On the selectivity in some Rh(III) catalyzed C-H activation cross-couplings

Article abstract of DOI:10.1016/j.crci.2012.08.003

In the last few years, Rh(III)-catalyzed CH functionalizations have made tremendous progress and, consequently, have recently received increasing attention. These CH activation reactions, generally involving a chelate assisting directing group, have been utilized to form valuable heterocycles and to run useful coupling reactions. In this paper, three different transformations are presented and discussed. In order to unequivocally determine the stereochemistry of some of these transformations, crystal structural analysis data are provided.

Full text of DOI:10.1016/j.crci.2012.08.003

C. R. Chimie 15 (2012) 1081–1085
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www.sciencedirect.com
Account/Revue
On the selectivity in some Rh(III) catalyzed C–H activation
cross-couplings
b
c
c,
Frederic William Patureau a, , Tatiana Besset , Roland Fro¨hlich , Frank Glorius
*
*
a Fachbereich Chemie, Technische Universita¨t Kaiserslautern, Erwin-Schro¨dinger-Strasse Geb. 52, 67663 Kaiserslautern, Germany
b Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, Netherlands
c Organisch-Chemisches Institut, Westfa¨lischen Wilhelms-Universita¨t Mu¨nster, Corrensstrasse 40, 48149 Mu¨nster, Germany
A R T I C L E I N F O
A B S T R A C T
Article history:
In the last few years, Rh(III)-catalyzed C–H functionalizations have made tremendous
progress and, consequently, have recently received increasing attention. These C–H
activation reactions, generally involving a chelate assisting directing group, have been
utilized to form valuable heterocycles and to run useful coupling reactions. In this paper,
three different transformations are presented and discussed. In order to unequivocally
determine the stereochemistry of some of these transformations, crystal structural
analysis data are provided.
Received 21 March 2012
Accepted after revision 7 August 2012
Available online 18 September 2012
Keywords:
C–H activation
Rh(III)-catalysis
´
ß 2012 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Oxidative olefination
Structural determination
´
´
R E S U M E
`
´
´
Ces dernieres annees, les fonctionnalisations de liaisons C–H catalysees au Rh(III) ont fait
des progre`s conside´rables, et par conse´quent, ont suscite´ l’attention de bon nombre de
´
chercheurs. Ces reactions d’activation de liaisons C–H impliquent souvent un groupement
´ ´
´
´
´ ´
directeur coordonnant, et ont ete largement employees pour la preparation d’heterocycles
et d’autres re´actions importantes de couplage. Dans ce compte rendu, nous souhaitons
revenir sur, et discuter, la re´giose´lectivite´ de trois diffe´rentes re´actions, structures
`
cristallographiques a l’appui.
´
´
´
´
ß 2012 Academie des sciences. Publie par Elsevier Masson SAS. Tous droits reserves.
1. Introduction
use air, or O2 as terminal oxidant, making these
promising leads for the future of organic chemistry
The construction of C–C bonds through C–H activation
techniques is on the rise, as it typically obviates the need
for costly and tedious pre-activation steps [1]. These
transformations are highly atom economical as they
usually produce little or no waste (in the case of redox
neutral C–H activation cross-couplings). These reactions
are usually easy to implement, operator friendly, and
scalable to some extent [2]. Even when large amounts of
oxidant are required, techniques have been elaborated to
[1,3]. Nevertheless, these reactions still suffer from
selectivity issues, an obvious problem as most substrates
have many different C–H positions between which the
catalyst must discriminate. In this account, we wish to
revisit the selectivity issues, which we have encountered
in several of our works on Rh catalyzed C–H activation
oxidative cross-couplings. We chose to highlight in
particular three topics: the pyrrole synthesis and its
reactivity switch between vinylic C–H and allylic C–H
activation (section 2.1), the double oxidative annulated
lactam synthesis and its peculiar trisubstituted exocyclic
double bond formation (section 2.2), and finally the
linear diene synthesis, and its many possible diaster-
eomers (section 2.3).
* Corresponding author.
E-mail addresses: patureau@chemie.uni-kl.de (F.W. Patureau),
glorius@uni-muenster.de (F. Glorius).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.08.003

