Hydroxamic Acids as Chemoselective (ortho-Amino)arylation Reagents via Sigmatropic Rearrangement

Article abstract of DOI:10.1002/anie.201703667

The use of readily available hydroxamic acids as reagents for the chemoselective (ortho-amino)arylation of amides is described. This reaction proceeds under metal-free, mild conditions, displays a very broad scope, and constitutes a direct approach for the metal-free attachment of aniline residues to carbonyl derivatives.

Full text of DOI:10.1002/anie.201703667

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Hydroxamic acids as chemoselective (ortho-amino)arylating
reagents via sigmatropic rearrangement
Authors: Saad Shaaban, Veronica Tona, Bo Peng, and Nuno Maulide
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703667
Angew. Chem. 10.1002/ange.201703667
Link to VoR: http://dx.doi.org/10.1002/anie.201703667
http://dx.doi.org/10.1002/ange.201703667

10.1002/anie.201703667
Angewandte Chemie International Edition
COMMUNICATION
Hydroxamic acids as chemoselective (ortho-amino)arylating reagents via
sigmatropic rearrangement
Saad Shaaban,[a] Veronica Tona,[a][+] Bo Peng[b][+] and Nuno Maulide*[a]
Abstract: The use of readily available hydroxamic acids as reagents
for chemoselective (ortho-amino)arylation of amides is presented in
this manuscript. The reaction proceeds under metal-free mild
conditions, displays a very broad scope and constitutes a direct
entry for the metal-free attachment of aniline residues to carbonyl
derivatives.
bottom reaction).
Nitrogen-containing arenes are of importance in Chemistry,
Biology and Materials. Many pharmaceuticals and natural
products contain aniline cores.[1] Over the past years, many
methodologies have been developed to introduce nitrogen into
aromatic moieties.[2]
The amide linkage belongs to a restricted group of key chemical
bonds of life.[3] Although research on amide bond formation is
well established, the activation of this bond has only become
more intensive in recent decades.[4] Among the most successful
methods is the treatment of a carboxamide with triflic anhydride,
which generates an activated intermediate with a myriad of
possible reaction pathways available.[5] The generation of this
reactive intermediate was well studied by Ghosez,[6] Charette,[7]
Movassaghi[8] and others.[9] Our group has also recently
contributed to this chemistry.[10]
N-aryl hydroxyamic acid derivatives were previously used to
achieve
a formal ortho C-H activation with C-O bond
formation.[11] This elegant intramolecular rearrangement, which
usually requires high temperature (Scheme 1a), has been
employed recently by Tomkinson under mild conditions for C-O
and C-N bond formation.[12] Primary and secondary aniline
derivatives are also well-known as ortho-directing groups for
metal-catalyzed C-H functionalization (Scheme 1b).[13]
We have recently shown that pyridine-N-oxides can serve as
meta-arylating reagents in the presence of activated alkynes via
thermal [3,3] sigmatropic rearrangement (Scheme 1c, top
reaction).[14] Additionally, we and others[15] have observed that
addition of pyridine-N-oxides to keteniminium intermediates
allows formation of an electrophilic enolonium-like species,
prone to interception by appropriate nucleophiles (Scheme 1c,
Scheme 1. a) Intramolecular rearrangement of hydroxamic acids. b) Metal-
catalyzed ortho C-H activation of aniline derivatives. c) Pyridine-N-oxides as
arylating or Umpolung reagents. d) Proposed metal-free ortho-amino-arylation
with hydroxamic acids via [3,3] rearrangment.
[a]
S. Shaaban, V. Tona[+] and Prof. Dr. N. Maulide
Institute of Organic Chemistry
University of Vienna
We thus hypothesized that readily available N-aryl hydroxamic
acid derivatives could be suitable reagents for an ortho-amino-
arylation process, as depicted in Scheme 1d. Herein, we report
a chemoselective and mild aminoarylation of amides, under
metal-free conditions, that delivers synthetically useful aniline
cores to carboxamide moieties.
At the outset, we hypothesized that several N,O-nucleophiles
might be able to promote an arylation reaction manifold. We
thus investigated structurally diverse species for this reaction, as
Währinger Straße 38, 1090 Wien
nuno.maulide@univie.ac.at
http://maulide.univie.ac.at
[b]
[+]
Prof. Dr. B. Peng[+]
Department of Chemistry
Zhejiang Normal University
688 Yingbin Road, Jinhua 321004, China
These two authors contributed equally.
Supporting information for this article is given via a link at the end of
This article is protected by copyright. All rights reserved.

