Novel, one-pot procedure for the synthesis of 2-arylethanol derivatives

Article abstract of DOI:10.1055/s-2008-1067021

An efficient one-pot synthesis of 2-arylethanol derivatives using ethylene sulfate as a C₂ building block is described. High yields are obtained upon trapping of aryllithium intermediates generated by halogen-metal exchange or directed metalation with ethylene sulfate. The resulting heteroaryl or phenylethanol derivatives represent versatile building blocks for the synthesis of annulated pyran derivatives by oxa-Pictet-Spengler reaction.

Full text of DOI:10.1055/s-2008-1067021

PAPER
1793
Novel, One-Pot Procedure for the Synthesis of 2-Arylethanol Derivatives
N
ovel Synthesis
o
of 2-Arylet
r
hanol
D
e
s
rivatives ten Schläger, Christoph Oberdorf, Bastian Tewes, Bernhard Wünsch*
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Hittorfstraße 58–62, 48149 Münster,
Germany
Fax +49(251)8332144; E-mail: wuensch@uni-muenster.de
Received 18 December 2007; revised 25 February 2008
silyl-protected 2-bromoethanol derivative [2-bromo-1-
Abstract: An efficient one-pot synthesis of 2-arylethanol deriva-
(tert-butyldimethylsiloxy)ethane] to afford the O-silyl-
tives using ethylene sulfate as a C2 building block is described. High
protected pyrazolylethanol derivative. After cleavage of
the silyl protective group with sodium fluoride/hydrogen
yields are obtained upon trapping of aryllithium intermediates gen-
erated by halogen–metal exchange or directed metalation with eth-
ylene sulfate. The resulting heteroaryl or phenylethanol derivatives bromide in methanol–water the pyrazolylethanol deriva-
tive was obtained in an overall yield of 13%.15 The low
represent versatile building blocks for the synthesis of annulated py-
ran derivatives by oxa-Pictet–Spengler reaction.
yield of this transformation clearly demonstrates the limi-
Key words: alcohols, electrophilic aromatic substitutions, hetero-
cycles, sulfates, lithiation
tation of this procedure. In order to get easy access to a
wide variety of aryl- and heteroarylethanol derivatives,
which are of great interest for the preparation of annulated
pyran derivatives by oxa-Pictet–Spengler reaction, an ef-
2-Arylethanol, as well as 2-arylethanamine, derivatives ficient and direct method for the synthesis of these deriv-
are of great interest as intermediates for the synthesis of atives is required. Herein we wish to report on a novel
pharmacologically active compounds. As an example 2- one-pot procedure for the direct synthesis of heteraryl-
(2-thienyl)ethanamine is required as a starting material for and phenylethanol derivatives from aromatic systems us-
the synthesis of the platelet aggregation inhibitor ticlopi- ing ethylene sulfate as a C2 building block. In a short com-
dine.1 In addition to the synthesis of pharmacologically munication, ethylene sulfate is mentioned to form a 2-
active compounds, 2-arylethanol and 2-arylethanamine pyridylethanol derivative from a 2-bromopyridine in only
derivatives can be used in (oxa)-Pictet–Spengler reactions 21% yield; an experimental procedure is not detailed.16 In
to prepare various aryl-annulated pyrans and pyridines, contrast to oxirane, ethylene sulfate represents a stable
including isochromanes and isoquinolines.2,3
solid, which is easy to handle and, moreover, is neither
toxic nor volatile.17
There are several multistep syntheses of 2-arylethanol de-
rivatives starting from aromatic compounds. For example, In the first attempt 2-bromoanisole (1a) was reacted with
a four-step procedure comprises Blanc chloromethyla- n-butyllithium at –78 °C to generate the aryllithium inter-
tion, followed by substitution with cyanide, saponifica- mediate 2a by halogen–metal exchange. Subsequently,
tion, and reduction4,5 to yield arylethanol derivatives. In the aryllithium intermediate 2a was trapped with ethylene
another procedure an aromatic aldehyde is reacted with sulfate (3) at –78 °C. The cooling bath was removed and
cyanide to afford an a-hydroxynitrile, which upon reduc- the mixture was stirred at room temperature to form the
tive hydrolysis6,7 and subsequent reduction8,9 leads to the lithium sulfate 4a. After 16 hours dilute sulfuric acid was
desired arylethanol derivative.
added and the reaction mixture was heated to reflux for 72
hours to hydrolyze the sulfuric acid ester 4a and produce
the 2-phenylethanol derivative 5a in 73% yield
(Scheme 1, Table 1). To the best of our knowledge this
procedure represents the first one-pot, high-yielding syn-
thesis of an arylethanol derivative starting from a benzene
derivative.
