Iodine(III)-Mediated Diazidation and Azido-oxyamination of Enamides

Article abstract of DOI:10.1002/chem.201501782

In this study we demonstrate that the combination of bis(tert-butylcarbonyloxy)iodobenzene and lithium azide in acetonitrile allows the diazidation of various enamide substrates. The azido-oxyamination of the same substrates can be carried out in the presence of 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO). Control experiments strongly suggest that this latter process occurs through a shift in nature of the in situ generated electrophilic species from a radical to a cation. Finally, the versatility of the novel compounds synthesized was also assessed by running various selective reactions on them.

Full text of DOI:10.1002/chem.201501782

DOI: 10.1002/chem.201501782
Full Paper
&
Azides
Iodine(III)-Mediated Diazidation and Azido-oxyamination of
Enamides
Sophie Nocquet-Thibault, Anita Rayar, Pascal Retailleau, Kevin Cariou,* and
Robert H. Dodd*[a]
Abstract: In this study we demonstrate that the combina-
tion of bis(tert-butylcarbonyloxy)iodobenzene and lithium
azide in acetonitrile allows the diazidation of various enam-
ide substrates. The azido-oxyamination of the same sub-
strates can be carried out in the presence of 2,2,6,6-tetra-
methylpiperidine N-oxide (TEMPO). Control experiments
strongly suggest that this latter process occurs through
a shift in nature of the in situ generated electrophilic species
from a radical to a cation. Finally, the versatility of the novel
compounds synthesized was also assessed by running vari-
ous selective reactions on them.
Introduction
In recent years, hypervalent iodine(III) derivatives have ap-
peared as highly efficient and versatile reagents,[1,2] notably for
the oxidative difunctionalization of various alkenes.[3] In partic-
ular, benziodoxole-based reagents have been shown to be su-
perior promoters for transferring a wide range of atoms and
functional groups.[4] However, their general utility is limited by
the need to be synthesized beforehand.[5] This drawback can
be overridden by in situ generation of the active species
through an “umpolung” strategy, which relies upon the succes-
sive exchanges of the hypervalent iodine(III) ligands to gener-
ate a novel electrophilic species.[6] We have adopted this strat-
egy to promote the ethoxybromination[7] and the ethoxychlori-
nation of enamides 1 by using a combination of (DiacetoxyIo-
do)Benzene (DIB) with lithium bromide and iron(III) chloride,[8]
respectively, which permitted the regio- and chemoselective
access to multipurpose synthons 2 and 3 (Scheme 1a). To fur-
ther broaden the scope of this strategy, we turned our atten-
tion from halogens to pseudohalogens. The azide ion can be
considered as a pseudohalide, which implies that its behavior
is similar to that of a halide. Thus, we envisaged that the same
umpolung strategy could be applied to azides to give a-azido
hemiaminals 4 (Scheme 1b). Given the vast synthetic utility of
organic azides,[9] this straightforward strategy appeared ideal
for the rapid assembly of value-added linchpins.[10]
Scheme 1. Umpolung strategy for the electrophilic pseudohalogenation of
enamides.
The basis for this study relied upon the feasibility of combin-
ing an azide with a hypervalent iodine(III) derivative to gener-
ate an electrophilic species (“N3+”) that is capable of reacting
with various double bonds. In a series of papers from the early
70 s, Zbiral was the first to study and report the reactivity of
a DIB-trimethylsilylazide (TMSA) combination with alkenes,[11]
for which he postulated the generation of mixed hypervalent
iodine(III) species that incorporated an azide ligand. Depending
on the reaction conditions that were employed, various difunc-
tionalized compounds could be obtained, although often as
mixtures. 15 years later this strategy was expanded upon by
Moriarty, who described the vicinal diazidation of alkenes by
using a PhIO/NaN3/AcOH combination.[12] In this case, the pro-
posed mechanism involves electrophilic activation by the
iodine and two successive nucleophilic additions of the azide.
The most sustained efforts in this area were deployed by
Magnus, who showed that the combination of iodosobenzene
and TMSA could trigger the b-azidation or the diazidation of
enol ethers.[13] He went on to study this reaction thoroughly[14]
and applied it to the synthesis of natural products.[15] Similar
combinations of reagents were later used by Kirshning as sur-
rogates for haloazides[16] and to synthesize a stable polymer-
[a] S. Nocquet-Thibault, A. Rayar, Dr. P. Retailleau, Dr. K. Cariou, Dr. R. H. Dodd
Centre de Recherche de Gif-sur-Yvette
Institut de Chimie des Substances Naturelles
UPR 2301, CNRS, LabEx LERMIT
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax: (+33)1-6907-7247
E-mail: kevin.cariou@cnrs.fr
robert.dodd@cnrs.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501782.
