Efficient chemoselective addition of grignard reagents to carbonyl compounds in 2-methyltetrahydrofuran

Article abstract of DOI:10.3184/030823409X460939

Compared with tetrahydrofuran (THF) as a solvent for the addition reactions between Grignard reagents and carbonyl compounds 2-methyltetrahydrofuran affords the corresponding adducts in higher yields with higher chemoselectivities. Moreover, 2-methyltetrahydrofuran can be readily recycled and reused, which lowers the cost of the process and makes the reaction greener.

Full text of DOI:10.3184/030823409X460939

370 RESEARCH PAPER
JUNE, 370–373
JOURNAL OF CHEMICAL RESEARCH 2009
Efficient chemoselective addition of Grignard reagents to carbonyl
compounds in 2-methyltetrahydrofuran
Weihui Zhong*, Yaotiao Wu and Xingxian Zhang
Key Laboratory of Pharmaceutical Engineering of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P.R. China
Compared with tetrahydrofuran (THF) as a solvent for the addition reactions between Grignard reagents and
carbonyl compounds 2-methyltetrahydrofuran affords the corresponding adducts in higher yields with higher
chemoselectivities. Moreover, 2-methyltetrahydrofuran can be readily recycled and reused, which lowers the cost of
the process and makes the reaction greener.
Keywords: 2-methyltetrahydrofuran, Grignard reactions, carbonyl compounds, alcohol synthesis
Solvents play important roles in organic synthesis and the
replacement of toxic and volatile solvents such as benzene
and dichloromethane by a variety of cleaner solvents has been
evaluated recently.1 The Grignard reaction is undoubtedly one
of the most important carbon-carbon bond-forming reactions
in organic synthesis as well as in medicinal chemistry.2
The traditional solvents such as Et2O and THF have been
widely used for the preparation of Grignard reagents.
However, the hazardous properties of Et2O such as
flammability and proneness to the formation of peroxides
limit its application in industry, while THF, due to its
complete miscibility with water, involves high costs in
recycling and drying. Therefore, the development of new and
environmentally benign solvents for the Grignard reaction
was desirable.
containing Grignard reagents, and being readily recoverable.3
Very recently, Schmalz and co-workers4 reported that
significant increase in enantioselectivities could be achieved
when the reactions were carried out in 2-MeTHF instead of
Et2O or THF.
Grignard reactions are often accompanied by so-called
abnormal reactions such as reduction, enolisation, and pinacol
coupling, and the corresponding products are shown in
Scheme 1 respectively as a, b, c. This prompted us to design a
procedure to suppress abnormal reactions by using 2-MeTHF
as solvent. Herein, we report comparative results of Grignard
reactions carried out in 2-MeTHF and THF and make an
assessment of the prospects of the former for its applications
both in laboratory practice and in industry.
Initially, we investigated the reaction between carbonyl
compounds (1) and n-BuMgBr (2a) using 2-MeTHF and THF
respectively as the solvent as n-BuMgBr is one of the most
typical structures to generate the side products (Table 1).5
It was found that a small amount of 2-MeTHF was enough to
afford a clear solution of Grignard reagent (its concentration
Among various solvents, 2-methyltetrahydrofuran (2-MeTHF)
has proved to be a greener and more environmentally friendly
solvent than THF, due to its specific characteristics such as
ready availability from renewable resources, being suitable
for the preparation of higher concentrations of bromine-
Table 1 The Grignard reactions of n-BuMgBr with aldehydes and ketones in 2-MeTHF and THFa
O
R1 R2
OH
R2
n-BuMgBr (2a)
+
R1
R2
R1
n-Bu OH
solvents
1
3
4
Entry
R1
R2
Yield (%)b
THF
2-MeTHF
3
4
3
4
1
2
3
4
5
6
7
8
C6H5
H
H
79
85
81
53
63
71
53
48
0
0
86 (3a)
87 (3b)
95 (3c)
72 (3d)
64 (3e)
90 (3f)
85 (3g)
59 (3h)
0
0
p-ClC6H4
p-MeOC6H4
C6H5
H
0
0
Me
Me
Me
Et
31
22
15
31
41
20
20
5
11
29
p-ClC6H4
p-MeOC6H4
C6H5
p-ClC6H4
Et
aAll reactions were carried out in THF or 2-MeTHF under nitrogen atmosphere using substrates 1 (20 mmol) and n-BuMgBr 2a
(24 mmol).
bIsolated yields based on 1.
