Versatile cp*Rh(III)-Catalyzed selective ortho-Chlorination of arenes and heteroarenes

Article abstract of DOI:10.1021/acscatal.6b02227

The ortho- and monoselective Cp*Rh(III)-catalyzed chlorination of a broad range of benzene derivatives and electron-rich heterocycles under mild reaction conditions is reported. Inexpensive and commercially available N-chloro-imides could be used as chlorinating agents in as low as substoichiometric quantities. Furthermore, two different reaction protocols were developed to allow for the use of substrates with various electronic properties and enable selective chlorination of a broad range of structural motifs. For electron-rich substrates, the reported protocols enable a perfectly regio-switchable and efficient direct chlorination.

Full text of DOI:10.1021/acscatal.6b02227

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Letter
Versatile Cp*Rh(III)-Catalyzed Selective ortho-
Chlorination of Arenes and Heteroarenes
Fabian Lied, Andreas Lerchen, Tobias Knecht, Christian Mück-Lichtenfeld, and Frank Glorius
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02227 • Publication Date (Web): 07 Oct 2016
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ACS Catalysis
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†
†
Fabian Lied , Andreas Lerchen , Tobias Knecht, Christian Mück-Lichtenfeld*, and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
ABSTRACT: The ortho- and mono-selective Cp*Rh(III)-catalyzed chlorination of a broad range of benzene-derivatives
and electron-rich heterocycles under mild reaction conditions is reported. Cheap and commercially available N-chloro-
imides could be used as chlorinating agents in as low as sub-stoichiometric quantities. Furthermore, two different reac-
tion protocols were developed to allow for the use of substrates with various electronic properties and enable selective
chlorination of a broad range of structural motifs. For electron-rich substrates the reported protocols enable a perfectly
regio-switchable and efficient direct chlorination.
KEYWORDS: halogenation, ortho-chlorination, Cp*Rh(III)-catalysis, arene- and heteroarene-functionalization, C–H bond
activation,
density
functional
theory
Recently, catalytic C–H activation has become one of the
most promising techniques for the step-economic prepa-
tion protocol. However, stoichiometric amounts of an
additional oxidant ((diacetoxyiodo)benzene) and a strong
acid (trifluoroacetic acid) were required, causing tremen-
dous limitations regarding the substrate scope. Only elec-
tron-donating substituted aryl-pyridines/-pyrimidines
1
ration of functionalized molecules. For many years, or-
ganic halides have been utilized as electrophiles in vari-
2
ous substitution reactions or as precursors for the syn-
3
12b
thesis of nucleophilic organometallic reagents. The de-
and -pyrazoles were tolerated.
velopment and broad application of transition metal cata-
lyzed cross-coupling reactions has further increased their
4
value, turning them into core building blocks. Hence, the
combination of direct C–H halogenation and established
cross-coupling transformations enables the development
of efficient synthetic routes towards natural products,
biologically active compounds and pharmaceuticals. Fur-
thermore, a vast array of important natural-products
contain chlorine-atoms, which, ideally can be readily
5
installed by late-stage C–H bond functionalization.
Recently, our group has reported the Cp*Rh(III)-catalyzed
ortho-bromination and ortho-iodination of several ben-
6
7
zene- as well as acrylic acid-derivatives and (electron-
8
rich) heterocycles. All of these examples showed a broad
applicability and good functional group tolerance. How-
ever, all attempts to achieve chlorination using the corre-
sponding N-chloroimides remained unsuccessful (Scheme
1).
Scheme 1. Rhodium(III)-Catalyzed C–H Halogenation
With the precedent reaction-protocols in hand it is obvi-
ous, that the direct C–H chlorination using the
Cp*Rh(III)-catalyst remains to be an extraordinarily chal-
lenging transformation. In line with our previous work on
Cp*Rh(III)–catalyzed halogenation (Scheme 1a), we aimed
to achieve i) a combined mild and additional oxidant-free
reaction protocol and ii) broader substrate scope for the
Cp*Rh(III)–catalyzed chlorination.
Although a variety of methods for the ortho-selective
9
chlorination of C–H bonds have been described using Pd,
10
11
Cu, and Ni, only two examples of the Cp*Rh(III)-
12
catalyzed C–H chlorination have been reported thus far.
The pioneering work by Xu and co-workers involved a
harsh reaction protocol for the selective arene-
chlorination using azaindoles as the directing group.
