CSIRO PUBLISHING Full Paper

www.publish.csiro.au/journals/ajc Aust. J. Chem. 2008, 61, 107–114

Ring Contractions of 3-Azido-4H-quinolizin-4-ones and3-Azido-4H-azino[1,2–x]pyrimidin-4-ones: a NovelApproach to 3-Aminoindolizines and their Aza Analogues

Simon Recnik,A Anton Meden,A Branko Stanovnik,A and Jurij SveteA,B

AFaculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerceva 5,PO Box 537, 1000 Ljubljana, Slovenia.

BCorresponding author. Email: jurij.svete@fkkt.uni-lj.si

Thermal transformations of 3-azido-4H-quinolizin-4-ones 4a,b and 3-azido-4H-azino[1,2–x]pyrimidin-4-ones 4c,d, avail-able from the corresponding heteroarylamines 2a–d, were studied. The reaction products were mostly dependent on thesolvent. Thus, heating of 3-azido-1-cyano-4H-quinolizin-4-one (4a) in toluene afforded 2-(pyridin-2-yl)fumaronitrile 5a,whereas 3-amino-1-cyano-4H-quinolizin-4-one (8) was obtained on treatment of 4a in a mixture of toluene and trifluoro-acetic anhydride. However, heating of 4a in acetic anhydride and in acetic acid resulted in a ring contraction to produce3-(diacetylamino)indolizine-1-carbonitrile 6a and 3-(acetylamino)indolizine-1-carbonitrile 7a, respectively. Similarly,ring contractions took place on heating ethyl 3-azido-4-oxo-4H-quinolizin-1-carboxylate 4b and 3-azido-4H-azino[1,2–x]pyrimidin-4-ones 4c,d in acetic anhydride or acetic acid to produce the N-acetylated 3-aminoindolizine derivatives 6b,7b and 3-aminoimidazo[1,2–x]azine derivatives 6c,d in 30–89% yields.The structures of compounds 5–8 were determinedby NMR spectroscopy and X-ray diffraction.

Manuscript received: 10 September 2007.Final version: 3 January 2008.

Introduction

Indolizines,[1] imidazo[1,2-a]pyridines,[2] and imidazo[1,2-b]pyridazines[3,4] are important heterocyclic systems with abridgehead nitrogen atom, because many of their syntheticand naturally occurring derivatives exhibit a broad rangeof biological activities. Consequently, there is a contin-uing interest in the synthesis of these azabicyclic sys-tems. The most common methods for the synthesis of(aza)indolizines are: (a) cyclocondensations of 2-alkylpyridines(or 2-aminopyridines) and their aza analogues with α-haloketones (Tschitschibabin reaction) or with acid anhydrides(Scholz reaction); (b) 1,3-dipolar cycloadditions of pyridiniumylides to various dipolarophiles;[1–6] (c) transition metal catal-ysed coupling/cycloisomerization of 2-halopyridines with termi-nal acetylenes;[7–11] (d) tandem Michael addition/amino nitrilecyclization of 2-(2-cyanoethenyl)-1,4-dihydropyridines;[12] and(e) three-component Ugi-type reactions between 2-(pyridin-2-yl)acetic acid (or a 2-aminopyridine) derivative, aldehyde, andisonitrile (or trimethylsilyl cyanide).[13–19] However, there areonly a few examples of ring contractions to the indolizine sys-tem in the literature,[20–22] while, to the best of our knowledge,ring contractions to imidazo[1,2–x]azines have not been reportedyet. These known examples include ring contractions of: (a)tetraalkyl 4H-quinolizine-1,2,3,4-tetracarboxylates,[20–26] and(b) 4-oxo-4H-quinolizine-3-diazonium tetrafluoroborates[27]

and dihydropyridothiazines (Fig. 1).[28]

2-Substituted 3-(dimethylamino)propenoates and relatedenaminones are versatile reagents for the preparation of avariety of heterocyclic systems, functionalized heterocycles,and natural product analogues.[29–39] Within this context, we

N

COOMe

COOMe

COOMe

COOMe

Refs 20–26 N

COOMe

COOMe

COOMe

N

EWG

N2 BF4

O

Ref. 27 N

EWG

COOR

ROH, ∆

N

S

SMe

CN

CN

Ref. 28

[O]

N

CN

CN

SMe

[O] or hν or acid or base

EWG � COOEt, CN R � Me, Et, n-Pr

� �

Fig. 1. Known ring contractions to the indolizine system.

developed a simple two-step synthesis of 3-amino substituted4H-quinolizin-4-ones[40] and 4H-azino[1,2–x]azin-4-ones.[41]

Diazotation of these heterocyclic amines gave stable heteroaryl-diazonium tetrafluoroborates as useful intermediates for furthertransformations.[27,42–46] Heating of these diazonium salts inprimary alcohols resulted in transformations where the reac-tion outcome was dependent on the heterocyclic residue. Thus,4-oxo-4H-azino[1,2–x]azine-3-diazonium tetrafluoroboratesunderwent ‘ring switching’ transformation into biologically

© CSIRO 2008 10.1071/CH07318 0004-9425/08/020107

108 S. Recnik et al.

Compound YX Yield [%]

2a–4a C�CN 64

2b–4b C�COOEt 67

2c–4c N 73

2d–4d N

CH

CH

CH

N 72

YN

X

N2 Cl

O

COOMe

NHCOOBnMe2N

2 steps

Refs 40, 41Y

N

X

NH2

O1

2a–d

3a–d

NaNO2, H2O, HCl, 0°C

Aq. NaN3, 0–20°C

YN

X

N3

O

4a–d

� �

Scheme 1. Preparation of heteroarylazides 4a–d.

active alkyl 1-heteroaryl-1,2,3-triazole-4-carboxylates.[42,43,46]

However, treatment of 4-oxo-4H-quinolizine-3-diazonium tetra-fluoroborates under identical conditions resulted in aza-Wolffrearrangement leading to alkyl indolizine-3-carboxylates.[27] Inextension, we focussed our attention on transformations of 3-azido-substituted 4H-quinolizin-4-ones 4a,b and 4H-azino[1,2–x]azin-4-ones 4c,d, available by azido-dediazonation of hetero-aryldiazonium salts 3a–d. Herein, we report the results of thisstudy, which showed that azides 4a–d undergo interesting ther-mal ring contractions to 3-(di)acetylaminoindolizines 6a,b and7a,b and 3-(diacetylamino)imidazo[1,2–x]azines 6c,d.

