Effective approach to ureas through organocatalyzed one-pot process

doi:10.1016/j.tetlet.2017.11.030

Tetrahedron Letters

Volume 59, Issue 17, 25 April 2018, Pages 1614-1618

https://doi.org/10.1016/j.tetlet.2017.11.030 Get rights and content

Highlights

•
Organocatalytic urea formation is described.
•
Non-toxic reagents are used instead of reported toxic reagents.
•
Mild reaction conditions and applicable to large scale synthesis.

Abstract

An efficient approach to N, N′-unsymmetrically substituted ureas 9 has been developed through the ammonolysis process of N-Boc protected anilines 7 with amines prompted by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). Moreover, a convenient protocol for the synthesis of the symmetric N, N'-substituted ureas 12 by one-pot diammonolysis process of Boc₂O with amines catalyzed by DABCO has also been achieved. With broad substrate scope and mild conditions, these two methods demonstrate practical preparation of both unsymmetrical and symmetrical ureas.

Graphical abstract

Introduction

The discovery of convenient methods for the formation of carbon-nitrogen bond has always been a focused area in synthetic organic chemistry, due to wide application in both natural product synthesis and industrial research and production.¹ As a prime instance, efficient methods toward preparation of urea and its analogous are very important in synthetic and medicinal chemistry, because these chemical subunits serve as substructures for numerous pharmaceuticals,² agrochemicals,³ as well as materials science.⁴ For example, the urea units are present in PI3K inhibitors (BEZ235, PKI-587)⁵, VEGFR inhibitors (Sorafenib, ABT-869, Lenvatinib, PD173074),⁶ TRPV antagonists (SB705498),⁷ and p38-MAP kinase inhibitors (BIBR796)⁸ (Fig. 1). Moreover, urea-containing scaffolds are frequently used in the design of bifunctional organocatalysts.⁹ Accordingly, tremendous efforts have been devoted to developing methods for the construction of urea motifs, and a number of powerful approaches have been reported.10, 11, 12, 13, 14, 15, 16, 18 However, most of the traditional methods for the preparation of urea or its derivatives involve the use of phosgene,¹⁰ metal-catalysts,¹¹ isocyanate,¹² azide,¹³ carbonyl imidazole derivatives¹⁴ and microwave-accelerated conditions,¹⁵ which are highly toxic, unstable, or challenging for large scale application. To pursue green processes, several methods through transition metal-catalyzed oxidative carbonylation of amines with CO¹⁶ or direct carbonylation of amine by CO₂¹⁷ are developed in recent years. However, the use of high pressure of CO/CO₂ gas still limits lab-scale application in medicinal chemistry.

With continuous focus in exploring practical synthetic methods for the synthesis of natural products and compounds with medicinal interests,¹⁸ we decided to develop a convenient method for the construction of urea scaffolds. The most straightforward urea synthesis uses activated carbamates as the starting materials or key intermediates. For example, very recently, Me₃SiCl, SiI₂H₂ or Tf₂O/Base were reported to activate the Boc-protected amines¹⁹ (Fig. 2. Eq. 1). Starting from unprotected amines, urea formation can also be achieved with the promotion of 4-dimethylaminopyridine (DMAP) in the presence of Boc anhydride²⁰ (Fig. 2. Eq. 2). Herein, we present efficient approach to obtain ureas with catalytic amount of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (Fig. 2. Eq. 3) or 1,4-Diazabicyclo[2.2.2]octane;triethylenediamine (DABCO) (Fig. 2. Eq. 4).

Section snippets

Results and discussion

As shown in Table 1, the reaction of Boc-protected 3-bromoaniline (7a) with benzylamine was used as the template for our investigation. Firstly, at room temperature, in DCM or acetonitrile as the solvent, only trace amount (≤5%) of urea product 9a was observed with 10% TBD, while no reaction can be detected with catalytic amount of DMAP or DABCO (Table 1, entries 1–4). When the reaction mixture was heated at 60 °C, the desired 9a was obtained in 65% yield (Table 1, entry 5). The reaction was

Conclusions

In summary, we established an efficient method to prepare N, N’-unsymmetrically substituted ureas 9 through the ammonolysis of N-Boc protected anilines 7 with amines prompted by TBD. Furthermore, one-pot approach, for the preparation of symmetric N, N'-substituted ureas 12 by the diammonolysis process of Boc₂O with 2 equivalents of amines, was also achieved, catalyzed by DABCO. The methods for the urea formation reported in this study are convenient, practicable and efficient. It can be applied

Acknowledgments

We thank the National Natural Science Foundation of China (No. 81673297), the Shanghai Municipal Committee of Science and Technology (No. 17431902500, 17JC1400200 and 15ZR1449000). We also thank Dr. Chang-Mei Si (School of Pharmacy, Fudan University) for helpful in preparation of manuscript.

