Rh(iii)-Catalyzed allylic C-H amidation of unactivated alkenes within situgenerated iminoiodinanes

Article abstract of DOI:10.1039/d1cc02283k

Rh(iii)-catalyzed allylic C-H amidation of substituted alkenes within situgenerated iminoiodinanes is demonstrated. The presented protocol is compatible with differently functionalized unactivated terminal alkenes and internal alkenes. In terminal alkenes

Full text of DOI:10.1039/d1cc02283k

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Rh(III)-Catalyzed allylic C–H amidation
of unactivated alkenes with in situ generated
iminoiodinanes†
Cite this: Chem. Commun., 2021,
57, 6428
Received 29th April 2021,
Accepted 27th May 2021
Pinki Sihag and Masilamani Jeganmohan
*
DOI: 10.1039/d1cc02283k
rsc.li/chemcomm
Rh(III)-catalyzed allylic C–H amidation of substituted alkenes with
Allylic functionalization of alkenes proceeding via p-allyl
in situ generated iminoiodinanes is demonstrated. The presented intermediates has been established as a predominant transfor-
protocol is compatible with differently functionalized unactivated mation for the synthesis of many important therapeutic and
terminal alkenes and internal alkenes. In terminal alkenes, branch biologically active compounds.6 White’s pioneering report on
selectivity was observed exclusively. Based on the detailed mecha- Pd(II)-catalyzed direct allylic functionalization of simple alkenes
nistic investigation, a possible reaction mechanism involving the via the p-allyl complex was a breakthrough in the allylic
in situ generated p-allyl as well as metal–nitrene intermediates has functionalization reaction as it avoids the requirement of
been proposed.
leaving groups at the allylic position.7 Very recently, high valent
transition metal complex catalyzed direct allylic functionaliza-
The construction of C–N bonds in a step economical manner tion of various internal as well as terminal alkenes has been
via transition metal-catalyzed C–H amination reactions has extensively explored by carrying out functionalization with
attracted much attention in organic synthesis due to the different hard N, C and O nucleophiles.8 In 2017, Blakey
ubiquity of nitrogen moieties in various natural and pharma- reported the reductive elimination assisted allylic amination
ceutical products.1 Among the widely utilized aminating of b-substituted styrenes using Cp*Rh(III) as the catalyst.8d,e
reagents, iminoiodinane is a viable nitrene precursor and an Subsequently, our group has reported a Cp*Ir-catalyzed allylic
efficient amidation source to carry out C–H insertion or aziri- amination of substituted internal alkenes.8f This assorted
dination reactions in inter- as well as intra-molecular manner.2 allylic functionalization of internal alkenes mainly requires
Che and Blakey have performed preliminary work involving a stoichiometric amount of metal oxidants. Furthermore,
in situ generation of iminoiodinanes for amidation of saturated Glorius, Blakey and Rovis have independently reported the
C–H bonds.2b,c This iminoiodinane precursor has been derived allylic amidation of various terminal alkenes using dioxazo-
by in situ oxidation of sulfonamide with the environmentally lones and tosyl azides as an amidation source involving metal
benign and easily available hypervalent iodine oxidants. This nitrene intermediate.8g–i However, the use of sulfonamide as a
also overcomes the pitfalls of the synthesis and characteriza- nitrene precursor in the direct allylic C–H activation of unac-
tion of iminoiodinanes.2 However, in the case of alkenes, tivated alkenes is still unexplored. With our continued interest
chemoselective or site-selective amination exhibits a competi- in direct allylic C–H activation,8f we sought to develop a
tion between allylic C–H bonds and olefinic p-bonds with methodology to functionalize unactivated olefins with sulfona-
nitrenoids by modulating/tuning the catalyst system.3,4 In the mide by avoiding the use of expensive metal oxidants.
