Critical modification to bulk scale synthesis of 2-amino-5-carboethoxy-4-hydroxypyrimidine

Article abstract of DOI:10.14233/ajchem.2017.20608

Pyrimidines and pyridines are choice for modern day medicinal chemistry. Pyrimidine synthons are synthesized form guanidine and different substituted malonates. One of such pyrimidine ring synthon is 2-amino-5-carboethoxy-4-hydroxy pyrimidine. The commercially deployed synthesis involved a mixture of KOH and guanidine carbonate and gradual temperature controlled addition of diethylethoxy methylene melonate giving a yellow precipitate. The precipitate is cooled to around 5 °C and recrystallized from ethanol-water mixture. Though purity is never an issue in this popular process, yields are very low (70-75 %). The GC analysis of reaction mixture indicated that almost starting material was left unreacted and the first yellow precipitate formation is the rate determining step. We report silica functionalized magnetic particles as material support for synthesis of 2-amino-5carboethoxy-4-hydroxy pyrimidine. The cyclization reaction yields are reported to be enhanced due to presence of “near-homogeneous” nanomaterial catalyst. The prominent catalyst of interest to us is Fe3O4@SiO2 of 40 nm size. The particles are produced by modified Stober process giving consistent yields and coating of SiO2. The structural characterization is performed with SEM, TEM, IR and the data are consistent across multiple batches. The use of 40 nm size Fe3O4@SiO2 enabled higher yields of cyclization step in synthesis of 2-amino-5-carboethoxy-4-hydroxy pyrimidine. The mechanism of catalysis is stabilization of hetero atoms on the acidic silica surface and hence formation of pyrimidine. The study with different sized nanoparticles has indicated 40 nm size seems to be optimum and ability of catalysis is reduced as the size of nanoparticles has increased. The reaction performed at different batch sizes has indicated that 5 % (w/v) catalyst is optimal in the reaction. This process modification has far reaching applications in medicinal chemistry and bulk drug synthesis.

Full text of DOI:10.14233/ajchem.2017.20608

Asian Journal of Chemistry; Vol. 29, No. 10 (2017), 2119-2122
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2017.20608
Critical Modification to Bulk Scale Synthesis of 2-Amino-5-carboethoxy-4-hydroxypyrimidine
1,2
2
1,2,3,*
M. CHANDRAPPA , GIRISH KUMAR and PHANI KUMAR PULLELA
1
2
3
Bigtec Pvt. Ltd., 59th "C" cross, 4th "M" Block, Rajajinagar, Bangalore-560 010, India
Department of Chemistry, School of Engineering and Technology, CMR University, Bangalore-562 149, India
Department of Chemistry, CMR Institute of Technology, ITPL Main Road, Bangalore-560 037, India
*
Corresponding author: E-mail: phanikumar.p@cmrit.ac.in
Received: 25 February 2017; Accepted: 13 April 2017;
Published online: 31 August 2017;
AJC-18503
Pyrimidines and pyridines are choice for modern day medicinal chemistry. Pyrimidine synthons are synthesized form guanidine and
different substituted malonates. One of such pyrimidine ring synthon is 2-amino-5-carboethoxy-4-hydroxy pyrimidine. The commercially
deployed synthesis involved a mixture of KOH and guanidine carbonate and gradual temperature controlled addition of diethylethoxy
methylene melonate giving a yellow precipitate. The precipitate is cooled to around 5 °C and recrystallized from ethanol-water mixture.
Though purity is never an issue in this popular process, yields are very low (70-75 %). The GC analysis of reaction mixture indicated that
almost starting material was left unreacted and the first yellow precipitate formation is the rate determining step. We report silica
functionalized magnetic particles as material support for synthesis of 2-amino-5carboethoxy-4-hydroxy pyrimidine. The cyclization
reaction yields are reported to be enhanced due to presence of “near-homogeneous” nanomaterial catalyst. The prominent catalyst of
interest to us is Fe
SiO . The structural characterization is performed with SEM, TEM, IR and the data are consistent across multiple batches. The use of 40
nm size Fe @SiO enabled higher yields of cyclization step in synthesis of 2-amino-5-carboethoxy-4-hydroxy pyrimidine. The mechanism
3
O
4
@SiO of 40 nm size. The particles are produced by modified Stober process giving consistent yields and coating of
2
2
O
3 4
2
of catalysis is stabilization of hetero atoms on the acidic silica surface and hence formation of pyrimidine. The study with different sized
nanoparticles has indicated 40 nm size seems to be optimum and ability of catalysis is reduced as the size of nanoparticles has increased.
