Synthesis of Cyclic N-Hydroxylated Ureas and Oxazolidinone Oximes Enabled by Chemoselective Iodine(III)-Mediated Radical or Cationic Cyclizations of Unsaturated N-Alkoxyureas

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DOI: 10.1002/adsc.201901135

Synthesis of Cyclic N-Hydroxylated Ureas and Oxazolidinone

Oximes Enabled by Chemoselective Iodine(III)-Mediated Radical

or Cationic Cyclizations of Unsaturated N-Alkoxyureas

Laure Peilleron,^aPascal Retailleau,^aand Kevin Cariou^a,*

a

Institut de Chimie des Substances Naturelles CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, Avenue de la

Terrasse, 91198 Gif-sur-Yvette, France

E-mail: kevin.cariou@cnrs.fr

Manuscript received: September 8, 2019; Version of record online: ■■■, ■■■■

Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201901135

Abstract: In this study we describe the reactivity of unsaturated N-alkoxyureas in the presence of different

combinations of a hypervalent iodine(III) reagent and a bromide source or TEMPO. Three complementary

cyclizations can be achieved depending on the reaction conditions. On the one hand, PIFA with pyridinium

bromide leads to an oxybromination reaction. On the other hand, bis(tert-butylcarbonyloxy)iodobenzene with

tetrabutylammonium bromide or TEMPO triggers aminobromination or aminooxyamination reactions,

respectively. Control experiments showed that the three reactions proceed through distinct mechanisms: the

first process is ionic while the other two follow a radical manifold.

Keywords: Hypervalent iodine; bromination; cyclization; radicals; TEMPO

Introduction

Other related diazabicyclooctane derivatives such

as relebactam^[5](2), ETX2514^[6](3) or IID572^[7](4) are

Cyclic N-hydroxylated ureas are a singular type of at the forefront of the development pipeline for the

heterocycle that have been incorporated into various fight against bacterial resistance.^[8]Antimicrobial re-

bioactive scaffolds to target anticancer^[1]or herbicidal sistance becomes an ever increasing threat^[9]so

activities^[2]with moderate success. This motif is also providing modular and versatile synthetic methods to

key to the activity of avibactam (1, Figure 1), a non β- access this type of compounds is critical, especially

lactam β-lactamase inhibitor^[3]that was discovered and since only few reactions can be used so far.

developed in the early 2000’s and was approved by the

Initial methods employed to access cyclic N-

FDA in 2015 in combination with Ceftazidime (a 3^rdhydroxylated ureas relied on the reaction of hydroxyl-

generation cephalosporin antibiotic) for the treatment amine with chloropropylcarbamates in an S_N2/lactam-

of severe Gram-negative bacteria infections.^[4]

isation sequence^[1]or on the double alkylation of N-

hydroxyureas with dibromoethane^[10]and were very

limited in term of scope.

The synthetic route to avibactam^[11]or its

analogues^[6,12,13]requires the formation of the urea

moiety using triphosgene after the construction of the

hydroxyamino-six-membered ring (Scheme 1a). This

implies that variations on the carbon backbone to study

structure-activity-relationships (SAR) generally require

to redevise the whole synthetic route.^[6]An alternative

approach would be to rely on a direct cyclization

protocol, but, so far, only a handful of examples have

been reported. In 2017, Beauchemin reported the

Cope-type hydroamination of five allyl N-hydroxyur-

°

eas at high temperature (175 C under micro-wave

Figure 1. Examples of diazabicyclooctane β-lactamase inhib-

itors.

irradiation) in the presence of triflimide to give N-

hydroxy-imidazolidinones (Scheme 1b).^[14]The sub-

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Scheme 2. Possible pathways for the bromocyclization of

unsaturated N-oxyureas.

sensitive and several groups have taken advantage of

this to develop cyclization processes that are concom-

itant with the loss of the oxygenated moiety.^[31–33]