However, only two methods are described in the literature
for the direct, one-pot synthesis of arylethanol derivatives
from aromatic compounds. In the first procedure a bro-
mobenzene derivative was converted into a Grignard re-
agent, which was reacted with oxirane to provide an
arylethanol derivative in 83% yield.10 Also thiophene de-
rivatives metalated in position 2 or 3 react with oxirane to
form 2-(2- or 3-thienyl)ethanol derivatives in good
yields.11–14 A great drawback of these procedures is the
handling of the gaseous, very toxic reagent oxirane. Ac-
cording to the second procedure, which was described in
the patent literature very recently, 1-methylpyrazole was
regioselectively a-metalated with n-butyllithium and the
resulting aryllithium intermediate was reacted with an O-
O
O
O
O
S
ArBr
1a–c
base
base
O
O
OLi
3
Ar
S
ArLi
2a–g
O
ArH
1d–g
4a–g
H2SO4
reflux
OH
Ar
SYNTHESIS 2008, No. 11, pp 1793–1797
Advanced online publication: 11.04.2008
x
x.
x
x
.
2
0
0
8
see Table 1
5a–g
DOI: 10.1055/s-2008-1067021; Art ID: T19607SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1794
T. Schläger et al.
PAPER
Table 1 Reaction Conditions and Yields
Compound
Generation of ArLi 2a–g
Product
Yield (%)
OMe
Me
Br
1a
n-BuLi, –78 °C
5a
73
OH
OH
MeO
Br
MeO
1b
1c
1d
n-BuLi, –78 °C
n-BuLi, –78 °C
n-BuLi, –78 °C
5b
5c
5d
62
53
79
OH
Br
S
S
S
S
HO
Ph
Ph
N
1e
1f
n-BuLi, –78 °C
n-BuLi, –78 °C
5e
5f
75
54
N
N
N
N
N
HO
HO
HO
Me
N
Me
N
Ph
N
Ph
N
1g
n-BuLi, t-BuOK, –78 °C
5g
38
In order to demonstrate the scope and limitation of the However, a considerable decrease in the yield was ob-
new procedure several examples were studied (Table 1). served when 1-phenyl-1H-pyrrole (1g) was reacted with
At first the regioisomeric 3-bromoanisole (1b) was ethylene sulfate in the hydroxyethylation procedure.
reacted in the same way to form the regioisomeric aryl- Though the pyrrolylethanol 5g was formed the yield was
ethanol 5b in 62% yield.
rather low (38%). This might be due to the low regioselec-
tivity during the metalation of 1-phenyl-1H-pyrrole (1g)
with potassium tert-butoxide and n-butyllithium.19 Meta-
lation occurred not only in the desired 2-position of pyr-
role but also in the ortho position of the phenyl moiety
resulting in regioisomeric ethanol derivatives, which had
to be separated by preparative HPLC. 1-Methylindole was
also subjected to this reaction sequence. According to
thin-layer chromatography the transformation seemed
quite promising. However, rapid decomposition occurred
during hydrolysis of the corresponding sulfuric ester with
dilute sulfuric acid. We assume that the instability of the
indole system during acid hydrolysis is responsible for the
observed decomposition of the product.
As an example for a sulfur-containing heterocycle 2-(3-
thienyl)ethanol (5c) was prepared in 53% yield by bro-
mine–lithium exchange of 3-bromothiophene (1c), trap-
ping of the 3-thienyllithium intermediate 2c with ethylene
sulfate and hydrolysis of the resulting sulfuric acid ester
4c with diluted sulfuric acid. For the synthesis of the re-
gioisomeric 2-(2-thienyl)ethanol (5d), thiophene (1d)
without further substituents served as starting material. In
this case the 2-thienyllithium intermediate 2d was gener-
ated by a-deprotonation of thiophene (1d) with n-butyl-
lithium.13 However, the variation of the generation of the
aryllithium intermediate 2d (deprotonation instead of
halogen–metal exchange) did not influence the yield of
the 2-(2-thienyl)ethanol (5d) (79%).
It should be noted that some of the prepared heteroaryl-
ethanol derivatives 5c, 5d,12 and 5f are highly volatile liq-
uids. The high volatility is of particular importance for the
workup procedure, since removal of residual solvent trac-
es using high vacuo led to dramatic loss of the products.
In addition to benzene and thiophene derivatives, nitro-
gen-containing heterocycles were also employed in this
reaction sequence. 1-Phenyl-1H-pyrazole (1e) was a-
lithiated with n-butyllithium at –78 °C to generate the
pyrazol-5-yllithium intermediate 2e.18 Trapping of 2e In literature only few examples are given for the oxa-
with ethylene sulfate and subsequent hydrolysis gave the Pictet–Spengler reaction of heteroarylethanol deriva-
pyrazolylethanol 5e in 75% yield. A comparable yield tives.2 Therefore, the thienylethanol 5d and the pyra-
(54%) was obtained with 1-methyl-1H-pyrazole (1f) as zolylethanol derivatives 5e and 5f were subjected to oxa-
the starting compound.