HO R1
O
O
R3MgX
O
HO R3
R1
HO
R1
H
R2
R2
R1
R2
R2
R2
R1
+
+
+
R1
R2
normal adduct
a
b
c
Scheme 1
* Correspondent. E-mail: pharmlab@zjut.edu.cn.

JOURNAL OF CHEMICAL RESEARCH 2009 371
can reach up to 3 mol L-1 in 2-MeTHF, but only about
1 mol L-1 in THF). Most of the substrates, especially the ones
with electron-donating groups at the para-position of aromatic
rings, showed higher chemoselectivities and higher yields of
the alcohols 3 could be obtained in 2-MeTHF than in THF
(Table 1, entries 3 and 6).
results are summarised in Table 2. To our delight, comparable
high yields of the desired products were obtained.
In the light of the encouraging results, we attempted to
apply the Grignard reaction in the synthesis of tramadol
hydrochloride9, whichisanon-addictive, non-opioidanalgesic
agent used for the treatment of moderate to moderately severe
pain. Tramadol hydrochloride 9 is traditionally prepared by
treatment of 3-methoxyphenylmagnesium bromide 2e with 2-
[(dimethylamino)methyl]cyclohexanone 10 in THF, followed
by precipitation as the hydrochloride in different solvents.6
We investigated this reaction both in 2-MeTHF and THF
under similar reaction conditions. Compared with previous
reported methodologies, the present protocol featured less
solvent, a shorter reaction time and higher conversion (Table 3).
In summary, addition reactions between carbonyl
compounds and Grignard reagents proceeded more smoothly
in 2-MeTHF than in THF. The higher chemoselectivities,
better yields of the adducts, together with the easy recycling
and reuse of the solvent make 2-MeTHF a good alternative to
THF. The methodology presented here may contribute to the
development of green strategy in industry.
Prompted by these intriguing results, a series of carbonyl
compounds (including an ester) and a nitrile were reacted
with n-BuMgBr so as to demonstrate the generality of the
Grignard reactions in 2-MeTHF. Studies were also carried
out with the Grignard reagents derived from benzyl chloride,
allyl bromide, and bromobenzene. The results are illustrated
in Table 2 and Scheme 2. As expected, all the aldehydes
generated the addition products 3 in excellent yields (Table 2,
entries 1–6, 13, 15, 17) and the troublesome reduction reaction
was not observed when 2-MeTHF was used as the solvent. The
Grignard reaction of ketones was equally effective to afford
good to excellent yields of the desired products (Table 2,
entries 7–12, 14, 16). The addition of Grignard reagents
to ester 5 and nitrile 7 in 2-MeTHF (Scheme 2) afforded
the corresponding products with good yields and good
chemoselectivities.
On the other hand, 2-MeTHF can not only be used as
reaction solvent, but also as the extraction solvent and it can be
readily recovered according to a known procedure. Grignard
reactions in the recycled 2-MeTHF were investigated and the
Experimental
Starting materials and solvents were purchased from commercial
sources and used without additional purification. Melting points were
determined with a Büchi B-540 capillary melting point apparatus
Table 2 The results of Grignard reactions in 2-MeTHFa
R2 R3
O
1) 2-MeTHF
R3MgX
+
R2
R1
R1
OH
2) NH4Cl, H2O
3
2
1
Entry
R1
R2
R3 MgBr
Time/h
Product 3,
yield/%b
1
2
Furan-2-yl
H
H
H
H
H
H
n-Bu MgBr (2a)
1
2
3i (91, 90c)
3j (79)
p-FC6H4
2a
3
Thiophene-2-yl
3,4-(OCH2O)C6H3
i-C4H9
2a
1
3k (92)
4
2a
1.5
1.5
1.5
1
3l (90)
5
2a
3m (89)
3n (88)
6
4-Methylthiazole-5-yl
2a
7
-(CH2)4-
m-ClC6H4
Furan-2-yl
Pyridin-2-yl
Me
2a
3o (72)
8
Et
2a
2
3p (58)
9
Me
Me
Me
2a
1.5
1.5
1.5
2
3q (89, 87c)
3r (78)
10
11
12
13
14
15
16
17
2a
Bn MgCl (2b)
3s(75)
3t (87)
-(CH2)5-
Ph
2b
H
Me
H
Me
H
Allyl MgBr (2c)
1
1.5
2
2
1.5
3u (96, 95c)
3v (94, 93c)
3w (89, 87c)
3x (78, 78c)
3y (97)
Ph
2c
Ph
Ph MgBr (2d)
Ph
2d
2d
Furan-2-yl
aThe reactions were carried out at room temperature under nitrogen atmosphere using carbonyl compounds (20 mmol) and
Grignard reagents (24 mmol).
