Rapid and straightforward one-pot expeditious synthesis of 2-amino-5-alkylidene-thiazol-4-ones at room temperature

Article abstract of DOI:10.1016/j.tetlet.2011.09.090

A new methodology has been developed towards the room temperature synthesis of novel 2-amino-5-alkylidenethiazol-4-ones from aldehydes, amines and rhodanine in one-pot. A heterogeneous dipolar catalyst has been utilized for this reaction. The unique prope

Full text of DOI:10.1016/j.tetlet.2011.09.090

Tetrahedron Letters 52 (2011) 6431–6438
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid and straightforward one-pot expeditious synthesis
of 2-amino-5-alkylidene-thiazol-4-ones at room temperature
⇑
Chhanda Mukhopadhyay , Suman Ray
Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new methodology has been developed towards the room temperature synthesis of novel 2-amino-5-
alkylidenethiazol-4-ones from aldehydes, amines and rhodanine in one-pot. A heterogeneous dipolar cat-
alyst has been utilized for this reaction. The unique properties of this catalyst effectively synthesize such
compounds at room temperature in contrast to all earlier reports.
Received 16 August 2011
Revised 14 September 2011
Accepted 16 September 2011
Available online 22 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Amino-5-alkylidenethiazol-4-ones
Dipolar catalyst
Silica-based substituted pyridine
Carbon-13 CP MAS NMR
BET surface area analysis
Thiazolidinone derivatives have been extensively used in drug
discovery.1 They are reported to have anticonvulsant,2 antibacte-
rial,3 antiviral4 and anti-diabetic5 properties. For example, pioglit-
azone and rosiglitazone were launched recently for type-II diabetes
mellitus. In fact 2-amino-5-alkylidene-thiazol-4-one core is found
in more than 15,000 molecules synthesized so far.6
acid catalyzed microwave assisted three component one-pot syn-
thesis of 2-amino-5-alkylidenethiazol-4-ones.16 However, it re-
quires high temperature (ꢀ150 °C) microwave heating which
promotes the aromatic aldehydes to undergo competitive Cannizz-
aro reaction under high temperature and in the presence of excess
secondary amine. They used double equivalent of aldehydes for
good yield and thus one equivalent is completely wasted. There-
fore it is no longer a green methodology.
We thus wish to disclose the development and implementation
of a new methodology for the synthesis of 2-amino-5-alkylide-
nethiazol-4-ones at room temperature. It works well with acti-
vated, neutral, hetero-aromatic and electron donating aromatic
aldehydes; cyclic and acyclic secondary amines, as well as aliphatic
primary amines. Moreover, preparation of these materials at room
temperature using greener solvents is a welcome change over the
existing methods.
We were particularly interested in the synthesis of 2-amino-5-
alkylidenethiazol-4-ones from aldehydes, rhodanine and amines at
room temperature. The amine acts as the catalyst in the Knoevena-
gel condensation and as a nucleophile in the second step and
therefore an excess of amine is required. However, use of excess
amine is detrimental to the yield.16 This is because of a competitive
Cannizzaro reaction, a typical reaction for aromatic aldehydes in
the basic media that yields aromatic acids and consumes alde-
hydes in the reaction mixture proven by 1H NMR spectra. Also at
high temperature and in excess base compound (1) is produced
as side products.14a,b which may arise from the nucleophilic dis-
placement of an alkylidene thiazolone group by means of the anion
generated on a second thiazolone moiety. Interestingly the amount
of this type of side product depended also on the temperature and
Numerous synthetic routes7–13 have been developed in order to
obtain this heterocyclic core. However, the described routes re-
quire additional steps with extended reaction times, high temper-
atures, and laborious work-up all of which are drawbacks of their
respective methodologies. Pulici and Quartieri tried to overcome
these drawbacks by a traceless two-step solid-phase synthesis14
that involves reaction of rhodanine with bromo-Wang resin [4-
(bromomethyl)phenoxymethyl polystyrene] in DMF under basic
condition, followed by a base catalyzed Knoevenagel condensation.
Finally an exhaustive piperidine-mediated cleavage in DME–TFE
(9:1) followed by silica gel-chromatography led to the recovery
of the expected 2-amino-1-yl-thiazol-4-one. Therefore, it still suf-
fers from a rather expensive solid support, additional steps of load-
ing of rhodanine on solid support and cleavage. Bourahla et al.
reported an efficient microwave assisted one-pot tandem reac-
tion15 which employed the aldimine instead of aldehyde. However,
it comprises a rather complicated sequence of reaction steps of
generation of aldimines, addition of rhodanine followed by the
addition of amines and each step requires microwave heating
around 80 °C. Additionally the primary amine used for aldimine
is completely wasted. In recent years, Anderluh et al. reported an
⇑
Corresponding author. Tel.: +91 33 23371104.
E-mail address: cmukhop@yahoo.co.in (C. Mukhopadhyay).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.090

