A novel one-pot method for the stereoselective synthesis of tetrahydropyrimidinones in a low melting mixture

Article abstract of DOI:10.1039/d0ob00697a

A direct and metal free one-pot method has been developed for the stereoselective synthesis of tetrahydropyrimidinone derivatives from a vinyl arene and formaldehyde using a tartaric acid-dimethylurea (TA : DMU) melt as a green reaction medium. The substrate scope of this method is very general and the tetrahydropyrimidinone (THPM) derivatives are synthesized in good yields with a high degree of diastereoselectivity. In this reaction, the melt plays a triple role as the solvent, catalyst and reagent.

Full text of DOI:10.1039/d0ob00697a

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DOI: 10.1039/D0OB00697A
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Novel one-pot method for the stereoselective synthesis of
tetrahydropyrimidinones in low melting mixture
Pramila Devi, Mallikharjuna Rao Lambu and Sundarababu Baskaran*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A direct and metal free one-pot method has been developed for
the stereoselective synthesis of tetrahydropyrimidinone
derivatives from vinyl arene and formaldehyde using tartaric acid-
dimethylurea (TA:DMU) melt as a green reaction medium. The
substrate scope of this method is very general and the
tetrahydropyrimidinone (THPM) derivatives are synthesized in
good yields with high degree of diastereoselectivity. In this
reaction, the melt plays a triple role as solvent, catalyst and
reagent.
Heterocyclic motifs such as pyrimidinone derivatives are key
structural units present in a wide variety of biologically active
molecules.1 The pyrimidinones are known to exhibit potent
biological activities such as antiarrhythmic,2 antihypertensive,3
antibacterial,4 antiproliferative5 as well as calcium channel
Fig. 1 Pyrimidinone based biologically important molecules.
Various metal mediated methods have been developed for the
synthesis of THPM derivatives, which include W(CO)6 catalyzed
oxidative carbonylation of diamine,17 ZnO mediated synthesis
of cyclic urea derivatives under microwave conditions,18
palladium-catalyzed synthesis of tetrahydropyrimidinones,19
indium facilitated synthesis of hexahydro-pyrimidine from
alkene and formaldimines,20 and iridium assisted
hydrogenation of pyrimidines.21 In 2006, Wu and co-worker
reported TMSCl mediated reaction of alkene with iminium ion,
derived from aldehyde and urea/thiourea, furnished the
corresponding 2-amino-4,5-dihydro-1,3-oxazine/1,3-thioazine
derivatives (Scheme 1a).22 Nevertheless, development of a
simple and efficient approach for the synthesis of THPMs is
highly desirable due to their broad spectrum of biological
activities.
modulator.6
Moreover,
hydropyrimidinones
exhibit
antineoplastic7 and anti-HIV activities8 by inhibiting
dihydroorotase and HIV-protease enzyme.9–11 Similarly,
12
monastrol (
1
)
exhibits potent antiproliferative activity by
inhibiting kinesin Eg5, a molecular motor protein, which is
responsible for the formation of bipolar spindle during cell
division. In addition, piperastrol (6) displays antiproliferative
activity against HT-29 (colon) and MCF-7 (breast) cell lines,14
whereas pyrimidinone-hybrid molecule (7), derived from
dihydropyrimidinone (DHPM) and palmitic fatty acid, exhibits
potent antiproliferative activity against gliomas cell line (Figure
1).15
The chromopynones are glucose uptake inhibitors that target
glucose transporters Glut-1 and 3, and thus stop the growth of
cancer cell. Intriguingly, tetrahydropyrimidinones (THPMs)
have also served as precursors in the biology-oriented
synthesis (BIOS) of pseudo natural chromopynones.16
Department of Chemistry, Indian Institute of Technology Madras,
Chennai, 600036, India. E-mail: sbhaskar@iitm.ac.in;
†Electronic Supplementary Information (ESI) available: General procedure,
experimental details and crystallographic data. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/x0xx00000x
Scheme 1 Synthesis of heterocyclic compounds from vinyl arene.