10.1002/anie.201703667
Angewandte Chemie International Edition
COMMUNICATION
depicted in Scheme 2. Much to our surprise, N,N-
dimethylaniline-N-oxide (2b), an apparently prime candidate for
this transformation, led to no detectable product. A similar fate
awaited nitrosobenzene 2c, probably due to low nucleophilicity.
Although the cyclic hydroxamic acid 2d was equally
unsuccessful, its acyclic variant 2e was uniquely able to mediate
aminoarylation of activated amide 1a in good yield. Following
optimization (see Supporting information for details), a very good
87% yield of aminoarylated product 3a was obtained. [16]
Scheme 2. Identification of hydroxamic acids as suitable (aminoarylating)
reagents.
Scheme 4. Substrate scope for different amide backbones
We thus set to explore the scope of this transformation. As seen
in Scheme 3, a large range of different functional groups were
tolerated in this reaction.
Alkyl, branched alkyl and aryl chains afforded the desired
products in good yield (3a-c). Other functional groups such as
an alkene (3d), alkyne (3e), ether (3g), nitrile (3h), or alkyl
chloride (3f) were also found not to interfere with this highly
chemoselective aminoarylation reaction.
More important, an ester, a free methyl ketone and even a
terminal carbaldehyde were tolerated. In all these cases,
activation took place selectively at the amide carbonyl furnishing
the α-aminoarylated products in chemoselective fashion and
good yield (3i-k). As shown in Scheme 4, it was also important
that the nature of the amide appears to play only a negligible
role, with several N-alicyclic and N-aliphatic amides successfully
undergoing aminoarylation (3l-3p). Morpholine 3q, presumably a
less electron-donating moiety provided only a modest yield of
product. Importantly, 8- and 12-membered-ring lactams were
smoothly α-arylated (3r and 3s respectively).
Scheme 3. Substrate scope for the chemoselective amide arylation.
Scheme 5. Substrate scope for differently protected hydroxamic acids.
This article is protected by copyright. All rights reserved.

