Synthesis of 5-alkoxyindolizines from oxazolo[3,2-a]pyridinium salts

Full text of DOI:10.1016/j.mencom.2007.03.027

Mendeleev
Communications
Mendeleev Commun., 2007, 17, 130–132
Synthesis of 5-alkoxyindolizines from
oxazolo[3,2-a]pyridinium salts
Eugene V. Babaev,*† Andrey V. Efimov, Alexander A. Tsisevich,
Aleksandra A. Nevskaya and Victor B. Rybakov
Department of Chemistry, M. V. Lomonosov Moscow State University, 119992 Moscow, Russian Federation.
Fax: +7 495 939 3020; e-mail: babaev@org.chem.msu.ru
DOI: 10.1016/j.mencom.2007.03.027
A new route to poorly available 5-alkoxyindolizines has been developed by reaction of oxazolo[3,2-a]pyridinium salts with
sodium alkoxides; the structures of three indolizines and one parent salt have been confirmed by X-ray diffraction analysis.
The indolizine ring is isomeric and isostructural to indole, and
substituted indolizines are frequently prepared as bioisosters
of biologically active indole derivatives. A well-known class of
psychotropic indole compounds (e.g., psillocine, psylocibine and
pindolole) belongs to the family of 5-hydroxy(alkoxy)indoles.
An isostructural class of indolizines bearing 5-OR group (A in
Scheme 1) may serve as the biomimetics of such indoles. This
class can be designed by a mental rearrangement of the indole
ring nitrogen into bridgehead positions.
pyridinium salts G (route a in Scheme 2). This reaction allowed
us to prepare 5-dialkylaminoindolizines H. Recently,13 this
methodology has attracted attention in industrial chemistry as
a source of a library of 5-substituted indolizines with potential
bioactivity. However, only secondary amines are suitable for
such a transformation, and with primary amines (route b) salts I
were formed instead of indolizines.
Therefore, it is unclear which other nucleophiles are suitable
for this new strategy of indolizine synthesis from oxazolo-
pyridines. Furthermore, the ring system of salts G may undergo
alternative modes of ring opening depending on the group R
and the nature of the nucleophile. Thus, salts G with R = H react
with secondary amines with pyridine ring opening (route c11),
whereas with alkoxide the C(2)–O bond cleavage was observed
(route d14). In this paper, we studied the direction of the reaction
of salts G (R = Me) with alkoxides to test the synthesis of
5-alkoxyindolizines A.
R''
8
R''
N
N
5
O
OR
O
A
B
Me
NC
Me
NC
NR2
R'
R'
O
N
N
c
a
Ar
H
N
N
NR2H
R = H
NR2H
R = Me
H
X
O
a,b
d
NR2
C
D X = OH
E X = Cl
F X = OMe
O
Ar
Ar
2
d
b
N
H
RO–
R = H
NH2R'
3
Scheme 1
c
ClO4
R = H, Me
R
R'
The entire class of 5-alkoxy(hydroxyl)indolizines is poorly
investigated since there is lack of synthetic methodologies
leading to this scaffold. Rare examples of preparation of the
members of class A include their synthesis from pyrrole
derivatives1–3 and by means of photolytic C-5 oxidation of
the indolizine ring.4 Structure B with the desired motif was
prepared via 1,3-dipolar cycloaddition.5 The most common
strategy to indolizine ring (the Chichibabin cyclization) failed
for the case of 6-methoxy-2-picoline.6 It is, however, possible
to annelate the pyrrole ring to pyridine by condensation of the
Guresci pyridone with α-bromoketones7,8 leading to 5-indo-
lizinones C, which are stable tautomers of desired 5-hydroxy-
indolizines D. We found9 that pyridone-like derivatives C
can be converted into 5-chloroindolizines E, which react with
MeONa leading to 5-methoxy-6-cyanoindolizines F. However,
simple 5-alkoxyindolizines A (without other substituents in the
pyridine ring) remain unknown.
O
G
N
N
Ar
N
OR
OR
Ar
R
I
Scheme 2
We found that the reactions of salts 1a–c with sodium methoxide
smoothly led to previously unknown 5-methoxyindolizines 2a–c.
Variation of the nature of alcohol was performed for salt 1a, and
its reactions with sodium ethoxide and sodium isopropoxide led
to corresponding 5-alkoxyindolizines 3, 4. All reactions were
usually complete in one or two days at room temperature (addi-
tional heating decreased the yields and purity of the products).