Furthermore, [Cp*RhCl ] acts simply as a promotor ra-
2
2
Herein, we present the selective and broadly applicable
Cp*Rh(III)–catalyzed chlorination. Two different reaction
protocols which address the electronic properties of the
substrate at hand have been developed (Scheme 1b). For
electron-rich substrates, we developed a less reactiver-
ther than as an active catalyst, seeing as the reaction also
1
2a
proceeds in the absence of the Rh-catalyst. Complemen-
tary to this report, the synthetic methodology developed
by Wang and co-workers offers an alternative mild reac-
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eagent-system, whereas for electron-poor substrates a we found the exclusive formation of the 3-chlorinated
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reagent-system with increased reactivity was employed.
benzamide 5-Cl’ (Table 2, Entry 1). This result shows that
electrophilic aromatic substitution (S Ar) is favored over
the C–H bond functionalization for substrates bearing an
electron-donating group (EDG).
Since previous studies using N-chlorosuccinimide (NCS)
or N-chlorophthalimide (NCP) as “Cl ”-source remained
E
+
fruitless, we were interested in finding Lewis-basic addi-
tives that could potentially enhance the reactivity of these
Driven by this discovery, we sought to find a new set of
conditions suited to override the inherent selectivity of
electron-rich substrates. Using 5 as a model substrate, we
explored chlorinating reagents that were less-electrophilic
than TCC yet more-electrophilic than NCS and NCP, in
13
reagents. We were pleased to find that certain pyridines
promote an increased reactivity of succinimide and
phthalimide reagents in Cp*Rh(III)-catalyzed C–H bond
functionalization
reactions.
With
N,N-
0
1
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+
diisopropylbenzamide 1 as model substrate we set out to
examine different combinations of electrophilic chlorinat-
ing conditions (Table 1). When NCS was applied in the
presence of [Cp*RhCl ] (5 mol%) and AgSbF (20 mol%)
combination with Lewis-basic activators of “Cl ” (Table 2).
Employing the sodium salt of dichloroisocyanuric acid
(
NaDCC)
or
1,3-dichloro-5,5-dimethylhydantoin
2
2
6
(DCDMH) as chlorinating agents, without any additive,
the desired product 5-Cl could be obtained in only 4%
and 11% yield respectively (Entries 2,3). Since Lewis-bases
had significantly enhanced the activity of the imide-
reagents, we investigated a variety of Lewis basic (mainly
with pentafluoropyridine as additive in DCE at 60 °C, the
desired product 1-Cl was observed in 6% yield by GC-MS
(
Table 1, Entry 1). By switching the reagent to NCP and
the additive to 2,4,6-trichloropyridine, a slight improve-
ment in the product formation could be achieved (15%
1
5
pyridine-derived) additives. 2-Trifluoromethylpyridine
was found to be the best activator for DCDMH affording
the desired product 5-Cl in a moderate yield of 51% (Entry
+
yield, Entry 2). Given that the “Cl ”-source was still not
reactive enough, we moved on to investigate more reac-
+
tive “Cl ”-sources keeping pyridine as activator-additive.
3
). Finally, 95% of the desired product could be obtained,
To our delight, selective product formation could be ob-
tained using trichloroisocyanuric acid (TCC) as chlorinat-
ing agent (Entry 3). Since TCC is reported to have an
when the catalyst loading was slightly increased to 5
mol% [Cp*RhCl ] in combination with AgSbF (30 mol%)
2
2
6
and 2-trifluoromethylpyridine (50 mol%) (Entry 6). Since
generally only 20 mol% of Ag is necessary in order to
abstract the chloride ligands from the Rh-catalyst and
thereby rendering it more cationic and active, it is inter-
esting to find a significant enhancement of product yield
upon increasing the silver loading from 20 to 3o mol%
“
active chlorine content” of 91.5% (percentage of chlorine
in the molecule that is active in the oxidation of hy-
14
droiodic acid), the reagent’s stoichiometry could be
decreased to 0.5 equivalents (Entry 4). Furthermore, the
catalyst loading could be reduced to 2.5 mol% (Entry 5).
Additionally, omitting the pyridine-additive only had a
minimal effect on the yield (Entry 6). Two control exper-
iments were then conducted. Reactions carried out either
in the presence of Ag but without Rh or in the absence of
both Rh and Ag with otherwise unchanged reaction con-
ditions proved the Cp*Rh(III)-catalyst to be essential for
this transformation (Entries 7,8).
(
Entries 5,6). We hypothesize, as we did in our previous
work, that a reason for this observation is that the bind-
ing of halides, liberated from the halogenation agent, to
the rhodium center serves as a main catalyst deactivation
8
pathway.
Table 2. Optimization for Electron-Rich Substrates
Table 1. Initial Optimization of Reaction Parameters
a
Determined by GC. For additional optimization data, see the
Supporting Information.
With these two sets of reaction conditions in hand (pro-
cedure A and B, Scheme 2), we explored the substrate
scope of the reaction. To start with, benzamide 1 was
successfully converted on a 10 mmol scale yielding the
desired product 1-Cl in excellent 91%. Benzamides featur-
ing electron-rich substituents in the para-position afford-
ed the corresponding chlorinated products in excellent
yields using procedure B (2-Cl, 5-Cl, 7-Cl). Furthermore,
electron-rich meta-substituted benzamides also afforded
a
Determined by GC. For additional optimization data, see the
Supporting Information.
With the optimized conditions in hand, we set out to
explore the scope of the reaction using this newly devel-
oped protocol. When we applied the standard reaction
conditions to the para-methoxy-substituted benzamide 5,
2
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ACS Catalysis
withdrawing effect introduced by the bromine substituent
the desired chlorinated products in good yields (3-Cl, 6-
1
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
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5
5
5
5
5
5
5
5
6
Cl). However, the minimal steric bulk imparted by the
methoxy-substituent in the meta-position does not suffice
to control the regioselectivity of the reaction, and a mix-
ture of two regioisomers (6a-Cl/6b-Cl) was obtained,
whereas in the case of meta-methyl substituted com-
pound 3, only one regioisomer could be observed. Disub-
stituted benzamides were also comparable with the de-
veloped protocol B (15-Cl). Unfortunately, introducing
steric bulk in the ortho-position completely shuts down
the reaction (4-Cl). Various para-substituted electron-
withdrawing groups on the arene-moiety were also well
tolerated using procedure A (10-Cl, 11-Cl, 12-Cl). Even
of 5-bromo-substituted thiophene 19, reaction progress
was sluggish, but the desired product 19-Cl was nonethe-
less obtained in 53% yield. 5-aryl substituted substrates
underwent chlorination in good to excellent yields. Reac-
tive functionalities such as aldehyde, fluoro, trifluorome-
thyl, methyl, chloro and bromo were all well tolerated, at
the para-, meta- and even ortho-position of the arene. To
our delight this strategy was also found to be applicable
to
benzo-fused
heterocycles
(benzothiophene-3-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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0
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9
0
carboxamide was readily chlorinated, see the Supporting
Information for details).
strongly EWG’s such as para-NO2 and para-CF , were
3
tolerated by procedure A, although the reaction condi-
tions had to be slightly modified (8-Cl, 9-Cl). Further-
more, meta- and ortho-fluorinated arenes could be trans-
formed into the corresponding chlorinated products in
good yields (13-Cl, 14-Cl).
[
Cp*RhCl2]2 (5 mol%)
AgSbF6 (30 mol%)
[Cp*RhCl2]2 (2.5 mol%)
AgSbF6 (10 mol%)
TCC (0.5 equiv)
N(iPr)2
O
N(iPr)2
N(iPr)2
O
2
-CF3-Pyridine (50 mol%)
DCDMH (2.0 equiv)
O
H
1,2-DCE, T
22 h
B: R = EDG
1,2-DCE, T
16 h
A: R = EWG
Cl
Cl
EDG
R
EWG
N(iPr)2
N(iPr)2
O
N(iPr)2
O
N(iPr)2
O
O
Cl
Cl
Cl
Cl
3
-Cl
4-Cl
0%
1
-Cl
91%
2-Cl
a
58%
B @ 60 °C
95%
A @ 60 °C
B @ 60 °C
A @ 60 °C
N(iPr)2
N(iPr)2
Cl
N(iPr)2
N(iPr)2
MeO
MeO
O
O
O
O
MeO
Cl
-Cl
5%
B @ 60 °C
Cl
6a-Cl
Cl
5
9
6b-Cl
7-Cl
88%
B @ 60 °C
68% (1:1.3)
B @ 60 °C
Scheme 3. Scope of Heteroarenes
N(iPr)2
N(iPr)2
N(iPr)2
O
N(iPr)2
Reactions were performed on an 0.4 mmol scale; isolated
yields are given. For more detailed reaction conditions, see
the Supporting Information.
O
O
O
F3C
Cl
O2N
Cl
9-Cl
59%
A @ 100 °C
Cl
Cl
10-Cl
73%
A @ 60 °C
Br
Cl
11-Cl
81%
A @ 60 °C
8
3
-Cl
2%
b
b,c
A @ 120 °C
N(iPr)2
N(iPr)2
F
N(iPr)2
O
N(iPr)2
F
O
O
O
F
Cl
2-Cl
3%
A @ 60 °C
Cl
13-Cl
68%
A @ 60 °C
Cl
Cl
15-Cl
85%
B @ 60 °C
1
8
14-Cl
65%
A @ 120 °C
Scheme 2. Scope of Arenes
Reactions were performed on a 0.4 mmol scale; isolated
yields are given. For more detailed reaction conditions, see
Scheme 4. Mechanistic Experiments
a
the Supporting Information. Reaction carried out on an 10
b
mmol scale. 5 mol% of [Cp*RhCl ] and 20 mol% of AgSbF
were used. Reaction performed on a 0.2 mmol scale.
To gain insight into the reaction mechanism, two sets of
experiments comparing the reaction rates of our standard
2
2
6
c
substrate 1 and its deuterated analogue 1-D were carried
5
Additionally, we could apply the developed protocol B to
the halogenation of electron-rich five-membered het-
eroarenes (Scheme 3). We were pleased to find that thio-
phene-2-carboxamides are well suited to undergo selec-
tive ortho-chlorination in the absence of 2-
out (Scheme 4). These results suggest that the C–H acti-
vation is not involved in the rate-determining step (k /kD
H
≈
1), but plays a significant role in the product determin-
16
ing step (KIE ≈ 5) due to its irreversibility. These find-
ings allow for speculation about the rate determining step
of the reaction which (1) does not involve the substrate
that ultimately undergoes C–H bond cleavage and thus
trifluoromethylpyridine.
Unsubstituted
N,N-
diisopropylthiophene-2-carboxamide 16 yielded its corre-
sponding product 16-Cl in 67% with no byproduct ob-
served. Due to the steric hindrance and the electron-
(
2) could either be the oxidative addition of the catalyst
into the N–X bond of the reagent or the dissociation of a
3
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Page 4 of 6
1
7
ligand from the metal to give the catalytically active spe-
cies.
try. The next step, replacement of the halogenated arene
with a new benzamide molecule at the Rh(III) atom, pro-
ceeds via a slightly exergonic step that is even unfavoured
for the ortho-iodination-product BzA-I. Hence, the rate-
determining step seems to be the dissociation of a ligand
from the metal to regenerate the catalytically active spe-
cies. The C–H activation step is endergonic, as is the re-
placement of the R–H with the next reagent molecule R–
X. The free energy of this exchange (E→A) clearly disfa-
vours the replacement of R–H with N-chlorosuccinimide
or N-chlorophthalimide (+5.7 and +4.0 kcal/mol, respec-
tively), resulting in very low concentrations of reactive
complex A when employing these reagents. With other
reagents, A is formed in concentrations high enough to
proceed with the (low barrier) halogenation reaction.
1
2
3
4
5
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0
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In summary, we have developed a Cp*Rh(III) catalyzed
mild and scalable direct C–H chlorination of various ben-
zene derivatives and electron-rich heterocycles. Two sets
of reaction conditions were developed to allow for the use
of a wide range of electronically diverse substrates and
enable a completely regio-switchable chlorination of elec-
tron-rich starting materials. Cheap and commercially
available N-chloro-imides could be utilized as chlorinat-
ing reagents in as low as substoichiometric quantities.
Scheme 5. Proposed Catalytic Cycle
To shed light on the possible pathways of the reactions,
the proposed catalytic cycle has been calculated with DFT
methods (PW6B95-D3//TPSS-D3/def2-TZVP, COSMO
solvation energies for dichloroethane, for details see SI)
(
Scheme 5). Free energies and free activation barriers in
kcal/mol for all steps of the cycle, using seven different
halogenating reagents NXP (X = Cl, Br), NXS (X = Cl, Br,
I), TCC and DCDMH are reported in Table 3.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI: .
Experimental procedures, spectroscopic data, mech-
anistic experiments and computational studies
Table 3. Free energies ΔG2 and free activation energies
98
≠
ΔG
cycle
in kcal/mol for the single steps of the catalytic
98
2
(
PDF) Optimized structures of all ground and tran-
sition states (SDF)
AUTHOR INFORMATION
Corresponding Author
*
*
E-mail: glorius@uni-muenster.de
E-mail: cml@uni-muenster.de
Author Contributions
†
F.L. and A.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Generous financial support by the DFG (Leibniz Award and
IRTG MünsterToronto), the European Research Council
under the European Community’s Seventh Framework Pro-
gram (FP7 2007-2013)/ERC Grant agreement no. 25936, and
the Alfried Krupp von Bohlen und Halbach Foundation (Al-
fried Krupp Prize for Young University Teachers) is gratefully
acknowledged. We thank Dr. Kathryn M. Chepiga for helpful
discussions.
Although the formation of B is predicted to be exother-
mic for all halogen compounds (except NIS), the free
energy barriers (24.4-29.0 kcal/mol) are too large to make
this pathway competitive with the direct substitution
mechanism. Thus, the appearance of a Rh(V) intermedi-
ate B, formed by oxidative addition of the reagent to the
Rh(III) species A can be unequivocally ruled out. Instead,
direct formation of C from A proceeds through transition
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with
a
low
free
energy
barrier
(
5.3-9.5 kcal/mol) and an almost linear N–Hal–C geome-
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