Results and DiscussionSynthesis and Transformations of Heterocyclic Azides4a–dStarting compounds 3-amino-4-oxo-4H-quinolizine-1-carbo-nitrile 2a, ethyl 3-amino-4-oxo-4H-quinolizine-1-carboxylate2b,[40] 3-amino-4-oxo-4H-pyrido[1,2-a]pyrimidine 2c, and3-amino-4-oxo-4H-pyrimido[1,2-b]pyridazine 2d[41] wereprepared from methyl (Z)-2-benzyloxycarbonylamino-3-(dimethylamino) propenoate 1[40] following the literature pro-cedures. Treatment of amines 2a–d with aqueous sodium nitritein the presence of hydrochloric acid at 0◦C gave the intermediateheteroaryldiazonium chlorides 3a–d, which were subsequentlyreacted with aqueous sodium azide at 0–20◦C to afford the cor-responding azido compounds 4a–d in 64–73% yields over twosteps (Scheme 1).

Next, thermal reactions of the azides 4a–d were studied.Heating of the azide 4a in toluene afforded (E)-2-(pyridin-2-yl)but-2-enedinitrile 5a in 90% yield. However, heating of4a in acetic anhydride gave 3-(diacetylamino)indolizine-1-carbonitrile 6a and (Z)-2-(pyridin-2-yl)but-2-enedinitrile (5′a)in 67% and 29% yields, respectively. Treatment of 4a

NN3

O

6aMajor product

CN

N

CN

NHAc

N

CN

NAc2

N

CN

CNand

Ac2O, ∆

4a

N

CN

Toluene, ∆

CN

5a

5�aMinor product

7a

(CF3CO)2O, toluene, ∆

AcOH, ∆

NNHCOCF3

O

CN

8a

Scheme 2. Thermal reactions of azide 4a.

in refluxing acetic acid afforded the monoacetylated prod-uct, 3-(acetylamino)indolizine-1-carbonitrile 7a, in 89% yield.However, when 3-azido-4H-quinolizin-4-one 4a was heatedin a mixture of toluene and trifluoroacetic anhydride, 3-trifluoroacetylamino-4H-quinolizin-4-one 8a was obtained in71% yield (Scheme 2).

Similarly, treatment of ethyl 4-oxo-4H-quinolizine-1-carboxylate 4b with acetic anhydride and acetic acid under refluxfurnished ethyl 3-(diacetylamino)indolizine-1-carboxylate 6band its monoacetylated analogue 7b in good yields. Next, wewere also interested if these ring contractions take place in thecase of aza-analogues of 3-azido-4H-quinolizin-4-ones, i.e. 3-azido-4-oxo-4H-pyrido[1,2-a]pyrimidine 4c and 3-azido-4-oxo-4H-pyrimido[1,2-b]pyridazine 4d. Indeed, heating of the azides4c and 4d in acetic anhydride furnished the corresponding ring-contraction products, 3-(diacetylamino)imidazo[1,2-a]pyridine6c and 3-(diacetylamino)imidazo[1,2-b]pyridazine 6d, in 81%and 30% yield, respectively (Scheme 3).

Mechanistic ConsiderationsAmong all products 5–8, only formation of 3-trifluoroacetyl-amino-4H-quinolizin-4-one 8a was expected – thermal elimina-tion of nitrogen from the azide 4a gave the intermediate nitrene 9,which was then treated with trifluoroacetic anhydride acid (con-taining small amounts of trifluoroacetic acid) to afford the finalproduct 8a (Scheme 4). However, we do not have a firm mecha-nistic explanation for the formation of isomeric butenedinitriles5a and 5′a. As reaction conditions were not strictly anhydrous,formation of dinitrile 5a in refluxing toluene could be explainedby addition of water (R = H) to the carbonyl group to give thehydrate 10, which undergoes ring opening into the intermediate11. Elimination of carbon monoxide and water from 11 then

Novel Approach to 3-Aminoindolizines 109

NN3

O

6b

COOEt

N

COOEt

NHAc

N

COOEt

NAc2

7b

N

N

N3

O6c

N

N

NAc2

4b

4c

Ac2O, ∆

AcOH, ∆

Ac2O, ∆

NN

N

N3

O6d

NN

N

NAc2

4d

Ac2O, ∆

Scheme 3. Thermal reactions of azides 4b–d.

furnish the (E)-dinitrile 5a. Accordingly, this transformationcould be regarded as a water-catalyzed eliminative ring-openingreaction. In acetic anhydride, traces of acetic acid (R = acetyl)could act as the nucleophilic promoter (or catalyst) in the trans-formation of 4a into 5′a. However, owing to the higher boilingpoint of acetic anhydride, fumaronitrile 5a isomerized into theless strained maleonitrile 5′a (Scheme 4).

The formation of 3-aminoindolizine, imidazo[1,2-a]pyridine,and imidazo[1,2-b]pyridazine derivatives 6 and 7 is even moredifficult to explain. A possible explanation might be that thermalrearrangement (ring contraction) of the azide 4 into the iso-cyanate 13 takes place first followed by hydrolysis (or acetolysis)and subsequent decarboxylation to give the amine 15. Reactionof 15 with acetic anhydride then gives the diacetylated amine 6,whereas reaction with acetic acid produces the monoacetylatedcompound 7 (Scheme 5).

Structure DeterminationThe structures of compounds 4a–d, 5a, 5′a, 6a–d, 7a, and 8awere determined by spectroscopic (IR, 1H NMR, 13C NMR,mass spectroscopy, and high resolution mass spectroscopy(HRMS)) methods and by analyses for C, H, and N. Compounds4a, 4c, and 4d were not prepared in analytically pure form.Their structures were confirmed by 13C NMR spectroscopy andHRMS.

