4-Methylenedioxolan-2-ones as convenient synthons for the preparation of natural products of the berbine and calycotomine series

Article abstract of DOI:10.1007/s11172-006-0293-0

Intramolecular amidoalkylation of nonactivated 3-(2-arylethyl)-4- hydroxyoxazolidin-2-ones in polyphosphoric acid gave oxazolo[4,3-a]isoquinolin- 3-one whose hydrolysis affords isoquinoline β-amino alcohols, calycotomine analogs. Using the developed proce

Full text of DOI:10.1007/s11172-006-0293-0

Russian Chemical Bulletin, International Edition, Vol. 55, No. 3, pp. 569—575, March, 2006
569
4ꢀMethylenedioxolanꢀ2ꢀones as convenient synthons for the preparation
of natural products of the berbine and calycotomine series

I. Yu. Titov, N. B. Chernysheva, Yu. B. Chudinov, A. A. Bogolyubov, and V. V. Semenov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 137 2960. Eꢀmail: vs@zelinsky.ru
Intramolecular amidoalkylation of nonactivated 3ꢀ(2ꢀarylethyl)ꢀ4ꢀhydroxyoxazolidinꢀ2ꢀ
ones in polyphosphoric acid gave oxazolo[4,3ꢀa]isoquinolinꢀ3ꢀone whose hydrolysis affords
isoquinoline βꢀamino alcohols, calycotomine analogs. Using the developed procedure,
13,13,13aꢀtrimethylberbine was synthesized.
Key words: βꢀamino alcohols, 4ꢀhydroxyoxazolidinꢀ2ꢀones, 1,5,6,10bꢀtetrahydrooxazoꢀ
lo[4,3ꢀa]isoquinolinꢀ3ꢀones, intramolecular amidoalkylation, calycotomine, 13,13,13aꢀtriꢀ
methylberbine, alkaloids, polyphosphoric acid, carbamates.
Berbines are of considerable interest for their versatile
biological activities.1 4ꢀHydroxyoxazolidinꢀ2ꢀones may
be convenient starting reagents for the preparation of comꢀ
pounds of this class, as on treatment with acidic reagents
they are converted into acyliminium species, which are
key intermediates in the intramolecular amidoalkylation.
4ꢀHydroxyoxazolidinꢀ2ꢀones are readily formed upon the
reaction of 4ꢀmethylenedioxolanꢀ2ꢀones with various
amines2,3 (Scheme 1). The 4ꢀhydroxyoxazolidinꢀ2ꢀones
that have a βꢀarylethyl substituent in position 3, in which
the benzene ring is activated by, for example, two methoxy
groups in positions 3 and 4, readily undergo intramolecuꢀ
lar amidoalkylation in acidic media, particularly, in anꢀ
hydrous formic or trifluoroacetic acids. The reaction is
carried out at room temperature, the acid (HCO2H or
CF3CO2H) serving as both the cyclizing reagent and the
solvent.
However, if the 3ꢀsubstituent in the oxazolidinone
molecule contains a nonactivated benzene ring, for exꢀ
ample, compound 3a (see Scheme 1), this oxazolidinone
does not undergo intramolecular amidoalkylation under
these conditions, being recovered unchanged (in some
cases, however, it is partially or completely dehydrated).
A temperature rise resulted in virtually complete resiꢀ
nification of the reaction mixture. This set the task of
selecting a new cyclizing reagent. We found that polyꢀ
phosphoric acid (PPA) may be an efficient and simultaꢀ
neously mild cyclizing reagent; in addition, PPA is a meꢀ
dium in which the reaction temperature can be varied
over a broad range without resinification of the reacꢀ
tion mixture. By performing the reactions in PPA at
80—100 °C, we prepared a number of oxazolo[4,3ꢀa]isoꢀ
quinolinꢀ3ꢀones 4 in high yields (see Scheme 1).
We synthesized a series of oxazolidinones 3a—k, 5a,b
(Schemes 1 and 2). The 1H NMR spectra exhibit a singlet
for the hydroxy group at 5.60—6.20 ppm, and the mass
spectra show molecular ion signals. However, in the case
of 2ꢀphenylethylamines 1a,b and 4ꢀmethylenedioxolanꢀ
2ꢀones 2a—d, mixtures of oxazolidinones 3a—d, f—h and
the products of their dehydration, 4ꢀmethyleneoxazolidinꢀ
2ꢀones, were formed. This is indicated by TLC and
1H NMR data; the latter contain signals for both the
hydroxy groups and the methylene protons as two characꢀ
teristic doublets at 4.05—4.22 ppm (J ≈ 2 Hz). In view of
the integral intensity ratio between the OH group and one
proton of the CH2 group, about 25% of the 4ꢀhydroxyꢀ
oxazolidinꢀ2ꢀones 3a—d,f—h formed initially are deꢀ
hydrated. The proton signals of the —CH2—CH2— fragꢀ
ment of the βꢀarylethyl substituent are manifested as two
multiplets at 2.50–3.50 ppm, each corresponding to 2H
in integral intensity.