The reaction performed at different batch sizes has indicated that 5 % (w/v) catalyst is optimal in the reaction. This process modification
has far reaching applications in medicinal chemistry and bulk drug synthesis.
Keywords: Pyrimidine, Magnetite nanoparticles, Solid support, 2-Amino-5-carboethoxy-4-hydroxypyrimidine.
resulted in substituted pyrimidine. This ring cyclization reported
to have a rate limiting step and there are few homogeneous
and heterogeneous catalysts reported for the same. Though
these catalysts often result in improved yields [22,23], cost of
the catalyst, difficulty in isolation, presence of traces by catalyst
in final product etc., prohibit their use in bulk drug or medicinal
chemistry synthesis [24-27]. The nanomaterial based catalysis
is not reported for pyrimidine synthesis and our group has
INTRODUCTION
Our group reported pyrimidine derivatives as one of the
first T-type calcium channel blockers [1,2]. The pyrimidine
ring is pharmacologically important functional group especially
in the broad fields of cardiovascular and psychotic drugs [3-5].
The pyrimidine group is recently been reported with numerous
pharmacological applications emphasizing the direction of
medicinal chemistry field and significance of heterocyclics
recently reported that Fe
3
O
4
@SiO acts as an inert support in
2
[
6-10]. Though it is believed that pyrimidines are less utilized
some organic reactions. This inert solid support catalyst was
shown to give significantly improved yields for reactions invol-
ving ring cyclizations [23,28,29]. The mechanism seems to
be intermediate stabilization due to its interaction with silica
surface. We have reported a similar mechanism for isoxazoline
formation and the improved yields seem to be specific for hetero-
cyclics [23]. In this paper, we reported the synthesis of substi-
as pharmacological synthons compared to other rings like
dihydropyrimidine [11,12], pyridines [13,14], furons [15,16],
thiophenes [17], thiazides [18], etc., the evolution of newer
medicinal chemistry leads are limited [19]. This is because the
pyrimidine synthesis reactions usually result in lower reactions
yields compared to other heterocyclics [20,21]. The recent
spurt in interest of pyrimidine compounds necessitates develop-
ment of viable synthetic methods. A simple condensation
reaction of acetoacetate or malonate with guanidine compound
tuted pyrimidine synthon using 40 nm sized Fe
3
O
4
@SiO as
2
“near homogeneous catalyst” and the improved yields observed
has possible applications in bulk drug and API synthesis.

2
120 Chandrappa et al.
Asian J. Chem.
cooled, washed with distilled water 3-4 times and silica coated
magnetite particles were separated using external magnet. b)
The particles which are washed in above process was suspen-
ded in 100 mL of 10 mM tris, 1mM EDTA and refluxed for
EXPERIMENTAL
All chemicals of laboratory grade and are procured from
SD Fine Chemicals India. The solvents are of analytical grade
and are from Merck Pvt. Ltd. and used as such without further
purification. Initial analysis of product identification was done
with comparison IR spectra with commercial reference com-
pound. The IR spectra recorded on Shimadzu IR affinity-1,
Model No. 311646. The melting points are the average of three
readings and recorded in a locally bought instrument.
0
.5 h at 90 °C on water bath. The Fe
3
O
4
@SiO was separated
2
using magnet and washed till the pH reaches 7. The silica func-
tionalized magnetic nanoparticles were stored in distilled water
and prior to use, the particles are separated with help of magnet
and dried overnight under oven. The characterization of silica
coated magnetic nanoparticles was performed by using IR
spectroscopy, SEM, TEM and EDS.
Synthesis of silanized magnetite nanoparticles (Fe
3
O
4
@SiO )
2
Synthesisof2-amino-5-carboethoxy-4-hydroxypyrimidine
Synthesis of Fe nanoparticles: In a 1 L three neck
3
O
4
3
with Fe O
4
@SiO : In a 20 L flask 1.070 Kg of KOH was
2
round bottom flask, 8.5 g of sodium nitrate, 5 g of sodium
hydroxide, were dissolved in 500 mL of distilled water and
the mixture was degassed with argon gas for 0.5 h at 90 °C on
water bath (solution 1). In separate beaker 6.95 g of iron(II)
sulfate was dissolved in 50 mL of distilled water having 10 mM
dissolved with 10 L of distilled water, stirred to get clear
solution and 5 g of silica functionalized magnetic nanoparti-
cles (Fe
3
O
4
@SiO ) was added. To the above mixture 2 Kg of
2
guanidine carbonate was added and stirring is continued for
dissolution. Temperature of the reaction mixture was main-
tained around 20 °C. Diethylethoxy methyl melonate (2.4 kg)
was added drop-wise over 3 h, the temperature of reaction
mixture was raised from 20 to 35 °C. A yellow solid was preci-
pitated and reaction was cooled. Then with the help of external
H
(
2
SO
4
and filtered it (solution 2). The NaNO
3
/NaOH mixture
solution 1) was cooled to below 60 °C, then the iron sulfate
filtrate (solution 2) was added slowly with constant flow rate
while continuing argon gas purging. The nanoparticle formation
was observed as black colour formation in solution. After few
minutes the argon gas aeration was removed and reaction mixture
was heated for 4 h at 90 °C under inert atmosphere (preferably
argon). The hot magnetite nanoparticle mixture was poured
magnet Fe
O
3 4
@SiO particles was removed, particles were
2
washed with acetone and dried. The reaction mixture was cooled
to 0-5 °C and pale yellow colour thick mixture was filtered
and washed with ice cold water and padded well. The product
was recrystallized from ethanol/water and dried in oven at 40 °C.
The dried product is divided into two parts and recrystallized
to 1 L beaker carefully, discarded the supernatants and Fe
O
3 4
particles were collected with the help of external barium ferrite
magnet. The magnetic particles were washed with distilled
water till pH of supernatant reached 7.
in 15 L of 60 % H O/40 % EtOH. The recrystallization was
2
hazy at first but goes clearer in appearance after 1 h of steam
heating. This compound is to crystallize and first sign is observed
at 39 °C and continued with slow cooling. The process was
done for both the parts and dried under vacuum oven. Yield:
Silica (SiO
2
) functionalization of Fe
3
O
4
nanoparticles:
The silica functionalization of Fe
O
3 4
was done by sonication
of TEOS in ethanol-water at pH 12. In a 1 L beaker 500 mL of
ethanol/water (4:1) was mixed well and pH adjusted to 12 using
NaOH. The magnetic nanoparticles were suspended ethanol/
water mixture and sonicated for 1 h. To the above sonicated
mixture 5 mL of TEOS was dissolved in 20 mL ethanol and
added slowly throughout the solution. The sonication continued
for more than 1 h and mixture was allowed to settle down. The
silica coated magnetic particles are collected under external
magnetic field and the supernatants were discarded. The
9
5 % (Scheme-I).
Synthesis of 2-amino-5-carboethoxy-4-hydroxy-
pyrimidine without Fe
as exactly same as mentioned above without using Fe
3
O
4
@SiO
2
:The compound is synthesized
@SiO
3
O
4
2
particles Overall yield: 70 %. Mass: 184.07 (M+1);Anal. calcd.
1
for C, 45.90; H, 4.95; N, 22.94; O, 26.20; H NMR:1.38 (1H,
13
t), 4.3 (2H, q), 8.5 (1H, m), 7.2 (2H, s), C NMR: 162, 170.6,
55.8, 168.5, 61, 142.
1
Fe
till the pH of solution reaches around 7.
