Ligand-Controlled Direct γ-C?H Arylation of Aldehydes

Article abstract of DOI:10.1002/anie.201913126

The first example of Pd^II-catalyzed γ-C(sp³)?H functionalization of aliphatic and benzoheteroaryl aldehydes has been developed using a transient ligand and an external ligand, concurrently. A wide array of γ-arylated aldehydes were readily accessed without preinstalling internal directing groups. The catalytic mechanism was studied by performing deuterium-labelling experiments, which indicated that the γ-C(sp³)?H bond cleavage is the rate-limiting step during the reaction process. This reaction could be performed on a gram scale, and also demonstrated its potential application in the synthesis of new mechanofluorochromic materials with blue-shifted mechanochromic properties.

Full text of DOI:10.1002/anie.201913126

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Accepted Article
Title: Ligand-Controlled Direct γ-C-H Arylation of Aldehydes
Authors: Haibo Ge, Bijin Li, Brianna Lawrence, and Guigen Li
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10.1002/anie.201913126
Angewandte Chemie International Edition
COMMUNICATION
Ligand-Controlled Direct γ-C-H Arylation of Aldehydes
Bijin Li, Brianna Lawrence, Guigen Li,* and Haibo Ge*
Abstract: The first example of Pd(II)-catalyzed γ-C(sp3)–H
functionalization of aliphatic and heteroaryl aldehydes was
developed using
a transient ligand and an external ligand,
concurrently. A wide array of γ-arylated aldehydes were readily
accessed without pre-installing any internal directing groups. The
catalytic mechanism was studied by performing deuterium-labelling
experiments which indicated that the γ-C(sp3)−H bond cleavage acts
as the rate-limiting step during the reaction process. This reaction
could be performed on a gram-scale, and it also showed its potential
applications
on
the
design
and
synthesis
with
of
new
mechanofluorochromic
materials
blue-shifted
mechanochromism properties.
Aliphatic aldehydes are the key intermediates in chemical
synthesis and widely exist in biologically active natural products,
pharmaceuticals, and organic functional materials.[1] The
development of efficient and concise methods for the
construction and derivatization of aliphatic aldehydes is of great
research interest in both academia and chemical industry.[1,2] In
fact, Ipso- and α-selective functionalization of aliphatic
aldehydes has been well documented in literature.[3] Direct β-
functionalization of aliphatic aldehydes has also been achieved
in recent years, via a radical, oxidative conjugated addition or
transient directing group-promoted C(sp3)–H activation
pathway.[4-5] However, direct γ-C(sp3)−H functionalization of
aliphatic aldehydes has not been achieved to date.
In most transition metal-catalyzed C(sp3)–H functionalization
processes, preference for the formation of a five-membered
palladacyclic intermediates is favored over its counterparts of
larger palladacyclic rings as proven by kinetic and
Scheme 1. Examples of five/six-membered ring palladium intermediate and
direct β- and γ-C−H arylation of aliphatic aldehydes and construction of new
mechanochromic materials.
thermodynamic
investigations
(Scheme
1A,
a1-a3).[6]
promote and accelerate the process.[8k,10-11] Yu and co-workers
have achieved γ-C(sp3)–H arylation of aliphatic alcohols and
amines based on this strategy.[8k,10a] Very recently, Maiti and co-
workers described the use of N-Ac-Gly-OH as an external ligand
to promote palladium-catalyzed iterative γ-C(sp3)−H arylation of
aliphatic acid.[10b] As a promising approach, we envisioned that
direct γ-C(sp3)−H functionalization of aliphatic aldehydes could
be achieved by using a transient directing group in combination
with an external ligand (Scheme 1C).
To verify this strategy, palladium-catalyzed direct C–H bond
arylation of 2-ethyl-2-propylhexanal (1a) with iodobenzene was
performed (Table S1). An extensive screening of reaction
parameters led us to the standard reaction conditions (10 mol %
Pd(OAc)2, 20 mol % L-phenylalanine (TDG6), 50 mol % 3-nitro-
5-(trifluoromethyl)pyridin-2-ol (L5), and 1.5 equiv AgTFA in
AcOH at 80 °C, under atmospheric N2), affording the desired
arylated product 2-phenethyl-2-propylhexanal (3a) in 67 % yield.
