One-pot synthesis of 3-aryl-substituted 1-hydroxy-2-acylindolizines

Article abstract of DOI:10.5560/ZNB.2012-0230

A new method for the formation of C-C bonds in a one-pot synthesis of 1-hydroxy-2-acyl-3-arylindolizines (acyl: 2-pyridylformyl, thienylformyl; aryl: phenyl, pyridyl, thienyl) from the reaction of 1,3-diketones with aldehydes has been evaluated. X-Ray dif

Full text of DOI:10.5560/ZNB.2012-0230

One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
Tobias Klouberta, Robert Kretschmerb, Helmar Go¨rlsa, Sven Kriecka, and
Matthias Westerhausena
a
Institut fu¨r Anorganische und Analytische Chemie, Friedrich-Schiller-Universita¨t Jena,
Humboldtstraße 8, 07743 Jena, Germany
Institut fu¨r Chemie, Technische Universita¨t Berlin, Straße des 17. Juni 135, 10623 Berlin,
b
Germany
Reprint requests to Prof. M. Westerhausen. Fax: +49 3641 948102. E-mail: m.we@uni-jena.de
Z. Naturforsch. 2012, 67b, 1151 – 1158 / DOI: 10.5560/ZNB.2012-0230
Received August 30, 2012
Dedicated to Professor Rainer Beckert on the occasion of his 60th birthday
A new method for the formation of C–C bonds in a one-pot synthesis of 1-hydroxy-2-acyl-3-
arylindolizines (acyl: 2-pyridylformyl, thienylformyl; aryl: phenyl, pyridyl, thienyl) from the reaction
of 1,3-diketones with aldehydes has been evaluated. X-Ray diffraction studies of single crystals have
provided structural information about the so-formed indolizines. In the crystalline state, the hydroxyl
units form intra- or intermolecular hydrogen bonds to the acyl functionalities. The color of these
indolizines depends on the pH value of the solvent.
Key words: Aza-Nazarov Cyclization, Fused-ring Systems, Indolizines, Multi-component Reaction,
Nitrogen Heterocycles
Introduction
ii) The choice of substituents at the N-methylide
moieties of the pyridinium ion is narrowed to acyl
groups [24] or hydrogen [25] and, hence, affects
position 3 of the indolizine.
iii) Furthermore, the applied oxidant when using ole-
fines may cause lower yields of the desired prod-
ucts [26].
Indolizines represent interesting targets in synthetic
chemistry due to the fact that they offer manifold appli-
cations as e. g. dyes [1], pharmaceuticals [2], and spec-
tral sensitizers [3 – 7]. While aromatic indolizines are
very scarce in nature, the fully reduced form of these
heteroaromatic bicyclic compounds, the so-called in-
dolizidines, are quite common [8]. Monomorine I [9], Moreover, to the best of our knowledge no synthesis
pumiliotoxines [10], and tashiromine [11] represent has been described for the preparation of indolizines
characteristic examples of this substance class. For bearing a hydroxyl group in position 1 and a keto func-
these applications of indolizines a well-defined sub- tionality (an acyl group) in position 2. Here, we de-
stitution pattern is required and has been the target of scribe an unprecedented synthesis of 3-aryl-substitued
diverse research efforts for the construction of substi- 1-hydroxy-2-acylindolizines from convenient starting
tuted indolizines [5, 12, 13]. Therefore, different tran- materials as well as their spectroscopic and structural
sition metal-mediated and metal-free strategies for the characteristics.
synthesis of substituted indolizines were investigated
Another cyclization reaction of 3-(pyridine-2-
over the last years [13 – 23]. The favored route is ylmethylene)pentane-2,4-dione [2-py-CH=C(Ac)2] in
based on the reaction of pyridinium N-methylides with acetic acid anhydride at 60 ◦C or in refluxing dimethyl-
alkynes (Scheme 1) or with olefines in the presence of sulfoxide yielded indolizines A and B, respectively,
an oxidant, but these strategies also cause the following with related substitution patterns (Scheme 2) [27, 28].
challenges:
Results and Discussion
i) In the reaction with alkynes two electron-with-
drawing groups have to be bound at the alkyne unit
restricting the substitution pattern in 1,2 position.
