RhIII-Catalyzed C?H Activation of Aryl Hydroxamates for the Synthesis of Isoindolinones

Article abstract of DOI:10.1002/chem.202002384

Rh^III-catalyzed C?H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho-substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho-substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural-product-like compounds, isoindolobenzazepines, in a one-pot two-step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.

Full text of DOI:10.1002/chem.202002384

Accepted Article
Accepted Article
Title: Rh(III)-catalyzed C-H Activation of Aryl-Hydroxamates for the
Synthesis of Isoindolinones
Authors: Herbert Waldmann, Saad Shaaban, Caitlin Davies, Christian
Merten, Jana Flegel, Felix Otte, and Carsten Strohmann
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: Chem. Eur. J. 10.1002/chem.202002384
Link to VoR: https://doi.org/10.1002/chem.202002384
01/2020

10.1002/chem.202002384
Chemistry - A European Journal
COMMUNICATION
Rh(III)-catalyzed C-H Activation of Aryl-Hydroxamates for the
Synthesis of Isoindolinones
Saad Shaaban,[a]§ Caitlin Davies,[a,b]§ Christian Merten,[c] Jana Flegel,[a,b] Felix Otte,[d] Carsten
Strohmann,[d] and Herbert Waldmann*[a,b]
Dedication ((optional))
[a]
Dr. S. Shaaban, C. Davies, J. Flegel, Prof. Dr. H. Waldmann
Max-Planck-Institute of Molecular Physiology
Department of Chemical Biology
Otto-Hahn-Straße 11, 44227 Dortmund (Germany)
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
C. Davies, J. Flegel, Prof. Dr. H. Waldmann
Technical University Dortmund
Faculty of Chemical Biology
Otto-Hahn-Straße 4a, 44227 Dortmund (Germany)
Prof. Dr. C. Merten
Ruhr University Bochum
Organic Chemistry II
Universitätsstraße 150, 44801 Bochum (Germany)
F. Otte, Prof. Dr. C. Strohmann
Technical University Dortmund
[b]
[c]
[d]
§
Department of Inorganic Chemistry
Otto-Hahn-Straße 6, 44227 Dortmund (Germany)
These authors contributed equally to this work.
Abstract: We report a Rh(III)-catalyzed C-H functionalization reaction
yielding isoindolinones from aryl-hydroxamates and ortho-substituted
styrenes. The reaction proceeds smoothly under mild conditions at
room temperature, and tolerates a range of functional groups.
Experimental and computational investigations support that the high
regioselectivity observed for these substrates results from the
presence of an ortho-substituent embedded in the styrene. The
resulting isoindolinones are valuable building blocks for the synthesis
of bioactive compounds. They provide easy access to the natural
product-like compounds, isoindolobenzazepines, in a one-pot-two-
step reaction. Selected isoindolinones inhibited Hedgehog (Hh)-
dependent differentiation of multipotent murine mesenchymal
progenitor stem cells into osteoblasts.
alkenes as coupling partners.[8] The latter reaction favors the
formation of the Heck-type intermediate via ß-hydride elimination
followed by
a
Michael-type addition. However, these
transformations require electron deficient alkenes and elevated
temperatures and as a result, their applicability is limited
(Scheme 1b-right). Direct formation of five-membered
isoindolinones from aryl-hydroxamates by coupling with styrenes,
i.e. the regioisomeric transformation for the formation of
dihydroisoquinolones (see Scheme 1c), has not been described.