10.1002/anie.201703667
Angewandte Chemie International Edition
COMMUNICATION
We then investigated different protecting groups on the
hydroxamic acid partner. As seen in Scheme 5, Boc-protected
hydroxamic acid 2f furnished the desired products - with a more
convenient functionality for post-reaction deprotection - in very
good yields (3t-3v). The Cbz- 2g and TFA-protected 2h also
gave the desired products (3w and 3x respectively) in good yield.
A Ts-protected hydroxamic acid 2i delivered the desired product
3y in low yield, presumably due to its poor nucleophilicity.
Finally, we examined different aryl moieties. As seen in Scheme
6, a variety of substituted-hydroxamic acids 2j-t smoothly
underwent the desired aminoarylation in moderate to good yield
(3z-3ai). This furnishes a possibility for further elaboration on the
final products.[17] Interestingly, whilst the m-Fluoro derivative led
to 1.1:1 mixtures of regioisomers, use of a m-methyl-substituted
hydroxamic acid favored the ortho product in 5.6:1 ratio.
Scheme 7. Derivatization of the product. a) amide 3t, TFA (10 equiv.) 1.5 h
then (0.1 M) KOH (10 equiv.) and reflux for 1h. b) amide 3e,
Cu(thiophenecarboxylate) (2 mol%), TsN3 (1.1 equiv.), 4 h. c) amide 3q,
MeMgBr (3.0 equiv.), THF, 2 h.
In conclusion, we herein report the first example of the use of
hydroxamic acids for aminoarylation of carboxamide
derivatives.[19] This transformation proceeds under mild
conditions and is highly chemoselective, always arylating the
amide component even in presence of ester, ketone or aldehyde
functionality. Aminoarylation offers
a range of interesting
opportunities in synthesis resulting from the presence of an
aniline in the final products, and our preliminary results highlight
this.
Acknowledgements
We are grateful to the University of Vienna for continued support
of our research program. Financial support for this work was
generously provided by the ERC (StG FLATOUT and CoG
VINCAT) and the DFG (Grants MA-4861/4-1 and 4-2).
Crystallographic analysis by Ing. A. Roller (Uni. of Vienna) is
acknowledged.
Scheme 6. Scope of substrate with different N-Aryl-hydroxamic acid.
Keywords: aminoarylation • chemoselective • hydroxamic acid •
amide • sigmatropic rearrangement
The presence of an aniline moiety in the final products offers a
considerable synthetic advantage, and we set out to showcase
this. As seen in Scheme 7, deprotection of the Boc group
enables formation of the 3-substituted oxindole 4a in good yield.
This amounts to a 2-step synthesis of oxindoles from amides
and hydroxamic acids. Other transformations possible include
3+2-cycloaddition to 4b or – in the case of a morpholine amide –
direct conversion to a ketone 4c upon treatment with a Grignard.
The latter reaction effectively connects the chemistry herein with
an access to α-aminoarylated ketones.[18]
[1]
[2]
Z. Rappoport, The chemistry of anilines, Wiley, 2007.
a) J. Hartwig, Acc. Chem. Res. 2008, 41, 1534−1544; b) S.
Raoufmoghaddam, Org. Biomol. Chem. 2014, 12, 7179-7193; c) K.
Shin, H. Kim, S. Chang, Acc. Chem. Res. 2015, 48, 1040-1052; d) P.
Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564-12649.
a) A. Greenberg, C. M. Breneman, J. F. Liebman, Amide linkage:
selected structural aspects in chemistry, biochemistry, and materials
science, Wiley, 2000; b) C. Montalbetti, V. Falque, Tetrahedron 2005,
61, 10827-10852; d) P. Bailey, T. Mills, R. Pettecrew, R. Price, Vol. 5,
Elsevier Ltd., 2005, pp. 201-294.
[3]
[4]
Recent reviews on metal-catalyzed amide bond activation: a) D. Addis,
S. Das, K. Junge, M. Beller, Angew. Chem. Int. Ed. 2011, 50, 6004-
6011; b) G. Menga, M. Szostak, Org. Biomol. Chem., 2016, 14, 5690-
5707; c) J. Dander, N. Garg, ACS Catal., 2017, 7, 1413-1423. Selected
examples on metal-catalyzed amide bond activation: d) R. Corriu, J.
Moreau, M. Pataud-Sat, J. Organomet. Chem. 1982, 228, 301-308; e)
R. Kuwano, M. Takahashi, Y. Ito, Tetrahedron Lett. 1998, 39, 1017-
1020; f) H. Sasakuma, Y. Motoyamaa, H. Nagashima, Chem. Commun.,
2007, 4916-4918; g) S. Das, B. Wendt, K. Möller, K. Junge, M. Beller,
This article is protected by copyright. All rights reserved.

