Novel synthetic approach toward C-substituted piperazine derivatives via C-N bonds formation of α-bromoarylethanones and ethanolamine

Article abstract of DOI:10.1002/jhet.1088

A new method for the synthesis of novel C-substituted piperazine derivatives bearing aryl substituents on 2,6-C positions has been developed by one-pot three-component sequential reaction of α-bromoarylethanones with ethanolamine in the presence of formic

Full text of DOI:10.1002/jhet.1088

E126
Novel Synthetic Approach Toward C‐Substituted Piperazine
Derivatives via C-N Bonds Formation of α‐Bromoarylethanones
and Ethanolamine
Vol 50
a
b
b
a
*
*
Gao Cao, Ai‐Xi Hu, Yan‐Li Xie, and Zhen Zhou
aSchool of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University,
Guangzhou 510006, People’s Republic of China
bCollege of Chemistry and Chemical Engineering, Hunan University, Changsha 410082,
People’s Republic of China
*
E-mail: g.cao@mail.scut.edu.cn or axhu@hnu.edu.cn
Received May 5, 2011
DOI 10.1002/jhet.1088
Published online 10 April 2013 in Wiley Online Library (wileyonlinelibrary.com).
A new method for the synthesis of novel C‐substituted piperazine derivatives bearing aryl substituents on
2,6‐C positions has been developed by one‐pot three‐component sequential reaction of α‐bromoarylethanones with
ethanolamine in the presence of formic acid. The structure of the novel compounds was established by nuclear
magnetic resonance (NMR), mass spectrometry (MS), and elemental analysis. In addition, the crystal structure of
4e was determined by single X‐ray crystallography and a possible reaction mechanism was proposed.
J. Heterocyclic Chem., 50, E126 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
The piperazine ring is a common structural motif and
pharmacophore found in a large number of drugs [1–3].
Piperazine derivatives can be used as main structure or
substituent of the drugs to obtain the desired pharmacological
activity or pharmacokinetic activity, they also can be served as
building blocks commonly used in the synthesis of
pharmaceutically active substances [4]. The synthesis
of piperazine derivatives only bearing nitrogen substitu-
ents has received considerable attention, whereas only a
comparatively small number of C‐substituted piperazine
derivatives have been prepared and evaluated for their
pharmacological properties [5–10]. In particular, a
recent study found that the C‐substituent of the piperazine
ring in drugs can be modified to reduce the side effects,
such as floxacin series drugs with methyl piperazine as
side‐chain significantly decreased the central nervous
system toxicity [11]. So, there is a clear demand for
efficient synthetic protocols to construct the C‐substituted
piperazine derivatives.
In the course of our studies on the C-N bonds formation
based on α‐bromoalkylaryl ketones [12–14], a new route
for preparing 4‐bis(2‐hydroxyethyl)‐2,6‐bisaryl pipera-
zines has been developed. The synthesis of the title com-
pounds was achieved by α‐bromoarylethanones reacted
with ethanolamine (MEA) in the presence of formic acid
(HCOOH) in N‐methyl‐2‐pyrrolidone (NMP) solution
(Scheme 1).
The α‐bromination of arylethanones (1) was accomplished
in high isolated yields under solvent‐free condition and in short
reaction times using 1‐butyl‐3‐methyllimidazolium tribromide
([Bmin]Br3) [15] as the bromine source (Table 1). The
bromination proceeds to take place at the carbon atom activated
by the C═O group with high selectivity. Following isolation of
the brominated products, the low viscosity, high density
trihalide‐based [Bmin]Br3 ionic liquid was easily recovered
and can be reused with minimal loss.
Then one‐pot three‐component sequential reaction of the
bromides (2) with MEA and HCOOH was taken in polar
aprotic solvent (NMP) [16] to give the title C‐substituted
piperazine derivatives. Finally, since the title piperazine
derivatives in the form of free amino base are readily
polymerizable, the obtained products were quickly converted
to its hydrochloride salts in ethanol solution of anhydrous
HCl, and then the products were separated and purified by
column chromatography. The progress of the reaction was
monitored by thin layer chromatography (TLC) and the
yields reported were estimated on the basis of isolated yields
(Table 2). The reaction conditions were not optimized yet. At
the beginning, we tried to isolate the crude products after acid
and then base extraction [17], but the yields of the desired
products were unacceptable (less than 5%).
Many reagents for nucleophilic substitution of α‐bromo-
ketones to form C-N bonds have been developed [18–20].
