Double Regioselective Asymmetric C-Allylation of Isoxazolinones: Iridium-Catalyzed N-Allylation Followed by an Aza-Cope Rearrangement

Article abstract of DOI:10.1002/anie.201710940

Isoxazolinones are biologically and synthetically interesting densely functionalized heterocycles, which for a long time were not accessible in enantioenriched form by asymmetric catalysis. Next to the deficit of enantioselective methods, the functionaliz

Full text of DOI:10.1002/anie.201710940

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Double Regioselective Asymmetric C-Allylation of Isoxazolinones:
Iridium Catalyzed N-Allylation Followed by an Aza-Cope-
Rearrangement
Authors: Stefan Rieckhoff, Jan Meisner, Johannes Kästner, Wolfgang
Frey, and René Peters
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.201710940
Angew. Chem. 10.1002/ange.201710940
Link to VoR: http://dx.doi.org/10.1002/anie.201710940
http://dx.doi.org/10.1002/ange.201710940

10.1002/anie.201710940
Angewandte Chemie International Edition
COMMUNICATION
Double Regioselective Asymmetric C-Allylation of
Isoxazolinones: Iridium Catalyzed N-Allylation Followed by an
Aza-Cope-Rearrangement
Stefan Rieckhoff,[a] Jan Meisner,[b] Johannes Kästner,[b] Wolfgang Frey,[a] and René Peters*[a]
Abstract: Isoxazolinones are biologically and synthetically
These difficulties were also reported in attempts to selectively
interesting densely functionalized heterocycles, which for a long time
achieve non-enantioselective C-allylations (Scheme 1, top).[10]
were not accessible in enantioenriched form by asymmetric catalysis. Herein, we describe the first catalytic asymmetric allylations of
Next to the deficit of enantioselective methods, the functionalization
of isoxazolinones is often plagued by regioselectivity issues due to
the competition of various nucleophilic centers within the
heterocycles. Here we report the first regio- and enantioselective C-
allylations of isoxazolinones. They also allowed for high
regioselectivity in favor of the linear allylation products, although Ir
phosphoramidite catalysts were used, which commonly result in
branched isomers. Our studies suggest that this outcome is the
result of a reaction cascade via an initial regio- and enantioselective
N-allylation providing a branched allyl intermediate, followed by a
spontaneous [3,3]-rearrangement permitting a chirality transfer.
isoxazolinones (Scheme 1, bottom). These reactions are
enabled by iridium phosphoramidite catalysts and proceed –in a
double sense– with very high levels of regioselectivity. On the
one side exclusive C-allylation of the heterocycles was found, on
the other side the reactions provided exclusively the linear
allylation products (Scheme 1, middle). This latter outcome was
initially unexpected, because iridium phosphoramidite catalysts
are otherwise well known to deliver, in general, branched
allylation products with very high levels of regioselectivity.[11-14]
4H-Isoxazol-5-ones
1
(isoxazolinones) are biologically
interesting five-membered heterocycles featuring an acyloxime
moiety.[1] They are double condensation products of β-ketoacid
derivatives and hydroxyl amine. Due to their dense
functionalization containing the imine-like C=N bond, a weak N-
O bond, a lactone-type moiety and an acidic, double activated
C-H bond they are interesting as synthetic building blocks.
Whereas the synthesis of β-amino acids via isoxazolinones was
reported already in 1992 by Batra et al.,[2] only recently the
exploration of the full potential of this class of heterocycles has
started, when it was found that the reactive N-O bond could be
used for the in-situ generation of metal vinylnitrene and/or
azametallacyclobutene intermediates by oxidative addition to
Pd(0) or Ir(I) and a subsequent decarboxylation step.[3] This
reactivity allowed access to various valuable N-containing
heterocycles.[3] We recently employed this kind of reactivity for
the regioselective synthesis of substituted pyridines[4] and
azirines.[5]
Isoxazolinones are also intensely investigated owing to their
attractive
pharmacological
properties.[1]
The
reported
investigations were so far largely limited to achiral or racemic
derivatives. So far only few enantioselective methods for an
asymmetric access of isoxazolinones have been reported.[6]
Recently, we have described the first catalytic asymmetric
generation of all-carbon substituted stereocenters[7] in
isoxazolinones using a planar chiral palladacycle catalyzing
asymmetric 1,4-additions.[8] A difficulty in this and other reactions
with C-centered electrophiles has been the regiocontrol due to
the competition of different nucleophilic centers (C, N, O).[9]
Scheme 1. Comparison of the present study with previous work.