6432
C. Mukhopadhyay, S. Ray / Tetrahedron Letters 52 (2011) 6431–6438
on the strength of the bases: in both cases, the greater the strength,
the higher the yield.
Therefore, use of equivalent amount of amine and low temper-
ature is the ideal condition for good yield and a clean reaction. In
that case an additional base catalyst must be used for Knoevenagel
condensation and the basicity must be lower than the amines to
reduce Cannizzaro reaction and side products (1) formation.
The one-pot synthesis was optimized on a model reaction
involving 2-bromobenzaldehyde, rhodanine and morpholine under
different conditions and the results are summarized in Table 1. The
reaction was first tried with 2-bromobenzaldehyde (1 equiv,
0.25 mol/L), rhodanine (1 equiv, 0.25 mol/L), excess (2 equiv,
0.5 mol/L) morpholine in aqueous ethanol for 12 h stirring at room
temperature. We isolated only small amount of compound (2).
However, 20% yield of compound (3) was obtained at 5 h under
O
R1
NH
O
N
S
R2
S
N
R3
(1)
R4
Table 1
Optimization of reaction conditionsa
Entry
Morpholine (equiv)
Base catalysts (0.1 equiv)
Acid catalysts
Solvents (ml)
Time (min)
Temperature (°C)
Isolated yields (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2.0
2.0
2.0
2.0
2.0
1.5
1.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
—
—
—
—
—
—
—
—
—
—
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
Dry EtOH (4 ml)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
H2O+EtOH (2+2)
12 h
5 h
90
70
75
80
90
120
40
45
50
52
80
96
100
5 h
30
80
80
75
30
30
30
80
30
30
30
30
30
30
30
30
0
20
47
55
64
69
76
0
10
17
34
35
70
81
85
39
AcOH (0.1 equiv)
FeCl3 (0.1 equiv)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
Silica (40 mg)
NaOH
K2CO3
DBU
Triethyl amine
DABCO
2,6-Dimethyl-pyridine
Pyridine
Trimethylamine N-oxide
a
Reaction and conditions: rhodanine (1 equiv, 0.25 mol/L), 2-bromobenzaldehyde (1 equiv, 0.25 mol/L), different amounts of morpholine, different acid catalysts, different
temperature, stirring.
MeO
MeO Si
MeO
SH
6(N)HCl
H2O
OH
OH
OH
O
SiO2
SiO2
OH
Reflux for
24h.
Dry toluene
Reflux, 18h.
f
d
e
g
Cl
h
i
N
N
f'
h'
g'
a
i'
c
O
O
O
(6)
O
O
O
b'
S
SiO2
SiO2
Si
SH
Si
b
e'
d'
a'
c'
Dry toluene
Et3N (excess)
Reflux, 18h.
(5)
+
(7)
Et3N.HCl
Scheme 1. Preparation of silica based substituted pyridine catalyst.
H
O
O
O
SiO2
S
Si
O
R2
(7)
40 mg
O
H
N
N
O
S
N
+
+
S
NH
R2
H
H2O (2 ml) + EtOH (2 ml)
N
S
Room temperature
1 eqv
1 eqv
1 eqv
0.25 mol/L
Stirring
(8)
Z-isomer
0.25 mol/L 0.25 mol/L
R2 = aryl.
Scheme 2. Preparation of 2-amino-5-alkylidenethiazol-4-ones.