Pictet–Spengler reaction using benzaldehyde as carbonyl
Synthesis 2008, No. 11, 1793–1797 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of 2-Arylethanol Derivatives
1795
(100 MHz): Mercury-400BB spectrometer (Varian); d relative to
TMS; coupling constants are given with 0.5 Hz resolution. Elemen-
tal analysis: CHN-Rapid Analysator (Fons-Heraeus). HPLC: Merck
Hitachi Equipment; UV detector: L-7400; autosampler: L-7200;
pump: L-7100; degasser: L-7614; column: LiChrospher 60 RP-se-
lect B (5 mm); LiCrOCART 250–4 mm cartridge; flow rate: 1.000
mL/min; injection volume: 5.0 mL; detection at l = 210 nm; sol-
vents (v/v): A: H2O with 0.05% TFA; B: MeCN with 0.05% TFA:
gradient elution: 0.0 min: 90.0% of A, 10.0% of B; 4.0 min: 90.0%
of A, 10.0% of B; 29.0 min: 0.0% of A, 100.0% of B; 31.0 min:
0.0% of A, 100.0% of B; 31.5 min: 90.0% of A, 10.0% of B; 40.0
min: 90.0% of A, 10.0% of B. Preparative HPLC: Merck Hitachi
Equipment; UV-Detector: L-7400; autosampler: L-7200; pump: L-
7150; column: phenomenex Gemini 5 mm C18 110A, 250–21.2
mm; eluent: MeCN–H2O–NH3 (25%) 140:60:5; flow rate: 5.0 mL
component (Scheme 2). Whereas the thienylethanol 5d
reacted with benzaldehyde and catalytic amounts of p-tol-
uenesulfonic acid to afford the thienopyran 6d in 23%
yield, the pyrazolylethanol derivatives 5e and 5f did not
provide annulated pyran derivatives using p-toluene-
sulfonic acid as catalyst. We assume that this failure is due
to the basicity of the pyrazole heterocycle20 leading upon
treatment with strong acids to protonated intermediates,
which are deactivated for the intramolecular electrophilic
aromatic substitution in position 4. Therefore, pyridinium
p-toluenesulfonate with reduced acidity was used instead
of p-toluenesulfonic acid. In fact, with the weak acidic
catalyst pyridinium p-toluenesulfonate the oxa-Pictet–
Spengler reaction of the pyrazole derivatives 5e and 5f (0–0.5 min), 20.0 mL (0.5–14 min; injection volume: 400 mL;
detection at 254 nm.
with benzaldehyde led to the pyranopyrazole derivatives
6e and 6f in 97% and 79% yield.
2-(2-Methoxyphenyl)ethanol (5a)
2-Bromoanisole (1a, 300 mL, 2.43 mmol) was dissolved in THF (35
mL), then 1.48 M n-BuLi in n-hexane (1.64 mL, 2.43 mmol) was
S
S
added dropwise over 30 min at –78 °C; the mixture was stirred at
–78 °C for 2 h. Then, ethylene sulfate (3, 361 mg, 2.92 mmol) in
THF (5 mL) was added dropwise. The mixture was stirred at r.t. for
16 h. H2O (10 mL) and concd H2SO4 (1.8 mL) were added and the
suspension was heated to reflux for 72 h. The soln was made alka-
line with 5 M NaOH (20 mL) and extracted with CH2Cl2. The com-
bined organic layers were dried (Na2SO4) and concentrated in vacuo
and the residue was purified by flash chromatography (4 cm diam-
eter, n-hexane–EtOAc, 8:2, Rf = 0.24) to obtain 5a as a pale yellow
oil; yield: 271 mg (73%).
O
6d 23%
O
a
OH
5d
R
N
R
N
N
HPLC: 97.9%, tR = 15.4 min.
b
N
An alternative synthesis of compound 5a is available.22
OH
2-(3-Methoxyphenyl)ethanol (5b)
3-Bromoanisole (1b, 300 mL, 2.39 mmol) was dissolved in THF (35
mL, then 1.48 M n-BuLi in n-hexane (1.62 mL, 2.39 mmol) was
added dropwise over 30 min at –78 °C; the mixture was stirred at
–78 °C for 2 h. Then ethylene sulfate (3, 355 mg, 2.87 mmol) in
THF (5 mL) was added dropwise. The mixture was stirred at r.t. for
16 h. H2O (10 mL) and concd H2SO4 (1.8 mL) were added and the
suspension was heated to reflux for 47 h. The soln was made alka-
line with 5 M NaOH (20 mL) and extracted with CH2Cl2. The com-
bined organic layers were dried (Na2SO4) and concentrated in vacuo
and the residue was purified by flash chromatography (4 cm diam-
eter, n-hexane–EtOAc, 8:2, Rf = 0.16) to give a colorless oil; yield:
225.1 mg (62%).
