Solvent-Free Ball-Milling Biginelli Reaction by Subcomponent Synthesis

Article abstract of DOI:10.1002/ejoc.201501039

We report here an understanding of systems chemistry on small molecules through covalent mechanochemistry. As a proof-of-concept, the multicomponent Biginelli reaction by subcomponent synthesis was considered as a model system. Reactions were performed un

Full text of DOI:10.1002/ejoc.201501039

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201501039
Solvent-Free Ball-Milling Biginelli Reaction by Subcomponent Synthesis
Prasit Kumar Sahoo,[a] Anima Bose,[a] and Prasenjit Mal*[a]
Keywords: Synthetic methods / Multicomponent reactions / Mechanochemistry / Biginelli reaction / Ball mill
We report here an understanding of systems chemistry on
small molecules through covalent mechanochemistry. As a
proof-of-concept, the multicomponent Biginelli reaction by
subcomponent synthesis was considered as a model system.
Reactions were performed under solvent-free, metal-free,
mechanochemical (ball milling) and ambient laboratory con-
ditions. Br+-catalyzed oxidation of benzyl alcohols led to the
product benzaldehydes and byproduct H+ which were fur-
ther promoted as component and catalyst, respectively, for a
cascade transformation to dihydropyrimidones within the
same reaction pot. Remarkably, in solution, the reaction sys-
tem could not be reproduced at room temperature even after
24 h.
ronmentally friendliness and inexpensive synthesis. High
yielding reactions, fewer byproducts and minimum purifica-
tion add extra significance to this method in organic syn-
thesis.[13] Organic synthesis of small molecules by mechano-
chemistry has been considerably explored,[13a] including
multistep synthesis, olefin metathesis,[14] amongst others. In
addition, we have also recently explored the research area
under mechanochemistry.[9b,10,15] Therefore, we anticipated
that ball-milling methodology could possibly be used for
the supply of mechanical energy and reactions might be
done in environmentally benign way.
Introduction
Many cascading chemical reactions are involved in the
process of haemostasis[1] which causes bleeding to stop.
These kinds of biological processes are examples of self-
sorting methodologies[2] in systems biology.[3] However, the
study of systems chemistry[4] offers a primary understand-
ing into the self-sorting principles[5] of molecular networks
that eventually assist us to gain new systems[6] with func-
tions and properties unlike any conventional materials.[7]
Also, a subcomponent self-assembly approach[8] under sys-
tems chemistry, is a synthetic method in which ligands of
metallo-supramolecular complexes are produced in situ
from their subcomponents. This systems chemistry method
has been established to be a promising technique for the
synthesis of high-purity metal complexes from complex
mixtures of reactants with a minimum number of reaction
steps[9] and possibly unexplored in organic synthesis.
Considering these aspects, we are demonstrating here a
unique example of a covalent (metal-free) approach in sys-
tems chemistry in which subcomponent and catalyst were
With rising public concern over alternative energy and
global warming, it is important to decrease the usage of
chemicals in routine chemical synthesis. Essentially, de-
veloping recyclable methodology and eliminating waste are
important aspects for doing reactions in a greener fash-
ion.[10] Recently, ball-milling mechanochemistry,[11] as a sol-
vent-free method for synthetic transformations has become
an area of research interest due to its benefits over solution-
based methods.[12] Many advantages are associated during
synthesis by mechanochemistry.[11d] This method has huge
importance for green processes due to time efficiency, envi-
[a] School of Chemical Sciences, National Institute of Science
Education and Research (NISER) Bhubaneswar,
Institute of Physics Campus, P. O. Sainik School, Bhubaneswar,
Odisha 751005, India
E-mail: pmal@niser.ac.in
http://www.niser.ac.in/~pmal/
Supporting information and ORCID(s) from the author(s) for
this article are available on the WWW under http://dx.doi.org/
10.1002/ejoc.201501039.
Figure 1. System chemistry model. a) Subcomponent synthesis and
b) multicomponent transformation.
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Solvent-Free Ball Milling Biginelli Reaction
synthesized and used for cascade post-synthetic transfor- Table 1. Optimization of reaction conditions for the synthesis of
5aj.
mations for the multicomponent Biginelli reaction (Fig-
ure 1) within a single ball-milling pot. Thus, under mecha-
nochemical conditions, we establish here a paradigm to
make a link between metal-free subcomponent synthesis
and a multicomponent transformation to understand sys-
tems chemistry in small molecules of thermodynamically
stable systems.
