N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of P–O bond

doi:10.1016/j.tet.2011.01.061

Tetrahedron

Volume 67, Issue 13, 1 April 2011, Pages 2462-2467

https://doi.org/10.1016/j.tet.2011.01.061 Get rights and content

Abstract

N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of P–O bond was investigated and a series of N3-ethoxymethylated heterocyclic compounds were synthesized. A mechanism in which diethyl phosphite acts as an efficient surrogate of ethanol was proposed and supported by several evidences.

Graphical abstract

Introduction

Dialkyl phosphites, as a kind of useful phosphorus-containing reagents, are widely applied to the synthesis of organophosphonate derivatives, which are an important class of biologically active compounds.1, 1(a), 1(b), 1(c), 1(d) A large number of useful transformations have been achieved during the past decades, in which dialkyl phosphites were used as standard nucleophilic species for the construction of C–P bonds, in which various compounds can act as the acceptor, such as imines (ketimines),2, 2(a), 2(b), 2(c), 2(d) carbonyl groups,3, 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g) α,β-unsaturated carbonyl compounds,4, 4(a), 4(b), 4(c), 4(d) nitroalkenes,5, 5(a), 5(b), 5(c) and so on. Recently, some new catalyst systems have also been developed to promote the fully using of dialkyl phosphites in different ways (Fig. 1). Among those efficient protocols toward the using of dialkyl phosphite derivatives, cleavage of P–H bond inevitably involved homolytic cleavage6, 6(a), 6(b), 6(c) as the source of P-centered radicals under radical-initiated conditions or heterolytic cleavage7, 7(a), 7(b), 7(c) (Fig. 1, path a). Besides, there are few reports showing that dialkyl phosphites could also participate in the construction of C–N and C–O bonds, involving the cleavage of C–O bond (path b).8, 8(a), 8(b) However, to the best of our knowledge, few efforts were devoted to improving P–O bond cleavage and further using dialkyl phosphites as an O-nucleophiles to achieve some interesting transformations (path c).

In the past decades, 3,4-dihydropyrimidinones (Biginelli compounds or DHPMs) and their derivatives have attracted considerable interest due to their heterocyclic scaffold9, 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g) and interesting pharmacological properties, such as calcium channel modulation, anti-hypertension, α_1a adrenergic agonistic and mitotic kinesin inhibition, and hepatitis B virus replication suppression.10, 10(a), 10(b) The N-substituted reaction of dihydropyrimidinones is one of the approaches to functionalized dihydropyrimidinones in order to achieve higher bioactive properties.9, 9(a), 9(b), 9(c), 9(d), 9(e), 9(f), 9(g) For instance, most of the pharmacologically attractive forms are N3-substituted analogues, which might exhibit anti-inflammatory, antihypertensive, analgesic, and anticancer activities.11(e), 11(f), 11(g), 11, 11(a), 11(b), 11(c), 11(d) Most N-alkylated pyrimidinones are obtained from S_N2 reaction in which pyrimidinone as a nucleophile reacts with an electrophile, such as an alkyl halide and alkyl sulfate. However, unexplained poor regioselectivity between N3 and N1 were obtained and in most cases N1-alkylated products of pyrimidinones were isolated as major products.9, 9(a), 9(b) These limitations have hindered the synthesis of N3-substituted pyrimidinone derivatives.

As part of our ongoing research program on the synthesis of 3,4-dihydropyrimidinone (DHPM) derivatives,12, 12(a), 12(b) we recently reported a regioselective synthesis of the N3-functionalized DHPM by reaction of DHPM with paraformaldehyde and various reagents in the presence of chlorotrimethylsilane.¹³ In continuation of our efforts to synthesize some new N3-functionalized DHPM derivatives, which might exhibit better biological responses and pharmacological properties, herein we described a novel and efficient synthesis of N-ethyoxymethyl-3,4-dihydropyrimidinone using a three component reaction between 3,4-dihydropyrimidinone, paraformaldehyde, and diethyl phosphite via the P–O bond cleavage of diethyl phosphite (Fig. 1, path c).