Initially, the 1,3-diketones 1 and 2 were prepared
via a “crossed” Claisen condensation of ethyl picol-
© 2012 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com

1152
T. Kloubert et al. · One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
Scheme 1. Schematic drawing of the indolizine synthesis from pyridinium methylides and alkynes.
to very good yields; additional information is given in
Table 1.
As depicted in Scheme 4, the reaction sequence is
initiated by deprotonation of the diketones (1 and 2)
leading to I, which participates in an equilibrium with
the corresponding enolates. Intermediate I reacts with
the aldehyde forming the aldol III that undergoes base-
induced dehydration to the corresponding intermediate
endione derivates V [36]. After protonation of V0 (a ro-
tamer of V) the cationic enol VI reacts in a conrota-
tory electrocyclization (aza-Nazarov cyclization [37])
to VII which finally forms the desired products 3e–3d
upon deprotonation.
Scheme 2. Indolizines A and B obtained from 2-Py-
CH=C(Ac)2.
inate with either acetophenone, 2-acetylpyridine, or
All four compounds were isolated as single crystals
2-acetylthiophene in toluene at 0 ◦C with yields be- which were suitable for X-ray diffraction studies. The
tween 72 and 95% in the presence of sodium hy- molecular structures are depicted in Figs. 1 to 4. Se-
dride [29]. As already discussed in some detail, β- lected bond lengths are summarized in Table 2. The
diketones tend to tautomerize [30 – 33] with the keto- numbering scheme of the indolizine backbone is iden-
enol equilibrium strongly dependent on the polarity tical for all derivatives. In the compounds 3a (Fig. 1)
of the solvent [34, 35]. In a subsequent reaction step, and 3c (Fig. 3) intramolecular hydrogen bonds exist
compounds 1 and 2 were treated with benzaldehyde, between the hydroxyl groups and the pyridyl nitro-
pyridine-2-carbaldehyde or thiophene-2-carbaldehyde gen atoms R. This arrangement is less favored if R is
in toluene under reflux conditions (Scheme 3). The re- a thienyl group as in 3b and 3d enabling only an in-
actions proceeded within six hours leading to the de- tramolecular hydrogen bond to the rather soft sulfur
sired 1-hydroxy-2-acyl-3-arylindolizines 3a–d in good base. Due to this fact derivative 3b forms intramolec-
Scheme 3. One-pot synthesis of 3-aryl-substituted 1-hydroxy-2-acylindolizines.

T. Kloubert et al. · One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
1153
Diketone
R0
R
Product
Yield (%)
77
Table 1. Substitution pattern and yield of
1-hydroxy-2-ketoindolizines 3.
1
C6H5
2-C5H4N
3a
OH
N
N
O
2
1
C6H5
2-C4H3S
3b
3c
67
82
2-C5H4N
2-C5H4N
2
2-C4H3S
2-C4H3S
3d
91
Scheme 4. Proposed mechanism for the condensation/cyclization cascade [R = 2-pyridyl, R0 = Ph (3a); R = C4H3S, R0 = Ph
(3b); R = R0 = Py (3c); R = R0 = C4H3S (3d)] [34, 35].

1154
T. Kloubert et al. · One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
Table 2. Selected bond lengths (pm) of the 1-hydroxy-2-acyl-
3-arylindolizines 3. For comparison reasons, 1-methoxy-2-
acyl-3-(2-pyridyl)indolizine 4 is included [38].
3a
3b
3c
3d
4
R
pyridyl
phenyl
thienyl
phenyl
Pyridyl
Pyridyl
thienyl
thienyl
pyridyl
pyridyl
R0
N1–C1
N1–C5
N1–C8
C1–C2
C2–C3
C3–C4
C4–C5
C5–C6
C6–C7
C7–C8
C6–O1
C7–Cexo
Cexo–O2
C8–C9
139.3(3) 138.8(5) 139.5(2) 138.8(4) 138.7(3)
140.6(3) 141.2(5) 140.8(2) 141.0(4) 141.0(3)
136.5(3) 138.1(5) 136.5(2) 137.4(4) 138.7(2)
135.1(3) 134.8(6) 135.0(2) 134.9(5) 134.9(3)
142.0(3) 142.2(6) 142.7(2) 142.9(5) 141.9(3)
135.4(4) 134.9(6) 135.8(2) 135.2(6) 135.4(3)
140.7(3) 142.1(6) 141.1(2) 141.8(5) 141.3(3)
139.2(4) 137.8(5) 138.5(2) 137.2(5) 139.1(3)
142.2(3) 142.3(5) 142.6(2) 141.6(4) 139.8(3)
141.7(3) 140.5(5) 142.1(2) 140.9(4) 139.6(3)
135.6(3) 135.9(4) 135.1(2) 136.5(4) 137.0(2)
147.5(4) 145.8(5) 147.2(2) 145.7(5) 148.3(3)
122.7(3) 124.1(4) 122.6(2) 123.8(4) 122.0(2)
148.3(3) 146.9(5) 147.7(2) 146.1(4) 145.9(3)
Fig. 2. Molecular structure model and numbering scheme of
3b determined by X-ray diffraction investigations (ORTEP,
50% probability ellipsoids, H atoms shown with arbitrary
radii).
