Redox-Neutral Coupling between Two C(sp3)?H Bonds Enabled by 1,4-Palladium Shift for the Synthesis of Fused Heterocycles

Article abstract of DOI:10.1002/anie.201908460

The intramolecular coupling of two C(sp³)?H bonds to forge a C(sp³)?C(sp³) bond is enabled by 1,4-Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp³)?C(sp³) cross-dehydrogenative couplings, this reaction operates under redox-neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho-bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp³)-C(sp³) bonds.

Full text of DOI:10.1002/anie.201908460

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Accepted Article
Title: Redox-Neutral Coupling between Two C(sp3)–H Bonds Enabled
by 1,4-Palladium Shift for the Synthesis of Fused Heterocycles
Authors: Ronan Rocaboy, Ioannis Anastasiou, and Olivier Baudoin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908460
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10.1002/anie.201908460
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
C–H Activation
Redox-Neutral Coupling between Two C(sp3)–H Bonds Enabled by 1,4-
Palladium Shift for the Synthesis of Fused Heterocycles
Ronan Rocaboy, Ioannis Anastasiou, and Olivier Baudoin*
Abstract: The intramolecular coupling of two C(sp3)–H bonds to
forge a C(sp3)–C(sp3) bond is enabled by 1,4-Pd shift from a
trisubstituted aryl bromide. Contrary to most C(sp3)–C(sp3) cross-
dehydrogenative couplings, this reaction operates under redox-
neutral conditions, with the C–Br bond acting as an internal oxidant.
In addition, it allows the coupling between two moderately acidic
primary or secondary C–H bonds, i. e. adjacent to an oxygen or
nitrogen atom on one side, and benzylic or adjacent to a carbonyl
group on the other side. A variety of valuable fused heterocycles were
obtained from easily accessible ortho-bromophenol and aniline
precursors. The second C–H bond cleavage was successfully
replaced with carbonyl insertion to generate other types of C(sp3)–
C(sp3) bonds.
C(sp3)–H activation at the ortho methyl group and reductive
elimination. We surmised that, if the second oxidative addition
leading to palladacycle A could be avoided, substrates similar to 1
could give rise to simpler dihydrobenzofurans via 1,4-Pd shift and
C(sp3)–H/C(sp3)–H coupling.
a) C(sp3)–H/C(sp3)–H cross-dehydrogenative couplings
MLn cat.
H
H
oxidant
b) C(sp3)–H/C(sp3)–H coupling via 1,4-Pd shift on a C(sp3) position: early
observations
C(sp3)–H activation
I
I
Pd
Ar
Pd(OAc)2 cat.
n-Bu4NBr, K2CO3
O
O
H
2
T
ransition-metal-catalyzed C–C bond formation via double C–H
H
H
DMF, 100 °C
(31%)
bond cleavage, often termed cross-dehydrogenative coupling (CDC)
has emerged as a promising transformation in organic synthesis.[1]
However, in contrast to C(sp2)–C(sp2) and C(sp2)–C(sp3) bond
formation, the construction of C(sp3)–C(sp3) bonds through CDC is
still very limited (Scheme 1a). So far, most of the existing methods
involve oxidative conditions and outer-sphere mechanisms which
require two weak C–H bonds, i. e. with a low bond dissociation
energy or high acidity. 1,n-Palladium shift, pioneered by Heck,[2]
represents a redox-neutral alternative to construct C–C bonds via
double C–H activation, thanks to an initial oxidative addition from a
C–X bond to a Pd0 catalyst.[3,4] Recently, we have exploited this
concept to generate remote C(sp2)–C(sp3) bonds via 1,4-Pd shift onto
a C(sp2) position and C(sp3)–H activation.[5,6] However, using
palladium shift to form C(sp3)–C(sp3) bonds is arguably more
challenging, due to the propensity of s-alkylpalladium species to
undergo protodemetallation or b-hydride elimination, especially at
high temperatures. Yet, early work from Dyker showed that
alkylpalladium intermediates, generated from C(sp3)–H activation at
methoxy groups, are competent to perform subsequent C(sp2)–H or
C(sp3)–H activation.[7] In particular, when iodoarene 1 was reacted
with catalytic Pd(OAc)2 and stoichiometric carbonate in DMF, the
dimeric products 2a and 2b were isolated (Scheme 1b).[7d]
Mechanistically, a first C–I oxidative addition to an in situ-generated
Pd0 complex triggers C(sp3)–H activation at the ortho methoxy group
to give a 5-membered palladacycle, which undergoes oxidative
addition of a second molecule of substrate 1 to give the palladium(IV)
intermediate A.[8] Reductive elimination from A forges the biaryl
bond and leads to the alkylpalladium(II) intermediate B. The latter
furnishes dibenzopyran 2a upon C(sp2)–H activation at the ortho aryl
group and reductive elimination, and dihydrobenzofuran 2b upon
1
A
Me
Me
Me
MeO
C(sp2)–H
activation
MeO
MeO
O
O
PdX
O
C(sp3)–H
activation
Me
2a (47%)
H
B
2b (31%)
c) This work
R2
R2
R2
C(sp3)–H activation
R1
Y
H
Y
H
Y
Pd0/L cat.