Heating of oxazolidinones 3a—i in PPA gives oxazoloꢀ
isoquinolines 4a—i in high yields. Compounds 3a—d, f—h
and the products of their dehydration are protonated to
give the same acyliminium species A and, therefore, they
can be used in the reaction without separation. Oxazolꢀ
idinones 3f—h are amidoalkylated much more readily in
PPA (even at 50 °C), giving rise to oxazoloisoquinolines
we prepared previously.3
In the 1H NMR spectra of compounds 4a—i, the proꢀ
tons of the —CH2—CH2— fragment are usually responꢀ
sible for four multiplets with a total integral intensity equal
to four protons and a singlet for the methyl group located
in position 10b of the oxazoloisoquinoline system. The
benzene ring protons give rise to a fourꢀ rather than fiveꢀ
proton multiplet, as contained in the starting oxazolꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 548—554, March, 2006.
1066ꢀ5285/06/5503ꢀ0569 © 2006 Springer Science+Business Media, Inc.

570
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
Titov et al.
Scheme 1
Scheme 2
R = H (a), Me (b)
nounced electronꢀdeficiency of the protonated pyriꢀ
dine ring.
It may be expected that amidoalkylation of the 5ꢀbenꢀ
zyl group of oxazolidinones 5a,b into the benzene ring
will result in a closure of a fiveꢀmembered ring (see
Scheme 2); however, on heating in PPA at 100 °C, 5a,b
are recovered unchanged (NMR).
These data lead to the conclusion that cyclization of
oxazolidinones 3e,i results in the closure of a sixꢀmemꢀ
bered ring to give the corresponding oxazoloisoquinoꢀ
lines 4e,i. As in most cases described in the literaꢀ
ture, 6ꢀexoꢀtrigꢀ rather than energetically less favorꢀ
able 5ꢀexoꢀtrigꢀcyclization takes place under these conꢀ
ditions.4
Subsequently, we studied hydrolysis of the tricyclic
compounds 4. Hydrolysis of the oxazolidinone moiety of
oxazoloisoquinoline could provide a route to βꢀamino
alcohols, which may serve as key intermediates in the
synthesis of various analogs of natural products, in parꢀ
ticular, berbines.
Numerous methods of hydrolysis of cyclic carbamates
are documented; however, the compounds we deal with
proved to be stable against both acid5 and alkaline hydroꢀ
lysis.6 First, hydrolysis of compounds 4a—c,f,g was carꢀ
ried out by heating with a 10ꢀfold molar excess of KOH in
a methanol—water mixture (1 : 1) at 120 °C in an autoꢀ
clave (Scheme 3). Amino alcohols 6 were isolated as
oxalates. The results are summarized in Table 1.
Comꢀ
pound
R1
Comꢀ
pound
R2
R3
1a
1b
1c
H
OMe
H
2a
2b
2c
2d
2e
Me
Me
Me
Et
—(CH2)5—
(CH2C(Me)2)2NH
Me
CH2Ph
Comꢀ
pound
R1
R2
R3
R2—R3
3a,j, 4a
3b, 4b
3c,k, 4c
3d, 4d
3e, 4e
3f, 4f
3g, 4g
3h, 4h
3i, 4i
H
H
H
H
Me
Me
Me
Et
—(CH2)5—
(CH2C(Me)2)2NH
H
Me
Me
Me
CH2Ph
OMe
OMe
OMe
OMe
Me
Et
Scheme 3
—(CH2)5—
Me
CH2Ph
X = CH (1a,b, 3a—i), N (1c, 3j,k)
idinones. This provides evidence for the fact that the
acyliminium species attacks an orthoꢀposition of the benꢀ
zene ring. In compound 4a, the signals for four aromatic
protons are resolved into four separate signals. The mass
spectra of the compounds contain molecular ion peaks, a
typical destruction pathway being elimination of the meꢀ
thyl group yielding the [M – 15]+ ions. The IR spectra of
compounds 3 and 4 exhibit an absorption band for the
carbamate C=O group.
Comꢀ
pound
R1
R2
R3
R2—R3
6a
6b
6c
6d
6e
H
H
H
OMe
OMe
Me
Me
Me
Et
—(CH2)5—
Me
Me
Oxazolidinones 3j,k do not undergo intramolecular
amidoalkylation, which is apparently due to the proꢀ
Me
Et

4ꢀMethylenedioxolanꢀ2ꢀones as synthons
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
571
Table 1. Hydrolysis of some cyclic oxazoloisoquinolines 4a—c,f,g
ral products. As an example, one can cite the synthesis of
13,13,13aꢀtrimethylberbine (7), which we carried out
starting from amino alcohol 6a (Scheme 4).
