Palladium-catalyzed site-selective C(sp3)-H arylation of phenylacetaldehydes

Article abstract of DOI:10.1021/acs.orglett.9b02650

We describe a Pd-catalyzed selective C-H arylation reaction of phenylacetaldehydes using l-valine as the transient directing group. This process showed a broad substrate scope and excellent selectivity in which a ligand-controlled functionalization of the

Full text of DOI:10.1021/acs.orglett.9b02650

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Site-Selective C(sp3)−H Arylation of
Phenylacetaldehydes
Bo-Bo Gou,† Hang-Fan Liu,† Jie Chen,* and Ling Zhou*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry &
Materials Science, National Demonstration Center for Experimental Chemistry Education, Northwest University, Xi’an 710127,
P.R. China
S
* Supporting Information
ABSTRACT: We describe a Pd-catalyzed selective C−H
arylation reaction of phenylacetaldehydes using L-valine as the
transient directing group. This process showed a broad substrate
scope and excellent selectivity in which a ligand-controlled
functionalization of the unactivated β-C(sp3)−H bond. In
addition, enantioselective arylation of phenylacetaldehydes was
preliminarily explored by utilizing a bulky chiral transient directing
group.
Scheme 1. Pd-Catalyzed Selective C−H Activation
alladium-catalyzed C−H activations is a powerful vehicle
Pfor C−C and C−X (heteroatom) bond formation during
the past decades.1 Substrates that contain an auxiliary directing
group have been broadly exploited in selective C−H bond
activation reactions,1,2 although preinstalling directing groups
on substrates reduce the overall efficiency. Recently, the
transient directing group has emerged as a hot topic in the field
of C−H bond activations3 because a reversible intermediate
such as imine could be formed between a substrate and a
ligand, simplifying the manipulation steps of traditional C−H
bond activations.4,5 Many remarkable endeavors have been
made to develop transient directing group strategy in C−H
bonds activations.3−5 Generally, C(sp2)−H bond activation is
prior than that of C(sp3)−H bonds in such metal-catalyzed
reactions.6 Many published examples report functionalization
of C(sp2 or sp3)−H bonds separately in different substrates.7
Studies on the selective C(sp2 or sp3)−H bond activation in
one molecule remains a challenge.8
We initiated to evaluate the palladium(II)-catalyzed cross
coupling reaction of 2-methyl-2-phenylpropanal (1a) and
iodobenzene (2a) in a cosolvent (hexafluoroisopropanol
(HFIP)/AcOH, 1/1) under a nitrogen atmosphere at 125
°C for 12 h in the presence of glycine (L1) as the ligand and
AgTFA as the additive (Table 1). Encouragingly, the expected
arylated product 3a and a small amount of diarylation product
3a′ (3%) were isolated, together with a C(sp2)−H activation
and cyclization product phenanthrene 4a in 27% yield. To
increase the reactivity and site selectivity of this conversion,
various ligands (L1−L8) were screened (entries 2−8). A
significantly increase in this reaction was realized with
substituted 2-aminopropanoic acids L2−L4 as the ligands
(entries 2−4), the yield of 3 was improved (61%, mono/di =
50:11) with the C(sp2)−H arylation completely prevented by
using L3 as the transient directing group (entry 3). Obviously,
α-substituted amino acids returned good selectivity of C(sp3)−
Recently, we reported a glycine assisted C(sp2)−H arylation
and in situ tandem reaction of phenylacetaldehydes, a variety
of functionalized phenanthrenes were prepared with a
satisfactory results (Scheme 1).9 On the basis of our and
other groups’ work, we envisioned that the β-C(sp3)−H
arylation of phenylacetaldehydes with aryl iodides would be
realized utilizing a similar strategy. We describe herein a new
protocol for the highly site-selective C(sp3)−H bonds
activation in one molecule under the assistance of a transient
directing group, delivering aldehydes with a homobenzylic
(stereo)centers (Scheme 1), which are highly prevalent in
natural products and medicinally relevant compounds.10 The
principal challenges of this approach arise from (1) the need to
find appropriate reaction conditions to efficiently avoid the
generation of a six-membered palladacycle11 and (2) selective
C(sp3)−H bonds activation to give β-mono- or β,β′-diary-
lation products.
Received: July 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02650
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Aryl Iodides
b
yield
entry
solvent
ligand additive
3a
3a′
3
8
11
7
22
4a
27
8
1
2
3
4
5
6
7
8
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (3/1)
HFIP/AcOH (1/3)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
HFIP/AcOH (1/1)
L1
L2
L3
L4
L5
L6
L7
L8
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgOAc
Ag2CO3
Ag2O
18
39
50
46
19
5
6
3
9
10
11
L3
L3
L3
L3
L3
L3
L3
L3
L3
42
43
46
28
24
18
30
19
15
6
4
6
5
c
12
trace
d
13
14
3
e
trace
trace
4
f
15
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (0.03
mmol), L3 (0.08 mmol), AgTFA (0.32 mmol), [HFIP/AcOH (1/1,
v/v) 1.0 mL], 12 h, N2. Isolated yields.
16
17
18
trace
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (0.03
mmol), L (0.08 mmol), additive (0.3 mmol), solvent (1.0 mL), N2,