RCO2– cat.
R1
Z
Z
Pd(L)O2CR
Z
R1
H
Br
H
H
4
C(sp3)–H activation/
1,4-Pd shift
3
C
Scheme 1. 1,4-Pd shift for the formation of C(sp3)–C(sp3) bonds from
two C(sp3)–H bonds.
In the past years, we and others showed that the introduction of
an appropriate ancillary ligand allows shutting down this
unproductive oxidative addition pathway and generating a variety of
ring systems via direct C(sp2)–C(sp3) reductive elimination.[9]
Moreover, it was shown that aryl bromides 3 (Scheme 1c) tend to
undergo 1,4-Pd shift via carbonate or carboxylate-mediated proton
transfer to generate alkylpalladium complex C.[10] Such
alkylpalladium intermediates can be trapped with boronic acids or
amines to give intermolecular C–C and C–N coupling products,[11] or
undergo b-H elimination to give olefins.[9a,12] Alternatively, we
hypothesized that C might undergo a second C(sp3)–H bond cleavage
at an ortho alkyl group, similar to B, to provide cyclic product 4 upon
reductive elimination from the corresponding palladacycle. This
pathway, avoiding the undesired self-condensation described in
Scheme 1b, could be potentially applicable to precursors containing
diverse Y and Z groups as well as C(sp3)–H bond types, to generate a
variety of fused heterocycles of interest for medicinal chemistry.
[*]
R. Rocaboy, I. Anastasiou, Prof. Dr. O. Baudoin
University of Basel, Department of Chemistry, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland
E-mail: olivier.baudoin@unibas.ch
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
1
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10.1002/anie.201908460
Angewandte Chemie International Edition
R2
Z
R2
H
cond. A or B
R3
R3
R1
Z
Br
R1
H
5, Z = O
6, Z = N–COCF3
7, Z = O
8, Z = N–COCF3
a) 2,3-dihydrobenzofurans[a]
CO2Me
CO2Me
CO2Me
MeO2C
F
OHC
F
CO2Me
O
O
O
O
O
O
O
O
7a, 92% (78%)[b]
7b, 40%
7c, 57%
7d, 91%
7e, 79%
7g, 88%[c]
7h, 70%
7f, 73%[c]
O
O
O
Ni-Pr2
N
CO2Me
CO2Me
7k (trans), 41%[c]
O
O
O
O
O
HO
OH
7i, 81%[c]
7j, 53%[c]
7l, 68%[c,d]
Bisphenol C
b) indolines[e]
Me
MeO2C
F
NC
N
COCF3
8a, 74%
N
N
N
N
H
COCF3
8b, 62%
COCF3
8c, 61%
COCF3
8d, 38%
8e, 45%[f]
Scheme 2. Synthesis of 2,3-dihydrobenzofurans and indolines via C(sp3)–H/C(sp3)–H coupling. [a] Conditions A: Pd(PCy3)2 (10 mol%), CsOPiv
(1.0 equiv), toluene, 140 °C (sealed tube). [b] Performed on a tenfold scale. [c] Performed at 160 °C. [d] Performed using 20 mol% Pd. [e]
Conditions B: Pd(PCy3)2 (10 mol%), AdCO2H (30 mol%), Rb2CO3 (1.5 equiv), toluene, 160 °C (sealed tube). [f] The amide hydrolysis product
was directly isolated.
Herein, we report the development of this Pd shift-based C(sp3)–
C(sp3) bond forming method.
Next, we considered the extension of the 1,4-Pd shift-induced
coupling to sp3 carbons adjacent to a nitrogen atom (Scheme 2b). We
were motivated by prior observations that o-bromo-N-methylanilines
tend to undergo demethylation under Pd0/L-catalyzed conditions,
presumably through 1,4-Pd shift and iminium formation.[16]
Gratifyingly, this undesired demethylation could be avoided upon
deactivation of the nitrogen atom with a trifluoroacetyl substituent
(substrate 6a), and after reoptimization of the reaction conditions (cat.