The configuration around the C=C double bond in isomeric2-(2-pyridinyl)but-2-enedinitriles 5a and 5′a was determined byNMR (heteronuclear multiple bond correlation technique) spec-troscopy on the basis of heteronuclear coupling constants, 3JC–H.Generally, the magnitude of the coupling constant 3JC–H is big-ger in the case of the trans-oriented nuclei (6–12 Hz) than inthe case of cis-oriented nuclei (2–6 Hz). In our case, a cou-pling constant of 3JC2′–H3 9.0 Hz was in agreement with the(E)-configuration of compound 5a, whereas a coupling constantof 3JC2′–H3 5.3 Hz was in agreement with the (Z)-configurationof compound 5b (Fig. 2).

NN3

O

CN

4a

NN

O

CN

9a

�N2

∆

NNHCOCF3

O

CN

8a

NN3

O

CN

4a HO R

R � H, Ac

110°C

NN

CN

NNRO O

H10

�N2

N N

CN

ROO

H

N CN

CN

�CO, �ROH

11

N

CN

5a

145°C CN

5�a

(CF3CO)2O, CF3COOH

��

Scheme 4. Proposed mechanisms for the formation of compound 8a andisomeric dinitriles 5a and 5′a.

The structures of compounds 6a, 6c, and 6d were determinedby X-ray diffraction (Figs 3–5).

Conclusions

In summary, heating 3-azido-4H-quinolizin-4-ones 4a,b, 3-azido-4H-pyrido[1,2-a]pyrimidine 4c, and 3-azido-4H-pyrimido[1,2-b]pyridazine 4d resulted in the formation of two typesof rearrangement products, 2-(pyridin-2-yl)but-2-enedinitriles5 and 5′ and 3-amino(aza)indolizine derivatives 6 and 7. Thereaction outcome depended on the reaction conditions, i.e. sol-vent and temperature. Thus, heating of 4a in toluene furnishedthe 2-(E)-(pyridin-2-yl)but-2-enedinitrile 5a as the only prod-uct. However, heating of 4a–d in acetic anhydride or aceticacid resulted in ring contraction to give the N,N-diacetylated3-amino(aza)indolizines 6a–d or the N-monoacetylated 3-aminoindolizines 7a,b, respectively. Transformations of the3-azidoquinolizinones 4a,b into 3-aminoindolizines 6a,b and7a,b represent novel examples of ring contractions in the4H-quinolizine series, whereas, to the best of our know-ledge, transformations of pyrido[1,2–x]azinones 4c,d into

110 S. Recnik et al.

YN

X

NN

NO

4a–d

N

X

NO

N

N12

NY

X

N

C

O13

NY

X

HN

14

�CO2

O

O

H

H2O

NY

X

NH2

15

AcOH or Ac2O

NY

X

N AcR

6a–d (R � Ac) 7a,b (R � H)

�N2

��

�

�

Scheme 5. Proposed mechanism for the formation of compounds 6 and 7.

N

C

CN

CN

H

5a(E )-isomer

3JC–H � 9.0 Hz (trans)

N

C

H

CN

CN

5�a(Z )-isomer

3JC–H � 5.3 Hz (cis)

Fig. 2. Structure determination by heteronuclear multiple bond correlationspectroscopy.

3-aminoimidazo[1,2–x]azines 7c,d represent the first examplesof ring contractions in the azaquinazoline series. Finally, thesering contractions might also be useful for the synthesis of3-amino(aza)indolizines, because heterocyclic amines 2, the pre-cursors of the azides 4, are easily available by conventional[30–32]

as well as by parallel synthesis.[47,48]

ExperimentalMaterials and General MethodsMelting points were determined on a Kofler micro hot stage.NMR spectra were obtained on a Bruker Avance DPX300at 300 MHz for 1H and 75.5 MHz for 13C nucleus, using[D6]DMSO and CDCl3, with TMS as the internal standard, assolvents. Mass spectra were recorded on an AutoSpecQ spec-trometer, whereas IR spectra were recorded with a Perkin–ElmerSpectrum BX Fourier Transform (FT) IR spectrophotometer.Microanalyses were performed by using a Perkin–Elmer CHNAnalyser 2400 II. Column chromatography was performed onsilica gel (Fluka; silica gel 60, 0.04–0.06 mm).

3-Amino-4-oxo-4H-quinolizine-1-carbonitrile 2a,[40] ethyl3-amino-4-oxo-4H-quinolizine-1-carboxylate 2b,[40] 3-amino-4-oxo-4H-pyrido[1,2-a]pyrimidine 2c,[41] and 3-amino-4-oxo-4H-pyrimido[1,2-b]pyridazine 2d[41] were prepared from methyl(Z )-2-benzyloxycarbonylamino-3-(dimethylamino)propenoate1[40] following literature procedures.

N10

C9

C1

C2

C8a

C8

C7

C6

C5

N4

C3

O16 N11

C14

C12

O13C15

C17

Fig. 3. ORTEP diagram of the molecule of compound 6a with labellingof non-hydrogen atoms. Ellipsoids are drawn at 50% probability level.Distances and angles are within expected ranges.

C8

C8a

N1

C2

C3O14

N9

C10

C12

O15C11

C13

C5

C6

C7

N4

Fig. 4. ORTEP diagram of the molecule of compound 6c with labellingof non-hydrogen atoms. Ellipsoids are drawn at 50% probability level.Distances and angles are within expected ranges.

Novel Approach to 3-Aminoindolizines 111

C10C13

C11

O15

N9

C3

C2

N1

C8a

C8

C7

C6

N5N4

C12

O14

Fig. 5. ORTEP diagram of the molecule of compound 6d with labellingof non-hydrogen atoms. Ellipsoids are drawn at 50% probability level.Distances and angles are within expected ranges.

General Procedure for the Preparation of α-Azidoazinones4a–dAqueous sodium nitrite (2.5 M, 4.4 mL, 11 mmol) was addedslowly to a stirred cold solution (0◦C) of heterocyclic amine 2(10 mmol) in 6 M hydrochloric acid (20 mL), and the resultingmixture was stirred on an ice bath for 15 min. Then aqueoussodium azide (2.5 M, 4.4 mL, 11 mmol) was added slowly andthe mixture was stirred at 0◦C for 1 h and at room temperature for1 h. The precipitate was collected by filtration, and washed withcold water (0◦C, 5 mL) and ethanol (2 mL) to give the azide 4.