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bound iodine azide.[17] Furthermore, the addition of an organo-
selenium species to the iodine(III)-azide combination was effec-
tive for the azido-selenation of various alkenes, including glu-
cals, presumably through the involvement of radical species.[18]
Although they need to be prepared beforehand, cyclic azido
benziodoxoles[5,19] can also act as azido donors in a wide array
of reactions with olefins. For instance, they have recently been
used for the zinc-catalyzed azidation of silyl enol ethers,[20] the
intermolecular[21] and intramolecular[22] oxyazidation of alkenes,
the copper-catalyzed oxoazidation of indoles,[23] and the aryl-
azidation of activated alkenes.[24]
acted as a superior promoter (entry 8), and it could also be
used with LiN3 (entries 9 and 10). This azide source was found
to be more convenient and robust to use than TMSN3, al-
though it was poorly soluble in CH2Cl2, but this could be over-
come by conducting the reaction in acetonitrile (entry 11).
Having found the optimal combination of reagents and sol-
vents, we then assessed the effect of the reaction temperature
on the efficiency and the stereoselectivity of the reaction (en-
tries 11–14). Accordingly, À158C was shown to offer the best
balance with respect to yield, reaction time, and diastereose-
lectivity (entry 13).
Based on our previous studies with enamides, we thought
that it would be more general and satisfying to develop a set
of conditions for the umpolung of pseudohalides that would
only differ by the nature of the salts.[25]
At this stage, we went on to explore the substrate scope of
the reaction. The benzylamine-derived enamide 1b reacted in
Table 2. Diazidation scope.
Results and Discussion
Building on our experience with halide salts, we initially aimed
to develop an ethoxy-azidation reaction. Unfortunately, the
Entry
SM[a]
R
PG
Time [h]
d.r.[b]
Yield [%][c]
[26]
combination of LiN3 or NaN3 with DIB in ethanol at various
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
Bn
Ph
Me
Ph
Bn
Ph
Bn
Ph
Ts
Ts
Ms
Bs[d]
Boc
Boc
Ac
1
1.25
1
1
1
1
1
1
80:20
90:10
70:30
75:25
ND
52
47
40
46
CM[e]
CM
18
61
43
temperatures led to either no conversion or to intractable mix-
tures, even after prolonged reaction times (Table 1, entries 1
and 2). Using trimethylsilylazide with DIB (entry 3) or with
iodosylbenzene (entry 4), or
a cyclic azido benziodoxole
ND
(entry 5) proved equally unsuccessful.
73:27
75:25
67:33
85:15
The more reactive PhenylIodine-bis(triFluoroAcetate)
(PIFA)[27] was found to be a suitable promoter when it was
used in conjunction with TMSN3 in dichloromethane to access
the bis-azido compound 5a in 19% yield (entry 6). Running
the reaction in acetonitrile did not help to improve the reactiv-
ity (entry 7), whereas bis(tert-butylcarbonyloxy)iodobenzene
Ac
COCF3
3
7[f]
10
1j
N-(Bs)-indole
24
[a] SM: starting material. [b] The relative stereochemistry of the major dia-
stereoisomer was attributed by analogy with 5a. ND: not determined.
[c] Yield of isolated product. [d] Bs: benzenesulfonyl. [e] CM: complex
mixture. [f] Additional 1 h at RT.
Table 1. Diazidation optimization.
a similar manner (Table 2, entry 2), as did the mesyl-
protected substrate 1c (entry 3) and the methyl-
amine derivative 1d (entry 4). The use of a carbamate
protecting group (Boc, entries 5 and 6) appeared in-
Entry
R
x
Y[a]
Solvent Temp. [8C] Time
d.r.[b] Yield [%][c]
compatible with this reaction, whereas amides (en-
tries 7–9) were well tolerated. Finally, the same condi-
tions were applied to N-benzenesulfonyl indole 1j to
give the desired product, after a prolonged reaction
time and with a mediocre 24% yield (entry 10).[12] It
should also be noted that aminoacrylates were found
to be unreactive under these conditions, even after
extended reaction times.