We envisioned that such a transformation might be realized by
attachment of a coordinating substituent to the ortho position of
the styrene. Coordination of this group to the Rh catalyst in the
expected seven-membered ring intermediate would favor the ß-
hydride elimination over the reductive pathway. Subsequent
cyclization would then enable the formation of the isoindolinone
(Scheme 1c).[9]
Transition-metal-catalyzed C-H bond transformations exploiting
different metals have emerged as powerful synthetic methods.[1]
Among them, cyclopentadienyl rhodium complexes (RhCp*Ln)
have been utilized for the C-H functionalization of aromatic
compounds employing different directing groups.[2] Since the first
report by Miura et al.,[3] RhCp* complexes have proven to be
efficient catalysts for the functionalization of C-H bonds adjacent
to benzamides. A variety of annulation partners have been
employed in C-C and C-X bond formation.[4] In particular, the
respective coupling of N-O-aryl-hydroxamates and alkenes
(predominantly styrenes) has successfully been used to
synthesize dihydroisoquinolones (Scheme 1a),[5] including
enantioselective transformations.[6] However, the synthesis of
isoindolinones, i.e. the five-membered ring analogues of the
dihydroisoquinolones, by RhCp*-mediated C-H functionalization
has been explored less frequently. Thus, Rovis et al. used diazo
compounds as annulation partners (Scheme 1b-left),[7] and
isoindolinones could also be formed with electron-deficient
1
This article is protected by copyright. All rights reserved.

10.1002/chem.202002384
Chemistry - A European Journal
COMMUNICATION
O
a) Rh(III)-catalyzedC-H functionalizationof benzamideswith styrenes
O
NH
O
Conditionsa
R
O
NH
O
O
OX
NH
R
N
H
[RhCp*Cl2]2
OR
N
NH
Ar
Ar
R
H
H
R
A
B
C
1
b) Rh(III)-catalyzedC-H functionalizationwith diazo compoundsor electron-deficientalkenes
O
CH2CH2OMs
H
Br
Me
R =
O
O
[RhCp*Cl2]2
[RhCp*Cl2]2
OR
OR
55%
Only A
69%
1 : 3.4 (A : B)
43%
1 : 7.5 (A : B)
84%
1 : 9.5 (A : C)
N
N
NH
1a, X = Piv
1b, X = Boc
H
H
N2
H
EWG
EWG
H
R'
R'
EWG
74%
1 : 10 (A : C)
93%
Only C
80%
Only C
84%
Only C
c) This work:
O
O
O
X
OR
N
Rh
Reductive
pathway
OR
Scheme 2. Effect of ortho-substituent of the styrene moiety and the OX-
protecting group. Reactions were performed using [RhCp*Cl2]2 (1.0 mol%),
CsOPiv (25 mol%) in MeOH [0.1M] at RT for 14h. Yields were determined by
1H-NMR using 1,3,5-trimethoxybenzne as internal standard. Ratios were
determined from the crude 1H-NMR spectrum.
N
[RhCp*Cl2]2
NH
X
H
H
Preferentialß-H
elimination
X
X= coordinating
group (OR, NHR)
Optimization of the reaction conditions were carried out. The use
of 1.0 mol% of [RhCp*Cl2]2 with a catalytic amount of potassium
acetate KOAc in methanol at room temperature resulted in the
formation of desired product C in 74% isolated yield (see
Supporting Information for details). With the optimized conditions
in hand, we then explored the scope of this transformation
(Scheme 3). A variety of alcohol and amine protecting groups
(OMs, NHTs, OAc and OTIPs) on the ortho-substituted styrene
were tested and were well tolerated, providing the five-membered
ring products in good yields ranging from 58% to 87% (3a, c-e).
Interestingly, the reaction also proceeded well when the free
alcohol (3b) was used. Different functional groups on the aryl-
hydroxamates (Cl, F, Me, OMe and NO2) were tolerated to yield
the desired adducts in good yields (3f-k, 3n-o). Whereas the
meta-methyl derivative yielded only a single regioisomer in high
yield (3l), its chloro-analogue gave a 1:1:3 mixture of regioisomers
(3m and 3m’).[11] The nitro-substituted benzamide 3p afforded the
product in lower yield. For this product the isoindolinone structure
was confirmed by means of crystal structure analysis (see
Supporting Information).
O
X
NH
Scheme 1. Rh(III)-catalyzed C-H functionalization of aryl-hydroxamates: a) with
styrenes. b) with diazo compounds or alkenes with an EWG. c) Our work with
styrenes bearing a coordinating side-arm in the ortho position.