Fig. 3. Molecular structure model and numbering scheme of
3c determined by X-ray diffraction investigations (ORTEP,
50% probability ellipsoids, H atoms shown with arbitrary
radii).
Fig. 1. Molecular structure model and numbering scheme of
3a as determined by X-ray diffraction investigations (ORTEP,
50% probability ellipsoids, H atoms shown with arbitrary
radii).
The ligand pattern mainly influences the C5–C6,
ular O–H···O bonds to the harder oxygen base of the C7–Cexo, N1–C8 bonds as well as the keto function
acyl substituent (Fig. 2). This bonding situation is quite of the acyl substituent. The parameters of derivatives
similar to that of the enol forms of asymmetric di- 3a and 3c are very similar because both compounds
acylmethanes [30 – 34]. Another possibility is the for- are stabilized by an intramolecular O–H···N hydrogen
mation of intermolecular O–H···O bonds between hard bond. In 3b and 3d the acyl moieties are rotated around
donor sites as favored for 3d leading to the formation the C7–Cexo bond, and the keto group is oriented to-
of dimers as shown in Fig. 4.
wards the hydroxyl group enabling intra- (3b) and in-

T. Kloubert et al. · One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
1155
tion of 3d to an ammonia/ammonium chloride buffer
(pH = 10) changed the color to green. The correspond-
ing UV/Vis spectra of 3d (4.0 × 10−5 mol L−1) under
acidic and alkaline conditions are displayed in Fig. 5.
Conclusion
A
straight-forward one-pot synthesis allows
the isolation of crystalline 1-hydroxy-2-acyl-3-
arylindolizines 3a–d with good to excellent yields.
Studied examples include indolizines with aryl groups
R0 being phenyl, 2-pyridyl and 2-thienyl. The sub-
stituents R of the acyl functions are based on 2-pyridyl
and 2-thienyl rings. The donor sites of these groups
significantly influence the molecular structures of
these indolizines. The pyridyl derivatives 3a and
3c crystallize as monomers with an intramolecular
stabilization via a O–H···N hydrogen bond as part of
a seven-membered ring, whereas indolizine 3b forms
an intramolecular O–H···O bond to the acyl moiety
due to the low donor strength of the thiophene unit
with a rather soft sulfur base. Another bonding mode
is realized by derivative 3d which prefers dimerization
via intermolecular O–H···O bonds.
Fig. 4. Structure model and numbering scheme of dimeric
indolizine 3d as determined by X-ray diffraction; the sec-
ond half of the molecule is generated by inversion symmetry
(ORTEP, 50% probability ellipsoids, H atoms drawn with ar-
bitrary radii).
Experimental Details
General
All chemicals were purchased from Acros Organics and
Sigma-Aldrich and used without further purifications. Mass
spectra were determined by using a Finnigan MAT SSQ 710
instrument. 1H and 13C NMR spectra were obtained with
Bruker Advance 200 (200 MHz) and Bruker Advance 400
(400 MHz) spectrometers. The atom numbering for the NMR
signals corresponds to that in Fig. 1. IR spectra were recorded
on a Bruker EQUINOX 55 instrument. Elemental analysis on
a Leco CHNS-932 apparatus gave values for C, H, N, and S
within ±0.2% of the expected data. Finally, UV/Vis spec-
tra were recorded with a Specord S600 spectrometer (Ana-
lytik Jena), and the uncertainty of the molar absorption co-
efficients corresponds to ±1.4%. The syntheses of 1 and 2
were performed according to literature procedures [27, 28].