1
2
3
4
Ac
Ac
Ac
PhIO
2.0 Na
2.0 Li
1.5 TMS MeCN
1.2 TMS CH2Cl2 À50
EtOH
EtOH
À20
À40
RT
7 d
7 d
2 d
6 d
ND
ND
ND
ND
CM[d]
CM
CM
CM
5
1.9 EtOH
–
0 to RT 30 h to 5 d ND
CM
6
7
8
COCF3
COCF3
COtBu
COtBu
COtBu
COtBu
COtBu
COtBu
COtBu
1.2 TMS CH2Cl2
1.2 TMS MeCN
1.2 TMS CH2Cl2
1.2 Li
1.5 Li
1.5 Li
1.5 Li
1.5 Li
1.5 Li
RT
RT
RT
RT
RT
RT
0
À15
À40
15 min
15 min
1 h
1 h
1 h
25 min
25 min
1 h
ND
ND
ND
ND
ND
70:30 52
80:20 42
80:20 52
19
8
27
21[e]
31
Overall, this process seemed to be quite capricious
and it was hampered by various side reactions, which
indicated the in situ generation of highly reactive in-
termediates, such as azido radicals, as previously
postulated.[14] The involvement of radical species
became apparent when trisubstituted pyrrolidine 6
was isolated as the main product, albeit in a modest
yield, from the reaction of allylamine-derived enam-
ide 1k (Scheme 2a). To account for the formation of
this compound, we postulated that a 5-exo-trig cycli-
9
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14
24 h
ND
ND
[a] Entries 1–4, y=2x; entries 6–8, y=2.0; entries 9–14, y=4.0. [b] The relative stereo-
chemistry of the major diastereoisomer was determined by X-ray diffraction analysis
of a mono crystal of 5a.[28] ND: not determined. [c] Yield of isolated product. [d] CM:
complex mixture. [e] Reaction run with 3.0 equiv of NaHCO3.
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The effect of the temperature was then assessed. Running
the reaction at 08C accelerated it without dramatically affect-
ing its efficiency (entry 4), whereas operating at room tempera-
ture greatly reduced the yield (entry 5). The optimization was
continued with enamide 1a, for which the reaction proceeded
sluggishly at À158C (entry 6). Lowering the amount of all re-
agents, even at RT, had little effect (entry 7). The better com-
promise, in terms of yield, reaction time, and selectivity, was
reached by running the reaction at 08C with only 1.2 equiva-
lents of bis(tert-butylcarbonyloxy)iodobenzene and 2.0 equiva-
lents of both TEMPO and lithium azide (entry 8). Under these
conditions, enamide 1k reacted rapidly and cleanly to give 8k
as the sole product in a good 67% yield (entry 9 vs. entry 4:
69% yield with 1.5 equiv of oxidant).
Scheme 2. Reactivity of allylamine-derived enamide 1k.
Having determined an optimal and robust set of conditions
for the oxy-azidation, we evaluated the enamide substrate
scope (Table 4). As we had observed with compounds 1a and
zation could have occurred from the radical intermediate 7k,
which resulted from the addition of an azido radical to the
starting enamide. To obtain more insight into this particular
case, we decided to run the same reaction in the presence of
1 equivalent of TEMPO[29] as a radical scavenger. In this case,
the main product was the oxyaminated adduct 8k, which pos-
sibly arose from the trapping of intermediate 7k by the
TEMPO radical (Scheme 2b). Moreover, diazido compound 5k
was also isolated, whereas virtually no traces of cyclized prod-
ucts were detected.
Table 4. Azido-oxyamination scope.
Entry SM[a]
R
PG
Time [h] d.r.
Yield [%][b]
74
Considering the apparent improved efficiency of the enam-
ide azido-oxyamination versus the diazidation,[30] we thought
that optimization of the former transformation would also be
worthwhile. By doubling the amount of TEMPO, the yield of
8k went up to 58% (Table 3, entry 2). By using only 2 equiva-
lents of LiN3, complete chemoselectivity was attained along
with a further improvement of the yield (entry 3).
1
2
3
4
5
1a
1b
1c
1d
1k
1l
Ph
Bn
Ph
Me
allyl
Me
Ph
Bn
Ts
Ts
2.25
3
90:10 77
95:5
Ms
Bs[c]
Ts
Ms
Boc
Boc
Ac
1
1
80:20 73
85:15 73
1
95:5
67
6
1
1
1
1
83:17 83
74:26 31
83:17 41
81:19 81
60:40 98
77:23 77
100:0 67
100:0 97
100:0 94
7
8
9
10
11
12
13
14
1e
1 f
1g
1h
1i
1m
1j
1n
Ph
Bn
Ph
Ac
COCF3
4
4[d]
1
À(CH2)5COÀ
N-(Bs)-indole
7[d]
7[e]
Table 3. Azido-oxyamination optimization.