5e: R = Ph
5f: R = Me
6e: R = Ph 97%
6f: R = Me
79%
Scheme 2
Reagents and conditions: (a) benzaldehyde, PTSA,
MeCN, reflux; (b) PhCHO, PPTS, MeCN, reflux.
Herein it is demonstrated that the nontoxic solid ethylene
sulfate represents an attractive alternative C2 building
block for the synthesis of arylethanol derivatives. The hy-
droxyethylation can be applied on carbocyclic as well as
heterocyclic aromatic systems. Irrespective of the forma-
tion of the required aryllithium intermediates (halogen–
metal exchange or directed metalation) high yields of
arylethanol derivatives are obtained. Some of the het-
eroarylethanol derivatives are reacted in an oxa-Pictet–
Spengler reaction to form heteroaryl-annulated pyran de-
rivatives.
HPLC: 99.6%, tR = 14.8 min.
An alternative synthesis of compound 5b is available.22
2-(3-Thienyl)ethanol (5c)
To a soln of 3-bromothiophene (1c, 500 mg, 3.07 mmol) in THF (20
mL), 1.6 M n-BuLi in hexane (1.90 mL, 3.04 mmol) was added
dropwise at –78 °C; the mixture was stirred for 15 min. Then a soln
of ethylene sulfate (3, 450 mg, 3.63 mmol) in THF (2 mL) was add-
ed dropwise. The mixture was stirred at –78 °C for 30 min and at r.t.
for 90 min. H2O (10 mL) and concd H2SO4 (3 mL) were added and
the mixture was heated to reflux for 4 h with vigorous stirring. The
mixture was made alkaline with 5 M NaOH (35 mL) and extracted
with CH2Cl2. The combined organic layers were dried (Na2SO4) and
filtered and the solvent was evaporated in vacuo. Purification of the
residue by flash chromatography (3 cm diameter, cyclohexane–
EtOAc, 7:3, Rf = 0.16) afforded a colorless liquid; yield: 210 mg
(53%).
Unless otherwise mentioned, moisture sensitive reactions were con-
ducted under dry N2. THF was dried with Na/benzophenone and
was freshly distilled before use. The concentration of n-BuLi was
determined by titration with 1,3-diphenylpropan-2-one p-toluene-
sulfonylhydrazone in THF under N2 atmosphere.21 TLC: Silica gel
60 F254 plates (Merck). Flash chromatography: Silica gel 60, 40–64
mm (Merck). Melting point: Melting point apparatus SMP 3 (Stuart
Scientific), uncorrected. MS: MAT GCQ (Thermo-Finnigan).
HRMS: MicroTof (Bruker Daltronics, Bremen), calibration with
sodium formate clusters before measurement. IR spectrophotome-
HPLC: 99.5%, tR = 12.0 min.
ter 480Plus FT-ATR-IR (Jasco). H NMR (400 MHz), 13C NMR
1
Synthesis 2008, No. 11, 1793–1797 © Thieme Stuttgart · New York

1796
T. Schläger et al.
PAPER
IR (neat): 3327 (O–H), 1044 (C–O) cm–1.
MS (EI, 70 eV): m/z (%) = 189 [MH+, 42], 188 [M+, 52], 158 [MH
– CH2OH, 41], 157 [M – CH2OH, 100], 77 [phenyl, 18].
1H NMR (CDCl3): d = 1.46 (t, J = 6.4 Hz, 1 H, ArCH2CH2OH),
2.91 (t, J = 6.4 Hz, 2 H, ArCH2CH2OH), 3.85 (q, J = 6.4 Hz, 2 H,
ArCH2CH2OH), 6.99 (dd, J = 5.2, 1.2 Hz, 1 H, H4thiophene), 7.04–
7.07 (m, 1 H, H2thiophene), 7.30 (dd, J = 5.2, 3.2 Hz, 1 H, H5thiophene).
Anal. Calcd for C11H12N2O (188.1): C, 70.19; H, 6.43; N, 14.88.
Found: C, 70.16; H, 6.55; N, 14.92.