Then, as for amides^[34]or ureas,^[35,36]either N- or O-

cyclization can take place, leading to N-oxyurea 6 or

N-oxycarbamimidate 7, respectively. The former gen-

erally arises from the activation of the nitrogen, while

the latter stems from the activation of the double bond,

as demonstrated by the group of Liu for the Cu(II)

Scheme 1. Existing methods to access cyclic hydroxyureas.

strates were obtained in a one-pot fashion from the mediated

oxidative

halocyclizations

of

N-

corresponding allylamines and an O-isocyanate^[15]but alkoxyamides.^[37]We assumed that careful tuning of

the reaction only worked for N-hydroxy derivatives. the iodine(III)/bromide combination should allow to

The group of Wang developed three copper-catalyzed steer the reaction selectively towards either modes of

cyclizations of unsaturated N-methoxy amides, among cyclization depending on the nature of the electrophilic

which only featured two examples of ureas in each bromination species that would be formed in situ.^[38–44]

study.^[16–18]The electrophiles can be O-benzoylhydrox- Interestingly, oxazolidinone oximes also constitute a

ylamines, or cyclic hypervalent iodine reagents. An rather underexplored class of heterocycles. Some

amine,^[16]an alkyne^[17]or an azide^[18]group can be members of this family have been studied by Narasaka

introduced during the cyclization (Scheme 1c).

for their electrophilic reactivity^[45,46]and some other

This shortage of practical and efficient cyclization were patented as antidepressant compounds more than

methods greatly limits the access to these heterocycles 40 years ago.^[47]However, their synthesis required the

and precludes rapid SAR studies for the development use of highly toxic phosgene oxide.

of crucially needed β-lactamase inhibitors. Herein, we

describe the direct, metal-free and chemoselective

synthesis of a broad range of diversely substituted Results and Discussion

cyclic N-oxyureas as well as their N-oxycarbamimi-

dates counterparts from unsaturated N-alkoxyureas.

Optimization of the Bromocyclization

We chose N-benzyloxyurea 5a bearing a p-methox-

ybenzyl (PMB) group as a model substrate to explore

the condition that would yield a chemoselective

Reaction Design

In order to broaden the range of substrates that could bromocyclization. In addition to the N- and O-

be attainable by a direct cyclization, we wished to cyclization onto the pending allyl chain, we expected

develop a reaction following a specific blueprint: that the electron-rich PMB could also participate in an

avoiding the use of transition metals, no heating and oxidative process, which would have to be avoided.

installing a linchpin for further derivatizations. Based First, a combination of lithium bromide and (diacetox-

°

on our previous studies on hypervalent iodine(III)^[19–24]

-

yiodo)benzene in dichloromethane at À 5 C was used

mediated halogenations,^[25–28]and in particular modular (Table 1, entry 1). Full conversion was reached after

halocyclizations,^[29,30]we chose to focus on the 1 h40 and a mixture of N-oxyimidazolidinone 6a,

bromocyclization of unsaturated N-oxyureas (5, oxazolidinone oxime 7a and the corresponding oxazo-

Scheme 2). These substrates are challenging in terms lidinone 8a was obtained in a 61% overall yield. When

of regio- and chemo-selectivity. First the NÀ O bond is compared to the reaction using N-bromosuccinimide

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Table 1. Optimization of the iodine(III)-mediated oxybromocyclization and aminobromocyclization of N-benzyloxy urea 5a.^[a]

Entry R

MBr_n

LiBr

NBS

LiBr

Solvent additive Temp. Time (min) Yield 6a (%) Yield 7a (%) Yield 8a (%) Yield 9a (%)

°

1

Ac

DCM MS 3 Å À 5 C 100

19

7

12

32^[b]

–

27

65

51

31^[b]

