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Mendeleev Communications
Mendeleev Commun., 2007, 17, 130­132

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.
R''
8

N
5

N O B Me O

R''

OR A Me NC O C N H H R' NC

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 oxazolopyridines. 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.
O N NR2
d RO­ R=H

N X D X = OH E X = Cl F X = OMe

R'

NR2 Ar
c NR2H R=H a NR2H R = Me

N

a,b

O N
3 2

d

Ar

Scheme 1

c

R G

ClO4

b H NH2R' R = H, Me

Ar

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 derivatives1­3 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 -bromoketones7,8 leading to 5-indolizinones C, which are stable tautomers of desired 5-hydroxyindolizines 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. We reported an efficient strategy10­12 to build the indolizine ring by a somewhat unusual conversion of oxazolo[3,2-a]

O N Ar OR OR

R' Ar

N N R I Scheme 2

A lecturer at the Higher Chemical College of the RAS.

We found that the reactions of salts 1a­c with sodium methoxide smoothly led to previously unknown 5-methoxyindolizines 2a­c. 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 (additional heating decreased the yields and purity of the products). Compounds 2­4 gave a positive Erlich test with p-dimethylaminobenzaldehyde (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

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Mendeleev Commun., 2007, 17, 130­132 Table 1 Characteristics of 5-alkoxyindolizines. Compound 2ab 2b 2c 3 4
a

Yield (%) 66 39 79 43 63

1

Mp/°C 1-H (s) 188­189 202­204 177­179 196­197 178­179 6. 6. 6. 6. 6. 90 78 61 80 79 3-H (s) 7. 7. 7. 7. 7. 96 95 73 88 86 6-H (s) 6. 5. 5. 5. 5. 03 95 77 97 99

H NMR ([2H6]DMSO) / Substituentsa 7-H [R] 8-H (s) 5-OR 4.14 4.07 4.03 4.37, 1.57 4.88, 1.51 2-Ar (m) 8.24, 8.03 8.22­8.20, 8.03­8.01 7.71­7.68, 7.55­7.52 8.21, 7.94 8.24, 8.03 [M+ 268 282 355 282 296 ]

m/z (%) [M ­ R] 253 267 340 253 254 (100) (100) (89) (100) (100)

6.81 (dd) 7.10 [2.28] 6.88 [2.64 (m)]c 6.75 (m) 7.04 6.75 (m) 7.03

(97) (96) (100) (84) (20)

According to the numbering of the indolizine ring. bSolvent (CD3)2CO. c1.80 ppm (m) for (CH2)n.
R' N Me ClO
4

O NO
2

O N Me ClO 1c
MeONa MeOH
4

Br

1a,b
RONa ROH

R' N

O

R N

OMe

NO 2a,b, 3, 4

2

Br 2c 1, 2 : a R ' = H b R ' = Me 3, 4 : R' = H R' OR O N Me Ar

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 oxazolopyridinium salts with 2-[p-bromo(chloro)phenyl] substituents in reactions with alkoxides led to very unstable products. Parent salts 1 were prepared by the phenacylation of methoxypyridines 5a­c followed by the cyclocondensation
C(10) C(6) C(11) C(12) C(5) O(3) C(4) C(2) C(15) C(1) C(19) C(18) C(17) Br(1)

2 R = Me 3 R = Et 4 R = Pri R' OR O N Me J Ar

C(14) C(16) O(12)

C(13)

C(7) C(20)

N(9) C(8) O(14) O(11)

Cl(1) O(13)

K Scheme 3
C(5) C(6) C(7) C(8) N(9) O(16) C(17) C(4)

1c
C(3) C(15) C(2) C(10) C(11) C(1) C(13) C(12) O(22) N(20) O(21) C(14)

the structures of 2­4. 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. The reaction mechanism most probably involves the attack of an RO anion at the carbon bridgehead position giving adduct J.
R' R Me 5a­c
i, H2SO4 ii, HClO4

2a
C(11) C(12) C(13) C(10) C(5) C(4) C(6) C(7)

OMe N

ArCOCH2Br MeCN

R' R Me N

O

O Ar

C(3) C(20) C(2) C(1) C(16)

C(19) C(15) C(18) C(17) Br(1)

C(8)

N(9) O(8) C(14)

6a­c R' R Me N ClO O Ar
C(6)
4

2c
C(5) C(4) C(3) C(15) C(2) C(10) C(1) C(11) C(12) O(21)

C(14)

C(7) C(8) N(9)

N(20) C(13) O(22)

1a­c 1, 5, 6: a R = R' = H b R = H, R' = Me c R + R' = (CH2)4 1, 6: a, b Ar = p-NO2C6H c Ar = p-BrC6H4
4

O(16) C(19) C(17) C(18)

4 Figure 1 X-ray crystal structures of compounds 1c, 2a, 2c and 4.

Scheme 4

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Mendeleev Commun., 2007, 17, 130­132

of N-phenacylpyridones 6a­c (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 9.5­9.7 ppm. The structure of salt 1c was confirmed by X-ray data§ (see Figure 1). 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. 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].