bIsolated yields based on 1.
cThe reactions were carried out in the recycled 2-MeTHF.
(CH2)3OH
HO C Bu-n
1) 2-MeTHF, r.t., 2h
O
O
n-BuMgBr
n-BuMgBr
+
2) NH4Cl, H2O
97% yield
n-Bu
6
5
O
CN
1) 2-MeTHF, reflux, 4h
Bu-n
+
2) NH4Cl, H2O
89% yield
7
8
Scheme 2

372 JOURNAL OF CHEMICAL RESEARCH 2009
Table 3 The preparation of tramadol hydrochloride (9) in 2-MeTHF and THFa
NMe2 HCl
OMe
O
HO
1) solvent
2) NH4Cl, H2O
NMe2
+
3) HCl(gas), i-ProH
MgBr
OMe
2e
10
9
Entry
Solvent
Amount/mL
Time/h
Yield/%b
1
2
2-MeTHF
THF
50
65
6
8
82
67
aBoth reactions were carried out under nitrogen atmosphere using 10 (0.1 mol) and 2e (0.12 mol).
bIsolated yields based on 10.
and are uncorrected. IR spectra were recorded on a Nicolet Avatar-
2-(4-Methoxyphenyl)hexan-2-ol (3f): Yellow oil.12 1H NMR
(500 MHz, CDCl3, d, ppm): 7.35–7.32 (m, 2H, ArH), 6.86–6.83 (m,
2H, ArH), 3.78 (s, 3H, OCH3), 2.10 (br s, 1H, OH), 1.80–1.72 (m,
2H, CH2), 1.52 (s, 3H, CH3), 1.25–1.11 (m, 4H, 2 ¥ CH2), 0.84 (t,
J = 7.0 Hz, 3H, CH3).
1
370 instrument. H NMR and 13C NMR spectra were measured on
a Bruker AVANCE III-500 spectrometer and Varian Mercury plus-
400 with tetramethylsilane (TMS) as an internal standard. Mass
spectra were measured with a Finnigan Trace DSQ instrument.
High resolution mass spectral (HRMS) analyses were measured on
an APEX (Bruker) mass III spectrometer using ESI (electrospray
ionisation) techniques. For chromatography silica-gel was purchased
from Qingdao Haiyang Chemical Co., Ltd. (200–300 mesh).
All spectroscopic data of the products were identical to those of
authentic samples.
The recovery and drying of 2-MeTHF were accomplished in a
distillation set-up consisting of a reboiler, a fractionation tower and
an overhead condenser with a liquid-liquid decanter. The aqueous
2-MeTHF (1.5 L) was added to the set-up. Then azeotropic distillation
was carried out for 5-8 h to remove the residual water gradually until
no more water phase appeared in the overhead decanterat 60°C.
The water phase was recycled to the next batch. The dry 2-MeTHF
was collected and when measured the reboiled product had less than
300ppm water. The total recycled yield was about 95%.
