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Selective Single Electron Transfer Reduction of Urea-type CarbonylsHuan-Ming Huang,[a] and David J. Procter*[a]

Abstract: Highly chemoselective single electron transfer reduction of urea-type carbonyls using SmI2H2OLiBr has been developed for the first time. The process is triggered by non-classical open-shell ketyl radical anions from urea derivatives under mild reaction conditions. The corresponding cyclic aminal products could be obtained in good to excellent yields without using pyrophoric alkali metal hydrides. Furthermore, a chemoselective switch between reaction pathways depending on different proton source is observed and delivers cyclic aminal and hemiaminal products respectively.

Introduction

Chemoselective reduction of functional groups has received prodigious research interest and emerged as an important and integral area in organic chemistry.[1] Compared to well-established reduction methods of carboxylic acid derivatives such as hydrogenation and alkali metal hydrides, selective reduction through radical strategies under mild reaction conditions are still less documented.[2]

Samarium diiodide (SmI2) has become one of the most widely used single electron transfer (SET) reagents since it is introduced by Kagan.[3] Besides its successful in carbon-carbon bond coupling[4] and complex generation via radical cyclization or cyclization cascade[5], this commercially available reagent has been frequently applied in the chemoselective reduction of various functional groups.[6] However, ketyl radical intermediates which generated by SmI2 are typically limited to aldehyde and ketone derivatives over the past forty years (Scheme 1A). Since 2008, we start to explore this limitation and develop the general reduction of unactivated carboxylic acid derivatives merging SmI2H2O with amine.[7] Recently, this powerful Sm(II)-based reductant has been successfully used in the reduction of lactone derivatives,[8a,b] carboxylic esters,[8c,d] acids,[8e] amides,[8f,g]

nitriles[8h] and selenoamides[8i].[8j-k] Inspired by these progress, the related cyclization and cyclization cascades triggered by these non-classical open-shell ketyl radical anions from carboxylic acid derivatives have also been developed by us and others.[7a,9]

It is well-known that urea derivatives are a kind of valuable organic compounds which widely used as catalysts, ligands in synthetic chemistry and useful building blocks in medicinal chemistry.[10] However, due to the resistance to SET reduction, [10b] the reduction of urea carbonyl group under mild reaction condition has been unmet challenge.[11] Khurana and co-workers

reported an elegant example of reduction of 2-thiobarbiturates to form cyclic aminal products (Scheme 1B). However, this method required 5 to 25 equiv. of NiCl2 and NaBH4 and limited to more reactive thiourea substrates.[12] In this work, we communicate the first example of highly chemoselective SET reduction of urea-type carbonyls using SmI2H2OLiBr (Scheme 1C). The formed cyclic aminal products could be important pharmaceutical core in medicinal chemistry.[13] Furthermore, a chemoselective switch is observed depending on the proton source.

Scheme 1. (A) Well-established SmI2-mediated Reduction; (B) Previous Work: Pyprophoric Alkali Metal Hydrides Required; (C) This Work: Reduction of Ureas Using SmI2H2OLiBr

Results and Discussion

We began our study by screening a variety of different additives for SmI2 in the reduction of urea derivatives. The model substrate 1a could be synthesized through commercially available 1,3-dimethylbarbituric acid in three steps. The starting material 1a was recovered with only 5 equiv. SmI2 (Table 1, entry 1). When SmI2 was activated by 100 equiv. of water, the corresponding reductive product 2a was only obtained in 7% (entry 2). Besides recovered 30% starting material, the rest was quite messy. Flowers has already demonstrated that adding LiBr to SmI2 (-0.9 V vs SCE) generates more reducing SmBr2 (-1.55 V vs SCE) in situ.[14] Recently, this SmI2H2OLiBr system has been used by Reissig[15] and us[9d-f] to promote cyclization and cyclization cascades successfully. Interestingly, merging SmI2H2O with LiBr, the cyclic aminal product 2a was obtained 78% yield (entry 3). Furthermore, the process was completely selective to the urea carbonyl. Notably, the improvement of yield did not observe while amounts of water was increased or decreased (entry 4&5). However, when SmI2 was reduced to 3

[a] Dr. H.-M. Huang, Prof. Dr. D. J. ProcterSchool of Chemistry,University of ManchesterOxford Road, Manchester,M13 9PL (UK)E-mail: david.j.procter@manchester.ac.uk

Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))

COMMUNICATION equiv., the cyclic product 2a was decreased to 53% yield with 27% of starting material 1a left (entry 6).

Table 1. Table Caption Optimization of the Reaction Conditions[a]

EntrySmI2

(equiv.)H2O

(equiv.)LiBr

(equiv.)

Yield [%][b]

1a 2a

1 5 - - 100 -2[c] 5 100 - 30 73 5 100 100 0 78 (75)[d]

4 5 200 100 - 715 5 50 100 - 736 3 100 100 27 53

[a] Reaction conditions: 1a (0.1 mmol, in THF) under N2, was added H2O, followed by SmI2 or the mixture of SmI2 and LiBr, then the reaction was quenched after 8 h. [b] Yield was determined by 1H NMR spectroscopy using 2,3,5,6-tetrachloronitrobenzene as internal standard. [c] The rest was very messy. [d] Isolated yield.

