Intermolecular, Branch-Selective, and Redox-Neutral Cp*IrIII-Catalyzed Allylic C?H Amidation

Article abstract of DOI:10.1002/anie.201901733

Herein, we report the redox-neutral, intermolecular, and highly branch-selective amidation of allylic C?H bonds enabled by Cp*Ir^III catalysis. A variety of readily available carboxylic acids were converted into the corresponding dioxazolones and efficiently coupled with terminal and internal olefins in high yields and selectivities. Mechanistic investigations support the formation of a nucleophilic Ir^III–allyl intermediate rather than the direct insertion of an Ir–nitrenoid species into the allylic C?H bond.

Full text of DOI:10.1002/anie.201901733

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Accepted Article
Title: Intermolecular, Branch-Selective and Redox-Neutral Cp*IrIII-
Catalyzed Allylic C–H Amidation
Authors: Tobias Knecht, Shobhan Mondal, Yian-Heng Ye, Mowpriya
Das, and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901733
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10.1002/anie.201901733
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Intermolecular, Branch-Selective and Redox-Neutral Cp*IrIII-
Catalyzed Allylic C–H Amidation
Tobias Knecht+, Shobhan Mondal+, Jian-Heng Ye, Mowpriya Das, and Frank Glorius*
Dedicated to Yitzhak Apeloig on the occasion of his 75th birthday
Abstract: Herein, we report the redox-neutral, intermolecular and
highly branch-selective amidation of allylic C–H bonds enabled by
Cp*IrIII catalysis. A variety of readily available carboxylic acids were
converted into their corresponding dioxazolones and efficiently
coupled with terminal and internal olefins in high yields and
selectivities. Mechanistic investigations support the formation of a
nucleophilic IrIII–allyl intermediate rather than the direct insertion of an
Ir-nitrenoid species into the allylic C–H bond.
Nitrogen moieties are present in many of the most privileged
structures found in pharmaceutical science.[1] Methods for the
formation of aliphatic carbon–nitrogen bonds, such as by
reductive amination or N-alkylation, are therefore naturally among
the most commonly used transformations in drug discovery.[2]
Furthermore, amide bond formation is another class of reaction
that is essential to medicinal chemistry.[3] However, these
reactions all typically require the synthesis of pre-functionalized
starting materials.
The interconversion of allylic C–H to C–N bonds by the insertion
of a metal-nitrenoid species into a C–H bond is a direct approach
to streamline the synthesis of aminated compounds, but these
methods often suffer from low regio- and chemoselectivity.[4]
Alternatively, White, Liu and others have demonstrated that linear
allylic amination can be selectively promoted through the coupling
of terminal olefins with tosylamides using palladium-catalysis
(Scheme 1A(i)).[5] In a complementary fashion, Blakey reported
the allylic amination of -substituted styrenes using Cp*RhIII as
the catalyst (Scheme 1A(ii)).[6] A common drawback of these
processes is that the use of amine nucleophiles generally involves
a reductive elimination pathway and thus, stoichiometric amounts
of oxidants are required to regenerate the catalyst.[7]
Scheme 1. General outline of allylic amination protocols via C–H activation.
Whereas several reports describe the electrophilic nature of
Cp*RhIII–allyl intermediates, which can be intercepted by
nucleophilic coupling reagents, the insertion of the allyl–metal
bond into an electrophile has yet to be described.[6,10] We aimed
to couple dioxazolones, derived from naturally abundant and
bioactive carboxylic acids with terminal and internal olefin
feedstocks by allylic C–H activation (Scheme 1B).[11] Importantly,
this electrophilic amidation approach would enable direct alkyl to
amide coupling, whilst obviating the need for external oxidants.