C. Mukhopadhyay, S. Ray / Tetrahedron Letters 52 (2011) 6431–6438
6433
Table 2
Preparation of 2-amino-5-alkylidenethiazol-4-onesa
Entry
Productsb (numbering)
Time (min)
Melting point (°C)
Isolated yieldsc (%)
H
S
MeO
O
1
120
202–204
65
N
MeO
8a
N
Me
H
Me
O
MeO
S
N
MeO
2
122
198–200
7923
N
8b
OMe
H
S
O
3
131
212–214
74
N
MeO
N
8c
OMe
H
S
O
4
125
148–150
8019
N
MeO
N
H
8d
HO
O
S
N
MeO
5
139
192–194
83
N
8e
H
H2N
O
S
N
6
104
212–214
88
N
8f
H
Cl
O
S
N
7
140
222–224
60
NH
8g
(continued on next page)

6434
C. Mukhopadhyay, S. Ray / Tetrahedron Letters 52 (2011) 6431–6438
Table 2 (continued)
Entry
Productsb (numbering)
Time (min)
Melting point (°C)
Isolated yieldsc (%)
H
O
S
N
Br
8
110
162–164
91
N
8h
H
N
O
S
N
9
112
172–174
96
N
8i
8j
H
N
O
S
N
10
11
12
13
110
100
130
128
214–216
228–230
210–212
236–238
80
85
87
85
N
Me
Me
H
S
N
O
N
8k
N
H
S
O
N
Br
N
8l
H
S
O
N
Cl
N
8m
H
S
Me
O
N
14
102
222–224
77
N
N
8n
Me

C. Mukhopadhyay, S. Ray / Tetrahedron Letters 52 (2011) 6431–6438
6435
Table 2 (continued)
Entry
Productsb (numbering)
Time (min)
Melting point (°C)
Isolated yieldsc (%)
H
Cl
O
S
N
15
95
188–190
81
N
8o
N
Me
H
MeO
O
S
N
16
104
172–174
82
N
8p
N
Me
H
S
O
N
Br
17
120
234–236
92
N
O
8q
H
S
O
18
100
196–198
65
N
Br
8r
N
Me
Me
H
Me
O
S
N
19
109
152–154
8922
8s
N
H
S
Cl
O
N
20
121
236–238
9014b
8t
N
O
a
Reaction and conditions: rhodanine (1 equiv, 0.25 mol/L), aldehyde (1 equiv, 0.25 mol/L), amines (1 equiv, 0.25 mol/L), 40 mg silica based substituted pyridine catalyst
(7), aqueous ethanol [(2+2) ml], room temperature, stirring.
b
The Z-diastereoselectivity is conformed by X-ray single crystal analysis of (8t) (entry 20).
References.
c
refluxing condition. Interestingly the yield increased to 47% in
90 min with AcOH as an additional acid catalyst. Therefore, con-
densation of rhodanine with amine is catalyzed by an acid. This
step was catalyzed also by different Lewis acids with an overall
yield of 40–55% under refluxing condition. However, maximum
of 64% yield was attained within 75 min at room temperature
when silica was used as an acid catalyst. Here the silanol groups
present on the silica surface coordinate with the carbonyl oxygen
to increase its electrophilicity17,18 and thereby reduces the time
of Knoevenagel reaction and temperature. Therefore, under low