2-(1-Methyl-1H-pyrazol-5-yl)ethanol (5f)
13C
NMR
(CDCl3):
d = 33.4
(ArCH2CH2OH),
62.7
To a soln of 1-methyl-1H-pyrazole (1f, 300 mg, 3.65 mmol) in THF
(20 mL), 1.6 M n-BuLi in hexane (2.30 mL, 3.68 mmol) was added
dropwise at –78 °C; the mixture was warmed to 0 °C and stirred for
1 h. Then the mixture was cooled to –78 °C and, subsequently, a
soln of ethylene sulfate (3, 544.1 mg, 4.38 mmol) in THF (4 mL)
was added slowly at –78 °C. The mixture was stirred at –78 °C for
1 h and at r.t. for 48 h. H2O (15 mL) and concd H2SO4 (4.5 mL) were
added and the soln was heated to reflux for 16 h with vigorous stir-
ring. The mixture was made alkaline by addition of 5 M NaOH (~30
mL) and extracted with CH2Cl2 (3 ×). The combined organic layers
were dried (K2CO3) and filtered and the solvent was removed in
vacuo. Purification of the residue by flash chromatography [4 cm
diameter, n-hexane–EtOAc, 2:8, Rf = 0.09 (EtOAc)] afforded a pale
yellow oil; yield: 249 mg (54%).
(ArCH2CH2OH), 121.5 (C4thiophene), 125.7 (C2thiophene), 128.0
(C5thiophene), 138.5 (C3thiophene).
MS (EI, 70 eV): m/z (%) = 128 [M+, 17], 97 [M+ – CH2OH, 100].
Anal. Calcd for C6H8OS (128.2): C, 56.22; H, 6.29. Found: C,
56.32; H, 6.59.
An alternative synthesis of compound 5c is available in a patent.14
2-(2-Thienyl)ethanol (5d)
Following the typical procedure for 5c using thiophene (1d, 500 g,
5.94 mmol) in THF (50 mL), 1.6 M n-BuLi in hexane (4.00 mL,
5.94 mmol), and ethylene sulfate (3, 890 mg, 7.13 mmol) in THF (4
mL). The mixture was stirred at –78 °C for 30 min and at r.t. for 2
h. H2O (20 mL) and concd H2SO4 (5 mL) were added with reflux
for 3 h. The mixture was made alkaline with 5 M NaOH (50 mL).
Purification of the residue by flash chromatography (3 cm diameter,
cyclohexane–EtOAc 7:3, Rf = 0.16) afforded a colorless liquid;
yield: 602 mg (79%).
HPLC: 96.9%, tR = 3.8 min.
IR (neat): 3298 (O–H), 1048 (C–O) cm–1.
1H NMR (CDCl3): d = 1.94 (br s, 1 H, ArCH2CH2OH), 2.89 (t,
J = 6.5 Hz, 2 H, ArCH2CH2OH), 3.82 (s, 3 H, NCH3), 3.88 (t,
J = 6.5 Hz, 2 H, ArCH2CH2OH), 6.09 (d, J = 2.0 Hz, 1 H, H4pyrazole),
7.39 (d, J = 2.0 Hz, 1 H, H3pyrazole).
HPLC: 98.4%, tR = 12.6 min.
IR (neat): 3345 (O–H), 1066 (C–O) cm–1.
13C NMR (CDCl3): d = 29.2 (ArCH2CH2OH), 36.6 (NCH3), 61.5
(ArCH2CH2OH), 105.0 (C4pyrazole), 138.5 (C3pyrazole), 139.7
(C5pyrazole).
MS (ESI+): m/z (%) = 127 [M + H+, 100].
HRMS-FAB: m/z [M + H+] calcd for C6H10N2O: 127.0883; found:
1H NMR (CDCl3): d = 1.56 (t, J = 6.4 Hz, 1 H, ArCH2CH2OH),
3.07 (t, J = 6.4 Hz, 2 H, ArCH2CH2OH), 3.85 (q, J = 6.4 Hz, 2 H,
ArCH2CH2OH), 6.87 (dd, J = 3.6, 1.2 Hz, 1 H, H3thiophene), 6.95 (dd,
J = 5.2, 3.6 Hz, 1 H, H4thiophene), 7.16 (dd, J = 5.2, 1.2 Hz, 1 H,
H5thiophene).
13C
NMR
(CDCl3):
d = 33.5
(ArCH2CH2OH),
63.7
127.0866.
(ArCH2CH2OH), 124.3 (C3thiophene), 125.8 (C4thiophene), 127.3
An alternative synthesis of compound 5f is available;15 however,
spectroscopic and analytical data are not given.
(C5thiophene), 140.9 (C2thiophene).
MS (EI, 70 eV): m/z (%) = 128 [M+, 11], 97 [M+ – CH2OH, 100].
2-(1-Phenyl-1H-pyrrol-2-yl)ethanol (5g)
Anal. Calcd for C6H8OS (128.2): C, 56.22; H, 6.29. Found: C,
56.64; H, 6.64.