Whereas there has been no reports on MEA as a nucleophile
© 2013 HeteroCorporation

February 2013
Novel Synthetic Approach Toward C‐Substituted Piperazine Derivatives via
C─N Bonds Formation of α‐Bromoarylethanones and Ethanolamine
E127
Scheme 1
agent of α‐bromoketones. However, MEA is a primary
amine and contains an active hydroxyl group, so there is a
synthetic difficulty in the reaction of α‐bromoketones with
MEA to form a single product, the pathway will meet with
major difficulties in terms of side reactions such as hydrogen
halide elimination, Williamson reaction, oxidation reaction,
etc. We have traced the oxidation product 2‐(2,4‐dichloro‐
5‐fluorophenyl)‐2‐oxoacetaldehyde [21] in this reaction.
Therefore, the finial C‐substituted piperazine derivatives
were obtained in a moderate yields.
Scheme 2 shows a plausible reaction mechanism of the
sequential reaction. The piperazine ring system may be effected
in two ways: (I) Firstly, reaction of MEA with α‐bromoary-
lethanones produced the corresponding substituted aminoke-
tones (A). At the same time, addition of carbonyl group with
primary amine (MEA) followed by dehydration also afforded
the intermediary imines (B), subsequent reductive amination
by HCOOH via Leuckart‐Wallach reaction [22] leads to C.
Next, a self‐consistent sequence nucleophilic substitution
between the aminoketones and C formed the key intermediates
D. Then D undergoes an intramolecular cyclization to give the
2,2′‐(2‐hydroxy‐2,6‐bisarylpiperazine‐1,4‐diyl) diethanols (E).
E, by losing a water molecule, forms a cyclic Schiff base
intermediate F. Subsequent reduction by HCOOH leads to
the desired product piperazine derivatives. (II) Initially, α‐
bromoarylethanones straightforward nucleophilicly attacked
by the MEA to afford the aminoketones. Consequently, the
resulting aminoketones (secondary amine) as a nucleophile,
attacked the starting material α‐bromoarylethanones again to
give the key intermediates D. Following, similarly to route I,
the desired products were obtained by the intramolecular
cyclization.
The structure and stereochemical properties of the representa-
tive compound 4e, 2,2′‐(2,6‐bis(2,4‐dichloro‐5‐fluorophenyl)pi-
perazine‐1,4‐diyl)diethanol hydrochloride was investigated by
X‐ray diffraction. Colorless crystals suitable for X‐ray diffraction
analysis were grown by slow evaporation of ethanol. The molec-
ular structure of 4e is illustrated in Figure1. The piperazine ring is
a distorted chair somewhat flattened at N2 and sharpened at N1.
The N atoms of the piperazine ring and the oxygen atoms of the
hydroxyl group act as hydrogen‐bond donors to the Cl atoms of
the hydrochloride formed intramolecular and intermolecular
hydrongen bonds. The combination of N—H···Cl and O—
H···Cl hydrogen bonds generates a cyclic centrosymmetric R42
(14) [23] aggregates of two molecules (Fig. 2).
CONCLUSIONS
To summarize, this is the first report, to the best of our
knowledge, on the synthesis of pharmaceutically important
C‐substituted piperazine derivatives by C-N bonds formation
of α‐bromo‐arylethanones and MEA. The title C-substituted
piperazines have novel structural features, and the two active
hydroxyl groups can be derived into other more complicated
compounds. Currently, work is in progress to further expand
the scope of this method.
Table 2
Synthesis of 4‐bis(2‐hydroxyethyl)‐2,6‐bisaryl piperazine hydrochlorides
(4).
Table 1
Results of the bromination of arylethanones (1) by [Bmin]Br3.
Time
(h)
Yield
(%)
Entry
Ar
M.p. (°C)
Entry
Ar
Time (min)
Yield (%)
a
b
c
d
e
f
C6H5
4‐MeC6H4
4‐EtC6H4
4‐MeOC6H4
2,4‐diCl‐5‐FC6H2
6‐MeOC10H6
2‐Cl‐4‐(4‐
12
16
16
18
20
20
24
35.2
32.1
34.8
30.5
35.7
38.6
25.8
265.2.266.7
271.6.272.4
270.5.271.5
269.3.270.5
283.6.284.6
225.6.227.3
254.5.255.4
a
b
c
d
e
f
C6H5
4‐MeC6H4
4‐EtC6H4
4‐MeOC6H4
2,4‐diCl‐5‐FC6H2
6‐MeOC10H6
10
6
5
90.1
90.8
90.2
92.6
83.2
93.6
87.8
8
16
10
12
g
g
2‐Cl‐4‐(4‐ClC6H4O)C6H3
ClC6H4O)C6H3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E128
G. Cao, A.-X. Hu, Y.-L. Xie, and Z. Zhou
Vol 50
Scheme 2. Possible mechanism for the synthesis of C‐substituted piperazine derivatives.