N-(Bs)-tetrahydropyridine
[a] SM: starting material. [b] Yield of isolated product. [c] Bs: benzenesul-
fonyl. [d] And an additional 1 h at RT. [e] And an additional 1 h at RT,
1.0 equiv of both LiN3 and TEMPO, and 0.6 equiv of PhI(OPiv)2.
Entry
SM
x
y
z
Temp.
[8C]
Time
[h]
d.r.[b]
Yield
[%][a]
1k, the reaction yields were consistently higher than for the di-
azidation of the same substrates. A range of sulfonyl-protected
enamides (entries 1–6) were first tested; the yields were gener-
ally above 70%, the regioselectivity was complete, and the dia-
stereoselective ratio was above 80:20. Moreover, although the
carbamate-protected enamides 1e and 1 f could not undergo
the diazidation reaction (see Table 2, entries 5 and 6), their
azido-oxyamination did proceed though with moderate yields
(entries 7 and 8). Very good yields and good levels of stereo-
selectivity were also obtained for amide substrates, including
acetamides 1g and h (entries 9 and 10), a trifluoroacetamide
1i (entry 11), and a caprolactam 1m (entry 12). Finally, cyclic
enamides, such as N-(Bs)-indole 1j (entry 13) and N-(Bs)-tetra-
hydropyridine 1n (entry 14), gave the desired products with
excellent levels of selectivity and yields.
1
2
3
4
5
6
7
8
9
1k
1k
1k
1k
1k
1a
1a
1a
1k
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
4
4
2
2
2
2
1.2
2
2
1
2
2
2
2
2
1.2
2
2
À15
À15
À15
0
1
6
5
2
1
7
6
2.25
1
ND
ND
ND
95:5
95:5
95:5
90:10
90:10
95:5
32[c]
58[d]
75
69
21
50[e]
51[f]
77
RT
À15
RT
0
0
67
[a] Yield of isolated product. [b] The relative stereochemistry of the major
diastereoisomer was determined by analogy with 8a, for which X-ray dif-
fraction analysis of a mono crystal was performed;[28] ND: not determined.
[c] Along with 16% of 5k. [d] Along with 20% of 5k. [e] After 6 h at
À158C, the conversion was not complete so the reaction was warmed up
to 08C for an additional 1 h. [f] After 5.5 h at RT, the conversion was not
complete so an additional 1.2 equiv of TEMPO and LiN3 were added to
reach completion in 30 min.
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At this stage, we sought after a mechanistic rationalization
to account for the formation of both types of products. Our in-
itial assumption, based on the formation of cyclic product 6
(see Scheme 2), was that the combination of PhI(OPiv)2 and
LiN3 led to the generation of azido radicals that, upon reaction
with enamide 1, would lead to intermediate 7. Subsequent re-
combination with another azido radical or SET oxidation fol-
lowed by trapping by an azide anion would account for the
formation of adduct 5 (Scheme 3). In the presence of TEMPO,
Scheme 3. Mechanistic proposal.
Scheme 4. Control experiments.
interception of 7 by a nitroxyl free radical would lead to com-
pound 8. Based on the known reactivity of TEMPO with iodine
(III) reagents,[31] an alternative scenario can be envisaged.[32] In
this case, the TEMPO radical would be oxidized to an oxy-am-
monium cation, which could be trapped to yield iminium inter-
mediate 9.[33] Eventually, nucleophilic trapping by an azide
anion would also deliver adduct 8.
We devised a series of control experiments to verify these
hypotheses. Initially, enamide 1k was submitted to the diazida-
tion reaction conditions in the presence of two equivalents of
BHT as a radical scavenger (Scheme 4a). However, only un-
reacted starting material and some degradation products were
observed, even after a prolonged reaction time, which further
supports the involvement of radical species in this reaction. As
for the oxy-azidation reaction, two potential radical probes
were synthesized and subjected to the reaction conditions to
complement the observations made with the N-allyl derivative
1k. Both O-allyl enamide 1o (Scheme 4b) and cyclopropyl en-
amide 1p (Scheme 4c) reacted sluggishly to give the a-TEMPO
azido aminals 8o and 8p as the major products in approxima-
tively 30% yield along with about 10% of the diazido adducts
5o and 5p.
bly via iminium intermediate 9b, with nearly identical yield
and selectivity as when using the I(III)/TEMPO combination.