1082
F.W. Patureau et al. / C. R. Chimie 15 (2012) 1081–1085
Scheme 1. Pyrrole synthesis.
2. Results and discussions
2.1. C–H activation for pyrrole synthesis
WhilestudyingtheC–Hactivationofa seriesofprotected
-amino acid precursors with RhCp* catalysts, we disco-
b
vered that the nature of the carboxylic acid protecting
groups was essential for directing which C–H position
would be functionalized (see molecules 1 and 3, Scheme 1)
[4]. Indeed, with an ester protected substrate (molecule 1),
only the allylic C–H functionalization is observed, whereas
with a nitrile protecting group (molecule 3), only the vinylic
one is functionalized (Scheme 1). This is explained by a
metallacycle rearrangement. Through deuterium control
experiments, it was established that the vinylic C–H
activation occurs first (intermediate I) and rearranges to
the allylic metallacycle, provided that an ester group can
stabilize it by chelation (intermediate II). The subsequent
alkyne insertion, rearrangement and reductive elimination
lead to a series of substituted pyrroles with exclusive
selectivity. The identity of these compounds was first
tackled through a series of advanced NMR techniques,
and then later in the X-ray structure of compounds 2b, 4a
Fig. 2. X-ray structure (Ortep view 30% probability level) of pyrrole 4a.
Fig. 1. X-ray structure (Ortep view 30% probability level) of pyrrole 2b.
Hydrogen atoms have been omitted for clarity.
Fig. 3. X-ray structure (Ortep view 30% probability level) of pyrrole 4b.

F.W. Patureau et al. / C. R. Chimie 15 (2012) 1081–1085
1083
˚
Fig. 4. X-ray structure (Ortep view 30% probability level) of lactam 6. Selected atomic distances (A): N1-H1 = 0.90(2), O12-H1 = 2.13(2), C9-C10 = 1.346(2),
C10-C11 = 1.453(2). Selected dihedral angle: C9-N1-012-C11 = -1.4(2)8.
n-butylacrylate, we came across a peculiar cyclization
reaction (Scheme 2) [5–7]. Through control experiments,
we established that: 1) the first step of the reaction is a
classical oxidative olefination (indeed, when 7 is engaged
under the catalytic conditions, the intramolecular cycliza-
tion product 8 is formed); 2) the second step does not go
through a Michael type addition, as the cyclic conjugate
addition adduct 9 did not lead to the product when
submitted to the reaction conditions. Thus, the product
may have formed through a second, vinylic C–H activation
event, followed by reductive elimination with the benz-
amide part. Nevertheless, an electrophilic mechanism
cannot be excluded. The configuration of the exo double
bond can be assigned through astute NMR experiments.
We were also fortunate enough to obtain crystals suitable
for X-ray crystal structural analysis (Fig. 4). This confirmed
that the double bond is exclusively Z-configured in lactam
product 6, a diasteroselectivity that is linked to the
Scheme 2. Annulated lactam synthesis.
intramolecular H-bond between N–H and ester moieties.
Indeed, usage of a substituted benzamide 10 leads to a
and 4b (Figs. 1–3, respectively). Structure 4a especially, is
interesting because it is the only tetra-substituted pyrrole of
the series, bearing four different substituents. Intriguingly,
only the depicted isomer is detectable in the reaction
mixture, which is arguably outstanding for a dehydrogena-
tive one stepcross-couplingoftwoverysimplecomponents.
The reader should also note that in the case of unsymme-
trical internal alkynes as coupling partners, the aryl moiety
is always on the side of the N atom (position 2 in the case of
4a), whereas the alkyl chain takes up position 3.
mixture of E and Z-configured products 11.
2.3. C–H activation for linear diene synthesis
While we discovered that
derivatives were suitable substrates for C–H activation
and oxidative olefination, we faced new type of
selectivity problem with competing -hydride elimination
a number of acrylate
a
b
pathways [8,9]. Especially in substrates in which two
functional groups are competing for the rhodacycle
intermediate, such as
a amino-acid precursors like methyl
2.2. Double C–H activation for annulated lactam synthesis
acetamidoacrylate derivatives (12, Scheme 3). The pro-
ducts are typically composed of a mixture of major Z and
In the course of studying the oxidative olefination
of primary benzamides with Michael acceptors such as
minor
E configured linear dienes, usually separable
through Silica gel column chromatography. Interestingly,
Scheme 3. Unnatural amino-acid precursor synthesis.