Low-melting mixture as a reaction medium is an emerging area
in organic synthesis due to their interesting physicochemical
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properties.23 Low-melting mixture, a sustainable reaction
medium, consists of nontoxic, non-volatile and biodegradable
compounds readily available from natural resources. Thus, the
synthetic versatility of eutectic mixtures as novel green
reaction medium is expanding very rapidly.24 Herein, we
describe a three-component based approach for the synthesis
of THPM derivatives using environmentally benign low melting
mixture as a green reaction medium.25
Table 2 Synthesis of tetrahydropyrimidinone in L-(+)-tartaric acid and
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dimethylurea melt
DOI: 10.1039/D0OB00697A
Entry
Time
(h)
Yield (%)
(dr)
Starting material
Product
1
22
59
We anticipated that an iminium ion, derived from urea and
aldehyde, upon addition to alkene followed by in situ
cyclization would provide an easy and direct access to
tetrahydropyrimidinone derivative. To test our assumption, 4-
2
3
14
17
76
68
methyl styrene (
8
) was treated with formaldehyde in citric
o
acid-dimethylurea (CA:DMU) melt at 70 C and the resultant
mixture was stirred at the same temperature for 26h. To our
delight, upon work-up it afforded tetrahydropyrimidinone
derivative (8a) in 37% yield. The structure of 8a was
23
21
69
76
4
5
unambiguously established on the basis of H NMR, 13C NMR,
1
HRMS, and IR analyses. In order to optimize the reaction
conditions, different melt combinations were explored and the
results are summarized in Table 1. Among the melts screened,
the tartaric acid- dimethylurea (TA:DMU) melt was found to be
the most effective green reaction medium for the synthesis of
22
73
63
(19:1)
73
THPM derivative (Table 1, entry 2).
Table 1 Optimization of reaction conditionsa
20
21
6
(19:1)
68
(19:1)
7
8
18
24
Entry
Reagent
Time (h)
Yield (%)b
69
(19:1)
1
2
CA:DMU(4:6) melt
TA:DMU(3:7) melt
TA:ChCl(1:2) melt
TFA:DMU in DCE
26
22
29
30
37
53
42
0
3c
4d
72
(19:1)
9
20
16
aReaction conditions: A mixture of 4-methyl styrene (1 equiv) and formaldehyde
(2 equiv) was used in 1.5g of melt. bYield based on the isolated product. cDMU
(1.5 equiv) was added. dA mixture of TFA (1 equiv) and DMU (2 equiv) was used in
DCE.
81
(19:1)
10
After optimizing the reaction conditions, the generality of this
methodology was examined with various substrates and the
results are summarized in Table 2. Under the reaction
conditions, the substituted styrene derivatives 9, 10, 11, 12
11
12
13
16
14
17
66
80
74
and 13 afforded the corresponding THPM derivatives 9a, 10a
,
11a, 12a and 13a, respectively, in good yields (Table 2, entries
1-4).26 Under similar reaction conditions, 1-(allyloxy)-4-
vinylbenzene (14) afforded THPM derivative 14a as the only
product in good yield (Table 2, entry 5). Intriguingly, the allyl
ether functional group was found to be stable under the
reaction conditions and moreover the unactivated alkene
moiety did not participate in the pyrimidinone reaction.
Unlike simple alkene, the electron rich 3,4-dihydropyran (21
)
reacted readily under the conditions to furnish bicyclic
tetrahydropyrimidinone derivative 21a in good yield (Table 2,
aReaction conditions: styrene (1 equiv), formaldehyde (2 equiv) in TA:DMU(3:7,
w/w) melt at 70 oC. Yield based on isolated product.
2 | J. Name., 2012, 00, 1-3
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entry 11). Similarly, electron rich 1-aryl-cycloalkene derivatives The 1,3-diamine functionality is a ubiquitous structural feature
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22 and 23 afforded the corresponding bicyclic THPM present in
derivatives 22a and 23a, respectively, in very good yields pharmaceuticals.29
(Table 2, entries 12 & 13). tetrahydropyrimidinone 8a on LiAlH4 reduction followed by
a
wide range of naDtuOrI:a1l0.10p3r9o/dDu0cOtBs006a9n7dA
The six-membered cyclic urea,
Encouraged by these observations, the scope of this reaction acid hydrolysis afforded 1-aryl-1,3-diamine 8c in very good
was further tested with 1,2-disubstituted styrene derivatives. yield (Scheme 4).30
Under the melt reaction conditions, cis-vinyl arene derivative
15 underwent smooth reaction to furnish trans-4,5-
disubstituted tetrahydropyrimidinone derivative 15a as the
only product in good yield (Table 2, entry 6). Remarkably, both
Scheme 4 Synthesis of 1,3-diamine.