product was dissolved in ethanol, anhydrous HCl was passed
through slowly. Finally, the ethanol was concentrated and the
residue were separated and purified by column chromatography
to give the title compounds 4a–4g.
EXPERIMENTAL
All melting points were measured on an X‐4 electrothermal
digital melting point apparatus and were uncorrected; NMR
spectra were recorded on a Bruker advance instrument, chemical
shifts (δ) are expressed in ppm; electro-spray ionization mass
spectrometry (ESI-MS) were recorded on a Finngan LCQ LC‐MS
spectrometer; element analyses were performed on a Perkin–Elmer
240 CHN analyzer; TLC was performed on E‐Merck pre‐coated 60
F254 plates and the spots were rendered visible by exposing to UV
light or iodine; the IUPAC names were obtained using the software
ChemDraw Ultra®, version 12.0. Every starting material was
obtained from commercial suppliers and was purified according to
the literature procedures.
General experimental procedure for the preparation of 4a–
4g. α‐Bromoarylethanones (0.04 mol) was dissolved in 50 mL
NMP, MEA (0.16 mol) was added dropwise at room
temperature. The resulting solution was stirred for 30 min, then
warmed to 60°C and stirred for further 1 h. After cooled down
to room temperature, 7.5 mL HCOOH (90.5%) was added, the
mixture was stirred and heated to reflux. After the reaction
finished, an excess of 80 mL water was added, the mixture was
extracted five times with 50 mL CH2Cl2. The extracts were
combined and dried over anhydrous Na2SO4. The CH2Cl2 was
removed by distillation, and then the free amino base crude
2,20‐(2,6‐diphenylpiperazine‐1,4‐diyl)diethanol hydrochloride
(4a). 1H‐NMR (CD3SOCD3+D2O, 400 MHz) δ: 2.70–2.81
(m, 4H, 2× NCH2), 3.39 (t, J = 12.0 Hz, 2H, OCH2), 3.46–3.66
(m, 6H, piperazine ring 3,5‐H, OCH2), 4.53 (d, J = 11.6 Hz, 2H,
piperazine ring 2,6‐H), 7.49–7.62 (m, 10H, benzene ring H). 13C
NMR (CD3SOCD3+D2O, 100 MHz) δ: 54.4, 54.6, 55.3, 58.3,
64.2, 127.1, 128.3, 129.2, 138.3; ESI‐MS (m/z): 326 (M+‐HCl),
308 (M+‐HCl‐H2O); Analysis calculated for C20H27ClN2O2: C,
66.19; H, 7.50; N, 7.72. Found: C, 66.23; H, 7.42; N, 7.83.
2,20‐(2,6‐di‐p‐tolylpiperazine‐1,4‐diyl)diethanol hydrochloride
1
(4b). H‐NMR (CD3SOCD3+D2O, 400 MHz) δ: 2.36 (s, 6H,
2× CH3), 2.83–2.87 (m, 4H, 2× NCH2), 3.50–3.61 (m,6H,
piperazine ring 3,5‐Ha, 2× OCH2), 3.71, 3.74 (dd, J = 10.0 Hz,
J = 2.8 Hz, 2H, piperazine ring 3,5‐He), 4.68 (d, J = 10.0 Hz, 2H,
piperazine ring 2,6‐H), 7.35 (d, J = 8.0 Hz, 4H, 2× benzene ring
2,6‐H), 7.53 (d, J = 8.0 Hz, 4H, 2× benzene ring 3,5‐H);
13C‐NMR (CD3SOCD3+D2O, 100 MHz) δ: 20.8, 54.1,
54.9, 55.1, 56.1, 63.9, 128.8, 130.2, 140.2; ESI‐MS (m/z):
354 (M+‐HCl), 336 (M+‐HCl‐H2O). Analysis calculated for
C22H31ClN2O2: C, 67.59; H, 7.99; N, 7.17. Found: C,
67.41; H, 8.05; N, 7.19.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Novel Synthetic Approach Toward C‐Substituted Piperazine Derivatives via
C─N Bonds Formation of α‐Bromoarylethanones and Ethanolamine
E129
63.7, 115.0, 128.5, 129.8, 158.3; ESI‐MS (m/z): 386 (M+‐HCl),
368 (M+‐HCl‐H2O). Analysis calculated for C22H31ClN2O4: C,
62.48; H, 7.39; N, 6.62. Found: C, 62.52; H, 7.30; N, 6.60.
