Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
[3 + 2]-Cycloaddition of Azaoxyallyl Cations with Hexahydro-1,3,5triazines: Access to 4‑Imidazolidinones Danqing Ji and Jiangtao Sun* Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China S Supporting Information *
ABSTRACT: A novel base-promoted [3 + 2] cycloaddition reaction of azaoxyallyl cations with hexahydro-1,3,5-triazines has been developed, affording 4-imidazolidinones in moderate to good yields under mild reaction conditions. This simple but efficient protocol features cycloaddition of two in situ formed reactive species in the absence of a transition-metal catalyst.
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multistep synthesis from ketone substrates. For example, a Strecker reaction (in the use of sodium cyanide) with ammonia followed by acid-mediated hydrolysis afforded an amidoamine intermediate. Then condensation with formaldehyde followed by reduction with sodium borohydride produced these 5,5disubstituted imidazolidin-4-ones (Scheme 1, eq 1).1b,c,f Clearly, this synthetic route is time-consuming with low efficiency. Thus, we decided to develop a straightforward protocol to target the 4-imidazolidinone scaffold. Recently, hexahydro-1,3,5-triazines have been employed as efficient aminomethylation reagents reported by the Krische group3 and others.4 Later, we5 and others6 further expanded the use of these triazines as formal 1,4- and 1,2-dipolar adducts in various annulation reactions to synthesize five to sevenmembered N-heterocycles (Scheme 1). On the other hand, azaoxyallyl cations, generated in situ from α-halo hydroxamates in the presence of a base,7 are formal reactive 1,3-dipoles that have been broadly applied in dearomative [4 + 3]-annulation with furans reported by Jeffrey8 and dearomative [3 + 2]annulation with indoles independently reported by Jeffrey and Wu.9 After that, a series of azaoxyallyl cation involved [3 + 3]-,10 [3 + 2]-,11 and [3 + 1]-cycloaddition12 reactions have been developed, respectively. Inspired by these elegant approaches and based on our experience in the chemistry of 1,3,5-triazines, we envisioned that the [3 + 2]-cycloaddition of azaoxyallyl cations with formaldehyde (in situ formed from 1,3,5-triazines) might occur upon the presence of a suitable base (Scheme 1, eq 2). Herein, we wish to report an efficient protocol to prepare 4-imidazolidinones, especially for the 5,5disubstituted ones in a single step.
midazolidin-4-ones are important motifs found in many biologically active compounds,1 such as nociceptin/orphanin FQ opioid peptide (NOP) receptor agonist Ro 64-6198,2a phospholipase D (PLD) selective inhibitor ML298,2b spiroimidazolidinone with anticonvulsant activity,2c and N,N′-methylenodidemnin A2d (strong cytotoxicity against human colon tumor cells HCT-116) (Figure 1). In particular, 5,5-
Figure 1. Examples of biologically active compounds that contain the 4-imidazolidinone core.
disubstituted-1-arylimidazolidin-4-ones, bearing a quaternary stereocenter at the 5-position, are potential pharmaceuticals with diverse biological activities.1,2 Despite their great importance, methods for synthesizing these types of compounds are rare. Moreover, the preparation of 5,5-disubstituted-1-arylimidazolidin-4-ones often relies on © XXXX American Chemical Society
Received: March 23, 2018
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DOI: 10.1021/acs.orglett.8b00951 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
dichloromethane were not suitable for this reaction (Table 1, entries 8 to 11), whereas the use of acetonitrile only gave a trace amount of 3aa (Table 1, entry 12). Then the reaction temperature was further evaluated (Table 1, entries 13−15). Lower temperature is detrimental to the reaction (Table 1, entry 13), and high temperature resulted in slightly decreased yields (Table 1, entries 14 and 15). Having established the optimal reaction conditions, we next explored the scope of hexahydro-1,3,5-triazines (Scheme 2).
Scheme 1. Previous Reports and Our Design
Scheme 2. Substrate Scope for Hexahydro-1,3,5-triazinesa,b
We commenced our studies by examining the reaction between α-bromo hydroxamate 1a and hexahydro-1,3,5-trazine 2a (Table 1). Initially, it was found that several inorganic and organic bases did promote the reaction, and the desired product 3aa was isolated in a range of yields in HFIP at 60 °C (Table 1, entries 1 to 7). Typically, t-BuOK was examined as the best one to give 3aa in 76% yield (Table 1, entry 1). Next, the solvents were screened. Unfortunately, THF, dioxane, toluene, and a
Table 1. Optimization of the Reaction Conditionsa
All reactions were performed with 1a (0.3 mmol), 2 (0.2 mmol), tBuOK (0.6 mmol), HFIP (1.5 mL) at 60 °C for 3 h. bIsolated yields.
entry
base
solvent
T (°C)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
t-BuOK K2CO3 Cs2CO3 t-BuONa Et3N DBU DMAP t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK
HFIP HFIP HFIP HFIP HFIP HFIP HFIP THF dioxane toluene CH2Cl2 MeCN HFIP HFIP HFIP
60 60 60 60 60 60 60 60 60 60 60 60 25 80 100
76 56 70 74 67 25 21 ND ND ND ND