An alternative synthesis of compound 5d is available;23 however,
To a soln of 1-phenyl-1H-pyrrole (1g, 100 mg, 0.70 mmol) in THF
(3 mL), 1 M t-BuOK in THF (700 mL, 0.70 mmol) and 1.6 M n-
BuLi in hexane (436 mL, 0.70 mmol) were added dropwise at –78
°C; the mixture was stirred at –78 °C for 1.5 h. Then a soln of eth-
ylene sulfate (3, 103.9 mg, 0.84 mmol) in THF (1 mL) was added
dropwise at –78 °C. The mixture was stirred at –78 °C for 1 h and
at r.t. for 2 h. H2O (2 mL) and concd H2SO4 (600 mL) were added
and the soln was heated to reflux for 16 h with vigorous stirring. The
mixture was made alkaline by addition of 5 M NaOH (5 mL) and
extracted with CH2Cl2. The combined organic layers were dried
(K2CO3) and filtered and the solvent was evaporated in vacuo. Pu-
rification of the residue by preparative HPLC afforded a pale yellow
oil; yield: 50 mg (38%).
spectroscopic and analytical data are absent.
2-(1-Phenyl-1H-pyrazol-5-yl)ethanol (5e)
A soln of 1-phenyl-1H-pyrazole (1e, 1.00 g, 6.94 mmol) in THF (70
mL) was cooled to –78 °C, 1.6 M n-BuLi in hexane (4.30 mL, 6.94
mmol) was added dropwise; the mixture was stirred at –78 °C for 2
h. Then a soln of ethylene sulfate (3, 1.03 g, 8.32 mmol) in THF (10
mL) was added slowly. The mixture was stirred at –78 °C for 1 h
and at r.t. for 26 h. H2O (30 mL) and concd H2SO4 (5 mL) were add-
ed and the mixture was heated to reflux for 24 h with vigorous stir-
ring. The soln was made alkaline with 5 M NaOH (60 mL) and
extracted with CH2Cl2. The combined organic layers were dried
(K2CO3) and filtered and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography (6 cm diameter, n-
hexane–EtOAc, 5:5, Rf = 0.13) to obtain 5e as a pale yellow oil;
yield: 981 mg (75%).
HPLC: 100%, tR = 17.9 min.
IR (neat): 3394 (O–H), 1034 (C–O) cm–1.
1H NMR (CDCl3): d = 1.53 (t, J = 6.1 Hz, 1 H, ArCH2CH2OH),
2.84 (td, J = 6.5, 0.5 Hz, 2 H, ArCH2CH2OH), 3.69 (q, J = 6.3 Hz,
2 H, ArCH2CH2OH), 6.16 (ddt, J = 3.3, 1.8, 0.8 Hz, 1 H, H3pyrrole),
6.24 (t, J = 3.1 Hz, 1 H, H4pyrrole), 6.79 (dd, J = 2.9, 1.8 Hz, 1 H,
H5pyrrole), 7.29–7.32 (m, 2 H, m-Hphenyl), 7.37 (tt, J = 6.9, 1.3 Hz, 1
H, p-Hphenyl), 7.42–7.47 (m, 2 H, o-Hphenyl).
IR (neat): 3328 (O–H), 3067 (C–Harom), 1598, 1501 (C=C) cm–1.
1H NMR (CDCl3): d = 2.11 (s, 1 H, ArCH2CH2OH), 2.91 (t, J = 6.5
Hz, 2 H, ArCH2CH2OH), 3.79 (t, J = 6.7 Hz, 2 H, ArCH2CH2OH),
6.29 (d, J = 1.6 Hz, 1 H, H4pyrazole), 7.38–7.48 (m, 5 H, Hphenyl), 7.60
(d, J = 1.6 Hz, 1 H, H3pyrazole).
13C
NMR
(CDCl3):
d = 30.2
(ArCH2CH2OH),
61.9
(ArCH2CH2OH), 108.2 (C3pyrrole), 108.5 (C4pyrrole), 122.8 (C5pyrrole),
126.5 (m-Cphenyl), 127.6 (p-Cphenyl), 129.4 (o-Cphenyl), 129.8 (Cphenyl),
140.3 (C2pyrrole).
13C
NMR
(CDCl3):
d = 29.7
(ArCH2CH2OH),
61.4
(ArCH2CH2OH), 106.1 (C4pyrazole), 125.9 (o-Cphenyl), 128.4 (p-Cphe-
nyl), 129.4 (m-Cphenyl), 139.7 (Cphenyl), 140.2 (C3pyrazole), 140.5
(C5pyrazole).
Synthesis 2008, No. 11, 1793–1797 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of 2-Arylethanol Derivatives
1797
Anal. Calcd for C12H13NO (187.1): C, 76.98; H, 7.00; N, 7.48.