We began our studies using 1-octene (1a) and methyl
dioxazolone (2a) as the substrates with [Cp*RhCl2]2 as the
catalyst and AgOAc as the base at 80 °C in DCE (Table 1). To
our delight we found that the product 3aa was formed in 62% yield
and with a 4:1 branch/linear (B/L) ratio (Table 1, entry 1). Upon
switching the catalyst from Cp*RhIII to Cp*IrIII, the yield was
increased to 86% and perfect branch-selectivity was observed
(entry 2). The amount of AgOAc was decreased to 10 mol% and
the reaction temperature was lowered to mild 40 °C without
influencing the reaction outcome (entry 3-4).[12]
More recently, Chang has introduced dioxazolones as stable
nitrene-precursors for the redox-neutral ortho-directed C–H
amidation of arenes avoiding Curtius-type rearrangements which
are known to be problematic in metal-nitrene chemistry.[8,9]
Based on our experience in Cp*RhIII-catalyzed allylic C–H
functionalization reactions, we assumed that
intermediate might have ambiphilic characteristics.[10]
a
RhIII–allyl-
[*]
T. Knecht[+], S. Mondal[+], Dr. J.-H. Ye, M. Das, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201901733
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Table 1. Reaction optimization.[a]
The loading of iridium pre-catalyst could also be lowered to
2 mol% when using 1.2 equiv. of 2a (entry 5). Additionally, the
solvent could be changed to dichloromethane (entry 6).
Whilst linear-selective allylic amination has been well explored,
branch-selective C–H amination has only been realized: i) in an
intramolecular fashion,[11,13] ii) through C–H oxygenation/allylic
substitution[14] or iii) by employing a sulfurdiimide reagent which
Entry
Catalyst
[Rh] 5%
[Ir] 2.5%
[Ir] 2.5%
[Ir] 2.5%
[Ir] 2%
AgSbF6
20%
AgOAc
200%
200%
10%
T
B/L
Yield[b]
62%
86%
90%
90%
86%
90%
1
2
80 °C
80 °C
80 °C
40 °C
40 °C
40 °C
4:1
undergoes an ene-reaction followed by
a
Pd-catalyzed
rearrangement.[15] This manuscript describes the direct
intermolecular branch-selective amidation of allylic C–H bonds.
With the optimized conditions in hand, we next analyzed the
sensitivity of this reaction protocol (Scheme 2). Pleasingly, the
product 1a could also be isolated in the same yield (89%) when
the reaction was conducted under air or standard reagent grade
CH2Cl2 was used.
10%
>20:1
>20:1
>20:1
>20:1
>20:1
3
10%
4
10%
10%
5[c]
6[d]
10%
10%
[Ir] 2%
10%
10%
[a] Conditions: 1a (0.10 mmol), 2a (0.15 mmol) in 1,2-dichloroethane (DCE)
under argon. [b] Yields determined by calibrated GC-FID analysis using
mesitylene as internal standard. [c] Using 1.2 equiv. of 2a. [d] Reaction run in
dichloromethane (DCM) and using 1.2 equiv. of 2a.
Scheme 2. Scope of the branch-selective allylic C–H amidation. Reaction performed on a 0.4 mmol scale in 2.0 mL of DCM under an argon atmosphere. Isolated
yields of major isomers reported. Boc = tert-butyloxycarbonyl. [a] Reaction performed on a 0.1 mmol scale. Yield determined by GC-FID analysis using mesitylene
as internal standard. [b] Product obtained in a 1:1 diastereomeric ratio. [c] 2.0 equiv. of 2 were used and the reaction time was 48 h. [d] 1.5 equiv. of 1 and 1.0
equiv. of 2 were used.
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At reduced catalyst loading (1 mol%) the product was still formed
in 78% yield. Performing the reaction at room temperature
reduced the yield of the product to 68%. Finally, the reaction was
scaled up to 4.0 mmol and no erosion in yield was observed (90%,
609 mg).
