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Tetrahedron 64 (2008) 749e756 www.elsevier.com/locate/tet

Synthesis and reactivity of 5-Br(I)-indolizines and their parallel cross-coupling reactions
Alexey G. Kuznetsov, Alexander A. Bush, Eugene V. Babaev*
Chemistry Department, Moscow State University, Moscow 119991, Russia Received 3 April 2007; received in revised form 18 October 2007; accepted 1 November 2007 Available online 7 November 2007

Abstract Poorly available 5 iodo and 5 bromoindolizines were prepared via regioselective lithiation of indolizines followed by halogenation. 5 Halogenoindolizines were found to be passive toward nucleophiles, whereas they may be trifluoroacetylated at C 3 and involved in reaction with DMAD giving cycl[3.2.2]azine. The first successful Suzuki coupling of 5 bromo(iodo)indolizines with different arylboronic acids (performed as a parallel synthesis) led to a series of 5 arylindolizines; the effect of substituents on the reaction yield was examined. ñ 2007 Elsevier Ltd. All rights reserved.

1. Introduction Indolizines are an important class of heterocyclic compounds with interesting photophysical and biological properties.1,2 There are nine non-equivalent positions around the bicyclic indolizine structure, and many strategies have been reviewed to prepare substituted indolizines with a different arrangement of functional groups.1 3 However, one important class of substituted indolizine, namely the 5-halogenoindolizines I, remains poorly available. One would expect that the position of the halogen in the indolizines I should be equivalent to the a-position in 2-halogenopyridines, and therefore a halogen could be easily substituted by nucleophiles. According to most theoretical calculations of indolizine reactivity (starting from earliest statements by Coulson4 and Fukui5), position 5 should be most favorable for nucleophilic attack. However, nucleophilic attack at C-5 was confirmed only for indolizines with an additional electron-withdrawing group at position 6 or 8. Two reported examples involve direct SNH amination at C-5 of 8-nitroindolizines6 and substitution of chlorine in 5-Cl-6-CN-indolizines by O-,

* Corresponding author. E mail address: babaev@org.chem.msu.ru (E.V. Babaev). 0040 4020/$ see front matter ñ 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2007.11.017

N- and S-nucleophiles;7 the reactivity of simple 5-halogenoindolizines remained unclear.8 It is hard to introduce a halogen atom at position 5 of indolizine by common methods, and our earlier attempts are shown in Scheme 1. The Chichibabin reaction (route (a)), a standard way to substituted indolizines, is useless for the target class I. 5-Chloro-2-methylindolizine has been once mentioned in the old patent.9 However, careful reinvestigation of reaction between 6-halogeno-2-picolines IIa and a-bromoketones proved10 that the condensation products have the structures IIb. The strategy that allows insertion of chlorine at position 5 (route (b)) is the reaction of 6-cyanoindolizine-5-ones IIIa (that are preferable tautomeric forms of 5-hydroxyindolizines IIIb) with POCl3 leading to 5-chloro-6-cyanoindolizines.7 Another strategy (route (c)) is the 1,3-dipolar cycloaddition of the pyridinium ylides derived from 2-chloro-N-phenacylpyridinium salts IVa leading to 3-aroyl-5-chloroindolizines.11,12 A similar reaction of 2-bromopyridinium ylide was also reported,13 however both 5-Cl- and 5-Br-derivatives are unstable and quickly lose halogen atom due to an unusual cyclization to tetracyclic structures IVb.11 13 In addition to the strategies listed in Scheme 1, a novel gold-assisted cycloisomerization of 2-propargylpyridines should be mentioned, since in a single example it led to a 1,2-substituted 5-bromoindolizine.14


750

A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756

E n BuLi R" N R' R" N Hal R" N OH R' IIIb O R' R" N IIIa (b) POCl3 Hal=Cl I R' (a) R" Hal=Cl,Br IIa CH3 N+ Hal Br O R' O IIb R" Li Hal Hal=Br,I (d)
+

E Hal=Cl,Br (c) N
+

+

N

E N

R'

E O

Hal Ar

O IVa
2

E=CO2Et; X=Cl, NO

X R"

IVb

CH3 N Br R'
+ -

Scheme 1.

In 1992 Renard and Gubin15 employed a promising method for the synthesis of a wide range of 5-substituted indolizines by direct lithiation of 2-phenylindolizine, and further reactions with different (mostly carbon) electrophiles. The only heteroatomic group inserted by this method was SiMe3. Earlier16 we have reinvestigated this procedure, suggested the optimized protocol of indolizine lithiation (due to observed low yields of products), and succeeded in the preparation of a 5-iodoindolizine capable of Suzuki cross-coupling. In this paper we report applications of this strategy (route (d)) to the synthesis of a series of 5-Br(I)-indolizines (with additional groups in the pyrrole and pyridine rings). We found that such compounds can be involved in Suzuki-coupling, and developed a convenient parallel protocol for this reaction leading to a library of poorly investigated 5-arylindolizines. Reactivity of 5-Br(I)indolizines toward simple nucleo-, electro- and dienophiles was also studied. 2. Results and discussion 2.1. Synthesis of 5-bromo(iodo)indolizines The starting indolizines 1a d were prepared by known procedures.17,18 The corresponding lithium derivatives 2a d were formed in THF at þ78 to þ80 C with n-BuLi (and TMEDA as co-reagent) using our optimized protocol for the direct lithiation of 2-substituted indolizines (Scheme 2).16 Reaction of 2a d with 1,2-dibromotetrafluoroethane as brominating agent led to 5-bromoindolizines 3a d in high yields (80 98%). The reaction of lithium derivatives 2a c with a THF solution of I2 gave 5-iodosubstituted indolizines
R3 N 1a-d
1 3