2,20‐(2,6‐bis(2,4‐dichloro‐5‐fluorophenyl)piperazine‐1,4‐diyl)
1
diethanol hydrochloride (4e). H‐NMR (CD3SOCD3, 400 MHz)
δ: 2.27 (t, J = 6.8 Hz, 2H, 1‐NCH2), 3.14–3.18 (m, 4H,
4‐+NCH2, piperazine ring 3,5‐Ha), 3.43–3.50 (m, 4H, piperazine
ring 3,5‐He, OCH2), 3.76 (t, J = 6.8 Hz, 2H, OCH2), 4.96 (d,
J = 11.2 Hz, 2H, piperazine ring 2,6‐H), 5.40 (s, 1H, OH), 7.94
(d, J = 6.0 Hz, 2H, 2× benzene ring 6‐H), 8.02 (d, J = 10.0 Hz,
2H, 2× benzene ring 3‐H), 11.07 (brs, 1H, +NH); 13C‐NMR
(CD3SOCD3+D2O, 100 MHz) δ: 54.2, 57.6, 59.5, 59.7, 64.7,
112.5, 119.2, 127.9, 132.5, 137.7, 161.4; ESI‐MS (m/z): 500
(M++2‐HCl), 498 (M+‐HCl), 497(M+‐HCl‐H). Analysis calculated
for C20H21Cl5F2N2 O2: C, 44.76; H, 3.94; N, 5.22. Found: C,
44.82; H, 3.88; N, 5.31.
2,20‐(2,6‐bis(6‐methoxynaphthalen‐2‐yl)piperazine‐1,4‐diyl)
diethanol hydrochloride (4f). 1H‐NMR (CD3SOCD3+D2O, 400 MHz)
δ: 2.27–2.34, 2.40–2.45 (m, 4H, 2× NCH2), 2.88–3.09 (m, 4H,
piperazine ring 3,5‐H), 3.33–3.61 (m, 4H, 2× OCH2), 3.86 (s,
6H, 2× OCH3), 3.98 (d, J = 9.2 Hz, 2H, piperazine ring 2,6‐H),
7.14–7.87 (m, 12H, 2× naphthalene ring H); 13C‐NMR
(CD3SOCD3+D2O, 100 MHz) δ: 54.3, 56.7, 58.2, 59.3, 60.2,
64.7, 105.2, 118.7, 125.6, 126.4, 126.9, 128.5, 129.2, 133.3,
136.4, 156.8; ESI‐MS (m/z): 524 (M++2), 523 (M++1), 522 (M+).
Analysis calculated for C30H35ClN2O4: C, 68.89; H, 6.74; N,
5.36. Found: C, 68.95; H, 6.80; N, 5.40.
Figure 1. X-ray structure of 4e, with displacement ellipsoids drawn at the
30% probability level. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
2,20‐(2,6‐bis(4‐ethylphenyl)piperazine‐1,4‐diyl)diethanol
hydrochloride (4c). 1H‐NMR (CD3SOCD3+D2O, 400 MHz)
δ: 1.21 (t, J = 7.6 Hz, 6H, 2× CH3), 2.63–2.72 (m, 6H, 1‐NCH2,
2× CH2), 2.77–2.83 (m, 2H, 4‐+NCH2), 3.36 (t, J = 12.0 Hz, 2H,
OCH2), 3.45–3.62 (m, 6H, OCH2, piperazine ring 3,5‐H), 4.66 (d,
J = 10.8 Hz, 2H, piperazine ring 2,6‐H), 7.36 (d, J = 8.0 Hz, 4H,
2× benzene ring 2,6‐H), 7.50 (d, J = 8.0 Hz, 4H, 2× benzene ring
3,5‐H); 13C‐NMR (CD3SOCD3+D2O, 100 MHz) δ: 14.6, 26.6,
54.6, 54.7, 55.8, 58.2, 64.3, 127.3, 129.7, 141.3; ESI‐MS (m/z):
382 (M+‐HCl), 364 (M+‐HCl‐H2O). Analysis calculated for
C24H35ClN2O2: C, 68.80; H, 8.42; N, 6.69. Found: C, 68.87; H,
8.35; N, 6.60.