In initial experiments, the reaction of Piv-protected benzamide 1a
with styrene 2a bearing an alkyl-mesylate (R = CH2CH2OMs)
tether was explored (Scheme 2). Gratifyingly, the resulting
reaction yielded isoindolinone C as the major product, albeit with
formation of the six-membered ring product A. In all previous
reports on related reactions, ortho-substituted styrenes have not
been used,[10] such that, subsequently we further investigated the
influence of the ortho-substituent of the styrene on the
transformation. To this end, the reaction was performed using the
OPiv-hydroxamate 1a with styrenes bearing Br and Me groups in
the ortho position. However, none of these styrenes afforded the
five-membered ring isoindolinone. Instead, a mixture of the six-
membered ring regioisomers A and B were obtained. In
accordance with previous reports[5a,c], styrene led to the formation
of A as the sole product. You et al. reported recently, the
formation of the five-membered ring with any styrenes using
OBoc-hydroxamates,[9] and we wondered whether this would also
be the case here. Therefore, the same reactions (Scheme 2) were
explored with OBoc-phenyl-hydroxamate 1b. In the presence of
this substituent the styrenes afforded exclusively product C in high
yield. Only styrene forms minor amounts of the six-membered ring
regioisomer A. These results show that the OBoc-phenyl-
hydroxamate 1b plays a crucial role in the formation of the five-
membered ring adduct. In addition, the finding that only the
mesylate-protected styrene with the OPiv-phenyl-hydroxamate 1a
yielded the desired isoindolinone C, supports the hypothesis that
a coordinating group in the ortho-position may favor an alternative
reaction pathway.
2
This article is protected by copyright. All rights reserved.

10.1002/chem.202002384
Chemistry - A European Journal
COMMUNICATION
O
O
X
1) [RhCp*Cl2]2 (1 mol%)
KOAc (0.25 eq.)
MeOH [0.1M], RT, 16 h
X
[RhCp*Cl2]2 (1 mol%)
KOAc (0.25 eq.)
O
OMs
O
N
R
NH
OBoc
OBoc
N
R
N
R
H
R
H
MeOH [0.1M], RT, 16 h
2) KOtBu (3.0 equiv.)
DCM [0.05M], RT, 30 min
R'
R'
1
2, (1.5 equiv.)
4a-r
1
2
3a-p
, (1.5 equiv.)
O
N
O
O
O
O
O
O
N
O
MsO
HO
AcO
N
N
OTIPs
NH
NH
NH
NH
H
Me
MeO
4a
4b
4c
4d
, 40%
, 79%
, 62%
, 69%
3a, 74%
3b, 49%
3c, 63%
3d, 58%
O
O
O
N
N
O
O
O
O
N
MsO
NHTs
NH
NHTs
NHTs
NH
NH
NH
Br
Cl
Cl
F
4e
4f,
4g
, 72%
55%
, 74%
N
O
O
O
3e , 87%
3f, 48%
3g, 28%
3h, 61%
O
N
N
N
O
O
O
O
MsO
MsO
MsO
MsO
Cl
Me
F
NH
NH
NH
NH
Cl
CF3
I
Cl
Cl
Me
4h
4i
4k
4l
, 58%
N
, 68%
, 72%
N
, 44%
N
O
O
O
O
N
3i, 77%
3j, 61%
3k, 74%
3l, 80%
O
O
MeO
MeO
TsO
MsO
O
O
Cl
MsO
MsO
OMe
Cl
MeO
NH
NH
NH
NH
4m
4n
, (1:1 r.r) 72%
, (1:1.1 r.r) 66%
Cl
O
O
O
N
O
O
N
O
OMe
N
N
O
3m
3n
3o
, 55%
(1:1.3 r.r.), 81%
O
, 40%
CF3
OMe
Me
O
4o, 50%
4p, 80%
4q, 31%
4r, 39%
MsO
NH
O2N
Scheme 4. Scope of isoindolobenzazepine substrates.