4a c with 76 95% yields. Although the 5-Br(I)-indolizines (oils or solids) obtained are unstable in air, they gave satisfactory analytical and spectroscopic data (see Section 4). The 1H NMR spectra of 3 and 4 were similar to the parent indolizines 1, and the initial signal 5-H (observed in 1) was absent in the spectra of 3 and 4. 2.2. Reactions of indolizines 3, 4 with common nucleo-, electro- and dienophiles In contrast to the theoretical predictions mentioned above, 5-halogenoindolizines appeared to be completely passive in their reactions with nucleophiles. Thus, heating of indolizines 3a c and 4a c with iPrONa (in iPrOH) or with morpholine (in the presence of tBuOK) at reflux for 24 h led only to unchanged starting materials. Analogously, no changes were observed in the reaction of 3a or 4a with diethyl sodiomalonate (in EtOH, reflux for 24 h). The reason why 5-Br(I)-indolizines behave differently from 2-Br(I)-pyridines may be explained by the general p-excessive character of the indolizine nuclei preserved in structures 3 and 4. Electrophilic substitution in indolizines usually occurs at position C-3; some exceptions have been found for 5-substituted indolizines. (Thus, 5-methylindolizines usually give mixtures of 1- and 3-substituted products.) We found that reaction of 5-bromoindolizine 3b with trifluoroacetic anhydride at 0 C led exclusively to the 3-COCF3 derivative 5 with 83% yield (Scheme 3). The regioselectivity of C-3 attack clearly followed from 1H NMR spectroscopic data: the signal of proton H3 disappeared, and all other peaks (excluding H8) underwent insignificant downfield shift.19 It should be

R1 R2
2

n BuLi THF, TMEDA

R3 Li N 2a-d R1 R2
1 2t 3

R C2F4Br2 or I2

3

Hal

N R
2

R1

3a-d Hal=Br 4a-c Hal=I
1 2

1 4: a: R =R =H, R =Ph; b: R =R =H, R = Bu; c: R =H, R = Bu, R =Me; d: R =Me, R =tBu, R3=H

1

3

2t

Scheme 2.


A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756

751

mentioned that the 5-bromo substituent slightly increases the basicity of the pyrrole fragment: protonation of indolizine 3b in CF3COOD occurred at C-3 (Scheme 3), and after 2 days the proton H-3 was completely exchanged, whereas the parent 5-H indolizine 1b during the same time underwent H/D exchange at C-3 only, in 25%.

Evidently, this [8×2] cycloaddition (with HBr elimination) is non-oxidative, and is similar to the behavior of 3-cyanoindolizine.20 2.3. Parallel cross-coupling reactions Although the halogen atom in indolizines 3 and 4 is not a leaving group in reactions with common nucleophiles, one would expect the possibility of its replacement in Suzukitype cross-coupling reactions. We investigated the reactions of 5-Br(I)-indolizines 3a c and 4a c with several arylboronic acids (listed in Table 1) using PdCl2 as the catalyst, 1,4-dioxane/ H2O as the solvent, and K2CO3 as the base. All 36 reactions were performed in parallel (heating, shaking, and filtration) using a SynCore parallel reactor. The resulting 5-arylindolizines 7a r were obtained in moderate to excellent yields (Scheme 4, Table 1). The yields in Table 1 allowed qualitative comparison of the reactivity of indolizines in the cross-coupling reaction depending on the nature of the substituents at positions 2, 5, and 6. Firstly, the reactivity of 5-Hal-2-tert-butylindolizines was found to be generally higher than that of the corresponding 2-phenyl derivatives; this was evident for 5-bromo (3a,b) and 5-iodo (4a,b) pairs of compounds. Secondly, the appearance of the 6-methyl group in close vicinity to the halogen atom at C-5 caused a decrease of reactivity (probably due to steric effects). This trend was clear for 5-bromo derivative

R N Nu (CF3CO)2O N Br CF O
3

Nu: ROor NR2H (NR2-) R N Br

CF3COOD for 3b DMAD Br

N+ D H(D)

for 3b

Toluene, 80 °C, 2h 3b (R=H) 3d (R=Me) for 3d MeO2C

N CO2Me 6

5

Scheme 3.

Another well-known reactivity type of indolizine is [8×2] cycloaddition of dienophiles across the positions 3 and 5 (see review, Ref. 20). The reaction was usually studied for 5-unsubstituted indolizines, and initial cycloadducts (e.g., with alkynes) underwent spontaneous oxidation to aromatic cycl[3.2.2]azines. We found that 5-bromoindolizine 3d does not react with ethyl acrylate, whereas its reaction with DMAD led to cycl[3.2.2]azine 6 in 87% yield (Scheme 3).
Table 1 The yields (%) for 5 arylindolizines Boronic acid Indolizine

N I

N Br

N I

N Br N I N Br

B(OH)2

76
MeO B(OH)2

7a

70

87

7g

49

87

7m

64

80

7b

73

78

7h

44

78

7n

41

B(OH)2

97
F3C B(OH) O

7c

86

90

7i

47

96

7o

32

2

84

7d

72

79

7j

44

90

7p

68

B(OH)2 Cl Cl B(OH)2

93

7e

82

87

7k

36

87

7q

70

96
CHO

7f

84

91

7l

52

95

7r

72


752
R' Hal N 3a-c 4a-c

A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756
R' N 7a-r R" Ar in 7 (R',R" see Table): a,g,m: p MeOC6H4; b,h,n: Ph; c,i,o: p CF3C6H4; d,j,p: 2 benzofuranyl; e,k,q: 3,4 diClC6H3; f,l,r: m CHOC6H4

+ ArB(OH)2 R"

PdCl2

1,4 dioxane H2O Ar K2CO3
t

3,4: a R'=H, R"=Ph; b R'=H, R"= Bu; c R'=Me, R"=tBu

Scheme 4.