10.1002/anie.201703667
Angewandte Chemie International Edition
COMMUNICATION
Angew. Chem., Int. Ed. 2012, 51, 1662-1666; h) M. Tobisu, K.
Nakamura, N. Chatani, J. Am. Chem. Soc., 2014, 136, 5587-5590; i) L.
Hie, N. Fine Nathel, T. Shah, E. Baker, X. Hong, Y. Yang, P. Liu, K.
Houk, N. Garg, Nature, 2015, 524, 79-83; k) S. Das, Y. Li, L-Q. Lu, K.
Junge, M. Beller, Chem. Eur. J. 2016, 22, 7050-7053; l) G. Menga, M.
Szostak, Org. Lett. 2016, 18, 796-799; m) L. Hie, E. Baker, S. Anthony,
J. Desrosiers, C. Senanayake, N. Garg, Angew. Chem., Int. Ed. 2016,
55, 15129-15132; n) Á. Fuentes de Arriba, E. Lenci, M. Sonawane, O.
Formery, D. Dixon, Angew. Chem., Int. Ed. 2017, 56, 3655-3659.
Gao, C. Sun, C. Xu, J. Zhu, J. Am. Chem. Soc., 2013, 135, 468-473; g)
X. Huang, J. Huang, C. Du, X. Zhang, F. Song, J. You, Angew. Chem.,
Int. Ed. 2013, 52, 12970-12974; h) D. Wang, X. Yu, X. Xu, B. Ge, X.
Wang, Y. Zhang, Chem. Eur. J. 2016, 22, 8663-8668; i) T. Morita, T.
Satoh , M. Miura, Org. Lett., 2017,DOI: 10.1021/acs.orglett.7b00569.
[14] X. Chen, S. Ruider, R. Hartmann, L. González, N. Maulide, Angew.
Chem., Int. Ed. 2016, 55, 15424-15428.
[15] a) D. Kaiser, A. De la torre, S. Shaaban, N. Maulide, Angew. Chem., Int.
Ed. 2017, DOI: 10.1022/anie201701538R1 ; b) D. Patil, S. W. Kim, Q.
H. Nguyen, H. Kim, S. Wang, T. Hoang, S. Shin, Angew. Chem., Int. Ed.
2017, 56, 3670-3674.
[5]
[6]
Selected reviews on the reactions of keteniminium intermediate: a) L.
Ghosez, J. Marchand-Brynaert, Adv. Org. Chem. 1976, 9, 421-532; b)
B. Snider, Chem. Rev. 1988, 88, 793-811; c) C. Madelaine, V. Valerio,
N. Maulide, Chem. Asian. J. 2011, 6, 2224-2239; d) D. Kaiser, N.
Maulide, J. Org. Chem., 2016, 81, 4421-4428.
[16] The use of N-oxides 2a and 2b led to the formation of the α-ketoamide
product in low yield. The use of 2c and 2d led to no observable
products and only starting material was recovered. For the α-oxidation
of amides with pyridine N-oxides, see: A. de la Torre, D. Kaiser, N.
Maulide, J. Am. Chem. Soc. 2017, 139, 6578-6581.
a) J. B. Falmagne, J. Escudero, S. Taleb-Sahraoui, L. Ghosez, Angew.
Chem., Int. Ed. Engl. 1981, 20, 879-880; b) I. Marko, B. Ronsmans, A.
M. Hesbain-Frisque, S. Dumas, L. Ghosez, B. Ernst, H. Greuter, J. Am.
Chem. Soc. 1985, 107, 2192-2194; c) L. Y. Chen, L. Ghosez,
Tetrahedron: Asymmetry 1991, 2, 1181-1184; d) C. Genicot, B.
Gobeaux, L. Ghosez, Tetrahedron Lett. 1991, 32, 3827-3830.
a) A. B. Charette, M. Grenon, Can. J. Chem. 2001, 79, 1694-1703; b) A.
B. Charette, S. Mathieu, J. Martel, Org. Lett. 2005, 7, 5401-5404; c) G.
Pelletier, W. S. Bechara, A. B. Charette, J. Am. Chem. Soc. 2010, 132,
12817-12819; d) W. S. Bechara, G. Pelletier, A. B. Charette, Nat. Chem.
2012, 4, 228-234.
[17] a) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire, Chem.
Rev. 2002, 102, 1359-1470; b) J. Corbet, G. Mignani, Chem. Rev. 2006,
106, 2651-2710; c) C. Johansson Seechurn, M. O. Kitching, T. J.
Colacot, V. Snieckus, Angew. Chem., Int. Ed. 2010, 51, 5062-5085.
[18] a) V. K. Aggarwal, B. Olofsson, Angew. Chem., Int. Ed. 2005, 44, 5516-
5519; b) X. Huang, N. Maulide, J. Am. Chem. Soc. 2011, 133, 8510-
8513; c) Z. Jia, E. Gálvez, R. M. Sebastián, R. Pleixats, Á. Álvarez-
Larena, E. Martin, A. Vallribera, A. Shafir, Angew. Chem. Int. Ed. 2014,
53, 11298-11301; d) S. Shaaban, A. Jolit, D. Petkova, N. Maulide,
Chem. Commun. 2015, 51, 13902-13905; e) D. Kaiser, L. F. Veiros, N.
Maulide, Chem. Eur. J. 2016, 22, 4727-4732.
[7]
[8]
[9]
a) M. Movassaghi, M. Hill, J. Am. Chem. Soc. 2006, 128, 14254-14255;
