An expeditious method for the preparation of 2-hydroxy-1,4-dioxane and Its Use in reductive alkylation of amines

Article abstract of DOI:10.1055/s-0029-1217101

Selective oxidation of diethylene glycol by a ruthenium(VIII) species, obtained in situ from ruthenium(III) chloride-sodium- periodate in the presence of a catalytic quantity of water, affords a monoaldehyde in the form of the internal acetal 2-hydroxy-1,4-dioxane. This compound was used in reductive alkylations of selected primary and secondary amines, demonstrating its utility in the preparation of target structures with the 2-(2-hydroxyethoxy)ethylamino unit. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217101

PAPER
255
An Expeditious Method for the Preparation of 2-Hydroxy-1,4-dioxane and Its
Use in Reductive Alkylation of Amines
Preparation and
U
s
e
of 2-Hydr
r
oxy-1,4-
i
a
GlaxoSmithKline Research Centre Zagreb Ltd, Prilaz baruna Filipovica 19, 10000 Zagreb, Croatia
Fax +385(1)6051001; E-mail: adrijana.x.vinter@gsk.com
b
c
Pliva Croatia Ltd, TAPI R&D, Prilaz baruna Filipovica 19, 10000 Zagreb, Croatia
Hegedusiceva 16, 10000 Zagreb, Croatia
Received 3 September 2009; revised 8 September 2009
Previously reported preparations of 2-hydroxy-1,4-diox-
ane (2¢) are based on catalytic oxygenation of 1,4-
dioxane3,4 and oxidative decomposition of N-nitrosomor-
pholine-3-carboxylic acid and some other N-nitrosomor-
Abstract: Selective oxidation of diethylene glycol by a rutheni-
um(VIII) species, obtained in situ from ruthenium(III) chloride–
sodium periodate in the presence of a catalytic quantity of water, af-
fords a monoaldehyde in the form of the internal acetal 2-hydroxy-
1,4-dioxane. This compound was used in reductive alkylations of pholine derivatives.5 Both methods, however, require
selected primary and secondary amines, demonstrating its utility in
complex catalytic systems and proceed with low selectiv-
the preparation of target structures with the 2-(2-hydroxy-
ity and yields. Liquid-phase photolysis has been shown to
ethoxy)ethylamino unit.
give a complex mixture of liquid and solid products.6
Key words: diethylene glycol, oxidations, reductive alkylations, 2-
Generally, oxidation of alcohols affords more reactive
hydroxy-1,4-dioxane, ruthenium(VIII) catalysis
carbonyl compounds, and therefore has a central role in
organic synthesis. It can be completed by classical oxida-
tion methods using stoichiometric quantities of inorganic
The 2-(2-hydroxyethoxy)ethylamino unit represents a
and organic oxidants.7–12 Important recent progress was
common structural element shared by many biologically
made by the development of catalytic methods using met-
active compounds of general formula 4 (Scheme 1). Our
al catalysts to mediate the selective oxidation of alcohols
search through databases revealed about 400 structures
in the presence of dioxygen or compounds in higher oxi-
that contain the 2-(2-hydroxyethoxy)ethylamino unit, in-
dation states containing oxygen.13–16
cluding approximately 20 biologically active and 7 com-
However, 1,4- and 1,5-diols are usually oxidized at one
site to the monocarboxylic acids, which undergo cycliza-
tion to form five- and six-membered lactones.17–20 Oxida-
tion of a,w-diols with chains longer than four or five
carbon atoms affords the corresponding polyesters.21
mercially available compounds. This structural unit is
present in acridine derivatives with antiviral activity,1 as
well as in monobenzhydrylpiperazines claimed as antihis-
taminics with strong sedative action.2
In the context of a wider project we became interested in
finding the most convenient route to compounds 4. Most
appealing appeared to be the method consisting of the ox-
idation of commercially available diethylene glycol
(DEG, 1) to monoaldehyde 2, followed by reductive alky-
lation of primary or secondary amines 3 (Scheme 1).