could also be used to obtain 3bc in a moderate yield and
regioisomeric ratio. The scope of the dioxazolone coupling
partner was next investigated. Cyclohexyl, benzyl, cyclopropyl
and piperidine substituted dioxazolones reacted smoothly to
afford the desired products with no loss in selectivity (3ca–3cc,
3cf). Product 3cd was obtained in a modest yield, presumably
due to ortho-directed C–H amidation side reactions. We next
applied the developed reaction protocol to naturally occurring and
bioactive carboxylic acids (Scheme 3). Probenecid could be
easily activated to form the amidated product 4a in 82% yield. In
addition, the dioxazolones derived from Citronellic acid and
Ibuprofen could be used to afford the corresponding products (4b,
4d) in 78% and 31% yield, respectively. Pleasingly, we were also
able to couple a protected amino acid with allylbenzene to afford
4c as a 1:1 mixture of diastereoisomers in 47% yield. The
utilization of internal olefins and complex dioxazolones are
complementary results to a fundamental work by Rovis that
appeared just prior to submission of this manuscript.[17]
We began scoping studies with respect to the olefin coupling
partner. Ether moieties and a ,-unsaturated ketone were well
tolerated under the reaction conditions and the corresponding
products were isolated in moderate to high yields (3ab–3ad) [16]
Esters, acrylates and an unsaturated ketone reacted smoothly to
afford the desired products with no side reactions observed (3ae–
3ag). The products of differently protected amines (3ah, 3ai) and
of the sulfonamide bearing Probenecid scaffold (3aj) were
obtained in high yields. An electron withdrawing aliphatic nitro-
group was also tolerated and (3ak) was isolated in moderate 54%
yield. It should be noted that diminished yields were generally
observed when conversions of both starting materials were low.
Compounds bearing multiple double bonds were selectively
amidated at the terminal allyl moiety (3al, 3am). We also
synthesized the protected drug Vigabatrin in a single step in 67%
yield (3an). Additionally, an Estrone derivative was successfully
amidated (3ao). Subsequently, we applied our reaction protocol
to different allylarenes, which were all well tolerated under the
reaction conditions (3ao–3av). However, electron-poor arenes
reacted more sluggish than electron-rich arenes (3aq, 3as).
Interestingly, when using an electron deficient CF3-substituted
arene the regioselectivtiy (B/L) decreased to 3.4:1. Besides the
functionalization of terminal olefins, internal olefins were also
investigated as substrates.
We then investigated the reaction mechanism. Considering that
Ir-netrenoid species are known to undergo C–H insertion[4,11,18]
,
we envisaged two mechanistic pathways: i) proceeding via C–H
activation and the formation of a metal–allyl species, or ii) the
direct insertion of a metal-nitrenoid species into the allyllic C–H
bond (Scheme 4). We started our investigations by comparing the
reaction outcome of allylbenzene (1ao) and (E)--methylstyrene
(1ao’) (Scheme 4A). In both cases the branch-amidated product
was formed, indicating that either the mechanism proceeds
through a metal–allyl species or isomerization is followed by C–H
insertion. Furthermore, we examined the reaction outcome using
(E)-4-octene (1bd) as the substrate, which led to the formation of
both products (3bd, 3bd’) in a 1:1 regiosiomeric ratio. According
to a C–H insertion pathway, only a single product would be
expected due to the symmetry of 1bd (Scheme 4B, upper
pathway). However, through the formation of a metal–allyl
species, the substrate becomes unsymmetrical and two different
products (3bd, 3bd’) would be expected (Scheme 4B, lower
pathway). Based on these results we propose the following
catalytic cycle (Scheme 4C). The pre-catalyst [Cp*IrCl2]2 is
activated through the abstraction of the halogen atoms by AgSbF6
and AgOAc to form the cationic catalyst I. The olefin substrate
associates to the metal center (II) followed by C–H activation to
form the allyl–Ir-complex III. This complex then undergoes
oxidative addition into the N–O bond, followed by the extrusion of
CO2 to form allyl–Ir-nitrenoid species (IV).[8b] The product is then
obtained after reductive elimination and proto-demetalation,
which concomitantly regenerates I.
Scheme 3. Functionalization of dioxazolones derived from complex carboxylic
acids. Products obtained in a 1:1 diastereomeric ratio. [a] 1.0 equiv of 1 and 2
equiv. of 2 were used.
.