In summary, mild and highly efficient protocol has been
19a, respectively, in good yields with developed for the synthesis of tetrahydropyrimidinones using
cis- and trans-1,2-disubstituted vinyl arene derivatives 15
underwent smooth reaction to furnish trans-4,5-disubstituted
THPM derivatives 15a
-20
a
-
excellent diastereoselectivity (dr = 19:1) (Table 2, entries 6-10).
The exclusive formation of trans-diastereomer can be
attributed to the generation of stable benzylic carbocation.
Based on these observations, a plausible mechanism for the
tartaric acid-DMU melt as a novel reaction medium. Under these
conditions, vinyl arenes reacted readily with formaldehyde to
furnish THPM derivatives in good yields with high degree of
diastereoselectivity. In this reaction, melt plays a triple role as
solvent, catalyst as well as reagent.
formation of THPM is shown in Figure 2. The iminium ion
derived from formaldehyde and dimethylurea, would react
with vinyl arene to generate a stable benzylic carbocation
A,
B,
which on subsequent intramolecular cyclization could then
lead to THPM derivative.
Acknowledgements
We thank DST-SERB (EMR/2016/004040), India, for financial
support and DST-FIST for providing instruments facilities. P. D.
thanks UGC-New Delhi for a research fellowship.
Fig. 2 Plausible mechanism for the formation of THPM derivative.
Notes and references
Moreover, under tartaric acid-diallylurea (TA:DAU) melt
1
(a) G. V. De Lucca, J. Liang, P. E. Aldrich, J. Calabrese, B.
Cordova, R. M. Klabe, M. M. Rayner and C.-H. Chang, J. Med.
Chem., 1997, 40, 1707; (b) B. Pasquier, Y. El-Ahmad, B.
Filoche-Romme, C. Dureuil, F. Fassy, P.-Y. Abecassis, M.
Mathieu, T. Bertrand, T. Benard, C. Barriere, S. El Batti, J.-P.
Letallec, V. Sonnefraud, M. Brollo, L. Delbarre, V. Loyau, F.
Pilorge, L. Bertin, P. Richepin, J. Arigon, J.-R. Labrosse, J.
Clement, F. Durand, R. Combet, P. Perraut, V. Leroy, F. Gay,
D. Lefrancois, F. Bretin, J.-P. Marquette, N. Michot, A. Caron,
C. Castell, L. Schio, G. McCort, H. Goulaouic, C. Garcia-
Echeverria and B. Ronan, J. Med. Chem., 2015, 58, 376; (c) M.
Gichinga, J. P. Olson, E. Butala, H. A. Navarro, B. P. Gilmour,
S. W. Mascarella and F. I. Carroll, ACS Med. Chem. Lett.,
conditions, 4-methyl styrene (
70 oC to furnish the corresponding bis-allyl THPM derivative 24
in 19% yield along with 3,5-diallyl-1,3,5-oxadiazinan-4-one (25
8) reacted with formaldehyde at
)
in 32% yield. However in TA:ChCl melt,27 dibenzylurea reacted
readily to furnish 3,5-dibenzyl-1,3,5-oxadiazinan-4-one (27) as
the only product in 72% yield (Scheme 2).28
2011,
2
, 882; (d) M. Vijjulatha and S. S. Kanth, Cent. Eur. J.
, 1064; (e) P. Babczinski, M. Blunck, G.
Chem., 2007,
5
Sandmann, K. Shiokawa and K. Yasui, Pestic. Biochem.
Physiol., 1995, 52, 45.
2
3
US Pat., WO93/04060, March 4, 1993.
Scheme 2 Reaction of diallylurea and dibenzylurea under melt conditions.
G. C. Rovnyak, K. S. Atwal, A. Hedeberg, S. D. Kimball, S.
Moreland, J. Z. Gougoutas, B. C. O’Reilly, J. Schwartz and M.
F. Malley, J. Med. Chem., 1992, 35, 3254.
(a) V. Ramachandran, P. Ramesh, K. Arumugasamy, S. K.
Singh, N. Edayadulla and S.-K. Kamaraj, J. Chem. Biol., 2016,
To demonstrate the scalability of this method, a gram-scale
reaction was performed with vinyl arene
8 under optimized
4
reaction conditions. The gram-scale reaction proceeded
smoothly and provided the corresponding THPM derivative 8a
in 56% yield which was in good agreement with the small-scale
reaction. Moreover, the melt medium can be recovered and
recycled. Using recovered melt, the THPM derivative (8a) was
isolated in 49% yield.