In a search for the most efficient and selective oxidation
system for conversion of 1 into 2/2¢ (Scheme 1), several
reagents were tested. Dess–Martin periodinane and pyri-
dine/sulfur trioxide/dimethyl sulfoxide/triethylamine
showed good oxidation capabilities. However, intensive
degradation of the product was observed during the work-
up procedure. Oxidation of 1 with pyridinium chlorochro-
mate in diisopropyl ether afforded product 2¢ in low
isolated yield (20–25%), the low yield presumably due to
intensive formation of polyesters. Ishi et al.17 reported the
selective oxidation of 1 by the zirconocene complex
Cp2ZrH2 in the presence of benzophenone as hydrogen
Spontaneous internal acetalization of 2 is expected to af-
ford the stable six-membered hemiacetal 2-hydroxy-1,4-
dioxane (2¢) (Scheme 1). This is an advantageous event
from the synthetic point of view, since both terminal func-
tionalities are mutually protected in 2¢.
O
O
reductive
amination
R2
oxidation
O
O
O
HO
OH
HO
O
HO
N
R1
R1R2NH
3
OH
1
2′
2
4
Scheme 1
SYNTHESIS 2010, No. 2, pp 0255–0258
x
x
.
x
x
.2
0
0
9
Advanced online publication: 06.11.2009
DOI: 10.1055/s-0029-1217101; Art ID: Z18609SS
© Georg Thieme Verlag Stuttgart · New York

256
A. Vinter et al.
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Table 1 Reductive Alkylation of Amines by Hemiacetal 2¢a
acceptor at 170 °C for ten hours. According to 13C NMR
data, the structure of the product isolated by distillation
corresponded to the open-chain aldehyde 2. When we re-
peated this experiment, aldehyde 2 was not observed, and,
apart from intensive polymerization, only traces of dialde-
hyde were detected by GC-MS at the end of the reaction.
OH
R1
N
O
O
OH
R1
R2
a
N
+
O
R2
H
2′
3a–f
4a–f
Amine 3
Product
Yield (%)
30
Our attention was attracted by a short paper by Sharpless
et al. reporting on the highest-valent ruthenium(VIII) ox-
ide as a powerful oxidant for the transformation of a vari-
ety of organic compounds.22 This reagent was generated
in the biphasic system carbon tetrachloride/water upon
treatment of ruthenium(III) chloride or ruthenium(IV) ox-
ide with oxidants such as sodium periodate (NaIO4), peri-
odic acid (HIO4), sodium hypochlorite (NaOCl), or
sodium bromate (NaBrO3), and a large promoting effect
of acetonitrile was also observed. Alkenes, alcohols, and
ethers are oxidized to carboxylic acids or their esters. The
authors concluded that the oxidation to aldehydes (as
obligatory intermediates) is fast, while the slower step is
their oxidation to the acids. According to the authors, the
small rate difference did not allow them to stop clearly at
the aldehyde stage.
3a
3b
4a
4b
NH2
NH
35
77
NH2
3c
4c
F
NH2
3d
4d
80
Cl
O
H2N
Cl
COOEt
3e
3f
4e
80
40
We concluded that the formation of the six-membered
hemiacetal 2¢, protected against further oxidation, would
favor the formation of the aldehyde. Soon we observed
that a biphasic system cannot be used for the oxidation of
diethylene glycol to 2/2¢ due to their high solubility in the
aqueous phase. Optimization of the Sharpless conditions
surprisingly revealed that this reaction can be carried out
with ruthenium(III) chloride hydrate–sodium periodate in
dichloromethane in the absence of acetonitrile, after the
addition of a small amount of water (0.6 mol/mol DEG),
sufficient to form ruthenium(VIII) oxide. 1H NMR moni-
toring of diethylene glycol oxidation in dichloromethane-
d2 after two hours of reaction time revealed that three
compounds were present in the mixture: approximately
16% of unchanged diethylene glycol 1, approximately
67% of 2¢, and approximately 17% of the corresponding
lactone. The open form of aldehyde 2 was not detected.