3b and its 6-methyl homologue 3c, and for the homologous pair of 6-H/6-Me-5-iodo-derivatives 4b,c. Interestingly, the difference in reactivity of 5-iodo and 5-bromo groups is negligible for 6-unsubstituted indolizines (cf. the yields for 3a and 4a or 3b and 4b), whereas for the 6-methyl series the yields of 5-iodoindolizine 4c were 2 3 times higher against 5-bromoindolizine 3c. 3. Conclusion Regioselective lithiation followed by halogenation opens a new route to previously poorly available 5-bromo- and 5iodoindolizines. Although these compounds are not stable in air, they can be involved in Suzuki-coupling reaction and serve as suitable precursors of a poorly investigated family of 5-arylindolizines. 5-Br(I)-indolizines kept p-excessive properties: they can not be involved in nucleophilic substitution reactions, but can react with some electrophiles and dienophiles. 4. Experimental 4.1. General All melting points are uncorrected. IR spectra were obtained using a UR-20 spectrometer. 1H and 13C NMR spectra were recorded on AM 400 Bruker spectrometer for 1H at 360 MHz (in DMSO-d6) and for 13C at 100 MHz (in DMSO-d6 or acetone-d6). THF was distilled over benzophenone/sodium and used immediately. TMEDA was distilled over sodium. The freshly prepared solution of n-BuLi in hexane (1.19 M) was titrated according to a known procedure.21 All boronic acids were supplied by Aldrich. All reactions involving air-sensitive reagents were performed using syringe septum cap techniques in oven-dried glassware under a dry argon/nitrogen atmosphere. Parallel cross-coupling and parallel evaporation were ¨ performed and accelerated using the BUCHI SynCore Reactor (with its filtration unit, vacuum pump V-501 and vacuum controller V-805).22 4.2. Preparation of 5-Br(I)-indolizines (general procedure) To a solution of indolizine 1a d (20 mmol) and TMEDA (22 mmol) in anhydrous THF (70 mL) at þ80 C, a solution of n-BuLi (18.5 mL, 1.19 M, 1.1 equiv) was added with stirring. The mixture was allowed to warm to þ20 C, and kept at this temperature for a further 2 h. A yellow color appeared. Then the mixture was cooled to þ80 C, and 1,2-dibromotetrafluoroethane (BrCF2)2 (22 mmol) or a dry THF (30 mL)

solution of I2 (22 mmol) was slowly added. The mixture was allowed to warm to room temperature and treated with a saturated solution of ammonium chloride. The organic layer was separated and the aqueous layer was extracted with dichloromethane. After drying over anhydrous Na2SO4 and evaporation of the organic solvents, the crude product was purified by column chromatography on silica gel (eluent hexane). 4.2.1. 5-Bromo-2-phenylindolizine (3a) From 2-phenylindolizine (1a). Yield of 3a: 80%; light yellow solid, mp: 85 87 C; 1H NMR: d¼7.87 (1H, s, H3), 7.70 7.68 (2H, m, Ph-H), 7.42 7.38 (2H, m, Ph-H), 7.36 (1H, d, H6, J67¼8.6 Hz), 7.29 7.24 (1H, m, Ph-H), 6.88 (1H, s, H1), 6.77 (1H, d, H8, J78¼7.0 Hz), 6.58 6.54 (1H, m, H7); elemental analysis calcd (%) for C14H10BrN (272.14): C 61.79, H 3.70, N 5.15; found: C 61.99, H 3.62, N 5.28. 4.2.2. 5-Iodo-2-phenylindolizine (4a) From 2-phenylindolizine (1a). Yield of 4a: 76%; light yellow solid, mp: 105 107 C; 1H NMR: d¼7.85 (1H, s, H3), 7.68 7.66 (2H, m, Ph-H), 7.42 7.35 (3H, m, Ph-H), 7.24 7.22 (1H, m, H6), 7.06 (1H, d, H8, J78¼7.7 Hz), 6.94 (1H, s, H1), 6.45 6.43 (1H, m, H7); elemental analysis calcd (%) for C14H10IN (319.14): C 52.69, H 3.16, N 4.39; found: C 53.01, H 3.43, N 4.58. 4.2.3. 5-Bromo-2-tert-butylindolizine (3b) From 2-tert-butylindolizine (1b). Yield of 3b: 97%; a yellow oil that formed crystals upon standing at 9 C; IR (neat): 1620, 1500, 1480 cm 1; 1H NMR: d¼7.35 (1H, s, H3), 7.28 (1H, d, H6, J67¼8.9 Hz), 6.73 (1H, d, H8, J78¼ 6.6 Hz), 6.55 6.50 (1H, m, H7), 6.48 (1H, s, H1), 1.35 (9H, s, tBu); 13C NMR (acetone-d6): 140.9, 133.8, 117.4, 117.1, 113.6, 109.1, 99.5, 99.4, 31.5 (C(CH3)3), 30.8 (C(CH3)3); elemental analysis calcd (%) for C12H14BrN (252.15): C 57.16, H 5.60, N 5.55; found: C 56.95, H 5.63, N 5.77; 1H NMR (CF3COOD): d¼9.30 (1H, m), 8.95 (2H, m, H6×H8), 8.03 (1H, s, H1), 6.43 (1H, s, 3-CHD), 2.46 (9H, s, tBu). 4.2.4. 5-Iodo-2-tert-butylindolizine (4b) From 2-tert-butylindolizine (1b). Yield of 4b: 95%; light green solid, mp: 57 59 C; IR (neat): 1615, 1490, 1475 cm 1; 1H NMR: d¼7.32 (1H, s, H3), 7.28 (1H, d, H6, J67¼8.9 Hz), 6.96 (1H, d, H8, J78¼6.8 Hz), 6.53 (1H, s, H1), 6.37 6.33 (1H, m, H7), 1.35 (9H, s, tBu); 13C NMR (acetone-d6): 140.2, 132.7, 121.6, 118.0, 117.3, 113.1, 99.5, 88.4, 31.6 (C(CH3)3), 30.7 (C(CH3)3); elemental analysis calcd (%) for C12H14IN (299.15): C 48.18, H 4.72, N 4.68; found: C 48.03, H 4.93, N 4.57.