In early experiments various iridacycle catalysts C1-C5[15,16]
bearing dibenzocyclooctatetraen (dbcot) spectator ligands were
surveyed in the model reaction of isoxazolinone 1a and the
branched racemic allylic carbonate 2A in 1,2-dichloroethane
(DCE) at 50 °C (Table 1, entries 1-5).[17] Pd(OAc)2 was initially
chosen as a cocatalyst (5 mol%) to allow for high C:N-
regioselectivity based on our previous work.[4,8] With all catalysts
C1-C5 the C-allylated regioisomer was formed exclusively.
Complete regioselectivity was also found for the allyl fragment,
but surprisingly the linear isomer was formed. Whereas
iridacycle C5 allowed for the highest yield (entry 5), the best
enantioselectivity was attained with C1, which was therefore
[a]
[b]
M.Sc. S. Rieckhoff, Dr. W. Frey, Prof. Dr. R. Peters
Universität Stuttgart, Institut für Organische Chemie
M.Sc. J. Meisner, Prof. Dr. J. Kästner
Universität Stuttgart, Institut für Theoretische Chemie
[a+b] Pfaffenwaldring 55, D-70569 Stuttgart, Germany
E-mail: rene.peters@oc.uni-stuttgart.de
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201710940
Angewandte Chemie International Edition
COMMUNICATION
selected for further optimization. The structure of C1 with R3 = 4-
enantioselectivity.
Other
bases
such
as
K2CO3,
H3CC6H4 was confirmed by X-ray crystal structure analysis.[18]
triazabicyclodecene (TBD) or NaOAc had a negative effect on
reactivity and yield (entries 8-10). We thus focused on soft
Lewis-acid additives and noted enantioselectivities comparable
to the use of Pd(OAc)2 with PtII, AuI and CuI cocatalysts (entries
12-14). With AgOAc the enantioselectivity was lower, but 3a was
formed with improved yield (entry 11). The best conditions using
Pd(OAc)2, which is suggested to facilitate the enolization of 1,
were then applied to various substrates 1 and 2 (Table 2).
Table 1. Optimization of the title reaction.
Table 2. Investigation of the scope of the C-allylation.[a]
Nr. 3
R1
R2
R3
yield(%)[b] er (%)[c]
1
2
3
4
3aA Ph
3aB Ph
3bB Ph
3aC Ph
CH2C6H4-4-Me
CH2C6H4-4-Me
Bn
Ph
82
91.5:8.5
98.5:1.5
85:15
C6H4-3-OMe 99
C6H4-3-OMe 77
Nr. [Ir] additive (x)
solv. rs C:N[a] rs li.:br.[b] yield er (%)[d]
(%)[c]
CH2C6H4-4-Me
C6H4-3-Br
C6H4-4-Br
C6H4-3-Cl
C6H4-4-Cl
C6H4-4-Me
Ph
83
85
81
90
81
71
77
90:10
1
2
3
4
C1 Pd(OAc)2 (5)
C2 Pd(OAc)2 (5)
C3 Pd(OAc)2 (5)
C4 Pd(OAc)2 (5)
DCE >50:1
DCE >50:1
DCE >50:1
DCE >50:1
>50:1
>50:1
>50:1
>50:1
66
88
54
69
87:13
5
6
7
8
9
3aD Ph
3aE Ph
3aF Ph
3aG Ph
3cA Ph
CH2C6H4-4-Me
CH2C6H4-4-Me
CH2C6H4-4-Me
CH2C6H4-4-Me
CH2C6H4-4-CF3
90:10
83:17
90:10
82.5:17.5
28:72
91.5:8.5
88.5:11.5
88:12