1084
F.W. Patureau et al. / C. R. Chimie 15 (2012) 1081–1085
no branched isomer was ever detected in this sort of
reaction using these conditions, significantly simplifying
the issue of selectivity. Because these molecules are highly
functionalized, it is generally trivial to determine the
absolute configurations of every single isomer through
standard NOE experiments, even within mixtures. In the
particular case of molecule E-13, an X-ray structure
confirmed the stereochemistry, also assigned by the help
of other methods (Fig. 5). A slight H-bonding effect
between the ester group and one of the vinylic C–H is
˚
visible (H5-O2 = 2.51 A), which may partly be linked to the
systematic formation of this minor isomer, through a H-
bonding directed b-hydride elimination (Table 1). We have
attempted to tune the electronic properties of the
substituents, but this only had a minor effect on the
regioselective outcome, and the resulting yields are usually
lower (Table 1)
3. Summary and conclusion
Herein, we have collected a few elements concerning
the study of the selectivity in three different Rh catalyzed
C–H activation cross-couplings. We think they bring some
more perspectives on these works, and clarify some of the
issues related with regioselectivity.
Data sets were collected with a Nonius KappaCCD
diffractometer. Programs used: data collection COLLECT
(Nonius B.V., 1998), data reduction Denzo-SMN (Z.
Otwinowski, W. Minor, Methods in Enzymology, 276
(1997) 307–26), absorption correction Denzo (Z. Otwi-
nowski, D. Borek, W. Majewski & W. Minor, Acta Cryst. A59
(2003) 228–34), structure solution SHELXS-97 (G.M.
Fig. 5. X-ray structure (Ortep view 30% probability level) of
a amino-acid
˚
precursor E-13. Selected atomic distances (A): C3-C4 = 1.338(3), C4-
C5 = 1.436(3), C5-C6 = 1.341(4), C6-C11 = 1.459(3), H5-O2 = 2.51(3).
Selected
dihedral
angles:
O2-C7-C3-C4 = 36.5(4)8,
C4-C3-N1-
C2 = À131.5(3)8, C6-C5-C4-C3 = 174.8(3)8, C16-C11-C6-C5 = 175.4(3)8.
Table 1
Crystallographic data.
2b
4a
4b
6
E-13
Formula
C21H19NO3
333.37
C20H16N2O
300.35
C16H16N2O
252.31
C15H17NO3
259.30
C14H15NO3
245.27
M
Crystal size (mm)
Color
0.35 Â 0.10 Â 0.02
colorless
6.5120 (7)
7.5339 (8)
17.536 (2)
90
0.25 Â 0.20 Â 0.10
colorless
8.3207 (2)
20.3346 (8)
9.8166 (5)
90
0.25 Â 0.20 Â 0.07
colorless
7.4414 (4)
13.5131 (7)
14.2305 (5)
90
0.35 Â 0.07 Â 0.05
colorless
4.0426 (3)
11.7557 (6)
14.3134 (12)
101.941 (4)
95.094 (7)
91.029 (3
662.42 (8)
1.54178
0.35 Â 0.05 Â 0.03
colorless
33.2953 (17)
5.8094 (2)
13.9664 (8)
90
˚
a (A)
˚
b (A)
˚
c (A)
a
b
g
(8)
(8)
(8)
94.574 (5)
90
107.628 (2)
90
103.936 (5)
90
109.925 (7)
90
3
˚
V (A )
857.59 (16)
1.54178
1.291
1582.96 (11)
1.54178
1.260
1388.85 (11)
1.54178
1.207
2539.7 (2)
1.54178
1.283
˚
l
(A)
rcalc (g cmÀ3
)
1.300
m
(mmÀ1
)
0.696
0.621
0.604
0.738
0.741
Z
2
4
4
2
8
Crystal system/space group
Monoclinic/P21
(No. 4)
Monoclinic/P21/n
(No. 14)
12312
Monoclinic/P21/c
(No. 14)
10008
Triclinic/P1 bar
(No. 2)
Monoclinic/C2/c
(No. 15)
8548
Reflections collected
Reflections unique/Rmerge
Reflection observed
5121
7107
2329/0.069
1861
2755/0.037
2470
2412/0.053
2043
2235/0.037
2018
2138/0.046
1818
(I ꢀ 2
s(I))
Refined parameter
R1 (oberserved data)
wR2 (all data)
228
210
176
177
168
0.056
0.038
0.107
–
0.044
0.117
–
0.044
0.124
–
0.054
0.155
–
0.153
Flack parameter
Max./min. residual
electron density
CCDC
0.0(5)
0.20/–0.16
0.15/–0.17
0.17/–0.18
0.29/–0.19
0.19/–0.21
864553
864554
864555
864556
864557

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1085
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