position all proceeded smoothly with moderate yields and thus
enabled further transformations of products via cross-coupling
reactions (3b−3e, 3k). Besides, 3m was also obtained when 2-
iodonaphthalene was employed. Generally, mixed products of
mono and diarylation were detected in this process.
Interestingly, methyl 4-iodobenzoate, 4-nitroiodobenzene, 4-
(trifluoromethyl)iodobenzene, and methyl 3-iodobenzoate
bearing strong electron-withdrawing groups or naphthyl
returned only monoarylation products (3f−3h, 3l, and 3m).
All of the reactions showed excellent site selectivity with
moderate to good reactivity. Nonetheless, the heterocyclic aryl
iodines such as 3-iodopyridine and 2,6-dichloro-4-iodopyridine
gave no desired products.
Afterward, we proceeded to explore the scope with regard to
the various substituted aldehydes by using a coupling partner
2f. As shown in Scheme 3, ortho-, meta-, and para substitutions
as well as disubstituted methylenedioxy and naphthyl are also
well tolerated in this reaction (3n−3w). Aldehyde bearing an
ethyl at the α-position was also suitable substrates for the
catalytic process to yield the desired product 3x. Remarkably,
arylation occurred only at the methyl group, and no benzylic
methylene product was detected under these conditions (3y).
Notably, no diarylation products were observed in these
reactions. Unfortunately, nonquaternary carbon aldehydes
such as 2-phenylpropanal and 2-methylpentanal returned no
desired product.
b
c
d
125 °C, 12 h. Isolated yields. Pd(TFA)2 as Pd source. Pd-
e
f
(PPh3)2Cl2 as Pd source. [PdCl(η3-C3H5)]2 as Pd source. PdCl2 as
Pd source.
H arylation, suggesting that the formation of the 5-membered
palladacycle is strengthened by the larger substituents of α-
amino acids, probably due to the Thorpe−Ingold effect
(entries 1 vs 2−4). 3-Aminopropanoic acid (L5) was also
tested and afforded poor selectivity (entry 5). No reaction was
detected when L6 was used (entry 6). Further screening of
ligand with either L7 or L8 afforded an inferior result (entries
7 and 8). A control experiment indicated that the transient
directing group was absolutely critical in this approach (entry
9). Then various palladium catalysts were conducted, but all
returned low yields (entries 12−15). Besides AgTFA, we
further used AgOAc, Ag2CO3, and Ag2O as silver salts, and the
desired product 3 also could be obtained with inferior reaction
performance (entries 16−18).
In order to gauge the scope and generality of the newly
established method, a series of structurally diverse aryl iodides
were tested under the optimal reaction conditions. The results
are shown in Scheme 2, where aryl iodides containing an
electron-donating group (3j) or electron-withdrawing groups
(3f−h, 3l) were well accommodated. Meanwhile, aryl iodides
with the substituents F, Cl, and Br at the para, meta, or ortho
B
DOI: 10.1021/acs.orglett.9b02650
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Aldehydes
Scheme 4. Scale up Reaction and Exploration of
Enantioselective Arylation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02650.
Experimental procedures, characterization data for all
new compounds, and copies of 1H and 13C NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chmchenj@nwu.edu.cn
*E-mail: zhoul@nwu.edu.cn
ORCID
Jie Chen: 0000-0001-6745-5534
Ling Zhou: 0000-0002-6805-2961
Author Contributions
a
Reaction conditions: 1 (0.2 mmol), 2f (0.4 mmol), Pd(OAc)2 (0.03
mmol), L3 (0.08 mmol), AgTFA (0.3 mmol), [HFIP/AcOH (1/1, v/
v) 1.0 mL], 12 h, N2. Isolated yields.
†B.-B.G. and H.-F.L. contributed equally.
Notes
To demonstrate the potential application of this newly
developed protocol, a scaled-up experiment using 1a with
methyl 4-iodobenzoate was conducted (Scheme 4). As a result,
arylated product 3f could be prepared in 47% yield under
similar conditions. Application of this strategy to the
enantioselective arylation of 1o was then examined, and the
reaction proceeded successfully with L-tert-leucine and
produced the corresponding product 3o (43%) with a
promising enantiomeric ratio (er) of 70:30 (Scheme 4).
Unfortunately, a detailed screening of a range of chiral amino
acids (C1−C10) and substrates returned no further improve-
ment of the enantioselectivity (see the SI for details).
In conclusion, we have achieved a palladium-catalyzed highly
site-selective C(sp3)−H arylation reaction of phenylacetalde-
hydes with aryl iodides by using a easily available transient
directing group. Attractive features of this method include
broad substrate scope and excellent regioselectivity, wherein
the functionalization of benzylic methylene or γ-C(sp2)−H
bonds could be effectively avoided. The detailed mechanistic
studies and further efforts to improve enantioselectivity with
this reaction using novel chiral amino acids are underway.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC-21672170), the Natural Science Basic Research Plan in
Shaanxi Province of China (2018JC-020, 2018JM2029), China
Postdoctoral Science Foundation (2018M643705), and the
Key Science and Technology Innovation Team of Shaanxi
Province (2017KCT-37) for financial support.
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DOI: 10.1021/acs.orglett.9b02650
Org. Lett. XXXX, XXX, XXX−XXX