5
6
7
8
9
C5 Pd(OAc)2 (5)
C1 Pd(OAc)2 (5)
C1 
DCE >50:1
DMF >50:1
DMF >50:1
DMF >50:1
DMF >50:1
DMF >50:1
DMF >50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
96
81
85
74
50
40
93
85
80
48
82.5:17.5
91.5:8.5
85:15
10 3dA Ph
11 3dB Ph
12 3eA Ph
13 3fA Ph
14 3bA Ph
15 3gB Ph
16 3hA Ph
17 3iA Ph
18 3jA Ph
CH2C6H4-4-OMe Ph
91.5:8.5
90.5:9.5
88.5:11.5
90:10
CH2C6H4-4-OMe C6H4-3-OMe 85
C1 K2CO3 (60)
C1 TBD (5)
62:38
CH2C6H4-4-CN
Ph
Ph
Ph
75
77
78
62.5:37.5
66.5:33.5
85:15
CH2C6H4-4-Br
10 C1 NaOAc (5)
11 C1 AgOAc (5)
Bn
91:9
Me
C6H4-3-OMe 71
89.5:10.5
89.5:10.5
91:9
12 C1 PtCl2(MeCN)2 (5) DMF >50:1
91:9
nPr
Ph
Ph
Ph
Ph
Ph
73
77
87
72
91
13 C1 AuCl(PPh3) (5)
14 C1 CuCl (5)
DMF >50:1
DMF >50:1
91:9
CH2CH2Ph
Ph
90.5:9.5
83:17
[a] Regioselectivity C-/N-allylation determined by 1H-NMR of the crude
product. [a] Regioselectivity linear/branched allyl fragment determined by 1H-
NMR of the crude product. [c] Determined by 1H-NMR of the crude product
using an internal standard. [d] Determined by HPLC. A minus sign indicates
that the other enantiomer was formed in excess.
19 3kA C6H4-4-OMe Bn
20 3lA C6H4-4-CF3 Bn
21 3mB C6H4-3-OMe Bn
[a] Regioselectivity C-/N-allylation & linear/branched determined by 1H-NMR of
the crude product. [b] Yield of isolated product after column chromatography.
[c] Determined by HPLC.
91:9
85.5:14.5
86:14
C6H4-3-OMe 77
A number of solvents were screened (THF, Et2O, diglyme,
MeOH, MeCN, DMSO), but reactivity and enantioselectivity
decreased (not shown). In contrast, DMF had a positive effect
on yield and enantioselectivity (entry 6). Entry 7 shows that
Pd(OAc)2 is, contrary to our expectations, not accountable for
the high C:N-regioselectivity, but has a positive influence on the
With aromatic residues R3 bearing electron-withdrawing or
donating meta- or para-substituents similar results were
obtained (entries 2-8) as for model substrate 2A (entry 1). Ortho-
substituents were not accepted. On a benzylic R2 various
This article is protected by copyright. All rights reserved.

10.1002/anie.201710940
Angewandte Chemie International Edition
COMMUNICATION
functional groups (CF3, OMe, CN) could be present (entries 9-
12). In addition, a bromo substituent was compatible with the
catalyst system (entry 13), like already seen for R3 (entries 4&5).
Good results were also achieved with alkyl or phenyl residues R2
(entries 15-18). R1 tolerated both donor (entry 19) and acceptor
substituents on an aromatic ring (entries 20-21). The (S,E)-
configuration of 3dA (entry 10) was determined by X-ray crystal
structure analysis (see graphic of Table 2).