This set of experiments implies that, although the initial step
of the diazidation process would involve a radical azido spe-
cies, the azido-oxyamination reaction involves an oxoammoni-
um species generated in situ from TEMPO. The incorporation
of the OTMP moiety would thus arise from an ionic manifold
rather than from the final trapping of a free radical.[35]
The highly versatile adducts that were isolated throughout
this study were then subjected to various transformations. Ini-
tially, the TEMPO moiety was oxidatively removed to give the
corresponding ketones 10a and 10b with moderate to good
yields (Scheme 5).[21] Subsequently, the azide moiety of ketone
10a could undergo a copper-catalyzed [3+2] cycloaddition
with phenylacetylene to give keto triazole 11 in excellent yield.
The particular structure of the diazido adducts could also
serve as the basis for further transformations. By taking advant-
age of the hemiaminal moiety, a Lewis acid-induced reduction
Although they are not fully conclusive with regard to the
nature (ionic or radical) of the reactive species, the two latter
experiments intimate a mechanistic dichotomy that depends
on whether or not TEMPO is present in the reaction mixture.
Indeed, it would be surprising that trapping by TEMPO would
systematically be faster than any intramolecular process, cycli-
zation (1k and 1o), or ring-opening (1p), the products of
which have not been observed. Finally, the oxy-ammonium re-
agent TEMPOBF4 was prepared[34] and reacted with enamide
1b (Scheme 4d). Oxy-azido adduct 8b was obtained, presuma-
Scheme 5. Functionalization of the oxyamino-azido adducts.
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with triethylsilane was performed to give a-azido-amide 12
(Scheme 6). Although this strategy allows discrimination of the
two azide groups, a double copper-catalyzed [3+2] cycloaddi-
tion could also be performed to deliver bis-triazole 13. Alterna-
tively, the reaction with benzyne, generated in situ, formed the
bis-benzotriazole 14.[21]
Representative procedure for azido-oxyamination
PhI(OPiv)2 (419 mg, 1.03 mmol, 1.2 equiv) was added to a suspen-
sion of (E)-N-phenyl-N-styryl-N-(4-methylbenzenesulfonamide) 1a
(300 mg, 0.86 mmol, 1.0 equiv), LiN3 (84 mg, 1.72 mmol, 2.0 equiv),
TEMPO (268 mg, 1.72 mmol, 2.0 equiv) and 3 Š molecular sieves
(300 mg) in MeCN at 08C. After 2.25 h, the reaction mixture was di-
luted with EtOAc, filtered over alumina (EtOAc), and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography on silica gel (petroleum ether/EtOAc 95:05) to afford the
desired product 8a (360 mg, 77%) as a white powder.
All synthetic methods and spectroscopic and analytical data are in-
cluded in the Supporting Information.
Acknowledgements
We thank the Institut de Chimie des Substances Naturelles for
financial support and a fellowship for S. N.-T.
Keywords: azides · enamides · hypervalent iodine · tempo ·
umpolung
Scheme 6. Functionalization of the diazido adducts.
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We have shown that the in situ umpolung of halide salts for
the oxidative difunctionalization of enamides could be extend-
ed to pseudohalide salts, such as lithium azide, thereby ena-
bling a diazidation reaction. To better understand the mecha-
nism of this reaction, TEMPO was used as a radical scavenger,
which ultimately led to the triggering of a divergent, but ulti-
mately interesting, reaction pathway. This discovery showcases
that caution must be taken when highly reactive species, such
as TEMPO, are used as mechanistic probes for processes that
involve hypervalent iodine(III) species. Nevertheless, it also per-
mitted the development of a highly efficient azido-oxyamina-
tion of enamides. Both lines of research, the umpolung of
pseudohalide salts and the in situ generation of electrophilic
oxyammonium species, appear to be highly promising reac-
tions and are currently being pursued further in our laboratory.
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Experimental Section
Representative procedure for diazidation
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of
(E)-N-phenyl-N-styryl-N-(4-methylbenzenesulfonamide)
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1
(EtOAc), and concentrated under reduced pressure. H NMR spec-
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Full Paper
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[28] CCDC 1405684 (5a) and 1059677 (8a) contain the supplementary crys-
tallographic data for this paper. These data are provided free of charge
by The Cambridge Crystallographic Data Centre.
Received: May 7, 2015
Published online on August 12, 2015
Chem. Eur. J. 2015, 21, 14205 – 14210
www.chemeurj.org
14210
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim