The Multiple Facets of Iodine(III) Compounds in an Unprecedented Catalytic Auto-amination for Chiral Amine Synthesis

Article abstract of DOI:10.1002/anie.201602022

Iodine(III) reagents are used in catalytic one-pot reactions, first as both oxidants and substrates, then as cross-coupling partners, to afford chiral polyfunctionalized amines. The strategy relies on an initial catalytic auto C(sp³)?H amination of the iodine(III) oxidant, which delivers an amine-derived iodine(I) product that is subsequently used in palladium-catalyzed cross-couplings to afford a variety of useful building blocks with high yields and excellent stereoselectivities. This study demonstrates the concept of self-amination of the hypervalent iodine reagents, which increases the value of the aryl moiety.

Full text of DOI:10.1002/anie.201602022

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201602022
German Edition: DOI: 10.1002/ange.201602022
À
C H Amination
The Multiple Facets of Iodine(III) Compounds in an Unprecedented
Catalytic Auto-amination for Chiral Amine Synthesis
Julien Buendia, Gwendal Grelier, Benjamin Darses, Amanda G. Jarvis, FrØdØric Taran, and
Philippe Dauban*
Abstract: Iodine(III) reagents are used in catalytic one-pot
reactions, first as both oxidants and substrates, then as cross-
coupling partners, to afford chiral polyfunctionalized amines.
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The strategy relies on an initial catalytic auto C(sp ) H
amination of the iodine(III) oxidant, which delivers an
amine-derived iodine(I) product that is subsequently used in
palladium-catalyzed cross-couplings to afford a variety of
useful building blocks with high yields and excellent stereose-
lectivities. This study demonstrates the concept of self-amina-
tion of the hypervalent iodine reagents, which increases the
value of the aryl moiety.
C
atalytic sequential reactions for the synthesis of complex
products are invaluable in modern organic chemistry.[1,2]
Equally important is the chemistry of hypervalent iodine
compounds, which has expanded in the last two decades.[3,4]
Accordingly, the design of new synthetic methods merging
these two research domains is a source of inspiration for the
organic chemists to address the issues of diversity and
sustainability. Trivalent iodine oxidants have become the
reagents of choice to perform selective transformations under
mild conditions. However, because they are often derived
from iodoarenes, their use in synthesis raises the problem of
the production of stoichiometric amount of aryl iodides. The
design of processes catalytic in iodine[5] and recyclable iodine
reagents[5a,6] has allowed this issue to be addressed. More
recently, an alternate solution has emerged with the report of
synthetic strategies valuing the ArI group. The latter has been
used as a building block in condensation reactions,[7] or for the
a-arylation of carbonyl compounds.[8] More significantly,
Scheme 1. Background for the design of the self-amination of iodine-
(III) reagents.
These transformations highlight the value of the iodoar-
ene side-product that has been previously considered as
waste. However, they rely on the use of an excess of the
iodine(III) reagent, thereby limiting their atom-economy and
efficiency. Moreover, with the aim to increase the molecular
diversity accessible through one-pot reactions, we sought to
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improve the variety of sequences combined with the C(sp )
H amination from a unique precursor. We hypothesized that
the iodine(III) oxidant could be used as both the oxidant and
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the substrate for the C(sp ) H amination reaction. This would
deliver a functionalized iodo compound that could, then, be
used for further cross-couplings. Such an unprecedented self-
reaction of iodine(III) oxidants should be optimal in terms of
sustainability and versatility, and increase the synthetic
potential of these reagents. Herein, we wish to report the
details of our investigations that have provided a proof of
À
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Greaney has reported the tandem C H/N H arylation of
indoles based on the coupling of both aryl groups of diaryl-
iodonium salts (Scheme 1a).[9a] At the same time, we designed
II
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a sequence of Rh -catalyzed C(sp ) H amination/sila-Sono-
gashira–Hagihara coupling that recycled the ArI moiety of
iodine(III) oxidants generated in the first step of the nitrene
addition (Scheme 1b).[10]
concept and the application to the successful design of several
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sequences of auto C(sp ) H amination/Pd-catalyzed cou-
plings (Scheme 1c).
Our first aim was to demonstrate the ability of iodine(III)
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[*] Dr. J. Buendia, G. Grelier, Dr. B. Darses, Dr. A. G. Jarvis, Dr. P. Dauban
Institut de Chimie des Substances Naturelles, CNRS UPR 2301
Univ. Paris-Sud, UniversitØ Paris-Saclay
oxidants to undergo a catalytic auto C(sp ) H amination
under the conditions reported for the stereoselective amina-
tion of hydrocarbons.[10–12] This required the preparation of
(diacetoxyiodo)arenes that were obtained in good to excel-
lent yields after oxidation of the corresponding aryl iodides
with sodium perborate (Table 1).[13,14] A screening of the
stoichiometry of the reagents then led us to find that the
sulfonimidamide 1 (1.0 equiv), in the presence of the chiral
RhII complex 2, reacts with a slight excess (1.1 equiv) of the
hypervalent reagent 3a to afford the self-aminated product at
1, av. de la Terrasse, 91198 Gif-sur-Yvette (France)
E-mail: philippe.dauban@cnrs.fr
Dr. F. Taran
CEA, IBiTecS, Service de Chimie Bioorganique et de Marquage
91191 Gif-sur-Yvette (France)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201602022.
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[a]
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Table 1: Catalytic auto-C(sp ) H amination of iodine(III) oxidants 3.
Table 2: Screening of conditions for the catalytic one-pot auto-C(sp ) H
amination/Suzuki–Miyaura cross-coupling.[a]
Entry
3
Yields
of 3
[%]
4
Yield
of 4
Entry
PhBXn
Pd Catalyst
Yield[%][b]
[%][b]
(n1 equiv)
(n2 mol%)
86
1
2
3
4
5
6
7
8
PhBPin (2.0)
PhBPin (2.0)
PhBF3K (2.0)
PhBMIDA (2.0)
PhBMIDA (2.0)
PhBMIDA (1.5)
PhBMIDA (1.5)
PhBMIDA (1.2)
Pd(PPh3)4 (10)
10
37
70
86
85
85
82
75
(87)[c]
1
2
90
88
91
Pd(dppf)2Cl2 (10)
Pd(dppf)2Cl2 (10)
Pd(dppf)2Cl2 (10)
Pd(dppf)2Cl2 (5)
Pd(dppf)2Cl2 (5)
Pd(dppf)2Cl2 (3)
Pd(dppf)2Cl2 (5)
63
3
4
5
76
82
75
[a] Reaction conditions: A mixture of 3a (0.22 mmol), 1 (0.2 mmol), and
2 (3 mol%) in 1,1,2,2-tetrachloroethane/MeOH 3:1 (1 mL) is stirred at
À358C for 72 h. The palladium complex (3 to 10 mol%), aqueous K2CO3
(5 equiv), and the boron reagent (0.24 to 0.4 mmol) in toluene (1 mL)
are added. The mixture is stirred at 908C for 15 h. [b] Isolated after
chromatography with a d.r. >98:2.
70
(75)[d]
75
85
6
86
complex (entry 2), the base, the solvent (Supporting Infor-
mation, Table S1), and the boron reagent[18] (entries 3 and 4).
We found that use of 2 equiv of the phenylboronic acid MIDA
ester[19] in the presence of 10 mol% Pd(dppf)2Cl2 in toluene
affords 5aa in 86% yield. Pleasingly, lowering the amount of
both the boron reagent and Pd(dppf)2Cl2 did not modify
significantly the yield (entries 5–8) and the product 5aa was
obtained in 85% yield using only 1.5 equiv of the MIDA
7
8
9
70
74
78
64[e]
34
boronate ester and 5 mol% Pd(dppf)2Cl2 (entry 6).
90[f]
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The one-pot auto C(sp ) H amination/Suzuki–Miyaura
reaction was then applied to several iodine oxidants (3) to
afford a small library of optically pure substituted benzylic
amines (Scheme 2). The yields were very good, being
generally greater than 75% over the two steps. The reaction
is compatible with various aromatic rings substituted at the
para, meta, or ortho position either by a chloro, an ether,
a cyano, an ester, or a nitro group. Moreover, the one-pot
reaction can be applied to the introduction of heterocycles
such as pyridine, quinoline, and furan ring, a result that
highlights the synthetic potential of the sequence. Com-
[a] Reaction conditions: A mixture of 3 (0.22 mmol), 1 (0.2 mmol), and
the catalyst 2 (3 mol%) in 1,1,2,2-tetrachloroethane/MeOH 3:1 (1 mL) is
stirred at À358C for 72 h. [b] Isolated after chromatography with a d.r.
>98:2. [c] On a 8 mmol scale. [d] After of 96 h of reaction. [e] Isolated
with a d.r.=9:1. [f] 4:1 mixture of regioisomers.
the benzylic position. Compound 4a was thus isolated in 90%
yield as a single diastereoisomer (entry 1).[15,16]
The self-amination was successfully extended to other
aromatic iodine(III) oxidants bearing a methoxy, an azido,
a phenyl, and a halo substituent (entries 2–7). The expected
products 4b–g were isolated with yields in the 64–91% range.
We also investigated the reactions with compounds 3h and 3i
pounds 5ad and 5ae are indeed not accessible through the
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application of the catalytic C(sp ) H amination reaction to
the biaryl precursor, as the presence of a basic nitrogen
induces the deactivation of the Lewis acid dirhodium(II)
complex, while the presence of a furan (compound 5af)[20] is
not compatible with the oxidizing conditions. Furthermore,
products 5 fa and to a lesser extent 5ga demonstrates that
a chemoselective coupling of the iodoarene can be performed
that raise the issue of regioselectivity. While product 4h
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resulting from the auto C(sp ) H amination at the meta-ethyl
group was exclusively obtained albeit with a modest yield of
34% (entry 8), indan derivative 3i led to a 4:1 mixture of
regioisomers with compound 4i isolated as the major product
(entry 9), a ratio that is in line with our previous results.[10]
We next turned our attention to combining this reaction
in the presence of other halogen substituents.
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Finally, we found that the auto C(sp ) H amination/
with one-pot metal-catalyzed cross-couplings. We first
Suzuki–Miyaura reaction allows the efficient coupling of vinyl
groups in the presence of potassium vinyltrifluoroborate salts
and of Pd(dppf)2Cl2 (Scheme 3).[21] This led to the introduc-
tion of either a styrenyl side chain or a linear alken-2-yl
substituent.[22] The one-pot reaction with vinyl boron reagents
provides a relevant solution to the issue of chemoselectivity
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decided to study the auto C(sp ) H amination/Suzuki–
Miyaura reaction.[17] Early attempts with phenylpinacol
boronic ester in the presence of Pd(PPh3)4 generated the
expected product 5aa with a low yield of 10% (Table 2,
entry 1). This result was improved by screening the palladium
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Scheme 4. Scope of the catalytic one-pot auto-C(sp ) H amination/
Sonogashira cross-coupling.
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Scheme 2. Scope of the catalytic one-pot auto-C(sp ) H amination/
Suzuki cross-coupling with aryl boron reagents.
successfully developed (Scheme 4). A rapid screening led us to
determine the optimal conditions for the coupling that include
the use of 1.5 equiv of the alkyne, 10 mol% Pd(PPh3)4,
30 mol% of CuCl, and 5 equiv of Et3N (Supporting Informa-
tion, Table S2). These were applied to various substrates 3 and
alkynes to afford the expected products 6, generally as
a single isomer with yields in the 43–88% range. A broad
range of functional groups is again well-tolerated by the
sequential reaction. The overall process also helps to address
the issue of chemoselectivity, for example in the case of the
3,4,5-trimethoxyarene derivative 6da. Such an electron-rich
aromatic substrate would indeed be oxidized by the iodine-
(III) reagent. Also worth mentioning is the sequence of auto
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C(sp ) H amination/Cu-catalyzed azide–alkyne cycloaddi-
tion/ Sonogashira reaction with phenylacetylene that leads to
the formation of compound 6cb in 73% yield over three steps.
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Finally, we demonstrated that the auto C(sp ) H amina-
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Scheme 3. Scope of the catalytic one-pot auto-C(sp ) H amination/
Suzuki cross-coupling with vinyl boron reagents.
tion can be combined with a Mirozoki–Heck coupling
(Scheme 5). Application of the optimal conditions (see
Table S3), thus, provides the functionalized cinnamoyl deriv-
atives 7 in good yields. This was compatible with the presence
of an ester, a cyano, and an amide functionality.
In conclusion, this study reveals the multiple facets of
iodine(III) reagents ArI(OAc)2, which can be used as
oxidants, substrates, and coupling partners in multistep
sequences to afford optically pure amines with yields of up
to 88%. We have demonstrated that the hypervalent iodine
that would be faced with a substrate bearing a benzylic site
and an alkene both likely to undergo the addition of the
rhodium-bound nitrene.
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We, then decided to combine the catalytic auto C(sp ) H
amination with other catalytic couplings to explore the
molecular diversity accessible with the self-oxidation of
iodine(III) reagents. Inspired by our previous study,[10] the
3
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one-pot auto C(sp ) H amination/Sonogashira reaction was
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Scheme 5. Scope of the catalytic one-pot auto-C(sp ) H amination/
Mizoroki-Heck cross-coupling.
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reagent can undergo an efficient catalytic auto C(sp ) H
amination that delivers a functionalized iodoarene. The latter
can be subsequently engaged in one-pot palladium-catalyzed
cross-couplings. Importantly, some of these compounds could
not be easily accessible through a reversed sequence of Pd-
catalyzed cross-couplings/auto C(sp ) H amination for che-
moselectivity reasons. The overall strategy accordingly high-
lights the value of hypervalent iodine reagents as hitherto
underestimated useful building blocks in synthesis.
3
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2079 – 2087.
3
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Acknowledgements
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[14] The iodine(III) oxidants are stable over months, except com-
pounds 3d and 3e, which should be used freshly prepared in the
We wish to thank the French National Research Agency
(program no. ANR-11-IDEX-0003-02 and CHARMMMAT
ANR-11-LABX-0039; fellowships to J.B. , G.G.) and the
Institut de Chimie des Substances Naturelles (fellowship to
A.G.J.) for their support. We thank Dr. Jennifer Ciesielski for
proofreading the manuscript.
one-pot reactions to ensure the best yields.
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[15] This auto C(sp ) H amination compares favorably with the
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C(sp ) H amination of 4-iodo-ethylbenzene. In the presence of
1.2 equiv of S*NH2 1, 3 mol% of the Rh-complex 2, and
1.4 equiv of the iodine(III) oxidant PhI(OPiv)2, compound 4a
was obtained in 84% yield.
3
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[16] Running the auto C(sp ) H amination with stoichiometric
À
Keywords: C H amination · cross-coupling ·
homogeneous catalysis · hypervalent iodine · tandem synthesis
amounts of the sulfonimidamide 2 and the iodine(III) reagent
3a generated compound 4a with a slightly lower yield of 86%.
[17] N. Miyaura, Top. Curr. Chem. 2002, 219, 11 – 59.
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[20] Compound 5af was obtained using potassium furyltrifluorobo-
rate.
[21] S. Darses, J.-P. Genet, Chem. Rev. 2008, 108, 288 – 325.
[22] Compound 5bc was contaminated by traces of the product
resulting from the coupling at the C2 position of the alkene,
which arises from the preparation of the potassium vinyltri-
fluoroborate reagent.
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