23

–

58

77

–

15

17

–

-

–

21

–

31

32

–

°

2

DCM MgO

À 5 C 15

°

3

Ac

À 5 C 90

°

4

5

C(O)CMe₃LiBr

C(O)CF₃LiBr

À 5 C 60

°

À 5 C 35

°

6

7

8

9

Ac

none

ZnBr₂

À 5 C 90

°

À 5 C 10

°

C₅H₅N·HBr DCM MgO

Bu₄NBr

À 5 C 15

°

DCM MgO

À 5 C 60

32

38

–

°

10

11

C(O)CMe₃Bu₄NBr

C(O)CF₃C₅H₅N·HBr MeCN MgO

DCM MgO

À 5 C 50

–

78

–

RT

10

^[a]Reaction conditions: to a solution of 5a in the solvent at the appropriate temperature were successively added, the additive, the

bromide and the hypervalent iodine reagent; isolated yields unless stated otherwise.

^[b]NMR yields.

(NBS) as the electrophilic bromination reagent (En- was employed, only the N-cyclization process took

try 2), the combined yield is lower, yet the relative place and 6a was isolated with 32% (Entry 9). Despite

amount of 6a arising from the N-cyclization process is extensive screening of the reaction parameters (see

higher.

Supporting Information), the aminobromocyclization

To trap the acetic acid generated during the reaction of 5a could only be improved to give 38% of 6a by

that would be responsible for the formation of 8a, using a combination of Bu₄NBr and bis(tert-butylcar-

magnesium oxide was used as the additive and only 6a bonyloxy)iodobenzene (Entry 10). As for the oxy-

and 7a were obtained (Entry 3). Variation of the bromocyclization of 5a, the use of PIFA with

acetoxy group of the iodine(III) reagent showed that, C₅H₅N·HBr at room temperature allowed the reaction

in combination with LiBr, bis(tert-butylcarbonyloxy) to be completed in 10 minutes, to give 7a in 78% yield

iodobenzene could favor the formation of N-oxy- (Entry 11).

imidazolidinone 6a in addition to 7a, while bis

(trifluoroacetoxy)iodobenzene (PIFA) led to 7a along

with spiro adduct 9a (Entries 4 & 5). By analogy to

Scope of the Oxy-Bromocyclization

what had previously been reported with PIFA for the We started the exploration of the scope of the oxy-

corresponding

N-methoxyamides^[48,49]

or

aryl- bromocyclization by varying the nature of the para

alkoxyureas,^[50]the latter would arise from the direct substituent of the N-benzyl group. Both electron

oxidation of the hydroxyl amine moiety into a donating (OMe, 5a) and withdrawing (NO₂, 5b)

nitrenium and subsequent nucleophilic trapping by the groups as well as a halogen (Br, 5c), a methyl (5d) or

PMB group. Indeed, in the absence of a bromide a hydrogen (5e) were equally tolerated and the

source, 9a was the sole product that could be isolated corresponding oxazolidinone oximes 7a–e were ob-

from the reaction (Entry 6). Keeping DIB as the tained in 74–85% yields (Scheme 3a). Having an allyl

oxidant, different types of bromide sources were group (5f) or an unprotected nitrogen (5g) was also

screened and were found to have a dramatic impact on possible, although the unprotected product 7g was

the course of the reaction. Zinc bromide favored the O- obtained with a lower yield (47%). The reaction also

cyclization process as well as the hydrolysis of the proceeded with a urea (5h) and gave oxazolidinone

oxime moiety and a mixture of 7a and 8a was imine 7h in 80% yield. The oxygen protecting group

obtained in a 79% combined yield (Entry 7). A could also be modified and the O-methyl, -allyl or- t-

comparable chemoselectivity was observed with pyr- butyl oximes 7i–k could be isolated with 68–91%

idinium bromide, although the hydrolysis could be yields. When the unsaturated chain was homologated,

avoided, thus furnishing 7a with 77% yield (Entry 8). the 6-exo cyclization went on smoothly (7l,70%).