AdCO2H/stoich. Rb2CO3, 160 °C)[13] indoline 8a was obtained in
74% yield. To the best of our knowledge, this is the first example of
1,4-Pd shift adjacent to a nitrogen atom leading to C–C bond
formation. Substituents were well tolerated on the arene ring (8b-e),
but unlike dihydrobenzofurans the indoline was not formed when
substituents were introduced on the carbons undergoing C(sp3)–H
bond cleavage (R1, R2). Despite this limitation, this method is also
complementary to indoline synthesis via direct Pd0-catalyzed C(sp3)–
H arylation.[17,15b] As illustrated with the structures of tasimelteon[18]
and silodosin (Figure 1),[19] the 2,3-dihydrobenzofuran and indoline
motifs are important substructures found in many pharmaceuticals.
We first explored the reactivity of aryl bromide 5a in standard
Pd0/L-catalyzed C(sp3)–H activation conditions (Scheme 2a). After a
quick optimization,[13] we found that the use of the well-defined
Pd(PCy3)2 complex and stoichiometric cesium pivalate as a mild
stoichiometric base allowed formation of 2,3-dihydrobenzofuran 7a
in 92% yield. As hypothesized, we did not observe the formation of
dimers analogous to 2a-b (Scheme 1b) under these conditions. The
reaction could be scaled up (78% yield on a tenfold scale) and
extended to other aryl bromides, easily accessible from phenol
precursors, to give dihydrobenzofurans 7b-e in moderate to very good
yields. The volatility of products 7b-c was likely responsible for their
moderate yields. Of note, a carbaldehyde was well tolerated (7d),
which is likely enabled by the use of the mildly basic cesium pivalate
as the stoichiometric base. Substitution was tolerated at the ortho
position to the second activated methyl group (7e), but not at the ortho
position to the bromine atom. Importantly, the reaction also
proceeded when an ester or amide group was installed as R1 (7f),[14]
R2 (7g-j) or both R1 and R2 (7k), with the latter being isolated as the
trans diasteroisomer. Other R1, R2 groups such as methyl led to a
complete loss of reactivity under these conditions, thus showing that
the current reaction is limited to primary and sufficiently acidic
secondary C(sp3)–H bonds. However, one should note that the
synthesized dihydrobenzofurans 7a-k are not accessible through
direct Pd0-catalyzed C(sp3)–H arylation from aryl halides, which
O
H
N
O
N
H
O
N
CF3
H2N
O
O
OH
tasimelteon
melatonin receptor agonist
silodosin
α1A-adrenoreceptor antagonist
requires the presence of
a quaternary center to favor the
intramolecular C–H activation step.[15] Moreover, a double reaction
was successfully conducted on a dibromo substrate (5l), easily
derived from Bisphenol C through electrophilic bromination and
methylation, to furnish bis(dihydrobenzofuran) 7l in good yield. In
this remarkable example, four C(sp3)–H bonds were activated and
two C(sp3)–C(sp3) bonds created.
Figure 1. Bioactive molecules containing the 2,3-dihydrobenzofuran
and indoline motifs.
2
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10.1002/anie.201908460
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Then, we set out to extend this method to the construction of 6-
membered rings (Scheme 3a). Keeping in mind the above reactivity
limitation to primary and acidic secondary C–H bonds, we found that
aryl bromide 9a containing an acetyl instead of methyl group in ortho
position to the methoxy group undergoing 1,4-Pd shift was a
competent substrate, furnishing chroman-4-one 10a in 72% yield
after further tuning the reaction conditions (cat. AdCO2H/stoich.
Cs2CO3, 120 °C).[13] The reaction was successfully extended to
arylalkylketones bearing substituents on the aromatic ring (10b-d), as
well as other alkyl groups (10e-f). Of note, such chroman-4-ones are
valuable heterocycles for drug discovery.[20]
bond formation (Scheme 3b). In principle, this reaction requires a
stoichiometric reductant to recycle Pd0 after the carbonyl insertion
step.[21] Given that cesium pivalate is the only stoichiometric reagent
in our case, we hypothesize that the catalyst turnover is provided by
anionic ligand exchange with pivalate, giving rise to palladium(II)
pivalate, which regenerates Pd0 through homocoupling of toluene.[22]
The 2,3-dihydrobenzofuran-3-ol products were moderately stable and
underwent facile dehydration when left in CDCl3 at room temperature
to give the corresponding benzofurans, as illustrated with 13f-g,
hence providing a new entry into this biologically important motif.[23]
Preliminary mechanistic investigations were conducted with
deuterated substrates. First, compound 9c-d3-1 was submitted to the
standard conditions forming chromanones (Scheme 4). Surprisingly,
no reaction occurred even after prolonged heating, in contrast to its
protiated isotopomer 9c.[24] At first glance, this result seems to
translate a very large kinetic isotope effect (KIE), typically observed
in tunneling.[25] Further investigations on this singular behavior are
ongoing. In addition, equimolar mixtures of 9c and 9c-d3-2 led to the
corresponding chromanone with a 50% deuterium content on the a-
carbonyl position at various conversions, diagnostic of an absence of
primary KIE at this position.[26] These two experiments indicate that
the first C(sp3)–H bond cleavage is turnover-limiting, in agreement
with the relative acidities of the corresponding C–H bonds.