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753

4.2.5. 5-Bromo-6-methyl-2-tert-butylindolizine (3c) From 6-methyl-2-tert-butylindolizine (1c). Yield of 3c: 92%; light yellow solid, mp: 28 30 C; 1H NMR: d¼7.35 (1H, s, H3), 7.19 (1H, d, H8, J78¼6.3 Hz), 6.52 (1H, d, H7, J78¼6.3 Hz), 6.41 (1H, s, H1), 2.35 (3H, s, Me), 1.35 (9H, s, t Bu); elemental analysis calcd (%) for C13H16BrN (266.18): C 58.66, H 6.06, N 5.26; found: C 58.52, H 6.20, N 5.51. 4.2.6. 5-Iodo-6-methyl-2-tert-butylindolizine (4c) From 6-methyl-2-tert-butylindolizine (1c). Yield of 4c: 87%; light yellow-green solid, mp: 39 41 C; 1H NMR: d¼ 7.38 (1H, s, H3), 7.18 (1H, d, H8, J78¼6.2 Hz), 6.51 6.49 (2H, m, H1×H7), 2.37 (3H, s, Me), 1.35 (9H, s, tBu); elemental analysis calcd (%) for C13H16IN (313.18): C 49.86, H 5.15, N 4.47; found: C 49.60, H 5.48, N 4.71. 4.2.7. 5-Bromo-1-methyl-2-tert-butylindolizine (3d) From 1-methyl-2-tert-butylindolizine (1d). Yield of 3d: 98%; yellow oil; 1H NMR: d¼7.30 (1H, d, H6, J67¼9.8 Hz), 7.28 (1H, s, H3), 6.68 (1H, d, H8, J78¼6.6 Hz), 6.54 6.51 (1H, m, H7), 2.43 (3H, s, Me), 1.37 (9H, s, tBu); elemental analysis calcd (%) for C13H16BrN (266.18): C 58.66, H 6.06, N 5.26; found: C 58.71, H 6.22, N 5.51. 4.3. 5-Bromo-2-tert-butyl-3-trifluoroacetylindolizine (5) by acylation reaction Trifluoroacetic anhydride (1 mL) was added with stirring to a solution of indolizine 3b (0.252 g, 1.0 mmol) in anhydrous THF (10 mL) at 0 C. The mixture turned yellow. The solution was kept at 0 C (1 h) and then treated with a saturated solution of ammonium chloride. The organic layer was separated and the aqueous layer was extracted with dichloromethane. After drying over anhydrous Na2SO4 and evaporation of the organic solvents, the crude product was purified by column chromatography on silica gel (eluent hexane/CHCl3; 9:1). The isolated product was 5-bromo-3-trifluoroacetyl-2-tertbutylindolizine 5a (0.291 g, 83%) as a deep yellow solid. Mp: 48 50 C; IR (Nujol): 1695, 1525, 1490 cm 1; 1H NMR: d¼7.36 (1H, d, H6, J67¼7.6 Hz), 6.87 (1H, d, H8, J78¼ 7.0 Hz), 6.80 6.76 (1H, m, H7), 6.53 (1H, s, H1), 1.38 (9H, s, tBu); 13C NMR (DMSO-d6): 177.8 (q, JC F¼34.4 Hz, CCOCF3), 148.3, 138.2, 123.8, 118.6, 118.5, 116.7 (q, JC F¼ 293.8 Hz, COCF3), 116.2, 115.8, 103.2, 32.3 (C(CH3)3), 30.8 (C(CH3)3); elemental analysis calcd (%) for C14H13BrF3NO (348.17): C 48.30, H 3.76, N 4.02; found: C 48.47, H 3.68, N 4.21. 4.4. Dimethyl 3-tert-butyl-4-methylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate (6) by [8×2] cycloaddition reaction Dimethyl acetylendicarboxylate (0.170 g, 0.146 mL, 1 mmol) was added to a solution of bromoindolizine 3d (0.266 g, 1.0 mmol) in anhydrous toluene (10 mL) at room temperature. The mixture was heated to 80 C and kept at this temperature for 2 h with stirring. The mixture was allowed

to cool to room temperature, the organic solvent was evaporated, and the crude product was purified by column chromatography on silica gel (eluent hexane/CHCl3; 9:1). The cycl[3.2.2]azine 6 was isolated as a deep yellow solid (0.260 g, 87%). Mp: 121 123 C; IR (Nujol): 1745, 1700, 1545 cm 1; 1H NMR: d¼8.27 (1H, d, H6, J67¼8.0 Hz), 7.96 (1H, d, H8, J78¼6.8 Hz), 7.91 7.86 (1H, m, H7), 3.94 (6H, s, 2COOMe), 2.76 (3H, s, Me), 1.57 (9H, s, tBu); 13C NMR (DMSO-d6): 167.5 (COOCH3), 163.8 (COOCH3), 142.7, 133.1, 127.1, 125.2, 124.5, 122.0, 121.9, 115.1, 112.0, 108.6, 52.9 (COOCH3), 51.7 (COOCH3), 33.9 (C(CH3)3), 31.1 (C(CH3)3), 12.2 (C(4)-CH3); MS m/z (%) 327 (66), 312 (6), 296 (20), 282 (5), 281 (18), 280 (100), 248 (6), 191 (6), 178 (8), 110 (9), 96 (5), 43 (11); elemental analysis calcd (%) for C19H21NO4 (327.38): C 69.71, H 6.47, N 4.28; found: C 69.62, H 6.43, N 4.18. 4.5. Parallel cross-coupling of 5-Br(I)-indolizines with arylboronic acids The experiments were performed in a SynCoreò module. The solutions of 5-Br(I)-indolizine derivative (1 mmol), arylboronic acid (1.1 mmol), and K2CO3 (2 mmol) in pure 1,4-dioxane (7 mL) and water (1 mL) at room temperature were placed in 24 Syncore flasks under a nitrogen atmosphere, and a solution of 0.1 M PdCl2 in water (0.05 mL, 0.5 mol %) was added to each flask. The flasks were shaken and heated at 80 C for 24 h. The flasks were cooled to room temperature and palladium black was removed by parallel filtration using a Buchi filtration unit under a nitrogen atmosphere. The filtrates were concentrated by parallel evaporation and water (5 mL) was added to each flask. Then the mixtures were manually extracted with CHCl3, the organic layers were dried over anhydrous Na2SO4, and evaporated. The residues were purified by column chromatography on silica gel. The parallel procedure was repeated for other 12 combinations of indolizines and boronic acids. 4.5.1. 5-(4-Methoxyphenyl)-2-tert-butylindolizine (7a) Column chromatography of residue using an eluent (hexane/CHCl3; 9:1) yielded 7a from 4-methoxyphenylboronic acid and 5-bromoindolizine 3b (70%) or 5-iodoindolizine 4b (76%) as a white solid. Mp: 113 115 C; 1H NMR: d¼ 7.54 7.52 (2H, m, 5-Ar), 7.19 (1H, d, H6, J67¼8.9 Hz), 7.08 (1H, s, H3), 7.05 7.03 (2H, m, 5-Ar), 6.67 6.64 (1H, m, H7), 6.32 (1H, s, H1), 6.26 (1H, d, H8, J78¼5.0 Hz), 3.87 (3H, s, OMe), 1.28 (9H, s, tBu); elemental analysis calcd (%) for C19H21NO (279.38): C 81.68, H 7.58, N 5.01; found: C 81.33, H 7.84, N 5.23. 4.5.2. 5-Phenyl-2-tert-butylindolizine (7b) Column chromatography of residue using hexane as an eluent yielded 7b from phenylboronic acid and 5-bromoindolizine 3b (73%) or 5-iodoindolizine 4b (80%) as a white solid. Mp: 68 70 C; 1H NMR: d¼7.62 7.60 (2H, m, 5-Ph), 7.52 7.44 (3H, m, 5-Ph), 7.23 (1H, d, H6, J67¼8.7 Hz), 7.10 (1H, s, H3), 6.69 6.65 (1H, m, H7), 6.35 (1H, s, H1), 6.30 (1H, d, H8,


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A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756

J78¼7.9 Hz), 1.28 (9H, s, tBu); elemental analysis calcd (%) for C18H19N (249.35): C 86.70, H 7.68, N 5.62; found: C 86.47, H 8.01, N 5.88. 4.5.3. 5-(4-Trifluoromethylphenyl)-2-tert-butylindolizine (7c) Column chromatography of residue using hexane as an eluent yielded 7c from 4-trifluoromethylphenylboronic acid and 5-bromoindolizine 3b (86%) or 5-iodoindolizine 4b (97%) as a yellow-green solid. Mp: 123 125 C; 1H NMR: d¼7.87 7.86 (4H, m, 5-Ar), 7.28 (1H, d, H6, J67¼9.0 Hz), 7.11 (1H, s, H3), 6.69 6.65 (1H, m, H7), 6.39 (1H, s, H1), 6.37 (1H, d, H8, J78¼6.1 Hz), 1.28 (9H, s, tBu); elemental analysis calcd (%) for C19H18F3N (317.35): C 71.91, H 5.72, N 4.41; found: C 71.63, H 5.98, N 4.67. 4.5.4. 5-(2-Benzofuranyl)-2-tert-butylindolizine (7d) Column chromatography of residue using hexane as an eluent yielded 7d from 2-benzofuranylboronic acid and 5-bromoindolizine 3b (72%) or 5-iodoindolizine 4b (84%) as a light yellow solid. Mp: 76 78 C; 1H NMR: d¼7.78 (1H, s, H3), 7.70 (1H, d, 5-Ar, J¼7.2 Hz), 7.58 (1H, d, 5-Ar, J¼ 7.7 Hz), 7.50 (1H, s, 5-H3), 7.41 7.34 (2H, m, 5-Ar), 7.31 7.27 (1H, m, 5-Ar), 7.12 (1H, d, H8, J78¼7.0 Hz), 6.77 6.74 (1H, m, H7), 6.49 (1H, s, H1), 1.39 (9H, s, tBu); elemental analysis calcd (%) for C20H19NO (289.37): C 83.01, H 6.62, N, 4.84; found: C 82.74, H 6.91, N 5.09. 4.5.5. 5-(3,4-Dichlorophenyl)-2-tert-butylindolizine (7e) Column chromatography of residue using hexane as an eluent yielded 7e from 3,4-dichlorophenylboronic acid and 5-bromoindolizine 3b (82%) or 5-iodoindolizine 4b (93%) as a yellow solid. Mp: 81 83 C; 1H NMR: d¼7.78 (1H, s, 5-H2), 7.70 (1H, d, 5-H20 , J¼7.4 Hz), 7.62 6.59 (1H, m, 5-H30 ), 7.28 (1H, d, H6, J67¼8.8 Hz), 7.09 (1H, s, H3), 6.69 6.66 (1H, m, H7), 6.39 (1H, s, H1), 6.36 (1H, d, H8, J78¼7.6 Hz), 1.28 (9H, s, tBu); elemental analysis calcd (%) for C18H17Cl2N (318.24): C 67.93, H 5.38, N 4.40; found: C 67.65, H 5.74, N 4.72. 4.5.6. 5-(3-Formylphenyl)-2-tert-butylindolizine (7f) Column chromatography of residue using an eluent (hexane/CHCl3; 9:1) yielded 7f from 3-formylphenylboronic acid and 5-bromoindolizine 3b (84%) or 5-iodoindolizine 4b (96%) as a yellow solid. Mp: 62 65 C; IR (neat): 1705, 1625, 1600, 1585 cm 1; 1H NMR: d¼10.05 (1H, s, CHO), 8.11 (1H, s, 5-H2), 7.99 (1H, d, 5-H20 , J¼8.0 Hz), 7.91 (1H, d, 5-H40 , J¼8.0 Hz), 7.74 7.70 (1H, m, 5-H30 ), 7.27 (1H, d, H6, J67¼8.9 Hz), 7.05 (1H, s, H3), 6.70 6.66 (1H, m, H7), 6.37 (1H, d, H8, J78¼6.2 Hz), 6.36 (1H, s, H1), 1.24 (9H, s, t Bu); 13C NMR (acetone-d6): 192.6 (CHO), 141.7, 138.5, 137.5, 136.1, 135.2, 134.9, 130.9, 130.5, 128.0, 119.1, 117.8, 111.8, 107.3, 98.8, 32.1 (C(CH3)3), 31.6 (C(CH3)3); elemental analysis calcd (%) for C19H19NO (277.36): C 82.28, H 6.90, N 5.05; found: C 78.27, H 6.96, N 4.60. LSMS: 278; 279.23

4.5.7. 5-(4-Methoxyphenyl)-6-methyl-2-tert-butylindolizine (7g) Column chromatography of residue using an eluent (hexane/CHCl3; 9:1) yielded 7g from 4-methoxyphenylboronic acid and 5-bromoindolizine 3c (49%) or 5-iodoindolizine 4c (87%) as a white solid. Mp: 139 141 C; 1H NMR: d¼ 7.28 7.25 (2H, m, 5-Ar), 7.15 (1H, d, H7, J78¼8.5 Hz), 7.10 7.06 (2H, m, 5-Ar), 6.56 (1H, d, H8, J78¼8.5 Hz), 6.51 (1H, s, H3), 6.24 (1H, s, H1), 3.86 (3H, s, OMe), 1.98 (3H, s, Me), 1.27 (9H, s, tBu); elemental analysis calcd (%) for C20H23NO (293.41): C 81.87, H 7.90, N 4.77; found: C 82.02, H 7.83, N 4.92. 4.5.8. 6-Methyl-5-phenyl-2-tert-butylindolizine (7h) Column chromatography of residue using hexane as an eluent yielded 7h from phenylboronic acid and 5-bromoindolizine 3c (44%) or 5-iodoindolizine 4c (78%) as a white solid. Mp: 79 81 C; 1H NMR: d¼7.59 7.55 (2H, m, 5-Ph), 7.51 7.47 (1H, m, 5-Ph), 7.39 7.36 (2H, m, 5-Ph), 7.18 (1H, d, H7, J78¼8.7 Hz), 6.58 (1H, d, H8, J78¼8.7 Hz), 6.47 (1H, s, H3), 6.27 (1H, s, H1), 1.98 (3H, s, Me), 1.22 (9H, s, tBu); elemental analysis calcd (%) for C19H21N (263.38): C 86.65, H 8.04, N 5.32; found: C 86.31, H 8.27, N 5.64. 4.5.9. 5-(4-Trifluoromethylphenyl)-6-methyl-2-tertbutylindolizine (7i) Column chromatography of residue using hexane as an eluent yielded 7i from 4-trifluoromethylphenylboronic acid and 5-bromoindolizine 3c (47%) or 5-iodoindolizine 4c (90%) as a yellow-green solid. Mp: 151 153 C; 1H NMR: d¼7.90 7.86 (2H, m, 5-Ar), 7.62 6.59 (2H, m, 5-Ar), 7.22 (1H, d, H7, J78¼8.5 Hz), 6.60 (1H, d, H8, J78¼8.5 Hz), 6.45 (1H, s, H3), 6.30 (1H, s, H1), 1.98 (3H, s, Me), 1.22 (9H, s, tBu); elemental analysis calcd (%) for C20H20F3N (331.37): C 72.49, H 6.08, N 4.23; found: C 72.24, H 6.33, N 4.57. 4.5.10. 5-(2-Benzofuranyl)-6-methyl-2-tert-butylindolizine (7j) Column chromatography of residue using hexane as an eluent yielded 7j from 2-benzofuranylboronic acid and 5-bromoindolizine 3c (44%) or 5-iodoindolizine 4c (79%) as a deep yellow solid. Mp: 77 79 C; 1H NMR: d¼7.71 (1H, d, 5-Ar, J¼6.7 Hz), 7.58 (1H, d, H7, J78¼8.6 Hz), 7.40 7.35 (1H, m, 5-Ar), 7.32 7.26 (2H, m, 5-Ar), 7.17 (1H, s, 5-H3), 7.03 (1H, s, H3), 6.56 (1H, d, H8, J78¼8.6 Hz), 6.35 (1H, s, H1), 2.25 (3H, s, Me), 1.27 (9H, s, tBu); elemental analysis calcd (%) for C21H21NO (303.41): C 83.13, H 6.98, N, 4.62; found: C 83.08, H 6.81, N 4.81. 4.5.11. 5-(3,4-Dichlorophenyl)-6-methyl-2-tertbutylindolizine (7k) Column chromatography of residue using hexane as an eluent yielded 7k from 3,4-dichlorophenylboronic acid and 5-bromoindolizine 3c (36%) or 5-iodoindolizine 4c (87%) as a yellow solid. Mp: 153 155 C; 1H NMR: d¼7.83 (1H, s, 5-H2), 7.75 (1H, d, 5-H20 , J¼9.0 Hz), 7.60 7.56 (1H, m, 5-H30 ), 7.21 (1H, d, H7, J78¼8.6 Hz), 6.58 (1H, d, H8,