In sharp contrast, when tetrabutylammonium bromide Adding another methylene (5m), proved detrimental

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Scheme 3. Scope of the oxy-bromocyclization and the amino-bromocyclization, control experiment in the presence of TEMPO. –

Reaction conditions: to a solution of 5 in the indicated solvent [0.02 M] at the indicated temperature, were successively added MgO

a

(2.4 equiv.), the bromide (2.4 equiv.) and the hypervalent iodine reagent (1.2 equiv.); isolated yields; Piv=C(O)C(CH₃)₃. ) An X-

ray crystal structure was obtained. ^b) c.m=complex mixture. ^c) E:Z ratio of 5o was 5:1. ^d) E:Z ratio of 5r was >19:1.

and the expected 7-member ring could not be isolated. for cinnamyl derivative 5r furnishing 7’r as the trans

We then scrutinized the effect of the substitution of the diastereoisomer (confirmed by X-ray analysis of a

double bond. The reaction worked well, following a 5- monocrystal).

exo cyclization mode with a methallyl (5n) a crotyl

(5o) and a cyclohexene (5p), to give 7n, 7o and the

spiro compound 7p with excellent yields. With a

Scope of the Amino-Bromocyclization

prenyl chain (5q), 7q was obtained in 18% yield while While the oxybromocyclization appeared to be fairly

the main adduct 7’q (45%) resulted from a 6-endo general, the aminobromocyclization scope proved to be

cyclization. This endo mode became the sole pathway more limited. Para substituted N-benzyl derivatives

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5a–e reacted similarly, giving 6a–e with yields

between 32% and 45% (Scheme 3b), significantly

lower than what was observed for 7a–e. If the allyl

group of 5f was tolerated, neither the unprotected

benzyloxyurea 5g, which decomposed, nor the N-

benzylurea 5h that remained intact were suitable

substrates for the reaction. Nevertheless, the reaction

did proceed with other substituents on the oxygen and

O-methyl, -allyl and -t-butyl oxyimidazolidinones 6i–

k were obtained with modest yields, in particular 6j

for which numerous side-products were also formed.

Finally, N-methallyl substrate 5n gave 6n with 21%

yield.

Discovery and Scope of the Amino-Oxycyclization

In view of the modest yields obtained for the amino-

bromocyclization reaction, we suspected that highly

reactive intermediates such as free radicals could be

involved. To test this hypothesis we ran the reaction in

the presence of the persistent radical TEMPO

((2,2,6,6-tetramethylpiperidin-1-yl)oxyl).^[51]Doing so,

the bromocyclization was totally shut down and, after

17 h, a cyclization with the incorporation of the

TEMPO moiety occurred instead,^[52]delivering oxy-

imidazolidinone 10a in 60% yield (Scheme 3c). Since

this process appeared far superior to the bromocyclyza-

tion in terms of efficiency, it was rapidly optimized

(see Supporting Information).

Without any bromide source, using an excess of

TEMPO (2.0 equiv.) in combination with bis(tert-

butylcarbonyloxy)iodobenzene for

a longer time

(21 h), 10a was isolated with 71% yield (Scheme 4).

Like for the previously explored processes, variation of

the para substituent of the N-benzyl group did not alter

the reaction and compounds 10b–e were obtained with

65%–74% yields. N-Allylated substrate 5f cyclized to

10f in 73% yield but the unprotected 5g decomposed Scheme 4. Scope of the amino-oxycyclization. – Reaction

°

conditions: to a solution of 5a in DCM [0.02 M] at À 5 C, were

under the reaction conditions, while N-benzyl urea 5h

did not react. The oxygen substituent could be changed

to a methyl, an allyl or a t-butyl and compounds 10i–k

were obtained with good yields. Although substrate

5m did not lead to the desired 7-membered ring, the 6-

membered 10l could be isolated in moderate yield.

Various substituents could be accommodated on the

double bond. With a methallyl (5n), a crotyl (5o), a

successively added MgO (2.0 equiv.), TEMPO (2.0 equiv.) and

bis(tert-butylcarbonyloxy)iodobenzene (1.2 equiv.); isolated

a)

yield; Piv=C(O)C(CH₃)₃

An X-ray crystal structure was

obtained.