Repeated analysis after four and six hours of reaction time
proved that the ratio of the products and unchanged dieth-
ylene glycol remained unchanged. Reaction conditions
were optimized by using a catalytic amount of rutheni-
um(III) chloride hydrate (0.003 mol/mol DEG) and an
equimolar quantity of sodium periodate at 40 °C in
dichloromethane. Under vigorous stirring, high conver-
sion and excellent selectivity toward hemiacetal 2¢ with a
low content of lactone was achieved. After filtration of in-
soluble material, hemiacetal 2¢ in the filtrate can be used
directly in reductive alkylation.
N
4f, 4g
Me N
NH
a Reagents and conditions: AcOH, NaBH3CN, CH2Cl2, r.t., 6 h.
b Isolated yield.
next reaction step (ester hydrolysis), which will not be
elaborated here.
An interesting observation was made during the reductive
alkylation of N-methylpiperazine (3f) (Table 1). Two
products, separable by chromatography on silica gel, were
formed; their NMR spectra differed significantly, but their
MS spectra contained identical molecular ions. Elementa-
ry analysis revealed ca. 10% of inorganic residue in
byproduct 4f, and ca. 4% of boron was determined by in-
ductively coupled plasma–optical emission spectrometry
(ICP-OES) using an auxiliary gas module, whereas in
product 4g only traces of inorganic material were present.
On the basis of the above data we concluded that a rela-
tively stable boronate 4f formed, which presumably
served as a ‘scorpion-type’ tetradentate ligand in the com-
plex. With only the above data as evidence, we hesitate to
propose a detailed structure of this boronate complex.
In conclusion, selective oxidation of diethylene glycol by
ruthenium(VIII) species, obtained in situ from rutheni-
um(III) chloride–sodium periodate in the presence of a
catalytic quantity of water, affords 2-hydroxy-1,4-diox-
ane (2¢), a monoaldehyde in the form of an internal acetal.
This compound proved effective in reductive alkylation of
selected primary and secondary amines, demonstrating its
utility in the preparation of target structures with the 2-(2-
hydroxyethoxy)ethylamino unit.
Reductive alkylation was tested on a selected set of
amines (Table 1). This reaction proved to be the most ef-
fective with arylamines, less effective with secondary
alkylamines, and the least effective with primary amines.
The yields in Table 1 are not optimized, except for that of
4e, a key intermediate required in another project, and
whose isolation and purification were optimized in the
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PAPER
Preparation and Use of 2-Hydroxy-1,4-dioxane
257
1H NMR (500 MHz, DMSO-d6): d = 1.18 (m, 2 H), 1.24 (d, J = 6.41
Hz, 2 H), 1.75 (m, 2 H), 2.50 (dt, J = 3.66, 1.83 Hz, 3 H), 3.42 (d,
J = 5.49 Hz, 2 H), 3.48 (m, 2 H), 3.52 (m, 1 H), 3.72 (d, J = 4.27 Hz,
2 H), 4.14 (m, 2 H), 4.28 (m, 2 H), 6.5 (d, 1 H).
13C NMR (126 MHz, DMSO-d6): d = 19.28, 22.01, 22.05, 30.40,
43.94, 52.18, 60.40, 60.62, 64.85, 72.59.