Proꢀ
duct
MeOH—H2O (120 °С)
DMSO—H2O (80 °С)
Yield
τ/h
Converꢀ
Yield
(%)
τ/h
(%)
sion (%)
Scheme 4
6a
6b
6c
6d
6e
92
74
60
87
Traces
64
105
165
80
~100
~100
~61
~100
<1
97
94
93
95
79
52
80
100
65
180
155
It can be seen that the greater the size of the 1ꢀsubꢀ
stituent in structure 4 (see Scheme 1), the longer the
reaction; the OMe groups located in positions 8 and 9
also significantly decrease the rate of hydrolysis. Indeed,
on attempted hydrolysis of compound 4g, the starting
oxazoloisoquinoline was recovered almost quantitatively,
while the final amino alcohol could be detected only by
chromatography. Obviously, this method is inapplicable
for preparative synthesis of substituted polyfuctionalized
amino alcohols. As an alternative, we used hydrolysis with
KOH in aqueous DMSO.7 In this case, the reaction temꢀ
perature was reduced to 80 °C, the reaction duration deꢀ
creased, and the yields of βꢀamino alcohols were higher
than in the previous method; in addition, this allowed the
preparation of compound 6d,
i. PPA, 100 °C, 26 h.
Benzylation of amino alcohol 6a with benzyl chloride
was carried out with phase transfer catalysis in toluene
in the presence of triethylbenzylammonium chloride
(TEBAC) and potassium iodide. Apparently, due to steric
hindrance, the reaction time is rather long (20 h). The
alkylation involves exactly the nitrogen atom, as the
1H NMR spectrum of the reaction product exhibits the
signal for the hydroxy group with δ 4.17 and integral inꢀ
tensity of 1H. The spectrum also contains signals for
three methyl groups with δ 1.04, 1.15, and 1.57, signals
for the —CH2—CH2— protons of the isoquinoline fragꢀ
ment, two doublets for the benzyl protons (J = 17.8 Hz,
δ 3.39 and 4.57), and signals for aromatic protons at
7.00—7.55 ppm with an overall integral intensity correꢀ
sponding to nine protons. 13,13,13aꢀTrimethylberbine (7)
was prepared through the intramolecular Friedel—Crafts
reaction by heating benzylated alcohol 8 at 110 °C in a
tenfold weight excess of PPA for 18 h. This was accompaꢀ
nied by the formation of a berbine skeleton upon C ring
closure.
which could not be obtained by
the previous method. The resultꢀ
ing compounds are analogs of
the alkaloid calycotomine.
Since amino alcohols 6 were
isolated as oxalates, the signals
Calycotomine
of the hydroxy and amino groups in their 1H NMR specꢀ
tra are manifested as broadened singlets with the chemiꢀ
cal shift 5.28—5.45 ppm. The IR spectra recorded for
amino alcohols exhibit no absorption band for the carboꢀ
nyl group of the starting compounds; the mass spectra
exhibit the molecular ions. The structures of the resulting
calycotomine analogs were additionally confirmed by
NOESY using compound 6d, whose spectrum contained
all the needed correlation signals.
1
The H NMR spectrum of compound 7 contains a
eightꢀproton multiplet in the field of aromatic protons.
No signals are present for the hydroxy group of the initial
compound or for the methylene protons of the hypoꢀ
thethical dehydration product of compound 8, and the
chemical shift (3.82 and 4.06 ppm) and coupling constant
(J = 12.4 Hz) of the benzyl protons have changed (with
respect to the starting compound 8).
The use of 4ꢀmethylenedioxolanꢀ2ꢀones as synthons
allows rather easy introduction of C5ꢀisoprenoid fragꢀ
ments, which is often difficult to attain by other methods.
Experimental
1
H NMR spectra were recorded on a Bruker DRX500 inꢀ
strument operating at 500.13 MHz. DMSOꢀd6 was used as the
solvent. Mass spectra were run on a Kratos MSꢀ30 instrument
(direct sample injection into the ion source, energy 70 eV, ionizꢀ
As noted above, amino alcohols 6 may be intermediꢀ
ates in the synthesis of a series of analogs of various natuꢀ

572
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
Titov et al.
ing chamber temperature 250 °C). IR spectra were measured on
a Perkin—Elmer 577 instrument (KBr pellets). The reactions
were monitored by TLC on Silufol UV254 plates in benꢀ
zene—ethyl acetate, 1 : 1 (A), 2 : 1 (B), and 9 : 1 (C) and propanꢀ
2ꢀol—ethyl acetate—25% aq. NH3, 7 : 9 : 4 (D) solvent systems.
The characteristics and yields of the reaction products are
summarized in Table 2, elemental analysis data are in Table 3,
and the 1H NMR spectra are in Tables 4—6.
methylꢀ1,5,6,10bꢀtetrahydrospiroo[1,3ꢀoxazolo[4,3ꢀa]isoquinoꢀ
lineꢀ1,4´ꢀpiperidine]ꢀ3ꢀone (4d).
Synethesis of compounds 3j,k (general procedure). A solution
of the specified dioxolanone 2 in acetonitrile (10 mL) was added
to a solution of 2ꢀ(2ꢀaminoethyl)pyridine (1b) (0.02 mol) in
acetonitrile (10 mL), and the reaction mixture was stirred
for 20 h. Then the solvent was evaporated, and the product
crystallized.