Washing of Fe @SiO to remove iron salts:The silica
3
4
O @SiO
2
are washed with distilled water and continued
RESULTS AND DISCUSSION
Synthesis of consistent 40 nm sized magnetic nanopar-
ticles: Our group was involved in development of function-
alized nanomaterials as a tool for reaction yield improvement
[19]. The technical challenge of this process is obtaining
consistent size nanoparticles. We performed about 40 different
3
O
4
2
coated magnetic nanoparticles synthesized by this process
could have traces of iron ions. To obtain pure silica functiona-
lized magnetic nanoparticles, the traces of ferrous and ferric
ions elimination was done by a) Fe
O
3 4
@SiO particles were
2
mixed with 100 mL of 0.3 M trisodium citrate at pH 6 in round
bottom and refluxed for 30 min at 90 °C. Then solution was
batches of silica functionalized Fe
3
O
4
nanoparticles and
O
OH
EtOOC
EtOOC
OEt
H
H N
2
KOH (aq)
N
EtOOC
N
NH2 .H CO
2
3
N
H
NH2
EtOOC
HN
Guanidine carbonate
Scheme-I: Synthesis of 2-amino-5-carboethoxy-4-hydroxypyrimidine
Fe O @SiO
3
4
2
N
NH2
Diethyl 2-
ethoxymethylene)
malonate
2
-amino-5-carboethoxy-4-
hydroxypyrimidine
(

Vol. 29, No. 10 (2017)
Critical Modification to Bulk Scale Synthesis of 2-Amino-5-carboethoxy-4-hydroxypyrimidine 2121
120
(a)
(b)
100
80
Smooth
Smooth
Smooth 1
Smooth
60
vbb0032
control1
40
vbb0022271
vbb002181
3
500 3000 2500 2000 1750 1500– 1250 1000 750 500
4000 3500 3000 2500 2000 1750 1500–1 1250 1000 750 500
Wavelength (cm )
1
Wavelength (cm )
Fig 1. IR spectra of functionalized magnetic nanoparticles
Fig 2. SEM and TEM images of Fe
3
O
4
@SiO
2
particles
characterized with each batch size of 100 g. Though IR is an
acceptable spectral technique to know batch to batch consis-
tency in quality control setting. The silica coated magnetic
nanoparticles are characterized by IR spectra. The blue peak
Element Weight (%) Atomic (%)
O K
27.29
12.72
59.99
100.00
52.77
14.01
33.22
Si K
image (Fig. 1a) shows the non-silanized Fe
3
O
4
particles. Three
characteristic peaks at 1250-1100 cm suggested that the silica
coating on Fe (silanization) and the another image (Fig. 1b)
-1
Fe K
Totals
O
3 4
shows batch to batch consistency of silica coating on magnetic
nanoparticles. However, techniques like SEM and TEM offer
more in depth analysis of the same. The SEM image (Fig. 2a)
shows the 40 nm sized particles and TEM image (Fig. 2b)
2
4
6
8
10
12
14
16
keV
shows the coating of silica is uniform on Fe
O
3 4
particles. The
3 4 2
Fig 3. EDS spectra of Fe O @SiO
Fe @SiO particles are not calcinated and the consistent
3
O
4
2
3
quality of particles is reflected in the data presented. Calcina-
tion is one of the major cost bottle neck for their use in process
chemistry due to low yield and high cost. Interestingly 40 nm
size seems to be optimal in removing the need for calcination
and their catalytic properties of particles is supreme at this
particle size. The EDS spectra (Fig. 3) shows that particles are
synthesized by modified Stober method have only Fe, O and
found to around 64000 nm per particle. A typical reaction
used about 5 % (w/v) of particles and the mechanism of
catalysis is improved because of surface area. As reported
earlier [1,2], the mechanism of cyclization of heterocyclics
via Fe
3
O
4
@SiO seems to be interaction of acidic surface with
2
heteroatoms thereby stabilizing the intermediate. The
mechanism reported for isoxazole [19] had rate limiting step
and incidentally pyrimidine reaction through Knoevenagel
condensation reported here also possess the same. The silica
surface area was adequate at 5 % w/v as shown in Table-1 and
increasing further catalyst condensation did not result in yield
improvement. But, lowering the catalyst concentration to < 1 %
has lowered the catalytic efficiency andTable-1 shows the yields.
It was observed and reported in literature that heterogeneous
catalysis often requires certain % of catalyst by (w/v) and of
theoretical catalytic surface area can be only be indicative
[20-23].
Si as elements. The elemental ratio state that the Fe
3
O particles
4
are coated by silica. All multiple batches synthesized during
this study have similar elemental ratio indicating the batch to
batch consistency.
Catalytic surface area: The magnetic nanoparticles
synthesized by modified Stober process yielded a Gaussian
distribution of particles of the size ranging from 30 to 200
nm. The maximum number of particles are found to be around
4
0 nm in size and the catalytic surface area was calculated
based on cube size of the particles. The catalytic surface area is

2
122 Chandrappa et al.
Asian J. Chem.