3p
, 18%
In order to gain insight into the reaction mechanism, we performed
the C-H functionalization using deuterium labelled styrene 2’
(Scheme 5, eq 1). The reaction led to the formation of the desired
product 3q with complete deuterium incorporation (from the
styrene). In addition, submission of starting materials similar to
the ß-hydride elimination intermediate to the optimized reaction
conditions did not yield the cyclization product (Scheme 5, eq 2
and 3). These findings supported the notion that the reaction does
not proceed via a Michael type addition which is in agreement with
the fact that RhCp* does not catalyze a hydroamination
reaction.[13]
Scheme 3. Scope of isoindolinone substrates.
For conversion of the isoindolinones into further compound
classes, we explored whether the coordinating group in the final
isoindolinone scaffold could be treated as a leaving group for ring
closure. We developed a one-pot-two-step reaction, where C-H
functionalization is followed by subsequent treatment of the
reaction mixture with base to afford isoindolobenzazepine
products 4. This scaffold is found in an alkaloid family isolated
from Berberis darwinii.[12] After brief optimization of the second
step (see Supporting Information for details), a series of these NP-
like compounds were synthesized (Scheme 4). Multiple aryl-
hydroxamates with electron donating and electron withdrawing
groups were successfully converted into the desired
isoindolobenzazepines (4a-r) in moderate to very good yields.
The para-chloro product (4g) allowed for structural confirmation
by X-Ray analysis (see the Supporting Information). Bromo- and
iodo-derivatives (4f and 4i) were also tolerated providing
opportunities for further synthetic elaboration. In addition, meta-
substituents (4m and 4n) and di-substitutions provided good
yields of the desired products. Electron donating and withdrawing
groups on the styrene also worked well affording the products in
moderate yields (4o, 4q and 4r). In particular, the CF3-styrene
provided the desired compound (4p) in excellent yield.
O
D
MsO
NH
O
D
Optimized
conditions
OBoc
(eq 1)
N
H
OMs
D
D
1b
2', 90% D
3q, 77%
D
90%
O
OPiv
Optimized
conditions
N
H
No cyclization
product
(eq 2)
(eq 3)
O
OMs
Optimized
conditions
NH2
No cyclization
product
Scheme 5. Mechanistic investigations.
3
This article is protected by copyright. All rights reserved.

10.1002/chem.202002384
Chemistry - A European Journal
COMMUNICATION
Based on these findings and previous reports[5a, 14], we propose
that the reaction starts with the formation of the active catalyst I.
Oxidative addition affords Intermediate II. Insertion of the styrene
would then give intermediate III which might undergo reductive
elimination to dihydroisoquinolone A.[14a] However, in this case,
intermediate III preferentially favors the ß-hydride elimination
pathway leading to rhodium hydride species IV. This would then
undergo migratory insertion into the olefin to yield the six-
membered ring rhodacycle V. Subsequent reductive elimination
followed by N-O bond cleavage should afford the desired
isoindolinone 3 (Scheme 6). For a deeper understanding of this
mechanism, a computational analysis of the key intermediates
using the OPiv-aryl-hydroxamate was performed. (see the
Supporting Information for details) (Scheme 7) Notably, it
indicates that the formation of key intermediate V* from III* is
energetically favored over the pathway leading to
dihydroisoquinolone A.
O
X
[Cp*RhCl2]2
KOAc
NH
O
OBoc
N
H
H
3
Cp*Rh(OAc)2
1b
I
HOAc
O
O
OBoc
X
N
Rh
Cp*
N
OBoc
Rh
H
Cp*
V
II
Ar
O
OBoc
O
H
X
OBoc
N
O
N
Rh
H
Rh Cp*
NH
Ar
ß-Hydride
elimination
Ar
A
III
IV
Scheme 6. Proposed mechanism based on experimental findings.
tBu
tBu
tBu
O
tBu
O
O
O
O
O
O
O
O
O
O
Cp*
O
N
N
Rh
N
OMs
N
Ms
Cp*
O
C
Rh
Rh
Rh
Ms
Cp*
H
O
H
OMs
II*
(0.0)
III*
(-0.25)
IV*
(-2.22)
V*
(-6.1)
tBu
O
M06-2X / 6-31G(2d,p)
Rh: LanL2DZ) /PCM(MeOH)
elative Gibbs Free Energies in kcal/mol
O
Cp*
O
Rh
OMs
N
A
A'
(-1.38)
Scheme 7. Calculated energies for the proposed intermediates with OPiv-hydroxamate.