Consideration of the huge amount of previous research on Ir-
catalyzed allylic substitutions raised the question, why in the
present case the linear allylation products are almost exclusively
formed. Our hypothesis was that the overall reaction might
proceed via an N-allylation forming a branched allyl isomer and
a subsequent [3,3]-sigmatropic rearrangement allowing for a
chirality transfer.[19] However, by continuously monitoring the
model reaction of 1a and 2A by 1H-NMR spectroscopy no N-allyl
intermediate was detectable. If this intermediate was formed, it
was too short-living due to a rapid rearrangement step. On the
other hand, thermal aza-Cope rearrangements of N-allylation
products of isoxazolinones have been reported to require very
high reaction temperatures (180 °C) to give full conversion after
several hours, whereas the experiments shown were performed
at 50 °C.[20] However, the anticipated corresponding N-allyl
intermediates could be isolated with substrates 2 bearing an
alkyl residue R3 (Table 3), as the rearrangement was much
slower for these substrates.
also proceeded with complete double regioselectivity, but in the
opposite sense. That means only the branched N-allyl isomer 4
was obtained. At the same time good to high enantioselectivity
was attained. The (S)-configuration of 4jH (entry 7) was
determined by X-ray crystal structure analysis (see graphic of
Table 3) and is in agreement with other Ir-catalyzed substitutions
using the same chiral ligand.[21] The slower rearrangement was
thermally enabled at 100 °C in DMF. It is not fully enantiospecific
and the er slightly decreased in this step. In the presence of the
Ir/Pd catalyst system, the stereochemical outcome was almost
identical under otherwise identical conditions. For the
rearrangement of 4aH we found that Pd(OAc)2 does not have a
significant accelerating effect.[22-24] Also for substrates with R3 =
aryl an acceleration by Pd(II) could not be observed (see e.g.
Table 1, entries 6 & 7) and an N-allyl intermediate was also not
detected in the absence of Pd(II) in this case.
For the formation of 3, different transition states (TS) might be
envisioned. Those placing R3 in a pseudoaxial position can be
ruled out, as they would lead to a (Z)-configured olefin moiety.
Scheme 2 shows a possible chair and boat TS, in which R3
adopts the pseudoequatorial position. Only the chair TS would
deliver the major enantiomer obtained.
Table 3. Investigation of the scope of the C-allylation.[a]
Scheme 2. Assumed pathways of the thermal [3,3]-rearrangement of the
major N-allylation enantiomer 4 to rationalize the stereochemical outcome.
DFT-calculations were conducted of both TS of 4bA. The
reactive chair conformation was set as the energy reference
(see Supporting Information). According to the calculations the
energy barrier via the boat transition state is higher, but only
around 0.9 kcal/mol and the TS energies are quite similar. This
small difference may explain a loss of er that we found for the
rearrangement step. However, because the experimentally
found loss is relatively small, in reality the energy difference
should be larger than suggested by the computational studies.
In conclusion, we have reported the first regioselective catalytic
asymmetric C-allylations of isoxazolinones. The surprising
finding that linear allylation products were formed using iridium
phosphoramidite catalysts which usually deliver branched
allylation products with very high levels of regioselectivity is
explained by sequential regio- and enantioselective N-allylation
providing a branched allyl system and [3,3]-rearrangement with
chirality translocation from the allyl part to the heterocycle via a
chair transition state.
Nr. 3/4 R1 R2
R3
yield(%)[b] er 4[c]
4 & 3
er 3[c]
1
2
aH Ph CH2C6H4-4-Me
nPr
iBu
64 & 94
43 & 98
94:6
90:10
aJ Ph CH2C6H4-4-Me
aK Ph CH2C6H4-4-Me
cH Ph CH2C6H4-4-CF3
gH Ph Me
90:10
86.5:13.5
3
4
5
6
7
(CH2)2Ph 81 & 54
94.5:5.5 90:10
nPr
nPr
nPr
nPr
73 & 88
67 & 76
54 & 93
79 & 94
95:5
92.5:7.5
87.5:12.5
90:10
iH Ph CH2CH2Ph
jH Ph Ph
90.5:9.5 88.5:11.5
90:10 86.5:13.5
[a] Regioselectivity C-/N-allylation & linear/branched determined by 1H-NMR of
the crude product. [b] Yield of isolated product after column chromatography.