The following compounds were prepared in this manner:

3-Azido-4-oxo-4H-quinolizine-1-carbonitrile 4aThe title compound was prepared from 3-amino-4-oxo-

4H-quinolizine-1-carbonitrile 2a (1.85 g, 10 mmol). Yield:1.352 g (64%) of a greenish solid, mp 136–139◦C. Elec-tron impact mass spectrometry (EI-MS): m/z 211 (M+).(Found: C 57.8, H 2.5, N 33.2. C10H5N5O requires C 56.9,H 2.4, N 33.2%.) νmax KBr/cm−1 3126, 2224 (CN), 2132 (N3),1665 (C=O), 1632, 1345, 754. δH (CDCl3) 7.25 (1H, ddd, J1.5, 6.8, 7.2, H7), 7.49 (1H, s, H2), 7.64 (1H, ddd, J 1.1, 6.8,9.0, H8), 7.96 (1H, dd, J 1.5, 9.0, H9), 9.11 (1H, dd, J 1.1, 7.2,H6). δC (CDCl3) 85.8, 116.6, 117.6, 123.8, 127.9, 127.9, 132.8,137.9, 142.7, 154.2. m/z 211.0501 (M+); C10H5N5O requiresm/z 211.0494 (M+).

Ethyl 3-Azido-4-oxo-4H-quinolizine-1-carboxylate 4bThe title compound was prepared from ethyl 3-amino-4-

oxo-4H-quinolizine-1-carboxylate 2b (2.32 g, 10 mmol). Yield:1.730 g (67%) of a greenish solid, mp 124–126◦C. EI-MS: m/z 258 (M+); fast atom bombardment mass spectro-metry (FAB-MS): m/z 259 (MH+). (Found: C 56.1, H 3.7,N 21.5. C12H10N4O3 requires C 55.8, H 3.9, N 21.7%.) νmaxKBr/cm−1 3102, 2121 (N3), 1702, 1660 (C=O), 1229, 1207.

δH (CDCl3) 1.41 (3H, t, J 7.2, COOCH2CH3), 4.38 (2H, q,J 7.2, COOCH2CH3), 7.20 (1H, ddd, J 1.1, 6.8, 7.5, H7), 7.58(1H, ddd, J 1.5, 6.8, 9.5, H8), 8.08 (1H, s, H2), 9.17–9.25 (2H,m, H6, H9). δC (CDCl3) 14.7, 61.5, 102.9, 117.1, 119.5, 124.6,127.7, 128.9, 132.1, 141.9, 154.7, 165.0. m/z 258.0755 (M+);C12H10N4O3 requires m/z 258.0753 (M+).

3-Azido-4H-pyrido[1,2-a]pyrimidin-4-one 4cThe title compound was prepared from 3-amino-4H-

pyrido[1,2-a]pyrimidin-4-one 2c (1.61 g, 10 mmol). Yield:1.366 g (73%) of a white solid, mp 130–132◦C. EI-MS: m/z187 (M+); FAB-MS: m/z 188 (MH+). (Found: C 51.6, H 2.5,N 36.1. C8H5N5O requires C 51.3, H 2.7, N 37.4%.) νmaxKBr/cm−1 3102, 2128, 2093 (N3), 1682 (C=O), 1497, 1335,766. δH (CDCl3) 7.19 (1H, ddd, J 1.1, 6.7, 7.4, H7), 7.64–7.69(2H, m, H8, H9), 8.09 (1H, s, H2), 8.98 (1H, dd, J 1.3, 7.4, H6). δC(CDCl3) 116.6, 119.0, 126.7, 127.1, 134.8, 143.6, 148.5, 154.3.m/z 187.0502 (M+); C8H5N5O requires m/z 187.0494 (M+).

3-Azido-4H-pyrimido[1,2-b]pyridazin-4-one 4dThe title compound was prepared from 3-amino-4H-

pyrimido[1,2-b]pyridazin-4-one 2d (1.62 g, 10 mmol). Yield:1.354 g (72%) of a yellowish solid, mp 114–117◦C. EI-MS:m/z 188 (M+); FAB-MS: m/z 189 (MH+). (Found: C 45.2, H2.1, N 43.3. C7H4N6O requires C 44.7, H 2.1, N 44.7%.) νmaxKBr/cm−1 3091, 2145 (N3), 1690 (C=O), 1538, 1319, 820. δH(CDCl3) 7.38 (1H, dd, J 4.1, 9.4, H8), 7.86 (1H, dd, J 1.9, 9.4,H9), 8.04 (1H, s, H2), 8.66 (1H, dd, J 1.9, 4.1, H6). δC (CDCl3)125.0, 125.3, 135.5, 141.2, 146.0, 146.2, 151.3. m/z 188.0450(M+); C7H4N6O requires m/z 188.0447 (M+).

Thermal Reactions of α-Azidoazinones 4a–d. GeneralProcedure for the Preparation of Compounds 5a, 5′a,6a–d, 7a,b, and 8aA solution of α-azidoazinone 4 (100 mg) in the appropriatesolvent was refluxed for 3–14 h. Volatile components were evap-orated under vacuum and the solid residue was purified bycolumn chromatography. Fractions containing the product werecombined and evaporated under vacuum to give compounds 5a,5′a, 6a–d, 7a,b, and 8a.

The following compounds were prepared in this manner:

(E)-2-(Pyridin-2-yl)but-2-enedinitrile 5aThe title compound was prepared from 3-azido-4-oxo-4H-

quinolizine-1-carbonitrile 4a (100 mg, 0.473 mmol) and toluene(15 mL) by refluxing for 8 h and column chromatography usingethyl acetate/n-hexane 1:1. Yield: 66 mg (90%) of a white solid,mp 94–96◦C. EI-MS: m/z 155 (M+). (Found: C 70.0, H 3.1, N26.7. C9H5N3 requires C 69.7, H 3.3, N 27.1%.) νmax KBr/cm−1

3048, 2237 (CN), 2218 (CN), 1576,1561,1427,794. δH (CDCl3)6.30 (1H, s, CH), 7.49 (1H, ddd, J 1.1, 4.5, 7.9, H5), 7.89–7.91(2H, m, H3, H4), 8.81 (1H, dd, J 1.2, 4.5, H6). δC (CDCl3)111.0, 114.8, 116.2, 123.8, 126.9, 131.8, 138.0, 147.9, 150.5.m/z 155.0489 (M+); C9H5N3 requires m/z 155.0483 (M+).