Synthetic Applications of the Cyclic Adducts

cyclohexenyl (5p), a prenyl (5q) and a cinnamyl group Several groups have used cyclic N-oxyureas as plat-

(5r), the cyclization proceeded by a 5-exo mode to forms to access bioactive ureas after the cleavage of

give 10n–r with moderate to excellent yields. In the the NÀ O bond.^[54,55]In a complementary approach, we

case of 10r, 19% of the corresponding ketone 11 were wished to further functionalize the various heterocycles

also isolated. The ketone presumably comes from the synthetized so as to keep the hydroxylamine moiety,

cleavage of the TMP to give the corresponding alcohol which is essential for β-lactamase inhibition activities.

that would be oxidized in the presence of TEMPO and First we explored the hydrogenolysis of the O-benzyl

the iodine(III) reagent.^[53]However submitting 10r group on compounds 6a, 7a and 10a (Scheme 5).

again to the reaction conditions for a prolonged time Using palladium on charcoal as the catalyst, N-

did not yield 11.

hydroxyimidazolidinone 12 could be isolated in 63%

yield avoiding the potential reduction of the alkyl

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Control Experiments

Although the three sets of reaction conditions that

were developed could appear as almost identical, the

outcome of the reaction can be drastically altered by

minor modifications. The strong dichotomy resulting

from the use of pyridinium bromide or tetrabutylam-

monium bromide (or other tetraalkyl bromides, see

Supporting Information) is particularly striking. These

variations indicate that the electrophilic species that

are generated in situ must be different enough to react

chemoselectively with the substrate. We first turned

our attention to the role of the N-oxy moiety for the

success of theamino-cyclization process (Scheme 6a).

Indeed, under the oxy-bromocyclization conditions

(PIFA with C₅H₅N·HBr), 7h was obtained in 80%

yield, while no reaction occurred in 1 h when 5h was

subjected to the amino-bromocyclization conditions

(Bu₄NBr with bis(tert-butylcarbonyloxy)iodobenzene).

Yet, if the reaction time was prolonged to 24 h, 7h was

eventually obtained. However, no reaction occurred

when 5h was reacted with TEMPO and bis(tert-

butylcarbonyloxy)iodobenzene. To gain further insight

on these transformations, substrate 5s bearing a vinyl

cyclopropyl was synthetized to detect^[56]putative

radical intermediates (Scheme 6b). The oxy-bromocyc-

lization proceeded smoothly giving a mixture of 5-

membered (7s) and 6-membered (7s’) rings, in line

with what was observed for prenylated substrate 5q,

without any detectable opening of the cyclopropyl. The

outcome was strikingly different when 5s was reacted

with TBABr and PhI(OPiv)₂. Only products arising

from an opening of the cyclopropyl ring differing by

the terminal substituent-Br (20), OPiv (21)and Cl (22)

– were isolated in a 44% combined yield. The latter

two products presumably were formed by the sub-

stitution of the un-hindered primary bromide in 20 by

residual pivalate (from the hypervalent iodine reagent)

and chloride (from the solvent). Finally, in the presence

Scheme 5. Derivatization of the cyclized compounds. – Isolated

yield.

bromide function. The same protocol could yield 13 of TEMPO and bis(tert-butylcarbonyloxy)iodoben-

from 7a with 60% yield. The main challenge in this zene, 5s was mostly converted into 23, with concom-

case was to avoid the hydrolysis of the oxime to the itant opening of the cyclopropyl, along with minor

oxazolidinone. Finally, the hydrogenolysis could be amounts of diene 24 resulting from the elimination of

carried out in the presence of the 2,2,6,6-tetrameth- the OTMP group (see ESI for details).