7 K. Gevald and H. J. Jansch, J. Prakt. Chem., 1976, 318, 313. 8 C. F. Lin, Y. F. Lin, Y. C. Lo, K. T. Chen and T. L. Su, Heterocycles, 2000, 53, 15. 9 E. V. Babaev, N. I. Vasilevich and A. S. Ivushkina, Beilstein J. Org. Chem., 2005, 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. 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 GÆttingen, Germany, 1997.

Received: 30th November 2006; Com. 06/2832
Crystallographic data. All X-ray intensities were measured using a CAD4 diffractometer at 293(2) K [l(MoK) radiation]. All structures were solved by a direct method and refined by a full-matrix least-squares technique against F 2 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 cm­3, m(MoK) = = 2.491 cm­1. Intensities of 1635 reflections were measured [w-scans with 120 s exposure per reflection, q < 26°] and 1574 independent reflections (Rint = 0.0297) were used in the further refinement. Refinement converged to R1 = 0.0444 was calculated against F 2 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 cm­3, m(MoK) = =0.101 cm­1. Intensities of 2261 reflections were measured [w-scans with 120 s exposure per reflection, q < 20°], and 2207 independent reflections were used in the further refinement. Refinement converged to R1 = 0.1770 was calculated against F 2 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 cm­3, m(MoK) = = 2.572 cm­1. 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 F 2 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 cm­3, m(MoK) = = 0.092 cm­1. Intensities of 3411 reflections were measured [w-scans with 60 s exposure per reflection, q < 28°] and 3263 independent reflections were used in the further refinement. Refinement converged to R1 = 0.0566 was calculated against F 2 for 2067 observed reflections with I > 2s(I ). Atomic coordinates, bond lengths, bond angles and thermal parameters 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 639127­639130 for 1c, 2a, 2c and 4, respectively. For details, see `Notice to Authors', Mendeleev Commun., Issue 1, 2007.
§

NMR spectra were recorded on a Bruker AC 400 instrument. The 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 using a protocol16 for pyrid-2-one. Yield, 73%, mp 39­40 °C. 1HNMR ([2H6]DMSO) d: 6.23 (s, 1H, 4-H), 3.78 (s, 3 H, 3-OMe), 2.66 (t, 2 H, 5-CH2, J5,6 6.0 Hz), 2.53 (t, 2 H, 8-CH2, J7,8 6.0 Hz), 2.28 (s, 3 H, 1-Me), 1.75 [m, 4 H, 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 30­40 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 182­184 °C. 1HNMR ([2H6]DMSO) d: 8.40­8.38 (m, 2 H, Ar), 8.30­8.28 (m, 2 H, Ar), 6.12 (s, 1H, 3-H), 6.07 (s, 1H, 5-H), 5.57 (s, 2 H, NCH2), 2.23 (s, 2 H, 6-Me), 2.12 (s, 3 H, 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 232­234 °C. 1HNMR ([2H6]DMSO) d: 8.03­8.00 (m, 2 H, Ar), 7.71­7.68 (m, 2 H, Ar), 6.03 (s, 1H, 4-H), 5.56 (s, 2 H, NCH2), 2.64 (t, 2H, 5-CH2, J5,6 6.0 Hz), 2.54 (t, 2 H, 8-CH2, J7,8 6.0 Hz), 2.13 (s, 3 H, 1-Me), 1.76 [m, 4 H, 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 272­274 °C. 1H NMR ([2H6]DMSO) d: 9.68 (s, 1H, 3-H), 8.54­8.50 (m, 2 H, Ar), 8.31­8.27 (m, 2 H, Ar), 8.24 (s, 1H, H-8), 7.77 (s, 1H, H-6), 2.86 (s, 3 H, 5-Me), 2.67 (s, 3 H, 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]isoquinolinium perchlorate 1c: yield 90%; mp 280­282 °C. 1HNMR (CF3COOH + [2H6]DMSO) d: 9.42 (s, 1H, 3-H), 7.96 (s, 1H, 10-H), 7.92­7.89 (m, 2 H, Ar), 7.81­7.78 (m, 2 H, Ar), 3.05 (t, 2 H, 9-CH2, J 6.0 Hz), 2.84 (t, 2 H, 6-CH2, J 6.0 Hz), 2.74 (s, 3 H, 5-Me), 1.81 [m, 4 H, 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 compounds gave satisfactory elemental analysis data. Crystal structures of the compounds 2a,c and 4 are shown in Figure 1. Other characteristics of 5-alkoxyindolizines 2­4 are given in Table 1.

1H

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