By employing (E)-1,3-diphenylpropene the product 3ba was
obtained in 76% yield. Even the highly volatile (E)-2-pentene
could be utilized to afford 3bb in 95% yield. A conjugated diene
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Acknowledgements
This work was
supported
by
the
Deutsche
Forschungsgemeinschaft (SFB 858, Leibniz Award). We also
thank Dr. Michael. J. James, Tobias Pinkert, Dr. Andreas Lerchen
and Frederik Sandfort for helpful discussions.
Conflict of Interest
The Authors declare no conflicts of interest.
Keywords: C–H activation • allylic Amination • redox-neutral •
branch-selective • carboxylic acids
[1]
[2]
[3]
E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257.
S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451.
a) E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606; b) A. El-Faham,
F. Albericio, Chem. Rev. 2011, 111, 6557.
[4]
For selected examples, see: a) H. M. L. Davies, J. R. Manning, Nature
2008, 451, 417; b) C. Liang, F. Collet, F. Robert-Peillard, P. Müller, R. H.
Dodd, P. Dauban, J. Am. Chem. Soc. 2008, 130, 343; c) J. L. Roizen, M.
E. Harvey, J. D. Bois, Acc. Chem. Res. 2012, 45, 911; d) G. Dequirez, V.
Pons, P. Dauban, Angew. Chem. Int. Ed. 2012, 51, 7384; Angew. Chem.
2012, 124, 7498; e) N. S. Dolan, R. J. Scamp, T. Yang, J. F. Berry, J. M.
Schomaker, J. Am. Chem. Soc. 2016, 138, 14658.
[5]
For selected examples, see: a) S. A. Reed, M. C. White, J. Am. Chem.
Soc. 2008, 130, 3316; b) G. Liu, G. Yin, L. Wu, Angew. Chem. Int. Ed.
2008, 47, 4733; Angew. Chem. 2008, 120, 4811; c) M. R. Luzung, C. A.
Lewis, P. S. Baran, Angew. Chem. Int. Ed. 2009, 48, 7025; Angew. Chem.
2009, 121, 7159; d) G. Yin, Y. Wu, G. Liu, J. Am. Chem. Soc. 2010, 132,
11978; e) C. C. Pattillo, I. I. Strambeanu, P. Calleja, N. A. Vermeulen, T.
Mizuno, M. C. White, J. Am. Chem. Soc. 2016, 138, 1265; f) S. R. Vemula,
D. Kumar, G. R. Cook, ACS. Catal. 2016, 6, 5295; g) R. Ma, M. C. White,
J. Am. Chem. Soc. 2018, 140, 3202.
[6]
For selected Cp*RhIII-catalyzed allylic functionalization reactions, see: a)
T. Cochet, V. Bellosta, D. Roche, J.-Y. Ortholand, A. Greiner, J. Cossy,
Chem. Commun 2012, 48, 10745; b) A. Archambeau, T. Rovis, Angew.
Chem. Int. Ed. 2015, 54, 13337; Angew. Chem. 2015, 127, 13535; c) Y.
Shibata, E. Kudo, H. Sugiyama, H. Uekusa, K. Tanaka, Organometallics
2016, 35, 1547; d) J. S. Burman, S. Blakey, Angew. Chem. Int. Ed. 2017,
56, 13666; Angew. Chem. 2017, 129, 13854. e) T. A. F. Nelson, S. B.
Blakey, Angew. Chem. Int. Ed. 2018, 57, 14911.
[7]
a) F. Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011, 40, 1926; b)
T. A. Ramirez, B. Zhao, Y. Shi, Chem. Soc. Rev. 2012, 41, 931; c) K.
Shin, H. Kim, S. Chang, Acc. Chem. Res. 2015, 48, 1040; d) H. Kim, S.
Chang, ACS. Catalysis 2016, 6, 2341; e) Y. Park, Y. Kim, S. Chang,
Chem. Rev. 2017, 117, 9247.
[8]
[9]
a) Y. Park, K. T. Park, J. G. Kim, S. Chang, J. Am. Chem. Soc. 2015,
137, 4534; b) J. Park, S. Chang, Angew. Chem. Int. Ed. 2015, 54, 14103;
Angew. Chem. 2015, 127, 14309; c) Y. Park, J. Heo, M.-H. Baik, S.