Fig. 5. UV/Vis spectrum of 3d (4.0×10−5 M) at pH = 1
(broken line) and 10 (solid line).
termolecular O–H···O bonds (3d). These changes lead
to a slight shortening of the C5–C6 and C7–Cexo bonds
as well as to an elongation of the N1–C8 and O2–Cexo
bonds.
The intense color of these indolizines and the ex-
tended conjugated π systems with Lewis basic donor
sites suggested an investigation of pH-dependent color
changes. A 1.5 × 10−3 mol L−1 solution of 3d in ace-
tonitrile which showed a bright red color was adjusted
to pH 1 with hydrochloric acid (0.1 mol L−1). The
color of the solution changed thereby to orange. Ex-
Synthesis and characterization of
1-hydroxy-2-(2-pyridylcarbonyl)-3-phenylindolizine (3a)
A solution of 1,3-bis(2-pyridyl)propane-1,3-dione (1)
(2.00 g, 8.84 mmol), benzaldehyde (1.00 g, 9.42 mmol),
piperidine (76 mg, 0.89 mmol), and glacial acetic acid
(106 mg, 1.79 mmol) in 50 mL of toluene was refluxed for
position of the 1.5 × 10−3 mol L−1 acetonitrile solu- 6 h. The reaction mixture was cooled to ambient temper-

1156
T. Kloubert et al. · One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
ature, and a red solid product was obtained by filtration Synthesis and characterization of
and washed several times with cold pentane. Yield: 2.15 g 1-hydroxy-2-(2-pyridylcarbonyl)-3-pyridylindolizine (3c)
of 3a (6.83 mmol, 77%). M. p.: 153.6 ◦C. – 1H NMR
A
solution of 1,3-bis(2-pyridyl)propane-1,3-dione
(400 MHz, 300 K, [D6]DMSO): δ = 12.17 (s, 1H, OH), 8.71
(1) (2 g, 8.84 mmol), pyridine-2-carbaldehyde (947 mg,
8.84 mmol), piperidine (76 mg, 0.89 mmol) and glacial
acetic acid (106 mg, 1.79 mmol) in 50 mL of toluene
was refluxed for 6 h. The reaction mixture was cooled
to room temperature, and the dark-brown solid product
was isolated by filtration and washed several times with
cold pentane. Yield: 2.30 g of 3c (7.29 mmol, 82%). M.
p.: 184.6 ◦C. – 1H NMR (400 MHz, 300 K, [D6]DMSO):
δ = 11.40 (s, 1H, OH), 8.62 (d, 3J(H13,H14) = 4.8 Hz, 1H,
H14), 8.59 (d, 3J(H18,H19) = 4.4 Hz, 1H, H19), 8.41 (d,
3J(H4,H5) = 6.2 Hz, 1H, H4), 8.10 – 8.04 (m, 1H, H12), 8.03
(d, 3J(H11,H12) = 7.6 Hz, 1H, H11), 7.70 – 7.764 (m, 2H,
(d, 3J (H13, H14) = 4.5 Hz, 1H, Pyr14), 8.06 (dt, 3J (H12
,
H11,13) = 8.0 Hz, 4J (H12, H14) = 4.0 Hz, 1H, Pyr12), 7.99
(d, 3J(H11,H12) = 8.0 Hz, 1H, Pyr11), 7.72 – 7.69 (m, 1H,
Pyr13), 7.56 (d, 3J(H4,H5) = 5.8 Hz, 1H, H4), 7.45 – 7.33
(m, 6H, H7,16,17,18,19,20), 6.45 – 6.40 (m, 2H, H5,6). – 13C
NMR (400 MHz, 300 K, [D6]DMSO): δ = 188.3 (C9), 154.4
(C10), 147.8 (C14), 139.5 (C12), 136.2 (C2), 131.6 (C15),
130.9 (C16,20), 129.1 (C17,19), 128.3 (C18), 128 (C13), 124.6
(C11), 123 (C3), 121 (C4), 119.4 (C7), 118.4(C8), 114.4 (C5),
114.1(C6). – IR (ATR): ν = 1709 m, 1625 vs, 1564 vs, 1514
s, 1482 m, 1459 m, 1446 m, 1415 s, 1386 m, 1366 s, 1310
w, 1298 m, 1273 vs, 1252 m, 1153 m, 1140 m, 1093 s, 1023
s, 1004 m, 943 s, 908 m, 875 m, 843 m, 816 m, 798 m, 758
m, 745 m, 731 cm−1, s. – Elemental analysis (C20H14N2O2,
314.34): calcd. C 76.42, H 4.49, N 8.91; found C 76.28,
H 4.52, N 8.73. – UV/Vis: λmax = 496 nm (ε = 1.23 × 104
L mol−1 cm−1).