Found: C, 76.81; H, 7.22; N, 7.34.
in vacuo. The residue was purified by flash chromatography (2 cm
diameter, n-hexane–EtOAc, 4:6, Rf = 0.14) to obtain 6f as a color-
less oil; yield: 67 mg (79%).
Compound 5g is mentioned in the literature;19 however, details of
the synthesis and interpretation of the 1H NMR data are not given.
HPLC: 96.9%, tR = 17.6 min.
IR (neat): 3032 (C–Harom), 1055 (C–O) cm–1.
4-Phenyl-6,7-dihydro-4H-thieno[2,3-c]pyran (6d)
1H NMR (CDCl3): d = 2.67 (dddd, J = 15.7, 4.7, 3.3, 1.4 Hz, 1 H,
ArCH2CH2O), 2.88 (dddd, J = 15.8, 9.0, 5.7, 1.4 Hz, 1 H,
ArCH2CH2O), 3.80 (s, 3 H, NCH3), 3.88 (ddd, J = 11.5, 9.0, 4.5 Hz,
1 H, ArCH2CH2O), 4.21 (ddd, J = 11.5, 5.7, 3.3 Hz, 1 H,
ArCH2CH2O), 5.65 (br s, 1 H, PhCH), 7.08 (s broad, 1 H, H3pyrazole),
7.30–7.38 (m, 5 H, Hphenyl).
13C NMR (CDCl3): d = 22.7 (ArCH2CH2O), 35.9 (NCH3), 63.1
(ArCH2CH2O), 76.1 (PhCH), 117.8 (C4pyrazole), 128.1 (Cphenyl),
128.5 (Cphenyl), 128.7 (Cphenyl), 135.3 (C3pyrazole), 136.1 (Cphenyl),
141.2 (C5pyrazole).
Thienylethanol 5d (0.06 g, 0.47 mmol) was dissolved in MeCN (7
mL). Then PhCHO (74.0 mg, 0.69 mmol), PTSA (360 mg, 1.88
mmol), and Na2SO4 (120 mg) were added and the mixture was heat-
ed to reflux for 66 h. After filtration, the soln was made alkaline by
addition of 2 M NaOH (15 mL), diluted with H2O, and extracted
with CH2Cl2. The combined organic layers were dried (Na2SO4) and
filtered and the solvent was evaporated in vacuo. Purification of the
residue by flash chromatography (3 cm diameter, cyclohexane–
EtOAc 9:1, Rf = 0.55) afforded a colorless solid, mp 37 °C; yield:
25 mg (23%).
MS (ESI+): m/z (%) = 215 [MH+, 35].
HPLC: 98.0%, tR = 21.2 min.
IR (neat): 3126 (C–Harom), 1049 (C–O) cm–1.
Anal. Calcd for C13H14N2O (214.1): C, 72.87; H, 6.59; N, 13.07.
Found: C, 73.19; H, 6.56; N, 12.72.
1H NMR (CDCl3): d = 2.83–2.89 (m, 1 H, ArCH2CH2O), 2.06–3.16
(m, 1 H, ArCH2CH2O), 3.93 (ddd, J = 11.6, 9.2, 4.0 Hz, 1 H,
ArCH2CH2O), 4.23 (ddd, J = 11.2, 5.6, 3.6 Hz, 1 H, ArCH2CH2O),
5.68 (t, J = 2.0 Hz, 1 H, PhCH), 6.48 (d, J = 5.2 Hz, 1 H, H3thiophene),
7.04 (d, J = 5.2 Hz, 1 H, H2thiophene), 7.28–7.37 (m, 5 H, Hphenyl).
13C NMR (CDCl3): d = 25.6 (ArCH2CH2O), 63.7 (ArCH2CH2O),
78.4 (PhCH), 122.3 (C3thiophene), 125.6 (C2thiophene), 128.2 (Cphenyl),
128.3 (Cphenyl), 128.4 (Cphenyl), 133.4 (Cphenyl), 136.1 (C3athiophene),
141.1 (C7athiophene).
References
(1) Sumita, K.; Koumori, M.; Phno, S. Chem. Pharm. Bull.
1994, 42, 1676.
(2) Larghi, E. L.; Kaufman, T. S. Synthesis 2006, 187.
(3) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
(4) Xie, Y. P.; Jian, M.; Li, Y. Z.; Chen, H.; Cheng, P. M.; Li,
X. Catal. Commun. 2004, 237.
MS (EI, 70 eV): m/z (%) = 216 [M+, 100], 139 [M+ – Ph, 48], 77
(5) Takahashi, K.; Shibagaki, M.; Matsushita, H. Chem. Lett.
1990, 311.
[Ph+, 41].
Anal. Calcd for C13H12OS: C, 72.19; H, 5.59. Found: C, 71.88; H,
5.73.
(6) Shaw, K. N. F.; Armstrong, M. D.; McMillan, A. J. Org.
