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

Article abstract of DOI:10.1002/adsc.201901135

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. (Figure presented.).

Full text of DOI:10.1002/adsc.201901135

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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,a Pascal Retailleau,a and Kevin Carioua,*
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 3rd hydroxylated ureas relied on the reaction of hydroxyl-
generation cephalosporin antibiotic) for the treatment amine with chloropropylcarbamates in an SN2/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
MBrn
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
DCM MgO
DCM MgO
DCM MgO
DCM MgO
DCM MgO
À 5 C 15
°
3
Ac
À 5 C 90
°
4
5
C(O)CMe3 LiBr
C(O)CF3 LiBr
À 5 C 60
°
À 5 C 35
°
6
7
8
9
Ac
Ac
Ac
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)CMe3 Bu4NBr
C(O)CF3 C5H5N·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 ZnBr2 for 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 SN2 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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[12] I. K. Mangion, R. T. Ruck, N. Rivera, M. A. Huffman,
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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*