References (21)

S.J. Choi et al.
J Appl Polym Sci
(2011)
E.I. Pereira et al.
J Agric Food Chem
(2012)
P. Wu et al.
Med Chem Commun
(2012)
Y. Wei et al.
Org Lett
(2010)
X. Huang et al.
Chem Commun
(2014)
R. Hili et al.
Nat Chem Biol
(2006)
K. Shin et al.
Acc Chem Res
(2015)
A.P. Kozikowski et al.
J Med Chem
(2004)
E.A. Terefenko et al.
Bioorg Med Chem Lett
(2005)
Q. Li et al.
Bioorg Med Chem Lett
(2005)
I. Gallou
Org Prep Proceed Int
(2007)
A.Y. Guan et al.
Chem Rev
(2014)
F. Musumeci et al.
J Med Chem
(2012)
H.K. Rami et al.
Bioorg Med Chem Lett
(2006)
J. Regan et al.
J Med Chem
(2002)
A.M. Hardman et al.
Org Biomol Chem
(2013)
S.S. So et al.
Org Lett
(2012)
H. Xu et al.
Science
(2010)
S.J. Connon
Synletters
(2009)
M. Ganesh et al.
J Am Chem Soc
(2008)
M.T. Robak et al.
J Am Chem Soc
(2007)
A.G. Doyle et al.
Chem Rev
(2007)

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

Cited by (21)

How achiral Brønsted acid is involved in co-catalyst model with chiral phosphoric acid for construction of quaternary carbon stereocenter
2024, Chem Catalysis
Chiral phosphoric acids, acting as bifunctional catalysts, play a dual role in activating both nucleophiles and electrophiles through non-covalent interactions. To enhance the activity of acid/base sites and create a favorable chiral steric environment, researchers have widely employed an efficient method, involving the introduction of an achiral Brønsted acid as reinforcement, in addition to structural modifications. However, the concrete catalytic model for this strategy remains relatively unexplored due to the increasing number of reaction sites on the catalysis heterodimer and the intricate spatial arrangement of multiple components in transition states. Here, we introduce a strategy of achiral Brønsted acid-assisted chiral-phosphoric-acid-catalyzed successive C–H functionalization/C–N cleavage and reassembly to construct an aza quaternary carbon stereocenter, in which the catalytic process and reaction mechanism were thoroughly investigated by in situ infrared studies and density functional theory calculations.
DMAP and TBPP-mediated synthesis of urea-substituted nucleobases and nucleosides
2023, Tetrahedron
Urea-functionalized nucleobases and nucleosides have emerged as versatile compounds with potential applications in a wide range of fields. Conventionally, the synthesis of urea involves the reaction of isocyanates with nucleobases and nucleosides. In contrast, this study presents a novel and efficient one-pot method for the synthesis of urea-substituted nucleobases and nucleosides without the use of isocyanates. The reaction was carried out in the presence of DMAP and TBPP, resulting in moderate to good yields of various urea-substituted nucleobases and nucleosides. Notably, N⁶-(N-threonyl-carbonyl)adenosine was also synthesized using this method. Furthermore, the synthesized compounds with adenine scaffold were evaluated for their binding affinity to adenosine receptors, but none of them exhibited binding, indicating a need for further modifications. These findings hold great promise for the facile synthesis of urea-functionalized nucleobases and nucleosides with potential applications in various fields.
Hydrosilane-Assisted Synthesis of Urea Derivatives from CO<inf>2</inf>and Amines
2020, Journal of Organic Chemistry
A methodology employing CO₂, amines, and phenylsilane was discussed to access aryl- or alkyl-substituted urea derivatives. This procedure was characterized by adopting hydrosilane to promote the formation of ureas directly, without the need to prepare silylamines in advance. Control reactions suggested that FeCl₃ was a favorable additive for the generation of ureas, and this 1,5,7-triazabicyclo[4.4.0]dec-5-ene-catalyzed reaction might proceed through nucleophilic addition, silicon migration, and the subsequent formal substitution of silylcarbamate.
2-Benzamide Tellurenyl Iodides: Synthesis and Their Catalytic Role in CO<inf>2</inf> Mitigation
2023, Chemistry - A European Journal
The metal- and column-free synthesis of pyridin-2-yl ureas carrying cyclic secondary amine substituents and establishing the mechanism of the reactions through a computational study
2023, Organic Chemistry Frontiers
Identification of diphenylurea derivatives as novel endocytosis inhibitors that demonstrate broad-spectrum activity against SARS-CoV-2 and influenza A virus both in vitro and in vivo
2023, PLoS Pathogens

View all citing articles on Scopus

View full text

Effective approach to ureas through organocatalyzed one-pot process

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

Acknowledgments

J Appl Polym Sci

J Agric Food Chem

Med Chem Commun

Org Lett

Chem Commun

Nat Chem Biol

Acc Chem Res

J Med Chem

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Org Prep Proceed Int

Chem Rev

J Med Chem

Bioorg Med Chem Lett

J Med Chem

Org Biomol Chem

Org Lett

Science

Synletters

J Am Chem Soc

J Am Chem Soc

Chem Rev