Section snippets

Reaction with 3,4-dihydropyrimidinone and paraformaldehyde

It has been reported that N3-hydroxylmethylated 3,4-dihydropyrimidinone could be achieved by treating 3,4-dihydropyrimidinone with aqueous formaldehyde and potassium carbonate at reflux temperature.14, 14(a), 14(b) According to our mechanism design, we expected that the N3-hydroxylmethylated 3,4-dihydropyrimidinones, which produced by the reaction between 3,4-dihydropyrimidinones and paraformaldehyde could subsequently react with diethyl phosphite and generate phosphorus-containing

Conclusion

In summary, we have executed a novel approach in which P–O bond cleavage of diethyl phosphite occurred and diethyl phosphite served as an equivalent of alcohol to achieve the synthesis of a series of N-ethoxymethylated heterocyclic compounds in high regioselectivity and yield. We are currently focused on promoting this novel transformation and further exploring the use in construction of more variable heterocyclic compounds. Further investigations in the mechanism of this reaction are also

General

All reagents were obtained commercially and used without further purification. Melting points were determined on an XT-4 electrothermal micromelting point apparatus and uncorrected. NMR spectra were recorded at 400 (¹H) and 100 (¹³C) MHz, respectively, on a Varian Mercury plus-400 instrument using CDCl₃ as solvent and TMS as internal standard. LC–Mass-spectra and mass-spectra were recorded on a TRACE DSQ instrument. All commercially available substrates were used as received. TLC was performed

Acknowledgements

We are thankful for the financial support from the National Nature Science Foundation of China (Nos. 20902073 and 21062017), the Natural Science Foundation of Gansu Province (No. 096RJZA116), and Scientific and Technological Innovation Engineering program of Northwest Normal University (nwnu-kjcxgc-03-64).

References and notes (17)

F. Palacios et al.
Chem. Rev.
(2005)
K. Moonen et al.
Chem. Rev.
(2004)
M. Kalek et al.
Adv. Synth. Catal.
(2009)
For selected examples,...C.O. Kappe et al.
Molecules
(2000)
R.V. Chikhale et al.
Eur. J. Med. Chem.
(2009)
K. Deres et al.
Science
(2003)
A.G. Gross et al.
J. Comb. Chem.
(2006)
A.N. Chiang et al.
Bioorg. Med. Chem.
(2009)
G.J. Grover et al.
J. Cardiovasc. Pharmacol.
(1995)
S.W. Fewell et al.
J. Biol. Chem.
(2004)
Z.-J. Quan et al.
Heterocycles
(2010)
H. Cho et al.
Tetrahedron Lett.
(1988)
D.E.C. Corbridge
Phosphorus: An Outline of Its Chemistry, Biochemistry and Uses
(1995)
S. Swaminathan et al.
Chem. Rev.
(1971)
A.K. Bhattacharya et al.
Chem. Rev.
(1981)
For elected examples of reaction of imines and ketimines,...P. Merino et al.
Adv. Synth. Catal.
(2008)
M. Ordóñez et al.
Tetrahedron
(2009)
S. Nakamura et al.
J. Am. Chem. Soc.
(2009)
J. Gambecka et al.
Mini-Rev. Med. Chem.
(2001)
For elected examples of addition to carbonyl compounds,...D.F. Wiemer
Tetrahedron
(1997)
H. Gröger et al.
Chem.—Eur. J.
(2000)
N.P. Rath et al.
Tetrahedron Lett.
(1994)
C. Qian et al.
J. Chem. Soc., Perkin Trans. 1
(1998)
T. Yamagishi et al.
Tetrahedron
(1999)
D.M. Cermak et al.
J. Org. Chem.
(1999)
X. Zhou et al.
Adv. Synth. Catal.
(2009)
F. Wang et al.
Chem.—Eur. J.
(2009)
E. Maerten et al.
J. Org. Chem.
(2007)
D. Zhao et al.
Chem.—Eur. J.
(2009)
D. Zhao et al.
Chem.—Eur. J.
(2009)

There are more references available in the full text version of this article.

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N-Alkoxymethylation of heterocyclic compounds with diethyl phosphite via cleavage of P–O bond

Abstract

Graphical abstract

Introduction

Section snippets

Reaction with 3,4-dihydropyrimidinone and paraformaldehyde

Conclusion

General

Acknowledgements

Chem. Rev.

Chem. Rev.

Adv. Synth. Catal.

Molecules

Eur. J. Med. Chem.

Science

J. Comb. Chem.

Bioorg. Med. Chem.

J. Cardiovasc. Pharmacol.

J. Biol. Chem.

Heterocycles

Tetrahedron Lett.

Phosphorus: An Outline of Its Chemistry, Biochemistry and Uses

Chem. Rev.

Chem. Rev.

Adv. Synth. Catal.

Tetrahedron

J. Am. Chem. Soc.

Mini-Rev. Med. Chem.

Tetrahedron

Chem.—Eur. J.

Tetrahedron Lett.

J. Chem. Soc., Perkin Trans. 1

Tetrahedron

J. Org. Chem.

Adv. Synth. Catal.

Chem.—Eur. J.

J. Org. Chem.

Chem.—Eur. J.

Chem.—Eur. J.