Isoindolinones are endowed with different bioactivities.[15]
Therefore the synthesized compounds were subjected to several
cell-based assays monitoring signal transduction through different
cancer-related pathways, as well as cellular processes such as
autophagy. Interestingly, several derivatives inhibited Hedgehog
Hh signaling is essential during embryonic development and is of
importance for stem cell homeostasis and tissue regeneration.[16]
Abnormal regulation of Hh signaling is involved in severe birth
defects and various types of cancer, including basal cell
17]
carcinoma and medulloblastoma.[16a,
Consequently, the
(Hh)-dependent
mesenchymal progenitor stem cells into osteoblasts.
differentiation
of
multipotent
murine
identification of Hh signaling inhibitors is of high interest. To
investigate the effect of selected isoindolinones and
4
This article is protected by copyright. All rights reserved.

10.1002/chem.202002384
Chemistry - A European Journal
COMMUNICATION
isoindolobenzazepines on Hh signaling,
a
Hh-dependent
specific marker alkaline phosphatase. The activity of this enzyme
osteoblast differentiation assay using C3H10T1/2 cells was
serves as
a
measure of Hh-dependent osteoblast
18]
employed for primary screening.[17,
The Hh pathway was
differentiation.[19] Remarkably, some isoindolinone derivatives
inhibited this process with half-maximal inhibitory concentrations
(IC50) of 1.1 ±0.5 µM (3m) and 2.1 ± 1.1 µM (3g) (Figure 1 and
Supporting informations, Figure 1).
activated using the Smoothened agonist purmorphamine. Active
Hh signaling leads to differentiation of mesenchymal stem cells
into osteoblasts and, thereby to expression of the osteoblast-
Figure 1. Influence of isoindolinones on Hh-dependent osteoblast differentiation of C3H10T1/2 cells. A: C3H10T1/2 cells were treated with 1.5 µM
purmorphamine and different concentrations of the compounds or DMSO as a control. After 96 h, the activity of alkaline phosphatase was detected using a
chemiluminescent substrate. The DMSO-purmorphamine control was set to 100%. Data are mean values ± SD and representative of two biological replicates, each
performed in three technical replicates. B: Chemical structures of the isoindolinones 3m, 3g, 3n and 3i. C: IC50 values of the isoindolinones, obtained from the
respective dose-response curve shown in A and the respective viability assays. To determine IC50 values, three-fold dilutions starting from 10 µM were used.
Compounds listed as ‘inactive’ showed no effect at the tested concentrations in the respective assay and therefore no IC50 was determined.
In conclusion, we describe the regiodivergent synthesis of
isoindolinones via a Rh(III)-catalyzed C-H functionalization of
aryl-hydroxamates with ortho-substituted styrenes. Both, the
OBoc-protecting group and the presence of an ortho-substituent
with a coordinating substituent on the styrene proved to favor the
formation of the five-membered ring. This method also provides
an alternative route for the synthesis of isoindolobenzazepine
derivatives, the underlying scaffold of a family of NPs. Mechanistic
experiments including DFT calculations support a mechanistic
hypothesis for product formation via ß-hydride elimination
followed by the formation of a six-membered ring rhodacycle.
Selected isoindolinones proved to be inhibitors of Hh dependent
osteoblast differentiation.
Foundation) through the Heisenberg programme (ME 4267/5-1 /
project number 418661145). The work has furthermore been
funded by the DFG under Germany’s Excellence Strategy (EXC-
2033 / project number 390677874).