2,20‐(2,6‐bis(2‐chloro‐4‐(4‐chlorophenoxy)phenyl)piperazine‐
1,4‐diyl)diethanol hydrochloride (4g). 1H‐NMR (CD3SOCD3+ D2O,
400 MHz) δ: 2.67–2.82 (m, 4H, 2× NCH2), 3.30 (t, J = 12.0 Hz, 2H,
OCH2), 3.45–3.61 (m, 6H, piperazine ring 3,5‐H, OCH2), 4.85
(d, J = 12.0 Hz, 2H, piperazine ring 2,6‐H), 7.14–7.90 (m,
14H, benzene ring H); 13C‐NMR (CD3SOCD3+D2O, 100
MHz) δ: 54.2, 56.5, 57.8, 59.3, 60.2, 65.0, 117.3, 118.6, 119.7,
127.6, 129.4, 129.9, 130.5, 133.4, 155.3, 160.1; ESI‐MS (m/z):
648 (M++2‐HCl), 646 (M+‐HCl). Analysis calculated for
C32H31Cl5N2O4: C, 56.12; H, 4.56; N, 4.09. Found: C, 56.23;
H, 4.60; N, 4.01.
2,20‐(2,6‐bis(4‐methoxyphenyl)piperazine‐1,4‐diyl)diethanol
hydrochloride (4d). 1H‐NMR (CD3SOCD3+D2O, 400 MHz)
δ: 2.78–2.87 (m, 4H, 2× NCH2), 3.34 (t, J = 12.0 Hz, 2H,
OCH2), 3.47–3.64 (m, 6H, piperazine ring 3,5‐H, OCH2), 3.78
(s, 6H, 2× OCH3), 4.45 (d, J = 11.6 Hz, 2H, piperazine ring
2,6‐H), 7.07 (d, J = 8.4 Hz, 4H, 2× benzene ring 3,5‐H), 7.52
(d, J = 8.4 Hz, 4H, 2× benzene ring 2,6‐H); 13C‐NMR
(CD3SOCD3+D2O, 100 MHz) δ: 52.7, 54.6, 54.9, 56.4, 57.2,
Selected crystallographic data for compound 4e.
C20H21Cl5F2N2O2, M = 536.64, 0.47 × 0.21× 0.20 mm3,
monoclinic, space group: P21/c, a = 12.2228(6), b = 7.0055(4),
Figure 2. A perspective view of the crystal packing along the c‐axis. H atoms bonded to C atoms have been omitted for clarity. Dashed lines indicate
hydrogen bonds. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E130
G. Cao, A.-X. Hu, Y.-L. Xie, and Z. Zhou
Vol 50
c = 27.7206(15) Å, β = 104.1140(10)°, V = 2302.0(2) Å3, Z = 4,
densitycalcd = 1.548 mg/m3, F(000) = 1096, intensity data of 5001
reflections were collected in the range −15 ≤ h ≤ 7, −8 ≤ k ≤ 8,
−30 ≤ l ≤35, GOF = 0.625, 1.51 < θ < 27.11°, Final R indices
[I > 2σ(I)] R1 = 0.0423, wR2 = 0.1124, R indices (all data)
R1 = 0.0640, wR2 = 0.1377, Largest diff. peak and hole:
0.432 and −0.281 e Å−3. CCDC 831723 contains the
supplementary crystallographic data for this article. Copies
of this information may be obtained free of charge from the
Director, CCDC, 12 Union Road, Cambridge, CBZ IEZ, UK.
Facsimile (44) 01223 336 033 deposit@ccdc.cam.ac.uk or
http//www.ccdc.com.ac.uk/deposit.
A. M.; Weingarth, D. T.; Wolff, M.; MacNeil, D. J.; Weber, A. E.;
Edmondson, S. D. Bioorg Med Chem Lett 2008, 18, 4833.
[8] Gust, R.; Keilitz, R.; Schmidt, K. J Med Chem 2002, 45, 2325.
[9] Di Fabio, R.; Griffante, C.; Alvaro, G.; Pentassuglia, G.; Pizzi, D.
A.; Donati, D.; Rossi, T.; Guercio, G.; Mattioli, M.; Cimarosti, Z.; Marchioro,
C.; Provera, S.; Zonzini, L.; Montanari, D.; Melotto, S.; Gerrard, P. A.; Trist, D.