Synthesis of compounds 4a—d (general procedure). A soluꢀ
tion of the specified dioxolanone 2 (0.025 mol) in CH2Cl2
(15 mL) was added to a solution of 1a (3.025 g, 0.025 mol) in
CH2Cl2 (20 mL). The reaction mixture was stirred for 24 h, the
solvent was removed in vacuo, and a tenfold (by weight) amount
of cold PPA was added to the residue. The mixture was stirred,
kept for 4 h at 120 °C (TLC monitoring), and cooled. Cold
water (250 mL) was added, and the precipitate was filtered off
and washed with water to neutral pH. In the synthesis of comꢀ
pound 4d, the reaction mixture after the addition of water was
neutralized with aqueous ammonia and workedꢀup as described
above.
The following new compounds were obtained: 1,1,10bꢀtriꢀ
methylꢀ1,5,6,10bꢀtetrahydro[1,3]oxazolo[4,3ꢀa]isoquinoꢀ
linꢀ3ꢀone (4a), 1,10bꢀdimethylꢀ1ꢀethylꢀ1,5,6,10bꢀtetraꢀ
hydro[1,3]oxazolo[4,3ꢀa]isoquinolinꢀ3ꢀone (4b), 10bꢀtrimethylꢀ
1,1ꢀcyclopentamethyleneꢀ1,5,6,10bꢀtetrahydro[1,3]oxazoꢀ
lo[4,3ꢀa]isoquinolinꢀ3ꢀone (4c), and 2´,2´,6´,6´,10bꢀpentaꢀ
The following new compounds were obtained: 4ꢀhydroxyꢀ
4,5,5ꢀtrimethylꢀ3ꢀ(2ꢀpyridinꢀ2ꢀylethyl)ꢀ1,3ꢀoxazolidinꢀ2ꢀ
one (3j), 4ꢀhydroxyꢀ4ꢀmethylꢀ3ꢀ(2ꢀpyridinꢀ2ꢀylethyl)ꢀ1ꢀoxaꢀ3ꢀ
azaspiro[4.5]decanꢀ2ꢀone (3k).
Synthesis of compounds 3e—i, 5a,b (general procedure). The
specified amine (0.01 mol) was added to a solution of diꢀ
oxolanone 2e (0.01 mol) in acetonitrile (10 mL). The solution
was left for 24 h at 40 °C, the solvent was evaporated, and
the resulting oil was crystallized from a tertꢀbutyl methyl
ether—petroleum ether mixture (1 : 1).
The following new compounds were obtained: 5ꢀbenzylꢀ
4ꢀhydroxyꢀ4,5ꢀdimethylꢀ3ꢀ(2ꢀphenylethyl)ꢀ1,3ꢀoxazolidinꢀ2ꢀ
one (3e), 4ꢀhydroxyꢀ3ꢀ[2ꢀ(3,4ꢀdimethoxyphenyl)ethyl]ꢀ4,5,5ꢀ
trimethylꢀ1,3ꢀoxazolidinꢀ2ꢀone (3f), 5ꢀethylꢀ4ꢀhydroxyꢀ3ꢀ
[2ꢀ(3,4ꢀdimethoxyphenyl)ethyl]ꢀ4,5ꢀdimethylꢀ1,3ꢀoxazolidinꢀ
2ꢀone (3g), 4ꢀhydroxyꢀ3ꢀ[2ꢀ(3,4ꢀdimethoxyphenyl)ethyl]ꢀ4ꢀ
methylꢀ1ꢀоxaꢀ3ꢀazaspiro[4.5]decanꢀ2ꢀone (3h), 5ꢀbenzylꢀ4ꢀ
hydroxyꢀ3ꢀ[2ꢀ(3,4ꢀdimethoxyphenyl)ethyl]ꢀ4,5ꢀdimethylꢀ1,3ꢀ
Table 2. Physicochemical characteristics and yields of synthesized compoundsa
Comꢀ
pound (system)
Rf
m.p./°C
Yield
(%)
IR,
MS, m/z (Irel (%))
ν(С=О)/cm–1
3e
3i
3j
0.70 (B)
0.30 (B)
0.37 (A)
0.41 (A)
0.62 (A)
0.57 (A)
0.67 (A)
0.82 (D)
0.77 (B)
0.49 (B)
0.10 (B)
0.27 (B)
0.52 (D)
130—131b
126—127b
172—174c
158—160c
147—149c
124—126c
158—160c
121—125c
114—115c
175—176c
174—175b
130—131b
89—93d
63
92
96
91
98
97.5
95
96
91
92
1736
1740
1744
1750
1743
1737
1754
1746
1744
1728
1684
1748
—
325 [M]+ (0.5), 307 (21.5), 216 (60.4), 128 (14.9), 105 (100)