9
, 31; (b) S. Shaikh, N. P. Shaikh, S. D. Salunke, and M. A.
Baseer, Heterocycl. Lett., 2015, , 443; (c) S. Baluja, R. Gajera,
and S. Chanda, J. Bacteriol Mycol., 2017, , 414.
5
5
5
D. Russowsky, R. F. S. Canto, S. A. A. Sanches, M. G. M.
D’Oca, A. de Fatima, R. A. Pilli, L. K. Kohn, M. A. Antonio and
J. E. de Carvalho, Bioorg. Chem., 2006, 34, 173.
6
7
(a) C. O. Kappe, Molecules, 1998,
and C. O. Kappe, Molecules, 2000,
3, 1; (b) B. Jauk, T. Pernat,
5, 227.
(a) P. K. Jadhav, P. Ala, F. J. Woerner, C.-H. Chang, S. S.
Garber, E. D. Anton and L. T. Bacheler, J. Med. Chem., 1997,
40, 181; (b) G. V. De Lucca, J. Liang and I. De Lucca, J. Med.
Scheme 3 Gram-scale synthesis of THPM derivative 8a.
This journal is © The Royal Society of Chemistry 20xx
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Page 4 of 4
COMMUNICATION
Journal Name
Chem., 1999, 42, 135; (c) J. L. Adams, T. D. Meek, S. M.
Mong, R. K. Johnson and B. W. Metcalf, J. Med. Chem., 1988,
31, 1355.
(a) M. E. Pierce, G. D. Harris, Q. Islam, L. A. Radesca, L.
Storace, R. E. Waltermire, E. Wat, P. K. Jadhav, and G. C.
Kӧnig, Org. Lett. 2012, 14, 4568; (d) S. Gore, K.VCiehwinArtthiclaepOanlllinye,
S. Baskaran, and B. Kӧnig, Chem. Commun., 2013, 49, 5052.
DOI: 10.1039/D0OB00697A
26 In the case of simple styrene, the reaction was found to be
very sluggish and the corresponding THPM derivative was
isolated in 14% yield.
8
Emmett, J. Org. Chem., 1996, 61, 444; (b) P. Gayathri, V. 27 Surprisingly, dibenzylurea did not form melt with tartaric
Pande, R. Sivakumar and S. P. Gupta, Bioorg. Med. Chem.,
acid even at 150 oC.
2001, , 305; (c) A. R. Katritzky, A. Oliferenko, A. Lomaka and 28 A. P. Venkov and T. A. Temnyalova, Synth. Commun., 1996,
M. Karelson, Bioorg. Med. Chem. Lett., 2002, 12, 3453. 26, 3217.
D. W. Pettigrew, R. R. Bidigare, B. J. Mehta, M. I. Williams 29 (a) N. B. Pham, S. Deydier, M. Labaied, S. Monnerat, K. Stuart
9
9
and E. G. Sander, Biochem. J., 1985, 230, 101.
10 (a) R. Garg and B. Bhhatarai, Bioorg. Med. Chem., 2004, 12
and R. J. Quinn, Eur. J. Med. Chem., 2014, 74, 541-551; (b) T.
Kammermeier and W. Wiegrebe, Arch Pharm, 1995, 328,
,
5819; (b) C. N. Hodge, P. E. Aldrich, L. T. Bacheler, C. H.
Chang, C. J. Eyermann, S. Garber, M. Grubb, D. A. Jackson, P.
K. Jadhav, B. Korant, P. Y. Lam, M. B. Maurin, J. L. Meek, M. J.
Otto, M. M. Rayner, C. Reid, T. R. Sharpe, L. Shum, D. L.
409; (c) X. Ji and H. Huang, Org. Biomol. Chem., 2016, 14,
10557; (d) Y. Liu, Y. Xie, H. Wang and H. Huang, J. Am. Chem.
Soc., 2016, 138, 4314; (e) J. Hu, Y. Xie and H. Huang, Angew.
Chem., Int. Ed., 2014, 53, 7272.
Winslow and S. Erickson-Viitanen, Chem. Biol., 1996,
3
, 301.
30 (a) H. A. Bates, N. Condulis and N. L. Stein, J. Org. Chem.,
1986, 51, 2228; (b) A. R. Pradipta and K. Tanaka, Bull. Chem.
Soc. Jpn., 2016, 89, 337.