It was noticed that the reaction failed to provide any desired
product in the absence of either TDG6 or a silver salt (Table S1,
entries 25 and 26).[12] Furthermore, after 3-nitro-5-
(trifluoromethyl)pyridin-2-ol (L5) was added into the reaction
system as an external ligand, the desired product was obtained
in a good yield (Table S1, entry 24) indicating that this ligand
plays a crucial role for this catalysis. This is in an agreement
with previous reports that the electron-deficient 2-pyridones
could act as an internal base to accelerate the C(sp2)−H and
C(sp3)−H bond cleavages.[8k,10-11]
Consequently, many efforts have been made on the formation of
five-membered palladacycle species for palladium-catalyzed
C(sp3)–H activation by many labs in this field.[5,7-9] On the other
hand, reports on direct C(sp3)–H functionalization via a six-
membered palladacycle are rare (Scheme 1A, a4-5).[10]
Mechanistically, direct functionalization of aliphatic aldehydes on
γ-carbons would require formation of
a
six-membered
palladacycle intermediate in the presence of a transient ligand
(Scheme 1C), making it an extremely challenging process.
Recently, the use of an external ligand in combination with a
directing group or transient directing group to promote formation
of six-membered or other sized palladacycle intermediates has
emerged as a promising strategy in the field of palladium
catalyzed C−H functionalization.[8k,10-11] The external ligand could
coordinate with and effectively stabilize the palladium
catalyst.[8k,10-11] Additionally, the external ligand could lower the
transition state energy of the C–H bond cleavage step and then
[]
B. Li, B. Lawrence, Prof. Dr. H. Ge. Department of Chemistry and
Chemical Biology, Indiana University-Purdue University Indianapolis,
Indianapolis, Indiana 46202, United States
E-mail: geh@iupui.edu
Prof. Dr. G. Li. Institute of Chemistry & BioMedical Sciences,
Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing
University, Nanjing 210093, P. R. China. Department of Chemistry and
Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061,
United States.
E-mail: guigen.li@ttu.edu
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201913126
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With the optimized reaction conditions in hand, the scope of
aliphatic aldehydes was evaluated. As shown in table 1, α-ethyl-
α,α-dialkyl substituted acetaldehyde derivatives provided the
corresponding γ-arylation products in good yields with excellent
site selectivity (3a-f and 3h). When 2,2-diethylhexanal was used
as a substrate, a 4 : 1 ratio of mono- and diarylated products
was observed under standard conditions (Table 1, 3g). However,
the mono-arylated product could be obtained in high selectivity
under modified reaction conditions. Additionally, phenyl, fluoro,
alkoxyl, phenoxyl, p-methoxyphenoxy, or p-fluorophenoxy
substituted alkylaldehydes were effective substrates (3i-n).
These substrates showed excellent γ-selectivity, and β- or δ-
arylated products were not observed for any reactions. There
are two possible reasons for this observation: (1)
Cyclopalladation via a 6-membered ring transition state is more
favorable to a 5-membered ring transition state due to the
relative rigidity of the cyclic system and the steric effect in the
latter case. (2) The formation of a 5,5-bicyclic palladium
intermediate is favorable and reversible, but the following step,
oxidation by iodobezene, requires a higher activation energy
compared with a 5,6-palladacycle. It should be mentioned that
with 2-ethyl-2-methylhexanal as a substrate, a mixture of β-, γ-,
and di-arylated products was obtained (Table 1, 3o). These
results suggest that formation of a 5,5-bicyclic palladium
intermediate is more favorable in this case due to the reduced
steric hindrance compared with the previous examples.
Delightfully, the catalytic system was also suitable for the
aliphatic aldehyde bearing a cyclic alkyl group (3p and 3q).
Unfortunately, non-quaternary aldehydes did not tolerate the
current conditions. It was also observed that heteroaryl
aldehydes were well tolerated under the current reaction system
(3r-3t). This represents the first example of γ-C(sp3)–H arylation
Table 1. Scope of aldehydes[a]
of
heteroaryl
aldehydes.