3-(N,N-Diacetylamino)indolizine-1-carbonitrile 6a and(Z)-2-(Piridin-2-yl)but-2-enedinitrile 5′aThese compounds were prepared from 3-azido-4-oxo-4H-

quinolizine-1-carbonitrile 4a (100 mg, 0.473 mmol) and aceticanhydride (10 mL) by refluxing for 12 h and column chromato-graphy using ethyl acetate/n-hexane 1:1. The minor product 5′aeluted first followed by elution of the major product 6a. Frac-tions of 6a and 5′a were combined separately and evaporatedunder vacuum to give 6a and 5′a.

112 S. Recnik et al.

Data for Compound 6a. Yield: 77 mg (67%) of colourlesscrystals, mp 131–134◦C. EI-MS: m/z 241 (M+); FAB-MS:m/z 242 (MH+). (Found: C 64.8, H 4.6, N 17.2. C13H11N3O2requires C 64.7, H 4.6, N 17.4%.) νmax KBr/cm−1 3417, 3114,2211 (CN), 1726 (C=O), 1513, 1207. δH (CDCl3) 2.32 (6H, s,2 × COCH3), 6.90 (1H, ddd, J 1.1, 6.8, 7.0, H6), 6.99 (1H, s, H2),7.20 (1H, ddd, 1.1, 6.8, 9.0, H7), 7.65 (1H, ddd, J 0.8, 1.1, 7.0,H5), 7.74 (1H, ddd, J 0.8, 1.1, 9.0, H8). δC (CDCl3) 26.1, 82.1,114.7, 115.8, 116.2, 118.8, 119.7, 121.8, 123.9, 137.1, 172.9.

Data for Compound 5′a.Yield: 21 mg (29%) of light pinkishcrystals, mp 115–116◦C. EI-MS: m/z 155 (M+). (Found: C 69.9,H 3.2, N 26.7. C9H5N3 requires C 69.7, H 3.3, N 27.1%.) νmaxKBr/cm−1 3059, 2235 (CN), 2220 (CN), 1577, 1560, 1431, 782.δH (CDCl3) 7.35 (1H, s, CH), 7.47 (1H, ddd, J 1.1, 4.6, 7.7, H5),7.80 (1H, ddd, J 0.8, 1.1, 9.0, H3), 7.89 (1H, ddd, J 1.3, 7.7, 9.0,H4), 8.66 (1H, ddd, J 0.8, 1.1, 4.6, H6). δC (CDCl3) 112.2, 114.1,115.2, 123.5, 127.1, 131.8, 138.3, 147.1, 150.9. m/z 155.0487(M+); C9H5N3 requires m/z 155.0483 (M+).

Ethyl 3-(N,N-Diacetylamino)indolizine-1-carboxylate 6bThe title compound was prepared from ethyl 3-azido-4-oxo-

4H-quinolizine-1-carboxylate 4b (0.100 g, 0.387 mmol) andacetic anhydride (10 mL) by refluxing for 7 h and columnchromatography using ethyl acetate/n-hexane 1:1. Yield: 86 mg(77%) of a greenish oil. EI-MS: m/z 288 (M+). (Found: C 60.7,H 5.7, N 9.1. C15H16N2O4 requires C 60.6, H 5.8, N 9.4%.) νmaxKBr/cm−1 3113, 2981, 1723 (C=O), 1689 (C=O), 1511, 1213,1045. δH (CDCl3) 1.40 (3H, t, J 7.2, COOCH2CH3), 2.31 (6H, s,2 × COCH3), 4.37 (2H, q, J 7.2, COOCH2CH3), 6.84 (1H, ddd,J 1.5, 6.8, 7.2, H6), 7.16 (1H, ddd, J 1.1, 6.8, 9.2, H7), 7.20 (1H,s, H2), 7.61 (1H, dd, J 1.5, 9.2, H8), 8.29 (1H, dd, J 1.1, 6.8,H5). δC (CDCl3) 15.0, 26.1, 60.2, 103.9, 114.1, 115.1, 119.2,120.7, 121.2, 123.5, 134.9, 164.8, 173.2. m/z 288.1121 (M+);C15H16N2O4 requires m/z 288.1110 (M+).

3-(N,N-Diacetylamino)imidazo[1,2-a]pyridine 6cThe title compound was prepared from ethyl 3-azido-4-oxo-

4H-pyrido[1,2-a]pyrimidine 4c (0.100 g, 0.534 mmol) and aceticanhydride (10 mL) by refluxing for 3 h followed by column chro-matography using ethyl acetate. Yield: 94 mg (81%) of a whitesolid, mp 142–144◦C. EI-MS: m/z 217 (M+); FAB-MS: m/z 218(MH+). (Found: C 60.6, H 5.2, N 19.1. C11H11N3O2 requires C60.8, H 5.1, N 19.3%.) νmax KBr/cm−1 3041, 1726 (C=O), 1710,1369, 1251, 1221, 742. δH (CDCl3) 2.34 (6H, s, 2 × COCH3),6.93 (1H, ddd, J 1.1, 6.8, 7.0, H6), 7.30 (1H, ddd, J 1.1, 6.8, 9.1,H7), 7.59 (1H, s, H2), 7.67–7.71 (2H, m, H5, H8). δC (CDCl3)26.2, 113.9, 119.1, 120.4, 121.8, 125.7, 131.7, 145.0, 172.9. m/z217.0865 (M+); C11H11N3O2 requires m/z 217.0861 (M+).