6436
C. Mukhopadhyay, S. Ray / Tetrahedron Letters 52 (2011) 6431–6438
temperature and in reduced reaction time the extent of Cannizzaro
reaction and side product (1) formation is reduced. Decreasing the
amount of morpholine to 1.1 equiv in the presence of silica catalyst
increased the yield to 76% because of further decrease in the side
product formation under limited supply of amines.
O
O
O
N
NH
S
N
S
S
S
Br
Br
N
N
O
O
(2)
(3)
(4)
However, when we used 1 equiv of each of rhodanine, aldehyde
and morpholine, in the presence of silica as Bronsted acid catalyst,
we isolated mainly the compound (4) and unreacted aldehyde.
Figure 1. ORTEP diagram of single crystal obtained from 5-(4-chloro-benzylidene)-
2-morpholine-1-yl-thiazol-4-one, (8t) showing the crystallographic numbering
(CCDC 836806).
O
O
O
O
C
R2
H
O Si
O
B
H
NH
S
O Si
O
B
H
_
O
S
R2
OH
NH
S
O
C
S
H
O
H
Oxygen lonepairs coordinates with
the silanol group on silica surface.
O
O
H
- H2O
O Si
O
B
NH
S
R2
S
H
O
Z-isomer
OH
C
O
H
H
NHR3R4
NH
S
S
R2
O
H
O
NH
-H / +H
O Si
O
B
R2
S
S
OH
O
NHR3R4
H
H
N
R2
S
H
S
3R4RN
pure covalent bonds
H-bond or other weak interactions.
-H / +H
-H2S
O
H
N
R2
S
NR3R4
Figure 2. Mechanism of preparation of 2-amino-5-alkylidenethiazol-4-ones.

