4,731,478, 1988; (c)
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1988.
6. Rampolla, D. C.; Patil, D. S.; Patel, D. A.; Sharma, R.;
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To a suspension of NaH (60% dispersion in mineral oil,
13.2 g, 0.33 mol) in DMF (70 mL), a solution of o-ethoxy-
phenol (30.0 g, 0.22 mol) in DMF (20 mL) was added.
After 30 min, allyl bromide (39.6 g, 0.33 mol) was added.
After the usual workup, compound 18 could be recovered
by column chromatography eluting with hexane–ethyl ace-
tate 9:1 (27.1 g, 70%): 1H NMR (400 MHz, CDCl3): d
6.92–6.85 (m, 4H, aromatic), 6.08 (m, 1H, CH@), 5.40
(dmultiplet, J = 17.3 Hz, @CHH), 5.26 (dmultiplet,
J = 10.8 Hz, @CHH), 4.59 (m, 2H, OCH2CH@), 4.08 (q,
2H, J = 6.9 Hz, CH2CH3), 1.43 (t, 3H, J = 6.9 Hz,
CH2CH3). 13C NMR (100.6 MHz, CDCl3): d 149.0,
148.6, 133.6, 121.2, 120.8, 116.7, 114.7, 114.0, 69.8, 64.3,
14.6; GC–MS: tR = 14.26 min, m/z (%) 178 (M+, 42), 137
(28), 109 (100), 81 (30). Anal. Calcd for C11H14O2: C,
74.13; H, 7.92. Found: C, 74.21; H, 7.86.
7. Hoorn, H. J.; Peters, T. H. A.; Pis, J.; Scigel, R. Synthon
B.V., WO 03037850, 2003.
8. Villasante, Prieto J.; Palomo, Nicolau F. Quimica Sintetica
S.A: US20060148046, 2006.
4.12. 2-(2-Ethoxyphenoxy)acetaldehyde 17
9. http://www.incb.org/incb/en/green_list.html.
10. Fuganti, C.; Grasselli, P. Chem. Ind. (London) 1977, 983.
11. (a) Pelter, A.; Peverall, S.; Pitchford, A. Tetrahedron 1996, 52,
1085–1094; (b) Sy, L.-K.; Brown, G. D. J. Nat. Prod. 1998,
61, 987; (c) Koike, T.; Murata, K.; Ikariya, T. Org. Lett.
2000, 2, 3833–3836.
12. (a) Ferraboschi, P.; Grisenti, P.; Manzocchi, A.; Santaniello,
E. J. Chem. Soc., Perkin Trans. 1 1990, 2469–2474; (b)
Donzelli, F.; Fuganti, C.; Mendozza, M.; Pedrocchi-Fantoni,
G.; Servi, S.; Zucchi, G. Tetrahedron: Asymmetry 1996, 7,
3129–3134.
Compound 17 (26.8 g, 0.150 mol) was treated with O3 in a
2:1 CH2Cl2 solution (150 mL) at ꢀ78 ꢁC. The reaction mix-
ture was treated with NaBH4. After the usual workup,
aldehyde 17 was recovered, and was employed without
any further purification (16.7 g, 62%): 1H NMR
(400 MHz, CDCl3): d 9.92 (t, 1H, J = 1.4 Hz, CHO),
7.03–6.83 (m, 4H, aromatic), 4.57 (m, 2H, OCH2CHO),
4.12 (q, 2H, J = 6.9 Hz, CH2CH3), 1.45 (t, 3H,
J = 6.9 Hz, CH2CH3). 13C NMR (100.6 MHz, CDCl3): d
200.4, 149.6, 147.7, 123.0, 120.8, 116.1, 113.9, 93.3, 64.2,
13. Tran, K.-V.; Bickar, D. J. Org. Chem. 2006, 71, 6640–
6643.