3-(N,N-Diacetylamino)imidazo[1,2-b]pyridazine 6dThe title compound was prepared from ethyl 3-azido-4-oxo-

4H-pyrimido[1,2-b]pyridazine 4c (0.100 g, 0.531 mmol) andacetic anhydride (10 mL) by refluxing for 4 h followed by col-umn chromatography using ethyl acetate.Yield: 35 mg (30%) ofa white solid, mp 155–156◦C. EI-MS: m/z 218 (M+); FAB-MS:m/z 219 (MH+). (Found: C 55.3, H 4.8, N 25.4. C10H10N4O2requires C 55.0, H 4.6, N 25.7%.) νmax KBr/cm−1 3428, 2932,1730 (C=O), 1714, 1220. δH (CDCl3) 2.34 (6H, s, 2 × COCH3),7.16 (1H, dd, J 4.5, 9.4, H7), 7.78 (1H, s, H2), 8.03 (1H, dd, J 1.5,9.4, H8), 8.39 (1H, dd, J 1.5, 4.5, H6). δC (CDCl) 26.1, 118.2,124.2, 127.0, 132.5, 138.7, 144.1, 172.6. m/z 218.0809 (M+);C10H10N4O2 requires m/z 218.0804 (M+).

3-(Acetylamino)indolizine-1-carbonitrile 7aThe title compound was prepared from 3-azido-4-oxo-4H-

quinolizine-1-carbonitrile 4a (100 mg, 0.473 mmol) and glacialacetic acid (10 mL) by refluxing for 14 h followed by columnchromatography using ethyl acetate. Yield: 84 mg (89%) of awhite solid, mp 167–169◦C. EI-MS: m/z 199 (M+); FAB-MS:m/z 200 (MH+). (Found: C 66.3, H 4.5, N 21.0. C11H9N3Orequires C 66.3, H 4.6, N 21.1%.) νmax KBr/cm−1 3233, 2212(CN), 1662 (C=O), 1576, 1517, 1376, 743. δH (CDCl3) 2.14(3H, s, COCH3), 6.95 (1H, ddd, J 1.2, 6.9, 7.0, H6), 7.06 (1H,s, H2), 7.20 (1H, ddd, J 1.1, 6.9, 9.0, H7), 7.66 (1H, dd, J 1.2,9.0, H8), 8.12 (1H, dd, J 1.1, 7.0, H5), 10.09 (1H, s, NH). δC(CDCl3) 23.5, 79.2, 111.7, 113.6, 117.5, 117.7, 121.2, 123.8,124.9, 135.6, 170.7.

Ethyl 3-(Acetylamino)indolizine-1-carboxylate 7bThe title compound was prepared from ethyl 3-azido-4-oxo-

4H-quinolizine-1-carboxylate 4b (100 mg, 0.387 mmol) andglacial acetic acid (10 mL) by refluxing for 14 h followed by col-umn chromatography using ethyl acetate.Yield: 71 mg (75%) ofa white solid, mp 123–126◦C. EI-MS: m/z 246 (M+); FAB-MS:m/z 247 (MH+). (Found: C 63.5, H 6.1, N 11.2. C13H14N2O3requires C 63.4, H 5.7, N 11.4%.) νmax KBr/cm−1 3286, 2982,1690 (C=O), 1667 (C=O), 1521, 1220. δH (CDCl3) 1.32 (3H, t,J 7.1, COOCH2CH3), 2.13 (3H, s, COCH3), 4.27 (2H, q, J 7.1,COOCH2CH3), 6.91 (1H, ddd, J 1.4, 6.8, 6.9, H6), 6.96 (1H,s, H2), 7.19 (1H, ddd, J 1.1, 6.8, 9.2, H7), 8.06–8.09 (2H, m,H5, H8), 9.99 (1H, s, NH). δC (CDCl3) 15.4, 23.5, 59.8, 101.7,110.7, 113.1, 119.4, 120.8, 123.4, 124.3, 133.2, 164.6, 170.5.m/z 246.1004 (M+); C13H14N2O3 requires m/z 246.1010 (M+).

4-Oxo-3-Trifluoroacetylamino-4H-quinolizine-1-carbonitrile 8aThe title compound was prepared from 3-azido-4-oxo-4H-

quinolizine-1-carbonitrile 4a (100 mg, 0.473 mmol) and a mix-ture of toluene (8 mL) and trifluoroacetic anhydride (6 mL) byrefluxing for 14 h followed by column chromatography usingethyl acetate/n-hexane 1:1. Yield: 94 mg (71%) of yellow crys-tals, mp 199–200◦C. EI-MS: m/z 281 (M+). (Found: C 51.6, H2.3, N 14.6. C12H6N3O2F3 requires C 51.3, H 2.2, N 14.9%.)νmax KBr/cm−1 3279, 2228 (CN), 1718 (C=O), 1654 (C=O),1627, 1194, 1161. δH (CDCl3) 7.30 (1H, ddd, J 1.1, 6.8, 7.5,H7), 7.70 (1H, ddd, J 1.1, 6.8, 9.1, H8), 8.06 (1H, dd, J 1.1,9.1, H9), 9.01 (1H, br s, NH), 9.05 (1H, s, H2), 9.15 (1H, dd, J1.1, 7.5, H6). δC (CDCl3) 83.5, 115.7, 116.7 (q, 1J(C–F) 288.2),117.6, 119.1, 123.8, 129.6, 135.7, 136.7, 144.7, 154.1, 156.3 (q,2J(C–F) 37.2).

X-Ray Structure Analyses for Compounds 6a, 6c, and 6dSingle-crystal X-ray diffraction data for compounds 6a, 6c, and6d were collected at room temperature on a Nonius Kappa CCDdiffractometer using the Nonius Collect software.[49] DENZOand SCALEPACK [50] were used for indexing and scaling of thedata. The structures were solved by means of SIR97.[51] Refine-ment was done using the Xtal3.4[52] program package and thecrystallographic plots were prepared by ORTEP III.[53] Crys-tal structures were refined on F values using the full-matrixleast-squares procedure. The non-hydrogen atoms were refinedanisotropically in all cases. The positions of hydrogen atomswere found in the difference Fourier map and their positionaland isotropic atomic displacement parameters were refined in thelast cycles. Absorption correction was not necessary. Regina[54]