C. Mukhopadhyay, S. Ray / Tetrahedron Letters 52 (2011) 6431–6438
6437
Therefore, condensation of rhodanine with aldehydes needed a
Recycling experiment
base catalyst, particularly when equivalent amounts of rhodanine,
aldehyde and morpholine were used. Therefore, reagent quantity is
optimized as 1 equiv of each of the amine, rhodanine and aldehyde.
In that case the use of a weak base catalyst and silica as a Bronsted
acid catalyst represents the most powerful methodology for room
temperature preparation of 2-amino-5-alkylidenethiazol-4-ones.
The yield decreased substantially when NaOH was used as a base
catalyst. Decreasing the base strength increased the yield probably
due to the minimization of side products with weaker base catalyst
though with higher reaction time. Pyridine as a base gave maxi-
mum yield. Further decrease in base strength resulted in incom-
plete conversion.
However, pyridine is potentially harmful to the experimentalist.
Therefore, we have designed and synthesized the following bifunc-
tional silica-based substituted pyridine catalyst (7) according to
Scheme 1 to avoid this harmful effect of pyridine.
Here 2-chloromethylpyridine provides straightforward possi-
bilities for catalyst design, together with a simple immobilization
procedure compared to other less- functionalized organocatalysts.
Using this catalyst a variety of 2-amino-5-alkylidenethiazol-4-
ones were synthesized from rhodanine (1 equiv, 0.25 mol/L),
amines (1 equiv, 0.25 mol/L), and a variety of aldehydes (1 equiv,
0.25 mol/L) according to Scheme 2. The products (Table 2) obtained
in excellent yields and were highly pure.
The possibility of recycling the catalyst was examined using the
reaction of rhodanine with 2-bromobenzaldehyde and pyrrolidine
under optimized conditions. The recycled catalyst could be used at
least eight times without any further treatment. A negligible loss in
the catalytic activity of silica based substituted pyridine catalyst
was observed (Recycling table in Supplementary data). The slightly
extended time for the recycles is probably due to the loss of some
amount of catalyst in the time of filtration.
In conclusion we have developed a rather novel protocol23 for
the one-pot three-component synthesis of 2-amino-5-alkylide-
nethiazol-4-ones from rhodanine, amines and aldehyde in room
temperature in contrast to all the earlier reported methods where
high temperature was required. It represents a powerfully green
technology procedure for the use of environmental friendly solvent
and prevention of unwanted waste production. Shorter reaction
times and one pot strategy make it convenient for parallel
synthesis.
Acknowledgments
One of the authors (S.R.) thanks the Council of Scientific and
Industrial Research, New Delhi for his fellowship (JRF). We thank
the CAS Instrumentation Facility, Department of Chemistry, the
University of Calcutta for spectral data. We also acknowledge grant
received from UGC funded Major project, F. No. 37-398/2009 (S.R.)
dated 11-01-2010. Moreover, the NMR Research Centre, IISc, Ban-
galore 560012 is gratefully acknowledged for the solid state car-
bon-13 CP-MAS NMR spectra of 7.
In all cases, the 1H NMR spectra revealed only one type of
methine proton which ensured the formation of only one type of
geometrical isomer and the Z-diastereochemistry was confirmed
by X-ray single crystal analysis (Fig. 1) of 5-(4-chloro-benzyli-
dene)-2-morpholine-1-yl-thiazol-4-one, (8t) (Table 2, entry 20)
(CCDC 836806).
Supplementary data
Mechanism
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.09.090.
Here Knoevenagel condensation preceded the condensation of
rhodanine with amine as confirmed from the 1H NMR spectra of
the isolated product obtained by quenching the reaction after
few minutes. The quenching was done by simply removing the cat-
alyst from the reaction mixture through filtration. The starting or-
ganic compounds remain in the homogeneous phase of aqueous-
ethanol. Since the catalyst is heterogeneous, it is outside the homo-
geneous phase.18 Water forms several hydrogen bonds between
the nitrogen atom of catalyst (7) and the organic molecules, there-
by acting as a bridge between the homogeneous and heteroge-
neous phases.18 Here water brings the active methylene groups
to the lone pair of electrons of pyridine nitrogen of the catalyst
through hydrogen-bonding (Fig. 2) and thereby favouring the ion-
ization into carbanion donor.18,20,21 The carbonyl oxygen coordi-
nates with the silanol17,18groups on silica surface increasing the
electrophilicity of the carbonyl carbon and thereby making it pos-
sible to carry out the reaction at room temperature and in short
time (Fig. 2).
References and notes
1. (a) Lee, C. L.; Sim, M. M. Tetrahedron Lett. 2000, 41, 5729; (b) Andres, C. J.;
Bronson, J. J.; D’Andrea, S. V.; Deshpande, M. S.; Falk, P. J.; Grant-Young, K. A.;
Harte, W. E.; Ho, H.-T.; Misco, P. F.; Robertson, J. G.; Stock, D.; Sun, Y.; Walsh, A.
W. Bioorg. Med. Chem. Lett. 2000, 10, 715.
2. (a) Troutman, H. D.; Long, L. M. J. Am. Chem. Soc. 1948, 70, 3436; (b) Mishra, S.;
Srivastava, S. K.; Srivastava, S. D. Indian J. Chem., Sect. B 1997, 36, 826.
3. Foye, W. O.; Tovivich, P. J. Pharm. Sci. 1977, 66, 1607.
4. Sudo, K.; Matsumoto, Y.; Matsushima, M.; Fujiwara, M.; Konno, K.;
Shimotohno, K.; Shigeta, S.; Yokota, T. Biochem. Biophy. Res. Commun. 1997,
238, 643.
5. (a) Ohishi, Y.; Mukai, T.; Nagahara, M.; Yajima, M.; Kajikawa, N.; Miyahara, K.;
Takano, T. Chem. Pharm. Bull. 1990, 38, 1911; (b) Momose, Y.; Meguro, K.; Ikeda,
H.; Hatanaka, C.; Oi, S.; Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440; (c) Peet, N.
P. IDrugs 2000, 3, 131.
6. According to
search.
a November 2004 SciFinder (http://www.cas.org/SCIFINDER/)
7. Khare, R. K.; Srivastava, M. K.; Singh, H. Indian J. Chem., Sect. B 1995, 34,
828.
8. (a) Hendrickson, J. B.; Rees, R.; Templeton, J. F. J. Am. Chem. Soc. 1964, 86, 107;
(b) Hurst, D. T.; Atcha, S.; Marshall, K. L. Aust. J. Chem. 1991, 44, 129; (c)
Sarodnick, G.; Heydenreich, M.; Linker, T.; Kleinpeter, E. Tetrahedron 2003, 59,
6311.
Study on optimization of catalyst loading and choice of solvent
9. Dzurilla, M.; Kristian, P.; Imrich, J.; Stec, J. Collect. Czech. Chem. Commun. 1983,
48, 3134.
10. (a) Seebacher, W.; Belaj, F.; Saf, R.; Brun, R.; Weis, R. Monatsh. Chem. 2003, 134,
1623; (b) Iwataki, I. Bull. Chem. Soc. Jpn. 1972, 45, 3218.
11. (a) Roessler, A.; Boldt, P. Synthesis 1998, 980; (b) Zimmermann, T.; Fischer, G.
W.; Olk, B. J. Prakt. Chem. 1990, 332, 540.
To study the effect of catalyst loading the reaction of rhodanine
with 2-bromobenzaldehyde and pyrrolidine was chosen as the
model reaction. The results show clearly that the silica based
substituted pyridine (7) is an effective catalyst for this transforma-
tion and 40 mg of the catalyst was the optimum usage under this
condition and the yields did not increase largely with higher
amount of catalyst. It should be noted that, the yield was best with
EtOH–water [(2+2) mL]. The yield decreased substantially when
the reaction was conducted in less polar solvents, such as CH2Cl2,
ACN, THF etc., (Optimization table in Supplementary data).
12. Taylor, E. C., Jr.; Wolinsky, J.; Lee, H.-H. J. Am. Chem. Soc. 1954, 76,
1870.
13. (a) Vachal, P.; Pihera, P.; Svoboda, J. Collect. Czech. Chem. Commun. 1997, 62,
1468; (b) Simpson, J.; Rathbone, D. L.; Billington, D. C. Tetrahedron Lett. 1999,
40, 7031; (c) Murata, M.; Fujitani, B.; Mizuta, H. Eur. J. Med. Chem. 1999, 34,
1061; (d) Gant, E. B.; Guiadeen, D.; Baum, E. Z.; Foleno, B. D.; Jin, H.;
Montenegro, D. A.; Nelson, E. A.; Bush, K.; Hlasta, D. J. Bioorg. Med. Chem. Lett.
2000, 10, 2179.