Entry
Step I
(conditions)
Yield of
Step II
Yield of
5aj [%]
2j [%][a]
Results and Discussion
1
2
3
IBX[b] (1.1 equiv.)
1 h
NBS (1.5 equiv.)
30 min
oxone (1 equiv.)
TBAB[c] (10 mol-%)
TEMPO (10 mol-%)
30 min
oxone (1 equiv.)
KBr (10 mol-%)
TEMPO (10 mol-%)
30 min
94
Ͼ 4 h
Ͼ 4 h
3.5 h
no reaction
Trace (Ͻ 3)
81
Metal-free oxidation reactions are common in pharma-
ceutical industries to avoid toxic metal contamination in
drugs.[16] Like hypervalent iodine,[17] Br+-catalyzed reac-
tions with oxone–TBAB[18] or NBS[19] (TBAB = tetra-
butylammonium bromide; NBS = N-bromosuccinimde) are
also popular as the metal-free oxidant. In Figure 1a, Br+-
catalyzed, green and solvent-free mechanochemical oxid-
ation of alcohols to aldehydes is described. Reactions were
carried out by using a combination of a catalytic amount
of potassium bromide (KBr), oxone and TEMPO
[(2KHSO5·KHSO4·K2SO4)-2,2,6,6-tetramethylpiperidin-1-
yl-oxy radical].[20]
Aldehydes obtained from the first step were used as a
component, and the byproduct H+ was the catalyst for the
following Biginelli reaction (Figure 1b). The first step of the
reaction was conceived as a covalent type of subcomponent
synthesis. However, the second step may be an example of
self-sorting in which dihydropyrimidones (DHPMs) were
Ͼ 98
Ͼ 98
4
5
Ͼ 98
Ͼ 98
3.5 h
3.5 h
91
95
Oxone (≈ 0.6 equiv.)
KBr (10 mol-%)
TEMPO (1 mol-%)
30 min
[a] Yields were determined by 1H NMR analysis. [b] IBX = 2-
iodoxybenzoic acid. [c] TBAB = tetrabutylammonium bromide.
obtained with benzaldehydes, 1,3-dicarbonyls (ethyl aceto- the oxidation was achieved by using 1 mol-% of TEMPO
acetate or acetyl acetone) and urea (or thiourea) as compo- in 30 min in near quantitative conversion. In general, it is
nents. Both steps were carried out in one pot and the total expected that in a constrained system the maximum pos-
system can be considered as an example of systems chemis- sible concentration of reacting partners is reached, which
try under the area of covalent mechanochemistry.[21]
puts the system under high stress and hence could lead to
Table 1 represents the optimization of the reaction condi- uncontrollable oxidation of newly formed aldehydes to the
tions. During optimization, the progress of the reactions corresponding acids. In contrast, the described methodol-
was checked by TLC or 1H NMR spectroscopy. In a typical ogy for alcohol oxidation (Figure 1a) might serve as an im-
run, milling apparatus was stopped and a small portion of portant example in which a solution-based oxidation reac-
sample was collected from the reaction vessel and exam- tion was achieved under solvent-free ball-milling condi-
ined. Once the reaction was finished, solid mass was taken tions, in higher efficiency, with better yields and no over-
in a flask, washed with appropriate solvents and filtered off. oxidized products. Furthermore, this methodology was un-
The most appropriate conditions (entry 5) were identified successful in ethyl acetate.[20]
in which both reaction steps cooperatively led to the final
The efficiency of this two-step mechanochemical meth-
products in reasonable yields. Generally, the multicompo- odology for the synthesis of DHPMs looks highly promis-
nent Biginelli reaction works in the presence of a catalyst ing. Products were isolated in very good to excellent yields
that could be either acid or base. On the contrary, in this at relatively shorter reaction times (Figure 2). This method-
methodology, no catalyst was required to be added exter- ology works for a wide range of electron-rich (5ae, 5af, 5ah
nally.
and 5ai), electron-deficient (5ag) aromatic and thiophenyl
Togo and co-workers reported the KBr–oxone–TEMPO aldehydes (5al).