ylpiperidin-1-yl)oxy group to give 52% of 14 from

10a, concomitantly with 35% of urea 15. The primary

bromide of 6a could efficiently be substituted by an

Mechanistic Proposal

azide to give 16. Staudinger reduction of the latter Based on all these observations a general mechanism

using triphenylphosphine and water gave primary proposal could be drafted. First, based on the isolation

amine 17. The TEMPO group could either be reduced of 9a (in which the PMB moiety reacts rather than the

to an alcohol such as 18 obtained from 10a using Zn allylic chain) when 5a was reacted with PIFA only

(0), or oxidized to a ketone such as 18 and 11 that (Table 1, entry 6), it appears that the initial activation

were isolated with 73 and 93% yields, respectively, of the double bond by the electrophilic iodine(III)

after reaction of 10o and 10r with m-CPBA.

reagent is not operative in our setting. Therefore,

starting from substrate 5 and the hypervalent iodine

(III) reagent A, three pathways leading to the three

different type of products can be envisioned

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Scheme 6. Control experiments with amide 5h and cyclopropyl 5s. – Reaction conditions: to a solution of 5 in the solvent at the

appropriate temperature were successively added, MgO, the bromide or the TEMPO and the hypervalent iodine reagent, the reaction

was stirred for the indicated time; isolated yields.

(Scheme 7). In the presence of an acidic source of olefin, presumably through the bromination of the

bromide such as pyridinium hydrobromide, ligand nitrogen atom to give G.^[64,65]The N-oxy function

exchanges around the iodine atom would give mixed seems essential for this pathway, as evidenced by the

species B that could undergo a reductive elimination to absence of N-bromocylization with urea 5h. Never-

give iodobenzene and an acetylhypobromite C (path- theless, over prolonged reaction time (see Scheme 6a),

way a). This highly electrophilic species^[57]could react the equilibria can eventually be shifted towards the

with the double bond of 5 to give bromiranium formation of B and C to give the O-bromocylization

intermediate D. Intramolecular (in an exo or endo product 7h. From G, an ionic pathway could lead to

fashion depending on the olefin substituents) addition imino-oxonium H and after reaction with the olefin to

of the carbonyl^[34]would give cyclic iminium E and aziridinium I. Opening of the latter by a bromide

finally compound 7. The formation of oxazolidinone 8 would give 6. The intermediacy of an oxonium was

(see Table 1) would probably occur from E in the previously proposed for the formation of the spiro

presence of traces of water (when using the highly adducts analogous to 9a from methoxyamides.^[48,49]

hydroscopic ZnBr₂for instance). Because the double Indeed, 9a could arise from the trapping of H by the

bond would be the one reacting with the electrophilic pending PMB group. Nevertheless, the opening of the

bromination species, this process can be equally cyclopropyl ring during the reaction of 5s under these

efficient for both N-oxy-ureas and N-alkyl-ureas such reaction conditions rather points towards a radical

as 5h. Additionally the

mechanism. This hypothesis is also consistent with the

formation of the bromonium is presumably stereo- 1:1 diastereomeric ratio observed for the formation of

specific, which is in line with the conservation of the 10o, which contrasts with the 5:1 ratio observed for

E:Z ratio into the d.r. ratio for 7o, 7p and 7’r (see 7o.Thus, from G, homolytic cleavage would give N-

Scheme 3). The formation of 7r’ as the trans isomer centered radical J whose reaction with the double bond

from E-5r (that was confirmed by X-ray crystallog- would lead to K. Recombination with a bromo radical

raphy) is consistent with the S_N2 ring opening of a would then give 6. Under the conditions described in

trans bromiranium.