More
importantly,
3-
benzylbenzothiophene-2-carbaldehyde 3s can be synthesized
on gram-scale in 75% yield, revealing this reaction can be
potentially conducted on
a
bench-scale in the future.
Furthermore, γ- and di-arylated products could be obtained by
using an aryl aldehyde as a substrate (3u).
Subsequently, we surveyed the scope of aryl iodides. To our
delight, a broad range of aryl iodides with either a para-, meta-,
or ortho- substituent provided the desired products in good
yields with 1a (Table 2, 4a-r). Bromo, chloro, or fluoro
substituents were well tolerated, enabling further manipulation of
the initial products (4c-4e, 4j-4l, 4q and 4s). Iodobenzenes
bearing either an electron-donating (alkoxyl or alkyl; 4a, 4h and
4r) or electron-withdrawing group (ester, cyano, trifluoromethyl,
or nitro; 4f-g, 4i and 4m-4p) were all compatible under the
standard conditions (4f-g, 4i and 4m-4p). It is also noteworthy
that a range of natural products containing aryl iodides from
different complex organic molecules including menthol, borneol,
and fenchyl alcohol could be effectively utilized (Table 2, 4t-4v).
All of these cases demonstrate the robustness of the present γ-
arylation methodology.
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol),
TDG6 (20 mol%), L5 (50 mol%), additives (0.3 mmol), solvent (0.15 mL), 80
°C, N2, 70 h. [b] Yields and ratio determined by 1H NMR using CH2Br2 as an
internal standard. [c] 1 (0.6 mmol), 2a (0.2 mmol). [d] 90 °C.
result in any D/H exchange (Scheme 2B). These results suggest
that the C−H bond cleavage is irreversible in the catalytic
process. Furthermore, the kinetic isotope effect (KIE) study was
performed and a significant KIE value (kH/kD = 2.9) was
observed (see SI, Part VI). This observation revealed that the
sp3 C−H bond cleavage of aliphatic aldehyde 1b is the rate-
limiting step in the process (Scheme 2C).
A tentative mechanism is proposed based on the above results
and previous reports (Scheme S2).[5,7-11] Initially, acid-promoted
reversible imine formation between aliphatic aldehyde 1b and
TDG6 provides the imine intermediate A. Coordination of this
intermediate to the palladium species and subsequent external
ligand L5-assisted γ-C−H bond activation produces the [6,5]-
bicyclic palladium intermediate C. Oxidative addition of
To gain some insights into the reaction mechanism, a series of
deuterium-labelling experiments were carried out (Scheme 2).
No H/D exchange was observed with 2-ethyl-2-propylpentanal
(1b) using acetic acid-D4 as the solvent (Scheme 2A).
Additionally, treatment of the deuterium-labeled substrate 1b-D5
under standard conditions in the absence of iodobene did not
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10.1002/anie.201913126
Angewandte Chemie International Edition
COMMUNICATION
palladium intermediate C by an aryl iodide forms the palladium
(IV) species D. Consequently, reductive elimination of the
nonplanar characteristic.[14] Therefore, we designed two novel
TPA-bearing
2-(4-(oxazol-2-yl)phenyl)acetonitrile-3-
palladium (IV) complex
D
followed by ligand dissociation
benzylbenzothio/furanphen (6a and 6b) molecules (Scheme 1C
and Table 3).
releases the γ-arylated product 3b and transient ligand TDG6.
Following the above studies, we devoted our efforts on the
potential application of this newly developed method.
Piezochromic luminescent molecular materials have attracted
considerable attention due to their great potential for various
applications, including optical displays, rewritable optical media,
chemosensors, security systems, etc.[13] Mechanochromism of
Table 2. Scope of aryl iodides[a]
Given that the heteroaryl aldehydes were compatible
substrates in Pd(II)-catalyzed γ-C(sp3)–H arylation, the direct
use of 3q and 3s as starting materials could streamline the
synthetic routes. Organic functional molecules 6a and 6b were
thus obtained by reaction of TPA-bearing 2-(4-(oxazol-2-
yl)phenyl)acetonitrile (5a) and 3s or 3q in the presence of the
conventional base, t-BuOK (Table 3). The photophysical
properties of 6a and 6b were subsequently investigated with
respect to absorption and emission maxima in toluene solution
(1.0 x 10-5 M), and emission maxima before and after grinding.