[c] Determined by HPLC.
The reaction stopped after the N-allylation step, arguably as a
result of the absence of
substituent for the rearrangement. In general, the N-allylation
a transition-state-stabilizing π-
This article is protected by copyright. All rights reserved.

10.1002/anie.201710940
Angewandte Chemie International Edition
COMMUNICATION
[14] Further selected examples: a) G. Lipowsky, N. Miller, G.Helmchen,
Angew. Chem. Int. Ed. 2004, 43, 4595; b) T. Graening, J. F. Hartwig, J.
Am. Chem. Soc. 2005, 127, 17192; c) H. He, X.-J. Zheng, Y. Li, L.-X.
Dai, S.-L. You, Org. Lett. 2007, 9, 4339; d) W.-B. Liu, H. He, L.-X. Dai,
S.-L. You, Org. Lett. 2008, 10, 1815; e) J. Y. Hamilton, D. Sarlah, E. M.
Carreira, J. Am. Chem. Soc. 2013, 135, 994; f) M. Chen, J. F. Hartwig,
Angew. Chem. Int. Ed. 2014, 53, 12172; g) M. Chen, J. F. Hartwig, J.
Am. Chem. Soc. 2015, 137, 13972.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG, PE 818/4-2).
Keywords: heterocycle • isoxazolinone • phosphoramidite •
quaternary stereocenter • regioselectivity
[15] Helmchen reported the first examples of iridium phosphoramidite
catalysts bearing dbcot ligands as much more stable alternative to the
corresponding cod complexes. For the initial study and further
examples see: a) C2: S. Spiess, C. Welter, G. Franck, J.-P. Taquet, G.
Helmchen, Angew. Chem. Int. Ed. 2008, 47, 7652; b) J. Qu, G.
Helmchen, Acc. Chem. Res. 2017, 50, 2539; c) C1: J. A. Raskatov, M.
Jäkel, B. F. Straub, F. Rominger, G. Helmchen Chem. Eur. J. 2012, 18,
14314; d) C3 & C5: K.-Y. Ye, L.-X. Dai, S.-L. You, Org. Biomol. Chem.
2012, 10, 5932.
[1]
Representative examples: a) Anti-obesity effect: B. Kafle, N. G. Aher, D.
Khadka, H. Park, H. Cho, Chem. Asian J. 2011, 6, 2073; b) anti-
androgenic activity towards tumor cells: T. Ishioka, A. Kubo, Y. Koiso, K.
Nagasawa, A. Itai, Y. Hashimoto, Bioorg. Med. Chem. 2002, 10, 1555;
c) T. Ishioka, A. Tanatani, K. Nagasawa, Y. Hashimoto, Bioorg. Med.
Chem. Lett. 2003, 13, 2655; d) anti-cancer and antibacterial activity: M.
S. Chande, R. S. Verma, P. A. Barve, R. R. Khanwelkar, R. B. Vaidya,
K. B. Ajaikumar, Eur. J. Med. Chem. 2005, 40, 1143; e) protein kinase
C inhibitors: J. P. Demers, W. E. Hageman, S. G. Johnson, D. H.
Klaubert, R. A. Look, J. B. Moore, Bioorg. Med. Chem. Lett. 1994, 4,
2451.
[16] For the corresponding cyclooctadiene (cod) derivatives, see e.g.: a) cod
derivatives of C1, C2, C3: X. Jiang, J. J. Beiger, J. F. Hartwig, J. Am.
Chem. Soc. 2017, 139, 87; b) cod derivative of C2: W. Chen, J. F.
Hartwig, J. Am. Chem. Soc. 2013, 135, 2068; c) cod derivative of C4:
B. Bartels, C. García-Yebra, G. Helmchen, Eur. J. Org. Chem. 2003,
1097; b) cod derivative of C5: W-B. Liu, C. Zheng, C.-X. Zhuo, L.-X.