literature, reports related to hypervalent iodine promoted
Hence, with the idea of amide functionalization of unacti-
iminoiodinane mainly include intramolecular cycloamidation vated olefins by avoiding the usage of metal oxidants, we began
reactions of saturated (sp3) C–H bonds catalyzed by dirhodium, our investigation by using allyl benzene and p-nitrobenzene
Mn-salen, ruthenium–porphyrin or disilver complexes and sulfonamide as model substrates for optimization studies (for
amidation of sp2 C–H bonds of ketoximes catalyzed by a detailed optimization studies, see the ESI†). Treatment of
[Cp*RhCl2]2.5
allylbenzene 1a (2.0 equiv.) with p-nitrobenzene sulfonamide
(2a) in the presence of [Cp*RhCl2]2 (2 mol%), AgSbF6 (8 mol%),
PhI(OAc)2 (2.0 equiv.) and Na2HPO4ꢀ2H2O (1.0 equiv.) in
CF3CH2OH for 24 h at 65 1C gave allylic C–H amidation product
3aa in 96% yield with upto 99% branched selectivity
(Scheme 1). The excess of allyl benzene is used in the reaction
Department of Chemistry, Indian Institute of Technology Madras,
Chennai – 600036, India. E-mail: mjeganmohan@iitm.ac.in
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data. See DOI: 10.1039/d1cc02283k
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various functionalized alkenes. Alkenes containing various
alcohol protection groups such as acrylate 1f, acetate 1g, and
tosylate 1h on reaction with 2a resulted in products 3fa–3ha in
56–86% yields. 6-Bromo-1-hexene (1i) and 10-bromo-1-decene
(1j) also show compatibility with this methodology and resulted
in 3ia and 3ja in 60% and 62% yields, respectively. Various
substituted allyl benzenes 1k–o were also examined. Substi-
tuted allyl benzene containing methyl 1k, methoxy 1l, chloro
1m, and fluoro 1n at the para position resulted in 3ka–3na in
80%, 75%, 65%, and 63%, respectively. 3-Methyl allyl benzene
(1o) also resulted in the expected product 3oa in 70% yield.
Furthermore, this reaction also shows compatibility with vinyl
cyclohexane (1p) and it has been observed that the functiona-
lization exclusively occurs at tertiary carbon yielding product
3pa in good yield of 70%. But, in the case of a smaller ring
system, vinyl cyclopentane (1q), functionalization occurs at the
ring carbon by shifting of double bonds, providing allylic
amidation product 3qa in 65% yield. The formation of unex-
pected product 3qa can be attributed to olefin isomerization
which leads to the internal alkenes followed by the formation of
the p-allyl intermediates and subsequent amination.
The reaction was further examined with various substituted
benzene sulfonamides (2b–g) (Scheme 3). para-Substituted
sulfonamides having electron-donating as well as electron-
withdrawing groups such as Cl (2b), Br (2c), Me (2d) and OMe
(2e) were well tolerated, resulting in products 3ab–ae in good
yields of 80%, 83%, 73% and 70%, respectively. In the case of
the reaction of ortho-nitro benzenesulfonamide (2f) with allyl
benzene (1a) the formation of linear and branched product
(3af0 and 3af) in 90% yield in 9 : 1 ratio was observed. Alkyl
sulfonamide 1c on reaction with ortho-nitro benzenesulfona-
mide (2f) resulted in product 3cf in 85% yield. Interestingly,
alkyl sulfonamide (2g) also shows reactivity toward the reac-
tion, giving product 3cg in 52% yield.
Scheme 1 Branched selective allylic C–H amidation.
due to the isomerization of allyl benzene into 1-phenyl-1-
propene. The structure of product 3aa was confirmed by single
crystal XRD (CCDC 2062182). The reaction was examined with
various solvents. The result shows that the alcoholic solvent,
HFIP, was also found to be effective, providing product 3aa in
86% yield. It can be concluded that the in situ formed iminoio-
dinane might be stabilized in alcoholic solvents such as TFE
and HFIP.9
With the optimal reaction conditions in hand, we set out to
explore the substrate scope for this C(sp3)–H amidation for
various terminal and internal alkenes. As shown in Scheme 2, a
variety of unfunctionalized as well as functionalized terminal
olefins were aminated in good to excellent yields with upto 99%
branched selectivity observed in 1H NMR of crude reaction
mixture. The reaction offers compatibility with various alkenes
containing a broad range of functional groups, giving rise to
different branched amidation products. Various linear unfunc-
tionalized alkenes such as 1-hexene (1b), 1-octene (1c), 1-
decene (1d) and 4-phenyl-1-butene (1e) were explored, and
branched products 3ba–3ea were obtained in excellent 96%,
97%, 97% and 65% yields, respectively.
To further investigate the effect of different functional
groups on the reaction course, the reaction was explored with
We next evaluated the substrate applicability of internal
alkenes with this methodology. The reaction was examined
with various unsymmetrical aryl–alkyl alkenes 1r–w (Scheme 4).
It was observed that the reaction was regioselective giving allylic
amidation products by the nucleophilic attack at the allylic
Scheme 2 Scope of various terminal alkenes.
Scheme 3 Scope of substituted sulfonamides 2b–f, 2g.