mediated oxidation of benzyl alcohols for 24 h in different
Regioselectivity[22] for the synthesis of DHPMs by using
solvents, such as CH3CN–water, dichloromethane or ethyl N-methyl urea was also established (Figure 3).[23] The reac-
acetate.[20] Over oxidation could not be controlled and a tions are controlled by steric effects and that leads to the
significant amount of benzoic acid formation was reported formation of a single regioisomer in all cases. In compari-
in several cases. These kinds of shortcomings are very com- son, 5bd was obtained in 88% yield after two steps, how-
mon in solution-phase oxidation chemistry. However, using ever, using aluminium-planted mesoporous silica catalyst
this methodology, under solvent free ball-milling conditions the reported yield was 86%.[24]
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. K. Sahoo, A. Bose, P. Mal
SHORT COMMUNICATION
Figure 4. Synthesis of DHPMs by using thiourea.
show, analysis of the 1H NMR spectra for NBS and oxone–
KBr–TEMPO mediated oxidation reactions are clean and
high yielding. Unfortunately, the second step was unsuc-
cessful using two oxidations systems (IBX and NBS) be-
cause the byproducts were not efficient enough catalysts for
the Biginelli reaction. Notably, the byproducts were 2-
iodosobenzoic acid (IBA) and succinimide from reactions
using IBX and NBS, respectively.
Figure 2. The overall (two-step) yields of DHPMs, reaction time
for the second step (with an additional 30 min for the first step)
and compound identification numbers are shown here.
Figure 3. Regioselective synthesis of DHPMs by using N-methyl
urea.
Furthermore, the reactions with thiourea also resulted in
DHPMs with good yield (Figure 4).
The systems chemistry approach under mechanochemis-
try described here, is a collection of two consecutive ther-
modynamically stable reaction systems of small molecules.
Complete success for two steps (DHPM synthesis) is de-
pendent upon active participation of products (aldehydes)
and byproducts (H+) of the first step. As shown in Table 1,
mechano-milling oxidation of alcohols to aldehydes was
Figure 5. a) Efficiency of NBS (method A) and oxone–KBr–
TEMPO (method B) mediated oxidations and b) and c) are the
respective H NMR spectra (in CDCl3).
1
To the best of our knowledge solvent-free NBS-mediated
successful with 2-iodoxybenzoic acid (IBX, entry 1),[10] N- oxidations of alcohols to aldehydes under the mechano-
bromosuccinimide (NBS, entry 2) and oxone–KBr– chemical conditions presented herein are new. The products
TEMPO (entry 3). As representative examples in Figure 5 obtained from these reactions were sufficiently pure (Fig-
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Solvent-Free Ball Milling Biginelli Reaction
Stang, Chem. Rev. 2011, 111, 6810–6918; f) K. Acharyya, S.
Mukherjee, P. S. Mukherjee, J. Am. Chem. Soc. 2013, 135, 554–
557.
K. Ruiz-Mirazo, C. Briones, A. de la Escosura, Chem. Rev.
2014, 114, 285–366.
ure 4) to be used directly for synthetic transformations. This
methodology is green, economical and does not use harsh
conditions. We hope that this methodology will serve as an
important addition to organic synthesis and industries.
In summary, we presented here a novel approach of sys-
tems chemistry for thermodynamically stable small mol-
ecules in the field of covalent mechanochemistry. This strat-
egy represents a new level of complexity in mechanochemi-
cal reactions by using ball-milling in which subcomponents
were synthesized and used for post-synthetic transforma-
tions in a multicomponent reaction within the same reac-
tion pot. Interestingly, we have also shown for the first time
that a byproduct obtained from a reaction system is used
as a catalyst for another reaction. The irreproducibility of
solution-based methodology for the synthesis of DHPMS
also demonstrates the superiority of this mechanochemical
system. We believe this environmental friendly and econom-
ical methodology will be an important addition to drug dis-
covery and development,[25] because DHPMs are well
known to have diverse biological activities[26] including anti-
cancer properties.[27] Finally, the systems chemistry we de-
scribed here for small molecules may branch out to a new
field of study in covalent mechanochemistry.[21]
[6]
[7]
a) E. R. Kay, D. A. Leigh, F. Zerbetto, Angew. Chem. Int. Ed.
2007, 46, 72–191; Angew. Chem. 2007, 119, 72; b) B. Lewan-
dowski, G. De Bo, J. W. Ward, M. Papmeyer, S. Kuschel, M. J.
Aldegunde, P. M. E. Gramlich, D. Heckmann, S. M. Goldup,
D. M. D’Souza, A. E. Fernandes, D. A. Leigh, Science 2013,
339, 189–193.
a) P. D. Frischmann, V. Kunz, V. Stepanenko, F. Würthner,
Chem. Eur. J. 2015, 21, 2766–2769; b) A. M. Castilla, W. J.