3-Phenylheptan-3-ol (3g): Yellow oil.13 1H NMR (400 MHz,
CDCl3, d, ppm): 7.37 (d, J = 7.2 Hz, 2H, ArH), 7.33 (t, J = 7.2 Hz,
2H, ArH), 7.22 (t, J = 7.2 Hz, 1H, ArH), 1.89–1.73 (m, 4H, 2 ¥ CH2),
1.70 (br s, 1H, OH), 1.29–1.00 (m, 4H, 2 ¥ CH2), 0.83 (t, J = 7.2 Hz,
3H, CH3), 0.75 (t, J = 7.2 Hz, 3H, CH3).
3-(4-Chlorophenyl)heptan-3-ol (3h): Yellow oil. 1H NMR (500 MHz,
CDCl3, d, ppm): 7.32–7.27 (m, 4H, ArH), 1.85–1.71 (m, 5H, 2 ¥
CH2, OH), 1.29–1.01 (m, 4H, 2 ¥ CH2), 0.82 (t, J = 7.5 Hz, 3H, CH3),
0.74 (t, J = 7.5 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3, d, ppm):
144.7, 132.0, 128.1 (2 ¥ CH), 127.0 (2 ¥ CH), 77.0, 42.3, 35.4, 25.6,
23.1, 14.0, 7.7; IR (neat): 3497, 2961, 2936, 2874 cm−1; MS (EI): m/z
(%) 226.1 (M+, 5), 197.1 (100), 169.0 (100), 151.0 (25), 111.0 (28),
77.0 (18); HRMS Calc. for C13H19ClO, 226.1124. Found 226.1113.
1-(Furan-2-yl)pentan-l-ol (3i): Brown oil.14 1H NMR (500 MHz,
CDCl3, d, ppm): 7.36 (d, J = 1.5 Hz, 1H, ArH), 6.32 (dd, J1 = 2.0 Hz,
J2 = 3.0 Hz, 1H,ArH), 6.22 (d, J = 3.0 Hz, 1H,ArH), 4.65 (t, J = 7.0 Hz,
1H, CH), 2.10 (br s, 1H, OH), 1.87–1.82 (m, 2H, CH2), 1.42–1.26
(m, 4H, 2 ¥ CH2), 0.90 (t, J = 7.0 Hz, 3H, CH3).
General procedure for the synthesis of 3 in 2-MeTHF.
A mixture of the aryl or alkyl halide (24.0 mmol) in anhydrous
2-MeTHF (15 mL) was added dropwise to magnesium turnings
(25.2 mmol, 0.6 g) {preactivated by 1,2-dibromoethane (0.5 mmol)}
under nitrogen atmosphere at room temperature. The mixture was
cooled in an ice bath to 0°C and then the carbonyl compounds
(20.0 mmol) in anhydrous 2-MeTHF (5 mL) was added dropwise
within 15 minutes and the mixture was stirred at room temperature
for 1 h. The reaction was monitored by TLC and quenched with
saturated NH4Cl. The layers were separated and the aqueous phase
was extracted twice with 2-MeTHF (2 ¥ 5 mL). The combined organic
extracts were dried over anhydrous sodium sulfate, concentrated
under reduced pressure and the crude product was purified by column
chromatography to give 3. The physical and spectroscopic data are
as follows.
1-(4-Fluorophenyl)pentan-l-ol (3j): Yellow oil.15 1H NMR (400 MHz,
CDCl3, d, ppm): 7.31–7.28 (m, 2H, ArH), 7.05–7.00 (m, 2H, ArH),
4.63 (t, J = 6.8 Hz, 1H, CH), 1.97 (br s, 1H, OH), 1.80–1.64 (m, 2H,
CH2), 1.40–1.19 (m, 4H, 2 ¥ CH2), 0.88 (t, J = 7.2 Hz, 3H, CH3).
1-(Thiophen-2-yl)pentan-l-ol (3k): Yellow oil.16 1H NMR (500
MHz, CDCl3, d, ppm): 7.23 (dd, J1 = 2.5 Hz, J2 = 3.5 Hz, 1H, ArH),
6.95–6.94 (m, 2H, ArH), 4.88 (t, J = 7.0 Hz, 1H, CH), 2.24 (br s, 1H,
OH), 1.88–1.79 (m, 2H, CH2), 1.44–1.25 (m, 4H, 2 ¥ CH2), 0.90 (t,
J = 7.0 Hz, 3H, CH3).