TABLE-1
as Calcium Channel Blockers, US Patent 7687511 (2010).
STUDY ON DEPENDENCE OF CATALYST (% w/v)
IN OVERALL REACTION YIELD
3. V. Ralevic and G. Burnstock, Drug News Perspect., 16, 133 (2003);
https://doi.org/10.1358/dnp.2003.16.3.876886.
4
.
W. Kobinger, A. Walland and R. Kadatz, Naunyn Schmiedebergs Arch.
Pharmacol., 292, 105 (1976);
https://doi.org/10.1007/BF00498579.
S. Koyama, J. Pharmacol. Exp. Ther., 233, 480 (1985).
M.S. Mohamed, S.M.Awad andA.I. Sayed, Molecules, 15, 1882 (2010);
https://doi.org/10.3390/molecules15031882.
Concentration ratio of
S. No.
Reaction yield (%)
catalyst (%)
1
2
3
4
5
6
7
8
< 1
1
2
3
5
7
10
77
85
87
91
95
90
82
76
5
6
.
.
7. S.G. Newman and K.F. Jensen, Green Chem., 15, 1456 (2013);
https://doi.org/10.1039/c3gc40374b.
8. R. Singh and A. Chouhan, World J. Pharm. Pharm. Sci., 3, 574 (2014).
9
.
A. Mathews, M. Joy, S.E. Thomas and J. Mathew, Int. J. Chem. Sci.,
3, 1603 (2015).
0. Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull. (Tokyo), 40,
170 (1992);
https://doi.org/10.1248/cpb.40.1170.
1
Without catalyst
1
1
Synthesis of pyrimidine by Knoevenagel condensation:
Dihydropyrimidines and pyrimidines are known for then T-
type calcium channel blocking activity [1,2]. The pyrimidines
have become a choice class of their medicinal chemistry because
of stability towards oxidation compared to dihydropyridines.
The preferred synthetic route for pyrimidines is through
Knoevenagel condensation of an aldehyde or ketone and an
acetoester. The reaction yields decreased due to the water mole-
cule generated in the reaction is an inhibitor of the reaction. in
situ removal of water and moisture absorbing materials are
the two options [25-27], which were often observed with
minimum success and inconsistent yields [25-27]. Recent
mechanism studies had suggested that moisture was not the
real problem and the catalysts offering more surface area have
11. C.O. Kappe, Molecules, 3, 1 (1998);
https://doi.org/10.3390/30100001.
1
1
2. C.O. Kappe, Acc. Chem. Res., 33, 879 (2000);
https://doi.org/10.1021/ar000048h.
3. S.A. Al-Issa, Molecules, 17, 10902 (2012);
https://doi.org/10.3390/molecules170910902.
4. S.B. Castor and J.B. Hedrick, J. Environ. Radioact., 102, 769 (2001).
5. R.J. Nevagi, S.N. Dighe and S.N. Dighe, Eur. J. Med. Chem., 97, 561 (2015);
https://doi.org/10.1016/j.ejmech.2014.10.085.
6. Z. Ke, Y.Y. Yeung, G.C. Tsui and S.P. Xiao, Progr. Heterocycl. Chem.,
27, 203 (2015);
https://doi.org/10.1016/B978-0-08-100024-3.00007-6.
7. S. Urban, B. Beiring, N. Ortega, D. Paul and F. Glorius, J. Am. Chem.
Soc., 134, 15241 (2012);
1
1
1
1
https://doi.org/10.1021/ja306622y.
18. A.J. Zillich, J. Garg, S. Basu, G.L. Bakris and B.L. Carter, Hypertension,
8, 219 (2006);
4
proven to be more useful [28-31]. The use of Fe
3
O
4
@SiO was
2
https://doi.org/10.1161/01.HYP.0000231552.10054.aa.
9. A.P. Taylor, R.P. Robinson, Y.M. Fobian, D.C. Blakemore, L.H. Jones
and O. Fadeyi, Org. Biomol. Chem., 14, 6611 (2016);
https://doi.org/10.1039/C6OB00936K.
first of its sort and near doubling of reaction yield is in expected
lines considering our similar observation with thiophenes,
terpyridine, quinazoline and isoxazole [23].