Ramsay, J. R. Nitschke, Acc. Chem. Res. 2014, 47, 2063–2073;
c) H. Bunzen, Nonappa, E. Kalenius, S. Hietala, E. Ko-
lehmainen, Chem. Eur. J. 2013, 19, 12978–12981; d) X.-P.
Zhou, Y. Wu, D. Li, J. Am. Chem. Soc. 2013, 135, 16062–
16065; e) D. H. Ren, D. Qiu, C. Y. Pang, Z. Li, Z. G. Gu,
Chem. Commun. 2014, 51, 788–791.
a) C. Giri, F. Topic, M. Cametti, K. Rissanen, Chem. Sci. 2015,
6, 5712–5718; b) C. Giri, P. K. Sahoo, R. Puttreddy, K. Ris-
sanen, P. Mal, Chem. Eur. J. 2015, 21, 6390–6393.
T. K. Achar, S. Maiti, P. Mal, RSC Adv. 2014, 4, 12834–12839.
a) R. S. Varma, Green Chem. 2014, 16, 2027–2041; b) G. Crav-
otto, E. C. Gaudino, P. Cintas, Chem. Soc. Rev. 2013, 42, 7521–
7534; c) D. Braga, L. Maini, F. Grepioni, Chem. Soc. Rev. 2013,
42, 7638–7648; d) S. L. James, C. J. Adams, C. Bolm, D. Braga,
P. Collier, T. Friscic, F. Grepioni, K. D. M. Harris, G. Hyett,
W. Jones, A. Krebs, J. Mack, L. Maini, A. G. Orpen, I. P. Par-
kin, W. C. Shearouse, J. W. Steed, D. C. Waddell, Chem. Soc.
Rev. 2012, 41, 413–447; e) T. Frisˇcˇic´, I. Halasz, P. J. Beldon,
A. M. Belenguer, F. Adams, S. A. J. Kimber, V. Honkimäki,
R. E. Dinnebier, Nature Chem. 2013, 5, 66–73; f) P. Balaz, M.
Achimovicova, M. Balaz, P. Billik, Z. Cherkezova-Zheleva,
J. M. Criado, F. Delogu, E. Dutkova, E. Gaffet, F. J. Gotor, R.
Kumar, I. Mitov, T. Rojac, M. Senna, A. Streletskii, K. Wieczo-
rek-Ciurowa, Chem. Soc. Rev. 2013, 42, 7571–7637; g) J. G.
Hernández, C. G. Avila-Ortiz, E. Juaristi, in Comprehensive Or-
ganic Synthesis II, 2nd ed., (Ed.: P. Knochel), Elsevier, Amster-
dam, 2014, pp. 287–314.
[8]
[9]
[10]
[11]
Experimental Section
Detailed experimental procedures are given in the Supporting In-
formation.
Supporting Information (see footnote on the first page of this arti-
cle): The file contains the details of experimental methods, spectro-
scopic investigations, synthetic procedure, characterization data
and spectra of the compounds.
[12]
[13]
S. Ley, M. O’Brien, R. Denton, Synthesis 2011, 1157–1192.
a) A. Stolle, T. Szuppa, S. E. S. Leonhardt, B. Ondruschka,
Chem. Soc. Rev. 2011, 40, 2317–2329; b) G.-W. Wang, Chem.
Soc. Rev. 2013, 42, 7668–7700; c) J. G. Hernández, E. Juaristi,
J. Org. Chem. 2010, 75, 7107–7111.
Acknowledgments
We are thankful to Department of Science and Technology (DST)
(New Delhi, India; Grant no. INT/FINLAND/P-06 and SR/S1/IC-
59/2010) for financial support. P. K. S. and A. B. are thankful to
University Grants Commission (UGC) and Council of Scientific
and Industrial Research (CSIR) (India), respectively for fellowship.
[14]
[15]
J.-L. Do, C. Mottillo, D. Tan, V. Strukil, T. Friscic, J. Am.
Chem. Soc. 2015, 137, 2476–2479.
a) S. Maiti, P. Mal, Adv. Synth. Catal. 2015, 357, 1416–1424;
b) T. K. Achar, P. Mal, J. Org. Chem. 2015, 80, 666–672; c) S.
Maiti, P. Mal, Synth. Commun. 2014, 44, 3461–3469; d) A.