Scheme 2. Deuterium labeling experiments.
Table 3. Synthesis of TPA-containing 2-(4-(oxazol-2-yl)phenyl)acetonitrile-3
benzylbenzothio/fur-anphens.
[a], [b] Absorption maximum and emission maximum in toluene (1×10-5 M). [c]
Emission maximum in pristine powder. [d] Emission maximum in ground
powder.
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol),
TDG6 (20 mol%), L5 (50 mol%), additives (0.3 mmol), solvent (0.15 mL), 80
°C, N2, 70 h. [b] 90 °C.
organic materials is mainly dependent on changes in physical
molecular packing modes. Derivatives of triphenylamine (TPA)
are ideal candidates to design mechanochromism materials due
to the TPA group being well known for its propeller-like
Figure 1. (A) Fluorescence images of 6a and 6b in toluene (1.0 × 10-5 M)
under UV light (365 nm). (B) The fluorescent images of 6a and 6b before and
after grinding after grinding.
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As shown in Figure 1 and Figures S1-2, their emission
wavelengths in toluene are located in the yellow-green region
(538 nm to 530 nm).
To our delight, organic functional molecules 6a and 6b clearly
exhibited blue-shifted mechanochromic luminescence properties
(Figure 1 and Figures S3-4). Grinding of the pristine powder 6a
and 6b led to a blue-shift with emission color change from
orange and red (λem = 591 and 602 nm) to yellow (λem = 540 and
541 nm), approximately 51 and 61 nm respectively (Figure 1 and
Figures S3-4). The fluorescence emission blue shift, after
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patterns of the unground powder of 6a displayed many sharp
and intense reflection peaks. After grinding, reflection peak was
not observed, indicating that a morphological transition from the
crystalline to amorphous phases (Figure S5).
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For
better
comparison,
we
have
used
3-
methylbenzo[b]thiophene-2-carbaldehyde instead of 3t as a
substrate to synthesize a new material molecule 6c (Scheme
S1). Grinding of the pristine powder 6c led to a blue-shift with
emission color change from orange (λem= 588 nm) to yellow (λem
= 554 nm), approximately 34 nm (Scheme S1 and Figures S6-8),
which show the importance of our method.
In conclusion, a highly selective γ-direct C−H arylation reaction
of aliphatic and heteroaryl aldehydes with aryl iodides has been
developed for the first time via a palladium-catalyzed sp3 C−H
bond functionalization process with L-phenylalanine as a novel
transient directing group and 3-nitro-5-(trifluoromethyl)pyridin-2-
ol as an external ligand. The deuterium-labelling experiments
have indicated that the γ-C(sp3)−H bond cleavage of the
aldehyde is the rate-limiting step in the catalytic process. This
methodology provides a straightforward access to TPA-bearing
2-(4-(oxazol-2-yl)phenyl)acetonitrile-3benzylbenzothio/furanphen,
which opens up a new avenue for the synthesis and discovery of
new mechanofluorochromic materials.
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Acknowledgements
We gratefully acknowledge NSF (CHE-1350541, CHE-1855735).
G.L. would like to acknowledge the financial support from the
National Natural Science Foundation of China (No. 21332005,
21672100) and Robert A. Welch Foundation (D-1361, USA).
[12]
It has been suggested that a silver salt could play a role of iodide
abstraction in a palladium-catalyzed C-H functionalization process.
Keywords: C-H functionalization • aldehydes • transient directing group •
palladium-catalyzed • mechanochromic materials
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COMMUNICATION
COMMUNICATION
The first example of Pd(II)-
Bijin Li, Brianna Lawrence, Guigen Li,* and
Haibo Ge*
catalyzed
functionalization of aliphatic
and heteroaryl aldehydes
γ-C(sp3)–H
Page No. – Page No.
have been established. This
approach opens up a new
avenue for the synthesis and
Ligand-Controlled Direct γ-C-H Arylation of
Aldehydes
discovery
mechanofluorochromic
materials.
of
new
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