H13,17), 7.50 (dd, J(H6,H7) = 8.2 Hz, J(H5,H7) = 2.8 Hz,
1H, H7), 7.26 (d, 3J(H16,H17) = 8 Hz, 1H, H16), 7.24 – 7.21
(m, 1H, H18), 6.59 – 6.55 (m, 2H, H5,6). – 13C NMR
(400 MHz, 300 K, [D6]DMSO): δ = 189.3 (C9), 154.1
(C10), 150.3 (C15), 148.8 (C19), 147.6 (C14), 138.6 (C12),
136.2 (C17), 135.9 (C2), 127.3 (C13), 125.7 (C16), 123.9
(C11), 121.9 (C4), 121.5 (C18), 120.2 (C3), 119.4 (C8),
118.4 (C7), 115.0 (C5), 114.6 (C1), 113.9 (C6). – IR (ATR):
ν = 1771 m, 1635 s, 1619 vs, 1586 vs, 1554 vs, 1514 s, 1496
m, 1457 s, 1445 s, 1432 s, 1370 m, 1303 m, 1274 vs, 1257
s, 1235 s, 1153 vs, 1092 vs, 1051 m, 1028 vs, 1006 s, 946
s, 851 m, 810 s, 785 cm−1, vs. – MS (EI): m/z (%) = 315
(50) [M]+, 209 [M–PyrCH2N]+, 158 (12) [M–2Pyr]+, 106
(33) [PyrCH2N]+, 78 (78) [Pyr]+. – Elemental analysis
(C19H13N3O2, 315.32): calcd. C 72.37, H 4.16, N 13.33;
found C 72.23, H 4.05, N 13.32. – UV/Vis: λmax = 448 nm
(ε = 1.40 × 104 L mol−1 cm−1).
3
4
Synthesis and characterization of
1-hydroxy-2-(2-thienylcarbonyl)-3-phenylindolizine (3b)
A
solution of 1-(2-pyridyl)-3-(2-thienyl)propane-1,3-
dione (2) (2.00 g, 8.65 mmol), benzaldehyde (1.00 g,
9.42 mmol), piperidine (74 mg, 0.87 mmol), and glacial
acetic acid (105 mg, 1.74 mmol) in 50 mL of toluene was
refluxed for 6 h. All solvents were removed, and the crude
product was purified by using a soxhlet extractor with pen-
tane as solvent. The product was obtained by slow evap-
oration of the solvent (red needles). Yield: 1.86 g of 3b
(5.71 mmol, 67%). M. p.: 118.1 ◦C. – 1H NMR(400 MHz,
300 K, [D6]DMSO): δ = 8.91 (s, 1H, OH), 7.92 – 7.89 (m,
2H, H4,13), 7.54 – 7.51 (m, 2H, H7,11), 7.42 – 7.34 (m, 4H,
H15,16,18,19), 7.31 (t, 3J(H17,H16,18) = 8.0 Hz, 1H, H17),
Synthesis and characterization of
1-hydroxy-2-(2-thienylcarbonyl)-3-thienylindolizine (3d)
A
solution of 1-(2-pyridyl)-3-(2-thienyl)propane-1,3-
7.07 (dd, 3J(H12, H11,13) = 3.9 Hz, 1H, H12), 6.56 – 6.52 (m, dione (2) (2.00 g, 8.65 mmol), thiophene-2-carbaldehyde
1H, H6), 6.48 – 6.45 (m, 1H, H5). – 13C NMR (400 MHz, (1.00 g, 8.92 mmol), piperidine (74 mg, 0.87 mmol), and
300 K, [D6]DMSO): δ = 184.0 (C9), 145.0 (C10), 135.4 glacial acetic acid (105 mg, 1.74 mmol) in 50 mL of toluene
(C11), 134.6 (C13), 133.2 (C2), 130.0 (C14), 129.8 (C15,19), was refluxed for 6 h. Then, all solvents were removed, and
128.8 (C16,18), 128.3 (C12), 127.7 (C17), 120.9 (C4), 120.0 the crude product was purified by using a Soxhlet ex-
(C2), 119.0 (C8), 118.1 (C7), 115.7 (C1), 114.6 (C6), 112.5 tractor with pentane as solvent. The product was obtained
(C5). – IR (ATR): ν = 3092 m, 1640 m, 1592 s, 1546 m, by slow evaporation of the solvent (bright-red needles).