Dai, S.-L. You, J. Am. Chem. Soc. 2012, 134, 4812.
[2]
[3]
a) S. Batra, M. Seth, A. P. Bhaduri, J. Chem. Res (S) 1992, 139; b) S.
Batra, M. Seth, A. P. Bhaduri, J. Chem. Res (M) 1992, 1025.
a) K. Okamoto, T. Oda, S. Kohigashi, K. Ohe, Angew. Chem. Int. Ed.
2011, 50, 11470; Angew. Chem. 2011, 123, 11672; b) K. Okamoto, T.
Shimbayashi, E. Tamura, K. Ohe, Chem. Eur. J. 2014, 20, 1490; c) K.
Okamoto, T. Shimbayashi, M. Yoshida, A. Nanya, K. Ohe, Angew.
Chem. Int. Ed. 2016, 55, 7199; Angew. Chem. 2016, 128, 7315.
S. Rieckhoff, T. Hellmuth, R. Peters, J. Org. Chem. 2015, 80, 6822.
S. Rieckhoff, M. Titze, W. Frey, R. Peters, Org. Lett. 2017, 19, 4436.
a) W.-T. Meng, Y. Zheng, J. Nie, N.-Y. Xiong, J.-A. Ma, J. Org. Chem.
2013, 78, 559; b) H. Zhang, B. Wang, L. Cui, X. Bao, J. Qu, Y. Song,
Eur. J. Org. Chem. 2015, 2143.
[17] The corresponding cyclooctadiene (cod) complexes were also
investigated and gave results that were comparable to the dbcot
complexes with usually somewhat lower enantioselectivity. For instance,
the corresponding experiment to Table 1, entry 1 using a cod spectator
ligand gave 74% product and an er = 85.5:14.5. We preferred to use
the dbcot complexes, because reproducibility with the cod complexes
was contrary to the dbcot complexes not satisfying, in particular after
storage of the catalysts for some weeks.
[18] CCDC-1574308 (catalyst C1, (R3=pMe-C6H4)), CCDC-1574318 (4jH),
CCDC-1574319 (3dA) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
[4]
[5]
[6]
[7]
a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis (Eds.: J. Christoffers, A. Baro), Wiley-VCH: Weinheim,
Germany, 2005; b) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005,
347, 1473.
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
[8]
[9]
T. Hellmuth, W. Frey, R. Peters, Angew. Chem. Int. Ed. 2015, 54,
2788; Angew. Chem. 2015, 127, 2829.
[19] a) W.-B. Liu, N. Okamoto, E. J. Alexy, A. Y. Hong, K. Tran, B. M. Stoltz,
J. Am. Chem. Soc. 2016, 138, 5234; b) J. Liu, C.-G. Cao, H.-B. Sun, X.
Zhang, D. Niu, J. Am. Chem. Soc. 2016, 138, 13103; c) M. Kawatsura,
H. Tsuji, K. Uchida, T. Itoh, Tetrahedron 2011, 67, 7686.
See, for instance: a) ref. 1; b) M. Atfani, W. D. Lubell, J. Org. Chem.
1995, 60, 3184; c) F. De Sarlo, Tetrahedron 1967, 23, 831; d) R.
Jacquier, C. Petrus, F. Petrus, J. Verducci, Bull. Soc. Chim. Fr. 1970, 7,
2690.
[20] M. J. S. Gomes, L. F. V. Pinto, P. M. C. Glória, H. S. Rzepa, S.
Prabhakar, A. M. Lobo, Chem. Cent. J. 2013, 7, 94.
[10] M. Moreno-Manas, M. Pérez, R. Pleixats, Tetrahedron 1994, 50, 515.
[11] Recent reviews: a) W.-B- Liu, J.-B. Xia, S.-L. You, Top. Organomet.
Chem. 2012, 38, 155; b) P. Tosatti, A. Nelson, S. P. Marsden, Org.