Compounds 2–4 gave a positive Erlich test with p-dimethyl-
aminobenzaldehyde (deep blue colour typical of indolizines).
In the 1H NMR spectra of indolizines (Table 1), two new aromatic
singlets of the formed pyrrole ring and the peaks of the RO
group were observed (whereas the methyl group, which was
initially present in salts 1, disappeared), thus clearly confirming
We reported an efficient strategy10–12 to build the indolizine
ring by a somewhat unusual conversion of oxazolo[3,2-a]-
†
A lecturer at the Higher Chemical College of the RAS.
– 130 –

Mendeleev Commun., 2007, 17, 130–132
Table 1 Characteristics of 5-alkoxyindolizines.
1H NMR ([2H6]DMSO) / Substituentsa
m/z (%)
[M – R]
Yield
(%)
Compound
Mp/°C
1-H (s) 3-H (s) 6-H (s) 7-H [R]
8-H (s) 5-OR
2-Ar (m)
[M+]
2ab
2b
2c
3
66
39
79
43
63
188–189
202–204
177–179
196–197
178–179
6.90
6.78
6.61
6.80
6.79
7.96
7.95
7.73
7.88
7.86
6.03
5.95
5.77
5.97
5.99
6.81 (dd)
[2.28]
7.10
6.88
4.14
4.07
4.03
4.37, 1.57
4.88, 1.51
8.24, 8.03
268 (97)
282 (96)
355 (100) 340 (89)
282 (84)
296 (20)
253 (100)
267 (100)
8.22–8.20, 8.03–8.01
7.71–7.68, 7.55–7.52
8.21, 7.94
[2.64 (m)]c
6.75 (m)
6.75 (m)
7.04
7.03
253 (100)
254 (100)
4
8.24, 8.03
aAccording to the numbering of the indolizine ring. bSolvent (CD3)2CO. c1.80 ppm (m) for (CH2)n.
Further cleavage of the oxazole ring gave rise to ylide structure
K, which undergoes final closure and dehydration to the pyrrole
ring. Interestingly, in the reaction of salt 1a with ButONa (or
ButOK), no indolizine was formed, and the starting material
was converted into unidentified tar. Probably, the more basic
tert-butoxide ion may cause deprotonation of the potentially
acidic 5-Me group of salt 1a followed by side chain reactions.
No reaction of salt 1a with PhONa was observed (maybe due
to a lower nucleophilicity of the phenolate anion). The nature
of the electron-withdrawing group at the phenyl group in the
2-position is crucial to the stability of 5-alkoxyindolizines. Thus,
indolizines 2a,b, 3, 4 with the 2-(p-nitrophenyl) group were
stable, whereas compound 2c with the 2-(p-bromophenyl) residue
decomposed on keeping. Attempts to prepare other oxazolo-
pyridinium salts with 2-[p-bromo(chloro)phenyl] substituents
in reactions with alkoxides led to very unstable products.
R'
O
O
NO2
Br
N
N
ClO4
1a,b
ClO4
1c
Me
Me
RONa
ROH
MeONa
MeOH
R'
O
OMe
R
N
N
NO2
Br
Parent salts 1 were prepared by the phenacylation of
methoxypyridines 5a–c followed by the cyclocondensation
2c
2a,b, 3, 4
1, 2: a R' = H
b R' = Me
2 R = Me
3 R = Et
4 R = Pri
C(19)
C(10)
C(5)
C(4)
O(3)
C(2)
C(18)
C(6)
3, 4:
R' = H
C(11)
C(12)
C(14)
Br(1)
C(17)
C(15)
C(1)
OR
N(9)
C(8)
C(7)
C(13)
C(16)
R'
R'
OR
O
O
C(20)
Ar
O(12)
Cl(1)
O(13)
N
N
Ar
O(14)
O(11)
Me
Me
J
K
1c
Scheme 3
O(21)
C(5)
C(15)
C(4)
C(3)
C(14)
the structures of 2–4. The mass spectra of 5-alkoxyindolizines
contained the molecular ion; however, the most intense peaks
were [M – R] corresponding to the cleavage of an alkoxy group.