385 [M]+ (12.9), 367 (6.8), 276 (2.7), 208 (3.6), 164 (100)
250 [M]+ (3.8), 232 (0.6), 206 (14.7), 178 (54.3), 105 (100)
290 [M]+ (4.7), 272 (1.1), 246 (12.7), 208 (43.8), 105 (100)
231 [M]+ (4.7), 216 (17.9), 172 (67.9). 145 (100)
245 [M]+ (2.1), 230 (19.3), 186 (32.4), 173 (12.8), 145 (100)
271 [M]+ (0.7), 256 (17.7), 212 (19.3), 173 (11.9), 145 (100)
328 [M]+ (0.9), 313 (100), 269 (1.4), 212 (3.4), 197 (2.8)
307 [M]+ (24.7), 234 (8.6), 216 (53.0), 172 (100)
368 [M]+ (0.8), 352 (15.3), 205 (58.2), 190 (9.5), 91 (100)
221 [M]+ (0.9), 203 (13.3), 135 (15.5), 91 (90.8), 87 (52.5), 43 (100)
235 [M]+ (0.5), 217 (72.7), 144 (26.7), 135 (16.6), 126 (100)
No [M]+, 190 (1.6), 172 (2.1), 146 (100.0),
3k
4a
4b
4c
4d
4е
4i
5a
5b
6a
52
96
92/97
130 (10.6), 115 (8.5)
6b
6c
6d
6e
7
0.54 (D)
0.62 (D)
0.59 (D)
0.64 (D)
0.65 (C,
3 times)
0.43 (C)
112—115d
129—131d
103—106d
162—165d
57—59e
74/94
61/93
87/95
0/79
67
—
—
—
—
—
219 [M]+ (1.1), 201 (0.5), 172 (1.4), 146 (100), 130 (3.3)
No [M]+, 231 (0.9), 195 (4.1), 184 (2.7), 146 (100)
265 [M]+ (4.3), 232 (40.5), 205 (100.0), 164 (82.8)
279 [M]+ (2.1), 261 (2.7), 207 (12.2), 203 (37.4), 164 (100)
277 [M]+ (40.0), 210 (82.5), 132 (100.0), 117 (57.5), 91 (57.6)
8
34—36b
68
—
No [M]+, 236 (81.9), 144 (13.8), 91 (100.0),
65 (7.4), 43 (7.4)
a Compounds 3f—h and 4f—h were described in our previous publication.3
b From tertꢀbutyl methyl ether (TBME).
c From a TBME—hexane mixture.
d From a TBME—ethyl acetate mixture .
e From nꢀhexane.

4ꢀMethylenedioxolanꢀ2ꢀones as synthons
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
573
Table 3. Elemental analysis data for compounds 3—5, 7, and 8
Comꢀ
pound
Found
Calculated
Molecular
formula
Comꢀ
pound
Found
Calculated
Molecular
formula
(%)
(%)
C
H
N
C
H
N
3e
3i
73.85
73.82
68.52
68.55
62.49
62.38
66.08
66.18
72.73
72.70
73.51
73.44
75.22
75.24
7.10
7.13
7.07
7.06
7.21
7.25
7.65
7.64
7.38
7.41
7.78
7.81
7.80
7.80
4.31
4.30
3.66
3.63
11.12
11.19
9.74
9.65
6.05
6.06
5.67
5.71
5.19
5.16
C20H23NO3
C22H27NO5
C13H18N2O3
C16H22N2O3
C14H17NO2
C15H19NO2
C17H21NO2
4d
4е
4i
5a
5b
7
73.08
73.13
78.13
78.15
71.87
71.91
65.16
65.14
66.35
66.36
86.58
86.59
81.29
81.31
8.61
8.59
6.91
6.89
6.88
6.86
6.83
6.83
7.29
7.28
8.38
8.36
8.55
8.53
8.57
8.53
4.55
4.56
3.83
3.81
6.31
6.33
5.96
5.95
5.04
5.05
4.75
4.74
C20H28N2O2
C20H21NO2
C22H25NO4
C12H15NO3
C13H17NO3
3j
3k
4a
4b
4c
C20H23
N
8
C20H25NO
Note. Compounds 6 are hydrated oxalates of variable composition. No elemental analysis data for these compounds are available, but
their structures were proved by 1H NMR and mass spectra.