Keywords: C-H functionalization • ortho-substituted styrenes •
RhCp* • isoindolinones • isoindolobenzazepines
[1]
[2]
a) B. Trost, Science 1991, 254, 1471; b) G. Dyker, Angew. Chem. Int. Ed.
1999, 38, 1698; c) H. Davies, J. Du Bois, J-Q. Yu, Chem. Soc. Rev. 2011,
40, 1855; d) J. Yamaguchi, A. Yamaguchi, K. Itami, Angew. Chem. Int.
Ed. 2012, 51, 8960.
Selected reviews on RhCp* catalysts: a) T. Satoh, M. Miura, Chem. Eur.
J. 2010, 16, 11212; b) N. Kuhl, N. Schröder, F. Glorius, Adv. Synth. Catal.
2014, 356, 1443; c) G. Song, X. Li, Acc. Chem. Res. 2015, 48, 1007; d)
T. Piou, T. Rovis, Acc. Chem. Res. 2018, 51, 170.
Acknowledgements
[3]
[4]
a) K. Ueura, T. Satoh, M. Miura, Org. Lett. 2007, 9, 1407; b) K. Ueura, T.
Satoh, M. Miura, J. Org. Chem. 2007, 72, 5362.
This work was supported by the Max-Planck-Gesellschaft. We
thank Dr. Sonja Sievers and the compound management and
screening center (COMAS) for compound screening. We also
thank Dr. Slava Ziegler and Dr. Andrey P. Antonchick for the
helpful discussion. S.S. thanks the Alexander von Humboldt
Foundation for funding. C.M. acknowledges financial support by
the Deutsche Forschungsgemeinschaft (DFG, German Research
Selected examples: a) D. Stuart, M. Bertrand-Laperle, K. Burgess, K.
Fagnou, J. Am. Chem. Soc. 2008, 130, 16474; b) N. Umeda, H. Tsurugi,
T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2008, 47, 4019; c) T. Hyster,
T. Rovis, J. Am. Chem. Soc. 2010, 132, 10565; d) A. Tsai, M. Tauchert,
R. Bergman, J. Ellman, J. Am. Chem. Soc. 2011, 133, 1248; e) C.
Grohmann, H. Wang, F. Glorius, Org. Lett. 2012, 14, 656; f) D. Yu, M.
Suri, F. Glorius, J. Am. Chem. Soc. 2013, 135, 8802; g) Y. Chen, F. Wang,
5
This article is protected by copyright. All rights reserved.

10.1002/chem.202002384
Chemistry - A European Journal
COMMUNICATION
W. Zhen, X. Li, Adv. Synth. Catal. 2013, 355, 353; h) N. Webb, S.
Marsden, S. Raw, Org. Lett. 2014, 16, 4718; i) K. Collins, F. Lied, F.
Glorius, Chem. Commun. 2014, 50, 4459; j) N. Semakul, K. Jackson, R.
Paton, T. Rovis, Chem. Sci. 2017, 8, 1015; k) T. Saiegh, H. Chédotal, C.
Meyer, J. Cossy, Org. Lett. 2019, 21, 8364; l) W. Kong, L. Finger, A.
Messinis, R. Kuniyil, J. Oliveira, L. Ackermann, J. Am. Chem. Soc. 2019,
141, 17198.
M. Yoshida, Y. Hashimotoa, H. Miyachi, Bioorg. Med. Chem. Lett.
2007,17,4895; e) D. Hamprecht, F. Micheli, G. Tedesco, A. Checchia, D.
Donati, M. Petrone, S. Terrenia, M. Wood, Bioorg. Med. Chem. Lett.
2007,17, 428; f) K. Speck, T. Magauer, Beilstein J. Org. Chem. 2013, 9,
2048.
[16] a) J. Briscoe, P.P. Therond, Nat. Rev. Mol. Cell Biol. 2013, 14, 416; b) G.