1
2
2
2
0. A. Chaudhary, P.K. Sharma, P. Verma and R. Dudhe, Anal. Univ.
Bucuresti Chim., 20, 123 (2011).
1. A. Dastan, A. Kulkarni and B. Török, Green Chem., 14, 17 (2012);
https://doi.org/10.1039/C1GC15837F.
Conclusion
2-Amino-5-carboethoxy-4-hydroxypyrimidine is a useful
synthon for medicinal chemistry and we reported herein a simple
and scalable synthesis for the same. The doubling of yield has
2. H. Sheibani, M. Seifi and A. Bazgir, Catalyst Synth. Commun., 39, 1055
(
2009);
represented that Fe
3
O
4
@SiO
2
does help in improvement of
https://doi.org/10.1080/00397910802474982.
3. G.V. Shiva Reddy, M. Chandrappa, F. Rahaman, B.N. Murthy and P.K.
Pullela, Asian J. Chem., 29, 124 (2017);
https://doi.org/10.14233/ajchem.2017.20155.
4. R.S. Vardanyan, G.G. Danagulyan, A.D. Mkrtchyan and V.J. Hruby,
Heterocycl. Commun., 17, 129 (2011);
2
2
reaction yields of heterocyclics. The Knoevenagel condensation
was reported to be a low yielding reaction [32,33] and we found
a practical and mild way to improve the reaction yield. The
Fe
3
O
4
@SiO particles are about 40 nm size and the size of the
2
https://doi.org/10.1515/hc.2011.025.
particles does play a role in reaction improvement. The optimum
catalytic ratio was about 5 % (w/v) and using less than 1 % (w/v)
results in reactions yields of uncatalyzed reactions. The marginal
decrease reaction yield at 7-10 % (w/v) catalyst needs further
study and in situ decomposition of product at higher catalytic
concentration needs be understood in future studies.
2
2
2
2
2
5. R.S. Varma, Tetrahedron, 58, 1235 (2002);
https://doi.org/10.1016/S0040-4020(01)01216-9.
6. V. Polshettiwar and R.S. Varma, Green Chem., 12, 743 (2010);
https://doi.org/10.1039/b921171c.
7. G.W. Kabalka and R.M. Pagni, Tetrahedron, 53, 7999 (1997);
https://doi.org/10.1016/S0040-4020(97)00264-0.
8. C.W. Lim and I.S. Lee, Nano Today, 5, 412 (2010);
https://doi.org/10.1016/j.nantod.2010.08.008.
9. R. Abu-Reziq, H. Alper, D. Wang and M.L. Post, J. Am. Chem. Soc.,
128, 5279 (2006);
https://doi.org/10.1021/ja060140u.
0. Q. Zhang, H. Su, J. Luo and Y. Wei, Green Chem., 14, 201 (2012);
https://doi.org/10.1039/C1GC16031A.
ACKNOWLEDGEMENTS
This study is partially supported by a grant for Dr. Phani
Kumar Pullela, with VGST/SMYSR/GRD-444/2014-2015
from Vision group on Science and Technology, Government
of Karnataka, India under the Seed Money forYoung Scientific
Researchers (SMYSR) scheme.
3
3
1. R.K. Sharma, S. Sharma, S. Dutta, R. Zboril and M.B. Gawande, Green
Chem., 17, 3207 (2015);
https://doi.org/10.1039/C5GC00381D.
REFERENCES
3
2. D.M. Barnes, A.R. Haight, T. Hameury, M.A. McLaughlin, J. Mei, J.S.
Tedrow and J.D. Riva Toma, Tetrahedron, 62, 11311 (2006);
https://doi.org/10.1016/j.tet.2006.07.008.
1
2
.
.
P.P. Kumar, S.C. Stotz, R. Paramashivappa,A.M. Beedle, G.W. Zamponi
and A.S. Rao, Mol. Pharmacol., 61, 649 (2002);
https://doi.org/10.1124/mol.61.3.649.
P.K. Pullela, P. Rangappa, S.R. Alapati and P.V. Subbarao, Substituted
Dihydropyrimidines, Dihydropyrimidones and Dihydropyrimidinethiones
33. K.C. Majumdar, A. Taher and R.K. Nandi, Tetrahedron, 68, 5693 (2012);
https://doi.org/10.1016/j.tet.2012.04.098.