1-(3,4-Dimethylenedioxyphenyl)pentan-l-ol (3l): Light yellow oil.17
1H NMR (500 MHz, CDCl3, d, ppm): 6.84 (s, 1H, ArH), 6.75 (d,
J = 1.5 Hz, 2H, ArH), 5.92 (s, 2H, CH2), 4.53 (t, J = 7.0 Hz, 1H, CH),
2.11 (br s, 1H, OH), 1.77–1.72 (m, 1H, CH2–Ha), 1.65–1.61 (m, 1H,
CH2–Hb), 1.36–1.18 (m, 4H, 2 ¥ CH2), 0.87 (t, J = 7.0 Hz, 3H, CH3).
2-Methyloctan-3-ol (3m): Yellow oil.18 1H NMR (500 MHz, CDCl3,
d, ppm): 3.69–3.64 (m, 1H, CH), 1.82–1.73 (m, 1H, CH), 1.73 (br s,
1H, OH), 1.44–1.21 (m, 8H, 4 ¥ CH2), 0.93–0.90 (m, 9H, 3CH3).
1-(4-Methylthiazol-5-yl)pentan-l-ol (3n): Yellow oil. 1H NMR
(500 MHz, CDCl3, d, ppm): 8.55 (s, 1H, ArH), 4.96 (t, J = 7.0 Hz,
1H, CH), 3.55 (br s, 1H, OH), 2.35 (s, 3H, CH3), 1.89–1.86 (m, 1H,
CH2–Ha), 1.73–1.68 (m, 1H, CH2–Hb), 1.40–1.22 (m, 4H, 2 ¥ CH2),
0.89 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3, d, ppm):
150.7, 148.1, 136.9, 67.3, 39.5, 27.8, 22.4, 15.1, 14.0; IR (neat):
3280, 2958, 2931, 2861 cm−1; MS(ESI): m/z 186.1 [M + 1]+, HRMS
Calc. for C9H15NOS, 185.0874. Found 185.0879.
1-Phenylpentan-l-ol (3a): Yellow oil.7 1H NMR (400 MHz, CDCl3,
d, ppm): 7.34 (d, J = 6.0 Hz, 2H, ArH), 7.30 (t, J = 6.0 Hz, 2H, ArH),
7.26–7.23 (m, 1H, ArH), 4.59 (t, J = 6.4 Hz, 1H, CH), 2.23 (br s, 1H,
OH), 1.77–1.64 (m, 2H, CH2), 1.38–1.19 (m, 4H, 2 ¥ CH2), 0.87 (t,
J = 6.8 Hz, 3H, CH3).
1-(4-Chlorophenyl)pentan-l-ol (3b): Light-yellow oil. 8 1H NMR
(400 MHz, CDCl3, d, ppm): 7.32–7.24 (m, 4H, ArH), 4.62 (dd,
J1 = 6.4 Hz, J2 = 12.8 Hz, 1H, CH), 2.00 (br s, 1H, OH), 1.79–1.61 (m,
2H, CH2), 1.39–1.18 (m, 4H, 2 ¥ CH2), 0.88 (t, J = 7.2 Hz, 3H, CH3).
1-(4-Methoxyphenyl)pentan-l-ol (3c): Colourless crystals.9
1
m.p. 41.3–42.1°C. H NMR (500 MHz, CDCl3, d, ppm): 7.26–7.23
(m, 2H, ArH), 6.88–6.85 (m, 2H, ArH), 4.58 (t, J = 7.0 Hz, 1H, CH),
3.79 (s, 3H, OCH3), 1.99 (br s, 1H, OH), 1.82–1.75 (m, 1H, CH2–Ha),
1.70–1.63 (m, 1H, CH2–Hb), 1.38–1.17 (m, 4H, 2 ¥ CH2), 0.87 (t,
J = 7.0 Hz, 3H, CH3).