1511 s, 1471m, 1416 s, 1359 s, 1288 s, 1227 s, 1144 Yield: 2.57 g of 3d (7.89 mmol, 91%). M. p.: 117 ◦C. –
m, 1078w, 1049 m, 1001 m, 958 m, 929 m, 910 m, 851 1H NMR (400 MHz, 300 K, [D6]DMSO): δ = 9.00 (s, 1H,
s, 781 m, 756 s, 727 s, 703 cm−1, vs. – MS (EI): m/z OH), 8.04 (d, 3J(H4,H5) = 6.2 Hz, 1H, H5), 7.95 (dd,3J
(%) = 319 (87) [M]+, 235 (100) [M–C4H4S]+, 207 (83) [M– (H12,H13) = 5.0 Hz, 4J(H11,H13) = 1.0 Hz, 1H, H13), 7.61
C5H4SO]+, 179 (100), 129 (77) [M–Ph–C5H4SO–H]+, 111 (d, 3J(H16,H17) = 5.1 Hz, 4J(H15,H17) = 0.9 Hz, 1H, H17),
(53) [C5H3SO]+, 78 (64) [C6H6]+. – Elemental analysis 7.57 – 7.53 (m, 2H, H7,11), 7.26 (dd, J(H15,H16) = 3.6 Hz,
3
(C19H13NO2S, 319.38): calcd. C 71.45, H 4.10, N 4.39, S 4J(H15,H17) = 1.1 Hz, 1H, H15), 7.14 – 7.10 (m, 2H, H12,16),
10.04; found C 71.78, H 4.08, N 4.37, S 10.07. – UV/Vis: 6.62 – 6.54 (m, 2H, H5,6). – 13C NMR (400 MHz, 300 K,
λ
max = 498 nm (ε = 1.27 × 104 L mol−1 cm−1).
[D6]DMSO): δ = 183.7 (C9), 145.0 (C10), 135.3 (C11),

T. Kloubert et al. · One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
1157
Table 3. Crystal data and data
collection and refinement de-
tails for the X-ray struc-
ture determinations of the in-
dolizines 3a, 3b, 3c, and 3d.
Compound
3a
3b
3c
3d
Formula
C20H14N2O2
314.33
−90(2)
monoclinic
P21/n
6.3272(6)
21.8442(11)
10.7914(9)
91.555(3)
1491.0(2)
4
C19H13NO2S
319.36
C19H13N3O2
315.32
−90(2)
monoclinic
C2/c
32.7942(12)
6.9605(2)
12.9961(4)
97.834(2)
2938.86(16)
8
1.43
0.9
10 001
3346/0.0362
2504
C17H11NO2S2
325.39
−140(2)
monoclinic
C2/c
19.2272(7)
9.0663(4)
18.0685(6)
110.073(2)
2958.4(2)
8
Mw, g mol−1
T, K
−140(2)
orthorhombic
P212121
9.2150(9)
10.0732(7)
16.2277(17)
90
1506.3(2)
4
1.41
2.2
7425
3360/0.0451
2862
0.0681
Crystal system
Space group
˚
a, A
˚
b, A
˚
c, A
β, deg
3
˚
V, A
Z
ρ, g cm−3
1.40
0.9
9083
1.46
3.6
8787
µ(MoKα ), cm−1
Measured data
Unique data/Rint
Data with I > 2σ(I)
R1 [I > 2σ(I)]a
wR2 (all data, on F2)a
Sb
3351/0.0790
1765
0.0574
0.1295
1.018
3356/0.0522
2646
0.0663
0.1723
1.148
0.0401
0.0984
1.031
0.1348
1.182
Flack parameter x
∆ρfin (max/min), e A
CCDC no.