6438
C. Mukhopadhyay, S. Ray / Tetrahedron Letters 52 (2011) 6431–6438
14. (a) Pulici, M.; Quartieri, F. Tetrahedron Lett. 2005, 46, 2387; (b) Kandeel, K. A.;
Youssef, A. M.; El-Bestawy, H. M.; Omar, M. T. J. Chem. Res., Synop. 2003, 11,
682.
22. Raouf, A. R. A.; Omar, M. T.; Omran, S. M. A.; El-Bayoumy, K. E. Acta Chim. Acad.
Sci. Hung. 1974, 83, 359.
23. General experimental procedure for the synthesis of 2-amino-5-
15. Bourahla, K.; Derdour, A.; Rahmouni, M.; Carreaux, F.; Bazureau, J. P.
Tetrahedron Lett. 2007, 48, 5785.
alkylidenethiazol-4-ones: A mixture of rhodanine (0.25 mol/L), amine
(0.25 mol/L), and ketone (0.25 mol/L) and 40 mg of silica based substituted
pyridine catalyst in aqueous ethanol [(2+2) ml] were stirred in room
temperature until the reaction is completed. The completion of the reaction
was indicated by the disappearance of the starting material in thin layer
chromatography. The products precipitated out once their formation started.
After completion of the reaction the crude product was filtered and the residue
was taken in DCM. It was again filtered to separate the product as filtrate from
the catalyst which is separated as residue. It was further purified either by
recrystallization from EtOAc/DCM (equal volume).
ˇ
16. Anderluh, M.; Jukic, M.; Petric, R. Tetrahedron 2009, 65, 344.
17. Ribeiro, S. M.; Ao, C.; Serra, A. C.; Gonsalves, A. M. d’A. R. Appl. Catal., A 2011,
399, 126.
18. Mukhopadhyay, C.; Ray, S. Catal. Commun. 2011, 12, 1496.
19. Andreani, A.; Rambaldi, M.; Locatelli, A.; Leoni, A.; Bossa, R.; Chiericozzi, M.;
Galatulas, I.; Salvatore, G. Eur. J. Med. Chem. 1993, 28(10), 825.
20. Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org. Chem. 1999, 64, 1033.
21. Mukhopadhyay, C.; Das, P.; Butcher, R. J. Org. Lett. 2011, 13, 4664.