Carballo, J. Honorato, G. de Lopes, T. Spohr, Cell. Commun. Signal.
2018, 16, 11.
[5]
a) S. Rakshit, C. Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc.
2011, 133, 2350; b) Y. Su, K. Han, G. Song, X. Li, Org. Lett. 2010, 12,
5462; c) N. Guimond, I. Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011,
133, 6449; d) M. Presset, D. Oehlrich, F. Rombouts, G. Molander, Org.
Lett. 2013, 15, 1528; e) M. Wodrich, B. Ye, J. Gonthier, C. Corminboeuf,
N. Cramer, Chem. Eur. J. 2014, 20, 15409; f) T. Hyster, D. Dalton, T.
Rovis, Chem. Sci. 2015, 6, 254; g) E. Trifonova, N. Ankudinov, M. Kozlov,
M. Sharipov, Y. Nelyubina, D. Perekalin, Chem. Eur. J. 2018, 24, 16570;
h) J. Barber, S. Scales, M. Tran-Dubé, F. Wang, N. Sach, L. Bernier, M.
Collins, J. Zhu, I. McAlpine, R. Patman, Org. Lett. 2019, 21, 5689.
For enantioselective rhodium-catalyzed alkene annulation processes: a)
B. Ye, N. Cramer, Science 2012, 338, 504; b) K. Hyster, L. Knörr, T.
Ward, T. Rovis, Science 2012, 338, 500; c) Z. Jia, C. Merten, R. Gontla,
C. Daniliuc, A. Antonchick, H. Waldmann, Angew. Chem. Int. Ed. 2017,
56, 2429; d) E. Trifonova, N. Ankudinov, A. Mikhaylov, D. Chusov, Y.
Nelyubina, D. Perekalin, Angew. Chem. Int. Ed. 2018, 57, 7714.
a) K. Hyster, E. Ruhl, T. Rovis, J. Am. Chem. Soc. 2013, 135, 5364; For
enantioselective rhodium-catalyzed diazo compounds annulation
process: b) B. Ye, N. Cramer, Angew. Chem. Int. Ed. 2014, 53, 7896;
other examples on rhodium-catalyzed diazo compounds annulation
process: c) Z. Qi, S. Yu, X. Li, Org. Lett. 2016, 18, 700; d) T. Zhou, B.
Lia, B. Wang, Chem. Commun. 2016, 52, 14117; e) S. Guo, Li. Sun, F.
Wang, X. Zhang, X. Fan, J. Org. Chem. 2018, 83, 12034; f) S. Guo, L.
Sun, Y. Liu, N. Ma, X. Zhang, X. Fan, Org. Lett. 2019, 21, 4082.
a) F. Wang, G. Song, X. Li, Org. Lett. 2010, 12, 5430; b) C. Zhu, J. Falck,
Chem. Commun. 2012, 48, 1674; c) Y. Lu, H. Wang, J. Spangler, K.
Chen, P. Cui, Y. Zhao, W. Sun, J. Yu, Chem. Sci. 2015, 6, 1923; d) L.
Wang, X. Liu, J. Shen, Q. Chen, M. He, Chem. Asian. J. 2018, 13, 756;
e) S. Wang, C. Li, J. Leng, S. Bukhari, H. Qin, Org. Chem. Front. 2018,
5, 1411; f) B. Ramesh, M. Tamizmani, M. Jeganmohan, J. Org. Chem.
2019, 84, 4058.
[17] L. Kremer, E. Hennes, A. Brause, A. Ursu, L. Robke, H. Matsubayashi, Y.
Nihongaki, J. Flegel, I. Mejdrova, J. Eickhoff, M. Baumann, R. Nencka,
P. Janning, S. Kordes, H. Schöler, J. Sterneckert, T. Inoue, S. Ziegler, H.
Waldmann, Angew. Chem. Int. Ed. 2019, 58, 16617.
[18] S. Peukert, K. Miller-Moslin, ChemMedChem, 2010, 5, 500.