DEG, RuCl3·xH2O, NaIO4, Cp2ZrH2, and amines 3a–d and 3f were
purchased from Aldrich; 6-aminoquinolone-3-carboxylic acid ethyl
ester 3e was prepared as reported.23 GC-MS spectra were recorded
on a Varian Saturn 2000 spectrometer [CP-sil 5 CB low-bleed/MS
30 m × 0.25 mm column, constant column flow (2.5 mL/min) of N2
as carrier gas, split ratio 1:25; temperature gradient applied from
60 °C, 25 °C/min, hold 0.90 min, total 10.0 min; CI auto mode: CI
storage level 19.0 m/z, ejection amplitude 15.0 m/z, background
mass 67 m/z, maximum ionization time 2000 ms, maximum reaction
time 40 ms, target TIC 5000 counts]. Sample preparation: about 40
mL of reaction mixture was dissolved in CH2Cl2 (2 mL); of this, 1
mL was injected into the instrument. Oxidation of DEG in CD2Cl2
was monitored by NMR spectroscopy. Samples were taken at 2 h in-
tervals. NMR spectra (1H, APT, COSY, edited HSQC and HMBC)
were recorded on a Bruker Avance III 600 NMR spectrometer using
standard Bruker pulse sequences.
MS (ES+): m/z (%) = 188.2 (99) [M + H+].
2-{2-[(3-Fluorophenyl)amino]ethoxy}ethanol (4c)
Compound 2 (3.5 g, 33.6 mmol) and 3-fluoroaniline (3c; 1.02 mL,
10.6 mmol) gave product 4c; yield: 1.60 g (77%).
1H NMR (500 MHz, DMSO-d6): d = 2.50 (s, 1 H), 3.36 (m, 1 H),
3.44 (d, J = 0.61 Hz, 2 H), 3.45 (m, 2 H), 3.52 (s, 2 H), 4.52 (d,
J = 3.05 Hz, 1 H), 4.60 (s, 1 H), 5.89 (t, J = 5.34 Hz, 1 H), 6.26 (m,
2 H), 6.26 (m, 2 H), 6.27 (d, J = 2.44 Hz, 2 H), 7.06 (m, 2 H).
13C NMR (126 MHz, DMSO-d6): d = 42.99, 60.59, 69.16, 69.21,
69.80, 72.97, 99.28, 102.56, 108.66, 130.58.
2-Hydroxy-1,4-dioxane (2¢)
A 0.5-L three-neck flask equipped with a mechanical stirrer was
charged with CH2Cl2 (300 mL), DEG (1; 21.5 mL, 0.23 mol), NaIO4
(48.36 g, 0.23 mol), and RuCl3 (0.16 g, 0.34 mol% of DEG). The
reaction mixture was vigorously stirred at 40 °C for 20 min. Subse-
quently H2O (2.56 mL, 0.14 mol) was added over 5 min and the stir-
ring was continued at 40 °C for an additional 6 h. The progress of
the reaction was monitored by GC-MS. After the reaction was com-
plete, the suspension was cooled to r.t. and filtered through diatoma-
ceous earth. The cake was washed with CH2Cl2 and the filtrate was
used in the next step without further purification.
1H NMR (600 MHz, CD2Cl2): d = 4.85 (dd, J = 5.2, 2.3 Hz, 1 H),
4.00 (m, 1 H), 3.73 (dd, J = 11.3, 2.0 Hz, 1 H), 3.66 (m, 1 H), 3.62
(m, 1 H), 3.61 (m, 1 H), 3.38 (dd, J = 11.5, 5.2 Hz, 1 H).
13C NMR (150 MHz, CD2Cl2): d = 90.22, 69.46, 65.44, 61.88.
MS (ES+): m/z (%) = 104.8 (90) [M + H+].
MS (ES+): m/z (%) = 200.1 (88) [M + H+].
HRMS–FAB: m/z [M + H+] calcd for C10H15NO2F: 200.1087;
found: 200.1078.
2-{2-[(2-Chlorophenyl)amino]ethoxy}ethanol (4d)
Compound 2 (3.5 g, 33.6 mmol) and 2-chloroaniline (3d; 1.10 mL,
10.56 mmol) gave product 4d; yield: 1.83 g (80%).
1H NMR (500 MHz, DMSO-d6): d = 2.50 (t, J = 1.83 Hz, 1 H), 3.28
(m, 1 H), 3.29 (m, 2 H), 3.31 (m, 2 H), 3.35 (m, 2 H), 3.47 (m, 2 H),
3.51 (m, 2 H), 3.60 (t, 2 H), 3.61 (d, 2 H), 3.62 (m, 2 H), 4.61 (d, 1
H), 7.24 (d, J = 1.53 Hz, 1 H).