Novel Approach to 3-Aminoindolizines 113

Table 1. Crystallographic data for compounds 6a, 6c, and 6d

Compound 6a 6c 6d

Formula C13H11N3O2 C11H11N3O2 C10H10N4O2

Formula weight 241.25 217.23 218.22Crystal system Monoclinic Orthorhombic MonoclinicSpace group P21/n Pbca P21/cCrystal colour Colourless Colourless ColourlessCrystal dimensions [mm3] 0.20 × 0.16 × 0.12 0.25 × 0.20 × 0.18 0.25 × 0.20 × 0.18a [Å] 12.9392(2) 6.4997(2) 5.80780(10)b [Å] 6.96080(10) 13.3176(4) 19.5381(4)c [Å] 13.8441(2) 24.8209(9) 8.9581(2)α [◦] 90 90 90β [◦] 103.9721(9) 90 96.2855(9)γ [◦] 90 90 90Data coll. temp. [K] 293 293 293Z 4 8 4µ [mm−1] 0.093 0.096 0.105Tmin, Tmax 0.982, 0.989 0.977, 0.983 0.980, 0.985λ [Å] 0.71073 0.71073 0.710732θ range [◦] 1.02–27.48 1.02–27.48 1.02–27.48Measured reflns 5231 4526 4380Independent reflns 2279 2178 2064Reflns for refinement 1785 1534 1587Goodness of fit 1.033 1.016 1.062R 0.045 0.047 0.039Rw 0.051 0.039 0.035

weighting scheme was used in all cases. Some details are givenin Table 1.

Crystallographic data (excluding structure factors) for thestructures in the present paper have been deposited with theCambridge Crystallographic Data Centre (CCDC) as supple-mentary publication numbers CCDC 659552–659554. Copiesof the data can be obtained, free of charge, on application toCCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)1223–336033 or email: deposit@ccdc.cam.ac.uk].

AcknowledgementsFinancial support from the Slovenian Research Agency through grants P0–0502–0103, P1–0179, and J1–6689–0103–04 is gratefully acknowledged.We thank the pharmaceutical companies Krka d.d. (Novo mesto, Slove-nia) and Lek d.d., a new Sandoz company (Ljubljana, Slovenia) for theirfinancial support. Crystallographic data were collected on a Kappa CCDNonius diffractometer in the Laboratory of Inorganic Chemistry, Faculty ofChemistry and Chemical Technology, University of Ljubljana, Slovenia. Weacknowledge with thanks the financial contribution of the Ministry of Sci-ence and Technology, Republic of Slovenia, through grant Packet X-2000and PS-511–102, which thus made the purchase of the apparatus possible.

References[1] W. Flitsch, in Bicyclic 5–6 Systems with One Ring Junction Nitro-

gen Atom: One Extra Heteroatom in Comprehensive HeterocyclicChemistry II (Eds A. R. Katritzky, C. W. Rees, E. F. V. Scriven)Vol. 8 (Ed. G. Jones) 1996, Ch. 8.09, pp. 237–248 (Elsevier Science:Oxford).

[2] A. S. Howard, in Bicyclic 5–6 Systems with One Ring Junction NitrogenAtom: No Extra Heteroatom in Comprehensive Heterocyclic Chem-istry II (Eds A. R. Katritzky, C. W. Rees, E. F. V. Scriven) Vol. 8 (Ed.G. Jones) 1996, Ch. 8.10, pp. 262–274 (Elsevier Science: Oxford).

[3] D. R. Sliskovic, in Bicyclic 5–6 Systems with One Ring Junction Nitro-genAtom:Two Extra Heteroatoms 1:1 in Comprehensive Heterocyclic

Chemistry II (Eds A. R. Katritzky, C. W. Rees, E. F. V. Scriven) Vol. 8(Ed. G. Jones) 1996, Ch. 8.12, pp. 363 (Elsevier Science: Oxford).

[4] M. Tišler, B. Stanovnik, in Azolo and Azinopyridazines and Some Oxaand Thia Analogues in Condensed Pyridazines Including Cinnolinesand Phthalazines (Ed. R. N. Castle) 1973, pp. 761–1056 (John Wiley& Sons: New York, NY).

[5] M. Shipman, in Indolizines in Science of Synthesis, Houben-WeylMethods of Molecular Transformations (Ed. E. J. Thomas) 2006, Vol.10, Ch. 10.16, pp. 745–787 (Georg Thieme Verlag: Stuttgart).

[6] G. Hajos, Z. Riedl, in Azaindolizines with Two Nitrogen Atoms in theFive-Membered Ring in Science of Synthesis, Houben-Weyl Methodsof Molecular Transformations (Ed. R. Neier) 2006, Vol. 12, Ch. 12.5,pp. 613–678 (Georg Thieme: Stuttgart).

[7] A. Ohsawa, Y. Abe, H. Igeta, Bull. Chem. Soc. Jpn. 1980, 53, 3273.doi:10.1246/BCSJ.53.3273

[8] A. Ohsawa, Y. Abe, H. Igeta, Chem. Pharm. Bull. (Tokyo) 1982, 30,881.

[9] A. V. Kel’in, A. W. Sromek, V. Gevorgyan, J. Am. Chem. Soc. 2001,123, 2074. doi:10.1021/JA0058684

[10] J. T. Kim, J. Butt, V. Gevorgyan, J. Org. Chem. 2004, 69, 5638.doi:10.1021/JO049259G

[11] Y. Liu, Z. Song, B. Yan, Org. Lett. 2007, 9, 409. doi:10.1021/OL062766V

[12] Š. Marchalín, B. Baumlová, P. Baran, H. Oulyadi, A. Daïch, J. Org.Chem. 2006, 71, 9114, and references therein. doi:10.1021/JO0615044

[13] K. Bedjeguelal, H. Bienaymé, A. Dumoulin, S. Poigny, Ph. Schmitt,E. Tam, Bioorg. Med. Chem. Lett. 2006, 16, 3998. doi:10.1016/J.BMCL.2006.05.014

[14] K. Bedjeguelal, H. Bienaymé, S. Poigny, Ph. Schmitt, E. Tam, QSARComb. Sci. 2006, 25, 504. doi:10.1002/QSAR.200540202

[15] T. Masquelin, H. Bui, B. Brickley, G. Stephenson, J. Schwerkoske,C. Hulme, Tetrahedron Lett. 2006, 47, 2989. doi:10.1016/J.TETLET.2006.01.160

[16] C. Blackburn, B. Guan, P. Fleming, K. Shiosaki, S. Tsai, TetrahedronLett. 1998, 39, 3635. doi:10.1016/S0040-4039(98)00653-4

[17] C. Blackburn, Tetrahedron Lett. 1998, 39, 5469. doi:10.1016/S0040-4039(98)01113-7