Table 4. 1H NMR spectra (DMSOꢀd6) of compounds 3e,i,j,k and 5a,b
Comꢀ
pound
δ (J/Hz)
Me
NCH2CH2Ar
PhCH2
Ar
Other signals
3e
3i
3j
0.97, 1.04, 1.13,
1.19 (all s,
6 H, Ме)
0.92, 1.09, 1.13,
1.23 (all s,
6 H, Ме)
2.85—2.95 (m, 2 H);
3.20—3.30, 3.35—3.45
(both m, 1 H each)
2.75—2.85 (m, 2 H);
3.20—3.30, 3.30—3.40
(both m, 1 H each)
2.88—3.05,
2.78, 2.93,
3.01, 3.21 (all d,
2 H, J = 12.6)
2.55, 2.86,
3.04, 3.16 (all d,
2 H, J = 12.3)
—
7.12—7.30 (m, 10 H)
5.83, 6.00 (both s,
1 H, ОН)
6.70—6.80 (m, 3 H);
7.18—7.38 (m, 5 H)
3.83, 3.85 (both s,
3 H each, ОМе); 5.99,
6.16 (both s, 1 H, ОН)
5.97 (s, 1 H, ОН)
1.08, 1.15,
1.27 (all s,
3 H each)
7.22 (t, 1 H, J = 7.2);
7.26 (d, 1 H, J = 7.2);
7.69 (t, 1 H, J = 8.4);
8.49 (d, 1 H, J = 8.4)
7.31 (t, 1 H, J = 7.7);
7.48—7.53 (m, 2 H);
8.15 (d, 1 H, J = 8.9)
3.37—3.49
(both m, 2 H each)
3k
1.52 (s, 3 H)
2.82, 3.37 (both distorted t,
2 H each, J = 8.7,
J = 10.1, J = 9.1; J = 9.4,
J = 11.3, J = 9.0)
—
—
5.97 (s, 1 H, ОН)
5a*
1.04, 1.27 (both s,
3 H each)
2.83, 3.14
(both d, 1 H each,
J = 12.4)
2.64, 3.14
(both d, 1 H each,
J = 12.4)
7.18 (t, 1 H, J = 7.8);
7.25 (t, 2 H, J = 7.8);
7.29 (d, 2 H, J = 7.8)
7.16—7.22, 7.23—7.28
(both distorted t, 2 H each,
J = 5.8, J = 7.9; J = 6.2,
J = 7.1); 7.28—7.31
5.84 (s, 1 H, OH);
7.83 (s, 1 H, NH)
5b
1.05, 1.15, 1.27,
1.43 (all s,
—
2.72, 2.75 (both s,
3 H each, ОMе);
5.79, 5.95 (both s,
1 H each, ОН)
6 H, Ме)
(d, 2 H, J = 5.8)
* This compound was isolated as one diastereomer pair; therefore, its spectrum contains no doubled signals.
oxazolidinꢀ2ꢀone (3i), 5ꢀbenzylꢀ4ꢀhydroxyꢀ4,5ꢀdimethylꢀ1,3ꢀ
oxazolidinꢀ2ꢀone (5a), 5ꢀbenzylꢀ4ꢀhydroxyꢀ3,4,5ꢀtrimethylꢀ1,3ꢀ
oxazolidinꢀ2ꢀone (5b).
Synthesis of compounds 4e—i (general procedure). A tenfold
weight of PPA was added to a mixture of oxazolidinones 3e—i,
and the mixture was stirred for 6 h at 80 °C (TLC monitoring)
and cooled. Cold water (150 mL) was added, and the precipitate
was filtered off and washed with water to neutral pH.
The previously described3 compounds 4f—h were prepared
here in higher yields: 4f, 96%; 4g, 95%; 4h, 93%. The following

574
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
Titov et al.
Table 5. 1H NMR spectra (DMSOꢀd6) of compounds 4a—e,i
Comꢀ
pound
δ (J/Hz)
10bꢀMe
(s, 3 H)
CH2CH2
Ar
Other signals
4a
4b
0.82
2.67—2.72 (m, 1 H);
2.82—2.89 (m, 2 H);
12.4 (q, 1 H, J = 11.2)
2.77—2.84, 2.86—2.96,
3.10—3.17 (all m, 1 H each)
7.14, 7.18 (both d, 1 H each,
J = 7.2, J = 7.5); 7.29—7.33,
7.62—7.69 (both m, 1 H each)
7.16—7.26 (m, 4 H)
1.22, 1.27 (both s, 3 H each, Me)
0.80
0.77 (distorted t, J = 8.4, J = 9.2, J = 8.7);
0.93—0.96, 1.05—1.09, 1.20—1.24,
2.16—2.21 (all m, 1 H each, Et);
1.48, 1.51 (both s, 3 H each, Me)
0.75—0.78, 1.06—1.70 (both m, 1 H each);
1.25 (d, 1 H, J = 11.9); 1.38—1.51,
1.54—1.68 (both m, 1 H each);
2.25 (d, 1 H, cycloꢀHex, J = 12.1)
0.71, 1.22, 1.70, 2.15 (all d, 4 H, J = 14.2,
CH2pyp); 1.20, 1.25, 1.36, 1.46 (all s,
3 H each, Mepyp); 3.21 (s, 1 H, NH)
1.37 (s, 3 H, Me); 3.13, 3.22 (both d, 1 H each,
J = 13.2, PhCH2)
4c
1.38
2.75—2.78, 2.83—2.92,
3.09—3.12, 3.86—3.89
(all m, 1 H each)
7.17—7.28 (m, 4 H)
7.18—7.31 (m, 4 H)
4d
0.83
1.26
2.79—2.84, 2.90—2.95,
3.11—3.23 (all m, 1 H each);
3.91 (q, 1 H, J = 11.7)
2.65—2.72, 2.81—2.90,
3.39—3.46, 3.50—3.58
(all m, 1 H each)
4e*
4i
7.54 (d, 1 H, J = 7.4);
7.24—7.33 (m, 5 H);
7.16—7.23 (m, 3 H)
6.78 (d, 2 H, J = 7.8);
7.21 (t, 1 H, J = 7.2);
7.30—7.37 (m, 4 H)
**
1.51,
1.63
**
0.62, 1.47 (both s, 3 H Me); 3.72, 3.74,
3.78, 3.81 (all s, 6 H, OМе)
4i***
1.57,
1.69
2.62—2.73, 2.73—2.83,
2.87—2.96, 3.20—3.28
4.06—4.13 (all m, 1 H each)
0.74, 1.48 (both s, 3 H, Ме); 2.23, 3.59 (both d,
1 H, J = 13.8, 13.2), 2.96 (d, 1 H, PhCH2,
J = 13.2); 3.83, 3.90, 3.88, 3.92 (all s, 6 H, OМe
* This compound was isolated as one diastereomer pair; therefore, its spectrum contains no doubled signals.