G.; Ratti, E.; Corsi, M. J Med Chem 2011, 54, 1071.
[10] Mercer, G. J.; Sigman, M. S. Org Lett 2003, 5, 1591.
[11] Liu, B.; Yang, C.‐H.; Xie, L.‐Y. Chem Online 2006, 4, 247.
[12] Cao, G.; Hu, A.‐X.; Xiao, X.‐R. Can J Chem 2007, 85, 29.
[13] Cao, G.; Hu, A.‐X.; Zou, K.‐S.; Xu L.; Cheng, J‐.L.; Tan, W.
Chirality 2008, 20, 856.
[14] Hu, A.‐X.; Cao, G.; Ma, Y.‐Q.; Zhang, J.‐Y.; Ou, X.‐M. Chin J
Struct Chem 2008, 27, 1235.
[15] Cinzia, C.; Elsa, L.; Daniela, P. Chem Commun 2004, 22, 2536.
[16] Perrine, D. M.; Ross, J. T.; Nervi, S. J.; Zimmerman, R. H. J
Chem Educ 2000, 77, 1479.
Acknowledgments. The authors gratefully thank the Natural Science
Foundation of Guangdong Province (No. 10451022401005172) for
the financial support for this project.
[17] After the reaction finished, 10% aqueous HCl solution (50 mL)
was added, and the mixture was washed three with CH2Cl2 (30 mL) to
remove the neutral compounds. After addition of a cold 30% aqueous
NaOH solution (30 mL) to the aqueous layer, the mixture was extracted
six times with CH2Cl2 (50 mL). The extracts were combined and dried
over anhydrous Na2SO4. The CH2Cl2 was removed by distillation, and
the residue was dissolved in ethanol, anhydrous HCl was passed through
slowly. Finally, ethanol was concentrated and the crystals were collected
on a filter to give the title compounds.
[18] Pal, M.; Swamy, N. K.; Hameed, P. S.; Padakanti, S.;
d Yeleswarapu, K. R. Tetrahedron 2004, 60, 3987.
[19] Kumpaty, H. J.; Bhattacharyya, S.; Rehr, E. W.; Gonzalez, A. M.
Synthesis 2003, 14, 2206.
[20] Jamode, V. S.; Jawanjal, S. D. Asian J Chem 2006, 18, 3163.
[21] 1H‐NMR data for 2‐(2,4‐dichloro‐5‐fluorophenyl)‐2‐oxoacetaldehyde
(CDCl3, 400 MHz) δ: 7.59 (d, J = 6.4 Hz, 1H, benzene ring 6‐H), 7.85 (d,
J = 9.2 Hz, 1H, benzene ring 3‐H), 9.88–10.47 (m, 1H, CHO).
[22] Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura,
M. J Org Chem 2002, 67, 8685.
REFERENCES AND NOTES
[1] Opatz, T. Eur J Org Chem 2004, 20, 4113.
[2] Becker, I. J Heterocycl Chem 2008, 45, 1005.
[3] Gitto, R.; Luca, L. D.; Ferro, S.; Grazia, S. D.; Giorgio, R. M. D.;
Festa, F.; Luca, G. D. J Heterocycl Chem 2010, 47, 54.
[4] Ananda Kumar, C. S.; Nanjunda Swamy, S.; Thimmegowda, N. R.;
Benaka Prasad, S. B.; Yip, G. W.; Rangappa, K. S. Med Chem Res 2007, 16,
179.
[5] Berkheij, M.; Sluis, L.; Sewing, C.; Boer, D. J.; Terpstra, J. W.;
Hiemstra, H.; Bakker, W. I. I.; Hoogenband, A.; Maarseveen, J. H. Tetrahedron
Lett 2005, 46, 2369.
[6] Bararjanian, M.; Balalaie, S.; Movassagh, B.; Bijanzadeh, H. R.
Tetrahedron Lett 2010, 51, 3277.
[7] Berger, R.; Zhu, C.; Hansen, A. R.; Harper, B.; Chen, Z.‐S.;
Holt, T. G.; Hubert, J.; Lee, S. J.; Pan, J.; Qian, S.; Reitman, M. L.; Strack,
[23] Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.‐L. Angew
Chem Int Ed Engl 1995, 34, 1555.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Copyright of Journal of Heterocyclic Chemistry is the property of Wiley-Blackwell and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.