Biomol. Chem. 2012, 10, 3147; c) J. F. Hartwig, M. J. Pouy, Top.
Organomet. Chem. 2011, 34, 169; d) J. F. Hartwig, L. M. Stanley, Acc.
Chem. Res. 2010, 43, 1461; e) G. Helmchen in Iridium Complexes in
Organic Synthesis (Eds.: L. A. Oro, C. Claver), Wiley-VCH, Weinheim
2009, pp. 211-250; f) G. Helmchen, A. Dahnz, P. Dübon, M. Schelwies,
R. Weihofen, Chem. Commun. 2007, 675.
[21] W. Chen, J. F. Hartwig, J. Am. Chem. Soc. 2012, 134, 15249.
[22] The rearrangement of 4aH was also studied in the presence of
Pd(OAc)2 (5 mol%) in DMF. The following conversions were found after
24 h: 97%@110 °C; 77%@100 °C (full conversion after 48 h);
55%@90 °C.
[23] Selected reviews on sigmatropic rearrangements: a) S. Jautze, R.
Peters, In Science of Synthesis: Stereoselective Synthesis, Evans, P.
A., Ed.; Thieme: Stuttgart, 2011; Vol. 3, Chapter 3.10, pp 443–467; b) U.
Nubbemeyer, Synthesis 2003, 961.
[12] Early studies on Ir-catalyzed allylic substitutions: a) R. Takeuchi, M.
Kashio, Angew. Chem. Int. Ed. 1997, 36, 263; b) J. P. Janssen, G.
Helmchen, Tetrahedron. Lett. 1997, 38, 8025; c) R. Takeuchi, M.
Kashio, J. Am. Chem. Soc. 1998, 120, 8647; d) B. Bartels, C. Garciá-
Yebra, F. Rominger, G. Helmchen, Eur. J. Inorg. Chem. 2002, 2569; e)
T. Ohmura, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 15164; f) C. A.
Kiener, C. Shu, C. Incarvito, J. F. Hartwig, J. Am. Chem. Soc. 2003,
125, 14272.
[24] For Pd-catalyzed [3,3]-rearrangements, see e.g.: a) H. Nakamura, Y.
Yamamoto, in Handbook of Organopalladium Chemistry for Organic
Synthesis 2002, vol. 2, pp 2919-2934; b) K. Akiyama, K. Mikami,
Tetrahedron Lett. 2004, 45, 7217; c) K. N. Fanning, A. G. Jamieson, A.
Sutherland, Curr. Org. Chem. 2006, 10, 1007; d) R. Peters, D. F.
Fischer, S. Jautze, Top. Organomet. Chem. 2011, 33, 139; e) J. M.
Bauer, W. Frey, R. Peters, Angew. Chem. Int. Ed. 2014, 53, 7634; f) R.
Peters, Z.-q. Xin, F. Maier, Chem. Asian J. 2010, 5, 1770.
[13] Very recently Hartwig et al. reported a detailed computational study
which suggested that a number of weak interactions including CH...O
hydrogen bonds contribute to the preference for the branched
regioisomers using iridacycle catalysts: S. T. Madrahimov, Q. Li, A.
Sharma, J. F. Hartwig, J. Am. Chem. Soc. 2015, 137, 14968.
This article is protected by copyright. All rights reserved.

10.1002/anie.201710940
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The first regio- and enantioselective C-
allylation of isoxazolinones
Stefan Rieckhoff, Jan Meisner, Johannes
Kästner, Wolfgang Frey, and René
Peters*
unexpectedly provided linear allylation
products, despite using iridium
phosphoramidite catalysts, which
typically provide branched isomers with
other nucleophiles. This outcome is
explained by a reaction cascade via an
initial N-allylation providing a branched
allyl system and a [3,3]-rearrangement
step.
Page No. – Page No.
Double Regioselective Asymmetric C-
Allylation of Isoxazolinones: Iridium
Catalyzed N-Allylation Followed by an
Aza-Cope-Rearrangement
This article is protected by copyright. All rights reserved.