A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756

755

J78¼8.6 Hz), 6.51 (1H, s, H3), 6.30 (1H, s, H1), 1.99 (3H, s, Me), 1.23 (9H, s, tBu); elemental analysis calcd (%) for C19H19Cl2N (332.28): C 68.68, H 5.76, N 4.22; found: C 68.85, H 5.75, N 4.27. 4.5.12. 5-(3-Formylphenyl)-6-methyl-2-tert-butylindolizine (7l) Column chromatography of residue using an eluent (hexane/CHCl3; 9:1) yielded 7l from 3-formylphenylboronic acid and 5-bromoindolizine 3c (52%) or 5-iodoindolizine 4c (91%) as a yellow solid. Mp: 116 118 C; IR (Nujol): 1690, 1600 cm 1; 1H NMR: d¼10.11 (1H, s, CHO), 8.06 (1H, d, 5-H20 , J¼6.9 Hz), 7.93 (1H, s, 5-H2), 7.83 7.89 (1H, m, 5-H30 ), 7.71 (1H, d, 5-H40 , J¼7.5 Hz), 7.23 (1H, d, H7, J78¼9.0 Hz), 6.61 (1H, d, H8, J78¼8.6 Hz), 6.45 (1H, s, H3), 6.30 (1H, s, H1), 1.99 (3H, s, Me), 1.22 (9H, s, tBu); elemental analysis calcd (%) for C20H21NO (291.40): C 82.44, H 7.26, N 4.81; found: C 82.38, H 7.38, N 4.85. 4.5.13. 5-(4-Methoxyphenyl)-2-phenylindolizine (7m) Column chromatography of residue using an eluent (hexane/CHCl3; 9:1) yielded 7m from 4-methoxyphenylboronic acid and 5-bromoindolizine 3a (64%) or 5-iodoindolizine 4a (87%) as a white solid. Mp: 146 148 C; 1H NMR: d¼ 7.66 7.54 (5H, m), 7.37 7.26 (3H, m), 7.18 7.06 (3H, m), 6.75 6.72 (2H, m), 6.37 (1H, d, H8, J78¼10.2 Hz), 3.88 (3H, s, OMe); elemental analysis calcd (%) for C21H17NO (299.37): C 84.25, H 5.72, N 4.68; found: C 84.06, H 5.98, N 4.91. 4.5.14. 2,5-Diphenylindolizine (7n) Column chromatography of residue using hexane as an eluent yielded 7n from phenylboronic acid and 5-bromoindolizine 3a (41%) or 5-iodoindolizine 4a (78%) as a white solid. Mp: 92 94 C; 1H NMR: d¼7.95 7.88 (2H, m), 7.73 7.67 (3H, m), 7.44 7.35 (5H, m), 7.24 7.22 (1H, m), 7.11 7.10 (1H, m), 7.01 (1H, s, H1), 6.99 6.97 (1H, m), 6.66 6.64 (1H, m, H7); elemental analysis calcd (%) for C20H15N (269.34): C 89.19, H 5.61, N 5.20; found: C 88.86, H 5.90, N 5.54. 4.5.15. 5-(4-Trifluoromethylphenyl)-2-phenylindolizine (7o) Column chromatography of residue using hexane as an eluent yielded 7o from 4-trifluoromethylphenylboronic acid and 5-bromoindolizine 3a (32%) or 5-iodoindolizine 4a (96%) as a white-green solid. Mp: 129 131 C; 1H NMR: d¼7.94 7.86 (4H, m), 7.63 7.58 (3H, m), 7.42 (1H, d, H6, J67¼7.2 Hz), 7.33 7.29 (2H, m), 7.20 7.16 (1H, m), 6.82 (1H, s, H1), 6.80 6.78 (1H, m, H7), 6.49 (1H, d, H8, J78¼ 10.8 Hz); elemental analysis calcd (%) for C21H14F3N (337.34): C 74.77, H 4.18, N 4.15; found: C 74.37, H 4.38, N 4.43. 4.5.16. 5-(2-Benzofuranyl)-2-phenylindolizine (7p) Column chromatography of residue using hexane as an eluent yielded 7p from 2-benzofuranylboronic acid and 5-bromoindolizine 3a (68%) or 5-iodoindolizine 4a (90%) as a deep

yellow solid. Mp: 169 171 C; 1 5-H3), 7.77 7.69 (4H, m), 7.63 (1H, m), 7.40 7.35 (3H, m), 7.33 (2H, m), 6.91 (1H, s, H1), 6.84 (1H, calcd (%) for C22H15NO (309.36): found: C 85.28, H 5.06, N 4.71.