1-Butylcyclopentan-l-ol (3o): Light-yellow oil.17 1H NMR (400 MHz,
CDCl3, d, ppm): 1.83–1.78 (m, 2H, CH2), 1.66–1.52 (m, 8H, 4 ¥ CH2),
1.45–1.22 (m, 5H, 2 ¥ CH2, OH), 0.92 (t, J = 6.8 Hz, 3H, CH3).
3-(3-Chlorophenyl)heptan-3-ol (3p): Yellow oil. 1H NMR (500
MHz, CDCl3, d, ppm): 7.42 (s, 1H, ArH), 7.23–7.20 (m, 2H, ArH),
7.19–7.16 (m, 1H, ArH), 2.15 (br s, 1H, OH), 1.85–1.72 (m, 4H,
2 ¥ CH2), 1.29–0.99 (m, 4H, 2 ¥ CH2), 0.82 (t, J = 7.0 Hz, 3H, CH3),
0.74 (t, J = 7.0 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3, d, ppm):
148.5, 134.1, 129.2, 126.4, 125.9, 123.7, 77.1, 42.3, 35.4, 25.6, 23.1,
14.0, 7.7; IR (neat): 3475, 2960, 2935, 2872 cm−1; MS (EI): m/z (%)
226.1 (M+, 4), 197.0 (100), 169.0 (97), 151.0 (22), 111.0 (50), 77.0
(58); HRMS Calc. for C13H19ClO, 226.1124. Found 226.1118.
2-Phenylhexan-2-ol(3d):Yellow oil.10 1H NMR (400 MHz, CDCl3,
d, ppm): 7.42 (d, J = 7.6 Hz, 2H, ArH), 7.32 (t, J = 7.6 Hz, 2H,
ArH), 7.22 (t, J = 7.6 Hz, 1H, ArH), 1.92 (br s, 1H, OH), 1.82–1.76
(m, 2H, CH2), 1.54 (s, 3H, CH3), 1.29–1.10 (m, 4H, 2 ¥ CH2), 0.84
(t, J = 7.2 Hz, 3H, CH3).
2-(4-Chlorophenyl)hexan-2-ol (3e): Yellow oil.11 1H NMR
(400 MHz, CDCl3, d, ppm): 7.36 (d, J = 6.4 Hz, 2H, ArH), 7.29
(d, J = 6.4 Hz, 2H, ArH), 2.58 (br s, 1H, OH), 1.82–1.72 (m, 2H,
CH2), 1.53 (s, 3H, CH3), 1.29–1.05 (m, 4H, 2 ¥ CH2), 0.84(t,
J = 7.2 Hz, 3H, CH3).

JOURNAL OF CHEMICAL RESEARCH 2009 373
2-(Furan-2-yl)hexan-2-ol (3q): Yellow oil.19 1H NMR(400 MHz,
CDCl3, d, ppm): 7.34 (d, J = 1.2 Hz, 1H, ArH), 6.30 (dd, J1 = 2.0 Hz,
J2 = 3.2 Hz, 1H, ArH), 6.18 (d, J = 2.0 Hz, 1H, ArH), 1.86–1.79 (m,
2H, CH2), 1.53 (s, 3H, CH3), 1.30–1.20 (m, 4H, 2 ¥ CH2), 0.87 (t,
J = 7.0 Hz, 3H, CH3).
We thank the National Key Technology R&D Program
[No: 2007BAI34B01] and National Natural Science
Foundation of China [20676123] for financial support.
Received 30 March 2009 ; accepted 25 April 2009
Paper 09/0518 doi: 10.3184/030823409X460939
Published online: 22 June 2009
2-(Pyridin-3-yl)hexan-2-ol (3r): Brown oil.20 1H NMR (500 MHz,
CDCl3, d, ppm): 8.52–8.51 (m, 1H, ArH), 7.72–7.69 (m, 1H, ArH),
7.33 (d, J = 9.0 Hz, 1H, ArH), 7.21–7.18 (m, 1H, ArH), 5.21 (br s,
1H, OH), 1.86–1.73 (m, 2H, CH2), 1.51 (s, 3H, CH3), 1.36–1.20 (m,
4H, 2 ¥ CH2), 0.82 (t, J = 7.5 Hz, 3H, CH3).