a) 1,4-Pd shift/C(sp3)–H activation[a]
O
O
O
R1
R1
cond. C
R2
R2
H
H
O
Br
9
10
O
O
O
O
Me
F
Et
O
O
O
O
10a, 72%
10b, 68%
10c, 62%
10d, 52%
O
O
O
O
O
O
Me
Me
Ph
F
F
cond. C
O
D
O
Br CD3
9c-d3-1
O
10e, 82%
10f, 55%
D
b) 1,4-Pd shift/nucleophilic addition[b]
O
<5% conv.
O
O
ca. 50% D
O
O
HO
Ar
F
F
F
cond. D
Ar
cond. C
CD3
R2
R2
O
O
O
Br
Br
Br
9c-d3-2
H
11
12
9c
1:1
OMe
OH
MeO
Scheme 4. Deuterium isotope effect.
OH
OH
OH
Me
F
In conclusion, we have successfully achieved the intramolecular
coupling of two C(sp3)–H bonds to forge a C(sp3)–C(sp3) bond using
the 1,4-Pd shift strategy. A variety of valuable fused heterocycles
were obtained from easily accessible ortho-bromo phenol and aniline
precursors. This reaction is so far limited to moderately acidic C–H
bonds, i. e. adjacent to an oxygen or nitrogen atom on one side and
benzylic or adjacent to a carbonyl group on the other side, but
extensions to less reactive C–H bonds are foreseen.
O
O
12b, 63%
R
O
O
12d, 59%
12a, 69%
12c, 78%
CF3
R
MeO
OH
OH
CDCl3, 25 °C
O
O
O
12e, 50%
12f, R = OMe, 57%
12g, R = F, 74%
13f, R = OMe, quant.
13g, R = F, quant.
Acknowledgements
Scheme 3. Divergent behavior of o-methoxyphenylketones. [a]
Conditions C: Pd(PCy3)2 (10 mol%), AdCO2H (30 mol%), Cs2CO3 (1.0
equiv), toluene, 120 °C (sealed tube). [b] Conditions D: Pd(PCy3)2 (10
mol%), CsOPiv (3.0 equiv), toluene, 160 °C (sealed tube).
This work was financially supported by the University of Basel,
Università degli Studi di Perugia and MIUR. We thank Prof. L.
Vaccaro for supporting the visiting studentship of I. A., Dr. D.
Häussinger for NMR experiments, Dr. M. Pfeffer for MS analyses
and Dr. A. Clémenceau for fruitful discussions.
In the absence of an enolizable position, the organopalladium
intermediate arising from 1,4-Pd shift could potentially attack the
ketone to give a tertiary alcohol.[21] Indeed, under more forcing
conditions arylketones 11a-g underwent 1,4-Pd shift/nucleophilic
addition to give the corresponding 2,3-dihydrobenzofuran-3-ols 12a-
g in average to good yields, thereby providing a conceptually simple
extension of the current method to a different type of C(sp3)–C(sp3)
Conflict of interest
The authors declare no conflict of interest.
3
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Angewandte Chemie International Edition
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Published online on ((will be filled in by the editorial staff))
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Keywords: C–H activation · domino reactions · heterocycles ·
palladium
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4
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10.1002/anie.201908460
Angewandte Chemie International Edition
C(sp3)–H activation/
1,4-Pd shift
C–H Activation
C(sp3)–H activation
Y
H
Y
H
Y
Pd0/L cat.
RCO2– cat.
R. Rocaboy, I. Anastasiou, O.
Z
Z
Pd(L)O2CR
Z
Baudoin*__________ Page – Page
H
Br
H
H
Z = O, NCOCF3
Y = –, CO
2,3-dihydrobenzofurans
indolines
chroman-4-ones
Redox-neutral Coupling between Two
C(sp3)–H Bonds Enabled by 1,4-
Palladium Shift for the Synthesis of
Fused Heterocycles
Catch phrase:
5
This article is protected by copyright. All rights reserved.