–
0.08(16)
0.356/−0.334
864 735
–
–
−3
˚
0.202/−0.251
0.181/−0.213
0.542/−0.439
864 734
864 736
864 737
a
R1 = Σ||Fo|–|F ||/Σ|Fo|; wR2 = [Σw(F2–F2)2/Σw(F2)2]1/2, w = [σ2(Fo2) + (AP)2+BP]−1, where
c
o
c
o
P = (Max(Fo2,0)+2F2)/3; b S = GoF = [Σw(Fo2–F2)2/(nobs–nparam)]1/2
.
c
c
134.9 (C13), 133.1 (C14), 128.4 (C12,15), 127.6 (C16,17), of compounds 3b to 3d were located by difference Fourier
121.6 (C4), 119.8 (C8), 117.9 (C7), 116.7 (C1), 115.1 (C5), synthesis and refined isotropically. The other H atoms were
112.8 (C6), 112.0 (C2). – IR (ATR): ν = 3425 m, 1633 m, included at calculated positions with fixed displacement pa-
1597 s, 1556 m, 1543 w, 1517 s, 1473 m, 1444 m, 1413 vs, rameters. All non-hydrogen atoms were refined anisotropi-
1348 s, 1276 vs, 1224 s, 1214 s, 1182 m, 1132 m, 1094 cally [40]. Crystallographic data as well as structure solution
m, 1055 m, 1042 m, 997 m, 944 s, 897 w, 856 s, 847 s, and refinement details are summarized in Table 3. The pro-
778 s, 713 cm−1, vs. – Elemental analysis (C17H11NO2S2, gram XP (Siemens Analytical X-ray Instruments, Inc.) was
325.40): calcd. C 62.75, H 3.41, N 4.30, S 19.71; found C used for structure representations.
62.52, H 3.49, N 4.32, S 19.69. – UV/Vis: λmax = 448 nm
CCDC 864734 (3a), CCDC 864735 (3b), CCDC 864736
(3c), and CCDC 864737 (3d) contain the supplementary
crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data request/cif.
(ε = 1.37 × 104 L mol−1 cm−1).
X-Ray structure determinations
The intensity data for the compounds were collected
on a Nonius KappaCCD diffractometer using graphite-
monochromatized MoKα radiation. Data was corrected
for Lorentz and polarization effects but not for absorp-
tion [39, 40].
The structures were solved by Direct Methods (SHELXS)
and refined by full-matrix least-squares techniques against
Fo2 (SHELXL-97) [41, 42]. The hydrogen atom of the hy-
droxyl group O1 of compound 3a and all hydrogen atoms
Acknowledgement
S. K. and R. K. acknowledge the Stiftung Stipendien-
Fonds des Verbandes der Chemischen Industrie (Frankfurt
a. M./Germany) for a Ke´kule´ scholarship. We also thank the
Friedrich Schiller University in Jena/Germany for financial
support.
[1] C. H. Weidner, D. H. Wadsworth, S. L. Bender, D. J.
Beltman, J. Org. Chem. 1989, 54, 3660 – 3664.
[2] G. S. Singh, E. E. Mmatli, Eur. J. Med. Chem. 2011, 46,
5237 – 5257.
[3] J. W. Weeler, Eur. Pat. Appl., EP 161 789 1985; Chem.
Abstr. 1985, 104, 170108.
[4] V. R. Vemula, S. Vurukonda, C. K. Bairi, Int. J. Pharm.
Sci. Rev. Res. 2011, 11, 159 – 163.

1158
T. Kloubert et al. · One-pot Synthesis of 3-Aryl-substituted 1-Hydroxy-2-acylindolizines
[5] K. Sarkunam, M. Nallu, J. Heterocyclic Chem. 2005, [26] X. Wei, Y, Hu, T. Li, H. Hu, J. Chem. Soc., Perkin
42, 5 – 11. Trans. I 1993, 2487 – 2489.
[6] T. L. Gilchrist, J. Chem. Soc., Perkin Trans. I 2001, [27] E. K. Pohjala, J. Heterocycl. Chem. 1977, 14, 273 –
2491 – 2515. 279.
[7] A. R. Katrizky, G. Qiu, B. Yang, H.-Y. He, J. Org. [28] E. Pohjala, Heterocycles 1974, 2, 585 – 588.
Chem. 1999, 64, 7618 – 7621.
[8] For an overview see: J. P. Michael, Beilstein J. Org.
Chem. 2007, 3, No. 27, and refs. therein.