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CH2), 1.72 (s, 1H, OH), 1.21 (s, 6H, 2 ¥ CH3).
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2-Phenylpent-4-en-2-ol(3v):Light-yellowoil.241HNMR(400MHz,
CDCl3, d, ppm): 7.44 (d, J = 7.6 Hz, 2H, ArH), 7.34 (t, J = 7.6 Hz,
2H, ArH), 7.25–7.22 (m, 1H, ArH), 5.67–5.58 (m, 1H, CH), 5.12
(t, J = 9.6 Hz, 2H, CH2), 2.68 (dd, J1 = 7.6 Hz, J2 = 14.0 Hz, 1H,
CH2–Ha), 2.50 (dd, J1 = 7.6 Hz, J2 = 14.0 Hz, 1H, CH2–Hb), 2.04 (br
s, 1H, OH), 1.54 (s, 3H, CH3).
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Diphenylmethanol (3w): Colourless crystals. M.p. 65.1–66.0°C
1
(lit.,25 65–66°C). H NMR (500 MHz, CDCl3, d, ppm): 7.39–7.37
(m, 4H, ArH), 7.35–7.32 (m, 4H, ArH), 7.28–7.25 (m, 2H, ArH), 5.84
(s, 1H, CH), 2.14 (br s, 1H, OH).
1,1-Diphenylethanol (3x): Colourless crystals. M.p. 79.3–79.8°C
(lit.,26 78–80°C). 1H NMR(500 MHz, CDCl3, d, ppm): 7.48–7.45 (m,
4H, ArH), 7.38–7.35 (m, 4H, ArH), 7.31–7.28 (m, 2H, ArH), 2.31
(br s, 1H, OH), 2.00 (s, 3H, CH3).
(2-Furyl)phenylmethanol (3y): Brown oil.27 1H NMR(400 MHz,
CDCl3, d, ppm): 7.43–7.31 (m, 6H, ArH), 6.30 (dd, J1 = 2.0 Hz,
J2 = 3.2 Hz, 1H, ArH), 6.10 (d, J = 3.2 Hz, 1H, ArH), 5.81 (s, 1H,
CH), 2.55 (br s, 1H, OH).
4-Butyloctane-1,4-diol (6): Light yellow oil.28 1H NMR (400 MHz,
CDCl3, d, ppm): 3.64 (t, J = 5.6 Hz, 2H, CH2), 2.54 (br s, 2H,
2 ¥ OH), 1.64–1.43 (m, 8H, 4 ¥ CH2), 1.34–1.23 (m, 8H, 4 ¥ CH2),
0.93–0.89 (m, 6H, 2 ¥ CH3).
1-Phenylpentan-1-one (8): Light yellow oil.29 1H NMR (400 MHz,
CDCl3, d, ppm): 7.96 (m, 2H, ArH), 7.57–7.53 (m, 1H, ArH), 7.47–
7.43 (m, 2H, ArH), 2.96 (t, J = 7.2 Hz, 2H, CH2), 1.76–1.69 (m, 2H,
CH2), 1.46–1.37 (m, 2H, CH2), 0.95 (t, J = 7.2 Hz, 3H, CH3).
Tramadol hydrochloride (9): Colourless crystals. m.p. 179.5–
1
180.3°C (lit.,30 180–181°C). H NMR (400 MHz, CDCl3, d, ppm):
11.47 (br s, 1H, HCl), 7.32–7.28 (t, J = 8.0 Hz, 1H, ArH), 7.09 (s, 1H,
ArH), 7.00 (d, J = 2.4 Hz, 1H, ArH), 6.80 (dd, J1 = 2.4 Hz, J2 = 8.0 Hz,
1H, ArH), 3.83 (s, 3H, OCH3), 3.04–2.98 (m, 1H, CH), 2.67 (d,
J = 5.2 Hz, 3H, CH3), 2.61–2.55 (m, 2H, CH2), 2.46 (d, J = 5.2 Hz,
3H, CH3), 2.44 (s, 1H, OH), 2.14–1.42(m, 8H, 4 ¥ CH2).