13C NMR (126 MHz, DMSO-d6): d = 42.84, 60.61, 68.93, 72.52,
111.71, 117.03, 118.25, 128.44, 129.31, 144.38.
MS (ES+): m/z (%) = 216.1 (93) [M + H+].
HRMS–FAB: m/z [M + H+] calcd for C10H15NO2Cl: 216.0791;
found: 216.0784.
Compounds 4a–d; General Procedure
To a soln of 2 in CH2Cl2 (40 mL, ca. 33.6 mmol) one of amines 3a–
d (0.84 equiv, 10.6 mmol) and AcOH (4.5 equiv, 52.8 mmol) were
added and the mixture was stirred overnight at r.t. The reaction mix-
ture was cooled in an ice bath, NaBH3CN (2.5 equiv, 31.4 mmol)
was added portionwise, and the mixture was stirred at r.t. for 4 h. Fi-
nally, the reaction mixture was washed with 5% aq NaCl (30 mL)
and 10% aq NaHCO3 (30 mL), the aqueous layers were extracted
with CH2Cl2 (2 × 20 mL each), and the combined organic layer was
evaporated; this yielded oily products 4a–d. The products were pu-
rified by column chromatography (silica gel, CH2Cl2–MeOH–
NH4OH, 90:9:0.5).
Ethyl 7-Chloro-1-cyclopropyl-6-[2-(2-hydroxyethoxy)ethylami-
no]-4-oxo-1,4-dihydroquinoline-3-carboxylate (4e)
Ester 3e (30.5 g, 0.84 equiv) was added at r.t. to a CH2Cl2 soln of 2
(550 mL, 0.120 mol), and then AcOH (28.5 mL, 4.2 equiv) was add-
ed dropwise. The resulting suspension was stirred at r.t. until all re-
agents had dissolved. The soln was cooled in an ice bath. NaBH3CN
(15.6 g, 2.5 equiv) was added in three portions, every 30 min, and
the mixture was stirred at 25 °C for an additional 4 h. Finally, the
reaction mixture was washed with 5% aq NaCl soln (300 mL) and
10% aq NaHCO3 soln (300 mL). The aqueous layers were extracted
with CH2Cl2 (50 mL each) and the combined organic extract was
evaporated; this gave 4e as an orange oily residue; yield: 31.3 g
(80%).
1H NMR (500 MHz, DMSO-d6): d = 1.08 (2 H), 1.23 (2 H), 1.27 (3
H), 3.39 (2 H), 3.49 (2 H), 3.52 (2 H), 3.63 (1 H), 3.66 (2 H), 4.20
(2 H), 4.62 (OH), 5.64 (NH), 7.38 (1 H), 8.02 (1 H), 8.34 (1 H).
13C NMR (126 MHz, DMSO-d6): d = 7.3, 14.2, 34.5, 42.7, 59.5,
60.2, 68.1, 72.2, 104.6, 108.3, 118.1, 124.4, 128.0, 131.5, 141.8,
146.4, 164.6, 171.9.
2-[2-(Benzylamino)ethoxy]ethanol (4a)
Compound 2 (3.5 g, 33.6 mmol) and benzylamine (3a; 1.15 mL,
10.6 mmol) gave product 4a; yield: 0.58 g (30%).
1H NMR (500 MHz, DMSO-d6): d = 1.99 (s, 1 H), 2.49 (m, 2 H),
2.75 (m, 2 H), 3.36 (d, J = 1.83 Hz, 2 H), 3.37 (d, J = 1.53 Hz, 2 H),
3.46 (m, 2 H), 4.30 (d, J = 6.10 Hz, 1 H), 7.24 (m, 2 H), 7.30 (m, 2
H), 7.38 (d, 2 H), 7.39 (m, 2 H), 7.48 (dd, J = 7.63, 1.53 Hz, 2 H).
13C NMR (126 MHz, DMSO-d6): d = 42.46, 50.68, 53.82, 57.00,
60.58, 65.75, 72.57, 128.81, 128.91, 129.09, 139.97.
MS (ES+): m/z (%) = 196.1 (80) [M + H+].
MS (ES+): m/z (%) = 395.0 (85) [M + H+]
HRMS–FAB: m/z [M + H+] calcd for C11H18NO2: 196.1338; found:
196.1321.
2-[2-(4-Methylpiperazin-1-yl)ethoxy]ethanol (4f)
1-Methylpiperazine (3f; 1.8 g, 2.08 mL, 18.7 mmol) and AcOH (5
mL, 87 mmol) were added to a soln of 2 (2.17 g, 20.9 mmol) in
CH2Cl2 (50 mL), and the reaction mixture was stirred overnight at
25 °C. The soln was cooled in an ice bath and NaBH3CN (3.17 g,
50.5 mmol) was added in portions over 20 min. The stirring was
continued at r.t. for 4 h. According to TLC (CH2Cl2–MeOH–
2-[2-(2-Methyl-1-piperidyl)ethoxy]ethanol (4b)
Compound 2 (3.5 g, 33.6 mmol) and 2-methylpiperidine (3b; 1.25
mL, 10.56 mmol) gave product 4b; yield: 0.71 g (35%).
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A. Vinter et al.
PAPER
NH3, 90:9:1.5), two major products had formed, with Rf = 0.4 and
0.7. The soln was extracted with brine (150 mL) and sat. aq
NaHCO3 (150 mL). Each aqueous layer was extracted with CH2Cl2
(50 mL). The sat. aq NaHCO3 layer was discarded. The brine layer
was extracted again with CH2Cl2 (2 × 50 mL) after correction of the
pH to 9 using 20% aq NaOH. The combined organic layers were
concentrated under reduced pressure; this gave a yellow oil (1.8 g)
containing mostly the faster-running product 4f (Rf = 0.7).
References
(1) Greenhalgh, N.; Hull, R.; Hurst, E.; Weston, N. Br. J.
Pharmacol. Chemother. 1956, 11, 220.
(2) Morren, H. GB Patent 817231, 1959.
(3) Grabowskiy, S. A.; Timerghazin, Q. K.; Kabal’nova, N. N.
Russ. Chem. Bull. 2005, 54, 2384.
(4) Wermeckes, B.; Beck, F. Chem. Ber. 1987, 120, 1679.
(5) Kim, H.-J.; Fischbein, J. C. Chem. Res. Toxicol. 2003, 16,
715.
(6) Houser, J. J.; Sibbio, B. A. J. Org. Chem. 1977, 42, 2145.
(7) Ley, S. V.; Norman, W.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
The brine layer at pH 9 was further extracted with CHCl3 (2 × 70
mL). The combined organic layers were concentrated under re-
duced pressure yielding a yellow oil (1.42 g) containing mostly
slower-running product 4g (Rf = 0.4).
(8) Sheldon, R. A.; Kochi, J. Metal-Catalyzed Oxidations of
Organic Compounds; Academic Press: New York, 1981.
(9) Cainelli, G.; Cardillo, G. Chromium Oxidation in Organic
Synthesis; Springer: Berlin, 1984.
(10) Besson, M.; Gallezot, P. Catal. Today 2000, 57, 127.
(11) DeNoy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis
1996, 1153.
(12) Arends, I. W. C. E.; Sheldon, R. A. Modern Oxidation of
Alcohols Using Environmentally Benign Oxidants, In
Modern Oxidation Methods; Bäckvall, J.-E., Ed.; Wiley-
VCH: Weinheim, 2004, 83–118.
The yellow oil containing the faster-running product 4f was purified
by column chromatography (silica gel, CH2Cl2–MeOH–
NH3, 90:5:0.5). Fractions containing pure product were collected
and concentrated under reduced pressure; this gave product 4f as a
white solid; yield: 883 mg (24%).
The yellow oil containing the slower-running product 4g was puri-
fied by column chromatography (silica gel, CH2Cl2–MeOH–
NH3, 90:5:0.5). Fractions containing pure product were collected
and concentrated under reduced pressure; this gave product 4g as a
transparent oil; yield: 880 mg (24%).
(13) Murahashi, S.-I.; Komiya, N. Oxidation Reactions, In
Ruthenium in Organic Synthesis; Murahashi, S.-I., Ed.;
Wiley-VCH: Weinheim, 2004, 53–93.
(14) Murahashi, S.-I.; Komiya, N. In Modern Oxidation
Methods; Bäckvall, J.-E., Ed.; Wiley-VCH: Weinheim,
2004, 165–222.
(15) Ji, H.-B.; Yuan, Q.-L.; Zhou, X.-T.; Pei, L.-X.; Wang, L.-F.
Bioorg. Med. Chem. Lett. 2007, 17, 6364.
(16) Mizuno, N.; Yamaguchi, K. Catal. Today 2008, 132, 18.
(17) Nakano, T.; Terada, T.; Ishi, Y.; Ogawa, M. Synthesis 1986,
774.
(18) Murahashi, S.-I.; Ito, K.; Noata, T.; Maeda, Y. Tetrahedron
Lett. 1981, 22, 5327.
(19) Murahashi, S.-I.; Noata, T.; Ito, K.; Maeda, Y.; Taki, H.
J. Org. Chem. 1985, 52, 4319.
(20) Saburi, M.; Ishii, Y.; Kaji, N.; Aoi, T.; Sasaki, I.;
Yoshikawa, S.; Uchida, Y. Tetrahedron Lett. 1989, 30, 563.
(21) Shvo, Y.; Blum, Y.; Reshef, D.; Menzin, M. J. Organomet.
Chem. 1982, 226, C21.
Product 4f
1H NMR (500 MHz, DMSO-d6): d = 4.58 (s, 1 H), 3.51 (t, J = 5.8
Hz), 3.49 (m, 2 H), 3.4 (t, J = 5.49 Hz, 2 H), 2.98 (ddd, J = 12.51,
9.16, 3.36 Hz, 2 H), 2.89 (dt, J = 12.82, 3.36 Hz, 2 H), 2.70 (dt,
J = 12.97, 4.04 Hz, 2 H), 2.63 (s, 3 H), 2.61–2.55 (m, 4 H).
13C NMR (126 MHz, DMSO-d6): d = 72.6, 68.6, 60.6, 57.7, 56.8,
46.9.
MS (ES+): m/z (%) = 189.23, 228.29 (94.2) [M + H+].
Product 4g
1H NMR (500 MHz, DMSO-d6): d = 4.63 (s, 1 H), 3.49–3.46 (m, 4
H), 3.39 (t, J = 4.88 Hz, 2 H), 2.44 (t, J = 6.1 Hz, 2 H), 2.38 (br s, 4
H), 2.28 (br s, 4 H), 2.13 (s, 3 H).
13C NMR (126 MHz, DMSO-d6): d = 72.6, 68.6, 60.6, 57.7, 55.1,
53.4, 46.1.
MS (ES+): m/z (%) = 189.2 (96) [M + H+].
(22) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
Acknowledgment
J. Org. Chem. 1981, 46, 3936.
(23) Cecchetti, V.; Tabarrini, O.; Sabatini, S.; Miao, H.;
Filipponi, E.; Fravolin, E. Bioorg. Med. Chem. 1999, 7,
2465.
The authors are indebted to Z. Osman for the development of the
GC-MS method, D. Gembarovski for HRMS spectra, as well as E.
Zendrini and A. Spezzaferri for ICP-OES metal determination.
Synthesis 2010, No. 2, 255–258 © Thieme Stuttgart · New York