Chang, J. Am. Chem. Soc. 2016, 138, 14020.
Scheme 4. Mechanistic experiments and proposed reaction mechanism.
In summary, we have developed a mild, intermolecular and highly
branch-selective allylic C–H amidation reaction under redox-
neutral conditions through the coupling of dioxazolones and olefin
feedstocks. The reaction mechanism was investigated and is
proposed to proceed through allylic C–H activation. We believe
that this method of acid-to-allylamide coupling will be of great
interest for the streamlined synthesis of alkylamines in bioactive
compounds.
For examples showing the practicability of dioxazolones, see: a) Y. Park,
S. Jee, J. G. Kim, S. Chang, Org. Process Rev. Dev. 2015, 19, 1024; b)
Y. Hwang, Y. Park, S. Chang, Chem. Eur. J. 2017, 23, 11147.
[10] a) S. Rakshit, F. W. Patureau, F. Glorius, J. Am. Chem. Soc. 2010, 132,
9858; b) A. Lerchen, T. Knecht, M. Koy, J. B. Ernst, K. Bergander, C. G.
Danilic, F. Glorius, Angew. Chem. Int. Ed. 2018, 57, 15248; Angew.
Chem. 2018, 130, 15468; c) T. Knecht, T. Pinkert, T. Dalton, A. Lerchen,
F. Glorius, ACS. Catal. 2019, 9, 1253.
[11] S. Y. Hong, Y. Park, Y. Hwang, Y. B. Kim, M.-H. Baik, S. Chang, Science
2018, 359, 1016.
[12] T. Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc.
Rev. 2016, 45, 2900.
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[13] For selected examples, see: a) K. J. Frauenhoffer, M. C. White, J. Am.
Chem. Soc. 2007, 129, 7274; b) E. Milczek, N. Boudet, S. Blakey, Angew.
Chem. Int. Ed. 2008, 47, 6825; Angew Chem. 2008, 120, 6931; c) D. N.
Zalatan, J. Du Bois, J. Am. Chem. Soc. 2008, 130, 9220; d) L. Wu, S.
Qiu, G. Liu, Org. Lett. 2009, 11, 2707; e) H. Lu, H. Jian, Y. Hu, L. Wojtas,
X. P. Zhangm, Chem. Sci. 2011, 2, 2361; f) S. M. Paradine, M. C. White,
J. Am. Chem. Soc. 2012, 134, 2036; g) S. M. Paradine, J. R. Griffin, J.
Zhao, A. L. Petronico, S. M. Miller, M. C. White, Nat. Chem. 2015, 7, 987.
[14] A. Sharma, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 17983.
[15] H. Bao, U. K. Tambar, J. Am. Chem. Soc. 2012, 134, 18495.
[16] Z. Wang, Z. He, L. Zhang, Y. Huang, J. Am. Chem. Soc. 2017, 140,
735.
[17] H. Lei, T. Rovis, J. Am. Chem. Soc. 2019, 141, 2268.
[18] X. Xiao, C. Hou, Z. Zhang, Z. Ke, J. Lan, H. Jiang, W. Zang, Angew.
Chem. Int. Ed. 2016, 55, 11897; Angew. Chem. 2016, 128, 12076.
,
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Tobias Knecht+, Shobhan Mondal,+ Jian-
Heng Ye, Mowpriya Das, and Frank
Glorius*
Page No. – Page No.
Intermolecular, Branch-Selective and
Redox-Neutral Cp*IrIII-Catalyzed
Allylic C–H Amidation
A new branch! A novel strategy for the mild, highly branch-selective and redox-
neutral allylic C–H amidation is described. Naturally occurring and abundant
carboxylic acids were activated to their corresponding dioxazolones and reliably
coupled with the petrochemical feedstock of terminal and internal olefins. The
synthetic value of this transformation was demonstrated in the coupling of complex
and bioactive scaffolds.
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