Chem. 1956, 21, 1149.
(7) Soicke, H.; Al-Hassan, G.; Frenzel, U.; Goerler, K. Arch.
Pharm. (Weinheim, Ger.) 1988, 321, 149.
(8) Tale, R. H.; Patil, K. M.; Dapurkar, S. E. Tetrahedron Lett.
2003, 44, 3428.
(9) Lanni, T. B.; Greene, K. L.; Kolz, C. N.; Para, K. S.; Visnick,
M.; Mobley, J. L.; Dudley, D. T.; Baginski, T. J.; Liimatta,
M. B. Bioorg. Med. Chem. Lett. 2007, 17, 756.
(10) Beinhoff, M.; Karakaya, B.; Schlüter, A. D. Synthesis 2003,
79.
1,4-Diphenyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (6e)
Pyrazolylethanol 5e (0.05 g, 0.27 mmol) was dissolved in MeCN (5
mL). Then PhCHO (40.5 mL, 0.39 mmol), PPTS (334 mg, 1.33
mmol), and Na2SO4 (100 mg) were added and the mixture was heat-
ed to reflux for 23 h. After filtration, sat. NaHCO3 and H2O were
added and the mixture was extracted with CH2Cl2. The combined
organic layers were dried (K2CO3) and the solvent was evaporated
in vacuo. The residue was purified by flash chromatography (2 cm
diameter, n-hexane–EtOAc, 8:2, Rf = 0.13) to obtain 6e as colorless
solid; yield: 71 mg (97%).
(11) Schick, J. W.; Hartough, H. D. J. Am. Chem. Soc. 1948, 70,
1646.
(12) Davies, W.; Porter, Q. N. J. Chem. Soc. 1957, 4958.
(13) Fuller, L.; Iddon, B.; Smith, K. J. Chem. Soc., Perkin Trans.
1 1997, 3465.
(14) Shiozawa, S.; Takada, K.; Hikage, N. JP 06199832 A, 1994.
(15) Krell, H. W.; Middeldorff, J.; Reiff, U.; von Hirschheydt, T.;
Voss, E. WO 2007017222, 2007.
(16) Lama, M.; Mamula, O.; Scopelliti, R. Synlett 2004, 1808.
(17) Lohray, B. B. Synthesis 1992, 1035.
(18) Micetich, R. G.; Baker, V.; Spevak, P.; Hall, T. W.; Bains,
B. K. Tetrahedron 1985, 23, 943.
(19) Faigl, F.; Schlosser, M. Tetrahedron 1993, 45, 10271.
(20) Kirschke, K. Houben–Weyl, 4th ed., Vol. E 8b, Part II;
Schaumann, E., Ed.; Georg Thieme Verlag: Stuttgart, 1994,
399–763.
IR (neat): 3031 (C–Harom), 1057 (C–O) cm–1.
1H NMR (CDCl3): d = 2.75 (br d, J = 16.0 Hz, 1 H, ArCH2CH2O),
3.07 (dddd, J = 15.9, 9.0, 5.5, 1.4 Hz, 1 H, ArCH2CH2O), 3.79 (ddd,
J = 11.4, 9.1, 4.0 Hz, 1 H, ArCH2CH2O), 4.14 (ddd, J = 11.4, 5.4,
3.4 Hz, 1 H, ArCH2CH2O), 5.68 (s, 1 H, PhCH), 7.23–7.52 (m, 11
H, 10 Hphenyl, 1 H3pyrazole).
MS (EI, 70 eV): m/z (%) = 276 [M+, 84], 275 [M – H, 100].
Anal. Calcd for C18H16N2O (276.1): C, 78.24; H, 5.84; N, 10.14.
Found: C, 77.91; H, 5.94; N, 10.10.
1-Methyl-4-phenyl-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole
(6f)
Pyrazolylethanol 5f (50.0 mg, 0.40 mmol) was dissolved in MeCN
(5 mL). Then PhCHO (60.4 mL, 0.59 mmol), PPTS (498 mg, 1.98
mmol), and Na2SO4 (150 mg) were added and the mixture was heat-
ed to reflux for 29 h. After filtration, sat. NaHCO3 and H2O were
added and the mixture was extracted with CH2Cl2. The combined
organic layers were dried (K2CO3) and the solvent was evaporated
(21) Suffert, J. J. Org. Chem. 1989, 54, 509.
(22) Gómez, C.; Macia, B.; Lillo, J. V.; Yus, M. Tetrahedron
2006, 62, 9832.
(23) Abarca, B.; Ballesteros, R.; Enriquez, E.; Jones, G.
Tetrahedron 1985, 41, 2435.
Synthesis 2008, No. 11, 1793–1797 © Thieme Stuttgart · New York