The structures of 5-alkoxyindolizines 2a, 2c and 4 were finally
confirmed by X-ray analysis (Figure 1). In the structures of all
indolizines clear alternation of single and double bonds along
the bicyclic perimeter was observed indicating a well-known
tetraene-like character of the indolizine nucleus.
C(2)
C(6)
C(7)
C(10)
N(20)
C(13)
C(11)
N(9)
C(1)
C(8)
C(12)
O(22)
O(16)
C(17)
2a
C(11)
The reaction mechanism most probably involves the attack of
an RO anion at the carbon bridgehead position giving adduct J.
C(10)
C(5)
C(12)
C(13)
C(19)
C(18)
C(3) C(20)
C(2)
C(4)
R'
OMe
R'
O
C(6)
C(7)
ArCOCH2Br
MeCN
C(15)
O
Br(1)
N
N
C(1)
C(17)
C(16)
N(9)
O(8)
R
R
Ar
C(8)
Me
5a–c
Me
6a–c
C(14)
2c
i, H2SO4
ii, HClO4
R'
O
C(5)
C(4)
C(3)
C(15)
O(21)
Ar
C(14)
N
C(6)
C(7)
R
C(2)
C(10)
C(12)
ClO4
1a–c
N(20)
Me
C(1)
C(11)
C(13)
N(9)
C(8)
O(16)
O(22)
1, 5, 6: a R = R' = H
b R = H, R' = Me
c R + R' = (CH2)4
1, 6: a, b Ar = p-NO2C6H4
c Ar = p-BrC6H4
C(17)
C(18)
C(19)
4
Figure 1 X-ray crystal structures of compounds 1c, 2a, 2c and 4.
Scheme 4
– 131 –

Mendeleev Commun., 2007, 17, 130–132
7
8
K. Gevald and H. J. Jansch, J. Prakt. Chem., 1976, 318, 313.
C. F. Lin, Y. F. Lin, Y. C. Lo, K. T. Chen and T. L. Su, Heterocycles,
2000, 53, 15.
E. V. Babaev, N. I. Vasilevich and A. S. Ivushkina, Beilstein J. Org.
Chem., 2005, 1, 9.
of N-phenacylpyridones 6a–c (using H2SO4 as a dehydrating agent)
(Scheme 4) and separated as perchlorates. The spectral changes‡
from pyridones 6 to oxazolo[3,2-a]pyridinium salts 1 clearly
confirm the closure of an aromatic ring: the singlet of the CH2
group disappeared in salts 1, and a new aromatic singlet (1H) of
the oxazole fragment is observed at 9.5–9.7 ppm. The structure
of salt 1c was confirmed by X-ray data§ (see Figure 1).
9
10 E. V. Babaev and A. V. Efimov, Khim. Geterotsikl. Soedin., 1997, 998
[Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 33, 964].
11 E. V. Babaev, A. V. Efimov, D. A. Maiboroda and K. Jug, Eur. J. Org.
Chem., 1998, 193.
12 E. V. Babaev, Lectures in Heterocyclic Chemistry, 2000, 37, 519.
13 P. Tielmann and C. Hoenke, Tetrahedron Lett., 2006, 47, 261.
14 E. V. Babaev, S. V. Bozhenko, D. A. Maiboroda, V. B. Rybakov and
S. G. Zhukov, Bull. Soc. Chim. Belg., 1997, 11, 631.
15 P. Dembech, A. Ricci, G. Seconi and P. Vivarelli, J. Chem. Soc. B,
1971, 2299.
This work was supported by the Russian Foundation for
Basic Research (project no. 04-03-32823-a).
References
1 B. R. Yerxa and H. W. Moore, Tetrahedron Lett., 1992, 33, 7811.
2 F. Gavina, A. M. Costero, M. R. Andreu and M. D. Ayet, J. Org. Chem.,
1991, 56, 5417.
3 M. Kim and E. Vedejs, J. Org. Chem., 2004, 69, 6945.
4 Y. Li, H. Y. Hu, J. P. Ye, H. K. Fun, H. W. Hu and J. H. Xu, J. Org.
Chem., 2004, 69, 2332.
16 G. C. Hopkins, J. P. Jonak and H. J. Minnermeyer, J. Am. Chem. Soc.,
1967, 32, 4040.
17 G. M. Sheldrick, SHELX97. Program Complex for the Crystal Structure
Solutiom and Refinement, University of Göttingen, Germany, 1997.