11 P. Y. Lam, Y. Ru, P. K. Jadhav, P. E. Aldrich, G. V. De Lucca, C.
J. Eyermann, C. H. Chang, G. Emmett, E. R. Holler, W. F.
Daneker, L. Li, P. N. Confalone, R. J. McHugh, Q. Han, R. Li, J.
A. Markwalder, S. P. Seitz, T. R. Sharpe, L. T. Bacheler, M. M.
Rayner, R. M. Klabe, L. Shum, D. L. Winslow, D. M.
Kornhauser, D. A. Jackson, S. Erickson-Viitanen and C. N.
Hodge, J. Med. Chem., 1996, 39, 3514.
12 T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King, S. L.
Schreiber and T. J. Mitchison, Science, 1999, 286, 971.
13 M. Gartner, N. Sunder-Plassmann, J. Seiler, M. Utz, I. Vernos,
T. Surrey, and A. Giannis, ChemBioChem, 2005, 6, 1173.
14 M. A. Bhat, A. Al-Dhfyan and M. A. Al-Omar, Molecules,
2016, 21, 1746.
15 (a) T. G. M. Treptow, F. Figueiro, E. H. F. Jandrey, A. M. O.
Battastini, G. C. Salbego, J. B. Hoppe, P. S. Taborda, S. B.
Rosa, L. A. Piovesan, C. D. R. D’Oca, D. Russowsky and M. G.
Montes D’Oca, Eur. J. Med. Chem., 2015, 95, 552; (b) F. S. De
Oliveira, P. M. De Oliveira, L. M. Farias, R. C. Brinkerhoff, R. C.
M. A. Sobrinho, T. M. Treptow, C. R. Montes D'Oca, M. A. G.
Marinho, M. A. Hort, A. P. Horn, D. Russowsky and M. G.
Montes D'Oca, MedChemComm, 2018, 9, 1282.
16 G. Karageorgis, E. S. Reckzeh, J. Ceballos, M. Schwalfenberg,
S. Sievers, C. Ostermann, A. Pahl, S. Ziegler and H.
Waldmann, Nat. Chem., 2018, 10, 1103.
17 F. Qian, J. E. McCusker, Y. Zhang, A. D. Main, M. Chlebowski,
M. Kokka and L. McElwee-White, J. Org. Chem., 2002, 67
4086.
18 Y. J. Kim and R. S. Varma, Tetrahedron Lett., 2004, 45, 7205.
,
19 (a) M. Morgen, S. Bretzke, P. Li and D. Menche, Org. Lett.,
2010, 12, 4494; (b) Y. Nishikawa, S. Kimura, Y. Kato, N.
Yamazaki and O. Hara, Org. Lett., 2015, 17, 888.
20 (a) I. M. Taily, D. Saha and P. Banerjee, Eur. J. Org. Chem.,
2019, 2019, 7804; (b) H. Zhou, H. H. Chaminda Lakmal, J. M.
Baine, H. U. Valle, X. Xu and X. Cui, Chem. Sci., 2017, 8, 6520.
21 G.-S. Feng, L. Shi, F.-J. Meng, M.-W. Chen and Y.-G. Zhou,
Org. Lett., 2018, 20, 6415.
22 Y. Zhu, S. Huang, J. Wan, L. Yan, Y. Pan and A. Wu, Org. Lett.,
2006, 8, 2599.
23 (a) Q. Zhang, K. De Oliveira Vigier, S. Royer and F. Jerome,
Chem. Soc. Rev., 2012, 41, 7108; (b) C. Russ and B. Kӧnig,
Green Chem., 2012, 14, 2969.
24 Organic transformation in melt (a) A. Punzi, D. I. Coppi, S.
Matera, M. A. M. Capozzi, A. Operamolla, R. Ragni, F.
Babudri and G. M. Farinola, Org. Lett., 2017, 19, 4754; (b) M.
J. Rodriguez-Alvarez, C. Vidal, J. Diez and J. Garcia-Alvarez,
Chem. Commun., 2014, 50, 12927; (c) C. Vidal, L. Merz and J.
Garcia-Alvarez, Green Chem., 2015, 17, 3870.
25 (a) S. Gore, S. Baskaran and B. Kӧnig, Green Chem., 2011, 13
,
1009; (b) S. Gore, S. Baskaran and B. Kӧnig, Adv. Synth.
Catal., 2012, 254, 2368; (c) S. Gore, S. Baskaran, and B.
4 | J. Name., 2012, 00, 1-3
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