Having established the optimized reaction conditions for selective reduction urea-type carbonyl of 1a, the scope of this reduction of urea deratives was investigated (Scheme 2). Firstly, different functional groups such as methoxy (2b) and trifluoromethyl (2c) were tolerated with 67% and 81% yields respectively. Several substrates with different chain on the carbon (2d, 2e&2f) were also tolerated. Hindered functional groups (2h&2i) were explored and obtained in moderate yields. Furthermore, the corresponding cyclic aminal products (2j&2k) were obtained in moderate yields with two aliphatic substituents. Different medicinally important heteroaromatic rings such as indole (2l&2m), benzothienyl (2n-2q), thienyl (2r) were also compatible in this reduction condition. Finally, the structure of reduced product 2b and 2l were confirmed by X-ray crystallographic analysis.[16]

Scheme 2. Scope of the Reduction of Urea Derivatives [a,b] [a] Reaction conditions: 1a (0.1 mmol, in 2 mL THF) under N2, was added H2O (100 equiv.), followed by the mixture of SmI2 (5 equiv.) and LiBr (100 equiv,), then the reaction was quenched after 8 h. [b] Isolated yield.

COMMUNICATION Interestingly, the cyclic aminal product 2g could be obtianed in 65% isolated yield under SmI2H2OLiBr conditions. However, we obtained the cyclic hemiaminal product 3g in moderate yield with SmI2t-BuOHLiBr conditions (Scheme 3).

Scheme 3. Reduction of Urea Derivatives Using Different Proton Sources.

We also performed gram scale experiment using 1g (3mmol, 1.09 g), the cyclic product 2g could be obtained without decreasing yield (63%, 0.66 g) (Scheme 4A). Several studies were conducted to gain insight into the reaction mechanism. The reduction of urea derivatives with SmI2D2OLiBr suggests that anions are generated and protonated by H2O in a series of four single electron transfers (Scheme 4B). The cyclic hemiaminal product 3g could be transferred to the cyclic aminal product 2g in quantitative yield under SmI2H2OLiBr conditions (Scheme 4C). This result shows that the product 3g may be the intermediate in the process of forming product 2g. A proposed mechanism is shown in Scheme 4D. Box and co-workers have already demonstrated that the spin density is delocalized in the barbituric acid system.[17] After reversible SET to the substrate 1, the amide radical anion intermediate 4 could be delocalized to the urea radical anion intermediate 5. Because of the hindered functional groups on the carbon atom, the urea radical anion 5 is more easily reduced to the hemiaminal 6 which could be obtained under SmI2t-BuOHLiBr condition. After dehydration, further reduction and protonation with excess more reductive SmI2H2OLiBr system, gives the cyclic aminal product 2.

Scheme 3. (A)Large Scale Experiment; (B) Labeling Study; (C) Preliminary Mechanistic Study; (D) Proposed Mechanism of the Reduction of Urea Derivatives.

Conclusions

In conclusion, we have developed the first example of highly chemoselective SET reduction of urea-type carbonyls triggered by non-classical open-shell ketyl radical anions from urea derivatives without using pyrophoric alkali metal hydrides. Merging SmI2H2O with LiBr has been successfully applied in the reduction of urea derivatives for the first time without using additional Lewis base ligands. Furthermore, a chemoselective switch between reaction pathways depending on different proton source is observed and delivers cyclic aminal and hemiaminal products respectively.

Experimental Section

General procedure A: SmI2-H2O-LiBr mediated reduction of barbiturates: To an oven-dried vial charged with anhydrous LiBr (868 mg, 10.0 mmol, 100 equiv) was added freshly prepared SmI2 (0.5 mmol, 5.0 mL, 0.1 M, 5 equiv) in THF, under a nitrogen atmosphere. The solution was stirred for 30 min at room temperature. An ovendried vial containing a stir bar was charged with barbiturate (0.1 mmol, 1 equiv) and placed under a positive pressure of nitrogen. THF (0.05 M, typically, 2.0 mL) and water (typically, 100 equiv) were added, followed by addition of the mixture of SmI2 and LiBr with vigorous stirring. After the specified time (typically, 8 h), the reaction was quenched by bubbling air through the mixture before dilution with CH2Cl2 (30 mL) and aqueous HCl (0.1 M, 20 mL). The aqueous layer was extracted with CH2Cl2 (3 × 20 mL) and the combined organic phases were dried over Mg2SO4, filtered and

COMMUNICATION concentrated. The crude product was purified by chromatography on silica gel.

Acknowledgements

We thank the EPSRC (EPSRC Established Career Fellowship to D.J.P.), the Leverhulme Trust (Research Fellowship to D.J.P.), and the University of Manchester (President’s Scholarship to H.H.) for funding.

Keywords: Reduction • Samarium • Urea • Single Electron Transfer • aminal

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Selective SET Reduction*

Huan-Ming Huang, David J. Procter*

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Selective Single Electron Transfer Reduction of Urea-type Carbonyls

Highly chemoselective single electron transfer reduction of urea-type carbonyls using SmI2H2OLiBr has been developed for the first time. The process is triggered by non-classical open-shell ketyl radical anions from urea derivatives under mild reaction conditions. The corresponding cyclic aminal products could be obtained in good to excellent yields without using pyrophoric alkali metal hydrides.

*one or two words that highlight the emphasis of the paper or the field of the study