5 A. Padwa, D. J. Austin, L. Precedo and L. Zhi, J. Org. Chem., 1993,
58, 1144.
6 E. V. Babaev, A. V. Efimov and D. A. Maiboroda, Khim. Geterotsikl.
Soedin., 1995, 1104 [Chem. Heterocycl. Compd. (Engl. Transl.), 1995,
31, 962].
Received: 30th November 2006; Com. 06/2832
§
Crystallographic data. All X-ray intensities were measured using a
‡
1H NMR spectra were recorded on a Bruker AC 400 instrument. The
CAD4 diffractometer at 293(2) K [l(MoKα) radiation]. All structures
were solved by a direct method and refined by a full-matrix least-squares
technique against F2 in an anisotropic approximation (for 2a, in an
isotropic approximation). The hydrogen atoms were placed in calculated
positions and refined in an isotropic approximation in a riding model
(1c, 2a,c) and found from the difference Fourier maps and refined in
an isotropic approximation (4). All calculations were performed using
SHELX-97.17
For 1c: crystals of C18H17BrClNO5 are monoclinic, space group P21/n,
a = 12.099(3), b = 8.446(3) and c = 18.265(5) Å, b = 107.61(2)°, V =
= 1778.9(9) Å3, Z = 4, M = 442.69, dcalc = 1.653 g cm–3, m(MoKα) =
= 2.491 cm–1. Intensities of 1635 reflections were measured [w-scans
with 120 s exposure per reflection, q < 26°] and 1574 independent reflec-
tions (Rint = 0.0297) were used in the further refinement. Refinement
converged to R1 = 0.0444 was calculated against F2 for 1574 observed
reflections with I > 2s(I).
For 2a: crystals of C15H12N2O3 are monoclinic, space group P21/c,
a = 6.855(2), b = 7.096(2) and c = 25.978(6) A, b = 94.96(2)°, V =
= 1259.0(6) Å3, Z = 4, M = 268.27, dcalc = 1.415 g cm–3, m(MoKα) =
= 0.101 cm–1. Intensities of 2261 reflections were measured [w-scans with
120 s exposure per reflection, q < 20°], and 2207 independent reflec-
tions were used in the further refinement. Refinement converged to
R1 = 0.1770 was calculated against F2 for 282 observed reflections with
I > 2s(I).
For 2c: crystals of C19H18BrNO are monoclinic, space group P21/c,
a = 12.516(5), b = 6.688(5) and c = 19.104(5) Å, b = 90.92(2)°, V =
= 1599.0(14) Å3, Z = 4, M = 356.25, dcalc = 1.480 g cm–3, m(MoKα) =
= 2.572 cm–1. Intensities of 1505 reflections were measured [w-scans
with 120 s exposure per reflection, q < 25°] and 1443 independent
reflections were used in the further refinement. Refinement converged
to R1 = 0.0537 was calculated against F2 for 878 observed reflections
with I > 2s(I).
For 4: crystals of C17H16N2O3 are monoclinic, space group P21/c,
a = 11.1579(2), b = 11.2795(4) and c = 12.2594(3) Å, b = 105.63(2)°,
V = 1485.86(7) Å3, Z = 4, M = 296.32, dcalc = 1.325 g cm–3, m(MoKα) =
= 0.092 cm–1. Intensities of 3411 reflections were measured [w-scans
with 60 s exposure per reflection, q < 28°] and 3263 independent reflec-
tions were used in the further refinement. Refinement converged to
R1 = 0.0566 was calculated against F2 for 2067 observed reflections
with I > 2s(I).
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference numbers 639127–639130 for 1c, 2a, 2c and 4,
respectively. For details, see ‘Notice to Authors’, Mendeleev Commun.,
Issue 1, 2007.
syntheses of compounds 1a, 5a and 6a were described elsewhere;10,11
compound 5b was obtained according to a published procedure.15
3-Methoxy-1-methyl-5,6,7,8-tetrahydroisoquinoline 5c was prepared
by the alkylation of the Ag salt of the corresponding pyridone with MeI
1
using a protocol16 for pyrid-2-one. Yield, 73%, mp 39–40 °C. H NMR
([2H6]DMSO) d: 6.23 (s, 1H, 4-H), 3.78 (s, 3H, 3-OMe), 2.66 (t, 2H,
5-CH2, J5,6 6.0 Hz), 2.53 (t, 2H, 8-CH2, J7,8 6.0 Hz), 2.28 (s, 3H, 1-Me),
1.75 [m, 4H, 6,7-(CH2)2]. Compound 5c was involved into the next step
without further purification.