Bose, P. Mal, Tetrahedron Lett. 2014, 55, 2154–2156.
M. Valko, H. Morris, M. T. D. Cronin, Curr. Med. Chem. 2005,
12, 1161–1208.
V. V. Zhdankin, in Hypervalent Iodine Chemistry, John Wiley &
Sons Ltd, 2013, pp. 145–336.
H. Hussain, I. R. Green, I. Ahmed, Chem. Rev. 2013, 113,
3329–3371.
a) S. Adimurthy, P. U. Patoliya, Synth. Commun. 2007, 37,
1571–1577; b) J.-C. Fan, Z.-C. Shang, J. Liang, X.-H. Liu, Y.
Liu, J. Phys. Org. Chem. 2008, 21, 945–953.
K. Moriyama, M. Takemura, H. Togo, J. Org. Chem. 2014, 79,
6094–6104.
a) J. Ribas-Arino, D. Marx, Chem. Rev. 2012, 112, 5412–5487;
b) J. Ribas-Arino, M. Shiga, D. Marx, Angew. Chem. Int. Ed.
2009, 48, 4190–4193; Angew. Chem. 2009, 121, 4254; c) J.
Wang, T. B. Kouznetsova, Z. Niu, M. T. Ong, H. M. Klukov-
ich, A. L. Rheingold, T. J. Martinez, S. L. Craig, Nature Chem.
2015, 7, 323–327.
[16]
[17]
[18]
[19]
[1] S. Zharikov, S. Shiva, Biochem. Soc. Trans. 2013, 41, 118–123.
[2] K. L. Morris, L. Chen, J. Raeburn, O. R. Sellick, P. Cotanda,
A. Paul, P. C. Griffiths, S. M. King, R. K. O’Reilly, L. C. Ser-
pell, D. J. Adams, Nature Commun. 2013, 4, 1480.
[3] J. Snoep, H. Westerhoff, in Systems Biology, vol. 13 (Eds.: L.
Alberghina, H. V. Westerhoff), Springer Berlin Heidelberg,
2005, pp. 13–30.
[4] a) N. Giuseppone, Acc. Chem. Res. 2012, 45, 2178–2188; b)
J. R. Nitschke, Nature 2009, 462, 736–738; c) R. F. Ludlow, S.
Otto, Chem. Soc. Rev. 2008, 37, 101–108.
[5] a) M. L. Saha, N. Mittal, J. W. Bats, M. Schmittel, Chem. Com-
mun. 2014, 50, 12189–12192; b) D. Lewing, H. Koppetz, F. E.
Hahn, Inorg. Chem. 2015, 54, 7653–7659; c) K. Pandurangan,
J. A. Kitchen, S. Blasco, E. M. Boyle, B. Fitzpatrick, M.
Feeney, P. E. Kruger, T. Gunnlaugsson, Angew. Chem. Int. Ed.
2015, 54, 4566–4570; d) J. E. Beves, J. J. Danon, D. A. Leigh,
J.-F. Lemonnier, I. J. Vitorica-Yrezabal, Angew. Chem. Int. Ed.
2015, 54, 7555–7559; e) R. Chakrabarty, P. S. Mukherjee, P. J.
[20]
[21]
[22]
C. O. Kappe, J. Org. Chem. 1997, 62, 7201–7204.
Eur. J. Org. Chem. 2015, 6994–6998
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6997

P. K. Sahoo, A. Bose, P. Mal
SHORT COMMUNICATION
[23] Q. Chen, L.-L. Jiang, C.-N. Chen, G.-F. Yang, J. Heterocycl.
Chem. 2009, 46, 139–148.
[24] H. Murata, H. Ishitani, M. Iwamoto, Org. Biomol. Chem. 2010,
8, 1202–1211.
[25] P. A. Wender, V. A. Verma, T. J. Paxton, T. H. Pillow, Acc.
Chem. Res. 2008, 41, 40–49.
[26] C. O. Kappe, Eur. J. Med. Chem. 2000, 35, 1043–1052.
[27] a) M. Gartner, N. Sunder-Plassmann, J. Seiler, M. Utz, I.
Vernos, T. Surrey, A. Giannis, ChemBioChem 2005, 6, 1173–
1177; b) T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W.
King, S. L. Schreiber, T. J. Mitchison, Science 1999, 286, 971–
974.
Received: August 11, 2015
Published Online: October 8, 2015
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