** The signals cannot be described due to overlap.
*** The spectrum was recorded in CDCl3.
Table 6. 1H NMR spectra (DMSOꢀd6) of compounds 6
Comꢀ
pound
δ (J/Hz)
1ꢀMe
CH2CH2
Ar
NH2+ + OH
(br.s, 3 H)
Other signals
6a
6b
0.85
0.94
2.79—2.83, 2.88—2.92, 3.10—3.14,
3.80—3.86 (all m, 1 H each)
2.72—2.85 (m, 1 H); 2.94—3.08 (m,
2 H); 3.39—3.47 (m, 1 H)
7.15—7.30
(m, 4 H)
7.11—7.23
(m, 4 H)
5.45
5.61
1.50, 1.65 (both s, 3 H each, Ме)
0.89—1.08, 1.62—1.83, 1.25—1.43,
2.21—2.35 (all m, 2 H, CH2Me);
0.80—0.91 (m, 3 H, CH2Me);
3.82, 3.86 (both s, 3 H each, OMe)
0.89—1.52, 1.38—1.72
6c
6d
6e
0.88
0.89
0.91
3.76—3.84 (m, 1 H); 2.92—3.09 (m,
2 H); 3.34—3.43 (m, 1 H)
2.83—2.87, 2.88—2.94, 3.10—3.15,
3.81—3.85 (all m, 1 H each)
2.64—2.72, 3.11—3.20
7.15—7.29
(m, 4 H)
6.72, 7.05
5.31
5.43
5.42
(both m, 10 H, cycloꢀHex)
3.86, 3.89 (both s, 3 H each, OMe)
(both s, 1 H each)
6.92, 7.12
(both s, 1 H each)
0.83—0.95, 1.71—1.84, 1.98—2.02
(all m, 2 H); CH2Me); 0.79—0.84
(m, 3 H, CH2Me); 3.84, 3.87
(both s, 3 H each, OМe)
(both m, 2 H each)
new compounds were obtained: 1ꢀbenzylꢀ1,10bꢀdimethylꢀ
1,5,6,10bꢀtetrahydro[1,3]oxazolo[4,3ꢀa]isoquinolinꢀ3ꢀone (4e),
1ꢀbenzylꢀ8,9ꢀdimethoxyꢀ1,10bꢀdimethylꢀ1,5,6,10bꢀtetraꢀ
hydro[1,3]oxazolo[4,3ꢀa]isoquinolinꢀ3ꢀone (4i).
Synthesis of compounds 6 (general procedure). Method 1.
Compound 4 (0.02 mmol), MeOH (20 mL), water (20 mL), and
KOH (11.2 g, 0.2 mmol) were placed in a 100 mLꢀautoclave and
kept for 64—180 h at 120 °C (see Table 1), methanol was evapoꢀ

4ꢀMethylenedioxolanꢀ2ꢀones as synthons
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
575
rated in vacuo, the residue was extracted with CH2Cl2 (5×35 mL),
and the extracts were combined and washed with water to neuꢀ
tral pH. The organic phase was dried and the solvent was evapoꢀ
rated in vacuo. The residue was dissolved in ether (200 mL) and
added to a solution of oxalic acid (2.52 g, 0.02 mol) in ether. The
precipitate was filtered off, washed with ether 2×5 mL, and
dried.