114 S. Recnik et al.

[18] H. Bienaymé, K. Bouzid, Angew. Chem. Int. Ed. 1998, 37,2234. doi:10.1002/(SICI)1521-3773(19980904)37:16<2234::AID-ANIE2234>3.0.CO; 2-R

[19] K. Groebke, L. Weber, F. Mehlin, Synlett 1998, 39, 5469.[20] O. Diels, K. Alder, Justus Liebigs Ann. Chem. 1932, 498, 16.

doi:10.1002/JLAC.19324980103[21] R. M. Acheson, G. A. Taylor, J. Chem. Soc. 1960, 1691. doi:10.1039/

JR9600001691[22] R. M. Acheson, G. A. Taylor, J. Chem. Soc. 1960, 4600. doi:10.1039/

JR9600004600[23] R. M.Acheson, J. M. F. Gagan, G.A.Taylor, J. Chem. Soc. 1963, 1903.[24] R. M.Acheson, J. K. Stubbs, J. Chem. Soc. C 1969, 2316. doi:10.1039/

J39690002316[25] R. M. Acheson, S. J. Hodgson, R. G. Wright, J. Chem. Soc., Perkin

Trans. 1 1976, 1911.[26] G. Kaupp, D. Hunkler, I. Zimmermann, Chem. Ber. 1982, 115, 2467,

and references therein. doi:10.1002/CBER.19821150709[27] S. Recnik, J. Svete, B. Stanovnik, Eur. J. Org. Chem. 2001, 3705.

doi:10.1002/1099-0690(200110)2001:19<3705::AID-EJOC3705>

3.0.CO;2-L[28] A. Kakehi, S. Ito, S. Yonezu, K. Marut, K. Yuito, M. Shiohara,

K. Adachi, Bull. Chem. Soc. Jpn. 1987, 60, 1867. doi:10.1246/BCSJ.60.1867

[29] B. Stanovnik, J. Svete, Mini-Reviews Org. Chem. 2005, 2, 211, andreferences therein. doi:10.2174/1570193054368864

[30] B. Stanovnik, J. Svete, Chem. Rev. 2004, 104, 2433, and referencestherein. doi:10.1021/CR020093Y

[31] B. Stanovnik, J. Svete, Synlett 2000, 1077, and references therein.[32] B. Stanovnik, J. Svete, Targets in Heterocycl. Syst. 2000, 4, 105, and

references therein.[33] U. Grošelj, G. Tavcar, D. Bevk, A. Meden, B. Žemva, B. Stanovnik,

J. Svete, Tetrahedron Asymmetry 2006, 17, 1715, and referencestherein. doi:10.1016/J.TETASY.2006.06.007

[34] S. Pirc, D. Bevk, R. Jakše, S. Recnik, L. Golic, A. Golobic, A. Meden,B. Stanovnik, J. Svete, Synthesis 2005, 2969, and references therein.

[35] J. Wagger, D. Bevk,A. Meden, J. Svete, B. Stanovnik, Helv. Chim.Acta2006, 89, 240, and references therein. doi:10.1002/HLCA.200690026

[36] U. Uršic, D. Bevk, S. Pirc, L. Pezdirc, B. Stanovnik, J. Svete, Synthesis2006, 2376, and references therein.

[37] S. Pirc, D. Bevk, A. Golobic, B. Stanovnik, J. Svete, Helv. Chim. Acta2006, 89, 30, and references therein. doi:10.1002/HLCA.200690010

[38] J. Wagger, S. Golic Grdadolnik, U. Grošelj, A. Meden, B. Stanovnik,J. Svete,TetrahedronAsymmetry 2007, 18, 464, and references therein.doi:10.1016/J.TETASY.2007.02.010

[39] C. Malavašic, B. Brulc, P. Cebašek, G. Dahmann, N. Heine, D. Bevk,U. Grošelj, A. Meden, B. Stanovnik, J. Svete, J. Comb. Chem. 2007,9, 219, and references therein. doi:10.1021/CC060114S

[40] R. Toplak, J. Svete, B. Stanovnik, J. Heterocycl. Chem. 1999, 36, 225.[41] R.Toplak, J. Svete, S. Golic Grdadolnik, B. Stanovnik, Collect. Czech.

Chem. Commun. 1999, 64, 177. doi:10.1135/CCCC19990177[42] S. Recnik, J. Svete, A. Meden, B. Stanovnik, Heterocycles 2000, 53,

1793.[43] T. Kocar, S. Recnik, J. Svete, B. Stanovnik, Arkivoc 2002, viii, 143.[44] S. Recnik, J. Svete, B. Stanovnik, Heterocycles 2002, 57, 2091.[45] S. Recnik, J. Svete, B. Stanovnik, Z. Natuforsch. 2004, 59b, 380.[46] B. Japelj, S. Recnik, P. Cebašek, B. Stanovnik, J. Svete, J. Heterocycl.

Chem. 2005, 42, 1167.[47] P. Cebašek, J. Wagger, D. Bevk, R. Jakše, J. Svete, B. Stanovnik,

J. Comb. Chem. 2004, 6, 356. doi:10.1021/CC034066C[48] P. Cebašek, D. Bevk, S. Pirc, B. Stanovnik, J. Svete, J. Comb. Chem.

2006, 8, 95. doi:10.1021/CC050073K[49] Nonius Collect Software 1998 (Nonius, BV: Delft, the Netherlands).[50] Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276, 307.[51] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giaco-

vazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R. Spagna, J.Appl. Cryst. 1999, 32, 115. doi:10.1107/S0021889898007717

[52] S. R. Hall, G. S. D. King, J. M. Stewart, The Xtal 3.4 User’s Manual1995 (University of Western Australia: Perth).

[53] M. N. Burnett, C. K. Johnson, ORTEP-III: Oak Ridge Thermal Ellip-soid Plot Program for Crystal Structure Illustrations, Oak RidgeNational Laboratory Report ORNL-6895, 1996 (Oak Ridge NationalLaboratory: Oak Ridge, TN).

[54] H. Wang, B. E. Robertson, Structure and Statistics in Crystallography(Ed. A. J. C. Wilson) 1985 (Adenine Press: New York, NY).