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Scheme 4 Scope of unfunctionalized internal alkenes. aA trace amount
(approx. 15 : 1) of other regioisomer was observed in 1H NMR.
sp3-carbon atom in most of the cases. The reaction of alkene 1r
with 2a provided a single product 3ra in yield of 62%. However,
on increasing the length of the carbon chain from hexyl to
octyl, expected products 3sa and 3ta were observed in good
yields of 70% and 82%, respectively. Similarly, the reaction of
p-Cl substituent on the aryl ring of alkenes with different alkyl
chain lengths 1u and 1v with 2a gave products 3ua and 3va in
67% and 45% yields, respectively. In the reaction of 1t and 1u
with 2a, a trace amount of other regioisomers 3ta0 and 3ua0 was
also observed, respectively. The reaction of symmetrical inter-
nal alkene 1w with substituted sulphonamides 2a–f provided
the expected products 3wa–wf in 58–75% yields, respectively.
The reaction of trans-4-octene under similar reaction condi-
tions did not result in the expected product.
Scheme 5 Diversification of various natural and therapeutic compounds.
Furthermore, this methodology was used for the diversifica-
tion of different naturally occurring and biologically pertinent
molecules resulting into amidation product in good to excellent
yields with upto 99% branched selectivity (Scheme 5). Phthala-
mide functionalized alkene 4a on reaction with 2a yielded
product 5aa in 58% yield. The reaction of cyclic monoterpene
chiral (ꢁ) menthol functionalized alkene 4b with 2a provided
amination product 5ba in 60% yield as a mixture of dia-
stereomers in the ratio of 1 : 0.3. Alkene functionalized with a
plant-derived natural product 4c, coumarin also reacts with 2a
resulting in amination product 5ca with 56% yield. The essen-
tial nonsteroidal anti-inflammatory drugs (NSAIDs) used in
Scheme 6 Synthetic transformation.
treating inflammation are profens or 2-aryl-propionic acids allylic amines 6a–b in good yields.10 Furthermore, to test the
such as ibuprofen, naproxen, ketoprofen, etc. Functionalization applicability of the methodology, a large scale (1 mmol scale)
of these profens 4d–f with 2a was carried out. In this reaction, reaction of 1a with 2a was carried out. In this reaction, desired
the expected products 5da–fa were obtained in good yields of product 3aa was obtained in excellent yield of 92%
86%, 78% and 82%, respectively. Plant growth promoter, (Scheme 6b).
clofibric acid functionalized alkene 4g also reacts with sulfo-
To get a better understanding of the reaction mechanism,
namide 2a giving expected product 5ga in 80% yield. Further- control experiments were carried out (Scheme 7). The reaction
more, the derivative of therapeutically relevant synthetic bile of allyl benzene (1a) with 2a and cinnamyl acetate (1a0) under
acid, dehydrocholic acid, 4h is functionalized with 2a, which the optimized reaction conditions resulted in the desired
resulted in amidation product 5ha in 75% yield.
amination product 3aa along with the recovery of cinnamyl
The synthesized nosyl functionalized terminal and internal acetate (1a0) (Scheme 7a). It clearly indicates that the formation
alkenes were converted into allylic amines using a thiol reagent of cinnamyl acetate as an intermediate is not involved in the
under basic conditions (Scheme 6a). Hence, treatment of allylic reaction. Furthermore, the reaction of 1a with iminoiodinane
sulfonamide products 3aa and 3wa with thioglycolic acid 2a0 as a nitrene precursor provided the desired amination
(8 equiv.) and lithium hydroxide (16 equiv.) in DMF yielded product 3aa in 58% yield which indicates the in situ formation
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source, using an environmentally benign hypervalent iodine
oxidant. The presented protocol is compatible with differently
functionalized unactivated internal alkenes as well as terminal
alkenes. A possible reaction mechanism involving p-allyl and
metal–nitrene intermediates has been proposed and supported
by mechanistic studies.
The authors thank the DST-SERB (CRG/2018/000606), India,
for the support of this research. P. S. thanks the IITM for the
fellowship. The authors would like to dedicate the manuscript
to Prof. Christian Bruneau for his outstanding contribution to
organometallic chemistry and catalysis.
Scheme 7 Mechanistic investigation.
Conflicts of interest
of iminoiodinane in the reaction medium (Scheme 7b).
Furthermore, the reaction of p-allyl rhodium complex 7 with
iminoiodinane 2a0 resulted in the formation of the amination
There are no conflicts to declare.
product 3ra in 42% yield (Scheme 7c) indicating the involve- Notes and references
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Scheme 8 Proposed mechanism.
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