Method 2. Dimethyl sulfoxide (20 mL), water (20 mL), and
KOH (11.2 g, 0.2 mmol) were added to 4 (0.02 mmol), and the
mixture was kept for 52—155 h at 80 °C (see Table 1). Water
(150 mL) and ether (300 mL) were added, and the organic phase
was washed to neutral pH, dried, and then workedꢀup as in
method 1.
reaction mixture was cooled, water (50 mL) was added, the
mixture was alkalized by aqueous ammonia, the product was
extracted with CH2Cl2 (3×15 mL), and the extracts were comꢀ
bined and washed with water to neutral reaction. The solution
was dried with Na2SO4 and the solvent was evaporated. The
residue was purified by flash chromatography (benzene) to give
0.93 (67%) of compound 7 as a light powder. 1H NMR, δ: 0.86,
1.32, 1.52 (all s, 3 H each, Me); 2.56, 2.72 (both t, 1 H each,
CH2CH2, J = 12.1 Hz); 2.82 (dd, 1 H, CH2CH2, J = 9.3 Hz);
3.07 (m, 1 H, CH2CH2); 3.82, 4.06 (both d, 1 H each, PhCH2,
J = 14.1 Hz); 7.03 (d, 1 H, HAr, J = 8.9 Hz); 7.06—7.21 (m,
5 H, HAr); 7.43, 7.54 (both d, 1 H each, HAr, J = 8.6 Hz).
The authors are grateful to Yu. A. Strelenko (Institute
of Organic Chemistry, Russian Academy of Sciences) for
conducting NMR experiments.
The following new compounds were obtained: 2ꢀ(1ꢀmethylꢀ
1,2,3,4ꢀtetrahydroisoquinolinꢀ1ꢀyl)propanꢀ2ꢀol (6a), 2ꢀ(1ꢀmeꢀ
thylꢀ1,2,3,4ꢀtetrahydroisoquinolinꢀ1ꢀyl)butanꢀ2ꢀol
(6b),
1ꢀ(1ꢀmethylꢀ1,2,3,4ꢀtetrahydroisoquinolinꢀ1ꢀyl)cyclohexaꢀ
nol (6c), 2ꢀ(6,7ꢀdimethoxyꢀ1ꢀmethylꢀ1,2,3,4ꢀtetrahydroisoꢀ
quinolinꢀ1ꢀил)propanꢀ2ꢀol (6d), 2ꢀ(6,7ꢀdimethoxyꢀ1ꢀmethylꢀ
1,2,3,4ꢀtetrahydroisoquinolinꢀ1ꢀyl)butanꢀ2ꢀol (6e).
References
1. A. A. Semenov, Ocherk khimii prirodnykh soedinenii [An Essay
on the Chemistry of Natural Products] Nauka, Novosibirsk,
2000 (in Russian).
2. N. B. Chernysheva, A. A. Bogolyubov, V. V. Semenov,
Khimiya geterotsikl. soedinenii, 1999, 241 [Chem. Heterocycl.
Compd., 1999, 35 (Engl. Transl.)].
3. N. B. Chernysheva, A. A. Bogolyubov, V. V. Murav´ev, V. V.
Elkin, V. V. Semenov, Khim. Geterotsikl. Soedinenii, 2000,
1409 [Chem. Heterocycl. Compd., 2000, 36 (Engl. Transl.)].
4. F. M. Menger, Tetrahedron, 1983, 39, 1013.
5. S. S. Canan, H. Koch, and L. H. Thoresen, J. Org. Chem.,
1951, 16, 84.
2ꢀBenzylꢀ1ꢀ(1ꢀhydroxyꢀ1ꢀmethyl)ethylꢀ1ꢀmethylꢀ1,2,3,4ꢀ
tetrahydroisoquinoline (8). Benzyl chloride (2.86 g, 0.023 mol)
in toluene (10 mL) was added over a period of 10 h to a mixture
of amino alcohol 6a (3.08 g, 0.015 mol) (as a free base), KI
(0.1 g), TEBAC (0.2 g), and K2CO3 (3.1 g) in anhydrous toluene
(15 mL), and the reaction mixture was refluxed for 20 h. The
solvent was removed in vacuo, the residue was treated with water
(30 mL), the product was extracted with CH2Cl2 (3×15 mL),
and the extracts were combined, washed with water to neutral
reaction, and dried by filtration through cotton wool. The solꢀ
vent was evaporated. The residue was triturated in hexane with
ether (4 : 1) to give 3.00 g (68%) of product 8 as a lightꢀyellow
powder. 1H NMR, δ: 1.09, 1.23, 1.63 (all s, 3 H each, Me);
2.74—2.82 (m, 1 H, CH2CH2); 2.95—3.05 (m, 2 H, CH2CH2);
3.33—3.40 (m, 1 H, CH2CH2); 3.76, 3.80 (both s, 3 H each,
OMe); 5.28 (br.s, 3 H, OH, NH2+); 7.05, 7.23 (both d, 1 H each,
6. J. G. Tikhe, K. A. Maegley, R. J. Almassy, and J. Li, J. Org.
Chem., 2002, 67, 8574.
7. V. Arivo, R. York, and R. F. Polany, Can. J. Chem.,
1977, 55, 24.
H
Ar, J = 8.7 Hz).
13,13,13aꢀTrimethylberbine (7). Compound 8 (1.45 g,
0.005 mol) and PPA (30 g) were heated for 18 h at 110 °C. The
Received December 29, 2005;
in revised form March 15 , 2006