Scheme 3c, when n-Bu₄NBr and TEMPO are both

When the source of bromide is a quaternary present, trapping with TEMPO would give 10. Alter-

ammonium salt, such as TBABr, the formation of bis natively, under these specific conditions, bis(acyloxy)

(acyloxy)bromate F, akin to the reagents previously bromate F could promote the oxidation^[61,66,67]of

reported by Kirschning^[58–62]and later by Muniz for TEMPO into the corresponding oxoammonium that

iodates,^[63]would take place (pathway b). The modu- would act as the electrophile. However, under the

lated reactivity of this Br(I) species would favor its optimized reaction conditions of Scheme 4, i.e. with-

reaction with the N-oxy-urea moiety rather than the out any bromide, the activation of the nitrogen would

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Scheme 7. General Mechanistic proposal.

occur directly with the hypervalent iodine(III) method can grant access to a broad range of diversely

derivative^[68]A to give L and then J (pathway c). This substituted cyclic N-hydroxylated ureas for which only

pathway is proper to N-alkoxy substrates and is few methods existed. The development of original non

ineffective for 5h. From J, in the presence of an excess β-lactam β-lactamase inhibitor by using this method-

TEMPO, exo cyclization followed by trapping would ology is currently undergoing in our group.

lead to 10.

Experimental Section

Conclusion

For full experimental data, see SupportingInformation.

By using iodine(III) reagents as the promoters, we

have been able to develop the chemoselective cycliza-

CCDC 1935798, 1935799, 1935800, and 1935801 (compounds

7c, 7’r, 10f, and 10k, respectively) contain the supplementary

tion of unsaturated N-hydroxylated ureas to give N-

oxyimidazolidinones or oxazolidinone oximes. In this

metal-free process, the oxy-cyclization happens

through an ionic mechanism, while the amino-cycliza-

tion takes place by a radical manifold. In this case, the

final trapping of the free radical can be achieved by a

crystallographic data for this paper. These data can be obtained

free of charge from The Cambridge Crystallographic Data

Centre via www.ccdc.cam.ac.uk/data_request/cif.

General procedure for the oxybromocyclization

bromine or by TEMPO. The diverse saturated hetero- To a solution of the urea derivative (1.0 equiv.) in anhydrous

acetonitrile (0.025 M) at room temperature, were added MgO

(2.4 equiv.), pyridine hydrobromide (2.4 equiv.) and PIFA

(1.2 equiv.). After stirring at room temperature for 10 min, the

reaction mixture was concentrated under reduced pressure

before purification by flash chromatography.

cycles obtained in this fashion can be further function-

alized, notably by using the added function as a

linchpin.

Overall, we have shown that using widely available

reagents and under rather similar conditions, cationic

or radical manifolds can be triggered to achieve highly

chemoselective transformations. In particular, this

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General procedure for the aminobromocyclization

To a solution of the urea derivative (1.0 equiv.) in anhydrous

°

CH₂Cl₂(0.02 M) at À 10 C (ice-salt bath), were added MgO

(2.4 equiv.), tetrabutylammonium bromide (2.4 equiv.) and PhI

°

(OPiv)₂(1.2 equiv.). After stirring at À 10 C for 1 hour, PhI

[14] M. A. Allen, R. A. Ivanovich, D. E. Polat, A. M. Beau-

chemin, Org. Lett. 2017 , 19 , 6574–6577.

(OPiv)₂(0.3 equiv.) was added every 30 minutes to reach

completion (2 or 3 additions). The reaction mixture was stirred

until completion then concentrated under reduced pressure

before purification by flash chromatography.

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General procedure for the aminooxycyclization

To a solution of the urea derivative (1.0 equiv.) in anhydrous

°

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The authors acknowledge the support of the CNRS. L.P. thanks

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Synthesis of Cyclic N-Hydroxylated Ureas and Oxazolidi-

none Oximes Enabled by Chemoselective Iodine(III)-

Mediated Radical or Cationic Cyclizations of Unsaturated N-

Alkoxyureas

Adv. Synth. Catal. 2019, 361, 1–11

L. Peilleron, P. Retailleau, K. Cariou*

Article Doi

Synthesis of Cyclic N-Hydroxylated Ureas and Oxazolidinone Oximes Enabled by Chemoselective Iodine(III)-Mediated Radical or Cationic Cyclizations of Unsaturated N-Alkoxyureas

DOI: 10.1002/adsc.201901135

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Article abstract of DOI:10.1002/adsc.201901135

Full text of DOI:10.1002/adsc.201901135

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