[9] H. M. Garaffo, T. F. Spande, J. W. Daly, A. Baldessari,
E. G. Gros, J. Nat. Prod. 1993, 56, 357 – 373.
[29] P. C. Andrews, G. B. Deacon, R. Frank, B. H. Fraser,
P. C. Junk, J. G. MacLellan, M. Massi, B. Moubaraki,
K. S. Murray, M. Silberstein, Eur. J. Inorg. Chem. 2009,
2009, 744 – 751.
[30] J. L. Burdett, M. T. Rogers, J. Am. Chem. Soc. 1964, 86,
2105 – 2109.
[10] J. W. Daly, T. Tokuyama, T. Fujiwara, R. J. Highet,
I. L. Karle, J. Am. Chem. Soc. 1980, 102, 830 – 836.
[31] J. Emsley, Chem. Soc. Rev. 1980, 9, 91 – 124.
[11] S. P. Mardsen, A. D. McElhinney, Beilstein J. Org. [32] J. Emsley, Structure and Bonding 1984, 57, 147 – 191.
Chem. 2008, 4, No. 8.
[33] F. Hibbert, J. Emsley, Adv. Phys. Org. Chem. 1991, 26,
[12] T. Uchida, K. Matsumoto, Synthesis 1976, 209 – 236.
255 – 379.
[13] F. J. Swinbourne, J. H. Hunt, G. Klinkert, Adv. Hetero- [34] J. Emsley, N. J. Freeman, J. Mol. Struct. 1987, 161,
cycl. Chem. 1978, 23, 103 – 170. 193 – 204.
[14] U. Bora, A. Saikia, R. C. Boruah, Org. Lett. 2003, 5, [35] S. Yamabe, N. Tsuchida, K. Miyajima, J. Phys. Chem.
435 – 438. A 2004, 108, 2750 – 2757.
[15] X. Fang, Y.-M. Wu, J. Deng, S.-W. Wang, Tetrahedron [36] In the condensation step other intermediate compounds
2004, 60, 5487 – 5493.
[16] N. A. Morra, C. L. Morales, B. Bajtos, X. Wang, H.
are conceivable. For the sake of clarity we depicted
only one variant.
Jang, J. Wang, B. L. Pagenkopf, Adv. Synth. Catal. [37] The term “aza-Nazarov cyclization” was introduced in:
2006, 348, 2385 – 2390.
M. A. Ciufolini, F. Roschangar, Tetrahedron 1997, 53,
[17] B. Yan, Y. Liu, Org. Lett. 2007, 9, 4323 – 4326.
11049 – 11060.
[18] I. V. Seregin, V. Gevorgyan, J. Am. Chem. Soc. 2006, [38] T. Kloubert, R. Kretschmer, H. Go¨rls, M. Wester-
128, 12050 – 12051. hausen, Acta Crystallogr. 2012, E68, o2631–o2632.
[19] A. V. Kel’in, A. W. Sromek, V. Gevorgyan, J. Am. [39] R. Hooft, COLLECT, Nonius KappaCCD Data Collec-
Chem. Soc. 2001, 123, 2074 – 2075.
tion Software, Nonius BV, Delft (The Netherlands)
[20] Y. Liu, Z. Song, B. Yan, Org. Lett. 2007, 9, 409 – 412.
1998.
[21] J. Kaloko, A. Hayford, Org. Lett. 2005, 7, 4305 – 4308. [40] Z. Otwinowski, W. Minor in Methods in Enzymology,
[22] H. Kim, K. Lee, S. Kim, P. H. Lee, Chem. Commun.
Vol. 276, Macromolecular Crystallography, Part A
(Eds.: C. W. Carter Jr, R. M. Sweet), Academic Press,
New York, 1997, pp. 307 – 326.
2010, 46, 6341 – 6343.
[23] J. Jacobs, E. van Hende, S. Claessens, N. De Kimpe,
Curr. Org. Chem. 2011, 15, 1340 – 1362.
[24] A. Padwa, D. J. Austin, L. Precedo, L. Zhi, J. Org.
Chem. 1993, 58, 1144 – 1150.
[25] Y. Miki, H. Hachiken, S. Takemura, Heterocycles 1984,
22, 701 – 703.
[41] G. M. Sheldrick, Acta Crystallogr. 1990, A46, 467 –
473.
[42] G. M. Sheldrick, Acta Crystallogr. 2008, A64, 112 –
122.