b) M. Movassaghi, M. Hill, O. Ahmad, J. Am. Chem. Soc. 2007, 129,
10096-10097; c) O. Ahmad, M. Hill, M. Movassaghi, J. Org. Chem.
2009, 74, 8460-8463.
[19] The analogous arylation of an ynamide is possible in low yield, as
shown below. Treatment of ynamide 5a with triflimide and N-phenyl
hydroxamic acid 2a leads to 6a in 30% yield.
a) S. Sforza, A. Dossena, R. Corradini, E. Virgili, R. Marchelli,
Tetrahedron Lett. 1998, 39, 711-714; b) V. Nenajdenko, I. Baraznenok,
E. Balenkova, J. Org. Chem. 1998, 63, 6132-6136; c) P.
Rashatasakhon, A. Padwa, Org. Lett. 2003, 5, 189-191; d) K. Xiao, J.
Luo, K. Ye, Y. Wang, P. Huang, Angew. Chem. Int. Ed. 2010, 49, 3037-
3040; e) A. Lumbroso, S. Catak, S. Sulzer-Mosse, A. De Mesmaeker,
Tetrahedron Lett. 2014, 55, 6721-6725; f) P. Huang, Y. Huang, K. Xiao
J. Org. Chem. 2016, 81, 9020-9027.
[10] a) C. Madelaine, V. Valerio, N. Maulide, Angew. Chem. Int. Ed. 2010,
49, 1583-1586; V. Valerio, C. Madelaine, N. Maulide, Chem. Eur. J.
2011, 17, 4742-4745; c) B. Peng, D. O'Donovan, I. Jurberg, N. Maulide,
Chem. Eur. J. 2012, 18, 16292-16296; d) B. Peng, D. Geerdink, N.
Maulide, J. Am. Chem. Soc. 2013, 135, 14968-14971; e) B. Peng, D.
Geerdink, C. Farès, N. Maulide, Angew. Chem. Int. Ed. 2014, 53, 5462-
5466; f) V. Tona, A. de la Torre, M. Padmanaban, S. Ruider, L.
González, N. Maulide, J. Am. Chem. Soc. 2016, 138, 8348-8351.
[11] a) L. Horner, H. Steppan, Justus Liebigs Ann. Chem. 1957, 606, 24-47;
b) S. Oae, T. Sakurai, H. Kimura, S. Kozuka, Chem. Lett. 1974, 671-
674; c) C. Cummins, R. Coates, J. Org. Chem. 1983, 48, 2070-2076; d)
A. Bassoli, G. Di Gregorio, G. Galliani, M. Riboldi, B. Rindone, S. Tollari,
F. Chioccara, Bull. Soc. Chim. Fr. 1988, 293-297; e) Y. Endo, T. Uchida,
S. Hizatate, K. Shudo, Synthesis, 1994, 10, 1096-1105; f) H. Wang, L.
Anderson, Org. Lett. 2013, 15, 3362-3365.
[12] a) C. Beshara, A. Hall, R. Jenkins, K. Jones, T. Jones, N. Killeen, P.
Taylor, S. Thomas, N. Tomkinson, Org Lett 2005, 7, 5729-5732; b) A.
Porzelle, M. Woodrow, N. Tomkinson, Eur. J. Org. Chem. 2008, 5135-
5143; c) A. Porzelle, M. Woodrow, N. Tomkinson, Org. Lett. 2010, 12,
812-815; d) A. Porzelle, M. Woodrow, N. Tomkinson, Org. Lett. 2010,
12, 1492-1495.
[13] Selected examples on the metal-catalzed ortho-activation of anilines; a)
C. Houlden, C. Bailey, J. Gair Ford, M. Gagné, G. Lloyd-Jones, K.
Booker-Milburn, J. Am. Chem. Soc., 2008, 130, 10066-10067; b) W.
Rauf, A. Thompsona, J. Brown, Chem. Commun., 2009, 3874-3876;
c) F. Patureau, F. Glorius, J. Am. Chem. Soc., 2010, 132, 9982-9983;
d) A. García-Rubia, B. Urones, R. Gómez-Arrayás, J. Carretero, Angew.
Chem., Int. Ed. 2011, 50, 10927-10931; e) C. Suzuki, K. Hirano, T.
Satoh, M. Miura, Org. Lett., 2013, 15, 3990-3993; f) B. Liu, Y. Fan, Y.
This article is protected by copyright. All rights reserved.

10.1002/anie.201703667
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Saad Shaaban, Veronica Tona, Bo Peng
and Nuno Maulide*
Page No. – Page No.
Hydroxamic acids as chemoselective
amino-arylating reagents via
sigmatropic rearrangement
Arylation with beNefits: The use of readily available hydroxamic acids as
reagents for chemoselective (ortho-amino)arylation of amides is presented in this
manuscript. The reaction proceeds under metal-free and mild conditions, displays a
very broad scope and constitutes a direct entry for the metal-free attachment of
aniline residues to carbonyl derivatives.
This article is protected by copyright. All rights reserved.