Reaction of 2-methoxypyridines 5b,c with phenacyl bromides. A solution
of 2-methoxypyridine (25 mmol) and phenacyl bromide (20 mmol) in
40 ml of MeCN was refluxed for 30–40 h. The precipitate was filtered
off and recrystallised from acetonitrile.
4,6-Dimethyl-N-(4-nitrophenacyl)pyridone 6b was prepared from pyridine
5b and p-nitrophenacyl bromide. Yield 39%; mp 182–184 °C. 1H NMR
([2H6]DMSO) d: 8.40–8.38 (m, 2H, Ar), 8.30–8.28 (m, 2H, Ar), 6.12 (s,
1H, 3-H), 6.07 (s, 1H, 5-H), 5.57 (s, 2H, NCH2), 2.23 (s, 2H, 6-Me),
2.12 (s, 3H, 4-Me). MS, m/z (%): 286 (19) [M+], 150 (14), 136 (48),
108 (100).
N-(4-Bromophenacyl)-1-methyl-5,6,7,8-tetrahydroisoquinoline-3-one
6c was prepared from pyridine 5c and p-bromophenacyl bromide. Yield
38%; mp 232–234 °C. 1H NMR ([2H6]DMSO) d: 8.03–8.00 (m, 2H, Ar),
7.71–7.68 (m, 2H, Ar), 6.03 (s, 1H, 4-H), 5.56 (s, 2H, NCH2), 2.64 (t,
2H, 5-CH2, J5,6 6.0 Hz), 2.54 (t, 2H, 8-CH2, J7,8 6.0 Hz), 2.13 (s, 3H,
1-Me), 1.76 [m, 4H, 6,7-(CH2)2]. Found (%): C, 60.04; H, 5.13; N, 3.87.
Calc. for C18H18BrNO2 (%): C, 60.01; H, 5.04; N, 3.89.
Perchlorates 1b,c were prepared according to the described procedure11
for perchlorate 1a.
5,7-Dimethyl-2-(4-nitrophenyl)oxazolo[3,2-a]pyridinium perchlorate
1b: yield 83%; mp 272–274 °C. 1H NMR ([2H6]DMSO) d: 9.68 (s, 1H,
3-H), 8.54–8.50 (m, 2H, Ar), 8.31–8.27 (m, 2H, Ar), 8.24 (s, 1H, H-8), 7.77
(s, 1H, H-6), 2.86 (s, 3H, 5-Me), 2.67 (s, 3H, 7-Me). Found (%): C, 49.08;
H, 3.46; N, 7.37. Calc. for C15H13N2O7Cl (%): C, 48.86; H, 3.55; N, 7.60.
2-(4-Bromophenyl)-5-methyl-6,7,8,9-tetrahydrooxazolo[3,2-a]isoquino-
linium perchlorate 1c: yield 90%; mp 280–282 °C. 1H NMR (CF3COOH +
[2H6]DMSO) d: 9.42 (s, 1H, 3-H), 7.96 (s, 1H, 10-H), 7.92–7.89 (m, 2H,
Ar), 7.81–7.78 (m, 2H, Ar), 3.05 (t, 2H, 9-CH2, J 6.0 Hz), 2.84 (t, 2H,
6-CH2, J 6.0 Hz), 2.74 (s, 3H, 5-Me), 1.81 [m, 4H, 7,8-(CH2)2]. Found
(%): C, 48.82; H, 3.68; N, 3.21. Calc. for C18H17ClBrNO5 (%): C, 48.84;
H, 3.87; N, 3.16.
Reaction of perchlorates 1 with sodium alcoholates (general procedure).
Perchlorate (0.5 mmol) was added to a solution of MeONa in methanol
(prepared from 7.4 mmol of sodium and 10 ml of anhydrous MeOH).
The reaction mixture was kept for 16 h at room temperature. The
precipitate was filtered off and recrystallised from acetonitrile. All com-
pounds gave satisfactory elemental analysis data. Crystal structures of
the compounds 2a,c and 4 are shown in Figure 1. Other characteristics
of 5-alkoxyindolizines 2–4 are given in Table 1.
– 132 –