[19] X. Wu, S. Ding, Q. Ding, N. S. Gray, P. G. Schultz, J. Am. Chem. Soc.
2002, 124, 14520.
[6]
[7]
[8]
[9]
During the preparation of this manuscript, S.-L. You et al. independently
and simultaneously developed a series of new ligands that also enable
the formation of isoindolinones from aryl-hydroxamates and styrenes: W-
J. Cui, Z-J. Wu, Q. Gu, S-L. You, J. Am. Chem. Soc. 2020, 142, 7379.
[10] The only examples where ortho-substituted styrene was used in this
chemistry was presented in reference 5a, but only on the Heck-type
reaction.
[11] The decrease in regioselectivity can be attributed to the increase in acidity
of the ortho C-H bond. This is in accordance with what was also observed
by Rovis et.al (ref 7a).
[12] For the isolation of these compounds, see: a) E. Valencia, A. Freyer, M.
Shamma, V. Fajardo, Tetrahedron Lett. 1984, 25, 599; selected
examples on the synthesis of lennoxamine: b) A. Padwa, S. Beall, C.
Eidell, K. Worsencroft, J. Org. Chem. 2001, 66, 2414; b) J. Fuchs, R.
Funk, Org. Lett. 2001, 3, 3923; c) G. Kim, J. Kim, W. Kim, Y. Kim,
Tetrahedron Lett. 2003, 44, 8207; d) D. Comins, S. Schilling, Y. Zhang,
Org. Lett. 2005, 7, 95; e) S. Couty, C. Meyer, J. Cossy, Tetrahedron Lett.
2006, 47, 767.
[13] K. D. Hesp M. Stradiotto, ChemCatChem. 2010, 2, 1192.
[14] a) L. Xu, Q. Zhu, G. Huang, B. Cheng, Y. Xia, J. Org. Chem. 2012, 77,
3017; b) T. Piou, F. Romanov-Michailidis, M. Romanova-Michaelides, K.
E. Jackson, N. Semakul, T. D. Taggart, B. S. Newell, C. D. Rithner, R. S.
Paton, T. Rovis, J. Am. Chem. Soc. 2017, 139, 1296.
[15] a) R. Belliotti, W. Brink, S. Kesten, J. Rubin, D. Wustrow, K. Zoski, S.
Whetzel, A. Corbin, A. Pugsley T. Heffner L. Wise, Bioorg. Med. Chem.
Lett. 1998, 8, 1499; b) A. Mertens, H. Zilch B. König, W. Schafer, T. Poll
W. Kampe, H. Seidel, U. Leser, H. Leinert, J. Med. Chem. 1993, 36,
2526; c) T. Honma, K. Hayashi, T. Aoyama, N. Hashimoto, T. Machida,
K. Fukasawa, T. Z. Iwama, C. Ikeura, M. Ikuta, I. Suzuki-Takahashi, Y.
Iwasawa, T. Hayama, S. Nishimura, H. Morishima, J. Med. Chem. 2001,
44, 4615; d) S. Lee, C. Shinji, K. Ogura, M. Shimizu, S. Maeda, M. Sato,
6
This article is protected by copyright. All rights reserved.

10.1002/chem.202002384
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
O
X
X
O
RhCp*
NH
OBoc
N
H
17 examples, up to 87% yield
Mechanistic investigations with calculations
Access to NPs scaffolds
Hh-pathway inhibitors
The first Rh(III)-catalyzed C-H functionalization toward the synthesis of isoindolinones with styrenes is presented. The use of styrenes
with a coordinating side-arm together with OBoc-aryl-hydroxamates completely switched the regioselectivity. Mechanistic investigations
supported the ß-Hydrid elimination pathway. This method gave an access to NPs scaffold (isoindolobenzazepines). Some of the
synthesized derivatives inhibited Hedgehog (Hh)-dependent differentiation of multipotent murine mesenchymal progenitor stem cells
into osteoblasts.
Institute and/or researcher Twitter usernames: ((optional))
7
This article is protected by copyright. All rights reserved.