H NMR: d¼8.32 (1H, s, 7.61 (1H, m), 7.51 7.49 7.28 (1H, m), 7.25 7.20 m, H7); elemental analysis C 85.41, H 4.89, N 4.53;

4.5.17. 5-(3,4-Dichlorophenyl)-2-phenylindolizine (7q) Column chromatography of residue using hexane as an eluent yielded 7q from 3,4-dichlorophenylboronic acid and 5-bromoindolizine 3a (70%) or 5-iodoindolizine 4a (87%) as a yellow solid. Mp: 142 144 C; 1H NMR: d¼7.83 (1H, d, 5-H2, J¼2.5 Hz), 7.75 (1H, d, 5-H20 , J¼8.4 Hz), 7.69 7.66 (1H, m, 5-H30 ), 7.61 7.58 (3H, m), 7.40 (1H, d, H6, J67¼ 10.8 Hz), 7.33 7.30 (2H, m), 7.20 7.16 (1H, m), 6.82 (1H, s, H1), 6.78 (1H, m, H7), 6.45 (1H, d, H8, J78¼9.8 Hz); elemental analysis calcd (%) for C20H13Cl2N (338.23): C 71.02, H 3.87, N 4.14; found: C 70.74, H 4.13, N 4.45. 4.5.18. 5-(3-Formylphenyl)-2-phenylindolizine (7r) Column chromatography of residue using an eluent (hexane/CHCl3; 9:1) yielded 7r from 3-formylphenylboronic acid and 5-bromoindolizine 3a (72%) or 5-iodoindolizine 4a (95%) as a yellow solid. Mp: >132 C (dec); IR (Nujol): 1695, 1605, 1580 cm 1; 1H NMR: d¼10.11 (1H, s, CHO), 8.23 (1H, s, 5-H2), 8.07 (1H, d, 5-H20 , J¼7.4 Hz), 7.99 (1H, d, 5-H40 , J¼6.3 Hz), 7.81 7.77 (1H, m, 5-H30 ), 7.62 7.57 (2H, m), 7.44 7.16 (5H, m), 6.82 (1H, s, H1), 6.77 (1H, m, H7), 6.49 (1H, d, H8, J78¼9.4 Hz); elemental analysis calcd (%) for C21H15NO (297.35): C 84.82, H 5.08, N 4.71; found: C 84.51, H 5.34, N 4.96. Acknowledgements This work was supported by Russian Foundation of Basic Research (RFBR Grant no. 07-03-00921).

Supplementary data Supplementary data associated with this article can be found in the online version, at doi:10.1016/j.tet.2007.11.017. References and notes
1. Flitsch, W. Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ress, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p 443. 2. Tielmann, P.; Hoenke, C. Tetrahedron Lett. 2006, 47, 261 and references therein. 3. (a) Swinborne, P. J.; Hunt, J. H.; Klinkert, G. Adv. Heterocycl. Chem. 1978, 23, 103; (b) Prostakov, N. S.; Baktybaev, O. B. Russ. Chem. Rev. 1975, 44, 1649 (in Russian); (c) Mosby, W. L. Heterocyclic Systems with Bridgehead Nitrogen Atom; Interscience: New York, NY, 1961; Part I, p 239; (d) Borrows, E. T.; Holland, D. O. Chem. Rev. 1948, 42, 611. 4. Longuet Higgins, H. C.; Coulson, C. A. Trans. Faraday Soc. 1947, 43, 87. 5. Fukui, K.; Yonezawa, T.; Nagata, C.; Shirgu, H. J. Chem. Phys. 1954, 22, 1433. 6. Kost, A. N.; Sagitullin, R. S.; Gromov, S. P. Heterocycles, Special Issue 1977, 7, 997.


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A.G. Kuznetsov et al. / Tetrahedron 64 (2008) 749e756 16. Kuznetsov, A. G.; Bush, A. A.; Rybakov, V. B.; Babaev, E. V. Molecules 2005, 10, 1074. 17. Tschischibabin, A. E. Ber. Dtsch. Chem. Ges. 1927, 60, 1607. 18. (a) Armarego, W. L. F. J. Chem. Soc. 1964, 11, 4226; (b) Reid, D. H.; Webster, R. G.; McKenzie, S. J. Chem. Soc., Perkin Trans. 1 1979, 2334. 19. In the case of C 1 substitution one would expect strong downfield shift of the signal of peri proton H8, see review: Babaev, E. V.; Torocheshnikov, V. N.; Bobrovsky, S. I. Chem. Heterocycl. Compd. (Engl. Transl.) 1995, 31, 1079. 20. Simonyan, V. V.; Zinin, A. I.; Babaev, E. V.; Jug, K. J. Phys. Org. Chem. 1998, 11, 201. 21. Taylor, R. J. K. Organocopper Reagents; Oxford University Press: New York, NY, 1994; p 52. 22. Babaev, E.; Belykh, E.; Dlinnykh, I.; Tkach, N.; Bender, W.; Shoenen berger, G. Best@Buchi Synthesis 2004, 34, 4. 23. The aldehyde 7f (in contrast to its analogs 7l, 7r) was very unstable in air and quickly decomposed to a green liquid. Although its 1H NMR spectra were in full agreement with the structure, LCMS data confirmed that 7f contains an impurity (12%) with an intractable peak M 404.

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